RxPG News : Haematology

Researchers revisit pulmonary arterial hypertension survival

Wed, 06 Jan 2010 04:59:12 PST

( from http://www.rxpgnews.com ) Setting out to determine the survival of patients with pulmonary arterial hypertension (PAH), researchers at the University of Chicago Medical Center and their colleagues also discovered that an equation used for more than 20 years to predict survival is outdated. Accordingly, they developed and recently published a new survival prediction equation that will impact clinical practice and the drug development process.

In PAH, the pulmonary arteries, which carry blood from the heart to the lungs to pick up oxygen, become restricted, forcing the lower right chamber of the heart to pump harder. This leads to shortness of breath, limited exercise capacity, fatigue, heart failure and death. Often the condition goes undetected until it is advanced. Untreated, patients with PAH have a very poor prognosis.

That prognosis is determined using an equation developed by a landmark National Institutes of Health study published in 1987, well before there were any Food and Drug Administration approved therapies for PAH. The first such therapy was approved in 1995; today there are seven.

Since 1987, great progress has been made in understanding and treating PAH, so a few years ago we decided that it was time to study contemporary survival, said Mardi Gomberg-Maitland, MD, MSc, Associate Professor of Medicine and Director of Pulmonary Hypertension at the University of Chicago Medical Center. Our results show that survival is vastly improved today. That led us to rework the NIH equation, which has been a standard measuring stick for more than 22 years.

Gomberg and her colleagues at the Medical Center and Northwestern University's Feinberg School of Medicine studied the survival of 576 PAH patients in their registry. Of these patients, 282 had idiopathic, familial, and anorexigen-associated PAH, which matches the conditions of the 187 patients in the pioneering NIH study.

Using the NIH equation, these 282 patients would have been expected to have one-, three- and five-year survival rates of 65%, 43% and 32%, respectively. In fact, their survival rates were much higher: 92%, 75% and 66%, respectively.

This new formula is important for patients who want to know what, on average, to expect from their disease and for doctors who want to give accurate advice, said Stephen L. Archer, MD, Harold Hines Jr. Professor and Chief of Cardiology at the University of Chicago Medical Center and co-author of the study. We hope others will test our work. If it is validated by others it could be a very useful tool.

H1N1 more risky than seasonal flu in children with sickle cell disease

Mon, 07 Dec 2009 04:59:36 PST

( from http://www.rxpgnews.com ) Infection with the H1N1 virus, or swine flu, causes more life-threatening complications than seasonal flu in children with sickle cell disease, according to research from Johns Hopkins Children's Center. The findings, to be presented on Dec. 7 at the annual meeting of the American Society of Hematology, warn parents and caregivers that such children are more likely to need emergency treatment and stays in an intensive-care unit.

The researchers analyzed the records of 118 children with sickle cell disease treated for any kind of flu at Hopkins Children's between September of 1993 and November of 2009. Of them, 28 were infected with the H1N1 virus, a new strain that emerged for the first time in April of 2009.

While both the seasonal flu and the H1N1 virus caused similar general symptoms like fever, cough and a runny nose in most of the children, sickle cell patients infected with H1N1 were three times more likely to develop acute chest syndrome, a leading cause of death among these patients, marked by inflammation of the lungs, reduced oxygen capacity and shortness of breath. H1N1-infected children were five times more likely to end up in the intensive-care unit, and were overall more likely to end up on a ventilator and more likely to need a blood transfusion than those with seasonal flu.

Another Hopkins Children's study, released earlier this year, found that children with sickle cell disease are hospitalized with seasonal flu nearly 80 times more often than other children.

The researchers say their findings point to the need to include children with sickle cell disease in the list of those who must be immunized against all flu strains, which already includes children with asthma, diabetes, heart disease and other chronic conditions.

Children with sickle cell disease are hospitalized about once a year for pain crises and other complications, so we should do everything we can to prevent hospitalization from the flu by using safe and effective vaccines, says lead investigator John J. Strouse, M.D. Ph.D., a pediatric hematologist at Hopkins Children's.

Named for the unusually sickle-shaped red blood cells caused by a genetic abnormality, sickle cell anemia affects nearly 100,000 Americans. The cells' abnormal structure reduces their oxygen delivery to vital organs and causes them to get stuck in the blood vessels, leading to severe pain and so-called sickling crises, which require hospitalization.

The CDC recommends that all children over 6 months of age get seasonal and H1N1 flu shots, except those who are allergic to eggs or have had a severe reaction to a flu vaccine in the past.

Vital discovery may save many from traumatic deaths

Thu, 05 Nov 2009 15:06:20 PST

( from http://www.rxpgnews.com ) Researchers have unravelled how certain proteins can enter the bloodstream and begin to kill the lining of blood vessels, resulting in uncontrolled internal bleeding. Their discovery could help save thousands from traumatic deaths, caused by car crashes or on the battlefield.

Building on this work, Charles Esmon, Oklahoma Medical Research Foundation - cardiovascular biology researcher, and a team of collaborators have discovered an antibody that could counter this deadly process.

'This discovery could open the door to new ways to treat soldiers hurt in IED - attacks, gunshot wound victims and people who suffer a traumatic injury,' said Esmon.

'When we realised that histones were so toxic, we immediately went to work looking for a way to stop their destructive tendencies.' Inside the cells, histones perform an important function, keeping DNA coiled and compressed inside the nucleus.

But the OMRF researchers found that when cells become damaged and burst -- either through injury, infection or diseases such as diabetes -- histones can enter the bloodstream and begin to kill the lining of blood vessels. This results in uncontrolled internal bleeding and fluid build-up in the tissues, which are life-threatening.

Working with Temple University's Marc Monestier, the group discovered antibodies - that can block the histones ability to kill.

'When a patient is suffering from severe bleeds, these antibodies could prevent multi-organ failure,' said Esmon.

The researchers have already tested the antibodies in pre-clinical trials, where they showed promising results and no adverse effects. A potential future step, said Esmon, would be human trials.

Esmon's research has already yielded two FDA-approved drugs.

The findings were published online in Nature Medicine.

The American Society of Hematology to honor inspirational hematologists with Mentor Awards

Tue, 03 Nov 2009 04:59:36 PST

( from http://www.rxpgnews.com ) (WASHINGTON, November 3, 2009) - The American Society of Hematology (ASH) is honoring two prominent hematologists with ASH Mentor Awards in recognition of the important role they play in the training and career development of hematologists early in their careers. Stuart H. Orkin, MD, and Arthur W. Nienhuis, MD, will receive their awards during the 51st ASH Annual Meeting in New Orleans.

Dr. Orkin, who will be receiving the Mentor Award for Basic Science, is the David G. Nathan Professor of Pediatrics at Children's Hospital/Harvard Medical School. He has mentored more than 70 highly successful academic physicians and scientists in the field of hematology, and is known to instill confidence in his trainees to think independently, to see the big picture, and to stay focused. One of his former trainees commented, It's never a question of time and commitment, it's just natural. You [can] send him an e-mail, you [can] call him up, [if] you've got a question, he's just there and makes the time to provide the kind of input that you're seeking.

Dr. Nienhuis is a member and emeritus director of the St. Jude Children's Research Hospital, and will be receiving the Mentor Award for Clinical Investigation. During his career at St. Jude, and prior to that at the National Institutes of Health (NIH), he has mentored many individuals, with more than 90 percent of his students and fellows remaining engaged in academic hematology-oncology or gene therapy research at leading research institutions worldwide. Some of his trainees have gone on to become presidents and directors at academic institutions or cancer centers, NIH Institute directors, department chairs, and editors-in-chief of Blood and Seminars in Hematology. According to one of his former trainees, Despite his being incredibly busy, even when he was president of ASH, he always had time to chat.

Drs. Nienhuis and Orkin will be formally presented with their awards prior to the Plenary Scientific Session on Sunday, December 6, at 1:30 p.m. in the Ernest N. Morial Convention Center in New Orleans.

The ASH Mentor Award was established in 2006 to recognize hematologists who have excelled at mentoring trainees and colleagues. Those selected to receive the award are chosen because they have shown a sustained commitment to mentoring, have made a significant, positive impact on their trainees' careers, and have advanced research and patient care in the field of hematology through their trainees and their trainees' trainees. Two awards are given each year, one in the basic sciences and one in clinical investigation and training. Awardees are selected from a group of candidates nominated by individuals whose careers they have helped shape.

Transfusions Risky For Cardiac Patients

Sat, 08 Aug 2009 13:45:23 PST

( from http://www.rxpgnews.com ) Blood transfusion to hospitalised cardiac patients doubles the risk of infection and quadruples the risk of death, according to a new study.

The analysis of nearly 25,000 'Medicare' patients in Michigan also showed that transfusion practices after heart surgery varied substantially among hospitals, a red flag that plays into the health care reform debate.

Blood transfusions are extremely common in the US. Some of the typical reasons for transfusions include prevention of anaemia and improving oxygen delivery in heart failure.

Blood transfusion is an area that could be well served with stronger, research-based guidelines, since the current clinical practice is all over the map, said study co-author Neil Blumberg, professor of pathology at the University of Rochester Medical Centre -.

'Doctors are simply doing what they were trained to do, but it turns out that their actions are more harmful than helpful in many cases,' Blumberg said.

'This is an instance in which clinical practice got way ahead of research. And changing the liberal use of transfusions is going to be difficult despite the evidence showing it is usually not essential.'

Blumberg and co-author Mary Rogers analysed patient records in 40 hospitals, from admission to 30 days after discharge.

All had received coronary artery bypass graft surgery from 2003 to 2006. They found that 30 percent of variation in transfusion practices seemed to be due to widely varied practices among hospital sites.

Also, blood use among women patients ranged from 72.5 percent to 100 percent, and blood use among men varied from about 50 percent to 100 percent.

Transfusions with donor blood were associated with infections of the genitourinary system, respiratory tract, bloodstream, digestive tract and skin, the study said.

The study was published in BMC Medicine.

NHLBI stops study of pulmonary hypertension treatment in sickle cell patients

Tue, 28 Jul 2009 03:59:36 PST

( from http://www.rxpgnews.com ) The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health has stopped a clinical trial testing a drug treatment for pulmonary hypertension in adults with sickle cell disease nearly one year early due to safety concerns. In an interim review of safety data from 33 participants who completed 16 weeks of treatment, researchers found that, compared to participants on placebo (dummy pill), participants taking sildenafil (Revatio) were significantly more likely to have serious medical problems. The most common problem was episodes of severe pain called sickle cell crises, which resulted in hospitalization. No deaths have been associated with the drug in the clinical trial.

Known as walk-PHaSST, the study was the first multicenter, randomized clinical trial to test the safety and effectiveness of sildenafil for pulmonary hypertension in patients with sickle cell disease, one of the most common genetic blood disorders in the United States. Pulmonary hypertension is a debilitating condition of high blood pressure in the arteries that carry blood to the lungs, which can lead to heart failure and death. Approximately 30 percent of sickle cell disease patients develop pulmonary hypertension, and even mild levels of pulmonary hypertension have been associated with sudden death in people with sickle cell disease.

The increase in sickle cell medical problems is concern enough for us to stop this clinical trial to protect the safety of our participants, said NHLBI Director Elizabeth G. Nabel, M.D. We will continue to look into the possible causes of these preliminary results. In the meantime, we encourage patients with sickle cell disease who are taking sildenafil for pulmonary hypertension to talk with their physicians about the potential risks and benefits of the medication and what actions they should consider, including whether to taper off this medication and how to best manage both sickle cell disease and pulmonary hypertension.

Because the medical problems experienced in walk-PHaSST were complications specific to sickle cell disease, The findings of the walk-PHaSST study should not be applied to other groups of patients with pulmonary hypertension where the drug has been found to be safe and effective, Nabel added.

Researchers are conducting extensive analyses of the study results, which could contribute to recommendations for treating pulmonary hypertension in patients with sickle cell disease. They will prepare reports of their research for publication in peer-reviewed journals.

The NHLBI stopped the study on July 7, 2009, based on the unanimous recommendations of the Pulmonary Complications of Sickle Cell Disease Data and Safety Monitoring Board (DSMB), an independent advisory group that has been monitoring the study since it began. This DSMB is composed of experts in sickle cell disease, lung disease, statistics, and bioethics.

Participants in walk-PHaSST have discussed the preliminary findings of the study with their study clinicians. They have been instructed to taper sildenafil treatment over a period of three to seven days to minimize problems associated with immediate withdrawal from the drug, such as worsening of symptoms of pulmonary hypertension. Researchers will continue to monitor participants and conduct further analyses to assess the findings.

Walk-PHaSST was designed to determine whether sildenafil lessens the symptoms of pulmonary hypertension, such as shortness of breath, by improving heart and lung function, in individuals with sickle cell disease who develop pulmonary hypertension. The primary outcome measure was the results of a six-minute walk test, a standard indicator of a person's heart and lung function. Hence, the name walk-PHaSST reflects the primary test used to assess effectiveness of the treatment (walk test) for Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy. Researchers also evaluated the safety of the drug for sickle cell disease patients through reports of adverse effects and laboratory tests.

Sildenafil is approved by the Food and Drug Administration for use in patients with pulmonary hypertension. In general, the drug treats pulmonary hypertension by relaxing the blood vessels in the lungs to allow blood to flow more easily. Since sildenafil is not FDA-approved to treat pulmonary hypertension in patients with sickle cell disease, the walk-PHaSST study was conducted under an investigational new drug application. The FDA was notified of the termination of the study on July 14.

Walk-PHaSST began recruiting participants in July 2007 and enrolled 74 patients over the age of 19 (average age 45). Participants had sickle cell disease and mild to severe pulmonary hypertension. They were randomly assigned to receive sildenafil or placebo for 16 weeks. Participants could also receive other therapies as needed to manage sickle cell and related complications. After completing the study treatment (or placebo), participants could choose to be part of the open-label follow-up phase of the study and continue to be assessed for up to one year. In the open-label study, participants and clinicians knew that sildenafil was being taken. When the study was stopped, 33 participants had completed the clinical trial.

Researchers found that 38 percent of participants taking sildenafil had serious adverse effects -- primarily sickle cell pain crises -- compared to 8 percent of participants in the placebo group.

Although these preliminary results are disappointing, we expect that the study's results, once fully analyzed, will provide important insights into the role of pulmonary hypertension in sickle cell disease, said Mark Gladwin, M.D., lead investigator of walk-PHaSST and director of the Vascular Medicine Institute at the University of Pittsburgh. Gladwin is also a special volunteer for the NHLBI and was formerly a senior investigator with the Critical Care Medicine Department at the NIH Clinical Center and chief of the NHLBI Pulmonary and Vascular Medicine Branch.

The design of the walk-PHaSST study was based on extensive evidence that sildenafil improves pulmonary hypertension regardless of its cause and on results of a small, open-label, nonrandomized pilot study led by Gladwin while he was at the NIH. The pilot study evaluated 12 sickle cell patients with mild or moderate pulmonary hypertension who were being treated with sildenafil and with hydroxyurea, a drug known to help reduce the numbers of episodes of sickle cell pain crises and acute chest syndrome, as well as hospitalizations and blood transfusions needed. In 2005, Gladwin and his colleagues reported that after about 6 months, sildenafil was well tolerated, decreased pulmonary blood pressure, and increased exercise capacity.

Walk-PHaSST emphasizes the importance of multi-site, blinded, randomized clinical trials to increase our understanding of both the benefits and the potential risks of specific treatments, noted Jonathan C. Goldsmith, M.D., NHLBI project officer of walk-PHaSST. As with all clinical studies, patient safety is paramount.

Walk PHaSST was conducted at the following locations:

Anemia linked with higher death risk in heart patients

Thu, 18 Jun 2009 15:42:04 PST

( from http://www.rxpgnews.com ) The presence of anaemia in patients with chronic heart failure is linked to a significantly higher risk of death.

Heart failure is a common and serious chronic illness. A large number of patients with heart failure also have anaemia, which is most likely a complication from poor heart function.

The aim of this study was to assess the impact of anaemia on the clinical outcomes of chronic heart failure - by a meta-analysis and systemic review of published literature.

A total of 97,699 patients with CHF were identified from the published studies. From a collective analysis, researchers found that when anaemia occurs, it worsens patient prognosis, making them more likely to be hospitalized or die from heart failure.

'Health professionals may need to improve current practices to better treat anaemia in patients with chronic heart failure,' said Lexin Wang, study co-author and head of the cardiovascular group at Charles Sturt University -, in Australia.

Even with contemporary medical treatment, the mortality rate from CHF is still high, reaching 40 percent in very sick patients, said a CSU release.

Given the clear association between anaemia, mortality rate and hospitalization rate, optimal treatment of anaemia, on top of other heart-failure-specific therapies, may reduce the rate of mortality and further improve patient's prognosis.

These findings will appear in Congestive Heart Failure journal.

Common chemotherapy drug triggers fatal allergic reactions

Mon, 08 Jun 2009 03:59:36 PST

( from http://www.rxpgnews.com ) CHICAGO -- A chemotherapy drug that is supposed to help save cancer patients' lives, instead resulted in life-threatening and sometimes fatal allergic reactions.

A new study from the Research on Adverse Drug Events and Reports (RADAR) pharmacovigilance program at Northwestern University Feinberg School of Medicine identified 287 unique cases of hypersensitivity reactions submitted to the FDA's Adverse Event Report System between 1997 and 2007 with 109 (38 percent) deaths in patients who received Cremophor-based paclitaxel, a solvent-administered taxane chemotherapy.

Adverse event reports generally only represent from 1 to 10 percent of actual incidence, so the number of hypersensitivity reactions and deaths is likely significantly higher. The severe allergic reactions are believed to be caused by Cremophor, the chemical solvent - a derivative of castor oil -- that is used to dissolve some insoluble drugs before they can be injected into the blood stream.

Two patients who died from an allergic reaction had early-stage breast cancer, which had been surgically removed, and were being treated with Cremophor-containing paclitaxel to prevent the cancer from coming back. Both of these patients had received medications before the chemotherapy to reduce the risk of hypersensitivity reactions.

The study was led by Charles Bennett, M.D., RADAR program coordinator and a professor of hematology/oncology at Northwestern's Feinberg School, and Dennis Raisch, a professor of pharmacy at the University of New Mexico.

The deaths of women with early-stage breast cancer are particularly disturbing because without the adverse reaction, they could have likely had 40 years of life ahead of them, Bennett said.

RADAR investigators also found that 22 percent of all fatalities occurred in patients despite patients having received premedication to prevent hypersensitivity reactions, while another 15 percent of such patients experienced life-threatening respiratory arrest.

The report was presented at the 45th Annual Meeting of the American Society of Clinical Oncology held recently in Orlando, Fla.

Cremophor-containing paclitaxel has been associated with hypersensitivity reactions, with responses ranging from mild skin conditions to more severe effects, including anaphylaxis and cardiac collapse. Current U.S. product labeling for Cremophor containing paclitaxel includes a black-box warning alerting physicians and patients of potential toxicity and recommending the use of corticosteroids and other medications before chemotherapy administration to reduce the risk of hypersensitivity reactions.

The results of our review suggest that physicians should be vigilant in monitoring the safety of their patients undergoing chemotherapy treatment, said Bennett, who also is the A.C. Buehler Professor in Economics and Aging at the Feinberg School and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Patients receiving Cremophor-based paclitaxel should be given medications to prevent hypersensitivity reactions, but what is sobering, as the study has shown and as the black-box warning indicates, women suffer anaphylaxis despite receiving steroid premedication, Bennett said. Physicians should be diligent in reporting adverse events to regulatory agencies to better monitor the impact of Cremophor on patient safety. Physicians may also want to consider exploring other alternative chemotherapy options that do not include Cremophor.

In addition to the two women with early-stage breast cancer who died after treatment with the Cremophor-based paclitaxel, four other women with early-stage breast cancer experienced life-threatening anaphylaxis reactions. Each of them had received prior medications to prevent the reactions.

The fatal outcomes observed in patients with early-stage breast cancer were particularly striking as this is a patient population with a good prognosis that is generally treated with curative intent, said Raisch.

For the report, Bennett and Raisch reviewed adverse event reports submitted to regulatory agencies in the U.S., Europe and Japan. The most common cancer diagnosis for these patients with allergic reactions was lung cancer followed by breast cancer and ovarian cancer.

Canadian biomedical engineering pioneer receives international award

Thu, 23 Apr 2009 03:59:36 PST

( from http://www.rxpgnews.com ) Countless individuals around the world are alive because of him. His 40 plus years of research have helped to make the use of life-saving devices such as prosthetic heart valves, vascular stents, vascular grafts, heart-assist devices, and heart-lung bypass systems almost commonplace. In the process, he has helped to establish Canada as a biomaterials leader.

John Brash, P.Eng., director of the School of Biomedical Engineering at McMaster University, and distinguished university professor, was recognized for these contributions with the presentation of the Founders Award by the Society for Biomaterials on April 22 in San Antonio, Texas.

I am honoured and humbled to receive this award given the calibre of past recipients, said Prof. Brash. It was a surprise when I was notified of the award. Much of the recognition must be shared with the numerous colleagues, peers, and students I have been fortunate to have worked with over the years.

Prof. Brash is only the second Canadian to receive this award, of which just 14 have been presented since it was established in 1987. Michael Sefton, university professor of chemical engineering and applied chemistry, University of Toronto, received the award in 2008. Selection for a Founders Award is based on long-term, landmark contributions to the discipline of biomaterials.

John has been a leading member of the world's biomaterials community for many years, said Michael Sefton, past-president of the Society for Biomaterials and chair of the awards committee. His seminal contributions to our understanding of the behaviour of proteins at interfaces and to the use of polyurethanes in medicine have been among the most important and long-standing contributions to the science of biomaterials.

Prof. Brash is internationally regarded for his work in at least three major areas: protein adsorption and blood compatibility, particularly as it relates to blood proteins and thrombus formation on artificial surfaces; biocompatible polyurethane based materials; and surface modification.

His literature contributions have guided the work of countless biomaterials scientists, said Heather Sheardown, associate professor of chemical engineering at McMaster. Another of John's important contributions is in the training of a new generation of biomaterials scientists who have gone on to work in academia and industry, continuing to advance the field and carrying with them a passion ignited during their time in the Brash lab.

Prof. Brash has trained some 50 Masters, PhDs and postdoctoral fellows. He is also called on to consult with numerous biomaterials-related companies.

Dr. Brash, whether interacting with fellow chemical engineers, biomaterials scientists or clinicians, has had a significant influence on the evolution of the field of biomaterials, said Stuart Cooper, professor and chair of the department of chemical and biomolecular engineering, at Ohio State University.

Discoveries by Prof. Brash can be found in some of Canada's most successful biomedical companies including Interface Biologics Inc. of Toronto and Angiotech Inc. in Vancouver.

The latter part of the 80s and early 90s ushered in the concept of designing biomaterials that were pro-active in their interaction with proteins and cells, explains Prof. Santerre, who is also chief scientific officer and co-founder of Interface Biologics. John's program in polyurethane research was among the first to build-in functional monomers that would capitalize on simulating the natural mechanisms of anti-coagulant function. Today, the bioactive concept is revolutionizing medical devices by merging the biopharmaceutical field and medical device sector to deliver implant therapies that accelerate healing associated with serious diseases.

Potential breakthrough for T-Cell lymphoma patients with drug that mimics folic acid

Tue, 09 Dec 2008 04:59:37 PST

( from http://www.rxpgnews.com ) NEW YORK (Dec. 8, 2008) -- Preliminary results of a pivotal Phase 2 clinical trial of pralatrexate (PDX), a drug that partially works by mimicking folic acid, showed a complete or partial response in 27 percent of patients with recurrent or resistant peripheral T-cell lymphoma (PTCL). PROPEL (Pralatrexate in patients with Relapsed Or refractory PEripheral T-cell Lymphoma) findings were presented by the study's principal investigator, Dr. Owen A. O'Connor of the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center and NewYork-Presbyterian Hospital, at the 50th Annual Meeting of the American Society of Hematology (ASH) in San Francisco.

The international, multicenter PROPEL trial is the largest ever conducted in patients with peripheral T-cell lymphoma -- a biologically diverse group of blood cancers that account for as many as 15 percent of non-Hodgkin's lymphoma (NHL) cases in the United States. There are currently no pharmaceutical agents approved for use in the treatment of either first-line or relapsed or refractory PTCL, and average five-year survival is approximately 25 percent.

These results indicate that pralatrexate produces a major durable response in patients for whom numerous prior treatments have been unsuccessful, says Dr. Owen A. O'Connor, director of the Lymphoid Development and Malignancy Program and chief of the Lymphoma Service at the Herbert Irving Comprehensive Cancer Center at NewYork-Presbyterian Hospital and Columbia University Medical Center, and associate professor of medicine at Columbia University College of Physicians and Surgeons.

Prior to enrolling in the trial, eligible patients had received a median of three (range of 1 to 12) prior systemic treatment regimens, including 16 percent of patients who had previously undergone an autologous stem cell transplant.

Presently, there are no FDA-approved drugs for patients with PTCL, whether it is in the front-line or for patients with relapsed or refractory disease. This underscores the need for new therapies to treat this challenging disease. Pralatrexate has the potential to play a clinically meaningful role in the treatment of these patients, adds Dr. O'Connor. Pralatrexate, designed to look like the natural vitamin folic acid, disrupts DNA synthesis in tumor cells. The drug is designed to selectively accumulate in tumor cells, after which it then induces programmed cell death, or apoptosis, in the cancer cell.

A total of 109 evaluable patients received 30 mg/m2 of pralatrexate intravenously once every week for six weeks followed by one week of rest per cycle of treatment. Patients also received vitamin B12 and folic acid supplementation. Response was assessed using standard International Workshop Criteria (IWC).

In the trial, 69 percent of patients who responded did so after cycle one of therapy. The median duration of treatment in responding patients was 179 days at the time of this analysis. The duration of response exceeded three months in 17 of 29 responders (59 percent), including 6 of the 17 patients who continued on treatment. An accurate estimate of the median duration of response cannot be reported at this time due to the current length of follow up. Patients will continue to be followed until the median duration of response can be accurately estimated.

The PROPEL trial is organized by Allos Therapeutics Inc., the maker of the drug. Since PROPEL has been given fast-track status, the company will submit pralatrexate for FDA approval once the Phase 2 data has been finalized -- sometime in the first half of 2009.

Pralatrexate was developed by a team of researchers at Memorial Sloan-Kettering Cancer Center (MSKCC) and the Southern Research Institute, including Dr. O'Connor, while at MSKCC. Dr. O'Connor and his colleagues identified the unique activity of pralatrexate in patients with lymphoma. Dr. O'Connor has continued to study pralatrexate at NewYork-Presbyterian/Columbia, now focusing on determining how the drug works in T-cell lymphoma, and on how best to combine it with other drugs to improve the treatment of patient with hematologic cancers.

Bone marrow stem cell niche discovered

Sun, 07 Dec 2008 17:36:10 PST

( from http://www.rxpgnews.com ) Researchers have identified the precise location of the bone marrow stem cell niche.

Linheng Li Lab of the Stowers Institute for Medical Research collaborated with several other facilities to develop a new technology - ex vivo - imaging of stem cells, or EVISC - to monitor the dynamic behaviour of stem cells.

This technology enabled the team to track the homing of haematopoietic stem cells -, which give rise to all blood cell types, after being transplanted in mice. The findings build on the Linheng Li Lab's 2003 discovery of the HSC niche.

A better understanding of the HSC niche may lead to more effective bone marrow transplants since a more precise understanding of the micro-environment that nurtures these therapeutically valuable cells will give physicians greater control over the entire process.

'Using the EVISC technology, we were able to confirm our 2003 findings that HSCs tend to home in to the inner bone surface,' said Yucai Xie, a pre-doctoral researcher and co-author of the paper, according to Stowers Institute release.

'Additionally, we were able to resolve a debate in the field about whether the bone-forming niche or the blood-vessel-forming niche actually nurtures HSCs, he added.

The findings came out Friday in the advance online publication of Nature.

Transcranial Doppler ultrasonography screening helps in preventing strokes in children with sickle cell disease

Sun, 07 Dec 2008 14:10:21 PST

( from http://www.rxpgnews.com ) Screening with an ultrasound machine has proved highly successful in preventing stroke among children with sickle cell disease, by identifying children who are then preventively treated with blood transfusions. Over an eight-year period at The Children's Hospital of Philadelphia, researchers found that the technique, transcranial Doppler ultrasonography (TCD), along with regular transfusions for children found to be at high risk, reduced stroke to one-tenth of the incidence found before TCD was introduced.

"We studied the impact of using TCD starting in 1998, when the technique became routine at our hospital and many other centers," said Janet L. Kwiatkowski, M.D., a pediatric hematologist at The Children's Hospital of Philadelphia. Kwiatkowski presented her group's results today at a press conference during the 50th annual meeting of the American Society of Hematology.

Childhood stroke has long been known to be a devastating complication of sickle cell disease, an inherited condition in which abnormal hemoglobin deforms red blood cells into sickle-shaped bodies that do not pass smoothly through blood vessels.

TCD is a noninvasive tool that uses ultrasound waves to measure the speed of blood flow in large vessels in the brain. An abnormally high speed is a marker of a narrowed vessel, and a sign of high risk for stroke.

After the multicenter Stroke Prevention Trial in Sickle Cell Anemia showed in 1998 the utility of TCD in detecting abnormal blood speeds and the benefit of transfusions in reducing stroke risk, the Sickle Cell Program at Children's Hospital began to routinely use TCD in screening sickle cell patients. "When we see an abnormal TCD result, we treat the child with preventive blood transfusions, given regularly every three to four weeks," said Kwiatkowski.

The current study compared the rate of stroke in children with sickle cell disease in the eight years before Children's Hospital began TCD screening with the eight years from 1998 to 2006. The researchers followed 475 children in the pre-TCD group and 530 children in the post-TCD group.

In reviewing patient records, the researchers measured overt strokes, other neurological events and indeterminate events—those that could not be classified based on available information. In the pre-TCD group, there were 21 patients with overt stroke, three with other neurological events and two with indeterminate events. In contrast, the post-TCD group had two patients with overt stroke, six with other neurological events and one with an indeterminate event.

Overall, the incidence of overt stroke in the pre-TCD group was significantly higher compared to the post-TCD group—an incidence of 0.67 per 100 patient years compared to 0.06 per 100 patient years. "The study confirmed that a program of TCD screening combined with regular transfusion therapy for children found to be at high risk of stroke is effective in preventing strokes," added Kwiatkowski.

Evaluation of new anti-coagulant drugs

Sun, 07 Dec 2008 14:01:46 PST

( from http://www.rxpgnews.com ) The largest study ever to examine the preventive use of blood-thinning medication to help prevent deadly blood clots in patients with cancer undergoing chemotherapy was presented in a press conference during the 50th Annual Meeting of the American Society of Hematology in San Francisco, CA. Additional research featured at the press conference includes studies that examine the use of three different investigational blood-thinning medications that belong to a new class of therapies called Factor Xa inhibitors. These studies evaluated the effectiveness of these medications in preventing blood clots: following major orthopedic surgery; in patients with atrial fibrillation; and in patients with deep-vein thrombosis.

Blood clotting, or coagulation, is an important process that prevents excessive bleeding when a blood vessel is injured. Usually, the body naturally dissolves the clot when the injury has healed; however, when a clot does not dissolve naturally, it can become extremely dangerous. Deep-vein thrombosis, a type of blood clot that typically forms in a major vein of the leg, and pulmonary embolism, which occurs when a blood clot detaches from its point of origin and travels to the lungs where it becomes wedged and prevents adequate blood flow, are known collectively as venous thromboembolism.

"Venous thromboembolism is a serious public health problem that affects almost 1 million Americans each year and is responsible for more deaths each year than breast cancer, HIV disease, and motor vehicle crashes combined," said J. Evan Sadler, MD, moderator of the press conference and Professor of Medicine and of Biochemistry and Molecular Biophysics, Washington University Medical School, St. Louis, MO. "The hematology community is committed to continuously improving treatments for these patients, and the exciting research presented today is another step forward in finding ways to eliminate this preventable leading cause of death."

Certain conditions can elevate a person's risk of clotting, including atrial fibrillation (an abnormal heart rhythm), previous heart attack, long periods of inactivity, some medications, and genetic or disease-related factors. Treatment typically consists of anticoagulants that help prevent clots from forming, medications that dissolve blood clots, catheter-directed thrombolysis (a surgical procedure where clot-dissolving medication is directed toward the blood clot), and thrombectomy, the surgical removal of a blood clot. Recognizing the deadly impact blood-clotting disorders have on millions of Americans every year, the American Society of Hematology has developed a new resource, www.bloodthevitalconnection.org, to help educate the public about these and other common blood diseases.

A Randomized Double-Blind Placebo-Controlled Study on Nadroparin for Prophylaxis of Thromboembolic Events in Cancer Patients Receiving Chemotherapy: The PROTECHT Study [Abstract #6]
Giancarlo Agnelli, MD, University of Perugia, Perugia, Italy

This study is the largest to determine that the preventive use of an antithrombotic medication can reduce the incidence of thromboembolic events in patients with cancer. It is well known that patients with cancer who receive chemotherapy are at high risk for developing deadly blood clots, but few large studies have confirmed whether the preventive use of a blood-thinning medication can reduce these events.

This multicenter, placebo-controlled, clinical outcome-based study was designed to evaluate the efficacy of nadroparin, a low-molecular-weight heparin, for the preventive treatment of thromboembolic events in cancer patients receiving chemotherapy. The primary outcome of the study was the combined occurrence of clinically overt venous or arterial thromboembolic events (i.e., deep-vein thrombosis of the lower and upper limbs, visceral and cerebral venous thrombosis, pulmonary embolism, acute myocardial infarction, ischemic stroke, acute peripheral arterial thromboembolism, and unexplained death of possible thromboembolic origin). Major bleeding was the main safety parameter.

In this study, 1,166 patients with advanced lung (279), colon (235), breast (165), ovarian (143), stomach (98), rectal (87), pancreatic (53), head and neck (36), and other cancers (54) were randomized to one of two treatment arms: once-daily subcutaneous injections of nadroparin (3,000 IU) or placebo. Twice as many patients were enrolled into the nadroparin group than the placebo group. Treatment was started on the first day of the current cycle of chemotherapy and was maintained for the overall duration of chemotherapy treatment or up to a maximum of four months.

Only 16 of the 769 patients treated with nadroparin had a thromboembolic event (2.1 percent) compared with 15 of the 381 patients (3.9 percent) in the placebo group, a 47.2 percent reduction in the risk of developing a thromboembolic event for the patients in the treatment arm. The drug also appeared to be safe as only five patients in the nadroparin group (0.7 percent) experienced a major bleeding episode, and the incidence of minor bleeding in the treatment arm was similar to that of the placebo group.

Venous thromboembolism occurred 11 times in both the nadroparin and placebo groups. Fifteen of these events occurred in patients with lung cancer (4 percent in the nadroparin arm and 8.8 percent in the placebo arm). Patients with pancreatic cancer also experienced a high overall rate of thromboembolic events (7.5 percent). While this study confirms that nadroparin reduces the incidence of thromboembolic events in cancer patients receiving chemotherapy, because of the disproportionately higher incidence of events in lung and pancreatic cancer patients, further studies should focus on patients in these two high-risk populations.

Idrabiotaparinux, a Biotinylated Long-Acting Anticoagulant, in the Treatment of Deep-Venous Thrombosis (EQUINOX Study): Safety, Efficacy, and Reversibility by Avidin [Abstract #32]
Harry Roger Buller, MD, PhD, Academic Medical Center, Amsterdam, Netherlands

This clinical trial found that six months of treatment with idrabiotaparinux, an anticoagulant and indirect Factor Xa inhibitor that links indraparinux to biotin, showed comparable efficacy to idraparinux alone with a trend toward less bleeding in patients with deep-vein thrombosis. Additionally, an infusion of avidin after the last idrabiotaparinux treatment led to a rapid reversal of the anti-Factor Xa activity, or the anticoagulant effect of the drug, which was sustained for at least five days. This study builds on previous research that showed similar efficacy and safety between once-weekly subcutaneous injections of indaparinux with standard treatment (low-molecular-weight heparin followed by a vitamin K antagonist) in the treatment of deep-vein thrombosis.

A total of 757 patients with symptomatic and confirmed deep-vein thrombosis were randomized to receive weekly subcutaneous injections of 3 mg idrabiotaparinux (385 patients) or 2.5 mg idraparinux (370 patients) for six months. The primary objective of the study was to determine whether idrabiotaparinux works in a similar manner to idraparinux (i.e., bioequipotency). The secondary objective of the study was occurrence of clinically relevant bleeding, death, or symptomatic recurrent venous thromboemolism at the end of six months of therapy.

A final objective included the reversal of the anticoagulant effect of idrabiotaparinux, as there are medically relevant instances, such as prior to surgery, when there is the need to reverse the effects of an anticoagulant. The reversal of the anticoagulant effect was measured after a 30-minute intravenous infusion of avidin (100 mg), a hen egg protein that binds with biotin to reverse the Factor Xa inhibiting activity of idrabiotaparinux. At the end of the initial six-month treatment with idrabiotaparinux, a subset of patients was re-randomized to receive avidin (those in the idrabiotaparinux arm) or placebo (those in both the idrabiotaparinux and idraparinux arms to preserve blinding). Avidin or placebo was infused between two and five hours after the last injection of idrabiotaparinux or idraparinux.

Anti-Factor Xa activity was measured just prior to the infusion, just after the infusion, and then every day for five days to ensure that the reversibility remained unchanged.

The study found that there was less clinically relevant bleeding (5.2 percent versus 7.3 percent) and less major bleeding (0.8 percent versus 3.8 percent) in those treated with idrabiotaparinux as compared with idraparinux. Rates of recurrent venous thromboembolism (2.3 percent versus 3.2 percent) and fatal or non-fatal pulmonary embolism (1.6 percent versus 1.8 percent) were similar with both idrabiotaparinux and idraparinux.

Levels of Factor Xa activity were identical in both treatment groups throughout the six-month study. Of the 52 idrabiotaparinux patients re-randomized to receive avadin or placebo, 41 were analyzed for reversal of Factor Xa activity (23 received avidin and 18 received placebo). At the end of the 30-minute infusion of avidin, mean anti-Factor Xa activity was reduced by 77.8 percent and was sustained for at least five days as compared with 2.4 percent for the placebo group. The infusion of avidin was well-tolerated with no allergic reactions observed.

Randomized, Parallel Group, Multicenter, Multinational Study Evaluating Safety of DU-176b Compared With Warfarin in Subjects With Non-Valvular Atrial Fibrillation [Abstract #33]
Jeffrey I. Weitz, MD, Henderson Research Centre, Hamilton, Canada

The primary objective of this study was to evaluate the safety of four dosing regimens of DU-176b in patients with non-valvular atrial fibrillation. This phase II study found that two regimens (30 mg and 60 mg once-daily) of an investigational oral Factor Xa inhibitor, DU-176b, are safe in patients with non-valvular atrial fibrillation, making the drug a potential substitute for warfarin, the conventional blood-thinning agent used in such patients to prevent stroke.

Dosing of warfarin is complicated because it interacts with many commonly-used medications and even certain foods. For that reason, patients receiving warfarin require regular blood testing to monitor the international normalized ratio (INR) to ensure that an adequate yet safe dose of warfarin is given.

A total of 1,146 patients with atrial fibrillation were randomized to receive either one of four fixed-dose regimens of DU-176b (30 mg once-daily, 30 mg twice-daily, 60 mg once-daily, 60 mg twice-daily) or warfarin (dose-adjusted to a target INR of 2.0 to 3.0) for 12 weeks. The primary endpoints of the study were the incidence of bleeding events (major and clinically relevant non-major) and elevated liver enzymes and/or bilirubin, which might be indicative of hepatic toxicity. Secondary endpoints included major adverse cardiovascular events, stroke, systemic embolism, acute myocardial infarction, hospitalizations due to cardiovascular conditions, or cardiovascular death.

The incidence of major and clinically relevant non-major bleeding events was significantly higher in the 30 mg and 60 mg twice-daily DU-176b regimens than it was in patients given warfarin (7.8 percent, 10.6 percent and 3.2 percent, respectively). In contrast, the incidence of major and clinically relevant non-major bleeding events with the 30 and 60 mg once-daily DU-176b regimens was comparable to that with warfarin (3.0 percent, 3.8 percent, and 3.2 percent, respectively). There were no significant differences in patients with elevated liver enzymes or bilirubin across all treatment groups, and there were no significant differences in the rates of secondary endpoints.

Once-Daily Oral Rivaroxaban Compared With Subcutaneous Enoxaparin Every 12 Hours for Thromboprophylaxis After Total Knee Replacement: RECORD4 [Abstract #35]
Alexander G.G. Turpie, MD, McMaster University, Hamilton, Ontario, Canada

This study concluded that investigational rivaroxaban, an oral Factor Xa inhibitor, is more efficacious than a current standard of therapy, enoxaparin, for the prevention of venous thromboembolism following total knee replacement surgery without significantly increasing the risk of bleeding. Coupled with previous research that demonstrated that post-operative rivaroxaban was more effective than pre-operative enoxaparin in preventing deep-vein clotting, along with an easier method of administration (oral versus subcutaneous injection), this study may change the way physicians prevent serious blood clots in patients undergoing major orthopedic surgery.

In this study, a total of 3,148 patients were randomized to receive either once-daily oral rivaroxaban (10 mg) starting six to eight hours after surgery or twice-daily subcutaneous injections of enoxaparin beginning 12 to 24 hours after surgery for 10 to 14 days. Patients underwent mandatory, bilateral venography (X-ray of the vein) between days 11 and 15.

The primary endpoint of the study was the combined occurrences of deep-vein thrombosis, non-fatal pulmonary embolism, and all-cause mortality up to day 17. The main safety endpoint was major bleeding observed after one dose of the drug until two days after the end of treatment. Efficacy was determined first by a test for non-inferiority in the per-protocol population of 1,702 patients, followed by a test for superiority in the intention-to-treat population of 1,924 patients.

The results indicated that rivaroxaban significantly reduced the incidence of adverse events (the combination of blood clots and death) by 31 percent as compared with enoxaparin, with no significant increase in the rate of major bleeding events. Rivaroxaban and enoxaparin appeared equally effective at preventing major venous blood clots and pulmonary embolism

Researchers aim to over-stress already taxed mantle cell lymphoma cells

Mon, 10 Nov 2008 04:59:37 PST

( from http://www.rxpgnews.com ) AUGUSTA, Ga. - Cancer cells are already stressed by the fast pace they require to grow and spread and scientists believe a little more stress just may kill them.

Think about an assembly line in a factory that is working five times faster than normal, said Dr. Kapil Bhalla, director of the Medical College of Georgia Cancer Center. There is a lot of stress but you need workers to keep going. Some of them fall out, some get bent out of shape.

His research team believes they can disrupt the over-stressed assembly line of mantle cell lymphoma and possibly similar cancers such as pancreatic, liver and breast, by taking away support needed for rapid protein turnover and by clogging up the mechanism for eliminating poorly made ones.

Mantle cell lymphoma, an aggressive cancer of the lymphatic system that mostly occurs in middle age, responds initially to chemotherapy and antibiotics, but often returns, said Dr. Bhalla. Patients have a median survival of three to four years. This cancer affects b lymphocytes, immune cells which make antibodies to fight infection. Ironically, in the process of rearranging genes to make antibodies to a specific invader, mistakes happen, and a would-be protector becomes cancer.

MCG researchers found that to keep their fast pace, these now-malignant cells need increased activity of heat shock protein 90. Cancer cells require hsp90 for keeping their proteins in active conformation to do their job. That is what cancer is addicted to, said Dr. Bhalla, Cecil F. Whitaker, Jr., M.D./Georgia Research Alliance Eminent Scholar in Cancer and Georgia Cancer Coalition Distinguished Cancer Scholar. Hsp90 is one of the more common molecular chaperones, which help proteins get made, moved, folded and function. Its levels and activity are upregulated in response to stress.

They also found that the usually busy endoplasmic reticulum of these cells, which is supposed to be making normal antibodies, is stressed by making hyperactive, cancer-associated proteins. Stepped-up protein production also means more misfolded proteins that the proteasome must deal with. It's all stressed-out machinery, Dr. Bhalla said.

To help push cancer cells over the edge, the researchers are inhibiting hsp90, so the cells lose the molecular chaperone function required to maintain their fast pace. This also puts more stress on the endoplasmic reticulum. Independently hsp90 inhibitors are known to selectively kill cancer cells. But researchers also are clogging up the proteasome, the machinery for chopping up misfolded proteins, recycling some products and eliminating what's left. Much like a sink won't work with a clogged garbage disposal, mantle cell lymphoma cells will start backing up. When a cell detects excessive misfolded proteins, it first has a protective response, but if the problem persists, it commits suicide.

With support from a five-year, $1.5 million grant from the National Cancer Institute, the researchers are using hsp90 and proteasome inhibitors to study protective versus lethal endoplasmic reticulum stress as a way to get rid of mantel cell lymphoma cells. The laboratory studies are being done in human mantle cell lymphoma cells as well as an animal model the researchers developed.

The drugs they are using already are in early clinical trials for a variety of cancers but have not yet been packaged together, Dr. Bhalla said. We kill cancer cells and a lot of them with this strategy. Still, at least one more inhibitor may get added to the mix. After the rather brutal attack at the cancer's molecular underpinnings, the immune system comes in to essentially mop the floor, but researchers have found cancer cells can still get a pass from an enzyme called IDO. A team of MCG researchers led by Dr. David Munn is exploring IDO's therapeutic potential in cancer. Fetuses use IDO to avoid rejection by the mother's immune system and tumors appear to use it as well. Dr. Bhalla suspects an IDO inhibitor, already under study for lung cancer and other tumors, likely will get a shot at mantle cell lymphoma as well.

'Old blood' linked to infection

Tue, 28 Oct 2008 03:59:37 PST

( from http://www.rxpgnews.com ) Blood stored for 29 days or more, nearly 2 weeks less than the current standard for blood storage, is associated with a higher infection rate in patients who received transfusions with the blood. In a new study presented at CHEST 2008, the 74th annual international scientific assembly of the American College of Chest Physicians (ACCP), researchers found that patients who received transfusions with blood stored for 29 days or more were twice as likely to suffer from nosocomial infections, including pneumonia, upper respiratory infections, and sepsis, with the oldest blood being associated with the most infections. Currently, federal regulations allow red blood cells to be stored up to 42 days, after which they must be discarded.

Stored red blood cells undergo changes that promote the release of a number of biochemical substances called cytokines, which can depress the recipients' immune function and leave them more susceptible to infection, said study author Raquel Nahra, MD, who conducted her research while at Cooper University Hospital, Camden, NJ. Those changes start around 14 days of storage and reach a maximum after the blood is discarded at 42 days.

Researchers from Cooper University Hospital examined the association between the age of packed red blood cells and the development of nosocomial infections (NOSO) in 422 patients receiving blood transfusions who were admitted to an ICU from July 2003 to September 2006. Researchers performed an analysis of the age of the first unit of blood, age of the oldest unit of blood (OL), the average age of the unit of blood, and the outcome of NOSO.

Previous data indicate that the average age of transfused blood is around 17 days old, said Dr. Nahra. In our study, the average age of blood was 26 days, and 70 percent of all the blood transfused was older than 21 days, suggesting that a large pool of available blood is old blood with higher levels of cytokines and more potential for an immunosuppressive effect.

The analysis showed that 11 percent of patients died, while 57 patients (13.5 percent) developed NOSO: 32 patients developed one NOSO, 21 developed two NOSO, and 4 developed 3 NOSO. Patients who developed NOSO had a significantly higher OL (28.5 days vs. 32 days), and a significantly greater number of units of blood (2 U vs. 3 U). Patients who received transfusions with blood that was 29 days or older were twice as likely to develop NOSO as those receiving transfusions with blood stored for 28 days or less. When the outcome of at least one infection was analyzed, a higher number of units of blood (>5 U) was found to be an independent predictor of infection. Furthermore, while the age of the first unit of blood transfused appeared to be associated with the development of infection, the age of the oldest unit showed the strongest relationship.

Many institutions, including Dr. Nahra's, use the oldest available blood first, to ensure that it does not go to waste. Researchers speculate that if strict regulation of blood storage were to occur (ie, shorter maximum storage allowance), the overall blood supply may decrease.

More cautious utilization of blood might help to alleviate, at in least part, a diminished blood supply that might result from such a change in policy, said study director and senior investigator David Gerber, DO, Cooper University Hospital. More studies are needed, and the overall implications of any such potential changes need to be formally assessed before any major changes in blood storage policy can be proposed.

The results of this study raise questions about current blood storage standards and transfusion practices and suggest additional research is needed in these areas, said James A. L. Mathers, Jr., MD, FCCP, President of the American College of Chest Physicians.

Einstein and Montefiore receive grants to expand disease-focused stem cell research

Fri, 03 Oct 2008 03:59:37 PST

( from http://www.rxpgnews.com ) The Empire State Stem Cell Board has awarded research planning grants to Albert Einstein College of Medicine and to Montefiore Medical Center. The grants, totaling $238,000, are part of $2 million in grants announced by State Health Commissioner Richard F. Daines, M.D. The funding, awarded to 18 medical colleges, medical centers and labs will strengthen New York State's capacity for stem cell research and could lead to the development of new therapies for Alzheimer's, diabetes, Parkinson's, ALS and other conditions.

Allen M. Spiegel, M.D., the Marilyn and Stanley M. Katz Dean said, Einstein considers this grant an important step in working collaboratively with scientists across New York State to broaden our understanding of stem cells. This knowledge could lead to breakthroughs in medical science that will have important implications for people suffering from many devastating diseases.

The ability to treat and heal patients with serious conditions such as liver disease and cancer through groundbreaking stem cell treatments represents the future of medicine, and it is very exciting for us to be part of this vital statewide initiative, said Steven M. Safyer, M.D., President and CEO of Montefiore Medical Center. Montefiore welcomes the opportunity to bring its strengths to this collaboration and create the synergy between biomedical advancement and its applications to patient care that can happen only in a premier academic medical center like ours.

The planning grant awarded to Montefiore will focus on the liver, which has a unique capacity for regeneration. Liver-directed cell therapy offers opportunities to treat or cure dozens of diseases where the liver itself is damaged or diseases that have a basis in the liver but result in disease in other organs of the body. This program will permit progress in developing new treatments for liver failure, genetic diseases and other disorders which can be addressed by such therapy.

The planning grant awarded to Einstein will focus on establishing a consortium for blood cell disease in New York State. Eric Bouhassira, Ph.D., Einstein's Ingeborg and Ira Leon Rennert Professor of Stem Cell Biology and Regenerative Medicine, said, What we're hoping to do is to create unique stem cells derived from patients with blood diseases like sickle cell anemia and hemophilia. Once we have these stem cells, we will be in a much better position to try to cure them, by either correcting the genes that cause the problem or by developing drugs that treat the underlying cause of these diseases.

Grant money received to date is part of a coordinated effort by both institutions to ramp up research and improve methods for deriving stem cell lines. The planning grants will allow Einstein and Montefiore to compete for much larger grants in the future.

In January, the Empire State Stem Cell Board awarded Einstein and Montefiore combined first-phase grants of more than $1 million. That funding supports activities at Einstein's Gottesman Institute for Stem Cell and Regenerative Medicine Research and at Montefiore. The two institutions work as partners conducting rigorous scientific study and developing novel therapies for patients.

With support from the Empire State Stem Cell program we can share our knowledge, leverage capabilities with other top medical researchers and clinicians, and increase our opportunities to discover and develop new treatments for a variety of clinical conditions and diseases, said Brian Currie, M.D., Vice President of Research at Montefiore.

Under the Empire State Stem Cell program, Einstein and Montefiore work within consortia aimed at linking research institutions and corporations, building and strengthening interdisciplinary research teams, establishing core research facilities, and developing stem cell training and education programs. Stem cell research aims to improve human health and alleviate disease by restoring cells, tissues, and organs lost to disease or injury. There are many areas in medicine where stem cell research could have a significant impact, particularly where a patient's cells or tissues are destroyed and must be replaced by tissue or organ transplants. Researchers believe that stem cell research also holds promise in treating and potentially curing diseases for which there are currently no adequate therapies.

The Empire State Stem Cell Trust Fund, created by the 2007-2008 state budget, will provide up to $600 million for stem cell research over 11 years, an allocation second only to that of California.

High blood pressure takes big toll on small filtering units of the kidney

Fri, 19 Sep 2008 03:59:37 PST

( from http://www.rxpgnews.com ) Take a kidney out of the body and it still knows how to filter toxins from the blood.

But all bets are off in the face of high blood pressure.

How does the kidney know how to do it and why does it break in hypertension? says Dr. Edward W. Inscho, physiologist in the Medical College of Georgia Schools of Medicine and Graduate Studies.

The kidneys filter about 200 quarts of plasma daily, eliminating about two quarts of waste product and extra water as urine, according to the National Institute of Diabetes and Digestive and Kidney Diseases. But the complete physiology remains a mystery.

He challenged colleagues to fill in important blanks in how this process works normally and how to make it work better in disease during the Sept. 19 Lewis K. Dahl Memorial Lecture at the 62nd High Blood Pressure Research Conference and Workshop in Atlanta.

One thing is clear: Hypertension takes a serious toll on the kidneys and damaged kidneys worsen hypertension. Dr. Inscho believes the kidneys' million hard-working filters, or glomeruli, are direct victims of high pressure. His research focuses on the minute arteries, or arterioles, that feed blood into each of them. These afferent arterioles are responsible for keeping blood pressure at a comfortable 60 mmHg inside glomeruli. At a healthy blood pressure of 120/80 mmHg, blood enters the artery at a mean pressure of 100 mmHg, but higher pressures mean the arterioles must work even harder to reach the 60 mmHg target. They seem up to the task at least initially, contracting to make it harder for blood to pass and reducing pressure in the process. We want to know how it does that, Dr. Inscho says as he watches the near instantaneous contraction.

He thinks he may at least know the messenger. The first reaction to high pressure actually is for the small vessel to stretch. That stretch prompts smooth muscle cells on the vessel wall to release ATP, a common molecule known as an energy source but also gaining acceptance as an extracellular messenger, he theorizes. It's an action-reaction kind of event.

When he puts ATP on the vessel it rapidly constricts; when he blocks the ATP receptor it won't. Unfortunately ATP works best in the face of normal pressures: constricting pressure about 25 percent as opposed to 2-3 percent when it's high. Still there are plenty of questions. Whether ATP is really released by the initial stretching is a critical one, he says. Whether ATP really comes from smooth muscle cells is another.

University of Southern California researcher Dr. Janos Peti-Peterdi thinks high pressures tugging the tethers connecting smooth muscle cells to others in the blood vessel wall may really be what releases ATP, a theory Dr. Inscho presented during the Sept. 19 meeting. It may be that hypertension changes the attachment of those tethers so they don't respond and the blood vessel can't either.

We are trying to figure out how all this fits together, says Dr. Inscho. Figuring out the critical steps of this amazingly elegant, amazingly precise and very complicated process will lead to better understanding of what gets corrupted by diseases such as hypertension and diabetes and maybe how to stop kidney destruction.

As scientists are finding with many diseases, Dr. Inscho says inflammation likely plays a big role. We know we can make these animals hypertensive, treat them with anti-inflammatories and prevent this whole process from occurring, he says of glomeruli destruction. I think that's pretty exciting, but we don't know exactly how we are doing that. Blood pressure is not affected, just the negative impact on the kidneys. Inflammation, he notes, is likely well-intended but ultimately ends up thickening blood vessel walls and hampering flexibility.

Better understanding of blood vessel constrictor needed to harness its power for patients

Thu, 18 Sep 2008 03:59:37 PST

( from http://www.rxpgnews.com ) To harness endothelin-1's power to constrict blood vessels and help patients manage high blood pressure or heart failure, scientists must learn more about how endothelin functions naturally and in disease states, says a Medical College of Georgia researcher.

Despite strong laboratory evidence that blocking endothelin-1 receptors would be an effective, targeted therapy for these two major health problems, the drugs failed patients, says Dr. Adviye Ergul, physiologist in the MCG Schools of Medicine and Graduate Studies.

These endothelin-1 receptors are logical targets for drugs to treat hypertension because of their key role in vasoconstriction, but the targets are moving and we don't know how one target plays off another, says Dr. Ergul, who discussed novel aspects of endothelin receptor interaction during the 62nd High Blood Pressure Research Conference and Workshop in Atlanta.

The current thinking in pharmacology is one hormone, one receptor equals boom: the effect. I think cells are much smarter, she says. This week, Dr. Ergul challenged colleagues across the country to consider emerging evidence that usual receptor communication is likely more complex than they thought and that disease may significantly alter communication.

Endothelin-1 receptors are known to interact: one way blood vessels keep a healthy tone, for example, is that a and b receptors on smooth muscle cells prompt constriction while b receptors on the lining of blood vessels work with nitric oxide to promote relaxation. Endothelin-1 receptors on the kidneys are a player as well, helping wring out excess water and salt. There is a delicate balance, says Dr. Ergul.

But there's apparently more to the relationships. She holds up a handful of recent journal articles which reflect mounting evidence that receptors actively work as teams of two or more. That teamwork could change their function. New technology enables scientists to literally watch receptors move closer together on a cell surface, clearly indicating that something is going on.

Numerous drugs have been developed that are antagonists that can block these receptors with the idea they can be used in hypertension and heart failure. In animal models, they worked well, she says. But in clinical trials they failed badly; a drug for heart failure actually worsened problems such as labored breathing and swelling in patients already having difficulty moving blood through their body.

The first antagonists blocked both known receptors: a and b; the next generation blocked one or the other but still didn't work. A notable exception is endothelin-1 antagonists that reduce excessive pressure and tissue buildup inside the blood vessels of patients with pulmonary hypertension. In addition to constricting blood vessels, endothelin-1 can help blood vessels grow bigger but too much can result in protein deposits that stiffen blood vessel walls.

Scientists have been scratching their heads over why blocking these receptors hasn't panned out; they've even looked for an atypical receptor that might explain it. But Dr. Ergul, an expert on endothelin-1's role in diabetes, believes the unexpected results are better explained by poorly understood relationships in normal and disease states. How receptors dimerize, how they get closer together on the cell surface, likely needs to affect our drug design, she says.

'Cancer was one of the best things to happen to me... but I worry about the future'

Tue, 10 Jun 2008 03:59:37 PST

( from http://www.rxpgnews.com ) London, UK: For Dan Savage, surviving testicular cancer has been a spur to him making the most of his life and taking more adventurous decisions, and he says, that in retrospect, it was probably one of the best things that has happened to him. But as he approaches the end of his fifth year in remission from the disease, when he will be signed off as cured by the medical profession, he worries that from now on he will have no regular medical checks that might pick up early signs of the cancer returning. It will be down to him to contact the cancer clinic if he is worried about any new symptoms.

Dan, aged 25, is now an award-winning artist. He has set up his own studio in York (UK) and specialises in creating glass artwork for architectural spaces. He is also an ambassador for Teenage Cancer Trust and will be speaking at the charity's Fifth International Conference on Teenage and Young Adult Cancer Medicine on Tuesday.

Dan was 20 and studying art at Lancaster University when he discovered a lump the size of half a pea in his right testicle. After having surgery at Lancaster he was transferred to St James's hospital in Leeds for chemotherapy.

The chemotherapy was largely precautionary. The outward appearance of the tumour suggested it had been caught early, but when they dissected it, they found it was quite developed, just on the brink of spreading and they didn't want to take that risk. Also they found that I had the most aggressive form of testicular cancer, teratoma, says Dan.

Dan feels he got off fairly lightly, although the chemotherapy made him very sick and he lost his hair. Looking back now, he says: Having cancer, for me, was one of the best things to happen. It gave me a real drive to succeed and make the most of my life. I know, from speaking to other cancer survivors, that many of them agree. I have gained more confidence. Starting up my own business isn't necessarily what I would have done prior to having cancer. Cancer didn't stop his studies: he went back to university, completed his degree and went on to do a Masters degree in Glass. He has also married his long-term girlfriend.

Dan has not suffered any particular problems following his treatment, although he finds he is more susceptible to common colds and other illnesses that are going around.

I'm much more aware now of my own body and if anything is slightly out of kilter, I'm probably a lot more paranoid about it, he says. On a day-to-day basis I'm fairly relaxed, but if I have an ache or pain I start to worry.

One thing I am getting a bit worried about is that I'm coming up to five years in remission, and will be signed off by the doctors in June. Thereafter it's up to me. People say I'm cured but I don't see it like that. Something could crop up. It worries me that I won't have any more medical checks. I know that if I find anything that's odd I can go straight back to the clinic rather than the GP, which is good because the GP route was a bit of a nightmare. So that is reassuring. But I get reassurance from having regular checks, from having a blood test and even if I don't hear anything after the blood test has been taken, I still know someone has seen it and it's OK. I would prefer to keep the checks going for longer.

Before his chemotherapy the doctors talked to him about fertility and he had sperm samples frozen. The samples were good quality, but, as he was young, fit and healthy (apart from the cancer), he knows he has a good chance of his fertility returning to normal levels, although he hasn't re-visited the fertility clinic to check yet.

Dan says he has become very health conscious in terms of fitness levels and diet. I drink a lot of green tea!

Cancer incidence and mortality in young people decreases with increasing deprivation

Mon, 09 Jun 2008 03:59:37 PST

( from http://www.rxpgnews.com ) London, UK: Results of research into the associations between cancer and socio-economic deprivation and affluence have shown that, in contrast to cancers in older people, the numbers of new cases and deaths from the disease in teenagers and young adults (TYAs) decrease with increasing deprivation.

Professor Jillian Birch told Teenage Cancer Trust's Fifth International Conference on Teenage and Young Adult Cancer Medicine today (Monday) that research by her group also showed increases in the incidence of a number of cancers, including two potentially preventable cancers among younger people: cervical cancer and melanoma.

Prof Birch, Director of the Cancer Research UK Paediatric and Familial Cancer Research group, University of Manchester (UK), explained: Strong associations with socio-economic deprivation and affluence are seen for many diseases. Overall cancer incidence and mortality increase with increasing deprivation. However, different cancers and age groups show different patterns. Geographical variations in incidence, trends over time, and associations with deprivation and affluence can point to lifestyle or other environmental factors as possible causes. Until recently, very little was known about the detailed patterns of cancer in TYAs, but my group has carried out a series of studies to rectify this. The most recent studies have looked at geographical variations, time trends and associations with deprivation.

Results show that in contrast to cancers in older people, in TYAs incidence and mortality decreases with increasing deprivation. This is because the more common types of cancers that occur in young people are associated with affluence, including lymphomas, brain tumours, germ cell tumours and melanoma. These cancers also show significant regional variations in incidence and are increasing over time. However, carcinoma of the cervix, which is one of the more common cancers seen in young women, shows increasing rates with increasing deprivation and an upward trend in incidence over time.

Prof Birch's team showed that the incidence of cervical cancer in TYAs had increased by 1.6% per year during 1979-2003. However, national data show that across all ages, incidence is falling. We therefore analysed trends in 15-39 year olds to look at the changing pattern with age. We found that in 15-19 year olds, rates were increasing by 6.8% per year and by 1.4% per year in 20-24 year olds, but rates were decreasing among those aged 25 and over, she said.

Similar analyses for melanoma showed increasing rates at all ages but a greater rate of increase in 20-29 year olds than at older ages. In 20-24 year olds the annual percentage change was 4.1 and 4.0 in 25-29 year olds, but declined to 3.3 in 30-34 year olds and 2.5 in 35-39 year olds.

Overall, the research showed that cancer incidence rates between 1979-2001, varied from 173 per million person years (per mpyr) in the North East to 208 per mpyr in the South East and South West [1]. National rates have increased during this time period by 1.5% per year. For the whole period, melanoma incidence varied from 12 per mpyr in the East Midlands and London, to 20 per mpyr in the South West. Incidence of melanoma increased nationally by 3.8% per year but the trend was strikingly different in different regions. During 1979-1983 highest rates of around 15 per mpyr were seen in the South and West of England but the rates increased over time more rapidly in the North, so that during 1999-2003 highest rates of between 22 and 32 per mpyr were seen in Northern regions.

Prof Birch said: It is important that public health messages about these two mainly preventable cancers are targeted appropriately. For other TYA cancers, the results of our analyses provide a basis for designing studies to look at possible causes.

Simon Davies, CEO at Teenage Cancer Trust said: It is worrying that cervical cancer and melanoma, two preventable cancers, are increasing in teenagers faster than in other groups. More education is desperately needed so young people can change their behaviour before it's too late. This is why Teenage Cancer Trust funds an education programme for teenagers and young adults throughout schools and colleges in the UK. We are targeting hundreds of thousands of teenagers this summer in our sun safety campaign, fronted by Leona Lewis.

Teenagers and young adults with cancer can face long delays before finally being diagnosed

Sun, 08 Jun 2008 03:59:37 PST

( from http://www.rxpgnews.com ) London, UK: Three studies to be presented at Teenage Cancer Trust's Fifth International Conference on Teenage and Young Adult Cancer Medicine today (Monday) have thrown light on the extent of delays that teenagers and young adults (TYAs) can face before being diagnosed with cancer, and on some of the reasons why this happens.

Tim Eden, Teenage Cancer Trust Professor of TYA Cancer at the University of Manchester, UK, will tell the conference that in a study of 115 patients with bone tumours, the time between the first symptom and a diagnosis (the symptom interval) ranged from four to 184 weeks with the average time being 15.2 weeks. A second study looked at 95 patients with a variety of tumours and found that the symptom interval ranged from two to 192 weeks with the average length being 9.5 weeks. The symptom interval is made up of the time it takes a young person to seek help and the delay by health professionals in recognising symptoms that require referral and prompt diagnosis.

A third study to be reported to the conference by Ms Sam Smith, a TYA Nurse Consultant in the Teenage Cancer Trust Unit at the Christie Hospital (Manchester, UK), shows that out of 207 young people with cancer who took part in an interactive survey, four out five sought medical help very quickly and only seven per cent delayed for a matter of months. Approximately half of the patients with Hodgkin lymphoma, brain and bone cancers had to visit their general practitioner (GP) four or more times before they were referred to a specialist.

Prof Eden said: It would appear that when we compare these data with studies of children with cancer, teenagers and young adults do face greater delays in diagnosis, particularly for bone and brain tumours and Hodgkin lymphoma. In our studies the professional interval has always been longer than patient symptom interval. There appears to be delay at primary, secondary and tertiary care levels. Interventions are being explored, both to educate the public, and young people in particular, to seek help for worrying symptoms and to empower them to push for referral to specialists. However, it would seem to be more important to raise awareness amongst professionals to recognise worrying signs and to trigger them to be more rapid in their response; in addition, they need to ensure simple and rapid referral pathways for investigation and subsequent treatment. Whether this will improve survival remains unclear but it will reduce anxiety, anger and distrust of doctors.

He added that from most of the research in this field it was difficult to conclude whether delays in diagnosis did definitely result in worse outcome for TYAs. There has been an improvement in survival for teenagers and young adults who develop cancer but it has not been so dramatic as seen in children. It is important to realise that there are other potential reasons for delays in diagnosis, including the particular mix of tumour types seen in this age group, with more resistant forms of cancer, and treatments not yet fully adapted to the tumour biology.

First early-detection blood test for Parkinson's shows promise

Tue, 11 Mar 2008 03:59:37 PST

( from http://www.rxpgnews.com ) NEW YORK (March 11, 2008) -- A test that profiles molecular biomarkers in blood could become the first accurate diagnostic test for Parkinson's disease, new research shows.

The screen relies on changes in dozens of small molecules in serum. These metabolomic alterations form a unique pattern in people with Parkinson's disease, according to a team led by researchers at the Weill Cornell Medical College in New York City.

They published the findings in the journal Brain.

A reliable blood test for Parkinson's disease would revolutionize not only the care of people with this debilitating illness, it would facilitate research as well, notes study senior author Dr. M. Flint Beal, chairman and Anne Parrish Titzell Professor of Neurology at Weill Cornell Medical College, and neurologist-in-chief at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

According to the National Parkinson Foundation, an estimated 1.5 million Americans have the neurodegenerative disease, and 60,000 new cases are diagnosed each year. Actor Michael J. Fox, boxer Muhammad Ali, and former U.S. Attorney General Janet Reno all suffer from Parkinson's, which strikes men and women in roughly equal numbers.

Right now, a Parkinson's diagnosis is made solely on a clinical review of symptoms -- we have no biologic test, notes Dr. Beal. At best, a symptom-based screen is still only 90 percent accurate, he adds.

That can cause real problems, because that remaining 10 percent of patients -- who may have look-alike conditions such as multi-system atrophy or progressive supranuclear palsy -- end up getting treated with Parkinson's drugs, Dr. Beal says. These medicines may appear to help them a little while, but in the meantime, they haven't been getting the treatment that's necessarily best for them.

An early-detection test would also be enormously useful in tracking the health of patients who may be at higher risk for Parkinson's, such as those with a family history of the disease.

Finally, the integrity of clinical trials is undermined by the lack of an accurate screen, Dr. Beal notes. Every time you do a clinical trial into Parkinson's and you have patients that are misdiagnosed, it enters 'noise' into the analysis, skewing the results. A truly reliable test could help eliminate that, the researcher notes.

That's why encouraging results for the new test -- based on a patient's metabolomic profile -- are so important.

Metabolomics is the study of changes in thousands of distinct, very small molecules found in body fluids or tissues. Anytime you have a genetic or environmental perturbation, these molecules are altered in specific ways, Dr. Beal explains.

Because Parkinson's treatment could itself trigger some of these alterations, the researchers first compared metabolomic patterns in the blood of Parkinson's patients who were not undergoing treatment versus those who were medicated. That gave us a 'medication-free' profile that we could use going forward, Dr. Beal explains.

In the next stage of the research, the team compared blood samples from 66 patients with Parkinson's disease against 25 healthy controls (most of whom were the patients' spouses). The metabolomic analysis included over 2,000 small molecules found in the blood.

We discovered a clear differentiation between the metabolomic profiles of the Parkinson's disease patients versus those of the controls, Dr. Beal says. No one molecule was definitive, but a pattern of about 160 compounds emerged that was highly specific to Parkinson's patients.

The significance of many individual compounds to the disease remains unknown and will be the focus of future study. But changes in a few well-known metabolites linked to oxidative stress were clearly linked to Parkinson's. These included low levels of the antioxidant uric acid; an increase in blood levels of another antioxidant, glutathione; and increased levels of a marker for oxidative damage called 8-OHdG.

Together, these and other compounds were arranged into a metabolomic pattern that identified Parkinson's disease with great accuracy, Dr. Beal says.

He stressed that more work needs to be done to validate the finding, and a test that might be used routinely by doctors is still a few years away.

We are currently enlarging the sample size and studying people at serial intervals, to see if this test might also serve as a benchmark for disease progression, Dr. Beal says. We are also looking at people who carry a gene for a familial form of Parkinson's, but who do not have the illness now. We hope to track them over time to see if this metabolomic profile is predictive of disease onset.

If those data prove as promising as this early trial, an early-detection blood test for Parkinson's disease could someday become a reality. According to Dr. Beal, That would be a big step forward for both the treatment and the study of this devastating illness.

Eltrombopag effective for hepatitis C patients with low blood-platelet counts

Fri, 28 Dec 2007 04:59:37 PST

( from http://www.rxpgnews.com ) NEW YORK (Dec. 28, 2007) -- For patients with hepatitis C, having a low blood platelet count is a frequent complication associated with advanced disease. This problem is compounded by the fact that standard antiviral treatment for the disease can further reduce platelet numbers to dangerously low levels, effectively denying these patients the treatment they urgently need. Now, research published in the New England Journal of Medicine finds that a new drug, eltrombopag, appears to significantly boost platelet counts, opening the door to effective treatment.

In this study, eltrombopag increased platelet counts in a dose-dependent manner, allowing more patients to complete the first 12 weeks of antiviral therapy -- an important treatment goal, says Dr. Samuel Sigal, who led the study at NewYork-Presbyterian Hospital/Weill Cornell Medical Center in New York City -- one of 22 study sites.

Dr. Sigal is assistant professor of medicine in the Division of Gastroenterology and Hepatology at Weill Cornell Medical College and assistant attending hepatologist in the Center for Liver Diseases and Transplantation at NewYork-Presbyterian/Weill Cornell.

The Phase 2 placebo-controlled study followed 74 patients with low platelet counts and cirrhosis of the liver due to hepatitis C virus (HCV) infection. Seventy-four percent of those randomized to take the lowest dose (30 milligrams daily) saw their platelet counts go up significantly, while 79 percent and 95 percent of the participants saw increases with the higher doses (50 or 75 milligrams daily, respectively). And, 12 weeks of antiviral therapy were completed by 36, 53 and 65 percent of patients at the three dose levels -- with increased numbers matched to the size of the dose. Underlining the trend, less than a quarter of patients receiving placebo completed their therapy.

The study identified side effects -- including headaches, dry mouth, abdominal pain and nausea. None were serious enough to discontinue the therapy.

It's estimated that 4 million people in the U.S. and 170 million worldwide carry the hepatitis C virus. HCV is transmitted primarily by blood and blood products. The majority of infected individuals have either received blood transfusions prior to 1990 (when screening of the blood supply for HCV was implemented) or have used intravenous drugs. More rarely, it can also be transmitted through sexual intercourse and perinatally (mother to baby).

The virus causes inflammation and scarring in the liver, and while it is curable in about half of those who have it, it can lead to significant liver damage, liver cancer and death in others. HCV infection is a common cause of cirrhosis and the most common reason for a liver transplant.

With other eltrombopag findings, NewYork-Presbyterian/Weill Cornell's Dr. James Bussel led research, also reported in the New England Journal of Medicine, finding the platelet growth factor successfully increased platelet counts and decreased bleeding in patients with Immune Thrombocytopenic Purpura (ITP), an autoimmune disease that dramatically reduces the number of platelets in their blood. (Dr. Bussel is an Advisory Board Member for GlaxoSmithKline; has received research grant support, lecture fees, and consulting fees from GlaxoSmithKline; and reports equity ownership in the company.)

The current study was sponsored by GlaxoSmithKline, which is developing eltrombopag. Eltrombopag (marketed as Promacta in the U.S. and Revolade in Europe) is an investigational oral, non-peptide platelet growth factor that induces the proliferation and differentiation of cells to produce platelets. While other drugs that restore normal platelet functions are infusions or injections, eltrombopag is a once-a-day pill.

Light and sound -- the way forward for better medical imaging

Wed, 12 Dec 2007 04:59:37 PST

( from http://www.rxpgnews.com ) Detection and treatment of tumours, diseased blood vessels and other soft-tissue conditions could be significantly improved, thanks to an innovative imaging system being developed that uses both light and sound.

The system uses extremely short pulses of low-energy laser light to stimulate the emission of ultrasonic acoustic waves from the tissue area being examined. These waves are then converted into high-resolution 3D images of tissue structure.

This method can be used to reveal disease in types of tissue that are more difficult to image using techniques based on x-rays or conventional ultrasound. For example, the new system is better at imaging small blood vessels, which may not be picked up at all using ultrasound. This is important in the detection of tumours, which are characterised by an increased density of blood vessels growing into the tissue.

The technique, which is completely safe, will help doctors diagnose, monitor and treat a wide range of soft-tissue conditions more effectively.

The first of its kind in the world, the prototype system has been developed by medical physics and bioengineering experts at University College London, with funding from the Engineering and Physical Sciences Research Council (EPSRC). It is soon to undergo trials in clinical applications, with routine deployment in the healthcare sector envisaged within around 5 years.

The emission of an acoustic wave when matter absorbs light is known as the photoacoustic effect. Harnessing this basic principle, the new system makes use of the variations in the sound waves that are produced by different types of soft human tissue to identify and map features that other imaging methods cannot distinguish so well.

By appropriate selection of the wavelength of the laser pulses, the light can be controlled to penetrate up to depths of several centimetres. The technique therefore has important potential for the better imaging of conditions that go deep into human tissue, such as breast tumours, and for contributing to the diagnosis and treatment of vascular disease.

The prototype instrument, however, has been specifically designed to image very small blood vessels (with diameters measured in tens or hundreds of microns) that are relatively close to the surface. Information generated about the distribution and density of these microvessels can in turn provide valuable data about skin tumours, vascular lesions, burns, other soft tissue damage, and even how well an area of tissue has responded to plastic surgery following an operation.

The development process has included theoretical and experimental investigations of photoacoustic interactions with soft tissue, development of appropriate computer image-reconstruction algorithms, and construction of a prototype imaging instrument incorporating the new technique.

Children with sickle cell disease, silent strokes show some relief with blood transfusions

Mon, 10 Dec 2007 04:59:37 PST

( from http://www.rxpgnews.com ) A group of children who have sickle cell disease and who experience silent strokes showed some relief from the silent strokes with blood transfusion therapy, researchers at Washington University School of Medicine in St. Louis have found.

The study's results will appear in a future issue of Pediatric Blood and Cancer but are available for review in its advance online publication.

In a Phase II study of 10 children with sickle cell disease who also had multiple silent strokes, or cerebral infarcts, the majority of families were committed to having their children receive blood transfusions for two years, showing that the therapy was feasible. In addition, the blood transfusion therapy helped to shrink the lesions on the brain caused by the infarcts and eliminated one lesion completely, said Allison A. King, M.D., a pediatric hematologist at St. Louis Children's Hospital and a researcher at Washington University School of Medicine. Lesions are small areas of damaged tissue thought to be due to blockage of small arteries in the brain.

Silent strokes are strokes that don't show the classic symptoms of overt strokes, such as numbness, tingling, headache or slurred speech. Blood transfusion therapy has been shown to be effective in preventing overt strokes in patients with sickle cell disease, but its effectiveness and the willingness of families to participate in long-term treatment to prevent silent strokes had not been tested.

Sickle cell disease is an inherited blood disorder affecting red blood cells that contain hemoglobin, a substance that carries oxygen from the air in the lungs to all parts of the body. In patients with this disease, red blood cells contain an abnormal type of hemoglobin that causes the normally round, flexible red blood cells to become sickle- or crescent-shaped. The sickle cells can't pass through tiny blood vessels, preventing blood from reaching the body's tissues, which can result in tissue and organ damage, pain and stroke.

Sickle cell disease affects about 70,000 people in the United States. It occurs in about 1 of every 500 African-American births and 1 of every 1,000 to 1,400 Hispanic-American births. While there is no cure for the disease, blood transfusions and bone marrow transplants have been shown to be effective treatments by replacing short-lived sickle cells with longer-lived healthy red blood cells, although bone marrow transplants have a 10 percent mortality rate because of the possibility of rejecting the bone marrow, complications such as seizures and a high risk of infection.

In the study, brain lesions in six patients shrank after two years of regular blood transfusions, and no new silent strokes occurred. One patient had a lesion disappear, however, that patient did not continue with further blood transfusions, and the lesion returned at more than three times its original size, suggesting the need for prolonged transfusions. A lesion grew larger in the seventh patient.

Many of the lesions occur in the frontal lobe of the brain, which controls the cognitive function or problem-solving area, or in the occipital lobe, which controls the visual processing center, King said. Neuroradiologists can locate the lesions using magnetic resonance imaging (MRI).

Because these lesions are usually in the frontal lobe, it is important to do cognitive testing on these children to determine any impairment, King said. We hope that by preventing further lesions through blood transfusions that we can preserve their ability to think and learn.

A total of 71 percent of the school-aged children in the study were receiving special education services and 57 percent had failed a grade in school. Previous School of Medicine research shows that 80 percent of students with silent strokes perform poorly in school.

King said the results of the trial were encouraging to health-care professionals treating children with sickle cell disease.

What we found in this trial is that families and children with sickle cell disease and who experience silent strokes are willing to commit to blood transfusion therapy for this condition, King said. If these children are left untreated, their risk for an overt stroke is very high, but if we use blood transfusion therapy, they may have a lower risk for overt stroke and no evidence of new silent infarcts on an MRI.

Results of this Phase II trial spearheaded a larger, Phase III study that is evaluating 1,800 children in the United States, Canada and Europe. That trial, called the Silent Cerebral Infarct Multi-Center Clinical Trial, is headed by Michael R. DeBaun, M.D., professor of pediatrics at the School of Medicine. Through it, researchers will further determine the effectiveness of blood transfusion therapy to prevent silent strokes in children with sickle cell disease and to prevent further cerebral injury.

Study proposes new theory of how viruses may contribute to cancer

Tue, 23 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) PITTSBURGH, Oct. 23 � A new study suggests that viruses may contribute to cancer by causing excessive death to normal cells while promoting the growth of surviving cells with cancerous traits. Viruses may act as forces of natural selection by wiping out normal cells that support the replication of viruses and leaving behind those cells that have acquired defects in their circuitry. When this process is repeated over and over, cancer can develop say study authors, led by Preet M. Chaudhary, M.D., Ph.D., professor of medicine at the University of Pittsburgh School of Medicine. Their findings are published by Public Library of Science in the Oct. 24 issue of PLoS ONE.

Infection with viruses has been linked to many human cancers, including some forms of Hodgkin�s and non-Hodgkin�s lymphomas, sarcomas and cancers of the throat and liver. Over the years, scientists have proposed a number of mechanisms to explain this link. One commonly held belief is that when a virus infects a cell, its genetic material alters the cell, making it grow uncontrollably, eventually leading to cancer. Some viruses also are thought to promote cancer by causing chronic inflammation. In his study, Dr. Chaudhary proposes that viruses also can lead to cancer in a less direct manner.

�We believe a separate mechanism may be at play in which a cellular insult, such as infection with a virus, selects a few pre-existing mutated clones of cells, promotes their further growth and multiplication, eventually leading to the emergence of fully cancerous cells. Consequently, similar to the role played by natural selection during evolution, excessive cell death, rather than its absence, may be a defining force that drives the initial emergence of cancer,� said Dr. Chaudhary. He named this model the Phoenix Paradigm in which cancer theoretically arises out of the ashes of dead cells.

The paradigm was developed based on a study of cells infected with the Kaposi�s sarcoma associated herpesvirus, or KSHV, also known as human herpesvirus 8 (HHV-8). The researchers examined a gene called K13 that activates a pathway previously implicated in cancer development. Cells with low K13 expression allowed KSHV to replicate, and these cells subsequently died off, the researchers noted. Cells with higher expression of K13 emerged after KSHV replication and showed defective expression of two key proteins that are known to promote cancer.

�This paradigm, if validated by further studies, has implications not only for an improved understanding of the processes involved in cancer, but also for the development of effective strategies for its prevention and treatment,� said Dr. Chaudhary.

Chemistry turns killer gas into potential cure

Mon, 15 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Despite its deadly reputation, the gas carbon monoxide (CO) could actually save lives and boost health in future as a result of leading-edge UK research.

Chemists at the University of Sheffield have discovered an innovative way of using targeted small doses of CO which could benefit patients who have undergone heart surgery or organ transplants and people suffering from high blood pressure.

Although the gas is lethal in large doses, small amounts can reduce inflammation, widen blood vessels, increase blood flow, prevent unwanted blood clotting � and even suppress the activity of cells and macrophages* which attack transplanted organs. The researchers have developed innovative water-soluble molecules which, when swallowed or injected, safely release small amounts of CO inside the human body.

Research carried out in the last decade had already highlighted possible advantages, as CO is produced in the body as part of its own natural defensive systems. However, the problem has been finding a safe way of delivering the right dose of CO to the patient. Conventional CO inhalation can run the risk of patients or medical staff being accidentally exposed to high doses. Now for the first time, thanks to chemistry, an answer appears to have been found.

The new CO-releasing molecules (CO-RMs) have been developed in partnership with Dr Roberto Motterlini at Northwick Park Institute for Medical Research (NPIMR) and with funding from the Engineering and Physical Sciences Research Council (EPSRC).

�The molecules dissolve in water, so they can be made available in an easy-to-ingest, liquid form that quickly passes into the bloodstream,� says Professor Brian Mann, from the University's Department of Chemistry, who led the research. �As well as making it simple to control how much CO is introduced into a patient�s body, it will be possible to refine the design of the molecules so that they target a particular place while leaving the rest of the body unaffected.�

The CO-RMs consist of carbonyls** of metals such as ruthenium, iron and manganese which are routinely used in clinical treatments. They can be designed to release CO over a period of between 30 minutes and several hours, depending on what is required to treat a particular medical condition.

As well as boosting survival rates and cutting recovery times, the new molecules could ease pressure on hospital budgets by reducing the time that patients need to spend in hospital, for example after an operation. They could even help some patients to avoid going into hospital in the first place.

Professor Mann added: �This project provides an excellent example of how non-biological sciences like chemistry can underpin important advances in healthcare.�

hemoCORM Ltd, a spinout company set up in 2004 by the University of Sheffield and NPIMR, is now taking the research towards commercialisation. It is hoped that, after further development work, Phase 1 clinical trials can begin in around two years, with deployment in the healthcare sector potentially achievable in around five years.

Anticlotting drug found to be safe in sickle cell patients

Thu, 11 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) CHAPEL HILL - An intravenous �blood thinner� widely used in patients with acute coronary syndromes and during coronary artery stent placement appears to be safe in patients with sickle cell disease and may have beneficial anti-inflammatory effects, a small study at the University of North Carolina at Chapel Hill School of Medicine has found.

�We have tested a potentially promising drug in sickle cell patients, and the drug appears to be well tolerated. This gives us the impetus to go ahead with further studies of eptifibatide in these patients,� said Dr. Leslie V. Parise, department chair and professor of biochemistry and biophysics at the UNC-Chapel Hill School of Medicine.

The hallmark of sickle cell disease is malformed red blood cells that can cause sudden painful episodes when they block small blood vessels. However, sickle cell patients are also at increased risk of developing multiple other complications, including strokes, lung complications and pulmonary hypertension.

The most frequent manifestations of sickle cell disorders are anemia and pain episodes. The episodic exacerbation of pain, often called �crises,� is unpredictable and may occur often in some patients.

The only drug presently approved for the treatment of sickle cell disease is hydroxyurea, which has been shown to reduce the frequency of painful episodes.

Parise emphasized the need for further study. �We did not test this drug in patients who are in crisis, and we cannot recommend that doctors prescribe this drug for sickle cell patients at this time,� she said.

The results of the study were published online (Oct. 6) in the British Journal of Haematology.

The researchers gave intravenous infusions of eptifibatide (brand name Integrilin) to four patients with sickle cell anemia who were not experiencing pain episodes. �They did well clinically. They did not experience any deleterious changes in their blood tests or have a pain episode,� said coauthor Dr. Kenneth I. Ataga, assistant professor of medicine at UNC-Chapel Hill.

In the current study, blood tests showed that while the patients� liver, kidney and other functions remained at baseline, several indicators of inflammation decreased, including levels of a protein called CD40L known to play a role in inflammation and in blood clotting.

Previous studies conducted by Sheritha Lee a graduate student in Parise�s lab showed that patients with sickle cell disease have CD40L levels that are as much as 30 times higher than in patients without the disease. Eptifibatide�s known ability to decrease CD40L led the researchers to study whether the drug might help sickle cell patients.

MIT uncovers key blood protein

Thu, 11 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) CAMBRIDGE, MA--Scientists working in the only lab at MIT doing hematology research have uncovered a protein that plays a key role in the recycling of iron from blood.

Their work, described in the October 11 Journal of Clinical Investigation, could lead to new therapies for certain inherited blood disorders such as beta-thalassemia, a condition that causes chronic anemia. The team is led by Jane-Jane Chen, a principal research scientist in the Harvard-MIT Division of Health Sciences and Technology (HST).

Two years ago Chen and colleagues showed that a protein, heme-regulated eukaryotic translational initiation factor 2 �-subunit (eIF2-alpha) kinase, or HRI for short, keeps mice with beta-thalassemia alive. This protein minimizes an abnormal and toxic imbalance of globin chains, the protein base for the hemoglobin found in red blood cells. Hemoglobin carries oxygen to our organs and carts away carbon dioxide waste.

In the new work, the team has found that HRI also plays a key role in the body's iron recycling process. Chen observed that this process falters in mice lacking HRI. As a result, less iron was available for use in the creation of new red blood cells.

A closer look revealed that HRI influences two mechanisms in this recycling process. First, a lack of HRI reduces levels of another protein called hepcidin. Hepcidin, recently discovered to be the master regulator of the iron cycle, releases iron from stores in the body and makes it available to be processed into hemoglobin. Without hepcidin, the body retains iron, but never puts it to work.

The team also found that HRI, which is expressed predominantly in the precursors of red blood cells, is expressed in macrophages. Macrophages are cells that literally reach out and grab dying red blood cells and eat them, digesting them and releasing the iron from their hemoglobin back into the system.

A lack of HRI causes these macrophages to lose their appetite, gobbling down fewer red blood cells. Instead of being digested and recycled, the red blood cells die and end up excreted through the kidneys. The result is a net loss of iron from the body.

With this new understanding of HRI's dual role in iron recycling-that it both keeps iron in the body and puts it to work-Chen is conducting a search for small molecules that might modulate the HRI signaling pathway. In turn, these compounds could potentially help diseased precursors of red blood cells survive and boost the iron recycling process.

�Perhaps we will find a compound that could help patients with beta-thelassemia or other diseases where HRI plays a role,� said Chen. Such conditions include a genetic disorder called erythropoietic protoporphyria (EPP), which causes photosensitivity and liver disease, as well as a condition called the anemia of inflammation in which the iron recycling process breaks down under the influence of stress, chronic disease, aging, or cancer.

Daisies lead scientists down path to new leukemia drug

Tue, 02 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) A new, easily ingested form of a compound that has already shown it can attack the roots of leukemia in laboratory studies is moving into human clinical trials, according to a new article by University of Rochester investigators in the journal, Blood.

The Rochester team has been leading the investigation of this promising therapy on the deadly blood cancer for nearly five years. And to bring it from a laboratory concept to patient studies in that time is very fast progress in the drug development world, said Craig T. Jordan, Ph.D., senior author of the Blood article and director of Translational Research for Hematologic Malignancies at the James P. Wilmot Cancer Center, at the University of Rochester Medical Center.

Clinical trials are expected to begin in England by the end of 2007. Investigators expect to initially enroll about a dozen adult volunteers who�ve been diagnosed with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) or other types of blood or lymph cancers, Jordan said.

Under development is dimethylamino-parthenolide (DMAPT), a form of parthenolide (PTL) that is derived from a daisy-like plant known as feverfew or bachelor�s button. DMAPT is a water-soluble agent that scientists believe will selectively target leukemia at the stem-cell level, where the malignancy is born. This is significant because standard chemotherapy does not strike deep enough to kill cancer at the roots, thus resulting in relapses. Even the most progressive new therapies, such as Gleevec, are effective only to a degree because they do not reach the root of the cancer.

DMAPT appears to be unique. It�s mechanism of action is to boost the cancer cell�s reactive oxygen species � which is like pushing the stress level of the cell over the edge � to the point where the cell can no long protect itself and dies, said Monica L. Guzman, Ph.D., the lead researcher on the DMAPT project and a senior instructor at the University of Rochester Medical Center.

Leukemia is different from most cancers and particularly hard to eradicate because leukemia stem cells lie dormant. Standard cancer treatments are designed to seek out actively dividing cells. But in studies so far, DMAPT can kill both dormant cells and cells that are busy dividing, Guzman said

Rochester investigators looked at whether DMAPT could eliminate leukemia in donated human cells, and in mice and dogs. In all cases, DMAPT induced rapid death of AML stem and progenitor cells, without harming healthy blood cells.

DMAPT also has shown potential as a treatment for breast and prostate cancer, melanoma, and multiple myeloma, Guzman said, although those studies have only been conducted in cell cultures to date.

�Once we begin seeing evidence from the clinical trials, it will give us more insight into the pharmacological properties of DMAPT and it will be easier to figure out its potential for other cancers,� Guzman said.

In addition to the studies of DMAPT, Guzman and Jordan also reported in the same issue of Blood on another new type of leukemia drug known as TDZD-8. Although this agent is at a much earlier stage of development, it also shows the ability to kill leukemia stem cells and may some day lead to better forms of treatment.

Novel strategy under study for aggressive leukemia

Mon, 24 Sep 2007 03:59:37 PST

( from http://www.rxpgnews.com ) A novel strategy to hopefully beat into oblivion one of the most aggressive forms of acute myelogenous leukemia combines the strengths of some of the newest leukemia agents, researchers say.

�These are not traditional chemotherapy regimens. These are targeted therapies that our earlier laboratory studies have shown have a synergistic effect,� says Dr. Kapil N. Bhalla, director of the Medical College of Georgia Cancer Center.

The strategy takes on the mutated protein receptor that enables the deadly proliferation of leukemic cells by degrading it with histone deacetylase and heat shock protein 90 inhibitors. It uses protein kinase inhibitors to reduce the function of any remaining protein and kills off leukemic cells with a natural cell death mechanism called TRAIL.

Dr. Bhalla recently received a five-year, $1.3 million grant from the National Cancer Institute that will enable his research team to do more preclinical testing of the strategy in human leukemic cells and an AML animal model.

About six years ago, researchers found the mutation in the FLT-3 gene that results in the mutated protein receptor on the cell surface. This receptor usually responds to a growth factor that gives rise to normal bone marrow cell proliferation. �But in this case, this mutated protein receptor is constantly triggered, is constantly on and it drives proliferation, promotes survival and shuts down differentiation,� Dr. Bhalla says.

Within weeks, leukemic cells take over the bone marrow, then spread throughout the body. �Patients typically develop abnormalities of white blood cell count and platelet count, anemia or weakness and present with either an infection because they don�t have enough white blood cells or bleeding,� he says.

�We don�t know what causes these mutations, but if you have FLT-3 mutation � about 30 percent of AML patients do � then the leukemia is generally more aggressive,� says Dr. Bhalla. For whatever reason, this aggressive leukemia occurs most commonly in the elderly which means, with the aging population, it�s likely to become even more common.

�If you just target FLT-3 with an inhibitor of its activity, that would not be enough,� says Dr. Bhalla. �If you combine it with something that also depletes its levels, that would be better. But if you deplete its levels, inhibit its activity and combine it with another leukemia cell death-inducing agent, it would be even better,� says Dr. Bhalla, who believes the laboratory work will evolve into a strategy that can be used effectively in the clinics, maybe even before the laboratory work is done.

A big plus is that several drugs that do each of these things already are being studied in patients. However, combined effects of these drugs have not been fully studied against leukemia cells, and the drugs just haven�t been used together in patients with leukemia.

For example, one of the histone deacetylase inhibitors Dr. Bhalla will study in the lab, LBH589, developed by Novartis Corp., he�s also studying in an early clinical trial for patients with leukemia and lymphoma for whom standard therapies have failed. Several FLT-3 kinase inhibitors are under study for a variety of cancers and MCG will soon join one of those studies for leukemia. Apo2L/TRAIL, developed by Genetech, is under study in a variety of solid tumors and leukemia. TRAIL activates on leukemic cells the same death-inducing stimulus immune cells use to kill cancer cells. �It�s a normal mechanism of killing offending cells,� says Dr. Bhalla.

�We have designed combinations of agents that we will be studying in mouse models and against patient-derived leukemia cells. This grant doesn�t fund a clinical trial, but it allows us to take patient samples and study them in vitro to further define why this gene confers poor survival and what combinations can work against it,� says Dr. Bhalla. He notes that since the drugs are new and have not previously been used together, issues such as unforeseen toxicity will need to be explored.

�We are studying the combination and how it kills, so when the combination goes into the patient, we will be able to get samples from patients, pre- and post-treatment, to see whether what we are observing in the lab works and, if there are patients who still don�t respond, why don�t they� says Dr. Bhalla.

Histone deacetylase and heat shock protein 90 inhibitors take direct hits at the mutant protein by targeting HSP 90, a molecular chaperone, which, in this case, improperly folds the protein, leaving it active and producing leukemic cells rather than healthy bone marrow cells as needed. Dr. Bhalla�s lab was the first to show the mutant protein kinase is particularly susceptible to depletion by targeting it with HSP 90 or histone deacetylase inhibitors. He also uncovered the synergy of kinase inhibitors.

�We are targeting HSP 90, which folds and keeps this abnormal protein in its active form,� he says. �By using this agent that targets HSP 90, you also take away many other mechanisms that drive cell proliferation and survival. Once you lower the threshold for cell death by depleting this protein, you use additional strategies to kill leukemic cells. It makes it more effective.�

Sexual function affected by stem cell transplant according to long-term study

Tue, 18 Sep 2007 03:59:37 PST

( from http://www.rxpgnews.com ) WASHINGTON, Sept. 18, 2007 -- A long-term study found that a type of stem cell transplant used for patients with life-threatening diseases, such as leukemia and lymphoma, results in decreased sexual function and activity for recipients. Further, males are likely to recover from these changes over time, while the sexuality of female patients remains compromised. In addition, neither male nor female long-term cancer survivors regained levels of sexual activity and function equal to those of their peers who have not had cancer, according to a Blood First Edition Paper prepublished online today. Blood is the official journal of the American Society of Hematology.

�Survival without a sex life should not be what cancer survivors settle for or what health-care professionals consider a successful outcome of cancer treatment,� stated lead study author, Karen Syrjala, PhD, co-director of the Survivorship Program at the Fred Hutchinson Cancer Research Center. �Sexual dysfunction in survivors of cancer needs to become a priority for research funding and a routine topic of discussion between doctors and their patients after cancer treatment.�

In an allogeneic hematopoeitic stem cell transplantation, patients with diseases of the blood, bone marrow, or certain types of cancers receive an infusion of new stem cells from a sibling or tissue-matched unrelated donor to replace the damaged or destroyed cells in their bone marrow needed for the production of blood cells. Before the transplant, high-dose chemotherapy is administered to kill residual cancer cells and to suppress the immune system so that the patient�s body will not reject the new tissue.

The results of questionnaires on sexual function were reported for 161 patients scheduled to receive this procedure at the Fred Hutchinson Cancer Research Center in Seattle. The patients ranged in age from 22-64 years with an average age of 41 and a nearly even split by gender.

Before the transplant, study participants completed an assessment of their sexual health at the clinic, and, after the procedure, surveys were mailed to the patients to complete at the six-month interval and after one, two, three, and five years. The response rate to the questionnaire averaged 84 percent with all participants completing one or more surveys during the five-year period.

The surveys included 37 questions in the areas of interest, desire, arousal, orgasm, satisfaction, activity, relationship, masturbation, and sexual problems. The male and female versions had the same content except for variations in the problems section according to sex. In addition, those who were not sexually active were provided with a list of possible reasons and asked to mark as many as applied.

At five years, the assessments were compared against a control group consisting of siblings or friends of the study patients that were within five years of the participant�s age and who were of the same gender, ethnicity, race, and educational background. If a local match was not available, the researchers recruited volunteers from the community that fit the criteria.

At the six-month mark, both genders had decreased sexual activity, but, by one year, sexual activity for the majority of the men (74 percent) had recovered to the levels seen at the beginning of the study. For women, recovery of sexual activity took longer, with just over half (55 percent) returning to sexual activity after two years. Though sexual activity was restored for these patients, for those who were sexually active at the five-year mark, 46 percent of the men and 80 percent of the women reported problems that disrupted sexual function.

According to the researchers, sexual dysfunction in transplant patients is likely caused by systemic therapies, such as total body irradiation and chemotherapy drugs known as alkylating agents, which are known to permanently damage endocrine glands that play a critical role in the development and regulation of the reproductive system.

In addition, chronic graft-versus-host disease (GVHD), a common complication of transplantation experienced by 65 percent of the patients in this study, may cause shrinkage of the vaginal tissues and changes to the vaginal lining that can contribute to sexual dysfunction in women. For males, testosterone levels and the cavernosal arteries of the penis are affected, eroding libido and erectile function.

Lack of interest or libido explained sexual inactivity in part for nearly 20 percent of female survivors at both six months and five years, suggesting that this problem did not improve over time. In contrast, for males, lack of interest or libido as a reason for inactivity declined from 14 percent to 6 percent between six months and five years.

At the five-year mark, the rates of sexual activity and sexual function for both male and female patients were below those of the control group, suggesting that they did not fully recover from the effects of the cancer itself or cancer treatments. Further studies are needed to determine if hormone treatments for both sexes or other therapies will help these patients achieve the same sexual function and activity as their peers.

The researchers also recommend that patients undergoing stem cell transplantation be made aware of potential changes in their sexuality and given resources to address these needs to help improve long-term quality of life. Men may benefit from reassurance that erectile function and sexual desire should improve by one to two years after treatment, but that methods such as testosterone replacement, erectile-function medications, and other adaptive strategies can be considered if problems continue. For women, methods that focus on communication with their partners about changes in sensation, strategies for enhancing libido, and use of vaginal lubricants, dilators, or vibrators to assist with adapting to genital changes may help to maintain sexual responsiveness.

Unique role for blood formation gene identified

Wed, 12 Sep 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Hanover, NH--All blood cell production in adults depends on the steady work of a vital gene that if lost results in early bone marrow failure, Dartmouth Medical School cancer geneticists have found. Their research reveals an unexpected role for the gene in sustaining the adult blood-forming system, and opens novel strategies for targeting the gene, which is often involved in a type of childhood leukemia.

�We have identified a new pathway that is essential for blood stem cell turnover,� said team leader Dr. Patricia Ernst, assistant professor of genetics and member of the Norris Cotton Cancer Center. The pathway could be exploited for treating a rare but aggressive infant leukemia, she added. These findings were reported in the September issue of Cell Stem Cell.

The investigators created a mouse model to track the function of a gene called MLL, which stands for Mixed Lineage Leukemia. The gene acts in bone marrow stem cells and controls key aspects of their growth to generate all the mature blood cells. If disrupted, it cannot work properly, and leukemia can ensue.

�MLL is the most commonly affected gene in childhood leukemia in children under a year of age; this particular type of leukemia has one of the worst success rates with the existing cancer therapies,� said Ernst, who first helped clarify the role of MLL as a postdoctoral fellow at Harvard.

Many childhood leukemias result from mutations called translocations, where gene pieces on chromosomes accidentally relocate and misalign. In infant leukemia, the chromosome containing the MLL gene breaks within MLL and ends up fused to a different gene. MLL fusion genes likely co-opt normal MLL functions in blood cells, leading to the overproduction of white cells and leukemia.

Previous studies indicated that MLL is critical for embryonic blood stem cell development, but its role for the adult system was unknown. In their mouse model, the researchers found that bone marrow failure occurred as early as 14 days after they induced the experimental loss of MLL, demonstrating the crucial role of MLL as �necessary for both the development and maintenance of the body�s blood supply,� according to the researchers.

�We have shown that the adult blood-forming system depends on the continuous actions of MLL,� Ernst said. Moreover, with the mouse model the scientists established to define normal MLL functions, they can begin exploring how to craft new anti-cancer treatments, she pointed out. �We and other groups can start designing targeted therapies that inhibit cancerous forms of MLL that occur in childhood leukemia and do not affect normal MLL function, which, based on our studies in mice, would be fatal for the patient.�

Small animal imaging facility is big boon to research

Thu, 30 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) When powerful magnets line up the body�s protons before radiofrequency waves can grab their attention away, it�s called spin physics.

When signals generated by the movement are mathematically transformed into dramatic images of hearts, lungs and other organs it�s called a magnetic resonance image.�Protons normally would be pointing in many different directions,� says Dr. Tom Hu, director of the Small Animal Imaging Program at the Medical College of Georgia. �But if you put an object in the MRI, the magnet will line up the protons and what that does is generate the original, steady state. Then, by applying different radio frequencies, pretty much like what you do with a car antenna, you can pursue radio frequencies to perturb the system and you pretty much listen to it.�

When Dr. Hu, a biochemist and biophysicist, tunes in he sees how calcium moves in and out of heart cells as the heart contracts and relaxes and how that movement doesn�t work so well in heart failure, a condition resulting in oversized hearts with difficulty beating.

He�s looking at whether the metallic manganese ion, which can travel in the same circles as calcium, can enhance the signal and subsequent images he gets of how calcium can�t get back into cells after a heart attack. �Once it�s disturbed, the cells die and the myocardium dies and you have scar formation,� says Dr. Hu whose ultimate goals include better ways to diagnose and treat heart failure, an increasingly common problem in the United States where improved cardiac treatment means many people are living with their heart disease. �Not only can you look at a living organ, you can also study the molecular aspects of this like the calcium ion,� says Dr. Hu who came to MCG in 2005 to start the Small Imaging Program in support of research initiatives, such as his, that have clinical promise.

The MRI that is the program�s centerpiece looks like the human version except the cylinder the patient lies in is obviously much smaller. However it has a stronger magnet than typical clinical grade units primarily because the organs of interest are so much smaller, says Dr. Nathan Yanasak, magnetic resonance scientist.

Many standard MRIs are 1.5 Tesla and high-end clinical units are 3 Tesla, a measure of the density and intensity of a magnetic field. MCG�s small animal MRI is 7 Tesla, not the strongest magnet available for research but one that enables good quality images of small organs which are comparable to those obtained by clinical machines. �It�s pretty close to clinical grade,� says Dr. Yanasak. �But since you are scanning something smaller you need a larger field of strength to get the animal images to look like a human image,� he says. The smallest heart they�ve imaged, for example, is that of a 3-gram mice (that�s a .105-ounce mouse). �It is better resolution in the sense that you have to have better resolution to see a brain this big,� Dr. Yanasak says, holding his fingers very close together.

The textbook answer for why scientists need high-tech imaging studies They are noninvasive, says Dr. Hu, which obviously makes them excellent clinical tools as well. �If you have an animal disease model, for pretty much any noninvasive technique, the advantage is it reduces animal use tremendously,� he says.

Like physicians do with patients, basic scientists now use technology to help monitor disease progression over time and even to see if treatments work. In his own work, for example, Dr. Hu watches development of heart failure by monitoring changes in calcium dynamic and heart structure.

Newer technology, on loan to the facility from Xenogen Corp, part of Caliber Life Sciences Corp., has enabled the lab to throw genetic expression into the mix. The optical scanning system uses luciferase, the same enzyme fireflies use to glow, to identify gene expression.

If you combine (luciferase) with certain genes and the genes are expressed, they glow,� says Dr. Hu. �For example, after a heart attack, you can look and see if certain genes are up-regulated, such as inflammatory genes. Now we take the same animal model back to the MRI machine and track how many cells have moved to the site of injury. So, we can combine the information and say, okay, potentially those cells that have been mobilized are due to the gene expression. We can try and link cause and effect so it becomes more of a valuable image,� says Dr. Hu. Right now he and Dr. Yanasak are fine-tuning how to make MRI and optical scanning work optimally together and how to also quantify gene expression.

The number of MCG scientists using the facility is significant and growing, says its director. Dr. Adviye Ergul, for example, is looking at blood flow in the brain of her diabetes model and Dr. William Hill is looking at stroke event and recovery.

�We are very open to any interesting ideas that generate interesting scientific data or grant funding opportunities,� says Dr. Hu. Goals include becoming an MCG core laboratory facility and adding a small animal PET scanner and ultrasound.

New cancer fighter may help ICU patients beat infections

Mon, 27 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) HSP 90 inhibitors, which are finding favor in fighting cancer, may also help battle overwhelming infection in intensive care patients, researchers say.

Studies in an animal model of sepsis, a major cause of ICU patient death, indicate HSP 90 inhibitors help degrade proteins perpetuating inflammation, says Dr. John D. Catravas, director of the Medical College of Georgia Vascular Biology Center.

Results include restored lung function, reduced blood vessel leakage, which can lead to dangerous swelling in the lungs, and fewer byproducts of inflammation such as white blood cells, MCG researchers report in the American Journal of Respiratory and Critical Care Medicine, a journal of the American Thoracic Society.

They already have begun looking at the impact of HSP 90 inhibitors on the function of other organs, such as the liver and kidneys, also typically impacted by sepsis.

�We would die without an inflammatory response, but unreined inflammation is bad,� says Dr. Catravas. That�s just what happens with overwhelming infection; inflammation, which helps the body eliminate invaders, essentially keeps working after invaders are gone and the new target is the body.

�These are proteins that initially are useful in combating an invading bacteria but then, in some of us that develop sepsis for reasons that are poorly understood, the inflammatory response is amplified and stays much longer than it should,� says Dr. Catravas, the paper�s corresponding author.

Heat shock proteins carry proteins where they are needed and fold them up nicely so they do the correct job. Dr. Catravas compares their two-protein configuration to a lobster with its claws closed while tending to �client� proteins.

�The hypothesis we worked on is that these HSP 90 inhibitors take the heat shock protein and move it into a different conformation,� says Dr. Catravas. The published research indicates they were correct and that inhibitors, fortunately, readily target proteins that no longer have a useful function.

�The HSP 90 inhibitor binds to a little pocket in the dimer, the two identical proteins that make up HSP 90 complex, and forces the two claws open,� he says. �As soon as they open, as soon as the three-dimensional conformation of the HSP dimer and the client protein change, other proteins start attaching to the complex.� The client protein then becomes susceptible to degradation. It was their earlier finding that inducible nitric oxide synthase, a major mediator of sepsis, is a client protein of HSP 90 that led to the inhibitor study.

For the study, researchers used what would be considered lethal doses of endotoxin to create a worse-case infection and pretreated animals with smaller doses of HSP 90 than those currently under study for a wide range of cancers.

They have begun looking at more clinically relevant infection levels and identifying the best time after the insult to give the lowest dose. However, Dr. Catravas has not ruled out HSP 90 inhibitors� potential to preventively treat patients at risk because patients seem to tolerate it well in the cancer clinical trials.

He hopes to move ahead soon with clinical trials of HSP 90 inhibitors, used in conjunction with antibiotics, in intensive care patients.

These manmade HSP 90 inhibitors work by attaching where the protein pair�s energy source, called ATP, should be. The body appears to have an endogenous version, ADP, which has one less phosphate than ATP and binds at the same site, also opening the protein claws and sending the client protein toward degradation.

Bench-to-bedside look at MSC research at Case Western Reserve conference in Cleveland

Fri, 24 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) CLEVELAND�Researchers from 22 countries will come to Cleveland for a bench to bedside examination of the developing mesenchymal stem cells (MSC) from regenerative medicine and stem cell research to therapeutics in patient care. The National Center for Regenerative Medicine for Stem Cell and Regenerative Medicine (NCRM) and founding partner Case Western Reserve University have organized the 2007 Adult Mesenchymal Stem Cells in Regenerative Medicine Conference, August 27-29, at the Marriott Hotel in downtown Cleveland, to highlight advances in MSC research. The conference is the first organized by the two groups on MSCs.

It leads off with Arnold Caplan, Case Western Reserve professor of biology and director of the Skeletal Research Center in the College of Arts and Sciences. In the late 1980s, science literature hinted of MSCs� existence, but it was research by Caplan - with Case collaborators Stephen Haynesworth (biology, associate dean of the College of Arts and Sciences), Stanton Gerson (director of NCRM and the Ireland Cancer Center) and Hillard Lazarus (director of the Blood and Marrow Transplant Program at the Ireland Cancer Center) - that led to the MSC discovery in Case labs.

When Caplan first discovered the MSCs, little was known about their potential uses, but that has changed. �MSC research is exploding and getting more recognition as the research moves into the clinic,� he said. �The therapeutic field has finally caught up with the research potentials.�

His discovery paved the way for a great deal of research, at Case and other institutions, to develop MSC applications.

Since MSCs were found to have regenerative properties, Caplan, Haynesworth and Gerson established Osiris Therapeutics, Inc., to take the lab research into human therapies. This company, although originally started in Cleveland, Ohio, relocated to Baltimore, Md., and has successfully become a publically traded company. Randall Mills, the CEO of Osiris, will give the concluding talk on Wednesday to provide insight into running clinical trials using MSCs to almost 300 doctors and researchers attending the conference.

�Educating researchers in methods and models in mesenchymal stem cell technology has been a priority of our key investigators Drs. Caplan and Gerson, who are part of the MSC 2007 organizing committee,� said Michael Gilkey, NCMR�s marketing and operations manager. �We also are establishing Cleveland in the biotechnology world as the place to be for stem cell research.�

Cleveland has been a leader in regenerative medicine and stem cell applications. The multi-institutional NCRM, including Case, University Hospitals Case Medical Center and the Cleveland Clinic, provides a comprehensive approach, including basic and clinical research as well as biomedical and tissue engineering, to develop new adult (non-embryonic) stem cell therapies for patients suffering from chronic and debilitating diseases including heart disease, cancer, genetic disorders and neurodegenerative diseases and injuries such as multiple sclerosis. Currently, NCRM has more than 27 ongoing clinical trials using adult stem cells and provides a comprehensive approach to developing therapies for patients suffering from chronic and debilitating diseases.

Caplan stated that Case Western Reserve and Cleveland health care institutions have done more protocols in MSC clinical research than other cities. Currently Osiris Therapeutic has clinical trials for MSC use in regenerating tissue and repairing the body injuries from cancer, Crohn�s disease, heart attacks and cartilage damage.

MSC research by Caplan and colleagues has focused on ways in which these cells can be used to restore and repair bone and cartilage. His most recent discovery was a method in which bone marrow cells were grown on three-dimensional scaffolds made of a substance called hyaluronon, which is found naturally in the body. Hyaluronon acts as a lubricant for joints, absorbing the impact caused by everyday movements. Hyaluronon also makes cartilage more elastic. Signals from hyaluronon trigger MSC to migrate to specific tissue. The results of the most recent research indicates great potential for treating musculoskeletal conditions such as fractures or bone loss.

Better life support for artificial liver cells

Thu, 23 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) COLUMBUS , Ohio -- Researchers at Ohio State University are developing technology for keeping liver cells alive and functioning normally inside bioartificial liver-assist devices (BLADs).

Such devices enable people who are suffering from acute liver failure to survive while their own liver cells regenerate, or until they receive a liver transplant. The person's blood or plasma circulates through the device. Inside, living cells -- usually pig or human liver cells -- perform normal liver functions.

For those liver cells to keep working, they need oxygen. Andre Palmer, an associate professor of chemical and biomolecular engineering at Ohio State, and his team are developing innovative ways to chemically modify and package hemoglobin -- the blood molecule in red blood cells that transports oxygen -- to deliver oxygen to liver cells in just the right way.

Palmer presented the project's preliminary results on August 23, 2007, at the American Chemical Society meeting in Boston .

In the body, liver cells are naturally exposed to a range of oxygen concentrations, called an oxygen gradient. But reproducing that natural gradient inside a BLAD is difficult.

If you don't recreate that oxygen gradient and the total amount of oxygen normally delivered, the liver cells in the BLAD won't function as well as they do in the body, Palmer said.

His solution has been to create different kinds of hemoglobin. One he seals inside microscopic polymer capsules; oxygen bound to the hemoglobin diffuses through the polymer over time to reach liver cells. Another is a type of hemoglobin-based oxygen carrier, which consists of long chains of hemoglobin molecules wound into balls that can then transport oxygen to liver cells.

The use of this technology with patients would require clinical trials, which Palmer admits are years away. For now, he is working to prove that he can adjust the oxygen gradient and the amount of oxygen his hemoglobins can transport to liver cells housed in a BLAD.

We've found that by using different types of hemoglobin-based oxygen carriers with different oxygen affinities and tuning the oxygen concentration, we can recreate natural oxygen gradients, Palmer said.

He began developing this technology while at the University of Notre Dame, and since 2006 has been continuing the work at Ohio State.

Though computer simulations had shown Palmer and his team that they could reproduce a natural oxygen gradient in principle, they have now conducted experiments on actual liver cells in the laboratory, and shown that they can do it in reality.

Tumors use enzyme to recruit regulatory T-cells and suppress immune response

Thu, 16 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) One way tumors fly under the radar of the immune system is by using IDO, an enzyme used by fetuses to help avoid rejection, to recruit powerful regulatory T cells that turn down the immune response, researchers say.

It was known tumors assemble a protective barrier of regulatory T cells, or Tregs, but how they are such able recruiters was an unknown, says Dr. David Munn, pediatric hematologist/oncologist at the Medical College of Georgia Cancer Center.

People have been very interested in how the tumor gets so many of these cells and how they get activated so they tend to be very aggressive, more suppressive in the tumor than they appear to be elsewhere in the body, Dr. Munn says of Tregs, major players in preventing autoimmune diseases such as arthritis and type 1 diabetes, where the immune system attacks body tissue.

Research published online Aug. 16 in The Journal of Clinical Investigation shows IDO, which seems to play a powerful role in tumor survival despite the relatively few number of cells in the tumors draining lymph nodes, directly activates existing Tregs which become strongly suppressive within a day. The number doesnt change a lot, but their activation state changes hugely, says Dr. Munn, corresponding author.

Studies in a tumor animal model show this rapid conversion occurs only in lymph nodes connected to tumors.

The findings further define a tumors survival strategy of first recruiting IDO, which helps recruit Tregs. Tregs then up-regulate the PD-L1/PD-L2 pathway, which has been shown to play an important role in the immune suppression caused by AIDS.

For the first time it creates a link between IDO, regulatory T cells and this novel pathway we dont know much about, says Dr. Munn. Interestingly its a link that appears to come full circle because, as researchers at the University of Perugia in Italy showed in 2003, in the test tube at least, Tregs also help recruit more IDO.

IDO appears to be a sort of linchpin; its a crossroads where a number of mechanisms, some of which are more powerful than IDO itself, come together, says Dr. Munn. Tregs, for example, are much more powerful than IDO. If you take a mouse and remove IDO, it compensates just fine. If you remove Tregs, the mouse dies. But if the tumor uses IDO to recruit and activate Tregs, that is a leverage point.

Therapies aimed at these new leverage points will be most effective when packaged with other emerging and existing treatments, he says.

The FDA has approved early clinical trials of the IDO inhibitor, 1MT, in coming months. A team, led by longtime collaborator Dr. Scott Antonia, hematologist/oncologist and co-leader of the Immunology Program at the H. Lee Moffitt Cancer Center and Research Institute, will begin phase 1 trials of 1MT in patients with lung and other tumors shortly. MCG is pursuing FDA approval to begin trials of the combination of 1MT and chemotherapy in breast cancer patients. Dr. Munn notes that while the IDO inhibitor seems to be a safe drug that doesnt cause autoimmune disorders in mice, it wont be used in patients with autoimmune disorders because it could worsen the disorders.

By combining IDO with chemotherapy, researchers hope to wipe the slate clean of the tumors manipulation of the immune response, says Dr. Munn. We have found that once the tumor gets a hold of the immune system, just giving an IDO inhibitor does not restore everything to normal. The tumor has too much influence on the immune system at that point.

Standard doses of chemotherapy reduce immune system function, creating a window where IDO likely can be more effective. That window may work for cancer vaccines too, which are still under study and getting mixed reviews. Recent reports indicate vaccines can actually increase the number of Tregs in mice with tumors, a problem when fighting cancer but a possible opportunity in which an IDO inhibitor might improve efficacy, Dr. Munn says. An antibody to the PD-L1/PD-L2 already under study in cancer may be another component of a total anti-tumor package.

We have data from a mouse model that while 1MT works modestly by itself, it works significantly better when combined with chemotherapy, says Dr. Munn. I think immunotherapy needs to learn from the finding with multi-agent chemotherapy, which is you need to orchestrate more than one approach. If you give one drug over and over again, the tumor invariably figures out a way to escape, so you always have to combine different strategies. Multiple approaches also reduce the chance of needing toxic levels of any of them.

Early clinical trials of the IDO inhibitor ideally will benefit patients for whom more standard therapies have failed and enable scientists to verify laboratory findings in people, Dr. Munn says. Scientists will carefully monitor Tregs to see if they show evidence of being activated by IDO now that they know what that looks like and de-activated by the IDO inhibitor. Theyll also have to see if Tregs circulating in the bloodstream are good indicators of whats happening or whether tumor biopsies will be needed.

IDO inhibitors potential against tumors as well persistent viruses such as HIV arose out of work MCG scientists, led by Dr. Munn and his long-time collaborator Dr. Andrew L. Mellor, director of the MCG Immunotherapy Center and Georgia Research Alliance Eminent Scholar in Immunogenetics. Their work published in Science in 1998 showed fetuses use IDO indoleamine 2,3-dioxygenase to locally disable a pregnant womans immune system and avoid rejection. They showed then that one way IDO suppresses the immune response is by degrading tryptophan, a natural amino acid important to T cells.

Later, they found that tumors and certain viruses such as HIV also appear to use IDO for protection from the immune response. However, the fact that IDO-expressing cells make up less than 1 percent of the cells in a tumor or its draining lymph node led MCG researchers to look for a population of powerful allies within the immune system that could explain the suppressive impact. Tregs seemed like a good choice. The 2003 paper by Italian scientists, followed by a 2006 paper that showed naïve T-cells exposed to IDO differentiated into Tregs, helped cement that some sort of relationship existed, prompting MCG researchers to further explore the relationship in a tumor animal model.

Its only been in the last year or two that people have begun to realize Tregs spend most of their time in a sort of resting state where they have the potential to be suppressive but are not at that moment, says Dr. Munn. That would make sense, because you dont want your immune system always shut off.

New study shows promise in reducing surgical risks associated with surgical bleeding

Fri, 10 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) CHICAGO (August 10, 2007) Surgeons may have a new patient safety tool to stop moderate surgical bleeding without some of the concerns associated with the current standard blood-clotting treatment. New research published in the August issue of the Journal of the American College of Surgeons shows that recombinant human thrombin (rhThrombin) reduces the risk of surgical complications associated with the use of plasma-derived bovine thrombin (bThrombin), which is currently the only commercially available stand-alone thrombin used to improve clotting during surgical procedures and stop bleeding.

Each year, bThrombin is used to treat more than one million patients who undergo surgical procedures in the United States. However, approximately 20 percent of these patients develop antibodies against bovine coagulation factors that can cross-react with human coagulation proteins and possibly lead to adverse effects, including severe bleeding and thrombosis. Due to these safety concerns, rhThrombin was developed as an alternative to bThrombin.

We constantly look for new ways to reduce risks in surgery and stopping surgical bleeding safely and effectively is of foremost interest to surgeons. The results from this phase III trial show that we can stop bleeding in 95 percent of patients within 10 minutes and do so without introducing foreign proteins that can carry greater risk of development of antibodies, said William C. Chapman, MD, FACS, Department of Surgery, Washington University, St. Louis (MO) School of Medicine. Im most encouraged by the increasing evidence that recombinant technology is safe and effective because it means that we may be able to avoid using blood or blood products from other people or animals and automatically diminish the risk of infection and the associated immunologic responses that have been noted in the past.

The randomized, double-blind comparative study included 411 patients who underwent surgical procedures at 34 U.S. medical centers across the country. One group of patients (n=206) was treated with bThrombin and a second group (n=205) was treated with rhThrombin, both of which were applied topically to the bleeding site(s) in combination with an absorbable gelatin sponge. The primary endpoint was the time it took for hemostasis to occur, as measured by the incidence of hemostasis within 10 minutes. Secondary endpoints included the incidence and severity of adverse events and the incidence of antiproduct antibodies.

The study demonstrated that both rhThrombin and bThrombin had comparable efficacy, with 95 percent of patients in each treatment group achieving hemostasis within 10 minutes. The two treatments had similar safety profiles, although antibody development was significantly lower in patients treated with rhThrombin compared with bThrombin (1.5 percent versus 21.5 percent, respectively).

Teamwork between 2 key proteins necessary for normal development and regulation of red blood cells

Mon, 06 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) RICHMOND, Va. (Aug. 6, 2007) Virginia Commonwealth University researchers studying hemoglobin genes, mutations of which play a role in genetic blood disorders like sickle cell anemia and beta-thalassemia, have identified two proteins that are responsible for regulating overlapping groups of genes during the development of red blood cells.

The findings may point researchers to future gene therapies for patients with sickle cell anemia and beta-thalassemia.

In an article pre-published online Aug. 3 as a First Edition Paper in the journal Blood, the journal of the American Association for Hematology, researchers reported that a protein called KLF2 coordinates with a related and well-studied transcription factor, EKLF, in the regulation of embryonic globin genes responsible for the development of mouse embryonic red blood cells.

EKLF plays a central role in the developmental regulation of the adult beta-globin gene, and is essential for the maturation and stability of adult red blood cells. KLF2 is a protein crucial for making embryonic red blood cells.

If EKLF and KLF2 can turn on the embryonic globin genes in adult cells we don't know if this is true yet - then these findings may provide a gene therapy approach for treating sickle cell anemia and beta-thalassemia. It is well-established that the expression of embryonic globin genes can help ameliorate these diseases, said Joyce A. Lloyd, Ph.D., associate professor of human genetics at the VCU Massey Cancer Center, and corresponding author for this study.

Lloyds team studied gene expression and red blood cell development in the mouse embryo. They used mouse embryos missing both the KLF2 and EKLF genes to show that embryonic globin expression is severely reduced, and that the embryos therefore are anemic, compared to mice missing KLF2 or EKLF alone.

This likely means that EKLF and KLF2, which are related transcription factors, regulate overlapping groups of genes in developing red blood cells. In the absence of both factors, they cannot compensate for each other, causing more serious defects in red blood cell development, Lloyd said.

According to Lloyd, the production of blood cells involves a complex differentiation pathway with interactions between many molecular players and proteins.

In humans, there are four globin genes clustered on chromosome 11 in the order in which they are turned on or expressed. These genes include the epsilon-globin gene, two gamma-globin genes and the beta-globin gene. Lloyd said that during fetal development, the embryonic epsilon-globin gene is active first, followed by the gamma-globin genes, and finally the adult form, beta-globin takes control following birth.

Understanding how genes are regulated or turned on and off is critical. In gene therapy, a normal gene can be inserted into cells to correct a genetic defect. However, according to Lloyd, in this case, the goal would be to insert a transcription factor into adult cells that would turn on an existing, silenced embryonic gene.

Study shows radiofrequency ablation highly effective in treating kidney tumors

Wed, 01 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) The patients underwent CT-guided radiofrequency ablation (RFA) at Wake Forest Baptist for kidney tumors ranging in size from 0.6 cm to 8.8 cm. A total of 125 tumors in 104 patients were treated over the period 2000 to 2006. In all of the patients, a biopsy had confirmed the presence of renal cell carcinomas (RCC), a common type of renal malignancy.

Of 95 tumors that were smaller than 3.7 cm (about 1.5 in.), all were completely eradicated by a single treatment, along with 14 of the larger tumors. Seven more of the 16 remaining larger tumors were eradicated after a second treatment, for a total 93 percent success rate for all 125 tumors. The results, reported in the August issue of the American Journal of Roentgenology, were based on follow-up exams over an average of about 14 months.

This is the largest treatment group to date of patients with biopsy-proven renal malignancies, said Ronald J. Zagoria, M.D., a professor of radiology at Wake Forest Baptist, an associate in urologic surgery, and lead author on the study. The results a high cure rate and low complication rate establish that at institutions with experience doing this procedure, this is an alternative method for treating small renal malignancies in patients who are not good surgical candidates.

RFA uses a needle-like treatment probe, guided by computed tomography (CT) as it is inserted through the skin into the tumor. The probes high-frequency alternating current heats the tumor tissue and destroys it. The technique has been used successfully in liver tumors since the early 1990s and has more recently been adapted for treatment of RCC.

Renal cell carcinomas that are smaller than 3.7 cm in diameter can be reliably and safely eradicated with percutaneous RFA, Zagoria and his colleagues conclude in the report. This result is regardless of the location or position of the RCC in the kidney. Larger tumors can also be eradicated with percutaneous RFA, they say, but with the larger tumors the risk of incomplete tumor destruction increases substantially. The authors also note that larger tumors near the middle of the kidney may be more difficult to ablate, possibly because they are close to large blood vessels or the ureter.

RFA is an outpatient procedure in which the patient is sedated but conscious and a local anesthetic is used at the puncture site. In the study being reported, 101 of the 104 patients went home the same day, and three were hospitalized after the procedure one for a planned treatment, another for treatment of bruising around the puncture, and a third for treatment of exacerbation of a heart condition.

A total of eight patients experienced complications, including temporary air pockets in the chest cavity, mild to severe pain after the procedure, pneumonia, and problems with their ureters. Generally, the report says, this study shows that the procedure ... has a very low rate of complications. Standard treatment for RCC has been a removal of the affected kidney, along with adjoining blood vessels and lymph nodes, known as a radical nephrectomy, although newer minimally invasive techniques, such as laparoscopic surgery, have also been used successfully.

Zagoria cautioned that RFA is not recommended if patients are good surgical candidates who are healthy, younger, and have two normal kidneys, because long-term follow-up is lacking and therefore the durability of cure is not confirmed. (The average age of patients in the study was about 70, with a range of 30-89.) However, he said, I think this is a big advance in treating renal tumors. The best candidates for RFA, he said, are patients with increased risk of complications from surgery and those with an hereditary condition that makes it likely they will require repeated treatments because of continual development of RCCs.

Scientists find why red beans and rice can be nauseating

Wed, 01 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) People cry foul when fowl is undercooked, but what about red beans and rice

Scientists have discovered how lectins, a family of proteins believed to be a natural insecticide that is abundant in undercooked legumes and grains, can make you feel temporarily miserable.

Its known that it can be a toxin, Dr. Paul L. McNeil, cell biologist at the Medical College of Georgia, says of the lectin protein thats commonly found in vegetables. Lectins, which bind strongly to carbohydrates that decorate cell surfaces, have a particular affinity for the heavy-carbohydrate coats of epithelial cells that line the gastrointestinal tract.

Researchers have long known that ingesting too much undercooked lectin can cause nausea, diarrhea and vomiting. What they didnt know was how lectin caused food poisoning.

Work published Aug. 1 in PloS One shows lectins disable GI tract cells, which are constantly bombarded while digesting food, from repairing tears in cells walls from all the activity. Repair normally occurs in seconds: internal membranes move up to patch the tear, the cell recovers and the one-cell layer lining of the GI tract remains intact.

If those individual cells cannot repair tears, they die, says Dr. McNeil. That means you have gaps in the integrity of the surface area of the epithelium and you are exposing the nasty internal world of your GI tract to your blood supply.

The epithelial lining is a continuous, natural barrier between digesting food in the GI tract and the blood supply. When intact, it allows only good stuff like nutrients to pass through.

Your body senses that lack of barrier function and tells you to eliminate the entire contents of the GI tract, says Dr. McNeil, noting that lectins apparent role as a natural insecticide and as a source of food poisoning are related. If you get vomiting and diarrhea you are going to eliminate the entire contents of your gastrointestinal tract, right And, you are not going to eat red beans again the next day, right That is probably the point if they are natural insecticides. Alcohol will do the same thing. When you drink too much alcohol, you can destroy the lining of your stomach.

But the scientist who first identified how injured cells patch themselves says lectin blocks this repair mechanism better than anything else hes seen. Interestingly, he and his colleagues showed in PloS Biology in 2006 how roughage which includes beans help people stay regular by causing more cell tears, which enables more mucus to escape from cells, essentially greasing the GI tract.

That same research team, which includes Dr. Katsuya Miyake, MCG cell biologist, and Dr. Toru Tanaka, pharmacologist at Josai University in Japan, has now shown lectin is also very good at blocking mucus expulsion from cells.

In fact, they discovered lectins role in stopping cell-patching and mucus release while researching roughage. The multipurpose lectin is a powerful stain the team used to look at mucus released by cells after tearing. They found if they used too much lectin there was no patching or mucus, just cell death.

Biologically its interesting because it might tell us more about the mechanism of repair, says Dr. McNeil, who wants to learn more about how lectin interferes with repair. We know the mechanism involves surface binding because you can add lectin and the cells cant repair. You take the same culture of cells, wash the lectin away, injure other cells in the culture and they repair fine. We also know its a very rapid, surface-initiated inhibition.

In addition to the immediate discomfort undercooked beans and rice can cause, long term concerns ingestion of lectin has also been linked to colorectal cancer and celiac disease, a common problem in which individuals are sensitive to gluten, a mixture of proteins derived from wheat flour that includes lectins. The small intestine of the celiac sufferer is unable to properly absorb nutrients after gluten ingestion.

Oddly, in a laboratory dish, safe from mechanical stresses that cause surface tears, lectin can make cells divide, which is quite the opposite of making cells sick, Dr. McNeil says. A recent Science paper implicated lectin in diabetes as well.

Its possible that this bioactive property of lectin that binds to our cells could have long-term consequences taken even in small amounts, he says, noting that thorough cooking destroys most but not all lectin. Maybe the bloating and gas is telling us something about lectin when its just a minor irritation.

He notes lectin is easily among the top-10 causes of food poisoning but is unlikely to be lethal because the body is so good at sensing the break in the GI barrier and eliminating the problem.

Penn researchers discover pathway that eliminates genetic defects in red blood cells

Wed, 01 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) PHILADELPHIA Researchers at the University of Pennsylvania School of Medicine have discovered a unique molecular pathway that detects and selectively eliminates defective messenger RNAs from red blood cells. Other such pathways known as surveillance pathways operate in a more general way, in many cell types. Knowing how this specific surveillance system works can help researchers better understand hereditary diseases, in this case, thalassemia, a form of anemia, which is the most common genetic disorder worldwide.

The results appear in the most recent issue of Nature Structural and Molecular Biology.

Cells have developed surveillance mechanisms that identify and destroy abnormal RNAs. Mistakes in a cells reading of RNA into protein can lead to the production of an abnormal protein, and this can result in abnormal cell function or death.

The form of thalassemia studied by the Penn group is caused by a mutation that allows the cells ribosome to read too far, making a protein that is too long. Thalassemias result from an underproduction of hemoglobin proteins the oxygen carrying molecule in blood hence the anemia. The particular mutation they study is carried by millions of people in Southeast Asia and is a major a cause of fetal loss and disease in adults. Specifically in this study they show how far the ribosome has to read into the RNA to trigger destabilization of the protein.

Several surveillance pathways have been identified over the last few years that recognize specific types of mutations in RNAs. For example, the most well-described pathway is one that recognizes nonsense mutations that result in an RNA that makes a protein that is too short. Duchenes muscular dystrophy and cystic fibrosis are examples of hereditary diseases that result from nonsense mutations.

We describe a surveillance pathway that targets RNA that is only found in red blood cells, says senior author Stephen A. Liebhaber, MD, Professor of Genetics and Medicine. More general surveillance pathways are in all cells. The specificity of this particular surveillance pathway has not been previously observed and predicts that theres something quite unusual about how RNAs are handled in red blood cells. Were interested in how this specific surveillance system works in red blood cells because such understanding will increase our knowledge of how these cells make high levels of hemoglobin and how defects in this system could contribute to genetic disorders and possibly be reversed.

This type of surveillance pathway that is regulated at the tissue level could also exist in other highly specialized cells, says first author Jian Kong, PhD, Senior Research Investigator. Investigating the mechanism of this pathway may help in understanding a wider range of genetic disorders.

Liebhaber is looking forward to further analysis of this surveillance pathway in order to determine why it is specific to red cells and to define the corresponding steps in gene expression in the red cell that are so unusual. Such information should lead to new ideas on how to manipulate this system in a variety of blood diseases.

Aggressive therapy best for certain AML patients

Wed, 01 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) COLUMBUS , Ohio A new study suggests that acute leukemia patients whose cancer cells show a genetic change that usually predicts a swift return of the disease following remission may remain disease-free longer when given aggressive therapy.

The findings apply to people with acute myeloid leukemia (AML) whose cancer cells have normal-looking chromosomes and a gene mutation called MLL-PTD.

Typically, these AML patients responded poorly following treatment with older standard therapies, often relapsing within a year. Of AML patients with normal chromosomes who lack the mutation, on the other hand, four in 10 are cured.

The new study suggests that treating patients who have the mutation with an aggressive therapy such as an autologous stem cell transplant while they are in remission might significantly extend their disease-free survival.

An autologous transplant uses stem cells taken from the patient's own blood.

The research was led by investigators at the Ohio State University Comprehensive Cancer Center. It is part of a larger study sponsored by the Cancer and Leukemia Group B (CALGB), a clinical cooperative group composed of oncologists from academic medical centers and community hospitals across the nation.

The findings were published in a recent issue of the journal Blood.

Our data is the first to show that AML patients with normal-looking chromosomes and this mutation do as well when treated aggressively as patients who don't have the mutation, says principal investigator Clara D. Bloomfield, professor of internal medicine and an internationally known AML specialist.

About 13,400 new cases of AML are expected this year, and about half will have cancer cells with chromosomes that show distinctive damage. The nature of that damage helps doctors determine a patient's therapy and estimate the patient's prognosis.

The remaining AML cases have cancer cells with normal-looking chromosomes. These cells lack the microscopic chromosome damage that guide therapy.

In 1994, however, a team of researchers that included Bloomfield discovered the MLL-PTD mutation in these patients. It was the first clinically useful marker to be identified in cases of AML with normal-looking chromosomes, and it was found to predict a short remission and poor response to therapy. About 8 percent of AML patients with normal-looking chromosomes have the mutation.

Studies done eight to 10 years ago showed that nearly 100 percent of these patients relapsed and died within two years, says first author Susan P. Whitman, a research scientist at Ohio State's Comprehensive Cancer Center.

This retrospective study set out to learn whether aggressive therapy provided through two CALGB clinical trials benefits patients with the mutation. It evaluated 238 people aged 18 to 59 with AML and normal-looking chromosomes. Of these, 24 (10 percent) had the MLL-PTD mutation.

All patients received an initial aggressive chemotherapy regimen (i.e., induction therapy) to induce remission. Those who achieved remission then received further aggressive therapy (i.e., consolidation therapy), usually an autologous stem cell transplant, with a few receiving intensive chemotherapy.

Of the 24 patients with the mutation, 22 had a complete remission. Of those, 13 relapsed within 1.4 years, but nine (41 percent) remained in remission when the study ended, with disease-free periods ranging from two to almost eight years.

We believe that the use of aggressive consolidation therapy may have contributed to the reduced number of early relapses in these patients, Bloomfield says.

We still must do larger studies to confirm these findings, to better understand this disease and to develop curative targeted therapies.

First case of successful ovarian tissue transplantation between two, nonidentical sisters

Wed, 01 Aug 2007 03:59:37 PST

( from http://www.rxpgnews.com ) A woman, whose ovaries had failed due to damage caused by chemotherapy and radiotherapy, has received a successful ovarian transplant from her genetically non-identical sister. The transplant restored her ovarian function, she started to menstruate and, after a year, doctors were able to recover two mature oocytes from her ovaries and fertilise them to produce two embryos.

This first case of a successful transplantation of ovarian tissue between two non-identical sisters is reported in the journal Human Reproduction today (Thursday 2 August) [1]. Professor Jacques Donnez, head of the department of gynaecology and professor and chairman at the Catholic University of Louvain in Brussels, Belgium, led the team that carried out the work [2].

In 1990, when she was 20, doctors treated Teresa Alvaro for beta-thalassemia an inherited blood disorder characterised by reduced or absent haemoglobin, which is the oxygen-carrying protein in red blood cells. She received chemotherapy and radiotherapy before having a bone marrow transplant from her 17-year-old sister, Sandra Alvaro, who had an identically matched tissue type (human leukocyte antigen (HLA) type), which meant that Teresas immune system would not recognise her sisters bone marrow as foreign and reject it.

The treatment was successful and Teresa was cured. However, in 1990 there were no procedures available for preserving her fertility before commencement of the treatment by, for instance, removing and freezing her eggs or ovarian tissue. The treatment caused complete ovarian failure, and her ovaries never recovered.

In July 2005, now aged 35, Teresa consulted Prof Donnez and his colleagues about the possibility of ovarian tissue transplantation from her sister to give her a chance of becoming pregnant.

Prof Donnez said: Having already provided bone marrow in 1990, her sister, who was now aged 32 and had never become pregnant, badly wanted to help her sister by donating some of her own ovarian tissue.

Although the option of oocyte donation from the sister to the patient was discussed, the patient refused this option. She preferred a transplant because she wanted to be responsible for the follicular maturation and considered that it was more natural than egg donation, for which her sister would have to undergo ovarian stimulation with follicle stimulating hormones and then oocyte retrieval. In addition, her sister had asked expressly to be the tissue donor and had refused to undergo ovarian stimulation for oocyte donation.

Analysis of the sisters HLA type showed that their genetically different cells coexisted successfully together (chimaerism) and that, therefore, no immuno-suppressive treatment would be required to prevent the ovarian graft being rejected. The earlier bone marrow transplant and resulting mixing of the sisters cells meant that Teresas immune system would recognise Sandras ovarian tissue as self rather than foreign.

In February 2006, Teresa and Sandra were anaesthetised together and three small sections of ovarian tissue were removed from Sandra via laparoscopy and within less than a minute were being sewn on to one of Teresas atrophied ovaries, also via laparoscopy. The sisters were discharged from hospital the day after surgery.

After six months Teresa started menstrual bleeding and this, together with differences in hormone levels, confirmed that ovarian function had been restored. Her menstrual cycles have continued ever since. A year after the transplant, the doctors retrieved two mature oocytes from her ovary and fertilised them with her husbands sperm via ICSI (intracytoplasmic sperm injection) they decided to use ICSI rather than attempting natural conception because the husband had a low sperm count. One of the resulting embryos developed to the two-cell stage and the other to the three-cell stage, but then both ceased to develop further, and so the embryos were not transferred to her uterus.

Prof Donnez said: We do not know why the embryos ceased to develop, but this also happens during normal cycles of IVF. The patient is planning more IVF attempts in the future.

He said that it was too early to say whether this procedure would ever be successful enough to enable a woman to become pregnant successfully and give birth to a live baby. However, the work did give hope to women who had not had an opportunity to freeze either their eggs or their ovarian tissue, and it emphasised the importance of leaving at least one ovary in place during any treatment because the ovary offered an excellent site for a subsequent transplant of ovarian tissue.

This method is an option for women who have not had their ovarian tissue cryopreserved, either because chemotherapy was given before 1996, or because cryopreservation was not proposed or not available in the hospital where the patient was treated, he said.

In theory, the procedure could also be used between two, unrelated women, as long as the two women were HLA compatible and if the donor had previously given bone marrow to the recipient, as in the case we are reporting here, he concluded.

Teresa Alvaro said: Early in 2005 my gynaecologist told me that the chemotherapy that I had to go through in 1990 in preparation for my bone marrow transplant had severely affected my fertility. A few months later I happened to read an article on an American woman who got pregnant after she had ovarian tissue transplanted from her twin sister. I didnt hesitate for a second and went to see Prof Donnez together with my sister. Our antigens appeared to be identical, and therefore the chances of rejection were minimal. The operation was a success. I can get pregnant the natural way. Thats something I could never have hoped for a couple of years ago.

Promising treatment target found in Hodgkin lymphoma

Mon, 30 Jul 2007 03:59:37 PST

( from http://www.rxpgnews.com ) BOSTON--Dana-Farber Cancer Institute scientists have identified a protein that prevents the body's immune system from recognizing and attacking Hodgkin lymphoma cells. Based on this finding, the researchers are now investigating targeted therapies to disable this molecular bodyguard and boost a patient's ability to fight the blood cancer.

If the strategy proves successful, patients might escape some of the long-term complications -- like heart damage and the threat of a second cancer -- caused by standard treatments that include radiation, said Margaret Shipp, MD, of Dana-Farber, who headed the study. A report will be posted online by the Proceedings of the National Academy of Sciences on July 30 and will appear in an upcoming print issue of the journal.

We're excited about this treatment lead, said Shipp, a medical oncologist. We are currently generating antibodies that can neutralize the 'bodyguard' protein, and wed like to fast-track this experimental therapy into clinical trials.

Nearly 8,200 people in the United States -- the great majority of them young adults -- will be diagnosed with Hodgkin lymphoma in 2007, according to the American Cancer Society, with an estimated 1,070 deaths. The cancer begins in the lymph nodes and channels that distribute infection-fighting white blood cells around the body. Its symptoms can include swollen glands in the neck, night sweats and fatigue.

The biological trademark of Hodgkin lymphoma is a type of giant, mutant white blood cell called the Reed-Sternberg cell that is found in the lymph node tumors. While most solid cancers consist almost entirely of tumor cells, says Shipp, Hodgkin tumors, which can reach the size of a basketball, contain only about 5 percent cancerous Reed-Sternberg cells; the rest are different types of immune cells recruited to fight the tumor, but they are ineffective.

You would expect with all these host immune cells attracted to the area of the tumor cells that they would mount a great antitumor response, Shipp says. But that's not the case. There are a lot of immune cells, but they're the wrong kind.

The immune army includes different types of T cells, such as T helper 1 (Th1) cells designed to recognize and kill foreign infectious agents and sometimes tumors, T helper 2 (Th2) cells, which normally control allergic responses, and T regulatory (Treg) cells that suppress other T-cell types and shut down an immune response when the job is done. The Hodgkin tumors are overloaded with Th2 and Treg cells that act as bodyguards for the cancer by weakening the Th1 immune response against it.

Przemyslaw Juszczynski, MD, PhD, Jing Ouyang, PhD, and colleagues from the Shipp laboratory, together with collaborators from Brigham and Women's Hospital, the Broad Institute and the University of Buenos Aires, hunted for the source of the cancer cells' protection. Using gene microarray chips, the scientists looked for genes that were active in Reed-Sternberg cells but not in cells of another non-Hodgkin B-cell lymphoma.

The comparison revealed that a gene called Gal1 was up to 30 times more active in the Reed-Sternberg cells, causing them to secrete large quantities of a protein -- Gal1 or Galectin 1 -- that turns down the Th1 immune response. The Shipp team then defined the mechanism for Gal1 overexpression in Hodgkin lymphoma. Next, they demonstrated that Th1 immune cells underwent apoptosis, or cell death, when treated with Gal1, leaving increased numbers of Th2 cells and the suppressive Treg cells. Using a gene-silencing technique, RNA interference or RNAi, they then turned off the Gal1 gene in Hodgkin Reed-Sternberg cells and showed that it blocked the death of infiltrating normal Th1 cells, making them an equal force to the Th2 cells.

Likely what's happening here is that the tumor cells essentially hijack a normal regulatory program and use it to avoid being knocked off by the immune response, explains Shipp, who is also a professor of medicine at Harvard Medical School. These observations provide an important explanation for why you have this ineffective immune response in Hodgkin lymphoma.

She adds that this bodyguard strategy may not be limited to Hodgkin lymphoma. One of the collaborating authors, Gabriel Rabinovich, PhD, of the University of Buenos Aires, has blocked Gal1 in mice with a form of the deadly skin cancer melanoma, and the animal's immune system succeeded in eliminating the cancer, Shipp says. We think it's very possible that this strategy will be applicable to other types of cancer.

UB scientist discovers novel iron-copper alliance

Mon, 23 Jul 2007 03:59:37 PST

( from http://www.rxpgnews.com ) BUFFALO, N.Y. -- Iron is the workhorse of trace minerals. An essential component of red blood cells, disruption of iron levels in the body will result in a myriad of serious conditions, and life cannot be sustained without it. In novel research, investigators at the University at Buffalos School of Public Health and Health Professions, have learned that iron is only one half of an all-important duo of trace minerals -- the other being copper -- that work in tandem to maintain proper iron balance, or homeostasis. It appears the workhorse has a helper. James F. Collins, Ph.D., UB assistant professor of exercise and nutrition sciences and biochemistry, discovered that when iron-absorption by cells lining the small intestine decreases during iron-deficient states, copper absorption increases. Collins now is exploring the relationship between these two trace minerals through a $1.38 million grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The work will be carried out using established models of intestinal iron absorption in humans, including iron and iron/copper-deficient rodents and cultured intestinal epithelial cells. This project is intended to test the overall hypothesis that increased copper transport during iron-deficiency is critical to enhance certain aspects of intestinal iron absorption, said Collins. Iron or copper deficiency causes anemia, and abnormal intestinal iron transport is associated with several common human pathologies, including anemia of chronic disease (ACD) and hereditary hemochromatosis (HH), different forms of which result from several common genetic defects. HH is an inherited metabolic disorder characterized by abnormally high absorption of dietary iron, which is deposited in body tissues and organs, where it may become toxic. ACD is a blood disorder caused by low body iron levels resulting from any medical condition that affects the production and lifespan of red blood cells, such as chronic infection, chronic immune activation resulting in inflammation, or malignancy.

In collaboration with Dr. Zihua Hu, Ph.D., a computational scientist at UBs New York State Center of Excellence in Bioinformatics and Life Sciences, we determined that several genes related to iron and copper homeostasis were strongly induced by iron deprivation across different developmental stages in the rat small intestine, said Collins. We will concentrate on understanding the role of two key proteins encoded by these genes: an intestinal iron transporter called divalent metal transporter 1 (Dmt1) and an intestinal copper transporter, the Menkes copper ATPase (Atp7a). The overall goal of the project is to answer three specific questions regarding the role of copper in intestinal iron transport, Collins noted: 1) Are Atp7a and Dmt1 solely responsible for enhancing dietary copper absorption during iron-deficiency 2) What are the molecular mechanisms leading to induction of the Atp7a and Dmt1 genes and 3) Which physiological processes related to intestinal iron ion homeostasis are enhanced by increased copper levels in enterocytes (cells of the superficial layer of the intestines) and in the liver We also expect to learn more about the mechanisms of dietary copper absorption, which currently are not well defined, Collins said. Furthermore, studies addressing the impact of increased enterocyte and liver copper levels during iron-deficiency have not been reported in the scientific literature to date, so this investigation is novel.

Effects of aging in stem cells

Mon, 23 Jul 2007 03:59:37 PST

( from http://www.rxpgnews.com ) There is little disagreement that the bodys maintenance and repair systems deteriorate with age, even as there is plenty of disagreement as to why. Stem cells combat the aging process by replenishing old or damaged cellsparticularly in the skin, gut, and bloodwith a fresh supply to maintain and repair tissue. Unfortunately, new evidence published in the open-access journal PLoS Biology suggests that this regenerative capacity also declines with age as stem cells acquire functional defects.

Stuart Chambers, Margaret Goodell, and their colleagues investigated the molecular mechanisms underlying aging of stem cells by looking at the gene expression profiles of aging hematopoietic stem cells (HSCs), the precursors of blood cells. They found that genes involved in the inflammatory and stress response became more active with age, while genes important for regulating gene expression and genomic integrity became less active. These results lend strong support to the notion that HSCs succumb to the wear and tear of aging, just like other cells, and shed light on the mechanisms of aging.

To study HSCs regenerative capacity over time, Chambers et al. isolated HSCs from young (aged 2 months) and old (aged 21 months) mice and then transplanted either young or old cells into mice whose bone marrow cells had been destroyed by radiation. The young and old HSCs gave rise to new marrow cells at roughly the same pace 4 weeks after transplantation. But at 8 and 16 weeks after transplantation, the old HSCs contributions had dropped considerably, suggesting that aging HSCs lose their repopulating capacity. Yet, because HSCs increased in number, overall blood production from HSCs remained stable.

The finding that genes involved in the inflammatory response are expressed more (called up-regulation) as HSCs age fits with evidence linking inflammation and aging in the kidney, brain, and arteries. It may also help explain why HSCs lose function. One of the up-regulated genes, P-selectin, encodes a cell surface adhesion molecule. Because transplanted HSCs depend on cell adhesion to colonize bone marrow properly, the researchers explain, inappropriate up-regulation of genes encoding P-selectin may interfere with this process.

The markedly reduced expression (or down-regulation) of genes involved in chromatin remodeling, an epigenetic regulator of gene expression, suggested that transcriptional activity might be dysregulated across the genome.

Though the dominant model attributes the physical effects of aging to an accretion of isolated genetic insults, these results link age-related decline to global mechanisms operating across the genome. In the researchers epigenetic view of aging, chromatin dysregulation provides a logical explanation for the numerous and diverse age-related changes observed at the molecular, cellular, and organismal levels. Over the normal course of aging, chromatin dysregulation leads to dysregulation of many genes, which in turn leads to a loss of normal cellular functions and a loss of growth regulation. These changes ultimately increase the risk of cancer, which, in many of its forms, increases dramatically with age. Future studies can investigate how epigenetic regulation, inflammation, and the stress response interact to better understand the molecular mechanisms of aging, and why so many of us face a high risk of cancer in our later years.

Computers pass dosage test for thrombosis drugs

Thu, 19 Jul 2007 03:59:37 PST

( from http://www.rxpgnews.com ) The largest ever study into the administration of blood thinning drugs like Warfarin has concluded that dosages calculated by computer are at least as safe and reliable as those provided by trained medical professionals.

Increasing evidence of the value of these anticoagulant drugs in a wide range of clinical disorders such as abnormal heart rhythm, or atrial fibrillation, has led to a rapid rise in their use around the world.

However, prescribing the right oral dose of anticoagulant to patients, even for experienced medical staff, can be problematic as individuals differ greatly in response to a given dose: too high a dose for an individual and the blood becomes too thin and can lead to internal bleeding, too low and the blood clots too readily.

Previous studies supporting the use of computer-assisted dosage have depended solely on laboratory results and have not been sufficiently large to determine whether observed improvements in normal blood clotting time known as the international normalised ratio or INR resulted in clinical benefit and improved safety.

But now results from a four-year clinical trial organised from The University of Manchester have shown that computer-assisted dosage is as good, if not better, at prescribing the correct dosage to normalise and maintain the correct INR in patients as dosages given by medical professionals.

The need for computer assistance arises from the massive demand for oral anticoagulants following their success at treating an increasing number of thrombotic and embolic conditions, said Professor Leon Poller, who headed the research in Manchesters Faculty of Life Sciences.

This increased demand has been overwhelming and stretched medical facilities worldwide to their limits. Computer dosage was introduced as a way to meet this demand but its safety and effectiveness had never been established.

The study, carried out in 32 medical centres across the European Union and involving more than 13,000 patients, analysed nearly 400,000 INR tests, divided evenly between manual and computer-assisted dosage.

The percentage of manual tests to give the correct INR was 64.7%, compared to 65.9% for computer-assisted dosage, confirming the effectiveness of the two programs tested by the team.

In terms of safety, the number of INR tests that resulted in clinical complications was 7.6% lower in all clinical groups with computer-assisted dosage, dispelling any safety concerns.

Indeed, while this overall figure may not be deemed significant, in the 3,208 patients with deep vain thrombosis or pulmonary embolism, the number of clinical events following treatment were significantly lower for computer dosage 9.1 per 100 patient-years with medical staff dosage was reduced to 6.1 in the computer arm.

The results are even more impressive when you consider that the comparisons were made against medical professionals based at centres that specialised in prescribing oral anticoagulants, said Professor Poller.

At the very least, our study confirms the clinical safety and effectiveness of computer-assisted dosage using the two systems we tested and should help to bring relief to overstretched medical professionals while providing reassurance to patients.

Enzyme eliminated by cancer cells holds promise for cancer treatment

Wed, 18 Jul 2007 03:59:37 PST

( from http://www.rxpgnews.com ) An enzyme that cancer cells eliminate, apparently so they can keep proliferating, may hold clues to more targeted, effective cancer treatment, scientists say.

In a high-stakes tit for tat, protein kinase G enables healthy cells to stay on task to proliferate, differentiate then provide a useful function. Cancer somehow reduces or eliminates PKG and cells get stuck proliferating.

The bottom line is, in normal tissue, you can see PKG being expressed; but tumors or cell lines that correlate with those tissues dont have nearly as much, says Dr. Darren Browning, cancer researcher at the Medical College of Georgia.

Cell lines used for all types of research appear to support his hypothesis. Many are actually cancer cells because of their proclivity to keep producing; Dr. Browning and others have shown PKG is lost in these cells. You split them once or twice and they kind of lose their character, he says.

The same appears true for tumors in people, says Dr. Browning, whose lab has found dramatic differences in PKG levels in tumors compared to even nearby, healthy tissue removed in surgery to ensure a cancer-free margin.

The findings made him wonder if the change in PKG level was just an artifact or was critical to cancer survival. A lot of proteins are lost by cancer cells, so we asked, What happens if we put PKG back into the cancer cells

He took metastatic colon cancer cells, created a system for reintroducing PKG, then put the cells into mice without an immune system. He admits he was disappointed that the PKG-enhanced cells grew but became very interested in how they grew.

Cancer cells without PKG created hard, solid tumors that spread. PKG-enhanced cells created a soft, non-invasive tumor that literally fell apart on contact and seemed to grow in little islands. After consultation with pathologists and others, he realized the PKG-enhanced cells were congregating around the few blood vessels. We know that cancer cells, particularly colon cancer cells, are very aggressive at bringing blood vessels into the tumor, he says. Cells poor at recruiting blood vessels dont grow well, which seems to be the case for PKG-enhanced colon cancer cells.

Now he wants to know how PKG nullifies aggressive metastatic cancer cells. We think PKG inhibits cancer by getting rid of a cancer-promoting gene called beta-catenin, which slows growth and blocks the tumors ability to recruit blood vessels that are needed to grow bigger, says Dr. Browning, who recently received a $720,000 American Cancer Society grant to pursue his hypothesis. His proposal was ranked number one by the ACS Cell Structure and Metastasis Study Section.

Hes already shown that PKG can reduce vascular endothelial growth factor, or VEGF; anti-VEGF drugs are the focus of numerous anti-cancer trials underway in the country because of VEGFs critical role in development of new blood vessels. Maybe by activating PKG or increasing PKG expression in tumors, we are going to reduce the amount of VEGF they produce, he says. We dont know whether PKG has a role in going from normal tissue to the initiation of a tumor, but we think its important to the tumor both in terms of angiogenesis and blocking metastasis. He points to one of his studies in which colon cancers spread to the lungs a common path for metastatic colon cancer was completely blocked by PKG expression.

A big part of the magic of PKG may be its impact on a gene called beta-catenin, which enables many stem cells, including those in the skin, bone marrow and colon, to proliferate throughout life. Little pits called crypts in the wall of the colon contain Wnt hormone which stimulate nearby stem cells, causing an increase in beta-catenin. The net effect is the colon makes new cells to replace cells lost to the ongoing grind of absorbing water and minerals from food and forming and eliminating waste.

As cells start moving out of the crypt, away from the Wnt hormone, beta-catenin levels go down so cells should stop dividing and start maturing. Essentially all colon cancers have an aberration in this beta-catenin system that prevents normal degradation and allows cell to keep proliferating.

In the normal cells that line the colon, you dont see very much beta-catenin. We think PKG in these cells keeps it that way to keep the cells from continuing to proliferate and spread, says Dr. Browning, who has already shown that in the test tube at least, adding PKG lowers beta-catenin levels. Interestingly, beta-catenin also is known to regulate VEGF expression in colon cancer.

In a nutshell, the first and most important genetic lesions leading to colon cancer cause increased beta-catenin levels, says Dr. Browning. We found PKG can knock down beta-catenin levels by up to 80 percent in some colon cancer cells and we think that is part of the mechanism by which PKG is able to block tumor angiogenesis and metastasis.

Hes excited by the implications and is involved in extensive collaborations to understand how PKG regulates beta-catenin and how it might be used in cancer therapies.

Evidence of PKGs effectiveness in fighting colon cancer in humans may already be available. Colon and rectal cancer is the third most common cancer in men and women in the United States but its rare in developing countries where residents eat less processed food and ingest more bacteria. Some of these bacteria make a protein, STa, which appears to prevent and even kill colon cancer cells. Dr. Browning believes that PKG is responsible for STas anti-cancer effects.

Bak protein sets stressed cells on suicide path, researchers show

Thu, 12 Jul 2007 03:59:37 PST

( from http://www.rxpgnews.com ) When a cell is seriously stressed, say by a heart attack, stroke or cancer, a protein called Bak just may set it up for suicide, researchers have found.

In a deadly double whammy, Bak helps chop the finger-like filament shape of the cells powerhouse, or mitochondrion, into vulnerable little spheres. Another protein Bax then pokes countless holes in those spheres, spilling their pro-death contents into the cell.

We found out Bak has a distinct function in regulation of the mitochondrial morphology, says Dr. Zheng Dong, cell biologist at the Medical College of Georgia and the Veterans Affairs Medical Center in Augusta and corresponding author on a paper published this week in Proceedings of the National Academy of Sciences. Bax, on the other hand, is not involved in morphological regulation but needs to be there to puncture holes.

One has to break up, kind of soften, the mitochondria for injury, and the other one actually punches the holes to kill it, says Craig Brooks, MCG graduate student and the papers first author.

Bak and Bax have similar structures and scientists have long suspected they play major, similar roles in programmed cell death, or apoptosis. These two proteins are very important for mitochondrial injury and subsequent apoptosis, says Dr. Dong.

To stress cells, they blocked oxygen supplies and used the common chemotherapeutic agent cisplatin, then documented that filamentous mitochondria became fragmented very early and quickly in apoptosis. Ironically they also found the deadly fragmentation results from Baks interaction with mitochondria-shaping proteins called mitofusins, which help mitochondria keep their filamentous shape in non-stressed cells. Dr. Dong suspects Bak may also play a role in mitofusin regulation in normal, non-stressful conditions.

In fact, the researchers suspect Bak, Bax and the contents they spill into the cell all have roles in keeping a cell functioning until a stressor kicks in.

They probably are both kept in check normally in the cell by other proteins, and when something happens that overwhelms the cell, it activates Bak and Bax to start cell death, says Mr. Brooks. Some of the same proteins, cytochrome c is the big one, are needed for daily mitochondrial function like making energy, but if they are released from the mitochondria, they activate a cell killing or apoptotic pathway, says Dr. Dhong, referencing the contents that spill from punctured mitochondria.

Looking at kidney cells and neurons in a Bak deficient mouse, they also showed that Bak and Bax need each other to successfully spawn cell suicide. If you have Bak but not Bax, the mitochondria still fragment but they dont die; if you have Bax but not Bak, you still have punctures in the mitochondria but with low efficiency, says Mr. Brooks.

Now they want to know exactly how Bak interacts with mitofusins, how the interaction is regulated and how it affects mitochondrial morphology, physiology and pathology. Their long-term goal for better understanding the cell suicide mechanism is developing drugs to block it in the case of a stroke, for example, or induce it to kill cancer.

Method to prevent hemorrhagic complications of thrombolytic therapy of blood clots is discovered

Mon, 02 Jul 2007 03:59:37 PST

( from http://www.rxpgnews.com ) A novel method to prevent hemorrhagic complications of thrombolytic therapy of blood clots is discovered.

Blood clot dissolution by thrombolytic therapy is an approved, safe and efficaceous therapy of acute ischemic stroke. It is in routine use world-wide, and prevents individuals from stroke-related long-term disability. Many safe therapy forms, however, are often associated with hazards, and therefore indications for therapy must be weighed on an individual basis. In stroke thrombolysis, it is the risk of perithrombolytic hemorrhage formation and expansive brain edema that are most feared complications, and may preclude from administering the therapy. Even after proper precautions, perithrombolytic hemorrhages occur in 6 to 10 % of treated patients. Therefore, experimental research is needed to clarify the mechanisms leading to these complications.

The now reported study led by Dr. Perttu J. Lindsberg from the Helsinki University Central Hospital investigated thrombolytics-related brain hemorrhage formation in an experimental stroke model in rats. It found that, in addition to the clot lysing effect, the drug used for this purpose, alteplase (recombinant tissue plasminogen activator) also possesses proinflammatory properties and activates and degranulates mast cells, a kind of tissue-based immune cell. On degranulation, mast cells release potent enzymes that cleave proteins (eg, chymase, tryptase, and metalloproteases) in the vessel wall. The result is increased vascular permeability, which can lead to hazardous brain edema and potentially to frank brain hemorrhage formation. A pharmacological mast cell stabilizer, cromoglycate, was administered before alteplase, and it reduced these detrimental effects significantly and led to improved neurological outcome and reduced mortality.

The amount of brain hemorrhage was reduced by 97% at 3 hours, by 76% at 6 hours, and by 96% after 24 hours of follow-up. Ischemic brain edema was reduced by 80% at 3 hours, by 55% at 6 hours and by 85% after 24 hours of follow-up. The mortality in control group was 29%, 64% in alteplase group, and 0% in a group treated with a combination of alteplase and cromoglycate. kromoglikaatti+alteplaasiryhmässä 0%). Furthermore, genetically engineered animals were used which lacked mast cells, and they showed minimal brain edema and alteplase-related hemorrhage formation. They also had improved neurological outcome and mortality compared with wild-type littermates. In addition to proteolytic enzymes, mast cells release vasodilators such as histamine as wellas heparin (s.c. blood thinning anticoagulant drug), which may locally prevent blood coagulation, predispose to bleeding and edema formation and ultimately lead to hazardous expansion of hemorrhagic and edematous brain events. The intracranial space is tight and does not allow expansion of its tissue content without harmful and potentially fatal consequences.

This study revealed a novel proinflammatory cellular mechanism related to an every-day dilemma in routine patient care that may provide a novel pharmacological target if confirmed in the clinical setting. At best, mast cell stabilization could eventually be applied as an adjuvant to thrombolysis.

Community Oncology explores pitched debate over anemia-fighting drugs

Tue, 26 Jun 2007 03:59:37 PST

( from http://www.rxpgnews.com ) The June issue of Elseviers Community Oncology takes an in-depth look at the charge that ESAs, generally considered vital to cancer patients quality of life, are overprescribed for profit. Scientists, oncologists, and critics of oncologists are in a heated debate now over the use of ESAs, or erythropoiesis-stimulating agentsdrugs that fight anemia by boosting levels of oxygen-carrying red blood cells and the protein hemoglobin.

Many cancer patients, suffering from fatigue and symptomatic anemia as side effects of their disease and its treatment, are prescribed ESAsalso known as EPO (epoetin alfa, or Procrit) and DARB (darbepoetin alfa, or Aranesp). New datamostly from studies of off-label useson potentially dangerous side effects such as blood clots, and on survival rates, are prompting some scientists to recommend that the US Food and Drug Administration effectively curtail the use of ESAs. Adding fuel to this debate is the fact that the drugs are costly, and some critics have accused oncologists of overprescribing them, swayed by drug company rebates.

The question is whether trained oncologists will be allowed to make the best clinical decision for each patient, or whether rationingwhich isnt based on scientific evidence but on an economic policy tug-of-warbecomes the standard, says Lee S. Schwartzberg, MD, Editor-in-Chief of Community Oncology. The current issue of the journal puts the debate in clear focus.

ESAs are intensively studied medications. After 15 years of well-designed clinical trials, we know that ESAs decrease the need for blood transfusions in cancer patients, increase hemoglobin, and improve quality of life in most patients with chemotherapy-induced anemia, says David H. Henry, MD, an editor of Community Oncology. He adds, Its clear that these drugs cost too much and that any profit from reimbursement should be corrected. But when used on-label, ESAs are safe. Still, the recent studies give us pause. They suggest we need to review all the data in a fair and balanced way. There has been too much emotional distraction.

The June issue of Community Oncology, which serves private practice-based clinicians, contains a point-counterpoint debate, an economic analysis of the cost of ESAs to practices, a report on toxicities from the RADAR project (Research on Adverse Drug Events And Reports) which closely monitors reports to the FDA on drug side effects, a review of ESA clinical studies, the point of view of a payer who plays a key role in ESA prescribing patterns, and a community oncology advocate who says that if insurers jump the gun on policy, both patients and practices could suffer. Its not an exaggeration to say that this controversy has serious implications for the future of cancer care in the United States, notes Dr. Schwartzberg.

A faster way to recover from chemotherapy and marrow transplant

Wed, 20 Jun 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Researchers at Childrens Hospital Boston report finding a new way to increase stem cells in blood, suggesting a possible treatment to help patients who undergo chemotherapy or bone marrow transplant for leukemia and other cancers recover their immune function more quickly. In the June 21 issue of Nature, they demonstrate that a stable analog of prostaglandin can enhance the blood-forming system, both during embryonic development and after its been damaged.

The discovery, made possible through high-volume drug screening in zebrafish, marks the first time stem-cell production has been induced by a small-molecule drug, says the studys senior author, Leonard Zon, MD, of the Childrens Hospital Boston Stem Cell Program and Division of Hematology/Oncology. Other studies, including one from Zon's own lab*, have identified ways of increasing formation of blood stem cells, which give rise to each of the bodys various blood cell types. However, the methods are technically complex and havent lent themselves to broad medical use.

The hospital now hopes to conduct a clinical trial of the drug, a long-active derivative of prostaglandin E2 known as dmPGE2. This compound was originally tested more than 20 years ago for patients with gastritis, but was never marketed as a drug.

Currently, patients undergoing bone marrow transplant must wait for marrow from a matched donor to replenish their stem cells and reproduce the full array of blood cell types, including all the cells of the immune system. When theres no suitable donor for a marrow match, patients can receive umbilical cord blood, which also contains blood stem cells. But the number of stem cells in one cord of blood is often not adequate for older children and adults, leaving them with diminished immune function and high risk for infections.

Zon and colleagues Trista North, PhD, and Wolfram Goessling, MD, PhD, both also of Childrens Stem Cell Program, zeroed in on dmPGE2 by screening more than 2,500 chemicals in zebrafish. Knowing that two genes, runx1 and cmyb, are required for blood stem cells to develop in vertebrate embryos, they looked for compounds that altered the expression (activation) of these genes. North spent six months placing 15,000+ tiny embryos in wells, each containing a different chemical five embryos to a well, 48 wells to a plate then checking each embryo 24 hours later to monitor its development and count its blood stem cells.

The screen identified 82 chemicals that markedly increased or decreased gene activity. Of these, 10 turned out to affect the prostaglandin pathway: five increased the formation of blood stem cells, and five decreased it. We werent specifically looking for prostaglandins, says Zon, a Howard Hughes Medical Institute investigator who is also a member of the Harvard Stem Cell Institute. This was a surprise finding.

A variety of experiments confirmed that prostaglandins, particularly dmPGE2, promote blood stem cell formation, while chemicals that block prostaglandin synthesis (such as aspirin or ibuprofen), suppress blood stem cell formation. Finally, in zebrafish whose marrow was depleted by irradiation, those given dmPGE2 recovered blood cell populations more quickly.

Prostaglandins are known to be released by the body when inflammation is present such as after an injury and may be among the compounds that aid recovery. So it makes some sense that prostaglandins would have the ability to enhance regrowth of cells, Zon says.

The zebrafish is ideal for investigating blood formation, says North. It reproduces quickly and in large number and has a blood-forming system that shares many similarities with that of mammals. Zebrafish embryos develop outside the mothers body and can take up chemicals through their skin, making it easy to test the developmental effects of large numbers of compounds very rapidly, while their transparent skin makes it possible to visualize the blood stem cells in live fish.

The researchers also confirmed their observations in mammalian models. When dmPGE2 was added to mouse embryonic stem cells in the lab, production of blood stem cells increased. In mice that underwent bone marrow transplant, treatment with dmPGE2 led to enhanced blood-stem-cell formation, and the stem cells remained present in the marrow more than six months after transplantation, indicating long-term engraftment. The fact that we confirmed the zebrafish discovery in a mammalian system suggests it may also be applicable in humans, says Goessling.

The clinical trial, projected to begin in 2008 at Childrens Hospital Boston in conjunction with the Dana-Farber/Harvard Cancer Center, will recruit patients undergoing cord blood transplant for leukemia. Patients will receive cord blood to replenish their blood systems, some of it treated with dmPGE2 to enhance blood-stem-cell formation. Having more stem cells should help the blood system to regrow faster and minimize complications, such as infections, says North.

Pre-cancerous blood diseases can be products of their environment

Thu, 14 Jun 2007 03:59:37 PST

( from http://www.rxpgnews.com ) When blood-forming stem cells misbehave, causing pre-cancerous conditions that can sometimes even progress to leukemia, the problem might not always lie with them. Rather, two studies in the June 15 issue of the journal Cell, published by Cell Press, reveal that a bad environment might be to blame.

Both reports show that defects in the bone marrowwhere blood cells are madecan spawn such pre-cancerous blood disorders in mice. Previously, such myeloproliferative syndromes were thought to be rooted in the blood cells themselves.

We show that the bone marrow microenvironment can make the blood cells become abnormal, like a type of pre-leukemic disease, said Louise Purton, who is affiliated with Peter MacCallum Cancer Centre in Australia, Massachusetts General Hospital, and the Harvard Stem Cell Institute. Such pre-cancerous conditions are often difficult to treat in humans, she added, mainly because not much is known about what causes the blood cells to act out.

The defect we see isnt intrinsic to the blood cells themselves, added Stuart Orkin, a Howard Hughes Medical Institute investigator at Childrens Hospital Boston and Chairman of Pediatric Oncology at the Dana-Farber Cancer Institute. Its a result of the interaction of the blood and support cells in bone marrow. We didnt predict that at all.

In addition to its important role in regulating the self-renewal and differentiation of blood stem cells, also known as hematopoietic stem cells (HSCs), the bone marrow microenvironment has been proposed to consist of various other niches or hematopoietic inductive microenvironmentsareas of the bone marrow that are highly specialized for the development of different kinds of maturing hematopoietic cells, Purton explained. This concept has been supported by the recent identification of specific niches for blood cells including B lymphocytes and megakaryocytes in the bone marrow, she said.

Purtons team found in an earlier study that mice lacking the retinoic acid receptor ãRARã one of three receptors that respond to a derivative of vitamin A, experience a 3-fold reduction in the number of HSCs. Now, her team has found that the animals also develop myeloproliferative disease, in which the stem cells in bone marrow produce too many blood cell progenitors and blood cells.

Unexpectedly, they reported, transplant studies revealed that this disease was caused by the bone marrow deficiency. Bone marrow from healthy mice transplanted into mice with the RARã-deficient microenvironment rapidly developed the blood disease, they showed, evidence that the microenvironment can be the sole cause of hematopoietic disorders.

Meanwhile, Orkins team set out to examine the role of so-called retinoblastoma protein (Rb)a critical player in controlling the cell cyclein blood cell development.

In the absence of Rb, blood stem cells leave the bone marrow and end up in the spleen and other places, Orkin said. It deregulates the process of stem cell differentiation and the animals get myeloproliferative disease.

As in Purtons study, Orkins team found that the animals condition resulted not from faults within HSCs themselves but rather as a consequence of an Rb-dependent interaction between myeloid-derived cells and their microenvironment.

The new understanding could help pave the way to novel therapies, according to the researchers. For instance, the findings provide an explanation for why normal blood-forming stem cells transplanted into patients with the myeloproliferative condition sometimes take on the characteristics of the disease they were meant to cure.

At the moment, most doctors focus only on the blood cell as being the cause of the disease, Purton said. Hopefully, the microenvironment will now also be considered as a potential cause, which might lead to better treatments for these patients in the future.

The findings emphasize the importance of environmental considerations for the success of stem cell therapies more generally, Orkin said. For bone marrow transplantations to work, you will need a decent environment in which to put them, he said. If you put stem cells in an environment that cant support them, it will be as if you didnt transplant them at all.

University of Pittsburgh researchers culture blood-forming stem cells from human fat tissue

Thu, 14 Jun 2007 03:59:37 PST

( from http://www.rxpgnews.com ) TORONTO, June 14 Researchers at the University of Pittsburgh School of Medicine have successfully isolated and cultured human hematopoietic stem cells from fat, or adipose, tissue, suggesting that they have found another important source of cells for reconstituting the bone marrow of patients undergoing intensive radiation therapy for blood cancers. They are presenting this ground-breaking research at the Tissue Engineering and Regenerative Medicine International Society (TERMIS) North American Chapter meeting being held June 13 to 16 at the Westin Harbor Castle conference center in Toronto.

Adipose tissue has the ability to rapidly expand or contract in accordance with nutritional constraints. In so doing, it requires rapid adjustment in its blood supply and supporting connective tissue, or stroma. Based on previous reports that the stromal vascular fraction of adipose tissue contains stem cells that give rise to pericytes cells surrounding small blood vessels the University of Pittsburgh School of Medicine researchers, led by Albert D. Donnenberg, Ph.D., professor and director of the Hematopoietic Stem Cell Laboratory, University of Pittsburgh Cancer Institute, isolated the stromal vascular fraction from human adipose tissue and expanded these cells by growing them in a specialized blood-culturing medium for 21 to 42 days.

Using a cell-sorting method known as flow cytometry, the researchers detected a broad spectrum of blood-forming, or hematopoietic, cells among the cultured cells at varying stages of differentiation. In particular, they observed both early and mature red blood cells. Moreover, they detected CD34+ cells at approximately the same frequency as is present in freshly isolated bone marrow. In bone marrow, CD34+ expression indicates the presence of progenitor cells which give rise to all of the different types of blood cells.

These data indicate that hematopoietic stem cells, or cells that give rise to them, are an integral part of normal adipose tissue, according to Dr. Donnenberg. We took cells from the stromal vascular fraction of normal adipose tissue and basically gave them bone marrow food to see what would happen. We were able to culture a variety of hematopoietic cells, including blood progenitor cells.

Dr. Donnenberg said that the use of a patients own bone marrow or blood-derived stem cells for bone marrow reconstitution carries some risk that these cells are contaminated with the patients own tumor cells. Since it has been shown in some cases that tumor cells contaminating bone marrow grafts are the source of recurrent malignancies after autologous transplantation, this might be a way of giving patients who need bone marrow reconstitution their own hematopoietic cells derived from a source other than their defective bone marrow, he explained.

Red cells count: Study shows pre-op levels affect post-op outcomes

Tue, 12 Jun 2007 03:59:37 PST

( from http://www.rxpgnews.com ) PROVIDENCE, R.I. [Brown University] Men over 65 with even slightly abnormal red blood cell counts either too low or too high are at greater risk of post-operative death or car-diac events following a major non-cardiac surgery, according to a new study by researchers at the Providence Veterans Affairs Medical Center and The Warren Alpert Medical School of Brown University.

Elderly patients are at risk for abnormal hematocrit values, or the number of red cells in the blood. These red cell counts are often too low, causing anemia, or too high, a sign of a condition called polycythemia. Elderly people are more prone to both anemia and polycythemia because theyre more likely to have health problems that affect red blood cells, such as kidney disease, gastrointestinal bleeding, malnutrition or cancer. The elderly are also more likely to have heart disease, which makes them more vulnerable to the stresses of surgery and puts them at greater risk of post-operative heart attacks and other cardiac complications.

But results from this new study, published in the June 13 issue of JAMA, are the first to show that even slightly abnormal pre-operative red cell counts can have serious post-operative conse-quences. The results also bring new meaning to hematocrit tests: Even though virtually all pa-tients get this screening before major surgery, doctors had little guidance on how to interpret test results that fall just outside the normal range.

Even though hematocrit tests are nearly universal before elective surgery, doctors dont have a reliable yardstick for gauging a normal or a mildly abnormal result. So the test, on many oc-casions, is not very helpful, said Wen-Chih Wu, M.D., lead author of the JAMA article, assistant professor of medicine at The Warren Alpert Medical School of Brown University, and staff car-diologist at the Providence Veteran Affairs Medical Center. One of my biggest hopes for this research is that it eventually helps doctors better interpret hematocrit test results to improve pa-tient outcomes.

Wu and his colleagues set out to evaluate the prevalence of pre-operative anemia and poly-cythemia and their effects on 30-day post-operative outcomes for veterans. Wu and his team mined data from the Veterans Affairs National Surgical Quality Improvement Program to conduct their work, looking at medical data of 310,311 veterans aged 65 or older who underwent major non-cardiac surgery. These surgeries, which ranged from total knee replacements to pros-tate surgeries to hernia repairs, took place between 1997 and 2004 in 132 Veterans Affairs Medical Centers across the United States.

Researchers used patients pre-operative hematocrit screening results, and a review of the scien-tific literature on hematocrit values, to put patients into one of three categories: anemic (hema-tocrit values of less than 39 percent), normal (hematocrit values of between 39 and 54 percent) and polycythemic (hematocrit values of 54 percent or higher). Then, from each point deviation from normal, researchers estimated increases in the risk of death or cardiac events mainly heart attack and cardiac arrest 30 days after surgery.

Results were clear: For every percentage point of hematocrit deviation from the normal range, death and cardiac event rates rose by 1.6 percent. This increase in risk was significant and steady. For example, a patient with a pre-operative hematrocrit value of 30 percent has a 14 per-cent increased risk of death 30 days after surgery while a patient with a pre-operative hematrocrit value of 24 percent has a 24 percent increase in their risk of dying.

We found that, in older men facing surgery, even a mild case of anemia or polycythemia can pose a problem, Wu said. The risk of death or a serious cardiac event started when hematrocrit values were 51 percent and higher values that were previously considered normal.

Wu said it was too early to tell if changes in medical care before or during surgeries such as blood transfusions or iron supplements could improve outcomes for the elderly with anemia. Right now, Wu and his team are currently studying the impact of different treatment options for the elderly with these low red blood cell counts.

Until those results are in, the current findings give doctors a better yardstick for measuring nor-mal hematocrit values: Some doctors may have different definitions of what a normal hema-trocrit result is for a patient facing surgery. By looking at post-operative outcomes, this study redefined the concept of normal hematrocrit values. For elderly patients about to undergo major surgery, maintaining a normal red blood cell count may be beneficial.

Dasatinib-high early response rate as first treatment for chronic myelogenous leukemia

Sun, 03 Jun 2007 02:03:32 PST

( from http://www.rxpgnews.com ) An established second-line drug for chronic myelogenous leukemia has high response rates when given to newly diagnosed patients as their first therapy for the disease, according to early results from a Phase II clinical trial at The University of Texas M. D. Anderson Cancer Center.

"Patients taking dasatinib achieve complete cytogenetic response - absence of the mutated protein that drives this disease - more rapidly than we've observed historically using the current front-line therapy. Side effects are very manageable," says Ehab L. Atallah, M.D., lead author of the study and a fellow in M. D. Anderson's Department of Leukemia. Atallah presented study results at the annual meeting of the American Society of Clinical Oncology in Chicago Saturday June 2nd, 2007. The clinical trial remains in progress with 35 patients enrolled.

Dasatinib, known commercially as Sprycel and produced by Bristol-Myers Squibb, was approved by the U.S. Food and Drug Administration a year ago for use by patients whose disease is unresponsive to or becomes resistant to the front-line therapy imatinib. Both drugs bind to and block a genetically flawed protein known as BCR-ABL, which causes the disease. Atallah explains that dasatinib binds to both forms BCR-ABL while imatinib blocks only one.

"Our hypothesis is that treating with dasatinib first will produce an earlier response, which may translate to a better overall survival," Atallah says. "We haven't proved that here, but these early results are encouraging."

Atallah and colleagues evaluated 35 patients who enrolled in the clinical trial between November 2005 and December 2006. Patients receive either 100 mg of dasatinib once daily or 50 mg twice daily.

Thirty four patients had been on the clinical trial for at least three months when Atallah and lead researcher Jorge Cortes, M.D., professor in the Department of Leukemia, evaluated their data. They found that 77 percent of patients at three months, 92 percent at six months and 95 percent at one year had a complete cytogenetic response.

This rapid response compares favorably to historical data on patients at M. D. Anderson who took imatinib as a first therapy, Atallah noted. Imatinib's complete response rates at six months are 54 percent at 400 mg daily and 85 percent for 800 mg daily. However, at 12 months, 72 percent of patients receiving imatinib 400 mg and 92 percent of those receiving 800 mg had a complete cytogenetic response.

Dasatinib side effects have been manageable and mainly low-grade, with 15 patients having to temporarily stop treatment.

The M. D. Anderson clinical trial is set to enroll 100 patients. The comparison to historical data provides insight into dasatinib's effect, but a randomized clinical trial comparing medications directly would present a more detailed picture.

Imatinib, known commercially as Gleevec and produced by Novartis Pharmaceuticals, was the first drug to target the fusion protein BCR-ABL that causes the disease. Before Gleevec, the median five-year survival rate for CML patients was 50 percent. Researchers reported last year that the five-year survival rate of patients taking imatinib is 95 percent.

About 4,500 people receive a diagnosis of CML in the United States each year, and an estimated 20,500 people are living with the disease, according to the Leukemia & Lymphoma Society.

World first medical treatment announced by researchers

Fri, 01 Jun 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Researchers at Queen Mary University London and the University of Leicester and have today (Friday June 1) announced a potential breakthrough in the treatment of a rare but devastating medical condition that can affect children and young people.

In a world first, the clinicians and scientists from the two universities have already treated one patient with promising results. Their preliminary data are published as a letter in the New England Journal of Medicine.

This is the first time research into a condition known as idiopathic pulmonary haemosiderosis has investigated the role of oxidative stress and it is also the first time treatment has been carried out based on the research.

Queen Mary University London and the University of Leicester have combined world-class expertise in Child Health, Pulmonary Disease and Oxidative Stress research, plus access to patients with this rare disease. This combination of factors is unique to this collaboration.

Jonathan Grigg, Professor of Paediatric Respiratory and Environmental Medicine at Queen Mary University London, said: Idiopathic pulmonary haemosiderosis is a rare disease, the cause of which is unknown.

Affected patients have episodes of bleeding in the lungs, which often need hospital admissions, and in some cases it can be life threatening. This is normally combated by the use of continuous oral steroids (which can have major side effects).

In a child local to Leicester, we were able to show, for the first time, that there was high levels of oxidative stress in the lungs. In addition, we treated the increased oxidative stress by using of an antioxidant, N-acetyl cysteine - which has no side effects. Since she has been on this treatment she has had no lung bleeds, and the steroid dose has been significantly reduced.

Dr Marcus Cooke, Senior lecturer in the Radiation and Oxidative Stress Section at the University of Leicester, added: It is a really good feeling to be involved in a project looking at oxidative stress, that can make such an enormous difference to a persons quality of life.

I think that we will see an increasing use of biomarkers of oxidative stress to support clinical decisions.

Dr Cooke said that idiopathic pulmonary haemosiderosis is a devastating condition. Characteristic of this condition is the accumulation of protein-bound iron in the lungs, a consequence of repeated bleeding in the lungs, coupled with inflammation and fibrosis. Ultimately this condition is usually fatal. Treatment to prevent the lung damage and prevent anaemia is a combination of corticosteroids and iron supplement.

Both chronic inflammation, and the presence of iron, released following bleeding into the lungs, can lead to a condition known as oxidative stress. Oxidative stress occurs when the production of free radicals, highly reactive chemicals, outweighs antioxidant defences. This leads to a great deal of damage to cells, and in particular DNA, the cells blueprint, and is likely to be responsible for the fibrosis, as the lungs try to repair the damage done by free radicals.

In order to establish whether oxidative stress was indeed associated with episodes of bleeding into the lungs, we measured a biomarker of oxidative stress, and a marker of damage to DNA specifically, in urine.

We noted that levels of oxidative stress increased significantly following every bleed. With this in mind, and on the basis that antioxidants can potentially boost the bodys natural defences, we began the patient on a course of the antioxidant drug N-acetyl cysteine. Five months into antioxidant therapy, the patient remains clinically well, and on a reduced dose of corticosteroids.

Researchers discover inherited mutation for leukemia

Thu, 31 May 2007 03:59:37 PST

( from http://www.rxpgnews.com ) COLUMBUS , Ohio Researchers have discovered the first inherited gene mutation that increases a person's risk for chronic lymphocytic leukemia (CLL), one of the most common forms of the disease.

The study shows that the inherited mutation greatly reduces the gene's protective activity. Furthermore, a second kind of change occurs later that turns the gene off altogether, leading to leukemia. This latter alteration is a chemical change that is not inherited.

The findings could help identify people at risk for chronic leukemia, but they also may provide new insights into the process of natural cell death. They may even lead to new strategies for treating the disease.

The research is to be published in the June 1 issue of the journal Cell. It was led by researchers at the Ohio State University Comprehensive Cancer Center.

The mutation was found in a gene called DAPK1, which normally helps trigger the death of cells before they become cancerous. Researchers identified the mutation by testing a family in which the father, four sons, a grandson and a distant female relative developed this form of leukemia.

The chemical change is called DNA methylation. Healthy cells use this process to silence unneeded genes. But abnormal DNA methylation can turn off genes that control cell growth, and that lead to tumor growth.

Our findings identify for the first time a gene that appears to be associated with hereditary CLL, says coauthor John C. Byrd, professor of internal medicine and a CLL specialist.

They also show the importance of the gene in the pathogenesis of CLL, and direct us to target this gene with therapies that might re-activate it.

The findings also provide evidence that some genes might contribute to cancer even when they are not silenced entirely.

This inherited change is remarkably subtle, says co-principal investigator Albert de la Chapelle, professor of molecular virology, immunology and medical genetics and a researcher with the Ohio State human cancer genetics program. It does not shut down the gene, but just lowers its expression somewhat.

Recently, many cancer geneticists have come to believe that such subtle changes are common causes of cancer, and this is one of the first, strong examples of that principle.

The study succeeded because it combined the field of gene mutation research and the new field of epigenetics, which identifies genes silenced by faulty DNA methylation, says Christoph Plass, professor of molecular virology, immunology and medical genetics and of veterinary biosciences, and also co-principal investigator on the study.

Our findings show that it's important to look for both genetic and epigenetic alterations when identifying problem genes, he says.

CLL is the most common form of adult leukemia, with 15,300 new cases and 4,500 deaths from the disease expected this year in the United States. The leukemia is slightly more common in men than women, and typically strikes people who are in their 50s, 60s and 70s.

About 90 percent of CLL cases are sporadic; that is, they have no genetic component.

But about one in 10 people with CLL have relatives who also develop the disease strong evidence of a hereditary predisposition. However, usually only two or three people within a family are affected, making it difficult to do the genetic studies needed to find possible mutations, Plass says.

The family examined in this research was identified by collaborator Henry Lynch at Creighton University.

The researchers are now studying the chemical pathway that regulates the gene, considering possible therapies, working to identify other CLL families and looking for other predisposing genes.

In 2005, other Ohio State Comprehensive Cancer Center researchers discovered a germline mutation in a gene for a microRNA that is implicated in CLL, suggesting that this may also be a predisposing mutation for the disease.

Clinical guidelines for blood conservation during cardiac procedures developed

Wed, 16 May 2007 03:59:37 PST

( from http://www.rxpgnews.com ) RICHMOND, Va. (May 16, 2007) A team of medical experts led by a Virginia Commonwealth University anesthesiologist and a thoracic surgeon from the University of Kentucky has established a set of clinical guidelines to help physicians decrease the need for blood transfusions in high-risk patients during cardiac operations.

The team, led by Bruce Spiess, M.D., professor in the Department of Anesthesiology at the VCU School of Medicine and director of VCURES Shock Research Center, and Victor A. Ferraris, M.D., chief of the Division of Cardiothoracic Surgery at the University of Kentucky's Albert B. Chandler Hospital, developed the guidelines, Perioperative Blood Transfusion and Blood Conservation in Cardiac Surgery. It appears as a standalone supplement to the May 2007 issue of the The Annals of Thoracic Surgery.

Blood must be viewed as a scarce resource that carries risks and benefits, said Spiess. This is a huge event for medicine. If these guidelines are adopted by a majority of cardiovascular centers in the world, we can decrease the amount of blood transfusions, blood usage and cost and blood shortages would be less frequent and not occur to such a degree.

There is very strong evidence that patients who receive more blood have more post operative infection, have more renal failure and have more lung dysfunction, he said.

According to the report, about 15 to 20 percent of patients undergoing cardiac procedures consume more than 80 percent of the blood products transfused at operation.

Ferraris agreed with the great significance of the guidelines.

The blood conservation practice guidelines generated under the auspices of the Society of Thoracic Surgeons represents a landmark undertaking, he said. This work should serve as a template for individual cardiothoracic surgeons and for institutions as they manage valuable and scarce blood component resources.

In the analysis, the committees from the Society of Thoracic Surgeons, chaired by Ferraris, and the Society of Cardiovascular Anesthesiologists' Task Force on Blood Transfusion, chaired by Spiess, collaborated over a period of four years in determining the evidence-based series of recommendation for practice.

They reviewed all available published evidence related to blood conservation during cardiac operations and identified preoperative and perioperative interventions that are likely to reduce bleeding and postoperative blood transfusion.

The guidelines suggest that institution-specific protocols should screen for high-risk patients, as blood conservation interventions are likely to be most productive for this high-risk subset.

Some evidence-based blood conservation techniques include drugs that increase preoperative blood volume or decrease postoperative bleeding; devices that conserve blood; and interventions that protect the patient's own blood from the stress of operation.

We already do most or all of these things here at the VCU Medical Center and have led the nation in implementing an entire program, said Spiess. We have not only been successful in cardiac surgery but also now have a full program for the whole hospital.

Cause of gender differences in blood pressure, kidney damage under study

Wed, 02 May 2007 03:59:37 PST

( from http://www.rxpgnews.com ) While men and women both get high blood pressure and related kidney disease, the path to get there is shorter, steeper and just different for men, researchers say.

They may end up at the same point, but the way they got there could be very different, says Dr. Jennifer C. Sullivan, pharmacologist/physiologist at the Medical College of Georgia Vascular Biology Center.

It's known that men tend to develop hypertension earlier than women and the increase in blood pressure occurs more rapidly than it does in women, until they hit menopause. I look at our spontaneously hypertensive rats and see the same dichotomy in blood pressure, Dr. Sullivan says of the animal model she studies. There are also differences in development of renal injury in the human population and chronic renal disease seems to be worse in men and I see the same thing in my animal model.

She's looking at these gender differences to find what protects females, at least for much of their life, work that led to her selection for the 2007 New Investigator Award of the American Physiological Society's Water and Electrolyte Homeostasis Section. She presented her work May 1 during the Experimental Biology Meeting Annual Meeting in Washington, D.C.

Female hormones can't account for all the difference, she says. It's not that easy. Men and women are more than just sex hormones. When she takes testicles out, for example, blood pressure and injury incidence drop some; when she takes ovaries out, blood pressure remains unchanged but kidney injury increases slightly. There are fundamental differences, I believe, in the physiology. They are going to end up at the same point but the way there could be very different.

So she's comparing in males and females some major players in blood pressure regulation and renal injury: the potential for blood vessels to relax and constrict and the amount of damage-producing free radicals.

She's finding that nitric oxide synthase, which makes nitric oxide, a signaling molecule that tells smooth muscles cells to relax, may make more nitric oxide in females. Just how active an enzyme is depends on how it's phosphorylized, or turned on by adding phosphate groups. Our preliminary data says that the phosphorylation status may increase nitric oxide production - and maintain kidney health - in females, Dr. Sullivan says.

In contrast is the powerful constrictor of blood vessels, angiotensin 2. In the outer most part of their kidneys, males have a lot of the AT1 receptors that enables angiotensin 2 to do harm. It's a vasoconstrictor when it binds with AT1, she says. It will cause proliferation, it will cause hypertrophy, it can stimulate the production of reactive oxygen species, so it does all sorts of bad things, she says.

Fortunately there are already drugs that block angiotensin 2's destructive action: angiotensin receptor blockers and ace inhibitors. Interestingly, clinical studies already have shown these drugs don't work as well in women. A lot of women are on these drugs too and I'm not sure it's doing them a lot of good, she says. One of her goals is to find out.

When she looks in the outer most part of the kidney, called the renal cortex, she also finds males have too many highly reactive and potentially damaging free radicals. Free radicals or reactive oxygen species have important jobs in the body, like cell signaling, but as with anything, it's all about balance.

When there are too many, it creates oxidative stress, a contributor to most major diseases, such as cancer and cardiovascular disease, as well as aging in general. In high blood pressure, free radicals damage proteins critical to blood vessels and the kidneys.

The body has natural mechanisms for keeping free radicals in check, including endogenous antioxidants. But if you get increases, it can overwhelm the natural ability of the body to take care of it, she says.

When she looks to see the toll all this takes on the kidneys, she finds about a 50 percent increase in the amount of protein excreted in the urine - a sure sign of kidney disease - in the males.

She notes that by age 70, the rates of cardiovascular disease and hypertension are similar in men and women and that older women tend to have higher blood pressures than age-matched men.

Cancer scientists create 'human' leukemia process to map how disease begins, progresses

Thu, 26 Apr 2007 03:59:37 PST

( from http://www.rxpgnews.com ) (Toronto, Canada April 26, 2007) -- Cancer researchers led by Dr. John Dick at Ontario Cancer Institute (OCI) have developed a method to convert normal human blood cells into human leukemia stem cells. The converted cells, when transplanted into special mice that permit the growth of human cells, can replicate the entire disease process from the very moment it begins. The findings are published in the journal Science.

Dr. Dick, Senior Scientist at OCI, the research arm of Princess Margaret Hospital, and a Professor in the Department of Molecular Genetics, University of Toronto, said: Most human leukemia research involves studying a patient's diseased cells or a cell line grown from those cells. However, since cancer takes many months or years to develop, just studying the cells at the end of the process does not let you know what the series of changes were that caused the cells to become leukemic, and when they happened.

With the method we developed, we have duplicated the natural process every step of the way. The method we developed opens the pathway generally to understanding the process of how cancer begins.

The scientific team of Frederic Barabe, James Kennedy and Kristin Hope introduced a specific leukemia gene into normal human stem cells and injected the genetically altered cells into mice that lacked immune systems. The result? 100% of the mice developed fatal leukemia that displayed the same characteristics and patterns of human disease.

For the past 20 years, said Dr. Dick, leukemia research has focused mainly on human cells where the disease already exists or by studying leukemia created in mouse cells. This study flipped it around to focus on asking which are the normal cells within which the disease arises and then how it evolves and progresses, all within the context of human cells.

So what we are building is a new approach and way of studying how leukemia arises in the first place. We found that with the leukemia gene we were using, the disease only arose from immature stem and progenitor cells. The leukemic stem cells that were created seemed to change as the human leukemia was grown for longer times in a series of transplanted mice. Our findings of how these leukemic stem cells functioned could explain several features of the leukemia in children and adults that also contain the same leukemia gene, MLL-ENL.

In 1994, Dr. Dick identified the first cancer stem cell in leukemia, following on the original discovery in 1962 of the blood stem cell by two other renowned OCI scientists, Drs. Ernest McCulloch and James Till -- a discovery that formed the basis of all current stem cell research. Dr. Dick, who holds the Canada Research Chair in Stem Cell Biology and is also Senior Scientist at the Toronto General Research Institute and at the McEwen Centre for Regenerative Medicine, University Health Network, recently published other findings showing that colon cancer arises from stem cells specific to the tumour.

Discovery of an HIV inhibitor in human blood points to new drug class

Thu, 19 Apr 2007 03:59:37 PST

( from http://www.rxpgnews.com ) A new study has pinpointed a natural ingredient of human blood that effectively blocks HIV-1, the virus predominantly responsible for human AIDS, from infecting immune cells and multiplying. The virus blocker might play a role in the progression of HIV to full-blown AIDS andbecause it works in a different way than existing antiretroviral inhibitorscould lead to the development of another class of drugs in the fight against the pandemic disease, researchers reported in the April 20, 2007 issue of the journal Cell, a publication of Cell Press.

The research team found that fragments of a relatively abundant blood molecule, which they call VIRUS-INHIBITORY PEPTIDE, or VIRIP, acts as a broad-based inhibitor of HIV-1. Moreover, they showed that a few amino acid changes in the fragment enhanced its antiretroviral potency by two orders of magnitude. VIRIP and its derivatives remained effective against drug-resistant HIV strains, making them highly promising for further clinical development, according to the researchers.

The findings reveal a new target for inhibiting HIV that remains fully active against viral strains that are resistant to other drugs, said study author Frank Kirchhoff of the University of Ulm in Germany. That's a big advantage.

Kirchhoff's group also provided evidence that HIV-1 does not easily develop resistance to VIRIP, at least in cell culture. Furthermore, their collaborators led by Wolf-Georg Forssmann of IPF PharmaCeuticals GmbH and Hannover Medical School found preliminary evidence showing that some derivatives of the peptide are highly stable in human blood plasma and are nontoxic even at exceedingly high concentrations.

According to the latest World Health Organization estimates, nearly 40 million people worldwide are living with HIV/AIDS, including more than 2 million children. Close to 4 million people became infected with HIV in 2006, and the virus was responsible for about 3 million deaths last year alone.

A variety of molecules in human blood have been implicated in the inhibition of HIV-1, the researchers noted. However, it had remained elusive which circulating natural compounds are most effective in controlling viral replication in the body.

In the new study, the researchers sifted through a comprehensive library of small peptides that had been filtered from the blood of patients with chronic kidney failure during dialysis, in search of those with anti-HIV activity. After sorting the more than one million blood peptides into 300 fractions, they focused on one that blocked HIV without toxic effects on cells.

Further examination revealed VIRIP as the active ingredient. A synthetic version of the peptide maintained its anti-HIV activity, excluding the possibility that some other factor was responsible.

VIRIP specifically targets a conserved region in the HIV-1 transmembrane glycoprotein known as gp41 fusion peptide. This peptide, which is normally buried in the viral envelope, becomes exposed during the process of viral entry and makes the first direct contact between the viral particle and host cell.

Thus, they showed, VIRIP plays an essential role in the ability of HIV to fuse with and infect its host's immune cells. That unique underlying mechanism allowed the inhibitor to remain effective against viral strains that are resistant to other antiretroviral drugs, they found.

Our data support the possibility that VIRIP may contribute to controlling HIV-1 replication in infected individuals and that derivates thereof are highly suitable for development of a new class of HIV-1 inhibitors targeting the highly conserved gp41 fusion protein, the researchers concluded.

There are now some 20 different HIV drugs in use, Kirchhoff said. However, the treatments all fall into one of four categories based on their modes of action, and a growing number of HIV strains are becoming drug resistant.

HIV resistance to one drug can lead to resistance to other drugs in the same class, a phenomenon known as crossresistance.

You want a lot of drug classes because multi-drug resistant viruses are starting to show up more and more, Kirchhoff said. In at least some industrialized countries, it is already a severe problem.

Geisinger launches extensive study on obesity and related liver problem

Mon, 16 Apr 2007 03:59:37 PST

( from http://www.rxpgnews.com ) DANVILLE, PA. - Relying on one of the largest collections of liver tissue samples ever acquired by a single organization, Geisinger Health System researchers have embarked on a massive study of one of the fastest growing liver problems.

Nonalcoholic fatty liver disease starts with the accumulation of fat on the liver, which leads to inflammation and scarring. It can progress to the point of permanent liver damage and lead to the potentially fatal cirrhosis. If the damage becomes too great, a liver transplant may be needed. Linked to America's increasing obesity problem, doctors have predicted a steep increase in the coming years.

The disease is asymptomatic in its early stages and many people don't know they have it initially. Geisinger Health System is leveraging several key system resources in an effort to develop a simple blood test to diagnose the disease. Early detection would likely help patients better manage the disease and could even save lives. Yet a major obstacle needs to be cleared first.

Right now, the only way to definitely diagnose the disease is through a liver biopsy, where a needle is inserted into the skin and liver tissue is collected. However, biopsies can pose health risks because of the potential for bleeding from the liver or for infection.

The goal is to develop a noninvasive blood test for the disease and then bring it to market so other physicians can use it, said Geisinger staff scientist Glenn S. Gerhard, MD.

To that end, Geisinger is uniquely positioned to develop such a test because of the array of resources the system has at its disposal.

Geisinger has collected more than 600 liver tissue and blood samples donated from patients who have undergone bariatric weight loss surgery. That work has been made possible through collaboration among Geisinger researchers, clinicians and surgeons.

Thanks to the very high participation rate of patients, the size of Geisinger's liver tissue and blood sample collection is among the largest of its kind in a research setting, Geisinger officials said.

Nonalcoholic fatty liver disease hasn't really been studied, in part, because investigators can't get access to samples, Gerhard said. Most people don't realize they have this diseasethey're walking time bombs.

The federal government estimates that the disease affects 2 to 5 percent of Americans, while another 10 to 20 percent of the population has fat in their liver, but no inflammation or liver damage.

As part of the project, investigators from the Weis Center for Research, the Center for Health Research, the Center for Nutrition and Weight Management, and the Department of Surgery are combing through Geisinger's $80 million Electronic Health Record to learn why some obese and overweight people develop nonalcoholic fatty liver disease and similar problems.

We need to look at what causes this disease and how we can treat it, Gerhard said. Our patients are graciously giving us the means to answer those questions.

Aside from the personal health toll, there's also a financial cost. For instance, a liver transplant costs about $370,000 on average, while bariatric surgery costs $40,000 in Pennsylvania, depending on the negotiated rate with the person's health plan. (These costs are not what the patient pays, but the average costs for the provider.)

Mailman School of Public Health researchers report blood DNA can be early predictor of liver cancer

Sun, 15 Apr 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Researchers at Columbia Universitys Mailman School of Public Health have discovered a means for early detection of liver cancer. Using DNA isolated from serum samples as a baseline biomarker, the scientists examined changes in certain tumor suppressor genes that have been associated with the development of liver carcinomas. This is the first study to prospectively examine potential biomarkers for early detection of liver cancer in high-risk populations, including those with chronic hepatitis B and C virus infections.

Since most hepatocellular or liver carcinomas (HCC) are diagnosed at an advanced and usually fatal stage, the development of screening methods for early detection is critical. HCC is one of the most common and rapidly fatal human malignancies. Worldwide, the almost 500,000 new cases and nearly equivalent number of fatalities illustrates the lack of effective therapeutic alternatives for this disease.

The Mailman School researchers and colleagues studied the blood of patients enrolled in a cancer screening program in Taiwan, who provided repeated blood samples prior to diagnosis. A total of 12,000 males and over 11,900 females recruited in 1991-2 are being followed. Screenings performed by the team of Mailman School scientists found changes associated with cancer in serum DNA, presumably released from the tumor, one to nine years before actual clinical diagnosis.

Certain clinical risk factors such as age and hepatitis B and C virus infections, are well documented risk factors for the development of HCC. According to the study findings, these factors coupled with smoking and alcohol status, and alterations found in this study in serum DNA, resulted in an overall predictive accuracy of 89% for detection of HCC.

These are extremely encouraging findings, says Regina Santella, PhD, professor of Environmental Health Sciences at the Mailman School of Public Health, director of the Columbias NIEHS Center for Environmental Health in Northern Manhattan, and principal investigator on the research. Having the tools to identify hepatocellular carcinoma at earlier stages, is truly a breakthrough for addressing the challenges that result from this highly lethal form of cancer.

Dr. Santella and the team of researchers previously found that several environmental factors including aflatoxin B1, a dietary mold contaminant sometimes found in peanuts and corn; polycyclic aromatic hydrocarbons, ubiquitous environmental contaminants; and 4-aminobiphenyl, a carcinogen found in cigarette smoke, are also associated with the development of HCC. While HCC incidence is highest in East Asia and Sub-Saharan Africa, it is also increasing in the U.S primarily as a result of HCV infection.

We are not only very excited about what this means in terms of early detection for hepatocellular cancer but optimistic about how it could also be applied to other cancers, observes Dr. Santella.

The full study findings are published in the April 15, 2007 issue of Clinical Cancer Research.

Major gene study uncovers secrets of leukemia

Wed, 07 Mar 2007 04:59:37 PST

( from http://www.rxpgnews.com ) Investigators at St. Jude Children's Research Hospital have discovered previously unsuspected mutations that contribute to the formation of pediatric acute lymphoblastic leukemia (ALL), the most common cancer in children. The discovery not only suggests novel methods for treating pediatric ALL, but also provides a roadmap for the identification of unsuspected mutations in adult cancers.

ALL is a tumor in which immature white blood cells that normally develop into immune system cells, called B or T lymphocytes, instead multiply rapidly and overwhelm the normal blood cells the body needs to survive.

The St. Jude team used microarrays, postage-stamp-sized chips that contain DNA fragments, which allowed researchers to investigate more than 350,000 markers called single nucleotide polymorphisms. Single nucleotide polymorphisms are individual variations in the DNA that are spaced across the human chromosomes. Single nucleotide polymorphisms function as flags for researchers, allowing them to detect specific deletions of DNA in a gene or increases in the number of specific genes at a level of detail that was previously unattainable. The St. Jude group used this approach to analyze leukemia samples from 242 pediatric patients with ALL. This identified an unexpectedly high frequency of mutations involving genes that function as master regulators of normal B-cell development and differentiation.

A report on this work appears in the March 7 online edition of Nature.

The results of our study demonstrate that it is possible to significantly speed the identification of the genetic lesions that are the underlying cause of not only ALL, but also many other cancers, including those affecting adults, said James Downing, M.D., scientific director and chair of the Pathology department at St. Jude. He is senior author of the paper.

The study found that 40 percent of patients with ALL had deletions or mutations in one of three so-called master genes that control the normal differentiation of immature progenitor cells into mature B lymphocytes.

The researchers found that the PAX5 gene was most frequently mutatedaltered in about 30 percent of patients. These mutations reduced the level of PAX5 protein in leukemic cells or resulted in the formation of PAX5 protein with defective function. Mutations were also found in other genes with important roles in B-cell differentiation including EBF1 and Ikaros.

Although the identification of such a high frequency of mutations in this pathway was surprising, it is important to note that the approach used provides a lower limit of the true frequency of these mutations, since not every gene in this pathway could be accurately analyzed using this methodology, Downing said.

The mutations identified in PAX5, EBF and Ikaros are likely to directly contribute to this block in normal lymphocyte differentiation, according to Downing. These genes encode proteins called transcription factors, which orchestrate the expression of a large number of other genes involved in B cell development. Together these genes coordinate the complex changes needed to induce progenitor cells to differentiate into B lymphocytes. In ALL, the leukemic cells fail to differentiate normally and instead remain blocked at an immature stage of development. Locked in this state, the leukemic cells continue to proliferate, and this continual growth of leukemic cells eventually kills the child.

The new insights into the differentiation of B cells are extremely valuable, said Ching-Hon Pui, M.D., chair of the Oncology department and American Cancer Society Professor at St. Jude. Pui co-authored the paper. The more we learn about why progenitor cells get stuck in the primitive, cancerous stage, the more likely we'll be able to design new therapies that eliminate them. That could help us continue our successful efforts to increase the survival rate of ALL.

One potential strategy for eliminating leukemic cells would take advantage of the discovery that mutations in the B-cell differentiation pathway are predicted to prevent progenitors from changing into normally functioning lymphocytes. Normally, the body eliminates differentiated B lymphocytes that have failed to assemble the right genes to make effective antibodies against the specific target they are supposed to attack. However, if these defective B lymphocytes do not differentiate because of the mutations, the body will not recognize them as defective immune cells and destroy them. Instead, these undifferentiated cells continue to multiply, causing ALL.

If we could design a drug that bypasses the roadblock to differentiation, we could push these cells to become fully mature B lymphocytes, Downing said. And then the body would recognize them as defective B lymphocytes and destroy them.

Leukemia drug turns mini-molecules up, cancer genes down

Thu, 01 Mar 2007 04:59:37 PST

( from http://www.rxpgnews.com ) COLUMBUS , Ohio New research shows that a form of vitamin A used to treat acute promyelocytic leukemia induces changes in an unusual class of small molecules called microRNAs (miRNAs) in the leukemic cells.

The study also shows that three of these miRNAs inhibit the action of two genes important for cancer development, helping to explain how the drug works.

The drug is called all-trans-retinoic acid (ATRA) and it is considered the gold standard for treating the disease.

The study showed that ATRA raises the levels of three particular miRNAs in leukemia cells and that this rise coincides with a fall in activity of two important cancer-causing genes. The three are identified as miRNA-15b, miRNA-16-1 and let-7.

Two of these, miRNA-15b and miRNA-16-1, reduce the activity of the Bcl-2 gene, which is over-active in many kinds of cancer. The protein produced by this gene blocks the normal process of cell death and helps keep cancer cells alive long after they should have died.

The remaining miRNA molecule, let-7, lowered the activity of the Ras oncogene, an important cancer-causing gene. (Oncogenes are normal genes that when mutated lead to cancer.)

Researchers at the Ohio State University Comprehensive Cancer Center led the study, which was published in a recent issue of the journal Oncogene.

The findings are important because they tell us that some miRNAs switch off genes that promote cancer, says first author Ramiro Garzon, a hematologist and oncologist at Ohio State's James Cancer Hospital and Solove Research Institute.

Acute promyelocytic leukemia occurs when cells that give rise to a form of white blood cell become stuck at an immature stage. The immature cells accumulate until they crowd out healthy white cells in the blood and bone marrow.

Our findings suggest that these three miRNAs help re-program the malignant cells to a more normal state, Garzon says, and that they are also important for normal differentiation.

In this study, the researchers used leukemia cells grown in the laboratory and cells donated by patients to study how the drug ATRA affects miRNA levels and how those changes affect the cells.

The investigators exposed the leukemia cells to the drug for up to 96 hours, causing the cells to mature. The treatment increased the level of eight miRNAs and a drop in one compared with untreated cells.

Of these, the researchers focused on miRNA-15b and miRNA-16-1, which are known to regulate the activity of the Bcl-2 gene. They found that high levels of the two miRNAs were associated with low Bcl-2 activity.

Next, they showed that the two miRNAs actually caused the drop in Bcl-2 activity. They did this by adding additional amounts of the two miRNAs to leukemia cells not treated with ATRA. Restoring the miRNAs caused a strong drop in Bcl-2 levels.

The researchers then looked at miRNA let-7, a known regulator of the Ras oncogene, and likewise found that high levels of this miRNA were associated with low Ras activity.

They established a cause and effect relationship as before, by adding additional let-7 to untreated leukemia cells.

Overall, Garzon says, our findings show that ATRA induces the expression of these three miRNAs, and through them regulates genes that need to be silenced for the cell to differentiate.

Putting an old drug to a new use

Mon, 12 Feb 2007 04:59:37 PST

( from http://www.rxpgnews.com ) We all know that iron deficiencies are dangerous, but also too much iron is bad for our health. Our body stores excess iron in various tissues, where it can lead to organ failure and even death if not treated before irreversible damage has occurred. Researchers from the Innsbruck Medical University, the University of Heidelberg, Germany, and the European Molecular Biology Laboratory (EMBL) now made a surprising discovery that may lead to new therapeutic approaches to treating such disorders. In this week's online issue of the journal Nature Medicine they report that a compound that was frequently used to treat high blood pressure can reverse iron overload in mouse models and has the potential to treat similar conditions in humans.

Our body needs most of its iron to make red blood cells. A lack of the metal can lead to dangerous anemias, but also too much iron can be detrimental as iron promotes the formation of toxic radicals leading to tissue damage. Iron overload is the consequence of one of the most common genetic disorders in Europe, hereditary hemochromatosis, which affects about one in 300 Europeans. Excess iron also accumulates after repeated blood transfusions and can cause organ failure over time. Günter Weiss, a clinician from the Innsbruck Medical University, and his collaborators from the University of Heidelberg and EMBL now found out that nifedipine, a substance commonly used to control blood pressure, helps the body deal with too much iron.

We observed in mice with iron overload that nifedipine helps mobilise iron from stores in the liver and enhances its excretion into the urine, says Weiss, an EMBL alumnus who now heads a lab at the Department for General Internal Medicine at the University of Innsbruck. These effects make nifedipine a promising candidate for a new drug to treat hereditary hemochromatosis and other iron overload disorders.

Combining electrophysiology, cell biology and molecular investigations, Weiss and his collaborators found out that nifedipine exerts its effect on iron metabolism by acting on a molecule called DMT-1. DMT-1 transports iron across cell membranes. This transport is increased ten to 100-fold by nifedipine, but how exactly the compound brings about its effect is still unknown. Nifedipine is known to block membrane channels that control Ca2+ influx into cells, but if it exerts its effect on iron transport indirectly by changing Ca2+ levels in the cell or by binding directly to DMT-1 in liver and kidney still needs to be determined.

Understanding the exact molecular mechanism underlying nifedipine's effect on iron transport would be a big step towards developing it into an effective therapy that can be used on patients, says Martina Muckenthaler, an EMBL alumna who is now at the University of Heidelberg. Taking nifedipine from bench to bedside could be quicker than for other substances, because it has already been used for years to treat patients with high blood pressure. From this we know the drug and its side-effects.

An important step on the way from laboratory to clinic will be targeted pharmacological modifications of the compound to separate nifedipine's effect on iron metabolism from its established action on blood pressure.

Our discovery is an excellent example of how the combination of basic research and the expertise of clinicians can yield results that are relevant to medicine and could ultimately benefit patients, says Matthias Hentze, Associate Director of EMBL and co-author of the study. In the Molecular Medicine Partnership Unit (MMPU) between EMBL and the Medical Faculty of Heidelberg University we integrate molecular biology and clinical medicine to gain an understanding of the basis of human diseases. It is very gratifying to see how the collaboration with EMBL alumni and the MMPU yields exciting progress in medicine.

New blood thinner studied for patients with leg and lung clots

Mon, 12 Feb 2007 04:59:37 PST

( from http://www.rxpgnews.com ) A new oral blood thinner is being compared to an old standby to see if it works as well and is easier to manage long term, researchers say.

Other medications and even diet can dramatically impact blood levels of warfarin, or Coumadin, increasing the risk of bleeding or clotting, says Dr. James R. Gossage Jr., pulmonologist at the Medical College of Georgia.

You eat too much broccoli or spinach and it sends your levels out of whack; almost every other medicine affects Coumadin, says Dr. Gossage, who calls warfarin a high-maintenance medication.

Unfortunately, many people, including those with a clot in their legs called deep vein thrombosis or their lungs called pulmonary embolism may need it for months or years, Dr. Gossage says.

An international study of 2,000 adult patients with these problems will determine if dabigatran, manufactured by Boehringer Ingelheim, a Germany based pharmaceutical company, makes long-term clot control easier.

Deep vein thrombosis or a pulmonary embolism generally are treated with intravenous blood thinners; really big clots also may need a clot-buster like tPA, says Dr. Gossage, a principal investigator on the study. Blood thinners keep the clot from growing while the body's endogenous clot-busters eliminate it. That can take a while, especially when clots measure several inches or more, so patients also need a blood thinner they can take at home for months or longer, depending on their diagnosis. When patients start taking warfarin, they need daily, then weekly monitoring until levels stabilize, then at least monthly checks as long as they take the drug, he says.

At the right level, the drug works well, inhibiting vitamin K, which is involved in the synthesis of several coagulation factors and found in abundance in green leafy vegetables, vegetable oils, cranberries and even licorice. It's very uncommon for a person taking warfarin to have a blood clot if his or her level is in the proper range, Dr. Gossage says.

The trouble is that a big helping of collard greens, for example, can dramatically reduce the drug's effectiveness and increase clotting risk. Patients are encouraged to eat stable diets, but even so, Dr. Gossage has patients whose blood levels, charted on a graph, look like a roller coaster.

Many common over-the-counter and prescription drugs contribute to the problem by affecting the liver mechanism that determines how much and how fast warfarin is eliminated, Dr. Gossage says. We are looking for medicines that are more like most others we take; they are not affected by our diet and by every other pill we take, he says.

Previous work with dabigatran indicates it could fit the bill. It works early in the clotting process, inhibiting thrombin, one of the main clotting factors. When you cut yourself, platelets start sticking, thrombin comes in and activates the whole cascade of coagulation factors that form a clot. Warfarin works later in the cascade, so getting something that works earlier may be even better, says Dr. Gossage.

Hopefully we won't have these big swings in the level and people won't have these periods where they are at great risk, says Dr. Gossage. I can give you a dose and it's going to work the same way whether you are eating broccoli or spinach or taking penicillin or some other antibiotic

This phase III study randomizes patients to warfarin or dabigatran and closely follows them for 18 months. If dabigatran appears ineffective, patients are moved to more standard therapy. All blood thinners can have the side effect of bleeding, he notes.

Immobility, blood vessel injury and anything that increases blood's tendency to clot, called hypercoagulability, are risk factors for clots. Most people think you have to have at least two of those, says Dr. Gossage.

Long plane rides or hospital stays can put patients at risk ; trauma, even an intravenous line needed for medicine, can injure vessels. A host of things contribute to hypercoagulability, including birth control pills, hormone replacement therapy, age, and perhaps smoking and obesity. Cancer, particularly solid tumors, is a big risk factor for clotting. Ironically its primary treatments, chemotherapy and radiation therapy, can narrow blood vessels and add to the risk.

An estimated 600,000 pulmonary embolisms occur each year in the United States and deep vein thrombosis is about twice as common. Many patients have both because a clot in the leg has nearly a straight shot to the lungs through the venous system.

Study finds endoscopic brain surgery pioneered in Pittsburgh effective in children with tumors

Thu, 08 Feb 2007 04:59:37 PST

( from http://www.rxpgnews.com ) PITTSBURGH Feb. 8, 2007 -- A first-of-its-kind study published in the February issue of the Journal of Neurosurgery: Pediatrics suggests endoscopic brain surgery, pioneered by surgeons at the University of Pittsburgh Medical Center, has the potential to be safer and often more effective than conventional surgery in children with life-threatening conditions.

This minimally invasive approach -- known as the Expanded Endonasal Approach (EEA) -- was pioneered and refined in adults over the last decade by surgeons at UPMC and the University of Pittsburgh School of Medicine and is now a viable option for tumors in children and in many instances for tumors that were once deemed to be inoperable.

Collaborating with colleagues at Children's Hospital of Pittsburgh of UPMC, surgeons have recently expanded its use to include children and have performed EEA on more than 50 pediatric patients, more than have been reported by any other center in the world.

In a retrospective study of the first 25 pediatric patients -- ranging in age from 3 to 18 -- who underwent EEA between January 1999 and August 2005 at Children's and UPMC, the surgeons found the approach may be safer than conventional surgical techniques in well-selected cases. More importantly, in certain cases it may offer an option to patients who otherwise would have no surgical alternative.

The traditional approach for removing benign or malignant tumors at the skull base has involved craniofacial approaches that require peeling away skin and soft tissue, as well as musculature over the facial elements. Often, this approach can be cosmetically disfiguring but may also involve the consequences of manipulating important neural tissue such as the optic nerve and the carotid artery. These issues are even more important in children because disrupting their facial plates, where their growth centers are, may have long-term implications. EEA involves using narrow scopes and surgical tools -- often developed by the surgeons themselves -- inserted through the nasal passage to remove tumors as large as baseballs.

This review of our first 25 pediatric cases is very encouraging in that we were able to remove the tumor in each and every case with minimal complications, said lead author Amin Kassam, MD, associate professor and interim chair, Department of Neurological Surgery at the University of Pittsburgh School of Medicine and UPMC. Minimally invasive endonasal surgery has many potential benefits over traditional surgery. Using these techniques we've developed, we are able to remove very large tumors without incisions and often with less risk of causing brain or nerve tissue damage as we are taking a more direct route to the tumor. Therefore, recovery may be faster with a shorter hospital stay.

Removal of the tumor was achieved in all patients in the study, and none suffered neurological damage, vascular injury or central nervous system infection, according to Dr. Kassam.

Gene knockouts reveal FoxOs' vital functions in cancer defense, health of stem cells

Thu, 25 Jan 2007 04:59:37 PST

( from http://www.rxpgnews.com ) BOSTONIn an elegant, multiple-gene knockout experiment, a team of Boston scientists has discovered that a trio of molecules, called FoxOs, are fundamentally critical in preventing some cancers, maintaining blood vessel stability, and in keeping blood-forming stem cells healthy.

The discoveries reveal potential new targets for cancer drugs and could further research on stem-cell based therapies for degenerative diseases, said the researchers at Dana-Farber Cancer Institute and Brigham and Women's Hospital, who are jointly publishing two reports in the Jan. 26 issue of Cell.

The researchers at Brigham and Women's found that mice engineered to lack genes for the FoxO1, FoxO3, and FoxO4 molecules had serious blood abnormalities. Without the FoxO gene-regulating molecules, the rodents' blood stem cells master cells that give birth to working blood cells while also renewing themselves ¬ divided too fast and burned out, said Gary Gilliland, MD, PhD, who is senior co-author of the two papers with Ronald DePinho, MD, of Dana-Farber.

If we didn't have these FoxO proteins to keep stem cells healthy, it is likely that we wouldn't be able to live for more than a few months, said Gilliland. Lead author of the stem cell paper is Zuzana Tothova, an MD-PhD student at Harvard Medical School working in Gilliland's lab.

In the companion paper, lead author Ji-Hye Paik, PhD, of Dana-Farber and colleagues from the DePinho lab report that the three FoxO molecules, known as transcription factors, normally function as tumor suppressors that override maverick cells threatening to grow too fast and form tumors. When FoxOs are eliminated, it may allow cancer to develop. The mice lacking FoxO proteins developed two types of cancer thymic lymphoma and hemangiomas, tumors caused by the uncontrolled growth of endothelial cells that form blood vessels.

DePinho's group identified two genes regulated by the FoxO molecules that might serve as points of attack for new cancer drugs.

This is going to expand our opportunities for drug discovery in what, arguably, is the most important pathway in cancer, said DePinho.

The FoxO1, O3, and O4 transcription factors regulate genes in the complicated cell signaling network known as PI3K-AKT, or simply PI3K. Scientists have discovered that PI3K signaling is intimately involved in fundamental cell processes such as metabolism, aging, and protecting the body against cancer. The PI3K circuit has been found to be disrupted in many forms of cancer, making it a hot topic in cancer research labs and drug company boardrooms.

Based on previous work in his laboratory, DePinho, working with Diego Castrillon, MD, PhD, (who is now at the University of Texas Southwest Medical Center), determined that the three FoxOs had redundant, overlapping functions: To uncover those functions, it would be necessary to engineer mice that lacked all three FoxO transcription factors.

To make the task even more difficult, mice lacking FoxO1 die in the womb. DePinho and Castrillon had to engineer mice whose FoxO genes would function normally during development, but would contain a mechanism allowing them to be switched off in adulthood at the scientists' will. It took DePinho's team about two years to get the system to work, which Gilliland hailed as a true tour-de-force of mouse genetics.

Mutant FoxOs have been implicated in leukemia, and for Gilliland, who studies blood cancers, the triple-knockout mice were an opportunity to dig deeper into the issue.

Unexpectedly, however, deletion of FoxO1, 03, and 04 caused blood cell abnormalities but not outright leukemia. A bigger surprise was that the blood stem cells were really in trouble without those transcription factors, he said, dividing too rapidly, losing their ability to renew themselves, and dying out. This means that FoxOs contribute to the longevity of stem cells, and if you take them away, you dramatically shorten stem cells' lives.

Looking further, Gilliland and his colleagues found that the damage was being caused by reactive oxygen species, or ROS, a toxic byproduct of cells' energy production. When the mice were treated with anti-oxidants, the stem cells regained health and longevity. So, the FoxOs are acting as natural antioxidants, said Gilliland. Conceivably, he added, drugs could be developed to manipulate the FoxO pathway and extend the lives of stem cells beyond their natural limits, which could aid their use in repairing diseased body tissues.

The results raised an important question: If the PI3K pathway and the FoxO factors are so prominent in cancer, why did the knockout mice lacking FoxO tumor suppressors not develop more types of cancers? It turns out that the cancer-causing pathway operates differently in different types of body tissues. For example, blood vessel cells in the mice's livers became malignant, but the same cells in the lung did not.

There is a remarkable context-specific aspect to this pathway, DePinho said. It is wired and regulated differently the same types of cells residing in different types of tissues. This is important knowledge, he said, for further research and for testing novel drugs in the right types of cancers.

DePinho and Gilliland emphasized the importance of the collaboration between Brigham and Women's and Dana-Farber, both of which are affiliated with Harvard Medical School, in producing the results reported in Cell.

Einstein's tea leaves inspire new blood separation technique

Tue, 16 Jan 2007 04:59:37 PST

( from http://www.rxpgnews.com ) Scientists at Monash University in Australia have developed a process for rapidly and efficiently separating blood plasma at the microscopic level without any moving parts, potentially allowing doctors to do blood tests without sending samples to a laboratory. The new method uses the same principle that causes tea leaves to accumulate at the center of the bottom in a stirred teacup, a phenomenon first explained by Einstein in the 1920s.

The research was done by Drs. Dian R. Arifin, Leslie Y. Yeo and James R. Friend, of Monash University's Micro/Nanophysics Research Laboratory in the Department of Mechanical Engineering. The researchers' findings are published in the current issue of the new open-access journal Biomicrofluidics (http://bmf.aip.org).

Separating blood plasma from red blood cells, proteins and other microscopic particles is an essential step in many common medical tests, including those for cholesterol levels, drugs in athletes, blood types in donors and glucose levels in diabetics. Current testing requires samples to be taken in a doctor's office and sent off to a laboratory and analyzed with a large centrifuge, a process that can take several days.

In the new method, a tiny amount of blood enters a fluid chamber, and a needle tip is placed close to the surface of the blood at an angle. A voltage is applied to the needle, generating ions around its tip that repel the oppositely charged ions close to it. This creates an airflow known as ionic wind that sweeps across the surface of the blood, causing it to circulate. The microscopic particles in the blood travel in a downward spiral because of the needle's angle relative to the surface.

When the fluid begins to circulate, one might intuitively expect the microscopic particles such as red blood cells would be pulled to the outside wall of the chamber owing to centrifugal force. But because of a phenomenon called the tea leaf paradox, the particles are instead pulled inward near the bottom of the chamber. Einstein proposed an explanation to this phenomenon in 1926 when he noticed that tea leaves collected at the center of the bottom of a stirred teacup instead of being expelled outward.

The tiny chamber of blood, like the teacup, is a cylinder of liquid that is rotated at the top while the base remains stationary. To satisfy a zero-velocity condition at the base, an inward force near the bottom of the liquid is generated, suppressing the centrifugal force there. Thus the microscopic particles spiral inward toward the bottom of the chamber like a miniature tornado, leaving a clear layer of plasma above.

Yeo anticipates the technology could be incorporated into a chip roughly the size of a credit card. He said the devices could be produced cheaply with current manufacturing techniques -- about 50 cents per chip -- but could still be five to 10 years away from mass production.

Role for proteomics in identifying hematologic malignancies

Thu, 11 Jan 2007 04:59:37 PST

( from http://www.rxpgnews.com ) BOSTON Scientists have identified a set of biomarkers that could help clinicians identify a group of hematologic malignancies known as myelodysplastic syndromes (MDS), which affect approximately 300,000 individuals worldwide and often progress to acute myeloid leukemia.

Reported in the advance issue of the Proceedings of the National Academy of Sciences (which appears on-line the week of January 8) the findings point to a possible new diagnostic method for these malignancies, which occur when blood cells remain in an immature stage within the bone marrow and never sufficiently develop into the mature cells necessary for proper hematologic functioning. The study was led by researchers at Beth Israel Deaconess Medical Center (BIDMC) and Heinrich Heine University in Duesseldorf, Germany.

Currently, a bone marrow biopsy is the only definitive means available to diagnose MDS, explains senior author Towia Libermann, PhD, Director of the Genomics Center at BIDMC and director of the Dana-Farber/Harvard Cancer Center Cancer Proteomics Core. And since this group of malignancies primarily affects elderly patients, such a procedure is particularly arduous and sometimes impossible.

Therefore, first author Manuel Aivado, MD, PhD, a member of the Libermann laboratory and Lecturer in Medicine at Harvard Medical School (HMS), devised a clinical study to test whether serum proteomic profiling might be used to identify biomarkers for MDS.

The large-scale study of proteins -- including their expression, modification, composition, structure and function -- the field of proteomics is proving instrumental in the identification of molecular biomarkers, such as those that indicate a particular disease, according to Libermann, who is also Associate Professor of Medicine at HMS.

Aivado and Libermann used a combination of two technologies -- protein fractionation and mass spectrometry to create proteome profiles from the serum of 218 patients (representing clinical trial participants from both the MDS Study Group in Duesseldorf and from BIDMC). Through these profiles, the investigators were able to successfully distinguish between cases of MDS, healthy control subjects and cases of non-MDS-related cytopenias (blood cell disorders).

Rather than uncovering a single biomarker, we were able to identify a protein signature [or spectrum], which reproducibly identified MDS patients among three separate and distinct patient cohorts, explains Libermann. Since many patients with autoimmune disorders are treated with cytotoxic drugs such as azathioprine or methotrexate, they become cytopenic and may be suspected of having MDS. By using this new profile, the need for bone marrow biopsies might also be reduced among this patient population.

In the second part of the study, the authors identified two separate chemokines CXCL4 and CXCL7 the first such molecular biomarkers for advanced MDS.

Proteomic profiling, using in-depth mass spectrometry, follows in the footsteps of genomics and represents a critical next step in understanding the pathophysiology of diseases, says Libermann. This study demonstrated for the first time that proteomic profiling can be used for biomarker discovery and diagnostic evaluation of hematologic malignancies, an important step in refining the diagnosis and, eventually, the treatment of this devastating malignancy.

Inflammatory genes linked to salt-sensitive hypertension

Wed, 27 Dec 2006 04:59:37 PST

( from http://www.rxpgnews.com ) One key to your high blood pressure might just be your inflammatory genes.

It may sound odd but mounting evidence suggests that inflammation, a part of the immune response implicated in diseases such as cancer, Alzheimer's and diabetes, may also help translate stress into high blood pressure.

There is a concept that hypertension is an inflammatory condition, says Dr. Haidong Zhu, molecular geneticist at the Medical College of Georgia. She's among the scientists who believe the connection between stress, inflammation and hypertension is the kidneys' ability to release sodium.

When stress activates the sympathetic nervous system (the fight-or-flight mechanism), the body increases production of interleukin 6, a pro-inflammatory factor, which ultimately leads to production of other inflammatory factors such as C reactive protein.

Stress also prompts the body to hold onto sodium to help temporarily raise blood pressure so you can deal with the situation, says Dr. Gregory Harshfield, director of MCG's Georgia Prevention Institute and an expert on what happens when the body doesn't let go afterward. It's called impaired stress-induced pressure natriuresis, which Dr. Harshfield has documented in young, healthy teens.

Dr. Zhu is now leading research to see if the reactions are related if sodium handling goes awry under stress because the teens have mutations in four sets of stress-activated inflammatory genes: interleukin 6, interleukin 6 receptor, cytokine signal transducer and C-reactive protein.

Our long-term goal is to be able to identify a subgroup of individuals with a certain genetic profile that has an increased risk of developing high blood pressure in a stressful environment, says Dr. Zhu, who recently received a two-year, $300,000 grant from the National Heart, Lung and Blood Institute

If she's right, these individuals could likely benefit from targeted therapy that might include a low-salt diet, physical activity and maybe anti-inflammatory drugs, says Dr. Zhu. Nearly one in three Americans is hypertensive and more than half have salt-sensitive hypertension, she notes.

Cardiovascular diseases, including hypertension, are complex diseases with a lot of gene-environment interaction, and stress is now a part of people's daily lives, she says.

We have found hypertension associated with inflammation and we have found stress associated with hypertension. There is evidence suggesting that in salt-sensitive hypertension there are increased levels of inflammation factors such as interleukin 6 and C-reactive protein, Dr. Zhu says. Even high-normal blood pressure is associated with a pro-inflammatory condition.

Additionally, animal studies have shown salt-sensitive hypertension induced by the powerful blood-vessel constrictor angiotensin 2 can be prevented by drugs that suppress the immune response and consequent inflammation.

There are many pieces of evidence and we are trying to link them together, says Dr. Zhu.

Her research team is looking at genetic variations of four inflammatory genes in 500 15- to19-year-olds with normal blood pressure. The teens, already enrolled in studies at MCG's Georgia Prevention Institute measuring the effects of stress on the cardiovascular system, were put on a diet for four days to regulate sodium intake, then came to the GPI where they rested for an hour, played a three-dimensional, racing video game for an hour, then rested for an hour. Blood and urine samples were taken throughout the period. For this study, researchers will also collect DNA material from the mouths of as many parents as possible to confirm their findings in the children.

Pilot data indicate that black teens with normal blood pressure and a certain variation of the interleukin 6 gene have significantly reduced sodium excretion in the urine following stress. Researchers have further implicated the inflammatory factor's role in blood pressure regulation by showing that following stress, circulating levels of interleukin 6 rise and are still up an hour after the stressor is gone.

Dr. Zhu suspects that even without the genetic variations, inflammation affects blood pressure under stress, so she'll be looking at its impact alone and in concert with the mutations.

We believe this research will provide novel insight into the interactions between stress, inflammation and genetics and their contribution to the pathogenesis of essential hypertension, she says.

Dengue and other hemorrhagic fevers: Towards a first potential treatment

Fri, 22 Dec 2006 04:59:37 PST

( from http://www.rxpgnews.com ) Globally, 60 to 100 million people are hit by Dengue, a viral disease transmitted by mosquitoes of the genus Aedes. The most severe form of this disease, which causes blood loss, can lead to a fatal shock-like state (Dengue Shock Syndrome) with or without associated haemorrhage, and is currently increasing in tropical countries. The pathological mechanisms of Dengue are still unknown and it has not been possible to produce any treatment or vaccine. The only current prevention method is vector control.

This context brought IRD immunology and virology specialists and their research partners (1) to focus on these little-known biological mechanisms that are set into operation on infection by the virus, responsible for increasing the permeability of vascular wall endothelial cells and hence blood loss. The researchers found evidence of the role played by particular enzymes, metalloproteinases, in the occurrence of this leakage.

Low concentrations of these enzymes are present naturally in the organism, and they are involved in the reconfiguration of organ tissues during human embryonic development or tissue repair, but also in the development of certain cancers. They attack specifically the intercellular cement that binds the vascular walls. The research team demonstrated, in vitro, that Dengue-virus infection of certain targeted cells of the immune system (the dendritic cells) triggered an inflammatory reaction, stimulating these same target cells to overproduce metalloproteinases (gelatinolytic matrix metalloproteinases MMP-9) and secrete them into the cellular supernatant (2). The quantity of enzyme produced therefore appears to be proportional to the concentration of viral particles present.

To verify that the metalloproteinases were the only agents responsible for the increased vascular permeability, the researchers performed tests on cell cultures of endothelial tissue, of the same type as that of the blood vessel walls. The supernatant of the infected cells, consequently containing the metalloproteinases, were brought into contact with this tissue. The vascular permeability, estimated by the quantity of supernatant passing through the endothelial tissue, appeared significantly higher. Conversely, the natural permeability of the tissue was restored when a specific inhibitor of these enzymes (SB-3CT) was added to the supernatant. Fluorescence microscope images of proteins of the intercellular cement, subjected to the action of the same supernatant, revealed that metalloproteinases act on the blood vessel walls like biological scissors: they destroy the protein bonds which maintain cell adhesion and hence keep them together. This action was, however, neutralized by specific metalloproteinase inhibitors.

A series of in vivo experiments following the same principle confirmed these hypotheses. A mouse model with blood circulatory system coloured blue was injected with supernatant containing these enzymes, on their own or in the presence of their inhibitor. This procedure not only reproduced the mechanisms of vascular rupture that originated blood leakage, but also and more significantly succeeded in neutralizing them.

This research sheds completely new light on Dengue's pathological strategy. The results provide a way of explaining the major role played by direct action of metalloproteinases on blood-vessel walls. The overproduction of these enzymes, linked to the viral infection and the inflammatory reaction it triggers, does not however appear to be restricted to Dengue. The mechanism described here could provide a molecular basis for a new model of the action of other known haemorrhage-inducing viruses, such as Ebola, Marburg, or Hanta. New lines of therapeutic research against these pathologies, for which no treatment yet exists, can now be envisaged. Indeed, clinical trials on Dengue are currently in preparation.

How blood flow dictates gene expression

Wed, 20 Dec 2006 04:59:37 PST

( from http://www.rxpgnews.com ) (PHILADELPHIA) -- Researchers at the University of Pennsylvania School of Medicine have pinpointed a key regulatory protein that translates blood flow into gene expression. The investigators showed that in a model of mouse embryonic development a transcription factor called Klf2, which resides in cells that line blood vessels, is activated by rapid, pulsed blood flow, as reported in the December issue of Developmental Cell. Understanding Klf2's role in blood vessel and muscle biology could help with fighting atherosclerosis.

We always knew that there had to be this line of communication from the vessel lining, or endothelium, to the smooth muscles, which never sees a blood cell, says senior author Mark Kahn, MD, Associate Professor of Medicine. That's where Klf2 fits: This is the first time, at a molecular level, that this chain has been demonstrated in an animal.

Swirling eddies of blood form when vessels branch, much like when a river divides. Atherosclerosis typically forms at these sites of so-called disturbed flow as opposed to regions of rapid blood flow through the main vessels. This relationship between atherosclerosis and flow has been known for decades. More recently, tissue- culture studies have shown that Klf2 is activated by increased blood flow, or fluid sheer stress.

Indeed, in this study Kahn; first author John S. Lee, MD, PhD, Instructor in the Department of Medicine; and colleagues show that the expression of Klf2 in a developing mouse embryo mirrors events in previous tissue-culture studies. They found that Klf2 is expressed on the high-flow side of developing mitral and aortic valves in the heart of a 14-day-old embryo.

The researchers surmise that the mechanical stimulus of blood flowing in a vessel leads to the upregulation of Klf2, which either activates or represses genes that control smooth muscle tone, that is the caliber of the vessel. (Tone is governed by how much a muscle contracts or relaxes.) These genes encode proteins that are either secreted or are on the cell surface of the endothelium and so influence how smooth-muscle cells contract or relax.

The researchers suggest that when Klf2 is expressed, smooth muscle cells lining the blood vessels maintain their ability to regulate vessel tone. However, when Klf2 is genetically deleted, or knocked out, from the blood vessels of mouse embryos, they had an abnormally high cardiac output, as measured by ultrasound, while the overall structure of their blood vessels was normal. These findings implicate loss of vessel tone as the primary defect in Klf2 knockout mice.

Now that Klf2 has been established as an important regulator of blood flow in live animals and is required for the development of a healthy cardiovascular system, the next step is to elucidate the role of Klf2 in normal adult blood vessels and in the pathogenesis of vascular diseases, such as atherosclerosis.

Blood transfusions raise heart patients' infection and death risk -- especially women

Tue, 19 Dec 2006 04:59:37 PST

( from http://www.rxpgnews.com ) ANN ARBOR, Mich. -- Blood transfusions save the lives of millions of heart surgery patients and others each year. But a new study suggests that patients who receive transfusions during heart bypass surgery have a higher risk of developing potentially dangerous infections, and dying, after their operation.

In fact, this increased risk may help explain a longstanding medical mystery: why women bypass patients are more likely than men to die in the first few months after surgery. Women are more likely to receive blood during heart bypass operations, which are performed on more than 465,000 Americans each year.

The findings, from the Patient Safety Enhancement Program (PSEP) at the University of Michigan Health System, are based on data from 9,218 Michigan bypass patients. After adjusting for factors such as the urgency of the operation, those who received blood transfusions from donors were five times more likely to die within 100 days of their operation than those who did not.

The paper is published in the December issue of the American Heart Journal. It builds on a previous U-M analysis that found that a difference in infection rates accounted for the difference in death risk between men and women bypass patients.

The U-M team, with the help of Neil Blumberg, M.D., of the University of Rochester Medical Center, focused on blood transfusions as a contributing factor. Prior research has shown that recipients of stored donor blood have more post-surgical infections, and that women receive more transfusions because they tend to have lower hemoglobin concentrations.

This new study connects the dots. To the best of our knowledge, this is the first study to state that allogeneic transfusions may be the reason why women have a greater post-bypass surgery mortality risk than men, says author Mary A.M. Rogers, Ph.D., M.S., PSEP, research director and research assistant professor of internal medicine. Allogeneic is the term for blood from another person.

The authors strongly note that blood transfusions can be life-saving, and that the infections observed in this study are not likely due to contamination of the blood. Rather, they may be due to other factors, including the patient's immune response to substances such as white blood cells that are present in stored donor blood. These findings may help guide hospitals and blood banks in deciding whether to filter donated blood to reduce the levels of white blood cells. This practice is increasingly common, but not yet universal, in the United States.

The study is based on analysis of data from all Medicare beneficiaries ages 65 and older who had coronary artery bypass operations in Michigan in a single year.

The researchers performed statistical analyses that took into account the patients' blood transfusion status, their co-existing diseases, age, race, sex, and whether the bypass operation was done on an elective, urgent or emergency basis. They looked at infections and deaths that were reported during the 100 days after surgery.

In all, about 88 percent of women received an allogeneic blood transfusion during bypass surgery, compared with nearly 67 percent of men. When the researchers adjusted for other factors, women were 3.4 times as likely as men to receive blood. This gender difference was evident regardless of whether the operation was elective, urgent or emergency.

The odds of having an infection of any kind were about three times greater in patients who received allogeneic blood than in patients who did not. The more blood they received, the higher their infection risk. This dose dependent relationship strengthens the evidence that transfusions may be related to infections.

No single type of infection stood out as more common among blood recipients, which suggests a body-wide immune response issue rather than a problem, for example, at the site of the incision.

The analyses revealed that women were more likely to experience an infection than men after bypass surgery, which appeared to be due to the increased number of transfusions in women. This resulted in an increased mortality rate in women. Overall, 9 percent of women and 6 percent of the men died within 100 days of their operation.

For patients who had banked their own blood ahead of the operation and who received only their own blood, the infection risk was similar to that of patients who received no blood transfusions. Rogers notes that patients should ask their doctors regarding banking their own blood if possible, when scheduled for a bypass operation or other kind of surgery.

In addition, physicians are increasing their use of transfusion alternatives such as blood expanders, blood substitutes and blood-conserving procedures during bypass surgeries.

The results also highlight the importance of the proper use of antibiotics and infection control practices in patients hospitalized for a surgical procedure, says Rogers.

The U-M team is investigating the issue further, including a new study funded by Blue Cross Blue Shield of Michigan Foundation to extend the research into elderly patients who recently underwent bypass surgeries in Michigan.

MCG joins study of best treatment approach for narrowed kidney arteries

Tue, 19 Dec 2006 04:59:37 PST

( from http://www.rxpgnews.com ) Whether reopening narrowed kidney arteries benefits patients is a $1.7 billion question a North American study hopes to answer.

One to three million Americans, most over age 50 and with uncontrolled high blood pressure, have narrowed renal arteries that can reduce kidney function, causing even more blood pressure problems.

If you have peripheral vascular disease, if you have uncontrolled hypertension, there is a possibility you also are going to have renal artery stenosis, says Dr. Harold Szerlip, nephrologist at the Medical College of Georgia. The problem is we don't know what to do about it if you do.

Despite the lack of hard evidence about the benefit, about 50,000 times a year, cardiologists and interventional radiologists opt to use stents to reopen renal arteries with significant blockages.

The question remains whether drugs that better control blood pressure and reduce cholesterol work as well or maybe even better.

We want to know, if we open up these blockages, do we protect their kidneys in the long term? Do we improve their blood pressure control? says Dr. Deepak Kapoor, interventional cardiologist.

The MCG doctors have joined the Cardiovascular Outcomes in Renal Atherosclerotic Lesions or CORAL study to help find answers.

The National Institutes of Health-funded study, led by the University of Toledo, is enrolling 1,100 patients at nearly 100 sites in the U.S. and Canada to compare medical management versus medicines coupled with stents, stainless steel scaffolds inserted into blood vessels and best known for their use in coronary arteries.

In fact, oftentimes during routine cardiac catheterization while physicians are maneuvering through the body's major arterial highway, the aorta, from the groin area to the heart, incidental narrowing of the renal arteries are found and may be stented.

While Dr. Kapoor believes the extra step of also visualizing the renal arteries doesn't add significant risk to the procedure, the jury is still out on the risk versus benefit of stenting. We make the kidneys look beautiful, but do we help the patient? he says.

There are data out there that suggest you will help maybe 20 percent, hurt 20 percent and in 60 percent it won't do anything, says Dr. Szerlip. The question is if you are hurting as many people as you are helping, who needs this procedure? This study is designed to answer that question.

For the study, patients suspected to have renal artery disease because of uncontrolled blood pressure, mild renal failure and peripheral vascular disease, will have a renal angiography study, the gold standard for visualizing renal arteries.

A single artery will have to be at least 60 percent blocked for patients to qualify. Participants will be randomized to stenting or medical therapy. They will be followed for three to six years. Lipid lowering and anti-hypertensive medications will be provided to all patients at no costs.

I have been working with this problem for years, not knowing what to do with my patients, says Dr. Szerlip. I am thrilled there is now a multi-center, nationally funded trial to give me answers so I can tell my patients.

Based on the current evidence, we don't have an answer, echoes Dr. Kapoor. I think this is going to give us one.

Preventing graft-versus-host disease disease after bone marrow transplant -- without toxicity

Mon, 11 Dec 2006 04:59:37 PST

( from http://www.rxpgnews.com ) Unless the donor is an identical twin, patients undergoing bone-marrow transplant (also known as hematopoietic stem cell transplant, or HSCT) must first receive powerful chemotherapy drugs to wipe out their immune system and prevent their bodies from rejecting the donated cells. Research from Childrens Hospital Boston and the Dana-Farber Cancer Institute has helped demonstrate that this punishing regimen increases the risk of graft-versus-host disease (GVHD), in which the donors cells mount an immune response against the patient. But the most recent findings also suggest that the risk for GVHD can be reduced by replacing a natural antibiotic protein, known as bactericidal/permeability increasing protein (BPI), which is depleted when patients undergo chemotherapy.

Now, a multicenter study is about to test this idea in HSCT patients, using a manufactured form of BPI known as rBPI21 (XOMA Ltd.) Unlike other treatments to prevent GVHD, BPI does not suppress the immune system and has shown virtually no toxicity.

Researchers Ofer Levy, MD, PhD, of Childrens Hospital Boston, and Eva Guinan, MD, of Childrens Hospital Boston and Dana-Farber Cancer Institute, will present their most recent findings and discuss the new clinical trial on December 11 at the American Society of Hematology (ASH) Annual Meeting in Orlando, Fla. (abstract # 2856).

The new trial is the culmination of over five years of collaborative research by Levy and Guinan in human patients. Many basic and translational studies, including our own, have provided a strong rationale for a trial of BPI in patients undergoing hematopoietic stem cell transplants, says Levy. Replenishing a natural host defense factor that is deficient due to chemotherapy makes theoretical and practical sense, and we hope that bringing our bench work to patients will reduce the complications they suffer.

GVHD occurs when immune cells from donor attack the recipient, and can lead to multiple organ failure and death. It strikes some 30-60 percent of transplant patients, depending on how closely matched the donor is, and is kept in check only by eliminating otherwise useful donor immune cells or by using powerful immune-suppressing drugs.

Studies in mice had shown that the chemotherapy regimens used in HSCT not only wipe out white blood cells (with the intended effect of suppressing the immune system), but also damage the intestinal lining. This breach of the lining allows endotoxin, which is produced by bacteria living in the intestines, to enter the bloodstream. The endotoxin, in turn, provokes an inflammatory response that mobilizes donor immune cells, helping to trigger GVHD.

Levy, in Childrens Division of Infectious Diseases, had long been studying BPI, which naturally blocks and neutralizes endotoxin.(1) BPI is found in neutrophils, the very white blood cells that are virtually wiped out by pre-transplant chemotherapy. Studies in mice had shown that blocking endotoxin reduces the incidence of GVHD after chemotherapy and HSCT.(2)

Intrigued by these findings, Levy and Guinan began to study endotoxin and BPI in human patients undergoing HSCT with pre-transplant chemotherapy. In 2003 they showed, in a study of 57 children, that patients blood endotoxin levels rise markedly within a week of the transplant.(3) And now, in a study of 30 patient:donor pairs to be presented at the ASH meeting, they show that patients undergoing HSCT also have a sharp drop in BPI levels just as their endotoxin levels are rising and that BPI deficiency is associated with a greater likelihood of GVHD.

BPI is markedly deficient 100 to 1000-fold lower in our transplant patients, says Guinan, associate director of the Center for Clinical and Translational Research at Dana-Farber. If we can replenish this host defense factor, we might be able to moderate the damaging effects of GVHD.

The multicenter clinical trial, expected to begin within the next few months, will test rBPI21 (opebacan, NEUPREX® [Nasdaq: XOMA]). rBPI21 has been in phase I, II, and III human trials, with evidence of benefit in children and adolescents with serious meningococcal infections, but has not yet been approved by the Food and Drug Administration.

Levy and Guinan will first conduct a small safety trial, gradually increasing the amount of BPI given and the duration of treatment. If BPI appears safe, they will quickly mount a randomized, controlled trial in 30 to 40 patients who are undergoing HSCT for cancer or blood diseases. Childrens/Dana-Farber will be the lead center, with four to five additional pediatric and adult sites at prominent medical centers around the country.

Our ultimate goal is to reduce the downstream complications of stem-cell transplant, says Guinan. BPI would make these transplants significantly less toxic.

Sticky proteins provide new insight into drug action

Tue, 14 Nov 2006 04:59:37 PST

( from http://www.rxpgnews.com ) How drugs such as adrenalin do primarily one thing in this case, increase the heart rate now makes more sense to scientists.

Any time you get a sudden jolt, adrenaline (a.k.a. epinephrine) is why your heart rate goes up, says Dr. Nevin A. Lambert, a biophysicist at the Medical College of Georgia. If your heart is about to stop and the doctor administers epinephrine, that is what he or she is trying to do.

New research, to be published in the Nov. 21 print issue of Proceedings of the National Academy of Sciences and already available online in Early Edition, may help explain how cells respond correctly to epinephrine.

Most drugs never get inside cells; they interact with external receptors that activate G proteins roaming inside cells. If you are going to change the way the cell works, you have to transduce a signal from outside a cell inside, says Dr. Lambert. It's like a relay. G proteins interact with receptors; they run into them, they collide with them. The receptor itself does not do anything other than turn on these G proteins.

There are only four classes of G proteins, but cells contain thousands of copies of them which interact with hundreds of surface receptors. Each G protein is actually three protein subunits stuck together: alpha, beta and gamma.

Textbooks have long said that once G proteins are activated, the alpha protein splits from the beta and gamma subunits, which are irrevocably stuck together as a beta-gamma pair. Each half of the now dissociated G protein can cause the cell to do something different. Sometimes they help each other out; sometimes they work at cross purposes, says Dr. Lambert.

With epinephrine, that should mean the alpha subunit enables production of cyclic AMP, which increases the heart rate, while the beta-gamma pair should activate ion channels, making cells less electrically excitable and decreasing the heart rate.

However, it has been known for some time that while epinephrine does increase cyclic AMP in heart cells, it does not activate ion channels. While this situation makes sense because the cell isn't asked to respond in two completely opposite ways, it has not been at all clear how the cell allows one response and suppresses the other.

That likely is because the G proteins activated by epinephrine receptors don't readily dissociate, contrary to the textbook picture. MCG researchers have also shown that at least one other class of G proteins does dissociate, suggesting the textbook picture is at least partly correct.

Why the difference? Previous work on G proteins, including the discovery of the G proteins and their role in signal transduction, was mostly done in test tubes using purified proteins. MCG researchers used a technique they developed to actually look at G protein function inside living human cells.

Their findings suggest that epinephrine interacts with a G protein that doesn't let go of the beta-gamma subunit.

There was a constant question about how drugs sometimes avoid doing unwanted things, says Dr. Lambert. This helps us understand how drugs can be specific. The flipside of the coin is some drugs acting on some receptors will have multiple actions because the G proteins do dissociate.

No doubt, the newfound information about G proteins is just one step toward better understanding how hundreds of receptors can act through just four classes of G proteins and produce so many physiologic results. It's like how can 100 cars drive down four roads and end up in 100 different places, Dr. Lambert says.

But it's a timely piece as science moves toward designer drugs, including some that could actually target G proteins directly, bypassing intermediary receptors, with the hope of getting a more robust response.

In Dr. Lambert's lab, MCG graduate student Gregory J. Digby, first author on the PNAS paper, is now looking at G protein subunits that do and don't fall apart with the long-range goal of designing ones that do what they want. Right now, it's all engineering for the sake of understanding how they work, says Dr. Lambert.

Researchers suspect it's literally the stickiness between the subunits that determine whether they split, and that the bottom line will be two classes of G proteins dissociating and two not.

Should patients undergoing surgery get ASA?

Mon, 23 Oct 2006 03:59:37 PST

( from http://www.rxpgnews.com ) Hamilton, ON - (Monday, Oct. 23, 2003) -- A national survey of Canadian surgeons by researchers at McMaster University found little consistency in their use of the blood thinner ASA in patients undergoing non-cardiac surgery.

To resolve the issue, Canadian surgeons say they would welcome a randomized controlled trial, and allow their patients to participate in it, said Dr. Rajesh Hiralal, who led the survey and is presenting its results today in Vancouver at the annual meeting of the Canadian Society of Cardiac Surgeons.

The findings are significant because non-cardiac surgery, such as hip replacements and cancer surgery, makes up 95 per cent of all surgery performed today and the numbers are growing. Cardiac surgery accounts for less than five per cent.

Close to 100 million adults world-wide and half a million Canadians - undergoes major non-cardiac surgery annually. Globally, upwards of one million of these patients go on to suffer a non-fatal heart attack, non-fatal cardiac arrest or death as a result of their surgery, said Dr. Hiralal.

One of the great tragedies is that despite the advances we've had in surgeries and anaesthesia, we have people potentially getting cures of their cancer, or a new hip, with a new lease on life, who either may die around the time of surgery because of heart complications or they may have a non-fatal event which can actually take their life three to six months later, said Dr. P.J. Devereaux, one of 15 McMaster researchers who undertook the survey.

As a blood thinner, ASA provides potential protection from the development of blood clots following surgery. However, most studies on its use have been conducted on patients undergoing cardiac surgery. There has never been a large trial to address whether or not ASA is effective for non-cardiac surgery.

To get a reading on current practices around the use of ASA, McMaster researchers sent a questionnaire to 1,850 Canadian surgeons who are members of the Canadian Orthopedic Association, the Canadian Association of General Surgeons and the Canadian Society of Vascular Surgery. More than 900 responded.

They found marked variability in practice between the three surgical specialties.

Among surgeons in general there is a lot of practice variation in how they are managing ASA at the time of surgery, said Dr. Devereaux. They are doing very different things and there is no consistency. They are uncertain if there is a real benefit and if that benefit outweighs the risk, even if there is, in fact, a risk.

Pall system to detect blood bacteria given CE mark

Tue, 05 Sep 2006 03:59:37 PST

( from http://www.rxpgnews.com ) East Hills, NY (September 5, 2006) -- Pall Corporation (NYSE: PLL) announced the CE marking of its eBDS System to detect bacterial contamination of red blood cells, the most widely transfused blood component. The Pall eBDS is a highly sensitive culture-based test routinely used by blood centers to detect bacterial contamination of platelets, the leading infectious cause of sickness and death from a transfusion. Results of a new study presented at the International Society of Blood Transfusion (ISBT) 2006 Congress show the efficacy of the system in also detecting bacteria that are commonly found as contaminants of red blood cells.

Since the availability of the Pall eBDS for detection of bacteria in platelets, there has been interest in applying the same technology to improve safety of red blood cells. Recent studies have documented sepsis and death caused by transfusion of contaminated red cells, with the bacteria Yersinia enterocolitica most often implicated. The U.S. FDA estimates that the rate of bacteria associated adverse reactions from Yersinia is one per 500,000 units of red cells, although they note that this rate may be underestimated. The U.S. Centers for Disease Control and Prevention (CDC) estimates bacterial contamination of red blood cells at one per million units whereas other nations have reported incidence as high as one in 65,000 units with a fatality rate of one in 104,400 units.

Despite the unknown actual number of cases, there is no question that transfusion of a contaminated red blood cell, especially if contaminated with gram-negative bacteria, is a rapid and catastrophic event with a quick onset of sepsis and greater than 60 percent mortality rate. Multiple studies have also documented a link between transfusion of red blood cells with nosocomial (hospital-acquired) infection. Critically ill patients who receive red cell transfusions are at increased risk of a nosocomial infection with a significant increase in mortality and/or length of stay in intensive care.

Adding bacterial detection of red cells along with platelets can have a significant impact on the safety of the blood supply, says Allan Ross, President, Pall Medical. The blood centers that employ the Pall eBDS for platelet testing can simply and readily use it to detect bacteria in red cells. This is a highly cost-effective way to help them ensure they can provide the safest blood for transfusion.

The Pall eBDS uses a novel approach to detection by measuring oxygen consumption as the marker for bacteria. If bacteria are present in the blood sample collected, an increasing amount of oxygen is consumed through the metabolic activity and proliferation of the bacteria during incubation, resulting in a measurable decrease in oxygen content.

The study presented to the ISBT tested the Pall eBDS on 662 red blood cell samples that had been inoculated separately with twelve different bacteria strains. Each sample was tested after 48 hours resulting in 100 percent detection of the contaminating bacteria. Pall, the leading global provider of filtration and other technologies to enhance the safety of the blood supply, conducted this study in response to the need to reduce the problem of bacterial contamination of blood components.

#1 Infectious Source of Transfusion-Transmitted Disease

Scientists learn more about how roughage keeps you 'regular'

Tue, 22 Aug 2006 03:59:37 PST

( from http://www.rxpgnews.com ) If you ever wondered just how a high-fiber diet helps keep you, well, regular, scientists may have the answer.

Their results suggest that as these bulky foods make their way down the gastrointestinal tract, they run into cells, tearing them and freeing lubricating mucus within.

More mucus is good, says Dr. Paul L. McNeil, cell biologist at the Medical College of Georgia and corresponding author on the study published online Aug. 21 and scheduled for the September print issue of PloS Biology. When you eat high-fiber foods, they bang up against the cells lining the gastrointestinal tract, rupturing their outer covering. What we are saying is this banging and tearing increases the level of lubricating mucus. It's a good thing.

The fact that consuming roughage increases mucus production was known, and years ago, Dr. McNeil discovered frequent cell injury and repair occur when we eat.

The new research ties the two together.

It's a bit of a paradox, but what we are saying is an injury at the cell level can promote health of the GI tract as a whole, says Dr. McNeil. Even though epithelial cells usually live less than a week, they are regularly bombarded, in most of us at least three times a day as food passes by. These cells are a biological boundary that separates the inside world, if you will, from this nasty outside world. On the cellular scale, roughage, such as grains and fibers that can't be completely digested, are a mechanical challenge for these cells, says Dr. McNeil.

But in what he and colleague Dr. Katsuya Miyake view as an adaptive response, most of these cells rapidly repair damage and, in the process, excrete even more mucus, which provides a bit of cell protection as it eases food down the GI tract.

In research published in 2003 in Proceedings of the National Academy of Sciences, Dr. McNeil showed proof of his then decade-old hypothesis that cells with internal membranes use those membranes to repair potentially lethal outer-membrane injuries. A recent paper published in Nature in collaboration with Dr. Kevin Campbell's laboratory at the University of Iowa showed how human disease, including certain forms of muscular dystrophy, can result from a failure of this mechanism.

An outer membrane tear is like an open door through which calcium just outside the cell rushes in. Too much calcium is lethal but that first taste signals the vulnerable cell it better do something quick. With epithelial cells, several of the internal mucus-filled compartments fuse together within about three seconds, forming a patch to fix the tear. In the process the compartments expel their contents so, almost like a bonus, extra mucus becomes available to lubricate the GI tract.

We have found a very natural way we can enhance mucus production, says Dr. Miyake, cell biologist and the study's first author. He and Dr. McNeil suspected for years that mucus escaped cells as a result of injury. You might have predicted it, but science is about testing predictions, says Dr. McNeil.

To test their theory, Dr. Miyake, co-director of MCG Cell Imaging Core Laboratory, began working on a method to reproduce cell injuries. Dr. Miyake developed a very potent cutting edge technology involving the two photon laser that allowed us to blast small holes in cells, mimicking what happens in the living animal. It also allowed us to assess in those living cells whether they could reseal, repair the damage and how they might respond biologically, namely in this case, whether they responded by secreting mucus as part of the healing process, Dr. McNeil says.

They found time and again that most cells did just that, including intact cells in a section of the GI tract. Epithelial cells are high-turnover cells but they have a built-in survivability, Dr. McNeil says.

The scientists aren't certain how many times cells can take a hit, but they suspect turnover is so high because of the constant injury. Potentially caustic substances, such as alcohol and aspirin, can produce so much damage that natural recovery mechanisms can't keep up. But they doubt a roughage overdose is possible.

Blood clots can be treated by injections at home

Tue, 22 Aug 2006 03:59:37 PST

( from http://www.rxpgnews.com ) Treatment of blood clots in the deep veins of the legs or the lungs with an older, less expensive form of the anticoagulant medication heparin can be just as safe and effective as similar treatment with a newer and more expensive heparin, according to a study led by Clive Kearon, professor of medicine at McMaster University, published in the August 23 issue of JAMA (The Journal of the American Medical Association).

When injected subcutaneously (beneath the skin), unfractionated (regular) heparin was shown in a randomized trial to work just as well as subcutaneous injection of the more expensive, low-molecular weight heparin in the treatment of venous thromboembolism.Traditionally, when unfractionated heparin is used in treatment, it is administered intravenously and accompanied by coagulation monitoring, which requires hospitalization. This standard approach includes ongoing dose adjustment in response to measurement of the APTT, a test that measures how fast the blood clots in a test tube under certain conditions.

The newer low-molecular weight heparins, which are administered by injection in fixed-weight doses, have gradually been replacing unfractionated heparin.

Kearon and colleagues conducted a randomized trial to study how fixed-dose, subcutaneous injection of unfractionated heparin compared to injection with the newer heparin in the treatment of blood clots in the legs or lungs.

The study was conducted from September 1998 through February 2004 at six university-affiliated clinical centres in Canada and New Zealand. Patients in the trial received either unfractionated or low-molecular-weight heparin administered subcutaneously every 12 hours. About 70 per cent of both groups were treated as outpatients. All patients received three months of warfarin (an anticoagulant drug) therapy.

Recurrent thromboembolism occurred in 3.8 per cent of the 345 patients in the unfractionated heparin group, and in 3.4 percent of the 352 patients in the low-molecular weight heparin group. The rate of major bleeding was comparable in the two groups.

The authors estimate that drug costs for a six-day course of treatment with low-molecular-weight heparin would be $712 (US), while unfractionated heparin would cost just $37 - assuming both drugs are administered in the regimens used in the study. The study indicates the potential for huge costs savings.

Fixed-dose subcutaneous unfractionated heparin is as effective and safe as low-molecular-weight heparin for initial treatment of patients with venous thromboembolism and is suitable for treatment at home, concluded Dr. Kearon, who is a physician at Hamilton Health Sciences. In addition, the results of this study question the value of APTT monitoring in patients who are treated with currently recommended doses of unfractionated heparin.

We've come a long way from having to spend several weeks in hospital with an intravenous heparin drip to a possible out-patient treatment that is safe, efficient, and less expensive, says Dr. Andreas Wielgosz, spokesperson for the Heart and Stroke Foundation.

Venous thrombosis after travel

Mon, 21 Aug 2006 03:59:37 PST

( from http://www.rxpgnews.com ) Traveling for more than 4 hours by air, car, bus or train is associated with an increased risk of venous thrombosis. In a large study (the MEGA study) of nearly 2000 people with a first thrombosis in the Netherlands, Dr Suzanne Cannegieter and colleagues from the Leiden University Medical Center looked at the risk factors for thrombosis compared with their partners, who did not have thrombosis. The results, published in the international open-access medical journal PLoS Medicine, showed that 233 of the people with thrombosis had traveled for more than 4 h in the 8 weeks preceding the event. Although the overall risk of developing thrombosis is still low, traveling in general was found to increase the risk of venous thrombosis 2-fold. The risk was highest in the first week after traveling, and the overall risk of flying was largely similar to the risks of traveling by car, bus, or train.

In particular groups of people the risk was increased. For example, the risk was up to 8-fold in people who also had a specific mutation in one of the genes involved in clotting (factor V Leiden); almost 10-fold in those who had a body mass index of more than 30 kg/m2; 4-fold in those who were more than 1.90 m tall; and more than 20-fold in those who used oral contraceptives. For air travel these findings of risk in particular groups were more apparent than for other modes of travel, and in addition, people shorter than 1.60 m had an almost 5-fold risk of thrombosis after air travel. However, the numbers of people in each of these groups was small and hence the estimates of risk must be interpreted carefully.

The authors conclude that the risk of venous thrombosis is moderately increased for all these modes of travel, and that in particular groups of people the risk is highly increased. The study could not show the mechanism of the increased risk, although the association of thrombosis with all types of travel, not just air travel, suggests that immobility is a key factor. Other mechanisms, such as reduced oxygen levels triggering clotting, may be involved in the particularly increased risk seen in air travel in some groups.

For those who have an increased risk, such as oral contraceptive users and individuals with factor V Leiden, the authors say that preventative measure such as exercises may be warranted. However, the study's results apply only to people younger than 70 y of age and it is likely that other characteristics exist that also increase the risk. These characteristics are being investigated in an ongoing study the World Health Organization Research Initiative into the Global Hazards of Travel (WRIGHT).

Finding paves way for better treatment of autoimmune disease

Tue, 08 Aug 2006 03:59:37 PST

( from http://www.rxpgnews.com ) A signaling molecule with an affinity for alcohol has yielded a rapid, inexpensive way to make large numbers of immune cells that work like beat cops keeping misguided cells from attacking the body.

The ability to easily make large numbers of these cells opens the door to improved treatment and a better understanding of autoimmune diseases such as type 1 diabetes and arthritis, Medical College of Georgia researchers say.

T cells are components of the immune system designed to attack invaders such as bacteria and viruses; regulatory T cells are a small subset that prevents the cells from also attacking body tissue.

Research published in the August issue of Nature Methods shows that, given the option, phospholipase D, which typically mixes with water, prefers alcohol. It's an apparently lethal choice for the signaling molecule that, in turn, also kills T cells that need phospholipase D to survive. Previously, it was unknown whether regulatory T cells required the molecule.

What we have found is that if you block this enzyme, almost all T cells die after three days but the regulatory T cells can survive, says Dr. Makio Iwashima, MCG immunologist and the study's corresponding author. After three days, we give them some food to grow and, in one week, you get about 90 percent pure regulatory cells.

The approach worked with laboratory-grade alcohol, called butanol, as well as beverage-grade ethanol.

Normally, regulatory T cells constitute about 5 percent of the T cell compartment, Dr. Iwashima says. Isolating them is doable but a long, expensive process.

When researchers gave some of the regulatory T cells to a mouse model of inflammatory bowel disease, the symptoms, including dramatic weight loss, went away. Animals showed no classic signs of inflammation, just a significant increase in regulatory cells.

MCG researchers have obtained funding from the Arthritis Foundation and the Juvenile Diabetes Research Foundation to see if the cell therapy will work as well in animal models for arthritis and type 1diabetes.

Our prediction and our hope is that we can restore balance, says Dr. Iwashima. The usual 5- to 95-percent ratio of regulatory cells to non-regulatory T cells is lost in those with autoimmune disease, he says. However, too many regulatory cells also can be a problem, he says, noting that cancer patients have higher levels of regulatory cells.

Regulatory T cell therapy also resolved symptoms in a model of graft versus host disease, a problem for some bone marrow transplant patients when immune cells from the donor start attacking. This finding indicates a potential role for helping transplant patients keep new organs, the researchers say.

Dr. Iwashima has an Alcoholic Beverage Medical Research Foundation grant to pursue alcohol's potential for helping isolate desirous regulatory cells. However, he cautions that his research findings are not a green light for patients with autoimmune disease to drink because of the negative health effects of regular alcohol consumption.

Dr. Iwashima and his colleagues believe the best way to optimize cell percentages is to do what the body does. In fact, they already are searching for an endogenous substance that interferes with phospholipase D.

Ultimately, that is the most natural way, if we can find the compound in our bodies that can do the job, Dr. Iwashima says. He theorizes that this natural substance helps destroy non-regulatory T cells when the body gets too many, say after fighting a big infection, and that it may not work well enough in people with autoimmune disease.

Test helps identify patients at low risk for recurring blood clots

Tue, 25 Jul 2006 03:59:37 PST

( from http://www.rxpgnews.com ) A test that measures the generation of a certain protein involved with blood clotting can help determine whether patients who have experienced a venous blood clot are at low risk of developing another blood clot, and thus avoiding anticoagulant treatment and its possible side effects, according to a study in the July 26 issue of JAMA.

Anticoagulant treatment for patients with venous thromboembolism (VTE - formation of blood clots, often involving the deep veins of the legs or in the lung) consists of heparin followed by vitamin K antagonists for at least 3 to 6 months. After discontinuation of anticoagulant treatment, a third of patients experience recurrence of VTE within the next 5 to 8 years, according to background information in the article. The case-fatality rate of recurrence is around 5 percent. Therefore, identification of patients who might benefit from indefinite anticoagulant treatment (i.e., patients in whom recurrent VTE is more likely than anticoagulation-associated severe bleeding) is now one of the foremost goals in thrombosis research. Because of the large number of risk factors, assessing the risk of recurrence in an individual patient is complex. A laboratory test that would detect multifactorial thrombophilia (increased tendency for blood clots) could help determine the overall risk of recurrent VTE.

Gregor Hron, M.D., of the Medical University of Vienna, Austria and colleagues conducted a study to determine whether by measuring thrombin generation (a protein in blood that causes clotting), patients with VTE could be stratified into high- and low-risk categories for recurrence of VTE. The study, conducted between July 1992 and July 2005, included 914 patients with first spontaneous VTE who were followed-up for an average of 47 months after discontinuation of vitamin K antagonist therapy. Thrombin generation was measured by a commercially available test.

Venous thromboembolism recurred in 100 patients (11 percent). The researchers found that patients without recurrent VTE had lower thrombin generation than patients with recurrence.

In this large prospective cohort study, we found that patients with a first spontaneous VTE and peak thrombin generation of less than 400 nM [the measurement nanomolar] after discontinuation of vitamin K antagonists have a low risk of recurrence. According to Kaplan-Meier analysis, the likelihood of recurrent VTE in these patients was as low as 7 percent after 4 years. Compared with patients who had higher levels, those with peak thrombin generation less than 400 nM had an almost 60 percent lower risk of recurrence. Most importantly, the group of patients with low peak thrombin generation represented two-thirds of the total patient population, the authors write.

we believe that our findings are of major clinical relevance. Using a simple commercially available laboratory method developed to measure thrombin generation, we were able to identify patients in whom the long-term risk of recurrent VTE is almost negligible. Considering the incidence rates of severe or fatal hemorrhage related to anticoagulant therapy and the case-fatality rate of recurrent VTE, patients with low peak thrombin generation (less than 400 nM) would almost certainly not benefit from indefinite anticoagulant therapy. Consequently, extensive thrombophilia screening appears to be unnecessary in this large, low-risk patient group, the researchers conclude.(JAMA. 2006;296:397-402. Available pre-embargo to the media at

Aggressive heart pacing may work best in some spinal cord patients

Thu, 20 Jul 2006 03:59:37 PST

( from http://www.rxpgnews.com ) Patients with recurring problems with the heart slowing or stopping after a neck injury damages their cervical spinal cord may need aggressive therapy to avoid further cardiovascular problems and even death, Medical College of Georgia researchers say.

A study subset of newly injured quadriplegics showed that less aggressive therapies, such as drugs and a pacemaker placed on top of the chest, simply were not sufficient, says Dr. Andres F. Ruiz-Arango, cardiology fellow and corresponding author of the article in the July/August issue of Cardiology in Review.

There is a group of these patients who are not going to survive acute hospitalization but you don't want them to die just because they need a pacemaker, says Dr. Ruiz-Arango.

Although the heart has an intrinsic pacemaker, its rate is affected by two systems: the sympathetic nervous system to speed it up and the parasympathetic nervous system to slow it down, says Dr. Gyanendra K. Sharma, noninvasive cardiologist and study co-author.

With a cervical spinal cord injury, the influence of the sympathetic nervous system called the fight or flight system because it responds to stress by enabling an increase in heart rate can be injured or lost while the impact of the parasympathetic system continues, he says.

The result can be a dangerously slow heart rate, called bradycardia, which causes blood pressure to fall, organs to get insufficient blood and oxygen and can progress to heart stoppage, says Dr. Vincent J.B. Robinson, nuclear cardiologist and study co-author.

It's the balance between sympathetic and parasympathetic nervous systems that keeps your heart rate in the normal range, says Dr. Ruiz-Arango. When patients lose this balance and start having dangerously slow rates, doctors typically try drugs, such as atropine and epinephrine, to increase heart rate and a transcutaneous pacemaker on the chest.

Their retrospective survey of 75 spinal cord injury patients at MCG Medical Center from January 2001-July 2003 included six with high cervical injuries, three of whom needed a permanent pacemaker.

It suggests transvenous pacing in which a lead is inserted into the heart may be a better first alternative in patients with ongoing difficulty maintaining their heart rate in the hours and days following an injury.

Nobody really knows the best therapy, says Dr. Sharma. This gives us some direction that if you see a very slow heart rate, if the patient's heart is stopping for three, four or five seconds, you think about putting in a transvenous pacemaker and see how they do and maybe put a permanent pacemaker in sooner rather than later.

Although essentially all patients with cervical spinal cord injuries have problems maintaining an adequate heart rate for a time, amazingly, even some with severed cords will not need a permanent pacemaker, Dr. Ruiz-Arango says.

That's one of many reasons why when patients have heart rate problems, doctors struggle with the best treatment approach, often opting for the least-invasive options.

Transvenous pacemakers can increase infection risk in already-compromised patients. Also gaining adequate access for lead insertion can be difficult in a neck secured because of a spinal injury. Risk of infection is a big problem because many of these patients have ongoing infections such as pneumonia, says Dr. Sharma. Fortunately we did not find pacemaker-related infections in this small cohort.

What doctors usually do is put a transcutaneous pacer on the chest and just kind of ride it out, says Dr. Robinson. But what we found by going over these patients' data was that external pacemakers do not seem to be reliable in these patients and patients run into a lot of problems.

Ironically, regular activities these patients need to survive, such as suctioning secretions, drawing blood and even bowel movements, can trigger activity of the vagus nerve, which mediates the parasympathetic system's influence on the heart.

One patient's heart stopped beating and he had a seizure when blood was drawn, Dr. Robinson noted. We put a pacemaker in and he has been fine ever since, he says. These patients have lost their sympathetic response so the vagal tone is always predominating. In patients showing ongoing symptoms, we found it's much more important to go ahead and put that transvenous pacemaker in and keep them stable.

While the researchers suggest rapid preventive action in patients with recurring episodes of bradycardia, strict treatment guidelines for these patients can't yet be developed because of the limited number of patients in their study, they say.

They already have begun a larger study with doctors at the 60-bed spinal cord injury unit at the Veterans Affairs Medical Center, also in Augusta.

HO-1 in sickle cell disease: friend or foe?

Tue, 18 Jul 2006 03:59:37 PST

( from http://www.rxpgnews.com ) Rochester, Minnesota -- Researchers have unexpectedly shown that sickle cell-associated kidney injury may be reduced by inhibiting the enzyme activity of a protein that commonly confers protection in other diseased states. The paper by Juncos et al., Anomalous renal effects of tin protoporphyrin in a murine model of sickle cell disease, appears in the July issue of The American Journal of Pathology.

Sickle cell disease (SCD), which affects greater than 70,000 individuals in the US, is an inherited hemoglobin disorder that causes some red blood cells to lose their smooth round shape and assume a crescent, or sickle, shape. Sickle cells can become lodged in small capillary blood vessels, with blockage of blood flow leading to pain, stroke, and damage to most organs including the lungs, spleen, kidneys and liver.

The mechanisms underlying SCD-associated kidney disease include various forms of secondary stress, such as changes in internal kidney blood flow, induction of oxidative injury, and influx of inflammatory cells. Researchers have thought that cells combat such stress through expression of heme oxygenase-1 (HO-1), a protective enzyme that is upregulated in SCD kidneys in humans and in mouse models. New research, however, suggests that in SCD HO-1 may not be as protective as previously thought.

In an attempt to understand the specific role of HO-1 in kidney injury, Juncos et al. examined SCD mice in the presence or absence of tin protoporphyrin (SnPP), a widely accepted inhibitor of the enzyme activity of HO. Short-term SnPP treatment successfully blocked HO activity in both normal and SCD mice, reduced kidney blood flow in normal and SCD mice, but did not affect the filtration capacity of the kidney in either group. However, when chronically administered, SnPP caused inflammation and fibrosis (scarring) in normal mice but not in SCD mice; in normal mice, SnPP induced genes related to fibrosis and inflammation, whereas in SCD mice, these genes were downregulated.

The scientists next examined the effect of SnPP on kidney injury induced by temporarily interrupting kidney blood flow (ischemia); the kidney in SCD mice is hypersensitive to such ischemia. Surprisingly, when mice were treated with SnPP, SCD kidneys were protected from ischemia-induced cell death and blood vessel blockage whereas normal kidneys exhibited cell death and injury. Thus, in contrast with its effects observed in normal mice, SnPP protected SCD kidneys from injury.

In other diseases, induction of HO-1 is protective by generating products such as carbon monoxide and bile pigments, both of which can reduce tissue injury; however, in larger amounts, these products may be toxic. It is possible that the degree of induction of HO-1 in SCD may generate toxic rather than protective amounts of these products. Additionally, along with its intended effect of inhibiting HO activity, SnPP may induce HO-1 protein, and this latter effect may underlie the observed cytoprotection. Finally, besides inhibiting HO activity, SnPP may concomitantly interrupt other pathways, independent of the HO system, that contribute to kidney injury in SCD.

In the process of analyzing the biologic significance of HO-1 in SCD, Juncos et al. uncovered an experimental strategy that reduced kidney injury in a mouse model of SCD. Further work will likely delineate the basis for the protective effects of SnPP in SCD, specifically, the dependency on inhibition of HO activity, increase in HO-1 protein, or some other as-yet-undefined mechanism.

Blood test predicts sickle cell disease complication, identifies patients at high risk of death

Tue, 18 Jul 2006 03:59:37 PST

( from http://www.rxpgnews.com ) A team of scientists with the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health has found that a hormone detected in a simple blood test can identify patients with sickle cell disease who have developed a life-threatening complication called pulmonary hypertension. The team has also found that the same hormone is a clear predictor of death in adult sickle cell patients.

The hormone, called brain natriuretic peptide or BNP, is released by the heart ventricles and helps predict death in heart failure patients. The new study is published in the July 19 issue of the Journal of the American Medical Association.

This is an important leap forward in research on sickle cell disease, said NHLBI Director Elizabeth G. Nabel, M.D. Having a marker in the blood that will not only help identify sickle cell patients with this deadly complication but also predict those at the highest risk â will aid in the care and treatment of these patients.

Sickle cell anemia is one of the most common genetic blood disorders in the United States. About 30 percent of sickle cell patients have pulmonary hypertension. In this condition, there is constant high blood pressure in the pulmonary arteries that supply the lungs. This pressure leads to narrowed arteries, causing the heart to work harder to pump blood. Pulmonary hypertension often leads to heart failure and it is a major risk factor for death in adults with sickle cell disease. Currently, echocardiograms and other heart tests are used to diagnose pulmonary hypertension, but there has not been a blood test to help detect the condition.

Previous research has found that in patients with pulmonary hypertension, higher levels of BNP are associated with greater pressure in the pulmonary arteries. NHLBI researchers theorized that BNP levels might also correlate with the severity of pulmonary hypertension and risk of death in sickle cell patients.

Lead scientist Roberto Machado, M.D., an investigator with NHLBI's Vascular Medicine Branch, and colleagues, including scientists in the NIH Clinical Center, measured BNP levels in 230 patients with sickle cell disease enrolled in the NIH Pulmonary Hypertension Screening Study between 2001 and 2005. In order to confirm a diagnosis of pulmonary hypertension, the patients were given echocardiograms and other measurements of heart function. BNP levels were also measured in 45 healthy African-American controls, since the disease is more prevalent in African-Americans.

The scientists found that high blood levels of BNP â greater than 160 pg/mL â in these patients independently predicted mortality, increasing the risk of death by as high as fivefold.

The team also found that BNP levels could help identify the patients with pulmonary hypertension. NIH study patients who had a BNP of 160 pg/mL or higher had a 78 percent chance of having pulmonary hypertension identified by echocardiogram.

We now have another tool to help diagnose pulmonary hypertension, Machado said. There is tremendous value in diagnosing this deadly complication early and accurately so we can aggressively treat the complication and try to improve the patientâ

Study looks for genetic predictors of hypertension

Mon, 19 Jun 2006 03:59:37 PST

( from http://www.rxpgnews.com ) The rare disorder is Liddle syndrome, first reported in 1963 in a 15-year-old Alabama girl diagnosed with a blood pressure of 180/110 mmHg, says Dr. Yanbin Dong, molecular geneticist and cardiologist at the Medical College of Georgia.

Interestingly, an inexpensive diuretic worked best to manage her problem. Tests years later found the reason was that genes involved in the channel that recycles sodium from food into the body were drastically mutated. This mutation enables sodium to come back into the body like a flood, says Dr. Dong.

Today he is looking at sodium channel genes implicated in Liddle syndrome to identify less severe changes that could be used to screen for hypertension risk in the general population.

My hypothesis is if Liddle syndrome is caused by these nasty, drastic mutations, maybe the majority of hypertension can be caused by milder, less nasty polymorphisms or variations in the same genes, says Dr. Dong who received a $1.43 million grant from the National Heart, Lung and Blood Institute to see if he is correct.

He's recruiting 300 healthy blacks ages 15 to 19 with normal blood pressure to a Georgia Prevention Institute study that first measures sodium-handling following environmental stress, then analyzes the genes of those who don't handle it well.

Dr. Dong is exploring findings by Dr. Gregory A. Harshfield, director of the Georgia Prevention Institute, showing that some healthy youths, particularly black youths, continue to retain sodium after the stress that drove up their blood pressure is gone. This impaired stress-induced pressure natriuresis occurs in about 36 percent of healthy black youths and 25 percent of healthy white youths, according to Dr. Harshfield's studies.

The body naturally increases blood pressure during stress, immediately by constricting blood vessels and longer term by directing the kidneys to retain more sodium and so increase blood volume, says Dr. Harshfield, a co-investigator on Dr. Dong's latest grant. His own studies have shown the importance of the interaction between salt and stress in regulating blood pressure.

The new study should provide additional insight into the relationship between salt and stress as well as diet and genetics, Dr. Dong says.

Study participants will be on a salt-restricted diet for four days, then come to the GPI on the fifth day to rest for an hour, play competitive video games and rest again. Blood pressure and sodium excretion will be measured before games are played, immediately afterward, then two hours later.

The five genes alphaENaC, betaENaC, gamma ENaC, SGK-1 and Nedd4-2 taken from blood samples will be analyzed so specific variations can be correlated with variations in a youth's ability to excrete sodium after stress has passed. Gene-to-gene interactions also will be studied.

Researchers say poor sodium-handling is a major player in hypertension and that a youth's reduced ability to excrete salt following stress is a sign of what's to come.

If Dr. Dong's hypothesis holds, young people with risky genetic variations could have advance warning of their increased hypertension risk and make changes such as salt intake restriction and stress reduction management to ideally avoid the problem.

The body needs sodium but doesn't produce it, Dr. Dong notes. Still most people get adequate sodium in their diets without adding salt to food.

High-dose Calcitriol (DN-101) with Docetaxel Reduced Thrombosis

Sat, 03 Jun 2006 09:02:37 PST

( from http://www.rxpgnews.com ) A clinical trial of a biologically active metabolite of Vitamin D3 demonstrated an unanticipated reduction of thrombosis in cancer patients. Thrombosis is a serious complication in advanced cancers and affects between 15 and 20 per cent of all cancer patients.

In a randomized trial involving 250 patients with advanced prostate cancer in 48 clinical sites, those receiving high-dose calcitriol (DN-101) along with Docetaxel experienced a significant reduction in both venous and arterial thromboses compared to patients receiving a placebo and Docetaxel. Calcitriol is a naturally occurring hormone and the biologically active form of Vitamin D.

While the clinical trial involved patients with advanced stages of prostate cancer, in vitro studies of myelogenous leukemia cells, monocytes and osteoblasts and observation in mice hold promise for improved safety in a wide range of cancers.

"This is a serendipitous outcome," says Dr. Venner. "It wasn't what we were looking for, but it offers an avenue of investigation that could result in a new class of anticoagulants, which could, in turn, significantly improve outcomes for cancer patients."

The study was primarily looking at the effects of DN-101 on PSA responses in patients with advanced prostate cancer and secondarily on survival rates. As part of the analysis of the data, its impact on reducing chemotherapy side effects was detected. The drug demonstrated a positive outcome on both survival and reduction of side effects. The effect on thrombosis that unexpectedly emerged from the study will be tested and confirmed in a recently activated phase III clinical trial.

New preservative increases shelf life of blood platelets - decreases risk of harmful reactions

Wed, 31 May 2006 03:59:37 PST

( from http://www.rxpgnews.com ) In the wake of mass casualties from either natural disasters, such as the earthquake in Indonesia, or combat situations in Iraq and Afghanistan extending the shelf life of platelets could have global implications for those in critical need of the blood product.

Platelets are the component of whole blood that control bleeding and prevent life-threatening hemorrhages. Patients undergoing a bone marrow transplant, cardiac surgery, chemotherapy, radiation treatment or organ transplants often require platelet transfusions.

We found that by storing the platelets in the artificial preservative, we were able to retain the quality of the blood product for seven days, as opposed to having to dispose of them after only five days, says lead author Joseph D. Sweeney, MD, director of transfusion services at The Miriam Hospital and professor at Brown Medical School.

In addition, Sweeney and his team were able to reduce up to 80 percent of the plasma in the platelets stored in preservative. Since plasma is responsible for the majority of the adverse reactions that transfusion patients may experience, this suggests that those receiving transfusions will better tolerate the new blood product.

Sweeney explains, Currently, platelets are stored in plasma and discarded after five days. Significantly reducing the amount of plasma would likely lessen the frequency of these adverse events.

The authors write that inadequate inventories of platelets due to their short shelf life and highly unpredictable demand, greatly limits blood centers' ability to provide platelets for essential transfusions. With a storage potential of seven days or longer, platelets can be more readily available to patients and provide a cost-savings to blood banks which discard millions of dollars worth of outdated platelets each year.

Researchers monitored two groups of platelets derived from whole blood donations. The first group of platelets was stored in plasma, while the second group was stored in the artificial preservative. On day seven, both groups of platelets met the current FDA requirements and the more stringent European requirements for use. Although both groups of platelets retained their quality for seven days, it's important to note that the platelets in the preservative had extremely low plasma levels.

The artificial preservative tested was unique because it contained glucose, which seems to be a key component in extending the shelf life of platelets. The preservative also contained sodium acetate and sodium bicarbonate.

Until now, preservatives containing glucose have not been successfully used for platelet storage because glucose carmelizes during sterilization, and the only way to prevent carmelization is to lower the pH levels to a point that could be harmful to the platelet, says Sweeney.

Sweeney was able to use a glucose containing preservative without harming the platelets by adding sodium bicarbonate to the storage container. The sodium bicarbonate protected the platelets from exposure to low pH levels.

Improvements in the quality and safety of blood products are continually being developed to enhance patient safety, Sweeney says. Advances in platelet storage will pave the way for the next generation of blood products, such as artificial platelets.

Protein expression holds promise for head and neck cancer detection

Wed, 10 May 2006 03:59:37 PST

( from http://www.rxpgnews.com ) Studies comparing protein expression in 78 patients with head and neck cancer to 68 healthy controls revealed numerous differences in protein expression, Medical College of Georgia researchers say.

We found scores and scores of proteins that were differentially expressed, says Dr. Christine Gourin, MCG otolaryngologist specializing in head and neck cancer and the study's lead author. We found there are at least eight proteins whose expression significantly differs between controls and people with cancer.

This protein fingerprint correctly classified study participants as cancer patients with a high degree of sensitivity and specificity 82 percent and 76 percent, respectively, according to research published in the current issue of Archives of Otolaryngology.

If these results hold up over time, they would suggest that this would be a good screening test for at-risk people, Dr. Gourin says. Right now there is no good, effective screening test for head and neck cancer short of physical examination. Unfortunately it takes the development of symptoms to warrant a visit to the doctor, such as a sore throat; ear, tongue or mouth pain; painful eating or swallowing; or a change in the voice. Sometimes the first sign is a lump in the neck which is already a sign of an advanced tumor that has spread to the lymph nodes.

Belated diagnoses translate to fairly dismal survival rates: less than 50 percent five years following diagnosis of stage three or four tumors, Dr. Gourin says. The rare patient who is diagnosed early faces much better odds: voice box cancer caught in stage one has about a 95 percent five-year survival, for example.The goal is to screen high-risk populations those with a history of alcohol and/or tobacco use as well as those with head- and neck-specific complaints who don't have those risk factors, says Dr. Gourin. She notes that about 20 percent of head and neck cancer patients have no history of alcohol or tobacco use.

Advanced proteomics technology which can be applied to many tumor types enables protein expression to be plotted on graphs that illustrate peaks and valleys. Sometimes the underexpression of a protein may be significant, Dr. Gourin says.

The unique patterns surfacing may one day provide more than screening. Study findings indicate the protein fingerprint also is highly successful at classifying specific types of head and neck cancer, correctly classifying 83 percent of oral cavity tumors and 88 percent of laryngeal tumors, as examples, researchers say.

Also, in a small subset of 12 patients, protein expression helped researchers correctly classify how cancers responded to treatment, indicating its effectiveness in long-term follow-up, Dr. Gourin says. We could easily use this to follow patients for life and detect any recurrence early as well as improve our ability to detect a second primary tumor, which occurs in about 8 percent of people, she says.

Clinical availability of a screening test for head and neck cancer is still years away, says Dr. Bao-Ling Adam, MCG cancer researcher and study co-author. But the researchers are continuing to make progress, already collecting more patient data to ensure that the patterns they have identified in the blood are effective biomarkers for head and neck cancer. Dr. Gourin is considering opening the study to other medical centers to increase numbers possibly into the thousands.

They also want to know if protein expression patterns found in the blood are expressed by cancer cells themselves, says Dr. Adam, who has begun doing proteomics studies on the cancerous tissue of surgery patients to find out. What we see in the blood could be from the cancer cells or from the body's response to cancer, she says.

If they are the same, the proteins also could yield novel therapeutic agents, Dr. Adam says.

This will help solidify the link between the protein patterns and cancer as well. For screening you really have to use body fluids: blood, saliva, urine, says Dr. Adam. When the normal cell transforms to a cancer cell, we want to see the changes within the cells. When we find the protein differences between cancer cells and normal cells, we can use this information to detect head and neck cancer.

Interestingly, to date they have not found any proteins expressed by cancer that are not expressed normally; the difference is a matter of degrees of expression, says Dr. Adam, who also is using proteomics to find a better biomarker than prostate specific antigen, or PSA, for prostate cancer.

Blood-compatible nanoscale materials possible using heparin

Sun, 07 May 2006 15:31:37 PST

( from http://www.rxpgnews.com ) Researchers from Rensselaer Polytechnic Institute have engineered nanoscale materials that are blood compatible using heparin, an anticoagulant. The heparin biomaterials have potential for use as medical devices and in medical treatments such as kidney dialysis.

The researchers prepared several materials with heparin composites or coatings, including carbon nanotubes, nanofibers, and membranes with nanosized pores, and then demonstrated the materials' high compatibility with blood. Heparin is a common therapeutic used to maintain blood flow or prevent clotting during medical procedures and treatments.

The researchers demonstrated the composite heparin membrane with nanopores could work as an artificial kidney, or dialyzer, by filtering the blood and maintaining its flow. The presence of this blood-compatible dialyzer could potentially eliminate the need for systemic administration of heparin to the patient during kidney dialysis, the researchers say.

The heparin-coated membranes are described in a paper titled "Ionic Liquid-Derived Blood Compatible Membranes for Kidney Dialysis," published online Apr. 24 in advance of print in the Journal of Biomedical Materials Research.

"These heparin composite membranes and fibers and coated carbon nanotubes are an enabling technology," says Saravanababu Murugesan, a recent doctoral graduate in chemical and biological engineering at Rensselaer and lead author of the paper. "Our results show these novel materials have great promise in the development of improved medical devices that are blood compatible."

Image displays blood compatibility of carbon nanotube when coated with heparin.

The research team is led by Robert Linhardt, the Ann and John H. Broadbent Jr. '59 Senior Constellation Professor of Biocatalysis and Metabolic Engineering at Rensselaer, and includes collaboration with Pulickel Ajayan, the Henry Burlage Professor of Materials Science and Engineering, and Omkaram "Om" Nalamasu, professor of materials science and engineering, at Rensselaer. Additional co-authors of the paper are Shaker Mousa, director of the Pharmaceutical Research Institute at Albany College of Pharmacy, and Aravind Vijayaraghavan, a recent doctoral graduate in materials science and engineering at Rensselaer. Funding for this research was provided by the National Institutes of Health.

Recent results related to this work have been published online in the journals Langmuir ("Blood Compatible Nanotubes ï¿½ Nano-based Neoproteoglycans," Mar. 11, 2006) and Biomacromolecules ("Preparation of Biopolymer Fibers by Electrospinning from Room Temperature Ionic Liquids," Jan. 26, 2006). Provisional patents have been filed by Rensselaer Polytechnic Institute.

Research in Linhardt's group at the Center for Biotechnology and Interdisciplinary Studies at Rensselaer focuses on complex carbohydrates such as heparin. After determining the structure of these molecules, researchers study their biological activities to establish a structure-activity relationship that may reveal lead compounds for new drug development. Recent discoveries include a synthetic method for preparation of heparin in quantities large enough for use in medical treatment.

Potential of HOXB4 and Hematopoietic Stem Cell Expansion

Thu, 04 May 2006 23:22:37 PST

( from http://www.rxpgnews.com ) Throughout life, the body's tissues are maintained and repaired by stem cellsself-renewing cells that differentiate into many mature cell types. Every day, for example, the human body makes billions of white blood cells, red blood cells, and platelets from hematopoietic (blood system) stem cells (HSCs) to replace cells lost by normal wear and tear. This process of hematopoiesis helps to maintain a healthy immune system, enables sufficient oxygen to be carried around the body, and ensures effective blood clotting after wounding.

Some people, however, do not have a fully functioning hematopoietic system. They may have been born with a genetic alteration that disrupts the function of some blood cells, or they may have had chemotherapy for cancer that has destroyed their hematopoietic system. One way to help such people, who are often prone to infection, is to provide them with a new supply of HSCs through transplantation. HSCs are found in small numbers in the bone marrow and peripheral blood, as well as cord blood, which is harvested from the umbilical cord at birth. Cord blood is increasingly being used to treat hematopoietic disorders, but the low number of HSCs present in a unit of cord blood means that transplanted cells can be slow to establish themselves (or engraft) in an adult recipient, prolonging the time the patient is susceptible to infections. Consequently, researchers are looking for ways to encourage HSC expansion before transplantation. Xiao-Bing Zhang, Hans-Peter Kiem and colleagues now report that overexpression of a stem cell self-renewal gene called HOXB4 in HSCs improves their expansion and engraftment in a nonhuman primate model, particularly early after transplantation.

Overexpression of human HOXB4 in mouse HSCs is known to induce their ex vivo expansion without compromising their ability to differentiate. It also encourages the expansion of hematopoietic precursor cells from human cord blood, both in culture and when transplanted into mice. However, because immunodeficient mice do not support the differentiation of all human hematopoietic lineages, they are not an ideal model in which to investigate human HSC transplantation. Zhang, Kiem, and colleagues, therefore, turned to nonhuman primates, a well-established preclinical model for HSC transplantation and gene therapy, to investigate further whether treatment with HOXB4 holds promise for HSC expansion before transplantation.

The researchers first isolated CD34+ cells from six experimental animalsCD34 is a protein that is expressed only by lymphoid and myeloid hematopoietic precursor cells, which together differentiate into all the different blood cells. Next, the researchers split the CD34+ cells from each animal into two batches. One batch was treated with a retrovirus expressing HOXB4 tagged with a green fluorescent protein marker (HOXB4GFP+); the control batch was treated with a retrovirus expressing a yellow fluorescent protein marker (YFP+). Three or nine to 12 days later, the batches of cells were mixed and transplanted back into their respective donor animals, whose hematopoietic system had in the meantime been destroyed by irradiation. The researchers then tracked the labeled cells as they repopulated the animals.

Zhang, Kiem, and colleagues showed that, in this competitive repopulation assay, HOXB4 overexpression greatly improved the engraftment of CD34+ cells, particularly when the cells were expanded ex vivo for an additional six to nine days before transplantation. Short-term engraftment (two weeks after transplantation) of HOXB4GFP+ cells was up to 56-fold higher than that of YFP+ cells. Over time, the percentage of HOXB4-expressing cells in the animals' blood declined, but remained higher than the percentage of control cells even after six months, suggesting that HOXB4 overexpression might also improve long-term engraftment. Finally, the researchers report that three and six months after transplantation both the myeloid and lymphoid hematopoietic lineages contained HOXB4GFP+ and YFP+ cells. HOXB4GFP+ cells were more common in the myeloid lineage than YFP+ cells, but in lymphocytes the pattern was reversed, indicating that HOXB4 overexpression may have a larger effect on the engraftment and differentiation of myeloid precursors than of lymphoid precursors.

These results suggest that HOXB4-mediated ex vivo expansion of stem cells could be one way to accelerate the engraftment of HSCs from sources that contain limited numbers of stem cells (such as cord blood). Because only small numbers of animals were used in this proof-of-principle study, more experiments will be needed before it is clear whether HOXB4 can be used to improve the expansion and engraftment of CD34+ cells in patients whose hematopoietic system has failed. As the researchers point out, the availability of recombinant HOXB4 protein makes it possible to treat HSCs directly, without the potential problems associated with genetic manipulation of the cells.

Broad Institute scientists awarded $18M CARE grant

Thu, 04 May 2006 03:59:37 PST

( from http://www.rxpgnews.com ) The research funded by this award should result in new insights into how genetic variation contributes to health and disease, said Stacey Gabriel, principal investigator of the grant and the director of the Genetic Analysis platform and the National Center for Genotyping and Analysis at the Broad Institute. We will work together with other members of the CARE network to combine new methods for measuring genetic variation with an unprecedented collection of large, well-characterized clinical cohorts.

Known as the candidate gene association resource, or CARE, this project will survey the DNA of 50,000 individuals, using large-scale genotyping technologies and advanced informatics, to highlight the differences contained in specific genes of interest. These candidate genes represent a prioritized list of the likely sources of inherited variation that are most relevant for human disease.

The sheer scale of this project with genetic data collected from as many as 50,000 participants allows for more in-depth analyses of diseases across multiple races and ethnicities, said NHLBI Director Elizabeth G. Nabel, M.D. The database will be a tremendous resource for scientists -- speeding identification of risk factors and genetic variants associated with disease and disorders.

While inherited differences within our genes likely play roles in common diseases that affect major organ systems, such as the heart, lung and blood, their contributions appear to be complex and multifaceted, and therefore, difficult for scientists to identify. The sequencing of the human genome and recent completion of the Haplotype Map (HapMap), a comprehensive catalogue of common genetic differences in humans, has laid the groundwork needed to begin this task. Combining this knowledge with the NHLBI's information about the incidence and progression of disease in diverse populations allows scientists to now draw meaningful inferences about the genes that contribute to human disease.

By applying new, cutting-edge genetic, genomic and statistical methods to cohorts collected by NHLBI-funded investigators, we will definitively test the most promising genes for association with many important diseases and pre-disease states, said Joel Hirschhorn, a principal investigator, an associate member of the Broad Institute and coordinator of its Metabolic Disease Initiative, and an assistant professor at Children's Hospital Boston and Harvard Medical School. The discoveries that stem from this work will enlighten us as to why some people become ill and others remain healthy, and can help focus future efforts to develop improved disease therapies and preventive measures.

Over a 4-year period, the scientists will complete a comprehensive analysis of more than 1,700 candidate genes in individuals enrolled in NHLBI disease studies. This includes cataloguing tiny differences in DNA sequence known as single nucleotide polymorphisms (SNPs, pronounced snips). By using advanced bioinformatic methods to correlate this data with the observed features of disease, the researchers will be able to estimate the frequency of a particular SNP in the overall population, to predict the level of disease risk that it confers, and to approximate the degree to which it contributes to the severity of a particular disease. Marcia Nizzari, a co-investigator and the director of informatics development for the Medical and Population Genetics program at the Broad Institute, will help lead this computational effort.

This project is truly groundbreaking in the scope of genes that will be examined, the number of patients examined, and the quality of clinical information that is available, said co-investigator David Altshuler, director of the Program in Medical and Population Genetics at the Broad Institute and an associate professor at Massachusetts General Hospital and Harvard Medical School. By working together with the other members of the CARE network and making the results of this large-scale, collaborative effort accessible to other researchers, we hope to dramatically accelerate the pace at which gene variants provide insight into the root causes of human health and disease.

Deferasirox may revolutionize the way chronic iron overload is treated

Sun, 23 Apr 2006 18:22:37 PST

( from http://www.rxpgnews.com ) Those with severe chronic anemias need frequent blood transfusions to remain healthy, but such frequent transfusions can cause a potentially deadly buildup of iron in the body, leading to heart and liver failure. The traditional treatment to remove excess iron is so onerous that many patients choose to forgo it, putting their own lives at risk. The results of an international study on deferasirox, a new drug that may revolutionize the way chronic iron overload is treated, will be published in the May 1, 2006, issue of Blood, the official journal of the American Society of Hematology.

The current standard therapy to rid the body of excess iron is deferoxamine, administered for as long as the patient continues to receive blood transfusions, which, for many patients, can be for the rest of their lives. Although its effectiveness and safety are well-established, the necessity for the drug to be delivered by slow subcutaneous or intravenous infusion for eight to 12 hours a night over a period of five to seven days makes it an inconvenient and painful choice for patients. Unlike deferoxamine, deferasirox is available in a once-daily, drinkable format, providing a promising alternative.

"The ease and convenience of deferasirox means that more patients needing frequent blood transfusions, especially young children, will be able to be successfully treated and lead normal, healthy lives," said Maria Domenica Cappellini, MD, of the University of Milan, Italy, and lead study author.

To compare the efficacy and safety of the two drugs, a multicenter trial of both children (some as young as two years old) and adults diagnosed with chronic iron overload was conducted in a dozen countries worldwide. People with beta-thalassemia, an inherited blood disorder, were selected for this study because complications of chronic iron overload have been best studied in those with this disease. All participants continued receiving regular blood transfusions to treat beta-thalassemia throughout the year-long study.

Participants were randomized into two groups: 290 received deferoxamine infusions five days a week; 296 drank deferasirox dissolved in water each day before breakfast. Drug dosages were determined by each patient's liver iron concentration (LIC) level; those with higher levels received increased doses. Since LIC values above 7 mg Fe/g dw are associated with increased morbidity and mortality, the primary goal of the trial was to reduce LIC levels in those with high values and maintain LIC levels in those with low values. At the beginning of the study, more than two-thirds of the participants had at-risk LIC levels.

Deferasirox proved to be equally as effective as deferoxamine in patients receiving the highest doses of the drug. A majority of these patients (nearly 60 percent), demonstrated sustained or reduced LIC levels during the study. For those receiving the lowest drug doses, the amount of deferasirox was found to be insufficient in these regularly transfused thalassemia patients.

Deferasirox was generally well-tolerated. The most common side effects were skin rash (affecting approximately 11 percent of patients) and gastrointestional problems, which occurred in 15 percent of the group and included abdominal pain, vomiting, diarrhea, and constipation. Most patients (92 percent) were able to complete the study, though a small number in each treatment arm discontinued because of safety reasons. Four deaths, determined to be unrelated to the study drugs, also occurred during the trial.

Research team to examine impact of genetics and exposure to secondhand smoke

Fri, 21 Apr 2006 03:59:37 PST

( from http://www.rxpgnews.com ) If those children also have a variation in at least one of four genes responsible for metabolizing nicotine, their risk may increase even more because nicotine might stay in the body longer and do more damage, an interdisciplinary research team says.

Researchers will study 585 children age 15-20 who have a parent, grandparent or both with essential hypertension and/or a heart attack by age 55.

What I hope to take away from this is more information for parents and caregivers to be able to share with them information about the risk of future disease that their behavior places on their child, says Dr. Martha Tingen, a nurse researcher at the Georgia Prevention Institute and principal investigator on the $220,000 National Institute of Nursing Research grant.

Researchers will look for adverse clinical cardiovascular measures, including reduced ability of arteries to dilate; the blood encountering increased resistance as it travels through vessels; higher blood pressure; and an increase in the size of the pumping chamber of the heart a result of pumping against elevated pressure.

Exposure to the damaging effects of nicotine and other pathogens in smoke may also cause a vicious cycle in the body.

It likely causes damage to cells on the inner wall lining of blood vessels, which results in less adaptive capacity of the vessels and arteries, which may then cause greater strain on the heart, says Dr. Tingen.

Children exposed to secondhand smoke who have a variation of one or more of the genes that metabolize nicotine CYP1A1, GSTM1, GSTT1 and CYP2A6 can experience cellular damage because the nicotine does not leave the body as quickly, she says.

And if that's happening, they're going to have more of these adverse pre-clinical cardiovascular measures that predispose them to developing cardiovascular disease, she says.

This research is particularly important because nearly 50 percent of people ages 17 and older are exposed to secondhand smoke in the workplace and each year in Georgia alone, 423,000 children are exposed to smoke at home. In the United States, 45,000-60,000 cardiovascular deaths each year are linked to non-smoker's exposure to secondhand smoke, Dr. Tingen says.

The first step will be to unfreeze the blood samples the children come from a 15-year longitudinal database kept by Dr. Frank Treiber, MCG vice president for research and a GPI child psychologist. Then Drs. Yanbin Dong and Haidong Zhu, MCG molecular geneticists, will perform the genotyping looking for children with variations in the identified genes. Dr. Gaston Kapuku, a GPI cardiologist, will help interpret the cardiovascular measures. The blood samples will then be sent to Advanced Bioanalytical Service Laboratories in London for analysis of cotinine levels, a metabolized version of nicotine and a reliable indicator of secondhand smoke exposure.

If kids are exposed in the home and they have genetic alterations that make nicotine stay in the body longer, then there's an increased likelihood that they're at greater risk for developing cardiovascular disease, says Dr. Tingen.