Scientists Identify Human Monoclonal Antibodies Effective Against Bird and Seasonal Flu Viruses

Monday, February 23, 2009

Researchers at the Dana-Farber Cancer Institute (Dana-Farber), Burnham Institute for Medical Research (Burnham) and the Centers for Disease Control and Prevention (CDC) have reported the identification of human monoclonal antibodies (mAb) that neutralize an unprecedented range of influenza A viruses, including avian influenza A (H5N1) virus, previous pandemic influenza viruses, and some seasonal influenza viruses. These antibodies have the potential for use in combination with other treatments to prevent or treat certain types of avian and seasonal flu.

The antibodies identified by the team of scientists neutralize a broad range of influenza A subtypes because they bind to the highly conserved stem region of H5 type hemagglutinin (HA). Binding to the stem prevents a conformational change in the protein that is necessary for viral entry into the host cell, thereby preventing further infection of host cells and the rise of escape mutants.

“The head portion of hemagglutinin is highly mutable, leading to the rise of forms of the virus that can evade neutralizing antibodies,” said Robert Liddington, Ph.D., professor and director, Infectious and Inflammatory Disease Center at Burnham and one of the investigators on the study. “However, the stem region of hemagglutinin is highly conserved because it undergoes a dramatic conformational change to allow entry of viral RNA into the host cell. It’s very difficult to get a mutation that doesn’t destroy that function, which explains why we aren’t seeing escape mutants and why these antibodies neutralize such a variety of strains of influenza.”

While more costly to produce than existing influenza drugs, therapeutic antibodies can be readily manufactured and stockpiled. In the event of a pandemic, the antibodies could be used in combination with antiviral therapies to contain the outbreak until a vaccine became available. The production of a new influenza vaccine takes six to nine months using conventional methods.

“There are clear settings where human monoclonal antibodies can be used strategically for both the prevention and early treatment of influenza infection and disease,” said Wayne A. Marasco, M.D., Ph.D., associate professor of medicine at Dana-Farber and Harvard Medical School. “At-risk individuals, such as first responders and medical personnel, exposed family members and coworkers and patients who cannot make antibodies because of pre-existing medical conditions or advanced age, could all benefit from this new type of therapy.”

In the study, the team of scientists used a human antibody phage display library to identify 10 mAb that bind to the stem of H5 type HA, the influenza protein responsible for viral entry into the host cell. The scientists determined the X-ray crystal structure of the mAb bound to the H5N1 HA, which showed that the heavy chain of the mAb inserts into a highly conserved pocket in the HA stem, inhibiting the conformational change required for membrane fusion and viral entry into the cell.

The scientists further showed that an unprecedented number of different types of bird flu and seasonal influenza viruses were inhibited and the mAb protected mice that were exposed to H5N1 virus. “Our human monoclonal antibody protected mice from the lethal H5N1 virus even when injected three days after infection. This is good news, but many antibodies can do this. What surprised us is that the same antibody protected mice from a lethal infection with a very different virus such as the H1N1 subtype that causes seasonal human infections; this is really remarkable,” said Dr. Ruben Donis, chief of the Molecular Virology and Vaccines Branch at CDC.

Vaccines consisting of attenuated or killed virus do not typically stimulate antibodies against the stem, perhaps because it is less accessible than the head region. In this study, the scientists used recombinant purified protein, not virus, so the antigenic part of the virus recognized by the antibodies was fully exposed.

Seasonal influenza occurs each year, causing mild to severe illness. Worldwide, more than 250,000 deaths from seasonal influenza occur annually. The best protection from seasonal influenza is yearly vaccination.

Influenza pandemics are worldwide outbreaks of disease that occur when a new influenza virus emerges for which people have little or no immunity. The disease spreads easily person-to-person, causes serious illness, and can spread across the country and around the world in a very short time. Health professionals are concerned that the continued spread of a highly pathogenic avian influenza A (H5N1) virus across eastern Asia and other countries represents a significant threat to human health. While vaccines can control influenza, they are not always effective because the vaccine must be updated each year. Vaccines against H5N1 in development have shown promise, but none has been reported to elicit a broad response in humans that would cover a broad range of different H5N1 virus strains. Antiviral medications, including the neuraminidase inhibitor oseltamivir (Tamiflu ®), is the primary treatment method, but has limited effectiveness if administered more than 24-48 hours after symptom onset.

The study was published online on February 22 in Nature Structural and Molecular Biology.

Source: Burnham Institute for Medical Research

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Time Stamp: 2/23/2009 at 3:08:19 PM UTC

Global Warning: Hotter Days, Increased Hospitalizations for Respiratory Problems

Friday, February 20, 2009

High summer temperatures, pushed higher by global climate change, may bring with them a spike in hospitalizations for respiratory problems, according to an analysis of data from twelve European cities, from Dublin to Valencia. The data comes from the "Assessment and Prevention of Acute Health Effects of Weather Conditions in Europe" (PHEWE), a multi-center, three-year collaboration between epidemiologists, meteorologists and experts in public health collaboration that investigated the short-term effects of weather in Europe.

As climate change has gone from a scientific theory to an accepted and encroaching reality, more extreme weather, including hotter summers, is anticipated around the planet. But the secondary effects of climate change are also coming into sharper focus.

The PHEWE project evaluated the effects of higher temperatures on hospitalizations for a number of different conditions in Europe. They found that for every degree increase over a temperature threshold, there was a four percent average increase in respiratory-related hospitalizations, but not for cardiovascular or neurovascular- related problems.

The results were published in the first issue for March of the American Thoracic Society's American Journal of Respiratory and Critical Care Medicine.

"The PHEWE project represents the first attempt to evaluate the effect of temperature on several morbidity outcomes using a standardized methodology in a multi-center European study," wrote Paola Michelozzi Ph.D., head of Environmental Epidemiology at the Department Epidemiology of the Local Health Authority, in Rome.

The study tracked hospital admissions in twelve European cities. Each city provided data for a minimum of a three-year period between 1990 and 2001 that included hospital admissions, meteorological and air pollution data. They then computed a "maximum apparent temperature"—Tappmax for each city, using an index that accounted for both air temperature and humidity. At the far ends of the spectrum, the researchers found that Dublin had a Tappmax of 14.7ºC (about 58ºF) whereas Valencia’s was 29.5ºC (about 85ºF). In most cities, each degree increase over 90 percent of the Tappmax, respiratory disease-related hospital admissions increased for all ages and especially in the 75+ age group.

Interestingly, while cardiovascular deaths are known to go up with the temperature, there was a slight decrease in hospitalizations. The researchers speculated that the acute onset of cardiovascular events could result in sudden deaths before medical treatment was possible.

"The contrasting pattern between admissions and mortality could also be related to differences in physiopathologic mechanisms," wrote Dr. Michelozzi. "...[C]ardiovascular deaths during hot days tend to occur suddenly in persons whose health is compromised. Respiratory mortality, on the contrary, tends to peak later than cardiovascular mortality, with effects observed up to three weeks after exposure..."

Despite the increase of respiratory-related hospitalizations overall, the observed effect was heterogeneous among cities, indicating the need for further study.

“This is in part due to differences in exposure, the large variability among the cities analyzed, the differences in adaptive capacity and the vulnerability of populations due to their socio-demographic characteristics, as well as differences in the preventive measures in place,” said Dr. Michelozzi. “Moreover, across European countries there is wide variation in healthcare and hospital admissions availability. Although all these differences are important, our results document an effect of high temperature on hospital admissions for respiratory causes in several cities, and this is the strength of the study.”

"These findings are important for public health because the prevalence of chronic diseases, such as COPD, is expected to increase in developed countries as a result of population aging," wrote Dr. Michelozzi. "Furthermore, under climate change scenarios, the increase in extreme weather events and certain air pollutants, especially ozone, are likely to further aggravate chronic respiratory diseases. Public health interventions should be directed at preventing this additional burden of disease during the summer season. The observed heterogeneity of the health effects indicates a need to tailor programs for individual cities."

Audio Caption: John Heffner, M.D. Past president of the American Thoracic Society, discusses the context and implications of this study

Audio Credit: American Thoracic Society

Source: American Thoracic Society

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Time Stamp: 2/20/2009 at 6:30:00 AM UTC

New Prognostic Indicator for patients with IPF

Friday, February 20, 2009

There may be a new way to predict mortality in patients with idiopathic pulmonary fibrosis (IPF), a devastating disease that slowly petrifies the lungs. Most patients live only three years after diagnosis on average; however, some remain stable for many years, while for others, the disease progresses more rapidly.

“There is no effective treatment [for IPF] and many patients, if eligible, are referred for lung transplantation. Identification of surrogate short-term measures of mortality is critical to the management and study of patients with IPF.” explained lead author Charlene Fell, M.D., of the Division of Respiratory Medicine at the University of Calgary.

The study found that maximal oxygen uptake during exercise, or VO2max, can predict mortality in IPF patients. VO2max is an integrated measure of cardiovascular, respiratory and neuromuscular function and is a standard measure during cardiopulmonary exercise testing.

The results were published in the first issue for March of the American Journal of Respiratory and Critical Care Medicine, published by the American Thoracic Society.

Dr. Fell and colleagues performed a retrospective analysis of 117 patients in the University of Michigan’s Specialized Center of the Pathobiology of Fibrotic Lung Disease database and analyzed their oxygen uptake during exercise with their subsequent mortality.

“We found that VO2max examined as a continuous variable does not predict mortality in IPF. However, baseline threshold VO2max of 8.3 ml/kg/min predicts mortality in these patients,” wrote Dr. Fell.

Those patients with a VO2max of less than 8.3 ml/kg/min had a risk of death more than three times that of patients whose VO2max was above the threshold. VO2max was compared with two other predictors of survival in IPF, oxygen desaturation during a six-minute walk test (6MWT) and resting arterial oxygen partial pressure (PaO2), and in both cases, VO2max was found to be a more robust predictor.

“Furthermore, VO2max is easier to use in the clinical setting than other predictors which require cumbersome calculations,” said Dr. Fell.

“One caveat to the VO2max predictor is that only a small number of patients had a VO2max below the 8.3 ml/kg/min threshold in our study, [so] further prospective studies are needed to validate these findings,” said Dr. Fell. “If the value of this predictor is proven in prospective studies, it may help clinicians prioritize patients for lung transplantation or identify patients for clinical trials.”

Research Article PDF: http://www.sflorg.com/comm_center/medical/pdf/p859_89_01.pdf

Source: American Thoracic Society

Permalink: http://www.sflorg.com/comm_center/medical/p859_89.html

Time Stamp: 2/20/2009 at 5:27:52 AM UTC

Gene Mutation Adds Risk in Child Kidney Transplants

Wednesday, February 18, 2009

Screening for mutations in a gene that helps the body metabolize a kidney transplant anti-rejection drug may predict which children are at higher risk for side effects, including compromised white blood cell count or organ rejection, according to new research.

Published online Feb. 18 by the Nature journal Clinical Pharmacology and Therapeutics, the study suggests this genetic approach could also help physicians tailor personalized anti-rejection drug doses to prevent adverse reactions, said senior investigators Alexander A. Vinks, Pharm.D., Ph.D., and Jens Goebel M.D., of Cincinnati Children’s Hospital Medical Center.

“There are better ways than just giving standard doses of these drugs, and in due course these types of technologies will be available worldwide to help patients,” said Dr. Vinks, director of the Division of Clinical Pharmacology and the Pediatric Pharmacology Research Unit at Cincinnati Children’s. “This pilot study shows personalized and prospective MMF dosing and monitoring may be feasible to reduce the high incidence of drug toxicity in children without compromising the drug’s protective effects against kidney graft rejection.”

MMF, or Mycophenolate Mofetil, is an immunosuppressive agent commonly used to prevent rejection in organ transplants, particularly in kidney transplants. After taken orally, the drug is quickly processed by the body into active form. During this time, patients with a specific point mutation in the gene that helps break down the drug, UGT, metabolize the drug slower. This point mutation, called UGT1A9-331, causes overexposure and adverse side effects in the affected children, the study concluded. UGT encodes the drug’s main metabolizing enzyme in the body, uridine diphosphate-glucuronosyl transferase.

Adverse side effects most commonly linked to MMF have included gastrointestinal complications (such as diarrhea) or leukopenia – a drop in white blood cell count that can put patients at higher risk for infections. In some instances, patients have to be taken off the drug or have their dosage reduced to the point where they risk rejection of the new organ.

The current study analyzed 38 children who had received kidney transplants. Sixteen of the children experienced adverse side effects from MMF therapy. In the adverse reaction group, nine children with the specific UGT point mutation developed leukopenia. The researchers found no strong association between UGT gene variants and diarrhea – the most common side effect linked to MMF – suggesting gastrointestinal reactions to the drug may be caused by other factors.

Some previous studies have linked UGT gene mutations and MMF-related side effects in kidney transplant recipients, while others have suggested a greater risk for adverse events in children. A review of earlier research combined with their current data led researchers in this study to conclude that pediatric kidney transplant recipients on MMF therapy have a significantly higher likelihood of drug-related complications than adult patients. One previous study compared 22 pediatric and 37 adult transplant recipients, all who started with the standard recommended doses of MMF. Among the children, 54.5 percent experienced adverse side effects compared to 21.6 percent of the adults.

Besides the UGT1A9-331 point mutation, other studies have also linked a second variation, called UGT2B7-900, to possible MMF overexposure and development of leukopenia, said Tsuyoshi Fukuda, Ph.D., co-author on the current study and a colleague in Dr. Vinks’ division at Cincinnati Children’s. The research team recently completed pharmacokinetic and biomarker studies – which analyze how the body metabolizes a drug – to solidify the connection between different variants of UGT and MMF overexposure in pediatric kidney transplant patients.

Researchers want to use data from these pharmacokinetic studies as a basis for showing whether increased MMF exposure in adults can also be linked to specific variations in the UGT gene, according to Dr. Fukuda.

The pilot study is part of the growing field of genetic-based pharmacology, or pharmacogenetics. Combining biology and information technology, researchers are developing computer-based algorithms that allow taking a few drops of blood and analyzing how quickly a person’s body will break down and absorb a drug based on their genetic makeup. The goal is to reduce drug-related side affects by optimizing drug doses for individual patients.

Dr. Goebel is medical director of Kidney Transplantation Program in the Division of Nephrology and Hypertension at Cincinnati Children’s. Also participating in this study were the divisions of Human Genetics and Biostatistics/Epidemiology at Cincinnati Children’s, the National Institutes of Health’s Pediatric Pharmacology Research Unit network, the Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, and the University of Arkansas for Medical Sciences and Arkansas Children’s Hospital, Little Rock, Ark.

Funding support came from the National Institutes of Health and a translational research initiative grant from Cincinnati Children’s.

Source: Cincinnati Children's Hospital Medical Center

Permalink: http://www.sflorg.com/comm_center/medical/p852_88.html

Time Stamp: 2/18/2009 at 4:41:13 PM UTC

Under Embargo Till: 17:00 UTC February 17, 2009
Posted: 17:00 UTC 02/17/2009

Tumor Suppressor Could Someday Regulate Fibrotic Diseases

Tuesday, February 17, 2009

A new study finds a cellular signaling pathway that could be responsible for some connective tissue diseases such as scleroderma. The study also suggests a new function for tumor suppressors in combating fibrotic diseases. The study is published in the February issue of Developmental Cell. The study was co-authored by Dr. Philippe Soriano, Professor of Developmental and Regenerative Biology and Oncological Sciences at Mount Sinai School of Medicine, and Dr. Lorin E. Olson, Postdoctoral fellow at Mount Sinai, and was initiated at the Fred Hutchinson Cancer Research Center in Seattle, Washington.

Systemic sclerosis, or scleroderma, is a group of autoimmune diseases that affects an estimated 300,000 people in the United States. These diseases are characterized by chronic autoimmune reactions, microvascular restriction, and widespread fibrosis of the skin and other organs or excessive levels of connective tissue. This can take place in the gastrointestinal system, skeletal muscle, heart, kidney, and lungs, and frequently can result in organ failure and death. “There is no known cause or cure for the diseases collectively known as scleroderma. This research could result in the development of treatments to alleviate the often painful symptoms associated with these kinds of diseases,” said Dr. Soriano.

For the study, gene targeted mice were manipulated with mutations that increase signaling activity by the Platelet Derived Growth Factor Receptor-alpha (PDGFRa). Increased PDGFRa activation in embryos leads to connective tissue hyperplasia and disrupts organ function, and increased PDGFRa activation in adult mice lead to systemic fibrotic disease in multiple organs. Loss of the tumor suppressor gene (Ink4a/Arf) accelerated fibrosis when combined with PDGFRa activation, revealing a possible new role for tumor suppressors in regulating fibrotic diseases.

This work provides insight into the signaling pathways involved in connective tissue disease and highlights a new role for tumor-suppressor genes in the regulation of fibrotic conditions. “This research is also important because it establishes an animal model for testing novel therapies for blocking aberrant PDGFRa signaling in human disease,” said Dr. Soriano.

Source: Mount Sinai Medical Center

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Time Stamp: 2/17/2009 at 17:00:00 UTC

Study Suggests New Treatment Approach May be Needed for Management of Depression in Some People With Bipolar Disorder

Thursday, February 12, 2009

In a study published in The American Journal of Psychiatry, a team of researchers led by Mayo Clinic psychiatrist Mark Frye, M.D., attempted to identify what factors make some people with bipolar depression more likely to experience treatment-emergent mania (TEM).

Bipolar disorder, also known as manic-depressive illness, is a mental illness characterized by severe mood instability that can be serious and disabling. The deep mood swings from high (mania) to low (depression) may last for weeks or months, causing great disturbances in the lives of the person who has the illness, along with family and friends. Drugs known as mood stabilizers have proven effective at controlling the manic phase of the illness, but treating the depressive phase is more problematic. Antidepressants, although effective for some individuals, can trigger a rapid mood switch from depression to mania, a phenomenon called treatment-emergent mania.

"TEM is a serious and sometimes volatile adverse event, and we wanted to better understand who was at risk for developing this problem," says Dr. Frye. People experiencing mania often exhibit poor judgment and impulsivity that can lead them to engage in highly unsafe or personally damaging behaviors, resulting in hospitalization, arrest and/or incarceration.

Dr. Frye's team did a secondary analysis of data obtained in an earlier study led by Robert Post, M.D., and the Bipolar Collaborative Network. In that earlier study, researchers followed 176 study participants diagnosed with bipolar depression to measure the effectiveness of three different antidepressants. The secondary analysis led by Dr. Frye focused on 44 patients who experienced TEM after starting an antidepressant. Dr. Frye's team compared this TEM group to 84 patients who responded favorably to an antidepressant and 44 patients who stopped taking the antidepressant due to lack of effectiveness or worsening depressive symptoms.

"We found that people who had minimal manic symptoms or a "mixed depression" presentation were at greatest risk for experiencing TEM," says Dr. Frye.

Experts have begun to acknowledge that the common understanding of bipolar illness, once thought to be a disorder with two distinct phases (a manic upswing and a depressive downswing), may be incomplete. A recent study of over 1,300 patients conducted by Joseph Goldberg, M.D., Mount Sinai School of Medicine, reported that two-thirds of the depressed bipolar patients had minimal or mild manic symptoms "mixed" together.

"We're learning that this illness does not occur in two neat, clear-cut phases, but rather a mix of the two," says Dr. Frye. "Our data would suggest that people with mixed depression may need to stay away from antidepressants and work with their health care providers to find alternative treatments, such as mood stabilizers, to help manage the depressive phase of their illness." Further research is encouraged to better understand the best treatment for these mixed presentations.

Other authors for this article include: Gerhard Helleman, Ph.D., David Geffen School of Medicine at UCLA, Los Angeles; Susan McElroy, M.D., University of Cincinnati College of Medicine; Lori Altshuler, M.D., David Geffen School of Medicine at UCLA, Los Angeles; David Black, Ph.D., Pediatric and Developmental Neuropsychiatry, National Institute of Mental Health (NIMH), National Institutes of Health (NIH), Bethesda, Md., and David Geffen School of Medicine at UCLA, Los Angeles; Paul Keck Jr., M.D., University of Cincinnati College of Medicine; Willem Nolen, M.D., Ph.D., University Medical Center Groningen, University of Groningen, the Netherlands; Ralph Kupka, M.D., Ph.D., Altrecht Institute for Mental Health Care and University Medical Centre, Utrecht, the Netherlands; Gabriele Leverich, Biological Psychiatry Branch, NIMH, NIH, Bethesda, Md.; Heinz Grune, M.D., Institute of Neuroscience, Newcastle University, Newcastle, England; Jim Mintz, Ph.D., University of Texas San Antonio; Robert Post, M.D., George Washington School of Medicine, Penn State College School of Medicine and Bipolar Collaborative Network, Bethesda, Md.; and Trisha Suppes, M.D., Ph.D., Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas.

Source: Mayo Clinic

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Time Stamp: 2/12/2009 at 6:09:38 PM UTC

Researchers Find Abnormal Cells in the Blood Years before Leukemia is Diagnosed

Thursday, February 12, 2009

Researchers have shown that abnormal white blood cells can be present in patients’ blood more than six years prior to the diagnosis of a chronic form of lymphocytic leukemia. This finding may lead to a better understanding of the cellular changes that characterize the earliest stages of the disease and how it progresses. The study, led by researchers at the National Cancer Institute (NCI), part of the National Institutes of Health, and the U.S. Food and Drug Administration, was published in the Feb. 12, 2009, issue of the New England Journal of Medicine.

"This finding emphasizes the need to better define predictors of cancer development," said NCI Director John E. Niederhuber, M.D. "Identifying the earliest indicators of cancer gives researchers an opportunity to study the window from the prediagnostic state to the transformation to disease. This may help define risk factors and may allow for the discovery of novel molecular targets for treatment of the disease."

Chronic lymphocytic leukemia (CLL) is a blood cancer that usually progresses slowly over many years. In this disease, abnormal white blood cells called B-cells accumulate in the blood and the bone marrow. The lymph nodes, spleen, and other organs may also be affected. Although CLL is the most common form of leukemia in adults in Western countries, little is known about what causes the disease or how it develops.

Previous research by the NCI/FDA team and others showed that some family members of CLL patients can have B-cells in their blood that have outer-surface proteins that are similar to proteins found on CLL cells. This abnormal condition, known as monoclonal B-cell lymphocytosis (MBL), occurs in over 10 percent of CLL family members and in about 3 percent to 5 percent of healthy adults over the age of 50, suggesting it might be a precursor of CLL.

In the current study, the research team identified 45 individuals among the more than 77,000 participants in the nationwide Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial who were cancer-free upon entering the trial, were later diagnosed with CLL, and had frozen blood samples available for analysis that had been collected upon their enrollment in PLCO. Using sophisticated laboratory techniques to analyze the blood samples, the researchers found that 44 of the 45 CLL patients had MBL between six months to more than six years prior to their CLL diagnosis. The MBL cells were identified by examining cell-surface proteins, or CLL markers, using a method called flow cytometry, and by using molecular techniques to confirm the presence of certain rearranged genes, known as immunoglobulin heavy variable (IGHV) group genes, found in CLL. In 41 patients, MBL was confirmed by both methods.

"Our findings indicate that MBL is present in virtually all of CLL patients prior to full-blown disease," said lead author Ola Landgren, M.D., Ph.D., of NCI’s Division of Cancer Epidemiology and Genetics. "This important discovery provides novel insights into the natural history of CLL and will open new fields of investigation for understanding its causes." The risk of developing CLL for individuals with MBL appears to be low — on average, it is estimated that each year, only about one percent of them will develop CLL, he noted.

"Next, it will be important to isolate MBL cells and to conduct additional molecular analyses," says Gerald Marti, M.D., Ph.D., of the FDA’s Center for Biologics Evaluation and Research, another study author. "This will provide insight into the differences in these cells that may influence why some transform into CLL whereas other do not."

Although the results might not have immediate implications for clinical practice, such as routine screening for MBL, the study will have an influence on CLL research. According to Neil Caporaso, M.D., another NCI author, "Identifying and studying MBL will provide insight that is not available when studying CLL itself. An important and unanswered question is what causes some individuals with MBL to progress to CLL while others remain disease free. Investigating MBL may help us to determine early risk factors for the disease and allows us to identify the precise molecular changes that occur in these cells that cause them to transform into CLL."

The NCI/FDA team says that the work underscores the importance of studying family history and progression of disease. Performing evaluations of members of cancer-prone families has been key to the identification and characterization of MBL; current work focuses on trying to identify molecular markers and environmental influences that predict risk and genes that influence CLL development. The team is working to characterize MBL better and to understand its biology to further define factors that lead to CLL. The team is also conducting studies that focus on related blood cancers and their precursors, including multiple myeloma and monoclonal gammopathy of undetermined significance.

Source: NIH

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Time Stamp: 2/12/2009 at 5:44:52 PM UTC

From Outer Space to the Eye Clinic: New Cataract Early Detection Technique

Thursday, January 8, 2009

Patients and Astronauts Benefit from NEI-NASA Collaboration

A compact fiber-optic probe developed for the space program has now proven valuable for patients in the clinic as the first non-invasive early detection device for cataracts, the leading cause of vision loss worldwide.

Researchers from the National Eye Institute (NEI), part of the National Institutes of Health, and the National Aeronautics and Space Administration (NASA) collaborated to develop a simple, safe eye test for measuring a protein related to cataract formation. If subtle protein changes can be detected before a cataract develops, people may be able to reduce their cataract risk by making simple lifestyle changes, such as decreasing sun exposure, quitting smoking, stopping certain medications and controlling diabetes.

“By the time the eye’s lens appears cloudy from a cataract, it is too late to reverse or medically treat this process," said Manuel B. Datiles III, M.D., NEI medical officer and lead author of the clinical study. "This technology can detect the earliest damage to lens proteins, triggering an early warning for cataract formation and blindness."

The new device is based on a laser light technique called dynamic light scattering (DLS). It was initially developed to analyze the growth of protein crystals in a zero-gravity space environment. NASA’s Rafat R. Ansari, Ph.D., senior scientist at the John H. Glenn Research Center and co-author of the study, brought the technology’s possible clinical applications to the attention of NEI vision researchers when he learned that his father’s cataracts were caused by changes in lens proteins.

Several proteins are involved in cataract formation, but one known as alpha-crystallin serves as the eye’s own anti-cataract molecule. Alpha-crystallin binds to other proteins when they become damaged, thus preventing them from bunching together to form a cataract. However, humans are born with a fixed amount of alpha-crystallin, so if the supply becomes depleted due to radiation exposure, smoking, diabetes or other causes, a cataract can result.

"We have shown that this non-invasive technology that was developed for the space program can now be used to look at the early signs of protein damage due to oxidative stress, a key process involved in many medical conditions, including age-related cataract and diabetes, as well as neurodegenerative diseases such as Alzheimer’s and Parkinson’s," said NASA’s Dr. Ansari. "By understanding the role of protein changes in cataract formation, we can use the lens not just to look at eye disease, but also as a window into the whole body."

The recent NEI-NASA clinical trial, reported in the December 2008 Archives of Ophthalmology, looked at 380 eyes of people aged 7 to 86 who had lenses ranging from clear to severe cloudiness from cataract. Researchers used the DLS device to shine a low-power laser light through the lenses. They had previously determined alpha-crystallin’s light-scattering ability, which was then used to detect and measure the amount of alpha-crystallin in the lenses.

They found that as cloudiness increased, alpha-crystallin in the lenses decreased. Alpha-crystallin amounts also decreased as the participants’ ages increased, even when the lenses were still transparent. These age-related, pre-cataract changes would remain undetected by currently available imaging tools.

"This research is a prime example of two government agencies sharing scientific information for the benefit of the American people," said NEI director Paul A. Sieving, M.D., Ph.D. "At an individual level, this device could be used to study the effectiveness of anti-cataract therapies or the tendency of certain medications to cause cataract formation."

The DLS technique will now assist vision scientists in looking at long-term lens changes due to aging, smoking, diabetes, LASIK surgery, eye drops for treating glaucoma, and surgical removal of the vitreous gel within the eye, a procedure known to cause cataracts within six months to one year. It may also help in the early diagnosis of Alzheimer’s disease, in which an abnormal protein may be found in the lens. In addition, NASA researchers will continue to use the device to look at the impact of long-term space travel on the visual system.

"During a three year mission to Mars, astronauts will experience increased exposure to space radiation that can cause cataracts and other problems," Dr. Ansari explained. "In the absence of proper countermeasures, this may pose a risk for NASA. This technology could help us understand the mechanism for cataract formation so we can work to develop effective countermeasures to mitigate the risk and prevent it in astronauts."

The NASA John H. Glenn Research Center is one of NASA’s 10 field centers, empowered with the resources for developing cutting-edge technologies and advancing scientific research that addresses NASA’s mission to pioneer the future in space exploration, scientific discovery and aeronautics research. Working in partnership with government, industry and academia, the Center serves to maintain the U.S. economy’s global leadership while benefiting the lives of people around the world.

Source: NIH

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Time Stamp: 1/8/2009 at 4:58:34 PM UTC

Obesity: Reviving the Promise of Leptin

Tuesday, January 6, 2009

The discovery more than a decade ago of leptin, an appetite-suppressing hormone secreted by fat tissue, generated headlines and great hopes for an effective treatment for obesity. But hopes dimmed when it was found that obese people are unresponsive to leptin due to development of leptin resistance in the brain. Now, researchers at Children’s Hospital Boston report the first agents demonstrated to sensitize the brain to leptin: oral drugs that are already FDA-approved and known to be safe. Findings were published January 7 by the journal Cell Metabolism.

In 1995, researchers reported in Science that they had isolated a protein that is present in normal mice, but not in an obese strain of mice called ob/ob, which lacked a gene also called ob. When either obese or normal mice were directly injected with the protein – now called leptin – they ate less and lost weight.

“Everyone in the field thought they would get the Nobel,” says Umut Ozcan, MD, of Children’s Division of Endocrinology. Unfortunately, when obese humans took the hormone, they lost weight only temporarily – then rebounded back. “Most humans who are obese have leptin resistance,” says Ozcan. “Leptin goes to the brain and knocks on the door, but inside, the person is deaf.”

For years, industry and academic laboratories have been searching for a drug to make peoples’ brains sensitive to leptin again, without success.

In the new study, Ozcan’s group first showed that the brain cells of obese mice have increased stress in the endoplasmic reticulum (ER) – a structure within the cell where proteins are assembled, folded into their appropriate configurations, and dispatched to do jobs for the cell. In the presence of obesity, the ER is overwhelmed and can’t function properly. This stress triggers a signaling cascade (the “unfolded protein response”) that tries to relieve the stress by increasing the level of molecular “chaperones,” which assist in protein folding, and by blocking more proteins from coming in.

Ozcan and colleagues then showed that ER stress, and the resulting activation of this signaling cascade, blocks leptin action in the brain. Most intriguingly, they showed that using chemical chaperones to reduce ER stress can re-sensitize the brain to leptin, and lead to weight loss when used in conjunction with leptin. “I think our study will bring new hope for the treatment for obesity,” says Ozcan.

Working first with mice made obese through a high-fat diet, they demonstrated that the animals developed ER stress in the hypothalamus, the main area of the brain where leptin signals. This in turn initiated the unfolded-protein response, rendering the mice extremely leptin-resistant. The team also created a strain of mice whose ER was weakened in the brain through deletion of a gene called XPB1 specifically in the neurons. These mice also developed ER stress and leptin resistance, and also became obese, despite having some of the highest leptin levels ever reported. As expected, the mice also ate more and gained more weight.

But when Ozcan and colleagues pretreated either group of mice with a chemical chaperone (either 4-PBA or TUDCA) leptin sensitivity increased as much as 10-fold, and the mice had significant weight loss with leptin treatment even when fed a high-fat diet.

Children’s researchers hope to eventually move the discovery to human trials. Both 4-PBA and TUDCA are safe in humans and already FDA-approved for clinical use. 4-PBA (Buphenyl) used in urea cycle disorders and in cystic fibrosis; TUDCA (tauroursodeoxycholic acid), used for centuries in traditional Chinese medicine, is currently used in some liver diseases. Both agents are under study for use in neurologic disorders such as Alzheimer’s disease and Huntington’s disease.

In related work in 2006, Ozcan and colleagues reported in Science that chemical chaperones reduce ER stress in a mouse model of type 2 diabetes, normalizing blood sugar and restoring insulin sensitivity.

In 1995, Amgen, Inc. (Thousand Oaks, CA) paid $20 million for commercial rights to recombinant human leptin, a record amount for a deal with an academic institution. In 2006, Amgen sold the rights to Amylin Pharmaceuticals (San Diego, CA). Amylin is testing leptin in combination with its diabetes drug, pramlintide.

The current study was supported by the Timothy Murphy Fund, Junior Faculty Start-Up Funds provided to Ozcan from Children’s Hospital Boston, and a Translational Research Award from Children’s Hospital Boston.

Source: Children's Hospital Boston

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Time Stamp: 1/6/2009 at 6:18:33 PM UTC

In Lung Cancer, Silencing One Crucial Gene Disrupts Normal Functioning of Genome

Wednesday, December 31, 2008

While examining patterns of DNA modification in lung cancer, a team of international researchers has discovered what they say is a surprising new mechanism. They say that “silencing” of a single gene in lung cancer led to a general impairment in genome-wide changes in cells, contributing to cancer development and progression.

In the January 1, 2009, issue of Cancer Research, a journal of the American Association for Cancer Research, they also report finding a strong link between modification of the key gene, MTHFR, and tobacco use by lung cancer patients – even if the patient had smoked for a short period of time.

The findings reinforce tobacco’s link to lung cancer development, but show that deactivating one specific gene through a process known as hypermethylation causes systemic dysfunction, or hypomethylation, in many genes, said the study’s senior investigator, Zdenko Herceg, Ph.D., head of the Epigenetics Group at the International Agency for Research on Cancer (IARC).

“We found that tobacco-mediated hypermethylation of MTHFR, and consequent partial or complete silencing of the gene, may trigger global hypomethylation and deregulation of DNA synthesis, both of which may contribute to cancer development,” he said.

This methylation process, which involves chemically modifying normal DNA in order to change its activity, is seen as an increasingly important factor contributing to so-called “epigenetic inheritance” in cancer development, Herceg said. An epigenetic event is when non-genetic factors cause a gene to change its expression, and this is different from cancer caused by mutated genes that produce errant protein.

“Tobacco smoke contains many carcinogens, most of which are believed to cause genome damage,” he said. “While there is evidence that the mutations induced by these tobacco carcinogens do play an important role in cancer development, our study reveals the novel – and surprising – role that silencing of normal genes plays in development of lung cancer.”

Cancer is often characterized by an imbalance in methylation, where hypermethylation (inactivation) in specific genes is accompanied by hypomethylation (a decrease in methylation in general) across many genes. But this process has not been well characterized, Herceg said.

In this study, researchers from IARC working with investigators from Russia, Canada, and the United States, quantified methylation patterns in a panel of five cancer-associated genes (CDH1, CDKN2A, GSTP1, MTHFR and RASSF1A) in tumor samples from 209 lung patients and in blood samples from 172 matched “healthy” volunteers.

Noncancerous lung tissue was also examined from 51 of the lung cancer patients.
Their analysis revealed that a high frequency of hypermethylation of MTHFR, RASSF1A and CDKN2A in lung tumors compared to control blood samples, but no significant increase in methylation levels of the other two genes.

Silencing of the RASSF1A and CDKN2A genes makes sense, said Herceg, because these are tumor suppressor genes known to be inactivated in lung cancer. But the role of MTHFR has been less clear, he said. The enzyme produced by the gene plays a role in processing amino acids into methionine, which the body uses to make proteins and other crucial molecules. Variants of MTHFR, for example, have been linked to increased risk of cardiovascular disease.

“Because the MTHFR gene product plays a role in the maintenance of the cell’s pool of methionine, silencing of MTHFR is likely to contribute to global hypomethylation, a phenomenon almost universally observed in human cancer that has been overlooked in favor of gene promoter-associated hypermethylation,” Herceg said.

Both global hypomethylation and hypermethylation “coexist in all tumors and can contribute to tumor development and progression through different mechanisms,” he said. The researchers say that these two processes likely reinforce each other. Global hypomethylation associated with MTHFR inactivation contributes to development of cancer by destabilizing the chromosome and activating oncogenes.

The researchers also discovered that methylation levels in RASSF1A were influenced by gender – men were much more likely to express this abnormally – and that methylation levels of CDH1, CDKN2A, GSTP1 and RASSF1A were not associated with smoking. While the findings contribute to the basic understanding of lung cancer development, they may also be useful in designing a “methylation signature” blood or sputum biomarker test to identify individuals who are at risk of developing the disease, the researchers say. “That may prove particularly beneficial in diagnosing patients exposed to passive smoking,” Herceg said.

Source: American Association for Cancer Research

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Time Stamp: 12/31/2008 at 5:00:04 PM UTC