duminică, 5 august 2012

First Indication Of People Naturally Protected Against Rabies Found In Remote Amazonian Communities

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Main Category: Tropical Diseases
Also Included In: Infectious Diseases / Bacteria / Viruses
Article Date: 03 Aug 2012 - 0:00 PDT Current ratings for:
First Indication Of People Naturally Protected Against Rabies Found In Remote Amazonian Communities
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Challenging conventional wisdom that rabies infections are 100 percent fatal unless immediately treated, scientists studying remote populations in the Peruvian Amazon at risk of rabies from vampire bats found 11 percent of those tested showed protection against the disease, with only one person reporting a prior rabies vaccination. Ten percent appear to have survived exposure to the virus without any medical intervention. The findings from investigators at the U.S. Centers for Disease Control and Prevention (CDC) were published in the August 2012 issue of the American Journal of Tropical Medicine and Hygiene.

"The overwhelming majority of rabies exposures that proceed to infections are fatal. However, our results open the door to the idea that there may be some type of natural resistance or enhanced immune response in certain communities regularly exposed to the disease," said Amy Gilbert with the CDC's National Center for Emerging and Zoonotic Infectious Diseases, who is the paper's lead author. "This means there may be ways to develop effective treatments that can save lives in areas where rabies remains a persistent cause of death."

Rabies experts estimate the disease kills 55,000 people each year in Africa and Asia alone, and appears to be on the rise in China, the former Soviet Republics, southern Africa, and Central and South America. According to the CDC, in the United States, human deaths from rabies have declined over the past century from 100 annually to an average of two per year thanks to an aggressive campaign to vaccinate domestic animals against the disease.

In general, people who believe they may have been exposed to rabies are advised to immediately seek treatment which involves post-exposure prophylaxis (PEP) - a series of injections - to prevent the exposure from causing an active infection. These preventive treatments, when administered promptly, are 100 percent successful at preventing disease. Scientists have documented only a small number of individual cases, including one last year in California, in which an exposure to rabies proceeded to infection and the victim survived. Most of those survivors still required intensive medical attention, including one case in Wisconsin in which doctors induced a coma, though this approach has not been successful in most subsequent cases.

This CDC study was conducted in collaboration with the Peruvian Ministry of Health as part of a larger project to understand better bat-human interactions and its relation to rabies and emerging diseases that may be transmitted by bats. For their research, scientists traveled to two communities (Truenococha and Santa Marta) in a remote section of the Peruvian Amazon where outbreaks of fatal infections with rabies caused by bites from vampire bats - the most common "natural reservoir" for the disease in Latin America - have occurred regularly over the last two decades. They interviewed 92 people, 50 of whom reported previous bat bites. Blood samples were taken from 63 individuals and seven (11 percent) were found to have "rabies virus neutralizing antibodies."

One out of the seven individuals reported receiving a rabies vaccination - which generates antibodies to the rabies virus?"but there was no evidence that the other six had received anti-rabies vaccine prior to the blood sampling or had sought out any medical attention for a bat bite, evidence that they had harbored the virus itself.

The researchers acknowledged that they could not conclusively determine whether the antibodies were caused by an exposure to the virus that was somehow insufficient to produce disease. But they believe their evidence "suggests that (rabies virus) exposure is not invariably fatal to humans."

Gilbert said non-fatal exposures may happen more often than some think because "unless people have clinical symptoms of the disease they may not go to the hospital or clinic, particularly where access is limited."

"We all still agree that nearly everyone who is found to be experiencing clinical symptoms of rabies dies," Gilbert said. "But we may be missing cases from isolated high-risk areas where people are exposed to rabies virus and, for whatever reason, they don't develop disease."

In the Amazon region where the study was conducted - the Province Datem del Maranon in the Loreto Department of northern Peru - vampire bats, which live off of mammalian blood, regularly come out at night and prefer to feed on livestock. But in the absence of those food sources, they are known to seek out a meal from humans. They can use their extremely sharp teeth and the anticoagulant that naturally occurs in their saliva (appropriately referred to as "draculin") to feed on a sleeping person without awakening them. The rabies virus circulates extensively among vampire bat colonies in the region, and when an infected bat feeds, it passes along the virus to its host.

"This type of thorough and persistent scientific rabies investigation lends continued support to the belief that even the most dangerous of infectious diseases may be amenable to treatment," said James W. Kazura, MD noted infectious disease expert and president of the American Society of Tropical Medicine and Hygiene (ASTMH). "Continued investment of resources is essential for us to protect the health and well-being of innocent people whose lives and livelihoods are needlessly threatened by infectious diseases like rabies."

Gilbert and her colleagues hope their findings will prompt further studies in remote, at-risk communities to see if the results are replicated. In an editorial accompanying the study, Rodney E. Willoughby, a pediatric disease specialist at Children's Hospital of Wisconsin, said if it turns out there are distinct populations of people with "complete or relative resistance to rabies," there could be the potential to use whole genome sequencing to help develop new, life-saving treatments for rabies infections.

"Careful, respectful genetic study of these genetically unique populations may provide information on which pathways in human biochemistry and physiology promote resistance to human rabies," he wrote. "Equally important, knowing that there is a continuum of disease, even for infectious diseases like rabies, should push us harder to try for cures when confronted by so-called untreatable infectious diseases...."

Gilbert noted that the study was done as part of a larger public health effort to address a series of rabies outbreaks in the Amazon, where some health officials are now considering conducting pre-emptive vaccination campaigns in areas where risk of rabies is high and availability of medical care low. She said that while her study highlights people who appear to have survived an exposure to the virus, the fact remains that rabies outbreaks in small communities in the region have left tragic results.

"These are very small villages and, when they witness ten people dying from what is a horrible disease, it is incredibly traumatic," Gilbert said. "We want to help raise awareness of the problem and try to develop a more proactive response."

Article adapted by Medical News Today from original press release. Source: Burness Communications
Visit our tropical diseases section for the latest news on this subject. Please use one of the following formats to cite this article in your essay, paper or report:

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Researchers Develop First Potential Medicine For Patients With Most Severe Form Of Congenital Hyperinsulinism

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Main Category: Diabetes
Also Included In: Pediatrics / Children's Health;  Genetics
Article Date: 04 Aug 2012 - 0:00 PDT Current ratings for:
Researchers Develop First Potential Medicine For Patients With Most Severe Form Of Congenital Hyperinsulinism
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A pilot study in adolescents and adults has found that an investigational drug shows promise as the first potential medical treatment for children with the severest type of congenital hyperinsulinism, a rare but potentially devastating disease in which gene mutations cause insulin levels to become dangerously high.

"There is currently no effective medicine for children with the most common and most severe form of hyperinsulinism," said study leader Diva D. De Leon, M.D., a pediatric endocrinologist at The Children's Hospital of Philadelphia. "Our new research shows that this investigational drug, a peptide called exendin-(9-39), controls blood sugar levels in people, a very promising result."

The study appears online ahead of print in the journal Diabetes.

In congenital hyperinsulinism (HI), mutations disrupt the insulin-secreting beta cells in the pancreas. Uncontrolled, excessive insulin levels thus sharply reduce blood glucose levels, a condition called hypoglycemia. If untreated, hypoglycemia may cause irreversible brain damage or death in children. Congenital HI occurs in an estimated one in 50,000 U.S. children, with a higher incidence among Ashkenazic Jews and certain other groups.

The standard treatment for some forms of congenital HI is diazoxide, a drug that controls insulin secretion by opening potassium channels in beta cells. However, this drug does not work in the most common types of HI, in which mutations prevent these potassium channels from forming.

When abnormal beta cells occur only in a discrete portion of the pancreas, precise surgery on the tiny organ can remove the lesion and cure HI. The Congenital Hyperinsulinism Center at The Children's Hospital of Philadelphia is a world leader in diagnosing such lesions and performing the curative surgery on newborns.

However, in roughly half of congenital HI cases, abnormal cells are diffused through the pancreas, and surgeons must remove nearly the entire pancreas. This leaves the majority of patients at high risk of developing diabetes.

The current study, which builds on previous research by De Leon and colleagues in animals, uses exendin-(9-39), which blocks the action of a hormone receptor, glucagon-like peptide-1 (GLP-1), in beta cells. The GLP-1 receptor is currently the target of drugs that treat diabetes, using the opposite effect from that investigated in this HI study.

The current pilot study included nine subjects, aged 15 to 47 years old, who had hyperinsulinism caused by mutations in potassium channels. None were being treated for HI at the time of the study, but all were at risk of hypoglycemia during periods of fasting.

In all nine subjects, the drug controlled blood glucose levels during fasting. Exendin also controlled insulin secretion in cell studies of beta cells taken from newborns with HI. The current research did not focus on the biological mechanisms that occurred, but De Leon said the results are encouraging enough to progress to a clinical study in children with HI over the next year.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our diabetes section for the latest news on this subject. Financial support for this study came from the National Institutes of Health (grant 1R03DK07835), the Lester and Liesel Baker Foundation, and the Clifford and Katherine Goldsmith Foundation. De Leon's co-authors, all from Children's Hospital, were Charles A. Stanley, M.D., Andrew C. Calabria, M.D., Changhong Li, M.D., and Paul R. Gallagher In addition to their positions at Children's Hospital, De Leon, Stanley and Li also are in the Perelman School of Medicine at the University of Pennsylvania.
"The GLP-1 Receptor Antagonist Exendin-(9-39) Elevates Blood Fasting Glucose Levels in Congenital Hyperinsulinism due to Inactivating Mutations in the ATP-sensitive Potassium Channel," Diabetes, published online Aug.1, 2012, to appear in print, October 2012. doi: 10.2337/db12-0166.
Children's Hospital of Philadelphia Please use one of the following formats to cite this article in your essay, paper or report:

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Seizures In Babies: Cutting-Edge Imaging Technique To Improve Diagnosis

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Main Category: Pediatrics / Children's Health
Article Date: 03 Aug 2012 - 10:00 PDT Current ratings for:
Seizures In Babies: Cutting-Edge Imaging Technique To Improve Diagnosis
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A cutting-edge technique, combining brain imaging and monitoring of its electrical activity, could improve early diagnosis and treatment of babies who suffer seizures.

Researchers at The Rosie Hospital, Cambridge, are investigating the new technique with funding from children's charity Action Medical Research.

In the UK over 2,000 newborn babies suffer seizures each year.1 Early diagnosis and treatment is vital, as seizures may cause lasting brain damage. However, seizures sometimes go unnoticed, as babies can have no obvious symptoms.

Dr Topun Austin at The Rosie Hospital was awarded £131,150 by Action Medical Research for the two year project. "Seizures remain a major challenge when caring for newborn babies," explains Dr Austin, "but can be difficult to diagnose as abnormal movements of the baby may be subtle or not even present."

Around two or three babies in every 1,000 born alive also suffer from seizures within a month of birth.2,3 Babies born very prematurely are especially vulnerable, as are babies who suffer from a lack of oxygen during birth.

Babies who are suspected of suffering from seizures are normally referred for specialist tests. "The current diagnostic test is an electroencephalogram (EEG), which measures electrical activity within the brain," explains Dr Austin. "EEG has limitations though, as it can only detect seizures occurring near the surface of the brain. It cannot detect abnormalities deeper within the brain."

Dr Austin is developing a new way to diagnose seizures, which combines existing EEG technology with a new optical imaging system. The technique could also help other people with seizures or epilepsy.

"When babies have a seizure, there is a large amount of electrical activity in the brain, which we are measuring with EEG," explains Dr Austin. "The amount of oxygen in the brain also changes, which we are measuring with the new optical system. This system works by shining near-infrared light into the brain, which is harmless and non-invasive."

Dr Austin hopes the new combined technique will boost understanding of what's happening inside the brain during seizures: "The ultimate aim is to develop the new system for routine use at the cot-side."

This project brings together a team of clinicians and scientists with a proven track record in developing new technologies to study the infant brain. Most of the work is being carried out in a new neonatal unit - one of the largest in the country - at the Rosie Maternity Hospital, Cambridge.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our pediatrics / children's health section for the latest news on this subject. 1. Rennie JM, Hagmann CF, Robertson NJ. Neonatal cerebral investigation. (2008) Cambridge University Press.

2. Panayiotopoulos CP. Chapter 5. Neonatal seizures and neonatal syndromes. The Epilepsies: Seizures, Syndromes and Management. Bladon Medical Publishing (Oxfordshire UK) 2005.

3. Davis AS et al. Seizures in extremely low birth weight infants are associated with adverse outcome. J Pediatr 2010; 157: 720-5.

Source: Action Medical Research

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'Seizures In Babies: Cutting-Edge Imaging Technique To Improve Diagnosis'

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Molecule Discovered That Converts Stem Cells Into Heart Cells

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Main Category: Heart Disease
Also Included In: Stem Cell Research
Article Date: 05 Aug 2012 - 0:00 PDT Current ratings for:
Molecule Discovered That Converts Stem Cells Into Heart Cells
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For years, scientists have been looking for a good source of heart cells that can be used to study cardiac function in the lab, or perhaps even to replace diseased or damaged tissue in heart disease patients. To do this, many are looking to stem cells. Researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham), the Human BioMolecular Research Institute, and ChemRegen, Inc. have been searching for molecules that convert stem cells to heart cells for about eight years - and now they've found one. Writing in Cell Stem Cell, the team describes how they sifted through a large collection of drug-like chemicals and uncovered ITD-1, a molecule that can be used to generate unlimited numbers of new heart cells from stem cells.

"Heart disease is the leading cause of death in this country. Because we can't replace lost cardiac muscle, the condition irreversibly leads to a decline in heart function and ultimately death. The only way to effectively replace lost heart muscle cells - called cardiomyocytes - is to transplant the entire heart," said Mark Mercola, Ph.D., director of Sanford-Burnham's Muscle Development and Regeneration Program and senior author of the study. "Using a drug to create new heart muscle from stem cells would be far more appealing than heart transplantation."

Searching for a needle in a haystack

Stem cells are important because they do two unique things - 1) self-renew, producing more stem cells and 2) differentiate, becoming other, more specialized cell types. To obtain a large number of a certain cell type, such as heart cells, the hard part is figuring out the signals that direct them to become the desired cell type.

Mercola's group has been hunting for heart-inducing signals for 15 years - in embryos and in stem cells. To find a synthetic molecule that might one day lead to a drug therapy to regenerate the heart, they joined forces with a team of medicinal chemists at the Human BioMolecular Research Institute led by John Cashman, Ph.D. With funding from the California Institute for Regenerative Medicine, they used sophisticated robotic technology to methodically test a large collection of drug-like chemicals, looking for that needle in a haystack that, when added to stem cells, results in cardiomyocytes. The winning compound was ITD-1.

Therapeutic applications

There's no shortage of therapeutic possibilities for ITD-1. "This particular molecule could be useful to enhance stem cell differentiation in a damaged heart," explained Erik Willems, Ph.D., postdoctoral researcher in Mercola's lab and first author of the study. "At some point, it could become the basis for a new therapeutic drug for cardiovascular disease - one that would likely limit scar spreading in heart failure and promote new muscle formation."

Mercola, Willems, and Cashman are now working with San Diego biotech company ChemRegen, Inc. to further develop ITD-1 into a drug that one day might be used to treat patients.

More scientific detail

The researchers discovered that ITD-1 blocks a cellular process known as TGF? signaling. TGF? (short for transforming growth factor-?) is a protein produced by one cell type to influence others' behaviors, such as proliferation, scarring, and even stem cell differentiation. TGF? works from outside the cell, binding to a receptor on the surface of a responding cell to initiate an intracellular signaling cascade that causes genes to be switched on or off, ultimately altering cellular behavior - in this case making heart muscle.

ITD-1 triggers degradation of the TGF? receptor, thus inhibiting the whole process. With TGF? signaling turned off, stem cells are set on a course toward cardiogenesis. ITD-1 is the first selective inhibitor of TGF?, meaning that it might also have applications in many other processes controlled by TGF?.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our heart disease section for the latest news on this subject. This research was funded by the California Institute for Regenerative Medicine, the National Heart, Lung, and Blood Institute of the U.S. National Institutes of Health, the Human BioMolecular Research Institute, the American Heart Association, the German Research Foundation, and the T Foundation.
The study was co-authored by Erik Willems, Sanford-Burnham and ChemRegen Inc.; Paul J Bushway and Joaquim Cabral-Teixeira, Sanford-Burnham; Dennis Schade, ChemRegen Inc. and Human BioMolecular Research Institute; Wenqing Cai, Sanford-Burnham; Patrick Reeves, Harvard Medical School; Marion Lanier, ChemRegen Inc. and Human BioMolecular Research Institute; Christopher Walsh, Salk Institute for Biological Studies; Tomas Kirchhausen, Harvard Medical School; Juan Carlos Izpisua Belmonte, Salk Institute for Biological Studies and Center for Regenerative Medicine in Barcelona; John Cashman, ChemRegen Inc. and Human BioMolecular Research Institute; Mark Mercola, Sanford-Burnham and ChemRegen Inc.
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Obesity: Are Americans Ready To Solve The Weight Of The Nation?

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Main Category: Obesity / Weight Loss / Fitness
Also Included In: Public Health
Article Date: 03 Aug 2012 - 1:00 PDT Current ratings for:
Obesity: Are Americans Ready To Solve The Weight Of The Nation?
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In a Perspective article appearing in this week's New England Journal of Medicine, public health researchers examine how recommendations in a new report from the Institute of Medicine (IOM) - "Accelerating Progress in Obesity Prevention: Solving the Weight of the Nation" - square with American's opinions about the obesity epidemic.

Over the last 30 years, rates of obesity have doubled among adults and tripled among children. The new IOM report summarizes growing evidence that these increases have been driven by a complex interaction of changes in the environments in which we live - our schools, our workplaces, our communities, in the media and in our food and beverage systems.

While praising the IOM report's scope and vision, Colleen L. Barry, PhD, MPP, associate professor of Health Policy and Management at the Johns Hopkins Bloomberg School of Public Health and lead author of "Are Americans Ready to Solve the Weight of the Nation?" says that it is critical to understand how the public thinks about the problem of obesity. Barry notes that one recent poll found that 64 percent of Americans believe personal decisions - overeating, lack of exercise, watching too much television - are the biggest contributors to obesity. However, only 18 percent of Americans attribute environmental factors, such as safe places for children to play, access and availability of healthy foods and exposure to junk food, as major contributors.

"If people think obesity is all about individuals and parents making bad choices, they will be much less likely to embrace changes in schools, communities and food marketing practices aimed at creating healthier environments," said Barry.

Jeff Niederdeppe, PhD, assistant professor of communication at Cornell University and a co-author of the article, emphasized the need for "a research-driven communication strategy to encourage a better understanding of the environmental determinants of obesity among the public, and to emphasize the importance of waging a collective response to the epidemic." The IOM report was accompanied by a four-part HBO documentary series, "The Weight of the Nation," which Niederdeppe described as a great example of the kind of communication partnerships that are needed.

However, communications efforts on obesity should include careful attention to "the potential to increase already high levels of stigma toward obese adults and children, which can have lifelong psychological, social and health consequences," according to Sarah E. Gollust, PhD, assistant professor at the University of Minnesota School of Public Health and a co-author of the Perspective article. Gollust noted that the IOM recognized this concern and explicitly included as a guiding principle the notion that obesity prevention should not be achieved at the expense of overweight or obese individuals' well-being.

The authors concluded that while widespread awareness of obesity's causes and consequences will be necessary, increased awareness alone will not be sufficient to put in place the extensive actions that the IOM report stipulated will be necessary. A favorable political environment as well as leadership in multiple sectors and grassroots advocacy will be needed to support the efforts of the public health community to reduce obesity.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our obesity / weight loss / fitness section for the latest news on this subject. Public opinion data reported in article was collected by the authors through a grant from the Robert Wood Johnson Foundation Healthy Eating Research program.
Johns Hopkins University Bloomberg School of Public Health Please use one of the following formats to cite this article in your essay, paper or report:

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Structural Analysis Opens The Way To New Anti-Influenza Drugs

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Main Category: Flu / Cold / SARS
Also Included In: Genetics;  Bird Flu / Avian Flu
Article Date: 05 Aug 2012 - 0:00 PDT Current ratings for:
Structural Analysis Opens The Way To New Anti-Influenza Drugs
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Researchers at the European Molecular Biology Laboratory (EMBL) in Grenoble, France, have determined the detailed 3-dimensional structure of part of the flu virus' RNA polymerase, an enzyme that is crucial for influenza virus replication. This important finding is published in PLoS Pathogens. The research was done on the 2009 pandemic influenza strain but it will help scientists to design innovative drugs against all the different influenza strains, and potentially lead to a new class of anti-flu drugs in the next 5-10 years.

The scientists focused on the endonuclease part of the viral RNA polymerase. The endonuclease is responsible for a unique mechanism called 'cap-snatching' that allows the virus to trick its host cell into producing viral proteins. In human cells the translation of messenger RNA (mRNA) strands into proteins requires a special structure, called the "cap", at the beginning of each mRNA. When the influenza virus infects a host cell its endonuclease "snatches" that cap from the cell's own mRNA. Another part of its RNA polymerase then uses it as the starting point for synthesizing viral mRNA. With the correct cap structure at the beginning, viral mRNA can then hijack the protein-production machinery of the infected cell to make viral proteins, which assemble into new viruses that will spread the infection.

The team led by Stephen Cusack, Head of EMBL Grenoble, analyzed crystals of endonuclease from the 2009 pandemic influenza strain using the high intensity X-ray beams at the European Synchrotron Radiation Facility (ESRF). The researchers were able to determine the 3D atomic structure of the enzyme and to visualize how several different small molecule inhibitors bind to and block its active site. If the active site of the endonuclease is blocked by an inhibitor the enzyme cannot bind its normal substrate, the host cell mRNA, and viral replication is prevented.

The active site of the endonuclease is shaped like a cave with two metal ions at the bottom. Cusack and colleagues found that all the inhibitors they studied bind to those two metal ions but, depending on their shapes, different inhibitors bind differently to the amino-acids of the cave's walls.

"Based on this detailed structural information we can now design new synthetic chemicals which bind even more tightly to the endonuclease active site and thus will potentially be more potent inhibitors of influenza virus replication," explains Stephen Cusack. "We can even try to build in anti-drug resistance by making sure the inhibitors only contact those amino acids that the virus cannot mutate since they are essential for the normal activity of the polymerase."

Because the cap-snatching mechanism is common to all influenza strains, new potent endonuclease inhibitors should be effective against seasonal flu, novel pandemic strains or highly pathogenic H5N1 bird flu. EMBL scientists are working with EMBL's spin-off company Savira pharmaceuticals, in partnership with Roche, to further develop influenza inhibitors. Promising candidates will be tested first for efficacy in cell culture, ultimately moving into clinical trials on humans.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our flu / cold / sars section for the latest news on this subject. This research was partly funded by the European commission, through the FP7 research grant awarded to the FluPharm project.
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Mechanism Of Lung Cancer-Associated Mutations Suggests New Therapeutic Approaches

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Main Category: Lung Cancer
Article Date: 03 Aug 2012 - 10:00 PDT Current ratings for:
Mechanism Of Lung Cancer-Associated Mutations Suggests New Therapeutic Approaches
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Vanderbilt-Ingram Cancer Center researchers have identified how one of the genes most commonly mutated in lung cancer may promote such tumors.

The investigators found that the protein encoded by this gene, called EPHA3, normally inhibits tumor formation, and that loss or mutation of the gene - as often happens in lung cancer - diminishes this tumor-suppressive effect, potentially sparking the formation of lung cancer. The findings, published July 24 in the Journal of the National Cancer Institute, could offer direction for personalizing cancer treatments and development of new therapies.

The ephrin family of receptors (EPH receptors) comprises a large group of cell surface proteins that regulate cell-to-cell communication in normal development and disease. EPH receptor mutations have been linked to several different cancer types.

Jin Chen, M.D., Ph.D., professor of Medicine, Cancer Biology and Cell & Developmental Biology, studies the cancer-associated roles of these receptors. While her lab has focused primarily on EPHA2 (and its role in promoting breast cancer and tumor blood vessel formation), she decided to look at a different ephrin receptor based on the findings of large genomic screens of lung tumors.

"A 2008 genome-wide study published in Nature identified 26 genes as potential drivers of lung cancer," Chen said. "One of them was EPHA3."

That study and others suggested that mutations in EPHA3 were present in 5 percent to 10 percent of lung adenocarcinomas. However, the studies did not reveal how these mutations might promote tumor formation or progression.

Chen wanted to investigate further whether mutations in EPHA3 were actually "drivers" of lung cancer or just neutral "passenger" mutations and how the mutations might promote tumor growth.

The researchers generated and analyzed 15 different mutations in the receptor. They found that at least two functioned as "dominant negative" inhibitors of the EPHA3 protein - that is, having a mutation in just one allele (or "copy" - humans have two copies of each gene) was enough to inhibit the function of EPHA3.

Chen and colleagues determined that normal or "wild type" EPHA3 inhibits a downstream signaling pathway (the Akt pathway) that promotes cell survival - so, normally, activation of EPHA3 acts as a "brake" on cell growth and survival and induces programmed cell death (apoptosis). When one EPHA3 allele is lost (due to a mutation), the receptor cannot be activated and the Akt pathway remains active, which promotes cell growth and survival.

To determine the impact of EPHA3 mutations on human lung cancer cases, biostatisticians Yu Shyr, Ph.D., and Fei Ye, Ph.D., helped Chen's group identify a mutational signature from existing patient data that strongly correlated with poor patient survival. The team also found that both gene and protein levels of EPHA3 were decreased in patient lung tumors.

While previous studies had linked EPHA3 mutations to lung cancer, the current study is the first to "connect the dots."

"The EPH family is such a big family that nobody had really connected the data from bench top - from the cell and biochemical studies - to human data," Chen said.

Together, the findings suggest that mutations in EPHA3 may be important drivers of a significant fraction of lung cancers. And the research team's identification of the biochemical and cellular consequences of EPHA3 mutations suggests that therapies that target a downstream pathway (such as Akt) might be beneficial for tumors with mutant EPHA3.

Shyr is a professor of Biostatistics, Cancer Biology and Preventive Medicine and is Director of the Center for Quantitative Sciences; Ye is an assistant professor of Biostatistics.

The research was supported by grants from the National Cancer Institute (CA095004, CA114301, CA117915, CA009592, CA090949) of the National Institutes of Health, the Department of Veterans Affairs and the Department of Defense.

Article adapted by Medical News Today from original press release. Source: Source: Vanderbilt-Ingram Cancer Center
Visit our lung cancer section for the latest news on this subject. Source: Vanderbilt-Ingram Cancer Center Please use one of the following formats to cite this article in your essay, paper or report:

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n.p. "Mechanism Of Lung Cancer-Associated Mutations Suggests New Therapeutic Approaches." Medical News Today. MediLexicon, Intl., 3 Aug. 2012. Web.
5 Aug. 2012. APA

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'Mechanism Of Lung Cancer-Associated Mutations Suggests New Therapeutic Approaches'

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