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  • richardmitnick 7:01 pm on May 14, 2015 Permalink | Reply
    Tags: , Medicine, Outsmart Ebola Together,   

    From WCG “A milestone and a roadmap: progress in the fight against Ebola” 

    New WCG Logo

    5 May 2015
    The Outsmart Ebola Together research team

    Summary
    Thanks to the huge level of support from World Community Grid, the team at the Scripps Research Institute has already received most of the matching data for the first target protein of the Ebola virus. While this data is being analyzed, the search now moves to another related protein with potential to help the fight against hemorrhagic fevers.

    Outsmart Ebola Together, a long-term scientific project whose goal is to find new drugs for curing Ebola and related life-threatening viral hemorrhagic fevers, is still in its early stages, but we’ve already reached a major milestone. Our first target was the newly revealed receptor-binding site of the Ebola surface protein, GP. GP is the molecule Ebola virus uses to fuse with a human cell and force its way inside. Armed with a new model of the binding site, and with the vast resources of World Community Grid, we set out to test this site against drugs that could potentially bond with it and prevent Ebola infection. This stage of work is now close to complete: we have received back from World Community Grid most of the data for the planned matchings of the Ebola surface protein against 5.4 million candidate chemical compounds.

    We are now analyzing this data. Drugs that simulations predict will bind well with the Ebola surface protein will go on to a next round of experiments, conducted in the lab with actual proteins and actual drug molecules. Our analysis may also yield general insights about how classes of drugs interact with viral proteins.

    Moreover, we are excited to announce that we are beginning work on a second target protein, the Lassa virus nucleoprotein.

    Like Ebola, Lassa is a “Group V” virus: in other words, both are viruses that have at their core a genome composed of “negative-sense”, single-stranded RNA. Both viruses produce a deadly hemorrhagic fever. While Lassa has received less publicity than Ebola, it is a more consistent killer. There are hundreds of thousands of cases of Lassa Fever every year in Western Africa, with tens of thousands of deaths. It is also the viral hemorrhagic fever most frequently transported out of Africa to the United States and Europe. There are no treatments approved for use in Lassa virus infection. Identification of a potent inhibitor of Lassa virus is imperative for public health.

    The Lassa virus’s nucleoprotein (NP) is so named because its first discovered function is to bind with, and so enclose and protect, the virus’s central strand of RNA. However, Lassa NP is a complex beast that has other functions as well. In particular, our lab discovered that the NP (almost paradoxically) is also responsible for digesting double-stranded RNA (dsRNA) created by the virus itself. Having gained entry to a human cell, the Lassa virus must copy its single-stranded RNA in order to produce viral proteins and replicate itself. This requires creating double-stranded RNA. However, the virus must keep this work secret. The presence of double-stranded RNA in the cytoplasm is a clear sign of a viral infection, and human cells are smart enough to detect this, triggering an effective immune response. Hence the importance of the Lassa NP, which rips apart the virus’s own dsRNA byproducts in order to keep its activities secret.

    We approach Lassa NP armed with our lab’s crystallographic structures, which clearly identify the shape of the NP and the site where the NP carries out its function of destroying double-stranded RNA. This site is a large cavity in the side of the protein; it is negatively charged, but is also bordered by a positively charged, protruding protein “arm”. These distinctive features are key to the site’s binding with dsRNA, and, we believe, should make it a good candidate for screenings against possible drugs.

    2
    Figure: Our lab’s structure for the Lassa NP protein. Portions important to the protein’s function of digesting double-stranded RNA include the “cavity” (glowing, particularly a manganese atom that helps bond RNA) and the adjacent “arm” (yellow).

    We will now prepare this target protein for matchings against millions of drugs using the resources of the World Community Grid. As with our previous matchings against the Ebola surface protein, drugs that do well in this “virtual screening” will go on to further tests with actual proteins in the lab. While this work is difficult and carries no guarantees, we hope that it will lead to the discovery of a drug that can prevent the Lassa NP from hiding the virus’s double-stranded RNA. We have already determined that doing this would allow human cells to detect and act against the Lassa virus more promptly and effectively, potentially saving lives.

    It’s amazing to us that we’ve been able to receive so many results so quickly, and we want to say thank you to everyone in the World Community Grid family who helped make this possible. There is much work ahead, but it’s immensely encouraging to know that we have the resources available to carry it out.

    See the full article here.

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    World Community Grid (WCG) brings people together from across the globe to create the largest non-profit computing grid benefiting humanity. It does this by pooling surplus computer processing power. We believe that innovation combined with visionary scientific research and large-scale volunteerism can help make the planet smarter. Our success depends on like-minded individuals – like you.”

    WCG projects run on BOINC software from UC Berkeley.

    BOINC is a leader in the field(s) of Distributed Computing, Grid Computing and Citizen Cyberscience.BOINC is more properly the Berkeley Open Infrastructure for Network Computing.

    CAN ONE PERSON MAKE A DIFFERENCE? YOU BET!!

    “Download and install secure, free software that captures your computer’s spare power when it is on, but idle. You will then be a World Community Grid volunteer. It’s that simple!” You can download the software at either WCG or BOINC.

    Please visit the project pages-
    Outsmart Ebola together

    Outsmart Ebola Together

    Mapping Cancer Markers
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    Uncovering Genome Mysteries
    Uncovering Genome Mysteries

    Say No to Schistosoma

    GO Fight Against Malaria

    Drug Search for Leishmaniasis

    Computing for Clean Water

    The Clean Energy Project

    Discovering Dengue Drugs – Together

    Help Cure Muscular Dystrophy

    Help Fight Childhood Cancer

    Help Conquer Cancer

    Human Proteome Folding

    FightAIDS@Home

    Computing for Sustainable Water

    World Community Grid is a social initiative of IBM Corporation
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  • richardmitnick 9:29 am on May 11, 2015 Permalink | Reply
    Tags: , Medicine,   

    From Rutgers: “Stroke Centers Reduce Risk of Dying, Rutgers Study Finds” 

    Rutgers University
    Rutgers University

    May 10, 2015
    Jennifer Forbes at 732-235-6356
    jenn.forbes@rwjms.rutgers.edu.

    1

    You are more likely to survive a hemorrhagic stroke if you are treated at a comprehensive stroke center, according to a new Rutgers and Robert Wood Johnson University Hospital study.

    The research published in the Journal of the American Heart Association indicates that patients – including those transferred within 24 hours from other hospitals – from a brain bleed were more likely to survive if they were cared for at such a facility.

    “Hemorrhagic stroke is complex and requires skilled medical interventions to improve a patient’s outcome,” said James S. McKinney, assistant professor of neurology at Rutgers Robert Wood Johnson Medical School and medical director of the Comprehensive Stroke Center at Robert Wood Johnson University Hospital and lead author of the study. “Based on the evidence presented in our study, we believe that more patients can survive hemorrhagic stroke with better utilization of the state’s comprehensive stroke centers.”

    Stroke is a leading cause of death and disability in the United States, according to the American Heart Association and American Stroke Association. Previous research had shown that comprehensive stroke centers improved clinical outcomes and reduced disparities in ischemic stroke caused by a blockage in blood vessels. The same may be true for patients who experience hemorrhagic stroke which causes bleeding in or around the brain and has a mortality rate of 40 to 50 percent.

    The researchers reviewed more than 36,000 anonymous patient records from 1996 to 2012, including admissions and discharge data for 87 New Jersey hospitals, each designated as a comprehensive stroke center, primary stroke center or non-stroke center, by the New Jersey Department of Health and Human Services. Their findings indicate that the neurosurgical and endovascular treatments that are available at state-designated comprehensive stroke centers are associated with lower mortality rates in patients with hemorrhagic stroke.

    There are 13 designated comprehensive stroke centers in New Jersey which must be staffed 24-hours-a-day, seven-days-a-week, with a neurosurgical team including diagnostic and interventional neuroradiologists. However, despite this availability, the study noted that only 40 percent of patients were admitted to a comprehensive stroke center during the study time period from 1996 to 2012, while the remaining 60 percent were admitted to either a primary stroke center or non-stroke center said McKinney.

    According to McKinney, variables other than comprehensive treatment contributed to improved outcomes, including age. “In our analysis, patients admitted to comprehensive stroke centers were, on average, five years younger than patients admitted to other hospitals,” he said. “In addition, patients transferred to comprehensive stroke centers were significantly younger in age than patients who remained in primary stroke or non-stroke centers.”

    The research team, all members of the Cardiovascular Institute of New Jersey, included Jerry Q. Cheng, assistant professor of medicine; Igor Rybinnik, assistant professor of neurology; and John B. Kostis, John G. Detwiler Professor of Cardiology, associate dean for Cardiovascular Research and director, Cardiovascular Institute of New Jersey. The study was funded, in part, by the Robert Wood Johnson Foundation.

    See the full article here.

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    Rutgers, The State University of New Jersey, is a leading national research university and the state’s preeminent, comprehensive public institution of higher education. Rutgers is dedicated to teaching that meets the highest standards of excellence; to conducting research that breaks new ground; and to providing services, solutions, and clinical care that help individuals and the local, national, and global communities where they live.

    Founded in 1766, Rutgers teaches across the full educational spectrum: preschool to precollege; undergraduate to graduate; postdoctoral fellowships to residencies; and continuing education for professional and personal advancement.

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  • richardmitnick 12:57 pm on May 6, 2015 Permalink | Reply
    Tags: , Medicine,   

    From Wash U: “Scientists find new link between diabetes and Alzheimer’s” 

    Wash U Bloc

    Washington University in St.Louis

    May 4, 2015
    Michael C. Purdy

    1
    Shannon Macauley, PhD, and David Holtzman, MD, neurology researchers at Washington University School of Medicine in St. Louis, have found a new link between Alzheimer’s disease and diabetes. Their research, in mice, suggests elevated blood sugar can harm brain function.

    Researchers have uncovered a unique connection between diabetes and Alzheimer’s disease, providing further evidence that a disease that robs people of their memories may be affected by elevated blood sugar, according to scientists at Washington University School of Medicine in St. Louis.

    While many earlier studies have pointed to diabetes as a possible contributor to Alzheimer’s, the new study – in mice – shows that elevated glucose in the blood can rapidly increase levels of amyloid beta, a key component of brain plaques in Alzheimer’s patients. The buildup of plaques is thought to be an early driver of the complex set of changes that Alzheimer’s causes in the brain.

    The research is published May 4 in The Journal of Clinical Investigation.

    “Our results suggest that diabetes, or other conditions that make it hard to control blood sugar levels, can have harmful effects on brain function and exacerbate neurological conditions such as Alzheimer’s disease,” said lead author Shannon Macauley, PhD, a postdoctoral research scholar. “The link we’ve discovered could lead us to future treatment targets that reduce these effects.”

    People with diabetes can’t control the levels of glucose in their blood, which can spike after meals. Instead, many patients rely on insulin or other medications to keep blood sugar levels in check.

    To understand how elevated blood sugar might affect Alzheimer’s disease risk, the researchers infused glucose into the bloodstreams of mice bred to develop an Alzheimer’s-like condition.

    In young mice without amyloid plaques in their brains, doubling glucose levels in the blood increased amyloid beta levels in the brain by 20 percent.

    When the scientists repeated the experiment in older mice that already had developed brain plaques, amyloid beta levels rose by 40 percent.

    Looking more closely, the researchers showed that spikes in blood glucose increased the activity of neurons in the brain, which promoted production of amyloid beta. One way the firing of such neurons is influenced is through openings called KATP channels on the surface of brain cells. In the brain, elevated glucose causes these channels to close, which excites the brain cells, making them more likely to fire.

    Normal firing is how a brain cell encodes and transmits information. But excessive firing in particular parts of the brain can increase amyloid beta production, which ultimately can lead to more amyloid plaques and foster the development of Alzheimer’s disease.

    To show that KATP channels are responsible for the changes in amyloid beta in the brain when blood sugar is elevated, the scientists gave the mice diazoxide, a glucose-elevating drug commonly used to treat low blood sugar. To bypass the blood-brain barrier, the drug was injected directly into the brain.

    The drug forced the KATP channels to stay open even as glucose levels rose. Production of amyloid beta remained constant, contrary to what the researchers typically observed during a spike in blood sugar, providing evidence that the KATP channels directly link glucose, neuronal activity and amyloid beta levels.

    Macauley and her colleagues in the laboratory of David M. Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology, are using diabetes drugs in mice with conditions similar to Alzheimer’s to further explore this connection.

    “Given that KATP channels are the way by which the pancreas secretes insulin in response to high blood sugar levels, it is interesting that we see a link between the activity of these channels in the brain and amyloid beta production,” Macauley said. “This observation opens up a new avenue of exploration for how Alzheimer’s disease develops in the brain as well as offers a new therapeutic target for the treatment of this devastating neurologic disorder.”

    The researchers also are investigating how changes caused by increased glucose levels affect the ability of brain regions to network with each other and complete cognitive tasks.
    ___________________________________________________________________________________________
    The research was supported by the National Institutes of Health (NIH); the National Science Foundation (NSF); and the JPB Foundation.

    Macauley SL, Stanley M, Caesar EE, Yamada SA, Raichle ME, Perez R, Mahan TE, Sutphen CL, Holtzman DM. Hyperglycemia modulates extracellular amyloid beta concentrations and neuronal activity in vivo. The Journal of Clinical Investigation, online May 4, 2015.

    See the full article here.

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    Washington University’s mission is to discover and disseminate knowledge, and protect the freedom of inquiry through research, teaching, and learning.

    Washington University creates an environment to encourage and support an ethos of wide-ranging exploration. Washington University’s faculty and staff strive to enhance the lives and livelihoods of students, the people of the greater St. Louis community, the country, and the world.

     
  • richardmitnick 7:17 am on April 27, 2015 Permalink | Reply
    Tags: , , Medicine   

    From AAAS: “Breast cancer drug may help men with prostate cancer” 

    AAAS

    AAAS

    24 April 2015
    Jocelyn Kaiser

    1
    Prostate cancer cells SPL/Science Source

    A new type of cancer drug originally aimed at women with rare, inherited forms of breast and ovarian cancer may also help a broader swath of patients, according to a small clinical study. The drug halted tumor growth in a third of men with a typically deadly form of advanced prostate cancer. Nearly all of those who responded had related mutations in their tumors, indicating the drug was targeting a common cell process, researchers reported here this week at the annual meeting of the American Association for Cancer Research (AACR).

    The drug blocks an enzyme called poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP), which helps cells repair a certain type of DNA damage. Oncologists are mostly testing PARP inhibitors in ovarian and breast cancer patients born with mutations in BRCA1 or BRCA2, two of the most infamous cancer-related genes. These mutations raise a woman’s risk for breast and ovarian cancer, as well as a man’s risk of prostate cancer, because they disable proteins that repair DNA damage that can result in additional cancer-spurring mutations. But flaws in either gene also make tumor cells vulnerable to PARP inhibitors, because the drugs further impair tumor cells’ DNA repair machinery. This combination renders tumor cells unable to fix DNA damage and they die, an idea known as synthetic lethality.

    In December, the first PARP inhibitor, AstraZeneca’s olaparib, received approval in the United States and Europe for ovarian cancer patients who had inherited a BRCA1 or BRCA2 mutation.

    But some cancer patients who lack such mutations have also seen their tumors shrink in trials. A team led by Johann de Bono of the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, both in London, suspected that these patients had inherited errors in other DNA repair genes or had acquired mutations in BRCA or the other genes in a tumor as it formed or grew. Three years ago, a large sequencing project found that such DNA repair gene defects are common in advanced prostate tumors.

    To test their hypothesis, de Bono’s group and collaborators, whose funding was independent from AstraZeneca, gave the drug to 50 men with metastatic castration-resistant prostate cancer, which means their tumors had stopped responding to drugs that block the hormones that drive prostate cancer growth. Of the 49 men who stayed in the trial, 33%, or 16 patients, responded to the drug, according to one of three measures—a drop in levels of tumor cells in the patient’s blood, a decline in blood levels of the biomarker prostate-specific antigen, or imaging scans that found their tumors shrank. When the researchers sequenced the patients’ tumor DNA, they found their hunch was correct: Fourteen of the 16 who responded had mutations in one or more of a dozen DNA repair genes in their tumors, and only two nonresponders had these mutations, reported Joaquin Mateo, a clinical fellow in de Bono’s lab, at the AACR meeting. (While three responders had inherited BRCA2 mutations, four had apparently new mutations in this gene.) Most of these patients responded to the drug for at least 6 months (four for more than 1 year), while those without such mutations usually got worse within 3 months.

    Although genetic tests of tumors are already used to determine whether certain drugs will work for several types of cancer, this is the first time researchers have found such a test for prostate cancer, de Bono’s group says. Olaparib could offer a new option for these men: The trial shows “this is a good swat at that disease,” said prostate cancer researcher William Nelson of Johns Hopkins University in Baltimore, Maryland, at an AACR press conference, adding that the prospect of genetic testing to identify prostate cancer patients who could benefit from olaparib “looks very promising.”

    The results also suggest that women with ovarian and breast cancer who lack an inherited BRCA mutation might still respond to PARP inhibitors, if they have DNA repair mutations in their tumors, de Bono’s group says. Ursula Matulonis of the Dana-Farber Cancer Institute in Boston, who presented results at AACR from a trial of olaparib combined with another drug for breast and ovarian cancer patients, said at the press conference that her team plans to explore that possibility by DNA testing biopsies from the patients.

    See the full article here.

    The American Association for the Advancement of Science is an international non-profit organization dedicated to advancing science for the benefit of all people.

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  • richardmitnick 11:24 am on April 26, 2015 Permalink | Reply
    Tags: , , , Medicine   

    From livescience: “Melanoma Tumor ‘Dissolves’ After 1 Dose of New Drug Combo” 

    Livescience

    April 24, 2015
    Laura Geggel

    1
    A CT scan of the woman’s tumor highlighted by the asterisk (C) before treatment and after treatment (D).
    Credit: The New England Journal of Medicine, Copyright 2015

    A large melanoma tumor on a woman’s chest disappeared so quickly that it left a gaping hole in its place after she received a new treatment containing two melanoma drugs, a new case report finds.

    Doctors are still monitoring the 49-year-old woman, but she was free of melanoma — a type of skin cancer that can be deadly — at her last checkup, said the report’s lead author, Dr. Paul Chapman, an attending physician and head of the melanoma section at the Memorial Sloan Kettering Cancer Center in New York.

    The woman took the same two drugs as more than 100 people with melanoma who took part in a recent study. For most of the study participants who took these drugs, the combination worked better than one drug alone. But the doctors were surprised by how well the drug combination worked to treat this particular woman’s cancer — they had not anticipated that a melanoma tumor could disappear so quickly that it would leave a cavity in the body — and thus wrote the report describing her case.

    “What was unusual was the magnitude [of recovery], and how quickly it happened,” Chapman told Live Science. However, doctors are wary of the drug combination because it does not work for everyone, and can have side effects, such as severe diarrhea.

    Both the study of the drug combination and the woman’s case report were published Monday (April 20) in the New England Journal of Medicine. The drug combination is part of a relatively recent approach to treating melanoma with medications that boost a person’s own immune system, called immunotherapy.

    One of the drugs in the combination was ipilimumab (sold under the brand name Yervoy), which works by removing an inhibitory mechanism that can stop certain immune cells from killing cancer cells.

    In the study, researchers combined ipilimumab with another drug, called nivolumab (brand name Opdivo), which can prevent immune cells called T cells from dying, Chapman said.

    The U.S. Food and Drug Administration has approved ipilimumab and nivolumab separately as melanoma drugs but has not approved their combined use. The researchers’ study was aimed at testing how the two drugs worked when used in tandem.

    In the study, doctors gave treatments to 142 people with metastatic melanoma (melanoma that has spread to other parts of the body) — some participants received the combination, and others received ipilimumab plus a placebo. Neither the participants nor their doctors knew who had received which treatment until the trial had ended.

    2
    A woman with melanoma developed a large tumor on her abdomen (A), but after one combination treatment of two immunotherapy drugs, it disappeared (B) within three weeks. Credit: The New England Journal of Medicine, Copyright 2015.

    The new drug combination had better results than the ipilimumab-plus-placebo treatment, the researchers found.

    In one analysis, the researchers focused on 109 patients who did not have a mutation in a gene called the BRAF gene. (BRAF mutations are linked to a number of cancers, including melanoma, and there are other melanoma drugs that target BRAF mutations.) Among the 72 people in this group who took the combination, 61 percent saw their cancer shrink, compared with just 11 percent of the 37 people in the group who took only ipilimumab.

    What’s more, melanoma was undetectable in 22 percent of the combination group at the end of the study, which was funded by Bristol-Myers Squibb, which makes the drugs. None of the people taking ipilimumab plus a placebo saw their melanoma disappear by the time the study had ended.

    Twenty-two percent may not sound high, but in the world of melanoma treatment, it is significant, said Dr. Sylvia Lee, an assistant professor of medicine at the University of Washington, Seattle Cancer Care Alliance and Fred Hutchinson Cancer Research Center. Lee was not involved in the new study, but she is working with patients who are receiving the drug combination in Seattle.

    A complete response to treatment is “the Holy Grail,” she said. “That’s what everyone wants, where all of the cancer disappears. We’re talking about patients with stage IV melanoma. Usually, in cancers, when someone has stage IV disease, for the majority of people, it’s no longer curable.”

    It’s unclear whether melanoma will reoccur in any of the patients in the new study. Doctors are following them to see whether the people who are taking the combination drugs live longer than expected, Chapman said.

    Side effects

    However, the ipilimumab with nivolumab combination comes with serious side effects, such as colitis (swelling of the colon), diarrhea and problems with the endocrine glands (which produce hormones).

    About 54 percent of the patients in the study who were taking the combination reported serious side effects, compared with 24 percent of the people taking only ipilimumab, the researchers found.

    The treatments are given three weeks apart, but some people can tolerate only one or two treatments out of the suggested four before they stop taking the medicine, Lee said. In the new study, about 60 percent of the participants taking the combination finished all four treatments, compared with 70 percent of the ipilimumab-only group.

    The side effects can be brutal, Lee said. “This is diarrhea that is 25 to 40 times a day,” she said.

    Future trials may help researchers refine the number of treatments needed and figure out how effective just one or two treatments can be. The current trial is over, but certain cancer centers are still offering the drug combination through an expanded access program, which is how the woman whose tumor disappeared got the medicine.

    Her case shows that immunotherapy can work quickly: Her tumor vanished within three weeks of receiving her first treatment, the researchers found.

    “I was astonished; I’d never seen anything like that,” Chapman said. “She said the tumor had just kind of dissolved.”

    However, the combination may pose a risk if it dissolves a tumor somewhere else the body, and leaves a hole behind.

    “I think that it is a huge concern,” Lee said. “It is something to consider if you do have a patient with a tumor [invading] a vital organ.”

    The medications are also pricey. Ipilimumab costs $120,000 for four treatments, and nivolumab is priced at $12,500 a month, the Wall Street Journal reported.

    Still, the drug combination may offer a new and promising treatment for people with melanoma if the FDA approves it, Chapman said.

    “It kind of confirms an assumption that we’ve all had for many decades: that the immune system can recognize cancers and can kill large tumors if properly activated,” Chapman said.

    See the full article here.

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  • richardmitnick 11:02 am on April 26, 2015 Permalink | Reply
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    From Brown: “Tapeworm drug shows promise against MRSA” 

    Brown University
    Brown University

    April 23, 2015
    David Orenstein

    1
    A nasty, dangerous superbug Methicillin-resistant Staphylococcus aureus — MRSA — kills thousands of people in America every year. A common tapeworm drug, already approved for use in humans, could be a new tool against MRSA. Image: NIH/NIAID

    A new study provides evidence from lab experiments that a drug already used in people to fight tapeworms might also prove effective against strains of the superbug MRSA, which kills thousands of people a year in the United States.

    The paper, published in the journal PLoS ONE, showed that niclosamide, which is on World Health Organization’s list of essential medicines, suppressed the growth of dozens of methicillin-resistant Staphylococcus aureus (MRSA) cultures in lab dishes and preserved the lives of nematode worms infected with the superbug. In these tests, both niclosamide and a closely related veterinary parasite drug, oxyclozanide, proved to be as effective (at lower concentrations) as the current last-resort clinical treatment, vancomycin.

    The drugs both belong to a family of medicines called salicylanilide anthelmintics and they both also trounced another “gram positive” pathogen, Enterococcus faecium, in lab tests.

    “Since niclosamide is FDA approved and all of the salicylanilide anthelmintic drugs are already out of patent, they are attractive candidates for drug repurposing and warrant further clinical investigation for treating staphylococcal infections,” wrote the lead author Rajmohan Rajamuthiah, a postdoctoral scholar in the Warren Alpert Medical School of Brown University and Rhode Island Hospital.

    Last year the team reported that after screening more than 600 drugs against infected nematode worms, it had found that the salicylanilide anthelmintic drug closantel appeared to be protective for the worms. That led to the new research, where they tested niclosamide and oxyclozanide.

    Encouraging experiments

    In their experiments, even low concentrations of the drugs allowed more than 90 percent of MRSA-infected worms to survive, compared to less than 20 percent survival among controls. In the petri dishes the drugs cleared gaping zones of growth inhibition in MRSA culture spread over the plate, while a control substance did nothing.

    Between the two, oxyclozanide proved to be a more effective MRSA killer, while niclosamide effectively suppressed MRSA growth but did not completely eradicate the bacteria. Although niclosamide proved to be “bacteriostatic” instead of “bactericidal” like oxyclozanide, it may still pack plenty of punch to keep MRSA in check and give the body’s immune system the upper hand, Rajamuthiah said.

    The researchers tested the effects of the drugs on mammalian cells, including sheep red blood cells (which fared just fine) and cancerous human liver cells (which happen to be easier to use than healthy liver cells). Niclosamide proved to be significantly toxic against the cancer cells, which other studies had shown before, but the drug is already approved for human use.

    The team also tested a hypothesis about how the drugs attack the bacteria. As they suspected, oxyclozanide appeared to work by disrupting the bacterial cell’s membranes, but there was no sign that niclosamide worked the same way.

    Further testing

    The researchers acknowledge that petri dishes and worms are not substitutes for people, and some issues need further investigation. For example, people have been shown to clear niclosamide out of their systems quickly, and the drug does a poor job of working its way out of the bloodstream and deep into tissues.

    “The low level of systemic circulation coupled with the rapid elimination profile of niclosamide suggests the necessity for further testing of the potential of niclosamide and oxyclozanide for treating systemic infections,” they wrote. “Further studies should include the evaluation of these compounds in systemic and localized infection models in rodents.”

    Rodent experiments are being planned.

    But there may also be an upside to the rapid clearance, Rajamuthiah said. That might limit the toxicity of the drug, and until it is tested, it’s not clear that quick clearance would undermine the drug’s performance against MRSA.

    “Remember that no one has ever tested niclosamide for treating bacterial infections,” he said.

    If niclosamide, which is already used in humans for one purpose, can also help them fight off a superbug, or if its apparently more effective and less toxic cousin oxyclozanide can gain approval for human use, doctors could obtain much needed ammunition against MRSA.

    “The relatively mild toxicity of oxyclozanide is encouraging based on in vitro tests,” Rajamuthiah said. “Since it has never been tested in humans and since it belongs to the same structural family as niclosamide, our findings give strong impetus to using oxyclozanide for further investigations.”

    Particularly important is that because oxyclozanide attacks the cell membrane instead of metabolic pathways, it may be more difficult for MRSA to develop resistance, Rajamuthiah said.

    In addition to Rajamuthiah, the paper’s other authors are senior and corresponding author Dr. Eleftherios Mylonakis, Beth Burgwyn Fuchs, Elamparithi Jayamani, Bumsup Kwon, and Wooseong Kim, all of Brown University and Rhode Island Hospital, and Annie L. Conery, and Frederick M. Ausubel of Massachusetts General Hospital.

    See the full article here.

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    Welcome to Brown

    Brown U Robinson Hall
    Located in historic Providence, Rhode Island and founded in 1764, Brown University is the seventh-oldest college in the United States. Brown is an independent, coeducational Ivy League institution comprising undergraduate and graduate programs, plus the Alpert Medical School, School of Public Health, School of Engineering, and the School of Professional Studies.

    With its talented and motivated student body and accomplished faculty, Brown is a leading research university that maintains a particular commitment to exceptional undergraduate instruction.

    Brown’s vibrant, diverse community consists of 6,000 undergraduates, 2,000 graduate students, 400 medical school students, more than 5,000 summer, visiting and online students, and nearly 700 faculty members. Brown students come from all 50 states and more than 100 countries.

    Undergraduates pursue bachelor’s degrees in more than 70 concentrations, ranging from Egyptology to cognitive neuroscience. Anything’s possible at Brown—the university’s commitment to undergraduate freedom means students must take responsibility as architects of their courses of study.

     
  • richardmitnick 7:04 am on April 23, 2015 Permalink | Reply
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    From DESY: “Scientists X-ray anti-inflammatory drug candidates” 

    DESY
    DESY

    2015/04/22
    No Writer Credit

    1
    Structure of the Spiegelmer NOX-E36 bound to its target protein CCL2. Credit: Dominik Oberthür/CFEL

    Using DESY’s ultra bright X-ray source PETRA III, scientists have decoded the molecular and three-dimensional structure of two promising drug candidates from the new group of Spiegelmers for the first time.

    DESY Petra III
    DESY Petra III interior
    PETRA III

    The results provide a deeper understanding of the mode of action of these substances that have already entered clinical trials. The researchers from the Universities of Hamburg and Aarhus (Denmark) together with colleagues from the biotech company NOXXON in Berlin present their work in the journal Nature Communications.

    Spiegelmers are a young group of promising pharmaceutical substances. They rely on the same building blocks as the nucleic acids RNA and DNA that fulfil various tasks in the organism – from storing genetic information and messaging to the regulation of genes. Artificial RNA or DNA molecules called aptamers can be tailored to bind to certain proteins with high specificity, blocking their function. Aptamers are well tolerated in the organism as they consist of natural building blocks. For these reasons, aptamers are seen as promising drug candidates. Since 2006, an aptamer for the treatment of age-related macular degeneration [AMD], an eye condition that can lead to blindness, is approved and on the market.

    Usually, RNA and DNA molecules are quickly degraded by enzymes within the body. This severely limits their application as pharmaceutical drugs. However, most biomolecules come in two mirror-image variants, the L-form and the D-form. Natural nucleic acids always exist in the D-form, while proteins are always build in their L-form in the body. Artificial aptamers that are constructed in the naturally not occurring L-form are not degraded by the organism. These mirror-image variants of aptamers are called Spiegelmers. “An advantage of Spiegelmers is that they are not targeted by the body’s enzymes,” explains Prof. Christian Betzel from the University of Hamburg.

    “Spiegelmers can be identified and optimised in the lab through a sophisticated evolutionary procedure. However, exact structure data of Spiegelmers have not been available until now,” says first author Dr. Dominik Oberthür from the Center for Free-Electron Laser Science CFEL, a cooperation of DESY, Max Planck Society and the University of Hamburg. If the exact structure of a Spiegelmer and its binding site at the target protein is known, its mode of action can be decoded and its structure could be further fine-tuned, if necessary.

    The team around Betzel used PETRA III’s bright X-rays to analyse the Spiegelmer NOX-E36 from NOXXON. It blocks the protein CCL2 that is involved in many inflammatory processes in the body. “If you target an inflammatory protein with a Spiegelmer, you have a good chance to tone down the inflammation in the body,” notes Betzel. NOX-E36 has already been successfully tested in a phase IIa clinical trial with patients.

    In order to analyse the structure of the drug candidate, the scientists first had to grow crystals of the Spiegelmer bound to its target protein CCL2. “Growing these crystals was quite a challenge,” recalls Betzel. Because it contradicts their natural function, most biomolecules are notoriously hard to crystallise.

    The crystals were analysed at the PETRA III measuring station P13, run by the European Molecular Biology Laboratory EMBL. Crystals diffract X-ray light, producing a characteristic pattern on the detector. From this diffraction pattern the structure of the crystal’s building blocks can be calculated – in this case the Spiegelmer’s structure, bound to its target protein. In the same manner, a group around Laure Yatime from the University of Aarhus solved the structure of another Spiegelmer: NOX-D20 binds to the protein C5a that is involved into many inflammatory processes, too. The group also reports the structure in Nature Communications.

    The analyses reveal the structure of both Spiegelmers with a spatial resolution of 0.2 nanometres (millionths of a millimetre) – that’s on the order of individual atoms. “I am delighted to finally have a high resolution visualization of the remarkable shapes of two Spiegelmer drug candidates,” comments Dr. Sven Klussmann, founder and chief scientific officer of NOXXON, and also co-author on both articles. “The structural data not only provide the first look at the unusual interaction of a mirror-image oligonucleotide with a natural protein but also deepens our understanding of the two molecules’ mode of action.”

    Reference:
    Crystal structure of a mirror-image L-RNA aptamer (Spiegelmer) in complex with the natural L-protein target CCL2; Dominik Oberthür, John Achenbach, Azat Gabdulkhakov, Klaus Buchner, Christian Maasch, Sven Falke, Dirk Rehders, Sven Klussmann & Christian Betzel; „Nature Communications“, 2015; DOI: 10.1038/ncomms7923

    Structural basis for the targeting of complement anaphylatoxin C5a using a mixed L-RNA/L-DNA aptamer; Laure Yatime, Christian Maasch, Kai Hoehlig, Sven Klussmann, Gregers R. Andersen & Axel Vater; „Nature Communications“, 2015; DOI: 10.1038/ncomms7481

    See the full article here.

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    desi

    DESY is one of the world’s leading accelerator centres. Researchers use the large-scale facilities at DESY to explore the microcosm in all its variety – from the interactions of tiny elementary particles and the behaviour of new types of nanomaterials to biomolecular processes that are essential to life. The accelerators and detectors that DESY develops and builds are unique research tools. The facilities generate the world’s most intense X-ray light, accelerate particles to record energies and open completely new windows onto the universe. 
That makes DESY not only a magnet for more than 3000 guest researchers from over 40 countries every year, but also a coveted partner for national and international cooperations. Committed young researchers find an exciting interdisciplinary setting at DESY. The research centre offers specialized training for a large number of professions. DESY cooperates with industry and business to promote new technologies that will benefit society and encourage innovations. This also benefits the metropolitan regions of the two DESY locations, Hamburg and Zeuthen near Berlin.

     
  • richardmitnick 6:38 am on April 23, 2015 Permalink | Reply
    Tags: , Medicine, , Vision   

    From New Scientist: “These neon-lit cells reveal new ways of preventing blindness’ 

    NewScientist

    New Scientist

    22 April 2015
    Andy Coghlan

    1
    (Image: Alain Chédotal/INSERM)

    These neon cells may be blinding, but targeting them could also help preserve sight. In this close-up image of blood vessels – shown in blue – that supply blood to the retina of a one-week-old mouse, the nuclei of cells lining their walls appear in fluorescent colours. The bright-yellow cells are the ones of interest: they could be targeted to help prevent blindness in ageing eyes.

    Age-related macular degeneration or AMD, often strikes in middle age, causing a person’s vision to deteriorate.

    2
    Picture of the fundus showing intermediate age-related macular degeneration

    A key driver of the disease is excessive growth of obtrusive blood vessels in the retina. A team led by Alain Chédotal of the Institute of Vision in Paris has now discovered that a protein called Slit2 contributes to the rapid increase in offending blood vessels.

    The yellow cells in the picture are the ones that are dividing. When this activity occurs in middle age, it triggers the excessive increase in blood vessels that results in AMD. By blocking Slit2, it might be possible to reduce this effect, says Chédotal.

    When the team genetically altered mice so that they couldn’t produce Slit2, the animals no longer overproduced the blood vessels that lead to blindness. The researchers think that drugs targeting Slit2 could generate new treatments for AMD.

    Pioneering treatments for AMD currently rely on replacing epithelial pigment cells in the retina that are damaged by the disease. A team in the US has used pigment cells made from human embryonic stem cells to reverse damaged sight, in one case allowing a blind man to ride his horse again.

    Journal reference: Nature Medicine, DOI: 10.1038/nm.3849

    See the full article here.

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  • richardmitnick 4:25 pm on April 21, 2015 Permalink | Reply
    Tags: , Medicine,   

    From Rutgers: “Rutgers Researchers Uncover Pain-Relief Secrets in Hot Chili Peppers” 

    Rutgers University
    Rutgers University

    April 20, 2015
    Rick Remington

    The workings of the ingredient capsaicin in calming nerves become more clear in a Newark lab.

    Anyone who has ever bitten unknowingly into a red hot chili pepper remembers the unhappy result – burning, painful sensations that make one’s mouth feel as though it has caught on fire. Yet the very chemical that causes that pain, capsaicin, has also become a popular pain-reliever found in over-the-counter and prescription medications.

    This irony about the calming effects of hot chili peppers is old news for capsaicin pros like Tibor Rohacs, an associate professor in the Department of Pharmacology and Physiology at Rutgers New Jersey Medical School. What’s new are Rohacs’ research findings as to how capsaicin works to calm painful nerves, muscles and joints.

    1
    Chili peppers contain the ingredient capsaicin that can relieve pain, a phenomenon at the heart of research at New Jersey Medical School.

    In a research paper published recently in Science Signaling, Rohacs and a team of NJMS researchers reported new findings on how a nerve mechanism is activated by capsaicin to block pain signals. “This study gives one potential piece in the puzzle of how capsaicin works as a local analgesic,” he said.

    Rohacs said his NJMS laboratory has been studying ion channels found in sensory nerve terminals that respond to heat and other stimuli. In particular, his work has focused on an ion channel known as TRPV1, the capsaicin receptor, and Piezo2, a newly identified ion channel that mediates touch sensation.

    “TRPV1 is a heat sensor, at least physiologically, and it has a chemical activator, capsaicin, which we all know is in chili peppers,” Rohacs explained. “They feel hot because they activate a heat-sensitive ion channel and they trick you into the sensation of heat. And it’s also pretty painful.

    2
    Tibor Rohacs of NJMS has specialized his research into capsaicin and its ability to relieve pain.

    “The idea is basically that this pain-causing, heat sensor ion channel does something to the nerve that in the long run sort of silences them or desensitizes them,” he said. “The desensitizing effect, I believe, has a number of different components and different timescales.”

    Rohacs said capsaicin has been a popular research target and that multiple factors account for its calming effects on the nerves. “We found that capsaicin completely silenced the Piezo2 channels that are activated by mechanical stimuli,” he said. “This may be an important part of how capsaicin inhibits mechanical pain.”

    His research also produced results that Rohacs found surprising.

    “It’s very fast, very robust, very long lasting,” he said. “The magnitude of the effect was to me the really surprising part.”

    Rohacs said the jury was still out on the practical application of capsaicin as a pain medication, including the creams and patches already on the market. A high concentration capsaicin remedy has to be injected along with a local analgesic that numbs the burning sensations until the remedy can begin desensitizing the nerves.

    Rohacs said his research will continue in multiple directions to gain a better understanding of just how the mechanosensors work, as well as how large amounts of calcium are released to help shut down pain signals.

    See the full article here.

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    Rutgers, The State University of New Jersey, is a leading national research university and the state’s preeminent, comprehensive public institution of higher education. Rutgers is dedicated to teaching that meets the highest standards of excellence; to conducting research that breaks new ground; and to providing services, solutions, and clinical care that help individuals and the local, national, and global communities where they live.

    Founded in 1766, Rutgers teaches across the full educational spectrum: preschool to precollege; undergraduate to graduate; postdoctoral fellowships to residencies; and continuing education for professional and personal advancement.

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  • richardmitnick 8:16 am on April 16, 2015 Permalink | Reply
    Tags: , , , Medicine   

    From Harvard: “Faster, Cheaper Testing” 

    Harvard University

    Harvard University

    April 13, 2015
    SUE McGREEVEY

    1
    By quantifying the number of tumor-marker-targeting microbeads bound to cells (lower images), the D3 system categorizes high- and low-risk cervical biopsy samples as accurately as traditional pathology (upper images). Image: Massachusetts General Hospital Center for Systems Biology

    A device developed by Harvard Medical School investigators at Massachusetts General Hospital may bring rapid, accurate molecular diagnosis of cancer and other diseases to locations lacking the latest medical technology.

    In their report appearing in PNAS Early Edition, the researchers describe a smartphone-based device that uses technology for making holograms to collect detailed microscopic images for digital analysis of the molecular composition of cells and tissues.

    “The global burden of cancer, limited access to prompt pathology services in many regions and emerging cell profiling technologies increase the need for low-cost, portable and rapid diagnostic approaches that can be delivered at the point of care,” said Cesar Castro, HMS instructor in medicine at Mass General and co-lead author of the report. “The emerging genomic and biological data for various cancers, which can be essential to choosing the most appropriate therapy, supports the need for molecular profiling strategies that are more accessible to providers, clinical investigators and patients. We believe the platform we have developed provides essential features at an extraordinary low cost.”

    The device—called the D3 (digital diffraction diagnosis) system—features an imaging module with a battery-powered LED light clipped onto a standard smartphone. It records high-resolution imaging data with its camera.

    With a much greater field of view than traditional microscopy, the D3 system is capable of recording data on more than 100,000 cells from a blood or tissue sample in a single image. The data can then be transmitted for analysis to a remote graphic-processing server via a secure, encrypted cloud service. The results can be rapidly returned to the point of care.

    For molecular analysis of tumors, a sample of blood or tissue is labeled with microbeads that bind to known cancer-related molecules; the sample is then loaded into the D3 imaging module. After the image is recorded and data transmitted to the server, the presence of specific molecules is detected by analyzing the diffraction patterns generated by the microbeads.

    The use of variously sized or coated beads may offer unique diffraction signatures to facilitate detection. A numerical algorithm developed by the research team for the D3 platform can distinguish cells from beads and analyze as much as 10 MB of data in less than nine-hundredths of a second.

    A pilot test of the system with cancer cell lines detected the presence of tumor proteins with an accuracy matching the current gold standard for molecular profiling. The larger field of view enabled simultaneous analysis of more than 100,000 cells at a time.

    The investigators then conducted analysis of cervical biopsy samples from 25 women with abnormal Pap smears—samples collected along with those used for clinical diagnosis—using microbeads tagged with antibodies against three published markers of cervical cancer.

    Based on the number of antibody-tagged microbeads binding to cells, D3 analysis promptly and reliably categorized biopsy samples as high-risk, low-risk or benign, with results matching conventional pathologic analysis.

    D3 analysis of fine-needle lymph node biopsy samples was accurately able to differentiate four patients whose lymphoma diagnosis was confirmed by conventional pathology from another four with benign lymph node enlargement. Along with protein analyses, the system was enhanced to successfully detect DNA—in this instance from human papillomavirus—with great sensitivity.

    In these pilot tests, results of the D3 assay were available in under an hour and at a cost of $1.80 per assay, a price that would be expected to drop with further refinement of the system.

    “We expect that the D3 platform will enhance the breadth and depth of cancer screening in a way that is feasible and sustainable for resource limited-settings,” said Ralph Weissleder, HMS Thrall Family Professor of Radiology at Mass General, director of the Mass General Center for Systems Biology and co-senior author of the paper. “By taking advantage of the increased penetration of mobile phone technology worldwide, the system should allow the prompt triaging of suspicious or high-risk cases. That could help to offset delays caused by limited pathology services in those regions and reduce the need for patients to return for follow-up care, which is often challenging for them.”

    In their further development of this technology, co-senior author Hakho Lee, HMS assistant professor of radiology at Mass General, noted, “The research team will investigate the D3 platform’s ability to analyze protein and DNA markers of other disease catalysts, including infectious agents and allergens, integrate the software with larger databases and conduct clinical studies in settings such as care-delivery sites in developing countries or rural settings and for home testing with seamless sharing of information with providers and/or clinical investigators.”

    Mass General has filed a patent application covering the D3 technology.

    “Compared with traditional analysis techniques, the D3 mobile platform generates robust biological data while being significantly more cost-conscious, operable by nonspecialist end users and well-suited to point-of-care settings,” said co-lead author Hyungsoon Im, HMS research fellow in radiology at Mass General. “We have field tested the wireless readouts in rural areas of northern New England without problems and believe this technology is poised to deliver fast, low-cost and accurate cancer and HPV diagnosis.”

    The study was supported by National Institutes of Health grants R01-HL113156, R01-EB010011, R01-EB00462605A1, T32CA79443 and K12CA087723-11A1; National Heart, Lung and Blood Institute contract HHSN268201000044C; and Department of Defense Ovarian Cancer Research Program Award W81XWH-14-1-0279.

    See the full article here.

    Harvard is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

    Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

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