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  • richardmitnick 1:05 pm on July 31, 2015 Permalink | Reply
    Tags: , , Medicine,   

    From New Scientist- “Ebola vaccine success: Race is now on to protect those at risk” 


    New Scientist

    31 July 2015
    No Writer Credit

    A vaccine can now protect against Ebola (Image: Cellou BinaniI/AFP/Getty Images)

    A vaccine for Ebola produced in just one year instead of the usual decade provides 100-per-cent protection against the disease. Preparations are already under way to make it available to healthcare workers and families wherever the virus remains at large.

    “This is a very good day,” says Seth Berkley, chief executive of the GAVI Alliance, the global organisation that has earmarked $390 million to extend availability of the VSV-ZEBOV vaccine beyond Guinea, the country where it has been successfully tested on more than 7500 people.

    The epidemic is now largely under control, but there have been 28,000 cases leading to 11,000 deaths in Guinea, Sierra Leone and Liberia. But cases are still coming to light, and the virus is still at large, lurking in the body fluids of survivors for as long as 6 months.

    “All affected countries should immediately start and multiply ring vaccinations to break chains of transmission and vaccinate all frontline workers to protect them,” says Bertrand Draguez, medical director of relief organisation Médecins Sans Frontières.

    The rapid availability of a vaccine would be a huge boost for citizens of those three countries and for all the health workers still operating in them to deal with new cases.

    Emergency authorisation

    Berkley says that the GAVI Alliance has already earmarked “considerable” funds that could make this roll out possible, and that discussions are under way with the governments of affected countries, the funders of the clinical trials, the manufacturer of the vaccine and the World Health Organization to decide how to move forward as fast as possible.

    Although the trial isn’t yet over, the WHO could theoretically issue an Emergency Use Authorisation before it ends. This would enable the vaccine to be legally deployed where needed.

    “When there’s a WHO recommendation, we will be willing to purchase and stockpile the vaccine until we get regulatory authorisation from individual governments,” Berkley says.

    The trial is still in progress, but evidence that the vaccine works arose by studying how well the vaccine protected health workers and family members associated with new cases of Ebola. They wanted to see how well this strategy of “ring vaccination” – immunising those people in closest contact with any new cases – protected those exposed.

    Rather than vaccinating only half the participants, and risking the lives of others by giving them a dummy vaccine, the researchers gave half the participants the vaccine immediately after they had contact with a newly diagnosed case, while the other half received it three weeks later.

    After three months, the result was resounding. No instant recipients were infected, but 16 of those receiving the vaccine three weeks later were. “This is an extremely promising development,” said Margaret Chan, director-general of the WHO. The results at three months were so impressive that all subsequent participants have since been receiving the vaccine immediately.

    Hard to store

    Developed initially by the Public Health Agency of Canada, the vaccine is a live but harmless virus called vesicular stomatitis virus, which normally infects animals, engineered to contain a key fragment from the Ebola virus. The immune systems of recipients make antibodies that prime for defence against the real virus.

    The race is now on to provide it wherever possible, pending negotiations between all the parties involved. “We can say that Guinea is now taken care of, but what happens in Sierra Leone and Liberia, and other countries where there are outbreaks such as Mali and Uganda,” says Berkley. “We need some type of procedure to say it’s OK to use it in these other settings.”

    Berkley said that the vaccine is not perfect. It must be stored at -80 °C, which is not easy to guarantee in tropical countries. It also may not protect against all strains of Ebola. Nor is it yet established how long immunity lasts.

    But other trials of vaccines against ebola are under way, says Margaret Harris of the WHO. In Liberia, the VSV-ZEBOV vaccine is being trialled head-to-head against a rival vaccine produced by Glaxo-Smith Kline, and a vaccine developed by the US Centers for Disease Control and Prevention in Atlanta, Georgia, is being tested in Sierra Leone.

    Harris said that cases are still coming to light, but they are waning in number. “We’ve had a very encouraging week, and for the first time we’ve seen a column of zeros where there are usually new cases.”

    See the full article here.
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  • richardmitnick 4:07 pm on May 29, 2015 Permalink | Reply
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    From SUNY Buffalo: “Engineers turn E. coli into tiny factories for producing new forms of popular antibiotic” 

    SUNY Buffalo

    SUNY Buffalo

    May 29, 2015
    Charlotte Hsu

    White filter disks holding antibiotics sit on petri dishes housing erythromycin-resistant Bacillus subtilis. The filter disks circled in red hold new forms of erythromycin created by University at Buffalo researchers, and the dark halo around them indicates that the drug has seeped out of the disk to kill the surrounding bacteria. Credit: Guojian Zhang

    Like a dairy farmer tending to a herd of cows to produce milk, researchers are tending to colonies of the bacteria Escherichia coli (E. coli) to produce new forms of antibiotics — including three that show promise in fighting drug-resistant bacteria.

    The research, published today (May 29) in the journal Science Advances, was led by Blaine A. Pfeifer, an associate professor of chemical and biological engineering in the University at Buffalo School of Engineering and Applied Sciences. His team included first author Guojian Zhang, Yi Li and Lei Fang, all in the Department of Chemical and Biological Engineering.

    For more than a decade, Pfeifer has been studying how to engineer E. coli to generate new varieties of erythromycin, a popular antibiotic. In the new study, he and colleagues report that they have done this successfully, harnessing E. coli to synthesize dozens of new forms of the drug that have a slightly different structure from existing versions.

    Three of these new varieties of erythromycin successfully killed bacteria of the species Bacillus subtilis that were resistant to the original form of erythromycin used clinically.

    “We’re focused on trying to come up with new antibiotics that can overcome antibiotic resistance, and we see this as an important step forward,” said Pfeifer, PhD.

    “We have not only created new analogs of erythromycin, but also developed a platform for using E. coli to produce the drug,” he said. “This opens the door for additional engineering possibilities in the future; it could lead to even more new forms of the drug.”

    The study is especially important with antibiotic resistance on the rise. Erythromycin is used to treat a variety of illnesses, from pneumonia and whooping cough to skin and urinary tract infections.

    E. coli as a factory

    Getting E. coli to produce new antibiotics has been something of a holy grail for researchers in the field.

    That’s because E. coli grows rapidly, which speeds experimental steps and aids efforts to develop and scale up production of drugs. The species also accepts new genes relatively easily, making it a prime candidate for engineering.

    While news reports often focus on the dangers of E. coli, most types of this bacteria are actually harmless, including those used by Pfeifer’s team in the lab.

    Over the past 11 years, Pfeifer’s research has focused on manipulating E. coli so that the organism produces all of the materials necessary for creating erythromycin. You can think of this like stocking a factory with all the necessary parts and equipment for building a car or a plane.

    With that phase of the research complete, Pfeifer has turned to the next goal: Tweaking the way his engineered E. coli produce erythromycin so that the drug they make is slightly different than versions used in hospitals today.

    That’s the topic of the new Science Advances paper.

    The process of creating erythromycin begins with three basic building blocks called metabolic precursors — chemical compounds that are combined and manipulated through an assembly line-like process to form the final product, erythromycin.

    To build new varieties of erythromycin with a slightly different shape, scientists can theoretically target any part of this assembly line, using various techniques to affix parts with structures that deviate slightly from the originals. (On an assembly line for cars, this would be akin to screwing on a door handle with a slightly different shape.)

    In the new study, Pfeifer’s team focused on a step in the building process that had previously received little attention from researchers, a step near the end.

    The researchers focused on using enzymes to attach 16 different shapes of sugar molecules to a molecule called 6-deoxyerythronolide B. Every one of these sugar molecules was successfully adhered, leading, at the end of the assembly line, to more than 40 new analogs of erythromycin — three of which showed an ability to fight erythromycin-resistant bacteria in lab experiments.

    “The system we’ve created is surprisingly flexible, and that’s one of the great things about it,” Pfeifer said. “We have established a platform for using E. coli to produce erythromycin, and now that we’ve got it, we can start altering it in new ways.”

    See the full article here.

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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

    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.

    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.


    “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.

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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


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

    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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  • richardmitnick 7:17 am on April 27, 2015 Permalink | Reply
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    From AAAS: “Breast cancer drug may help men with prostate cancer” 



    24 April 2015
    Jocelyn Kaiser

    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.

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  • richardmitnick 11:24 am on April 26, 2015 Permalink | Reply
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    From livescience: “Melanoma Tumor ‘Dissolves’ After 1 Dose of New Drug Combo” 


    April 24, 2015
    Laura Geggel

    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.

    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
    Tags: , , Medicine   

    From Brown: “Tapeworm drug shows promise against MRSA” 

    Brown University
    Brown University

    April 23, 2015
    David Orenstein

    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
    Tags: , , Medicine,   

    From DESY: “Scientists X-ray anti-inflammatory drug candidates” 


    No Writer Credit

    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

    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.”

    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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    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’ 


    New Scientist

    22 April 2015
    Andy Coghlan

    (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.

    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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