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  • richardmitnick 9:09 am on August 28, 2015 Permalink | Reply
    Tags: , Hep C, Medicine,   

    From Yale: “One in four hepatitis C patients denied initial approval for drug treatment” 

    Yale University bloc

    Yale University

    August 27, 2015
    Ziba Kashef

    1
    Shutterstock

    Nearly one in four patients with chronic hepatitis C (HCV) are denied initial approval for a drug therapy that treats the most common strain of the infection, according to a Yale School of Medicine study.

    The finding, published Aug. 27 in PLOS ONE, identifies a new barrier to caring for patients with this severe condition.

    Prior to the FDA approval of novel antiviral therapies for HCV in 2014, treatment options for patients were limited, requiring weekly injections of interferon-based therapy that caused severe side effects. The new regimens revolutionized treatment and offered patients an oral therapy with cure rates exceeding 90%. However, the high cost of care led insurers to impose new restrictions on drug authorization.

    In light of the new restrictions, the study authors hypothesized that while most patients would be able to access antiviral therapy, some would experience delays in approval and others would be denied. Led by Dr. Joseph K. Lim, associate professor of medicine and director of the Yale Viral Hepatitis Program, the investigators reviewed records of 129 patients who were prescribed a combination of two drugs (sofosbuvir and ledipasvir, or SOF/LED) between October and December 2014.

    “The first key finding is that upon initial request for treatment, approximately one in four patients are denied,” said Dr. Albert Do, internal medicine resident and co-first author with Yash Mittal, M.D. “That proportion is surprising.”

    The researchers also found that certain subsets of patients were more likely to receive initial approval, including those with advanced liver disease such as cirrhosis and those on public insurance, either Medicare or Medicaid. “It is significant that factors beyond disease state and medical necessity now affect one’s likelihood of accessing HCV treatment,” said Mittal.

    While most patients in the study eventually received approval for treatment through the insurance appeals process, the delays are concerning, said Lim, as time is critical for patients on the verge of developing cirrhosis or liver failure. “It could make the difference for those who can be treated and remain stable long-term, versus those who have gone past the point of no return and will require liver transplantation or succumb to their illness,” he noted.

    This study adds to a growing body of literature on the hepatitis C “cascade of care,” in which attrition occurs at every step from diagnosis, confirmation, linkage to care, and treatment, Lim explained. He hopes the study triggers further research and discussion about this new barrier to HCV care.

    “Delay in access may further challenge our ability to cure hepatitis C in this country,” Lim said. “Some patients are told they must wait until they have advanced liver disease before they can undergo potentially curative treatment. We hope these data may help inform national policy discussions on promoting more rational, patient-centered approaches to HCV treatment access.”

    Other Yale authors include Annmarie Liapakis, Elizabeth Cohen, Hong Chau, Claudia Bertuccio, Dana Sapir, Jessica Wright, Carol Eggers, Kristine Drozd, Maria Ciarleglio, and Yanhong Deng.

    See the full article here.

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    Yale University Campus

    Yale University comprises three major academic components: Yale College (the undergraduate program), the Graduate School of Arts and Sciences, and the professional schools. In addition, Yale encompasses a wide array of centers and programs, libraries, museums, and administrative support offices. Approximately 11,250 students attend Yale.

     
  • richardmitnick 6:40 am on August 25, 2015 Permalink | Reply
    Tags: , , Medicine   

    From AAAS: ” Revealing the hidden dangers of dietary supplements” 

    AAAS

    AAAS

    20 August 2015
    Jennifer Couzin-Frankel

    1
    Internist and amateur detective Pieter Cohen is outraged that some of the supplements on the market are unsafe. Dominick Reuter

    Pieter Cohen’s brush with death came at a most inconvenient time: just as he was about to nail another menacing ingredient in a dietary supplement.

    Hiking last August in New Hampshire with his wife and three children, Cohen, an internist at Cambridge Health Alliance in Massachusetts, stumbled and fell. A rock punctured his left calf. “It was a little cut, but deep,” recalls his wife, Lauren Budding. By the next day, bacteria were coursing through Cohen’s bloodstream. The leg turned red and swelled. His blood pressure dropped precipitously. Cohen was rushed to a community hospital and soon after by ambulance to a trauma unit in Boston.

    Doctors worked feverishly to stabilize him and stop the spread of infection. Over the next few days, the threat of death ebbed, though the risk that he would never walk normally remained. Cohen, meanwhile, fretted about the same matters he usually did: consumers, including his patients, who might be swallowing dietary supplements spiked with drugs. Bedbound and in searing pain, he asked for his computer. His wife refused.

    “I’m like, ‘I’m sorry, this person needs to sleep,’” she told the hospital staff. So Cohen had his mother smuggle in the laptop, along with data sets concealed inside The Boston Globe. “I could work on the manuscript when Lauren wasn’t looking,” he reasoned.

    Eleven days after the accident, and after the fourth of what would be five surgeries, Cohen and two collaborators submitted their paper to Drug Testing and Analysis. The report was unnerving: At least a dozen supplements sold in the United States for weight loss, enhanced brain function, and improved athletic performance contained a synthetic stimulant. The compound, which Cohen and his co-authors named DMBA, resembled methamphetamine in its chemical structure. It had never been tested in people, only in two animal studies from the 1940s. “Its efficacy and safety are entirely unknown,” they wrote.

    By now ensconced in a hospital bed in his living room and waiting for skin grafts to heal, Cohen appealed to the journal: “I can’t walk, I’m totally available. Can you guys crank this review?” The paper was published online a month later, last October. In April of this year, the U.S. Food and Drug Administration (FDA) issued warning letters to 14 companies selling products containing DMBA. “The FDA considers these dietary supplements to be adulterated,” it wrote. And boom, Cohen was on to his next project.

    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 12:13 pm on August 23, 2015 Permalink | Reply
    Tags: , , Medicine,   

    From Scripps: “Hands-On Research 101: Internships Introduce Undergrads to Biomedical Science in Action” 

    Scripps

    Scripps Research Institute

    August 24, 2015
    Madeline McCurry-Schmidt

    1
    SURF Intern Joshua David says the internship at TSRI gave him new opportunities to learn about biomedicine. (Photo by Cindy Bruaer.)

    When Joshua David saw scientists from The Scripps Research Institute (TSRI) discussing Ebola virus research on the news last year, he wanted to help.

    “I discovered that Scripps is one of the top places looking at Ebola virus at the molecular level,” said David, an undergraduate chemistry major at Virginia Commonwealth University. “The scientists at Scripps are trying to help people who are suffering and dying right now.”

    David quickly got in touch with Ebola researchers at TSRI and learned about the institute’s Summer Undergraduate Research Fellows (SURF) Program, organized by the TSRI Office of Graduate Studies. The SURF Program is a 10-week internship program at TSRI that has brought 38 undergraduates to TSRI’s California and Florida campuses this year. It’s one of several outreach programs, including a summer high school internship program where another 30 students work side-by-side with researchers.

    As a SURF intern, David flew into San Diego in June and spent his summer in Associate Professor Andrew Ward’s lab.

    Learning New Techniques

    David said the internship gave him new opportunities to learn about biomedicine.

    “I’m very interested in structural biology and virology; however, these courses are not offered at my university,” David explained. “Coming here is a great opportunity because it allows me learn techniques used in these fields and gain general knowledge of each field in the process.”

    Under the guidance of C. Daniel Murin, a graduate student in the Ward lab, David learned how to build 3-D structures of proteins involved in Ebola virus attacks. The SURF program emphasizes hands-on research, so David learned to use a technique called electron microscopy (EM) to study exactly how Ebola virus interacts with antibodies.

    “I wanted to take him through that process, so he can go through it almost independently by the end of the summer,” said Murin.

    David worked with Murin on several projects, including studies involving the experimental Ebola virus treatment ZMapp, which has also been the topic of previous studies at TSRI.

    David said one challenge this summer was tackling how to use a molecular imaging program necessary for research with EM.

    “Then I just had to sit down and figure it out,” he said. “It took me about eight hours, but now I understand how to do it.”

    Helping Patients

    David hopes to bring together research and patient care in a future career as a physician-scientist. As a high school student, David interned in a hospital’s intensive care unit. He watched as patients succumbed to diseases like acute respiratory distress syndrome (ARDS)—where doctors have few treatments to offer.

    A technique like EM could give David and other scientists a better look at the proteins involved in disease—from Ebola to ARDS—and lead to new treatments.

    “You can understand how things work in cells at the atomic level, and that really interests me,” said David.

    Before David headed back to Virginia at the end of the summer, he presented a poster outlining his work to peers and supervisors at TSRI. It was chance to show what he’s learned—and why he wants to be part of the next generation of scientists.

    About the Summer Undergraduate Research Fellows (SURF) Program

    TSRI’s 10-week SURF program provides participants the opportunity to perform cutting-edge research in one of 250 laboratories side-by-side with TSRI’s world-renowned faculty. The goals of the program are to:

    Make program participants feel comfortable in a lab setting and increase their research skills
    Teach participants to think critically about the theory and application of biomedical research
    Increase the participants’ proficiency in communicating scientific concepts
    Increase the number of underrepresented and first-generation to college students who consider careers in biomedical research.

    Students can choose to apply to either the La Jolla campus in California or the Jupiter campus in Florida. Learn more at TSRI’s Education website.

    See the full article here.

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    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

     
  • richardmitnick 10:04 am on August 21, 2015 Permalink | Reply
    Tags: , , , Medicine   

    From CMU: Carnegie Mellon-Led Team Identifies Structure of Tumor-Suppressing Protein 

    Carnegie Mellon University logo
    Carnegie Mellon university

    August 20, 2015
    Jocelyn Duffy, jhduffy@andrew.cmu.edu, 412-268-9982

    1
    An activated PTEN dimer that contains two non-mutant proteins (A) can transform the functional lipid (D) on the cellular membrane (E) into a chemical form that tunes down cancer predilection. Dimers that contain a mutated protein (B), or PTEN monomers can not transform the functional lipid.

    An international group of researchers led by Carnegie Mellon University physicists Mathias Lösche and Frank Heinrich have established the structure of an important tumor suppressing protein, PTEN. Their findings provide new insights into how the protein regulates cell growth and how mutations in the gene that encodes the protein can lead to cancer. The study is published online in Structure, and will appear in the Oct. 6 issue.

    Phosphatase and tensin homolog (PTEN) is a known tumor suppressing protein that is encoded by the PTEN gene. When expressed normally, the protein acts as an enzyme at the cell membrane, instigating a complex biochemical reaction that regulates the cell cycle and prevents cells from growing or dividing in an unregulated fashion. Each cell in the body contains two copies of the PTEN gene, one inherited from each parent. When there is a mutation in one or both of the PTEN genes, it interferes with the protein’s enzymatic activity and, as a result inhibits its tumor suppressing ability.

    “Membrane-incorporated and membrane-associated proteins like PTEN make up one-third of all proteins in our body. Many important functions in health and disease depend on their proper functioning,” said Lösche, who with other researchers within Carnegie Mellon’s Center for Membrane Biology and Biophysics aim to understand the structure and function of cell membranes and membrane proteins. “Despite PTEN’s importance in human physiology and disease, there is a critical lack of understanding of the complex mechanisms that govern its activity.”

    Recently, researchers led by Pier Paolo Pandolfi at Harvard Medical School found that PTEN’s tumor suppressing activity becomes elevated when two copies of the protein bind together, forming a dimeric protein.

    “PTEN dimerization may be the key to understanding an individual’s susceptibility for PTEN-sensitive tumors,” said Lösche, a professor of physics and biomedical engineering at Carnegie Mellon.

    In order to reveal how dimerization improves PTEN’s ability to thwart tumor development, researchers needed to establish the protein’s dimeric structure. Normally, protein structure is identified using crystallography, but attempts to crystallize the PTEN dimer had failed. Lösche and colleagues used a different technique called small-angle X–ray scattering (SAXS) which gains information about a protein’s structure by scattering X-rays through a solution containing the protein. They then used computer modeling to establish the dimer’s structure.

    They found that in the PTEN dimers, the C-terminal tails of the two proteins may bind the protein bodies in a cross-wise fashion, which makes them more stable. As a result, they can more efficiently interact with the cell membrane, regulate cell growth and suppress tumor formation.

    Now that more is known about the structure of the PTEN dimer, researchers will be able to use molecular biology tools to investigate the atomic-scale mechanisms of tumor formation facilitated by PTEN mutations. The researchers also hope that their findings will offer up a new avenue for cancer therapeutics.

    In addition to Lösche and Heinrich, who are also research associates at the National Institute of Standards and Technology (NIST), and Pandolfi, co-authors of the study include: Srinivas Chakravarthy of Argonne National Laboratory and the Illinois Institute of Technology; Hirsh Nanda of Carnegie Mellon and NIST; Antonella Papa of Monash University in Melbourne; Alonzo H. Ross of the University of Massachusetts Medical School; and Rakesh K. Harishchandra and Arne Gericke of Worcester Polytechnic Institute.

    The research was funded by the Department of Commerce, the National Institutes of Health’s National Institute of General Medical Sciences (GM101647) and National Institute of Neurological Disorders and Stroke (NS021716), and the National Science Foundation (1216827). The research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility and the NIGMS-supported BioCAT facility.

    See the full article here.

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    Carnegie Mellon Campus

    Carnegie Mellon University (CMU) is a global research university with more than 12,000 students, 95,000 alumni, and 5,000 faculty and staff.
    CMU has been a birthplace of innovation since its founding in 1900.
    Today, we are a global leader bringing groundbreaking ideas to market and creating successful startup businesses.
    Our award-winning faculty members are renowned for working closely with students to solve major scientific, technological and societal challenges. We put a strong emphasis on creating things—from art to robots. Our students are recruited by some of the world’s most innovative companies.
    We have campuses in Pittsburgh, Qatar and Silicon Valley, and degree-granting programs around the world, including Africa, Asia, Australia, Europe and Latin America.

     
  • richardmitnick 9:22 am on August 21, 2015 Permalink | Reply
    Tags: , , Medicine, Sepsis,   

    From Wyss at Harvard: Wyss improves sepsis device 

    Harvard University

    Harvard University

    Wyss Institute

    August 20, 2015
    Kat J. McAlpine

    1
    This blood-cleansing device connected to a dialysis-like circuit has a dense pack of hollow fibers whose inner surfaces are covered with the Wyss Institute’s genetically engineered Mannose-binding lectin (MBL) protein, called FcMBL. When septic blood is streamed through the device, FcMBL effectively extracts viruses, fungi, and parasites as well as toxins and dead pathogen fragments released into the bloodstream by antibiotic killing. Image courtesy of the Wyss Institute

    New model of blood-cleansing device has been simplified and is closer to clinical use

    A team of scientists at the Wyss Institute last year described the development of a device to treat sepsis that works by mimicking the human spleen. The device cleanses pathogens and toxins from blood flowing through a dialysis-like circuit. Now the team has developed an improved device that works with conventional antibiotic therapies and is better positioned for near-term use in clinics.

    The improved design is described in the October issue of Biomaterials.

    Sepsis is a common and frequently fatal medical complication that can occur when the body attempts to fight off serious infection and the resulting widespread inflammation can cause organs to shut down, blood pressure to drop, and the heart to weaken. This can lead to septic shock, which eventually kills more than 30 percent of septic patients in the United States. In most cases, the pathogen responsible for triggering the septic condition is not pinpointed, so clinicians blindly prescribe an antibiotic course in a blanket attempt to stave off the infectious bacteria and halt the dangerous inflammatory response.


    Download here.
    This video explains how sepsis induced by an overload of blood pathogens can be treated with the Wyss Institute’s improved pathogen-extracting, spleen-mimicking device. Blood is flown through a cartridge filled with hollow fibers that are coated with a genetically engineered blood protein inspired by a naturally occurring human molecule called Mannose-binding lectin (MBL). MBL is found in our innate immune system and binds to toxic invaders, marking them for capture by immune cells in the spleen. Courtesy of the Wyss Institute

    But sepsis can be caused by a wide-ranging variety of pathogens that are not susceptible to antibiotics, including viruses, fungi, and parasites. What’s more, even when antibiotics successfully kill the invading bacteria, dead pathogens fragment and release toxins into the patient’s bloodstream.

    “The inflammatory cascade that leads to sepsis is triggered by pathogens, and specifically by the toxins they release,” said Wyss Institute founding director Donald Ingber, who leads the Wyss team developing the device. Ingber is the Judah Folkman Professor of Vascular Biology at Boston Children’s Hospital and Harvard Medical School and a professor of bioengineering at the Harvard John A. Paulson School of Engineering and Applied Science. “Thus, the most effective strategy is to treat with the best antibiotics you can muster, while also removing the toxins and remaining pathogens from the patient’s blood as quickly as possible.”

    The Wyss team’s blood-cleansing approach can be administered quickly, even without identifying the infectious agent. This is because it uses the Wyss Institute’s proprietary, pathogen-capturing agent, FcMBL, which binds all types of live and dead infectious microbes, including bacteria, fungi, viruses, and the toxins they release. FcMBL is a genetically engineered blood protein inspired by a naturally occurring human molecule called mannose-binding lectin (MBL), which is found in the innate immune system and binds to toxic invaders, marking them for capture by immune cells in the spleen.

    Originally, the device was conceived to operate similarly to a dialysis machine: Infected blood in an animal — and potentially one day in a patient — is flowed from one vein through catheters to the device. There, FcMBL-coated magnetic beads are added to the blood, and then bead-bound pathogens are extracted by magnets inside the device before the cleansed blood is returned to the body through another vein.

    The improved device removes the complexity, regulatory challenges, and cost associated with the magnetic beads and microfluidic architecture of its predecessor, but retains the FcMBL protein’s ability to bind to all kinds of live or dead pathogens and toxins. The optimized system uses hollow fiber filters found in dialysis cartridges already approved by the FDA whose inner walls are coated with the FcMBL protein. In animal studies, treatment with this new pathogen-extracting device reduced the number of E. coli, Staphylococcus aureus, and endotoxins circulating in the bloodstream by more than 99 percent.

    “Using the device, alone or alongside antibiotics, we can quickly bring blood back to normal conditions, curtailing an inflammatory response rather than exacerbating it,” said the paper’s first author, Tohid Fatanat Didar, a postdoctoral fellow at the Wyss institute and a research fellow at Boston Children’s Hospital. “If all goes well, physicians will someday be able to use the device in tandem with standard antibiotic treatments to deliver a one-two punch to pathogens, synergistically killing and cleansing all live and dead invaders from the bloodstream.”

    With the improved blood-cleansing therapeutic device proving extremely effective in small-animal studies, the Wyss team is planning to move to large-animal studies as the next step to demonstrating the proof of concept that is required before it can advance to human clinical trials.

    “Seeing our system work in animal models gives us confidence that this could work in humans, because we are successfully treating animals infected with human pathogens,” said Wyss senior staff scientist Michael Super, who works on the Institute’s Advanced Technology Team and is also an author on the new study.

    “Since the development of earlier prototypes of the device, we’ve applied the Wyss model of de-risking the technology to prime it for commercialization,” said Ingber. “Our goal is to see this move out of the lab and into hospitals as well as onto the battlefield, where it can save lives, within years rather than decades.”

    This work was supported by the Defense Advanced Research Projects Agency and the Wyss Institute for Biologically Inspired Engineering at Harvard University.

    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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  • richardmitnick 3:06 pm on August 19, 2015 Permalink | Reply
    Tags: , HCV, Medicine   

    From Rockefeller: “Expression of a single gene lets scientists easily grow hepatitis C virus in the lab” 

    Rockefeller U bloc

    Rockefeller University

    August 19, 2015
    Eva Kiesler | 212-327-7963

    1
    Researchers engineered cultured cells to contain a red marker that moves into the nucleus upon HCV infection. Nothing happened when normal cells were exposed to HCV (top), but when the researchers expressed the protein SEC14L2, some nuclei changed color from blue to purple (bottom).

    Worldwide, 185 million people have chronic hepatitis C [HCV]. Since the late 1980s, when scientists discovered the virus that causes the infection, they have struggled to find ways to grow it in human cells in the lab — an essential part of learning how the virus works and developing new effective treatments.

    In a study published in Nature on August 12, scientists led by The Rockefeller University’s Charles M. Rice, Maurice R. and Corinne P. Greenberg Professor in Virology and head of the Laboratory of Virology and Infectious Disease, report that when they overexpressed a particular gene in human liver cancer cell lines, the virus could easily replicate. This discovery allows study of naturally occurring forms of hepatitis C virus (HCV) in the lab.

    “Being able to easily culture HCV in the lab has many important implications for basic science research,” says Rice. “There is still much we don’t understand about how the virus operates, and how it interacts with liver cells and the immune system.”

    Scientists have long attempted to understand what makes HCV tick, and in 1999 a group of German scientists succeeded in coaxing modified forms of the virus to replicate in cells in the laboratory. However, it was soon discovered that these forms of the virus were able to replicate because they had acquired certain “adaptive” mutations.

    This was true for all samples from patients, except one, and left scientists with a puzzling question for more than a decade: what prevents non-mutated HCV from replicating in laboratory-grown cell lines? Rice and colleagues hypothesized that one or more critical elements might be missing in these cell lines.

    To test this idea, they screened a library of about 7,000 human genes to look for one whose expression would allow replication of non-mutated HCV. When the scientists expressed the gene SEC14L2, the virus replicated in its wild-type, non-mutated form. Even adding serum samples from HCV-infected patients to these engineered cell lines resulted in virus replication.

    “Practically speaking, this means that if scientists want to study HCV from an infected patient, it’s now possible to take a blood sample, inoculate the engineered cells, and grow that patient’s form of the virus in the lab,” says first author Mohsan Saeed, a postdoc in Rice’s laboratory.

    It’s not entirely clear how the protein expressed by SEC14L2 works, says Saeed, but it appears to inhibit lipids from interacting with dangerous reactive oxygen species, a process that prevents HCV replication.

    Recent advances in HCV treatment have made it possible for millions of people to be cured of the virus. “New therapies, however, are extremely expensive and not perfect,” Saeed notes. “As more patients are treated, drug resistant forms of HCV are emerging. Having a cell culture system where patient isolates can be grown and tested for resistance or susceptibility to alternative antiviral drug combinations should be useful for optimizing re-treatment strategies for those that fail treatment.”

    Even though effective therapies for HCV do exist, there is still much we need to understand about the virus, adds Saeed — and understanding how HCV interacts with its host cell can help scientists learn more about similar viruses for which effective treatments have yet to be developed. “The lessons learned from one disease can be true for other diseases as well,” he observes.

    See the full article here.

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    Rockefeller U Campus

    The Rockefeller University is a world-renowned center for research and graduate education in the biomedical sciences, chemistry, bioinformatics and physics. The university’s 76 laboratories conduct both clinical and basic research and study a diverse range of biological and biomedical problems with the mission of improving the understanding of life for the benefit of humanity.

    Founded in 1901 by John D. Rockefeller, the Rockefeller Institute for Medical Research was the country’s first institution devoted exclusively to biomedical research. The Rockefeller University Hospital was founded in 1910 as the first hospital devoted exclusively to clinical research. In the 1950s, the institute expanded its mission to include graduate education and began training new generations of scientists to become research leaders around the world. In 1965, it was renamed The Rockefeller University.

     
  • richardmitnick 2:20 pm on August 19, 2015 Permalink | Reply
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    From Hopkins: “Return on investment in biomedical research on the decline, Hopkins researchers say” 

    Johns Hopkins
    Johns Hopkins University

    8.19.15
    Stephanie Desmon

    1

    As the amount of money spent on biomedical research in the United States has grown over the past 50 years, there has been diminished return on investment in terms of life expectancy gains and new drug approvals, two Johns Hopkins Bloomberg School of Public Health researchers say.

    In a report published Monday in the Proceedings of the National Academy of Sciences, the researchers found that while the number of scientists has increased more than nine-fold since 1965 and the National Institutes of Health’s budget has increased four-fold, the number of new drugs approved by the Food and Drug Administration has only increased a little more than two-fold. Meanwhile, life expectancy gains have remained constant, at roughly two months per year.

    “The idea of public support for biomedical research is to make lives better. But there is increasing friction in the system,” says co-author Arturo Casadevall, professor and chair of the Department of Molecular Microbiology and Immunology at the Bloomberg School. “We are spending more money now just to get the same results we always have, and this is going to keep happening if we don’t fix things.”

    Casadevall, who did the research with Anthony Bowen, a visiting scholar at the Bloomberg School and an MD/PhD student at Albert Einstein College of Medicine in New York, says that understanding the issues that are making the scientific process less efficient is a key to remedying the underlying problems.

    “There is something wrong in the process, but there are no simple answers,” Bowen says. “It may be a confluence of factors that are causing us not to be getting more bang for our buck.”

    Among the factors, they suggest, is that increased regulations on researchers—everything from the lengthy process of gaining consent to take blood samples for a study to cataloguing every trip to a conference for government oversight—add to the non-scientific burdens on scientists who could otherwise spend more time at the bench. Some have argued that the “easy” cures have been found and that to tackle Alzheimer’s disease, most cancers, and autoimmune diseases, for example, is inherently more complex.

    Casadevall and Bowen also cite “perverse” incentives for researchers to cut corners or oversimplify their studies to gain acceptance into top-tier medical journals, something that has led to what they call an epidemic of retractions and findings that cannot be reproduced and are therefore worthless.

    “The medical literature isn’t as good as it used to be,” Casadevall says. “The culture of science appears to be changing. Less important work is being hyped, when the quality of work may not be clear until decades later when someone builds on your success to find a cure.”

    One recent study estimated that more than $28 billion, from both public and private sources, is spent each year in the United States on preclinical research that can’t be reproduced, and that the prevalence of these studies in the literature is 50 percent.

    “We have more journals and more papers than ever,” Bowen says, “but the number of biomedical publications has dramatically outpaced the production of new drugs, which are a key to improving people’s lives, especially in areas for which we have no good treatments.”

    For the study, the researchers searched through public databases for published medical literature, looked at NIH investment data, FDA new drug approvals, data on life expectancy gains, and other similar data.

    The authors acknowledge that new drug approvals and life expectancy rates are not the only measures by which to judge the efficiency of biomedical research. But, they argue, when it comes down to it, when someone is sick, they either need medicine or surgery to save their lives and many times the medicines haven’t been developed. Also, they say, life expectancy is a good measure of the overall system, because gains have been made due to research into seat belts and pedestrian safety as well as due to medical therapies.

    Casadevall says that many of the best drugs being used to treat conditions today were developed many decades ago, including insulin for diabetes and beta-blockers for cardiac conditions. From 1965 to 1999, the NIH budget grew exponentially. Over the next four years, the budget doubled before a steady decrease from 2003 to 2014, which is larger than apparent because of the rapidly rising costs of scientific experiments. The cost per new drug, in millions of dollars of NIH budget, has grown rapidly since the 1980s, they say.

    Casadevall doesn’t doubt that more cures are out there to be found and that a more efficient system of biomedical research could help push along scientific discovery.

    “Scientists, regulators and citizens need to take a hard look at the scientific enterprise and see which are problems that can be resolved,” he says. “We need a system with rigor, reproducibility, and integrity, and we need to find a way to get there as soon as we can.”

    See the full article here.

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    Johns Hopkins Campus

    The Johns Hopkins University opened in 1876, with the inauguration of its first president, Daniel Coit Gilman. “What are we aiming at?” Gilman asked in his installation address. “The encouragement of research … and the advancement of individual scholars, who by their excellence will advance the sciences they pursue, and the society where they dwell.”

    The mission laid out by Gilman remains the university’s mission today, summed up in a simple but powerful restatement of Gilman’s own words: “Knowledge for the world.”

    What Gilman created was a research university, dedicated to advancing both students’ knowledge and the state of human knowledge through research and scholarship. Gilman believed that teaching and research are interdependent, that success in one depends on success in the other. A modern university, he believed, must do both well. The realization of Gilman’s philosophy at Johns Hopkins, and at other institutions that later attracted Johns Hopkins-trained scholars, revolutionized higher education in America, leading to the research university system as it exists today.

     
  • richardmitnick 6:26 am on August 18, 2015 Permalink | Reply
    Tags: , , Medicine,   

    From MIT: “Quick test for Ebola” 


    MIT News

    February 24, 2015
    Anne Trafton

    1
    A new paper diagnostic device can detect Ebola as well as other viral hemorrhagic fevers in about 10 minutes. The device (pictured here) has silver nanoparticles of different colors that indicate different diseases. On the left is the unused device, opened to reveal the contents inside. On the right, the device has been used for diagnosis; the colored bands show positive tests. Photo courtesy of Jose Gomez-Marquez, Helena de Puig, and Chun-Wan Yen

    When diagnosing a case of Ebola, time is of the essence. However, existing diagnostic tests take at least a day or two to yield results, preventing health care workers from quickly determining whether a patient needs immediate treatment and isolation.

    A new test from MIT researchers could change that: The device, a simple paper strip similar to a pregnancy test, can rapidly diagnose Ebola, as well as other viral hemorrhagic fevers such as yellow fever and dengue fever.

    “As we saw with the recent Ebola outbreak, sometimes people present with symptoms and it’s not clear what they have,” says Kimberly Hamad-Schifferli, a visiting scientist in MIT’s Department of Mechanical Engineering and a member of the technical staff at MIT’s Lincoln Laboratory. “We wanted to come up with a rapid diagnostic that could differentiate between different diseases.”

    Hamad-Schifferli and Lee Gehrke, the Hermann L.F. von Helmholtz Professor in MIT’s Institute for Medical Engineering and Science (IMES), are the senior authors of a paper describing the new device in the journal Lab on a Chip. The paper’s lead author is IMES postdoc Chun-Wan Yen, and other authors are graduate student Helena de Puig, IMES postdoc Justina Tam, IMES instructor Jose Gomez-Marquez, and visiting scientist Irene Bosch.

    Color-coded test

    Currently, the only way to diagnose Ebola is to send patient blood samples to a lab that can perform advanced techniques such as polymerase chain reaction (PCR), which can detect genetic material from the Ebola virus. This is very accurate but time-consuming, and some areas of Africa where Ebola and other fevers are endemic have limited access to this kind of technology.

    The new device relies on lateral flow technology, which is used in pregnancy tests and has recently been exploited for diagnosing strep throat and other bacterial infections. Until now, however, no one has applied a multiplexing approach, using multicolored nanoparticles, to simultaneously screen for multiple pathogens.

    “For many hemorrhagic fever viruses, like West Nile and dengue and Ebola, and a lot of other ones in developing countries, like Argentine hemorrhagic fever and the Hantavirus diseases, there are just no rapid diagnostics at all,” says Gehrke, who began working with Hamad-Schifferli four years ago to develop the new device.

    Unlike most existing paper diagnostics, which test for only one disease, the new MIT strips are color-coded so they can be used to distinguish among several diseases. To achieve that, the researchers used triangular nanoparticles, made of silver, that can take on different colors depending on their size.

    The researchers created red, orange, and green nanoparticles and linked them to antibodies that recognize Ebola, dengue fever, and yellow fever. As a patient’s blood serum flows along the strip, any viral proteins that match the antibodies painted on the stripes will get caught, and those nanoparticles will become visible. This can be seen by the naked eye; for those who are colorblind, a cellphone camera could be used to distinguish the colors.

    “When we run a patient sample through the strip, if you see an orange band you know they have yellow fever, if it shows up as a red band you know they have Ebola, and if it shows up green then we know that they have dengue,” Hamad-Schifferli says.

    This process takes about 10 minutes, allowing health care workers to rapidly perform triage and determine if patients should be isolated, helping to prevent the disease from spreading further.

    Warren Chan, an associate professor at the University of Toronto Institute of Biomaterials and Biomedical Engineering, says he is impressed with the device because it not only offers faster diagnosis, but also requires smaller patient blood samples, as just one test strip can detect multiple diseases. “It’s a step up from what everyone else is doing,” says Chan, who was not involved in the research. “They’re targeting diseases that are really relevant to what’s going on in the world at this point, and have shown that they can detect them simultaneously.”

    Faster triage

    The researchers envision their new device as a complement to existing diagnostic technologies, such as PCR.

    “If you’re in a situation in the field with no power and no special technologies, if you want to know if a patient has Ebola, this test can tell you very quickly that you might not want to put that patient in a waiting room with other people who might not be infected,” says Gehrke, who is also a professor of microbiology and immunology at Harvard Medical School. “That initial triage can be very important from a public health standpoint, and there could be a follow-up test later with PCR or something to confirm.”

    The researchers hope to obtain Food and Drug Administration approval to begin using the device in areas where the Ebola outbreak is still ongoing. In order to do that, they are now testing the device in the lab with engineered viral proteins, as well as serum samples from infected animals.

    This type of device could also be customized to detect other viral hemorrhagic fevers or other infectious diseases, by linking the silver nanoparticles to different antibodies.

    “Thankfully the Ebola outbreak is dying off, which is a good thing,” Gehrke says. “But what we’re thinking about is what’s coming next. There will undoubtedly be other viral outbreaks. It might be Sudan virus, it might be another hemorrhagic fever. What we’re trying to do is develop the antibodies needed to be ready for the next outbreak that’s going to happen.”

    The research was funded by the National Institute of Allergy and Infectious Disease.

    See the full article here.

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  • richardmitnick 7:37 pm on August 17, 2015 Permalink | Reply
    Tags: Alzheimer’s disease, , Medicine,   

    From Rockefeller: “A newly discovered molecular feedback process may protect the brain against Alzheimer’s” 

    Rockefeller U bloc

    Rockefeller University

    August 17, 2015
    Wynne Parry | 212-327-7789

    1
    Ready to ship: Within cells displaying features of Alzheimer’s, the researchers found high concentrations of WAVE1 and the amyloid-β precursor protein within the Golgi, an organelle in which proteins are packaged for shipping. These appear in the cell above as bright, yellow clusters.

    It is a hallmark of Alzheimer’s disease: Toxic protein fragments known as amyloid-β clumped together between neurons in a person’s brain. Neurons themselves make amyloid-β, and for reasons that aren’t fully understood, its accumulation ultimately contributes to the memory loss, personality changes, and other symptoms that patients with this degenerative disease often suffer from.

    New research by Rockefeller University scientists and their colleagues have identified a series of naturally occurring molecular steps—known as a pathway—that can dampen the production of amyloid-β. These results, reported in Nature Medicine on August 17, suggest a new route in the search for Alzheimer’s therapies.

    “Our discovery centers on a protein called WAVE1, which we found to be important in the production of amyloid-β. The reduction of WAVE1 appears to have a protective effect against the disease,” says study author Paul Greengard, Vincent Astor Professor and head of the Laboratory of Molecular and Cellular Neuroscience. “When levels of amyloid-β rise, there is an accompanying increase in another molecule, AICD, which reduces the expression of WAVE1. This has the effect of reducing the production of amyloid-β.

    “By targeting steps within this newly discovered pathway,” he adds, “it may be possible to develop drugs to reduce amyloid-β that potentially could be used to either treat or prevent Alzheimer’s disease.”

    WAVE1 is known to help to build filaments of a protein called actin that serve as basic components of cellular structures. In the current study, the team, including first author Ilaria Ceglia, who conducted this work while a research associate in the lab, examined the levels of WAVE1 in mouse and cellular models of Alzheimer’s disease and found that they were unusually low. Research done by a collaborator at Columbia University found this was also true for the brains of human patients with the disease.

    To take a closer look at the relationship between amyloid-β and WAVE1, the researchers tested the brains and memories of mice genetically altered to produce high levels of amyloid-β and varying levels of WAVE1. They found a dose-dependent response: Mice brains with low WAVE1 levels produced less amyloid-β, and these animals performed better on memory tests.

    Next, the researchers wanted to know how WAVE1 affects the production of amyloid-β. The precursor to this Alzheimer’s protein is not harmful by itself, and does not normally yield brain-damaging products. However, sometimes the precursor is processed in such a way that it produces disease-promoting amyloid-β.

    The team found high levels of both the amyloid precursor protein and WAVE1 in a compartment within the cell known as the Golgi, which acts as a sort of shipping department. Here proteins are packaged before they are sent out to various destinations within the cell. In the case of the amyloid precursor protein, the first destination is the cell’s outer membrane. From there, it travels into the compartments within the cell, where it is processed to produce amyloid-β.

    Because the formation of structural filaments is critical to the process by which cargo buds off and leaves the Golgi, the researchers suspected a role for WAVE1. Their experiments showed an interaction between WAVE1 and the amyloid precursor protein, and confirmed that WAVE1 mediates the formation of cargo vesicles containing amyloid precursor protein.

    “The result is a negative feedback loop,” says corresponding author Yong Kim, a research assistant professor in the lab. “More amyloid-β means more AICD. Our experiments reveal that AICD travels into the nucleus where it reduces the expression of WAVE1. Less WAVE1 means less precursor protein in cargo traveling to the membrane for conversion into amyloid-β. In Alzheimer’s disease, this negative feedback appears to lose its protective effect, and the next step for us is to figure out how.”

    See the full article here.

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    Rockefeller U Campus

    The Rockefeller University is a world-renowned center for research and graduate education in the biomedical sciences, chemistry, bioinformatics and physics. The university’s 76 laboratories conduct both clinical and basic research and study a diverse range of biological and biomedical problems with the mission of improving the understanding of life for the benefit of humanity.

    Founded in 1901 by John D. Rockefeller, the Rockefeller Institute for Medical Research was the country’s first institution devoted exclusively to biomedical research. The Rockefeller University Hospital was founded in 1910 as the first hospital devoted exclusively to clinical research. In the 1950s, the institute expanded its mission to include graduate education and began training new generations of scientists to become research leaders around the world. In 1965, it was renamed The Rockefeller University.

     
  • richardmitnick 11:13 am on August 15, 2015 Permalink | Reply
    Tags: , , Lassa virus, Medicine   

    From Broad Institute at Harvard: “New insights on an old virus 

    Harvard University

    Harvard University

    Harvard Broad Institute
    Broad Institute of Harvard and MIT

    August 13th, 2015
    Angela Page

    1
    New research from Broad scientists lends new understanding to Lassa virus, which kills at least 5,000 people every year. Pictured are Pardis Sabeti and Edwin Konuwa of the Kenema Government Hospital.Photo courtesy of the Sabeti Lab.

    Between 2013 and 2015, an outbreak of Ebola virus killed more than 11,000 people. Broad Institute researchers quickly deployed real-time sequencing efforts that confirmed that the virus was primarily spreading through human-to-human contact rather than between animals and humans and that the viral genome was mutating. This work had a profound impact on how public health officials diagnosed the disease and developed strategies to contain it.

    That research was feasible largely because institute member Pardis Sabeti and her team had already been working on another deadly virus affecting West Africa: Lassa virus. In 2007, the Sabeti lab discovered genetic evidence that humans might be able to develop resistance to Lassa. They quickly set up a field site in Nigeria at the Irrua Specialist Teaching Hospital and formed collaborations with researchers from Tulane University working in Sierra Leone. Since then, the group has been sequencing the genomes of Lassa viral content in human blood samples. Those data now collectively form the largest catalog of information to date on Lassa Virus (LASV) available in the world. They were published this week, along with the team’s analyses, in the August issue of the journal Cell.

    Like Ebola, Lassa is a fatal, hemorrhagic fever virus. It kills at least 5,000 people each year, most of whom live in Sierra Leone, Nigeria, Liberia, and Guinea. Despite its impact, little research had been done on the virus until 2009. The same was true of Ebola before the recent outbreak. “Lassa and Ebola are not only potential global threats, but have likely been circulating in communities for many years,” said Sabeti. “It is a greatly overlooked public health challenge but also an opportunity to set up capacity to diagnose, treat and research these viruses now, before the next major outbreak.””Because of the potential for such large and severe outbreaks, it’s important that we perform research that allows us to better understand how these viruses transmit, how they evolve, how long they’ve been with us—we need to answer very fundamental questions and sequencing can help us address some of them,” said Kristian Andersen, one of three co-first authors on the new Cell paper. Andersen—now an assistant professor at the Scripps Research Institute in La Jolla, California—led the Lassa work while a post-doctoral researcher in Sabeti’s lab.

    This was a massive, international collaborative effort involving researchers from 19 different institutions across the academic, government, non-profit, medical, and commercial sectors. “It took many years to form this consortium and set up the infrastructure and many months to develop the sequencing protocols,” said fellow co-first author Christian Matranga, a research scientist at Broad. “But these efforts led to many technical leaps, which enabled discoveries that would not have been otherwise possible.”

    2
    Mambu Momoh of Kenema Government Hospital and Kristian Andersen. Photo courtesy of the Sabeti Lab

    Andersen and his colleagues sequenced 196 LASV genomes, including 11 collected from the rodent species that serves as the virus’ natural reservoir. The data allowed them to confirm that, in contrast to Ebola, Lassa patients typically contract the disease through individual “spillover” events from the animal to human population—that is, the virus is rarely transmitted between human patients.

    “Lassa is probably less transmissible than Ebola—either from rodent to human, or from human to human,” Andersen explained. “Presumably, however, since many rodents are infected and live in households, there may be more ‘opportunities’ for transmission from rodent to human to occur.” This means that strategies for containing Lassa could be fundamentally different from those used to contain Ebola and would focus more on the rodent reservoir population rather than minimizing human-to-human contact.

    The data also allowed the team to determine the most recent common ancestor of all modern Lassa virus strains: it existed more than 1,000 years ago. This calculation support Sabeti’s original suspicion that humans have been under natural selection to evolve resistance to the virus. “If that’s the case,” Andersen said, “the virus would need to have been around for quite a long time.”

    The team also examined the diversity of viral species infecting humans and rodents and found much more diversity among the latter. Because the rodents can be infected without becoming ill or dying, they are considered chronic carriers in whom there is more opportunity for the virus to mutate and evolve. Surprisingly, the researchers also saw a few human samples containing more diverse viral strains than normal, suggesting that some people might be infected for longer than previously thought.

    Andersen and his team at Scripps, as well as researchers at Broad, Tulane, and Irrua are now launching an effort to sequence healthy individuals across West Africa to determine whether the virus is present as a chronic, symptom-free infection in many more people than are typically diagnosed. “We’re also looking at how many people have antibodies to these viruses—both to Ebola and Lassa,” Andersen said, explaining that antibodies are developed whenever an individual becomes infected, even if they don’t present any symptoms.

    The diversity findings may also point to an immune escape mechanism wherein the virus develops mutations that allow it to evade an infected host’s immune response. “We found that, of the within-host mutations that affect protein structure, a surprisingly high number fall in parts of a Lassa surface protein targeted by the human immune system,” said Jesse Shapiro, a co-first author based at the University of Montreal. “This could have implications for vaccine design because it might mean that the virus is able to evade vaccine-induced immunity.” But the team also found that these particular mutations are rarely passed from one host to another, suggesting that, while they do provide adaptive immune escape within the host, “they may be evolutionary dead-ends that are unfit to transmit,” Shapiro said. The team is now undertaking further research to follow up on the immune escape hypothesis.

    While the research is exciting from a scientific perspective, Andersen said, “People are dying every day.” He noted that work like this is critical to better understanding the disease in order to someday make a real difference for patients and their families.

    Paper Cited: Andersen, Shapiro, Matranga, et al. Clinical Sequencing Uncovers Origins and Evolution of Lassa Virus. Cell. DOI: 10.1016/j.cell.2015.07.020

    Other Broad Researchers: Aaron M. Berlin, Bruce Birren, James Bochicchio, Eleina M. England, Hilary K. Finucane, Michael Fitzgerald, Stephen K. Gire, Andreas Gnirke, Andrea Ireland, Eric Lander, Niall J. Lennon, Joshua Z. Levin, Aaron E. Lin, Christian B. Matranga, Caryn McCowan, Mahan Nekoui, Eric Phelan, Elizabeth M. Ryan, Stephen F. Schaffner, B. Jesse Shapiro, Rachel Sealfon, Matthew Stremlau, Shervin Tabrizi, Ridhi Tariyal, Barbara Tazon-Vega, Ryan Tewhey, Sarah Winnicki.

    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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