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  • richardmitnick 10:56 am on February 16, 2017 Permalink | Reply
    Tags: , , Medicine, , Using (MRI) to study the brains of infants who have older siblings with autism   

    From U Washington: “Predicting autism: Researchers find autism biomarkers in infancy” 

    U Washington

    University of Washington

    February 15, 2017
    No writer credit

    By using magnetic resonance imaging (MRI) to study the brains of infants who have older siblings with autism, scientists were able to correctly identify 80 percent of the babies who would be subsequently diagnosed with autism at 2 years of age.

    Researchers from the University of Washington were part of a North American effort led by the University of North Carolina to use MRI to measure the brains of “low-risk” infants, with no family history of autism, and “high-risk” infants who had at least one autistic older sibling. A computer algorithm was then used to predict autism before clinically diagnosable behaviors set in. The study was published Feb. 15 in the journal Nature.

    This is the first study to show that it is possible to use brain biomarkers to identify which infants in a high-risk pool — that is, those having an older sibling with autism — will be diagnosed with autism spectrum disorder, or ASD, at 24 months of age.

    2
    Annette Estes, left, plays with a child at the UW Autism Center.Kathryn Sauber

    “Typically, the earliest we can reliably diagnose autism in a child is age 2, when there are consistent behavioral symptoms, and due to health access disparities the average age of diagnosis in the U.S. is actually age 4,” said co-author and UW professor of speech and hearing sciences Annette Estes, who is also director of the UW Autism Center and a research affiliate at the UW Center on Human Development and Disability, or CHDD. “But in our study, brain imaging biomarkers at 6 and 12 months were able to identify babies who would be later diagnosed with ASD.”

    The predictive power of the team’s findings may inform the development of a diagnostic tool for ASD that could be used in the first year of life, before behavioral symptoms have emerged.

    “We don’t have such a tool yet,” said Estes. “But if we did, parents of high-risk infants wouldn’t need to wait for a diagnosis of ASD at 2, 3 or even 4 years and researchers could start developing interventions to prevent these children from falling behind in social and communication skills.”

    People with ASD — which includes 3 million people in the United States — have characteristic social communication deficits and demonstrate a range of ritualistic, repetitive and stereotyped behaviors. In the United States, it is estimated that up to one out of 68 babies develops autism. But for infants with an autistic older sibling, the risk may be as high as one out of every five births.

    This research project included hundreds of children from across the country and was led by researchers at four clinical sites across the United States: the University of North Carolina-Chapel Hill, UW, Washington University in St. Louis and The Children’s Hospital of Philadelphia. Other key collaborators are at the Montreal Neurological Institute, the University of Alberta and New York University.

    3
    Stephen Dager.Marie-Anne Domsalla

    “We have wonderful, dedicated families involved in this study,” said Stephen Dager, a UW professor of radiology and associate director of the CHDD, who led the study at the UW. “They have been willing to travel long distances to our research site and then stay up until late at night so we can collect brain imaging data on their sleeping children. The families also return for follow-up visits so we can measure how their child’s brain grows over time. We could not have made these discoveries without their wholehearted participation.”

    Researchers obtained MRI scans of children while they were sleeping at 6, 12 and 24 months of age. The study also assessed behavior and intellectual ability at each visit, using criteria developed by Estes and her team. They found that the babies who developed autism experienced a hyper-expansion of brain surface area from 6 to 12 months, as compared to babies who had an older sibling with autism but did not themselves show evidence of autism at 24 months of age. Increased surface area growth rate in the first year of life was linked to increased growth rate of brain volume in the second year of life. Brain overgrowth was tied to the emergence of autistic social deficits in the second year.

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    MRI technician Mindy Dixon and Stephen Dager review a magnetic resonance spectroscopic image of a child’s brain chemistry.University of Washington

    The researchers input these data — MRI calculations of brain volume, surface area, and cortical thickness at 6 and 12 months of age, as well as sex of the infants — into a computer program, asking it to classify babies most likely to meet ASD criteria at 24 months of age. The program developed the best algorithm to accomplish this, and the researchers applied the algorithm to a separate set of study participants.

    Researchers found that, among infants with an older ASD sibling, the brain differences at 6 and 12 months of age successfully identified 80 percent of those infants who would be clinically diagnosed with autism at 24 months of age.

    If these findings could form the basis for a “pre-symptomatic” diagnosis of ASD, health care professionals could intervene even earlier.

    “By the time ASD is diagnosed at 2 to 4 years, often children have already fallen behind their peers in terms of social skills, communication and language,” said Estes, who directs behavioral evaluations for the network. “Once you’ve missed those developmental milestones, catching up is a struggle for many and nearly impossible for some.”

    Research could then begin to examine interventions on children during a period before the syndrome is present and when the brain is most malleable. Such interventions may have a greater chance of improving outcomes than treatments started after diagnosis.

    “Our hope is that early intervention — before age 2 — can change the clinical course of those children whose brain development has gone awry and help them acquire skills that they would otherwise struggle to achieve,” said Dager.

    The research team has gathered additional behavioral and brain imaging data on these infants and children — such as changes in blood flow in the brain and the movement of water along white matter networks — to understand how brain connectivity and neural activity may differ between high-risk children who do and don’t develop autism. In a separate study published Jan. 6 in Cerebral Cortex, the researchers identified specific brain regions that may be important for acquiring an early social behavior called joint attention, which is orienting attention toward an object after another person points to it.

    “These longitudinal imaging studies, which follow the same infants as they grow older, are really starting to hone in on critical brain developmental processes that can distinguish children who go on to develop ASD and those who do not,” said Dager. “We hope these ongoing efforts will lead to additional biomarkers, which could provide the basis for early, pre-symptomatic diagnosis and serve also to guide individualized interventions to help these kids from falling behind their peers.”

    The research was funded by the National Institutes of Health, Autism Speaks and the Simons Foundation.

    See the full article here .

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    The University of Washington is one of the world’s preeminent public universities. Our impact on individuals, on our region, and on the world is profound — whether we are launching young people into a boundless future or confronting the grand challenges of our time through undaunted research and scholarship. Ranked number 10 in the world in Shanghai Jiao Tong University rankings and educating more than 54,000 students annually, our students and faculty work together to turn ideas into impact and in the process transform lives and our world. For more about our impact on the world, every day.

    So what defines us — the students, faculty and community members at the University of Washington? Above all, it’s our belief in possibility and our unshakable optimism. It’s a connection to others, both near and far. It’s a hunger that pushes us to tackle challenges and pursue progress. It’s the conviction that together we can create a world of good. Join us on the journey.

     
  • richardmitnick 10:19 am on February 14, 2017 Permalink | Reply
    Tags: , , Medicine, Stem Cells Step Forward   

    From HMS: “Stem Cells Step Forward” 

    Harvard University

    Harvard University

    Harvard Medical School

    Harvard Medical School

    February 8, 2017
    NANCY FLIESLER

    For first time, iPS cells flag potential drug for blood disease.

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    Red blood cells were successfully made via induced pluripotent stem cells from a Diamond-Blackfan anemia patient. Image: Daley lab, Boston Children’s.

    Researchers at Harvard Medical School and Boston Children’s Hospital were able, for the first time, to use patients’ own cells to create cells similar to those in bone marrow and then use them to identify potential treatments for a blood disorder.

    The work was published Feb. 8 in Science Translational Medicine.

    The team derived the so-called blood progenitor cells from two patients with Diamond-Blackfan anemia (DBA), a rare, severe blood disorder in which the bone marrow cannot make enough oxygen-carrying red blood cells.

    The researchers first converted some of the patients’ skin cells into induced pluripotent stem (iPS) cells. They then got the iPS cells to make blood progenitor cells, which they loaded into a high-throughput drug-screening system.

    Testing a library of 1,440 chemicals, the team found several that showed promise in a dish. One compound, SMER28, was able to get live mice and zebrafish to start churning out red blood cells.

    The study marks an important advance in the stem cell field. iPS cells, theoretically capable of making virtually any cell type, were first created in the lab in 2006 from skin cells treated with genetic reprogramming factors. Specialized cells generated by iPS cells have been used to look for drugs for a variety of diseases—except for blood disorders, because of technical problems in getting iPS cells to make blood cells.

    “iPS cells have been hard to instruct when it comes to making blood,” said Sergei Doulatov, former HMS research fellow at Boston Children’s and co-first author on the paper with doctoral student Linda Vo and research fellow Elizabeth Macari. “This is the first time iPS cells have been used to identify a drug to treat a blood disorder.”

    DBA is currently treated with steroids, but these drugs help only about half of patients, and some of them eventually stop responding. When steroids fail, patients must receive lifelong blood transfusions, and quality of life for many patients is poor. The researchers believe SMER28 or a similar compound might offer another option.

    “It is very satisfying as physician-scientists to find new potential treatments for rare blood diseases such as Diamond-Blackfan anemia,” said Leonard Zon, HMS Grousbeck Professor of Pediatrics and director of the Stem Cell Research Program at Boston Children’s and co-corresponding author on the paper.

    “This work illustrates a wonderful triumph,” said co-corresponding author George Q. Daley, dean of HMS and associate director of the Stem Cell Research Program.

    Making red blood cells

    As in DBA itself, the patient-derived blood progenitor cells, studied in a dish, failed to generate the precursors of red blood cells, known as erythroid cells. The same was true when the cells were transplanted into mice. But the chemical screen got several “hits”: in wells loaded with these chemicals, erythroid cells began appearing.

    Because of its especially strong effect, SMER28 was put through additional testing. When used to treat the marrow in zebrafish and mouse models of DBA, the animals made erythroid progenitor cells that in turn made red blood cells, reversing or stabilizing anemia.

    The same was true in cells from DBA patients transplanted into mice. The higher the dose of SMER28, the more red blood cells were produced, and no ill effects were found. Formal toxicity studies have not yet been conducted.

    Circumventing a roadblock

    Previous researchers have tried for years to isolate blood stem cells from patients. They have sometimes succeeded, but the cells are very rare and cannot create enough copies of themselves to be useful for research. Attempts to get iPS cells to make blood stem cells have also failed.

    The HMS and Boston Children’s researchers were able to circumvent these problems by instead transforming iPS cells into blood progenitor cells using a combination of five reprogramming factors. Blood progenitor cells share many properties with blood stem cells and are readily multiplied in a dish.

    “Drug screens are usually done in duplicate, in tens of thousands of wells, so you need a lot of cells,” said Doulatov, who now heads a lab at the University of Washington. “Although blood progenitor cells aren’t bona fide stem cells, they are multipotent and they made red cells just fine.”

    SMER28 has been tested preclinically for some neurodegenerative diseases. It activates a so-called autophagy pathway that recycles damaged cellular components. In DBA, SMER28 appears to turn on autophagy in erythroid progenitors. Doulatov plans to further explore how this interferes with red blood cell production.

    Zon and Daley have been awarded NIH funding from the National Heart, Lung and Blood Institute’s Progenitor Cell Translational Consortium to further explore several promising compounds identified through the study.

    The study was supported by grants from the National Institutes of Health (R24-DK092760, R24-DK49216, UO1-HL100001, R01HL04880, AQ42R24OD017870-01), Alex’s Lemonade Stand, the Taub Foundation Grants Program for MDS AQ43 Research and the Doris Duke Medical Foundation. Additional funding came from a National Science Foundation Graduate Research Fellowship and NHLBI grant 1F32HL124948-01.

    See the full article here .

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    HMS campus

    Established in 1782, Harvard Medical School began with a handful of students and a faculty of three. The first classes were held in Harvard Hall in Cambridge, long before the school’s iconic quadrangle was built in Boston. With each passing decade, the school’s faculty and trainees amassed knowledge and influence, shaping medicine in the United States and beyond. Some community members—and their accomplishments—have assumed the status of legend. We invite you to access the following resources to explore Harvard Medical School’s rich history.

    Harvard University campus

    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.

     
  • richardmitnick 8:31 am on February 9, 2017 Permalink | Reply
    Tags: , Focused on developing the medical school arm of the new Free Aleppo University., , Harvard Scholar at Risk fellow Mahmoud Hariri, Medicine   

    From Harvard: “Hands of a healer, heart of a Syrian” 

    Harvard University
    Harvard University

    February 8, 2017
    Colleen Walsh

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    Syrian trauma surgeon and Harvard Scholar at Risk fellow Mahmoud Hariri is working on ways to improve medical training in Syria. He plans to return home when his Harvard term is up.
    Stephanie Mitchell/Harvard Staff Photographer

    Experience as a trauma surgeon drives Scholar at Risk in mission to aid medical community in war-torn homeland

    Sometimes he goes by John White. Sometimes he’s Abdulaziz Adel. At Harvard he is Mahmoud Hariri. His many names are a product of his life in Syria, where being a doctor treating the wounded is often as dangerous as being a rebel fighting the regime of Bashar al-Assad.

    There have been 400 documented attacks on medical facilities since the Syrian war began in 2011 and close to 800 medical workers killed, according to figures from the U.S.-based nongovernmental organization Physicians for Human Rights. The assaults have been executed almost entirely by the Assad government or its allies, according to the NGO, and have targeted civilians with ruthless precision.

    Hariri, a surgeon and currently a Harvard Scholars at Risk fellow, has witnessed firsthand those brutal campaigns and their horrific aftermath: bodies marred by barrel bombs (cylinders crammed with explosives and shrapnel); burned remains of medical students kidnapped and murdered for the crime of trying to aid the injured; a woman, nine months pregnant, who lost her baby when a sniper’s bullet pierced its skull.

    Tragedy dominated Hariri’s daily reality the past several years in Aleppo, the city where he was born and first devoted his life to helping others.

    “Medicine was my ambition since I was a child,” the 50-year-old physician said on a recent afternoon in his Harvard office on Story Street, thousands of miles removed from the devastation of his home city, where hundreds of thousands have died since fighting broke out in 2011. “They used to call me, since I was in the middle school, ‘How are you, doctor? Where are you going, doctor?’”

    When it was time to pick a specialty, Hariri opted for general surgery because of its “practical chance to save lives.” He didn’t imagine that his days removing gallbladders, fixing hernias, and teaching at Aleppo University would help prepare him to be a trauma surgeon saving lives on the front lines. He was wrong.

    The father of four turns to his computer to pull up a video of a group of medical personnel working feverishly in an improvised Aleppo operating room. “That’s me,” he says, pointing to blue rubber-gloved hands holding a beating heart spurting blood from a hole torn open by shrapnel. (The patient survived.)

    After shadowing and assisting David Nott, a London specialist and war surgeon who visited Aleppo in 2013 for six weeks, Hariri was on his own. Soon he was performing complex surgeries — vascular, lung, and open-heart — with lives in the balance.

    At Harvard, he is helping others gain the experience they need to become doctors in his war-ravaged country, where skilled medical professionals are increasingly rare. Hariri, who is being hosted by the Harvard Humanitarian Initiative and the Harvard T.H. Chan School of Public Health’s Department of Global Health and Population, is focused on developing the medical school arm of the new Free Aleppo University.

    “It’s accredited and registered with the World Health Organization,” said Hariri, adding, “It’s our university.”

    He is also working on building a network of doctors, medical educators, and experts who can continue to train young doctors in Syria whose postgraduate work was interrupted by civil war. Hariri and his Syrian team are connecting via the web specialists from the United States, the United Kingdom, and Saudi Arabia with Syrian students for interviews, oral exams, and online tests.

    In Aleppo, Hariri helped coordinate an underground network of physicians and makeshift hospitals, safe houses filled with supplies where doctors can perform emergency surgeries. To avoid being targeted by bombs they removed sirens and lights from their ambulances and camouflaged the trucks’ bright yellow paint with mud. They trained themselves to do everything, from patient record-keeping to preparing for and responding to chemical attacks.

    “Step by step we learned how to organize the work.”

    Harari is convinced that education is the light that will show his country the way out of conflict.

    “Fighting extremism starts from education,” he said, “not from the fight. I believe that education, education is the key for freedom, self-dignity, development, and getting rid of all extremism. For that reason I am working on this with my friends.”

    In 2014, his friends in the Syrian medical community promised to nominate him for the Harvard fellowship if the surgeon promised them something as well: he would return. Hariri chuckled as he recalled the agreement. Going back, he said, has never been in question. His response to those who ask him about seeking asylum in the United States is always the same.

    “I need to go back home,” he tells them. “I believe that my home needs me. I have to work for them.”

    In the spring, after his fellowship ends, Hariri will stay true to his promise, heading first to Turkey, where he will leave his family, and then back to Syria to continue his work.

    “I know that the future looks grim … I don’t expect that something good will be happening soon. But in spite of this, we do believe that we have to do our best.”

    See the full article here .

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    Harvard University campus

    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.

     
  • richardmitnick 1:34 pm on February 7, 2017 Permalink | Reply
    Tags: , Biomathematics, , Medicine, New study is an advance toward preventing a ‘post-antibiotic era’,   

    From UCLA: “New study is an advance toward preventing a ‘post-antibiotic era’ “ 

    UCLA bloc

    UCLA

    February 07, 2017
    Stuart Wolpert

    UCLA biologists identify drug combinations that may be highly effective at reducing growth of deadly bacteria

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    UCLA’s Elif Tekin, Casey Beppler, Pamela Yeh and Van Savage are gaining insights into why certain groups of three antibiotics interact well together and others don’t.

    A landmark report by the World Health Organization in 2014 observed that antibiotic resistance — long thought to be a health threat of the future — had finally become a serious threat to public health around the world. A top WHO official called for an immediate and aggressive response to prevent what he called a “post-antibiotic era, in which common infections and minor injuries which have been treatable for decades can once again kill.”

    A team of UCLA biologists has been responding to the challenge, exploring possible ways to defeat life-threatening antibiotic-resistant bacteria. In 2016, they reported that combinations of three different antibiotics can often overcome bacteria’s resistance to antibiotics, even when none of the three antibiotics on its own — or even two of the three together — is effective.

    Their latest work, which is published online and appears in the current print edition of the Journal of the Royal Society Interface, extends their understanding of that phenomenon and identifies two combinations of drugs that are unexpectedly successful in reducing the growth of E. coli bacteria.

    A key to the study is an understanding that using two, three or more antibiotics in combination does not necessarily make the drugs more effective in combating bacteria — in fact, in many cases, their effectiveness is actually reduced when drugs are used together — so the combinations must be chosen carefully and systematically. The new paper also provides the first detailed explanation of how the scientists created a mathematical formula that can help predict which combinations of drugs will be most effective.

    The scientists tested every possible combination of a group of six antibiotics, including 20 different combinations of three antibiotics at a time.

    Among the three-drug combinations, the researchers found two that were noticeably more effective than they had expected. Those groupings used treatments from three different classes of antibiotics, so the combinations used a wide range of mechanisms to fight the bacteria. (Five of the three-drug combinations were less effective than they expected, and the other 13 groupings performed as they predicted.)

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    Pamela Yeh. Reed Hutchinson/UCLA

    “So many bacteria are now so resistant to antibiotics,” said Pamela Yeh, the study’s senior author and a UCLA assistant professor of ecology and evolutionary biology. “We have a logical, methodical way to identify three-drug combinations to pursue. We think it’s vital to have this framework for identifying the best possible combinations of antibiotics.”

    The researchers have identified cases where the effects of the interactions are larger than the sum of the parts.

    “Doctors may want to super-efficiently kill the bacteria, and that is what these enhanced interactions make possible,” said lead author Casey Beppler, who was an undergraduate in Yeh’s laboratory and is now a graduate student at UC San Francisco.

    For the current study, the scientists evaluated the drug combinations on plates in a lab. Beppler said a next step will be to test the most effective combinations in mice.

    In addition to reporting on how well various combinations of antibiotics worked, the paper also presents a mathematical formula the biologists developed for analyzing how three or more factors interact and of explaining complex, unexpected interactions. The framework would be useful for solving other questions in the sciences and social sciences in which researchers analyze how three or more components might interact — for example, how climate is affected by the interplay among temperature, rainfall, humidity and ocean acidity.

    The biologists are gaining a deep understanding of why certain groups of three antibiotics interact well together, and others don’t, said Van Savage, a co-author of the paper and a UCLA professor of ecology and evolutionary biology and of biomathematics.

    Beppler said more research is needed to determine which combinations are optimal for specific diseases and for specific parts of the body. And the researchers now are using the mathematical formula to test combinations of four antibiotics.

    Co-authors of the new research are Elif Tekin, a UCLA graduate student in Savage’s laboratory; Zhiyuan Mao, Cynthia White, Cassandra McDiarmid and Emily Vargas, who were undergraduates in Yeh’s laboratory; and Jeffrey H. Miller, a UCLA distinguished professor of microbiology, immunology and molecular genetics.

    Yeh’s research was funded by the Hellman Foundation. Savage’s research was funded by a James S. McDonnell Foundation Complex Systems Scholar Award and from the National Science Foundation. Beppler received funding from the National Institutes of Health Initiative to Maximize Student Development.

    See the full article here .

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    UC LA Campus

    For nearly 100 years, UCLA has been a pioneer, persevering through impossibility, turning the futile into the attainable.

    We doubt the critics, reject the status quo and see opportunity in dissatisfaction. Our campus, faculty and students are driven by optimism. It is not naïve; it is essential. And it has fueled every accomplishment, allowing us to redefine what’s possible, time after time.

    This can-do perspective has brought us 12 Nobel Prizes, 12 Rhodes Scholarships, more NCAA titles than any university and more Olympic medals than most nations. Our faculty and alumni helped create the Internet and pioneered reverse osmosis. And more than 100 companies have been created based on technology developed at UCLA.

     
  • richardmitnick 8:24 am on February 7, 2017 Permalink | Reply
    Tags: , Cholera, International Center for Diarrheal Disease Research known as the ICDDRB in Dhaka, Medicine, , Vibrio cholerae   

    From NYT: “Turning the Tide Against Cholera” 

    New York Times

    The New York Times

    FEB. 6, 2017
    DONALD G. McNEIL Jr.
    Photographs by ISMAIL FERDOUS FOR THE NEW YORK TIMES

    Two hundred years ago, the first cholera pandemic emerged from these tiger-infested mangrove swamps.

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    It began in 1817, after the British East India Company sent thousands of workers deep into the remote Sundarbans, part of the Ganges River Delta, to log the jungles and plant rice. These brackish waters are the cradle of Vibrio cholerae, a bacterium that clings to human intestines and emits a toxin so virulent that the body will pour all of its fluids into the gut to flush it out.

    Water loss turns victims ashen; their eyes sink into their sockets, and their blood turns black and congeals in their capillaries. Robbed of electrolytes, their hearts lose their beat. Victims die of shock and organ failure, sometimes in as little as six hours after the first abdominal rumblings.

    Cholera probably had festered here for eons. Since that first escape, it has circled the world in seven pandemic cycles that have killed tens of millions.

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    A fisherman in August in the Sundarbans, where cholera first emerged.

    Artists of the 19th century often depicted it as a skeleton with a scythe and victims heaped at its feet. It stalked revelers at a masked ball in Heinrich Heine’s “Cholera in Paris” and kills the protagonist in Thomas Mann’s “Death in Venice.” Outbreaks forced London, New York and other cities to create vast public water systems, transforming civic life.

    Today cholera garners panicky headlines when it strikes unexpectedly in places like Ethiopia or Haiti. But it is a continuing threat in nearly 70 countries, where more than one billion people are at risk.

    Now, thanks largely to efforts that began in cholera’s birthplace, a way to finally conquer the long-dreaded plague is in sight.

    A treatment protocol so effective that it saves 99.9 percent of all victims was pioneered here. The World Health Organization estimates that it has saved about 50 million lives in the past four decades.

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    A child was treated at the International Center for Diarrheal Disease Research in Dhaka, Bangladesh, in August. It is the world’s largest diarrhea hospital.

    Just as important, after 35 years of work, researchers in Bangladesh and elsewhere have developed an effective cholera vaccine. It has been accepted by the W.H.O. and stockpiled for epidemics like the one that struck Haiti in 2010. Soon, there may be enough to begin routine vaccination in countries where the disease has a permanent foothold.

    Merely creating that stockpile — even of a few million doses — profoundly improved the way the world fought cholera, Dr. Margaret Chan, secretary general of the W.H.O., said last year. Ready access to the vaccine has made countries less tempted to cover up outbreaks to protect tourism, she said.

    That has sped up emergency responses and attracted more vaccine makers, lowering costs. “More cholera vaccines have been deployed over the last two years than in the previous 15 years combined,” Dr. Chan said.

    A Revolution in Recovery

    The treatment advances relied heavily on research and testing done at the International Center for Diarrheal Disease Research, known as the ICDDR,B, in Dhaka.

    4
    A mother enters ICDDR,B with her child. The facility treats 220,000 patients a year.

    Although Dhaka may not be the first place one might look to find a public health revolution, the center is famous among experts in gut diseases.

    While its upper levels are quiet and scholarly, the center’s ground floor is the world’s largest diarrhea hospital. Its vast wards treat 220,000 patients a year, almost all of whom recover within 36 hours. Doctors there save hundreds of lives a day.

    The ICDDR,B was originally the Cholera Research Laboratory, founded in 1960 by the United States as part of that era’s “soft diplomacy.” Research hospitals were built in friendly countries both to save lives locally and to act as sentinels for diseases that might threaten America.

    The wards, which in the rainy season extend into circus-size tents in the parking lot, contain long rows of “cholera cots.” On each iron or wood frame is a plastic sheet with a hole in the middle. A bucket beneath the hole catches diarrhea, while another beside the cot fills with vomit. An IV pole completes the setup.

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    The ICDDR,B wards contain long rows of “cholera cots.” Each has a plastic sheet with a hole in the middle. A bucket beneath the hole catches diarrhea and another is placed next to the cot for vomit. An IV pole completes the setup. Usually, the only patients who stay long in the hospital are malnourished infants.

    Defying expectations, the ward smells only of the antiseptic that the floors are constantly mopped with.

    Patients with severe watery diarrhea arrive around the clock, many of them carried in — limp, dehydrated and barely conscious — by friends or family. A nurse sees each one immediately, and those close to death get an IV line inserted within 30 seconds.

    It contains a blend of glucose, electrolytes and water. Cholera spurs the intestines to violently flush themselves, but it does not actually damage the gut cells. If the fluid is replaced and the bacteria flushed out or killed by antibiotics, the patient is usually fine.

    Within hours, patients start to revive. As soon as they can swallow, they get an antibiotic and start drinking a rehydration solution. Most walk out within a day. The techniques perfected here are so effective that the ICDDR,B has sent training teams to 17 cholera outbreaks in the past decade.

    Usually, the only patients who stay long in the hospital are infants so malnourished that another bout of diarrhea would kill them. They live for up to a month in a separate ward with their mothers, who are taught how to cook nutritious porridges from the cheapest lentils, squash, onions, greens and oil.

    Only about 20 percent of the patients at the center have cholera. The rest usually have rotavirus, salmonella or E. coli. The same therapy saves them all, but the cholera cases are more urgent because these patients plummet so precipitously toward death.

    “I thought I was dying,” Mohammed Mubarak, a gaunt 26-year-old printing press worker, said one afternoon from his cot. His roommates had carried him in at 7 that morning, unconscious and with no detectable pulse.

    Now, after six liters of intravenous solution, he was still weak but able to sit up and drink the rehydration solution and eat bits of bread and banana.

    “His stool is changing from rice-water to green, so he is recovering,” said Momtaz Begum, the ward nurse who monitors the buckets and makes sure patients take in as much liquid as they lose.

    Mr. Mubarak had first fallen ill at about 2 a.m., a few hours after he drank tap water with his dinner. “Usually I drink safe water, filtered water,” he explained. “But I drank the city water last night. I think that is what did this.”

    Cholera, born in the swamps, arrived long ago in Dhaka. The city is home to more that 15 million, and a third of the population lives in slums. In some places, water pipes made of rubbery plastic are pierced by illegal connections that suck in sewage from the gutters they traverse and carry pathogens down the line to new victims, like Mr. Mubarak.

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    8
    The Korail slum in Dhaka. In some slums, water pipes suck in sewage from gutters. Cholera is a constant threat to hundreds of millions of people lacking safe drinking water in China, India, Nigeria and many other countries.

    Vibrio cholerae travels from person to person via fecal matter. In 1854, the epidemiologist John Snow famously traced cases to a single well dug near a cesspit in which a mother had washed the diaper of a baby who died of cholera and nd convinced officials to remove the well’s pump handle.

    Because cholera is a constant threat to hundreds of millions of people lacking safe drinking water in China, India, Nigeria and many other countries, scientists have long sought a more powerful weapon: a cheap, effective vaccine.

    Now they have one.

    Preventing a Plague

    Injected cholera vaccines were first invented in the 1800s and were long required for entry into some countries. But many scientists suspected they did not work, and in the 1970s studies overseen by the ICDDR,B confirmed that.

    In the 1980s, a Swedish scientist, Dr. Jan Holmgren, invented an oral vaccine that worked an impressive 85 percent of the time. But it was expensive to make and had to be drunk with a large glass of buffer solution to protect it from stomach acid.

    Transporting tanks of buffer was impractical. Making matters worse, it was fizzy, and poor Bangladeshi children who had never tasted soft drinks would spit it out as soon as it tickled their noses.

    In 1986, a Vietnamese scientist, Dr. Dang Duc Trach, asked for the formula, believing he could make a bufferless version. Dr. Holmgren and Dr. John D. Clemens, an American vaccine expert who at the time was a research scientist for the ICDDR,B, obliged.

    9
    Jan Holmgren, Dr. Dang Duc Trach (his friends called him Dr. Chuck) and Dr. Clemens in a photo taken while on a vacation in Switzerland.

    “This isn’t an elegant vaccine — it’s just a bunch of killed cells, technology that’s been around since Louis Pasteur,” said Dr. Clemens, who is now the ICDDR,B’s executive director.

    He and Dr. Holmgren lost touch with Dr. Dang, largely because of Vietnam’s isolation in those days. But seven years later, Dr. Dang notified them that he had made a new version of the vaccine. He had tested it on 70,000 residents of Hue, in central Vietnam, and had found it to be 60 percent effective.

    Although his was not as effective as Dr. Holmgren’s, it cost only 25 cents a dose. If enough people in an area can be made immune through vaccination, outbreaks often stop spontaneously.

    In 1997, Vietnam became the first — and thus far, only — country to provide cholera vaccine to its citizens routinely, not just in emergencies. Cases dropped sharply, according to a 2014 study, and in 2003 cholera vanished from Hue, where the campaign focused most heavily.

    But Dr. Dang had not conducted a classic clinical trial, and Vietnam’s vaccine factory did not meet W.H.O. standards, so no United Nations agency was allowed to buy his vaccine.

    10
    “This isn’t an elegant vaccine — it’s just a bunch of killed cells, technology that’s been around since Louis Pasteur,” said Dr. Clemens, center.

    Because no pharmaceutical company had an incentive to pay for trials or factories, his invention languished in “the valley of death” — the expensive gap between a product that works in a lab and a factory-made version safe for millions.

    In 1999, Dr. Clemens approached what is now the Bill & Melinda Gates Foundation, which was just getting organized.

    “They were literally operating out of a basement then,” he said. “I got a letter from Bill Gates Sr. It was very relaxed, sort of, ‘Here’s $40 million. Would you mind sending me a report once in a while?’

    “But without that,” Dr. Clemens continued, “this wouldn’t have seen the light of day.”

    With that money, Dr. Clemens reformulated Dr. Dang’s vaccine, conducted a successful clinical trial in Calcutta and found an Indian company, Shantha Biotechnics, that could make it to W.H.O. standards.

    Rolled out in 2009 under the name Shanchol, it came in a vial about the size of a chess rook, needed no buffer and cost less than $2 a dose. Even so, there was little interest, even from the W.H.O.

    The vaccine lacked the publicity campaign that pharmaceutical companies throw behind commercial products, and “cholera ward care” was saving many lives — when it could be organized. The new vaccine was not used in a cholera outbreak in Zimbabwe in 2009, or initially in Haiti’s explosive outbreak in 2010.

    The “valley of death” lengthened: Without customers, Shantha could not afford to build a bigger factory. The impasse was broken only when Dr. Paul Farmer, a founder of Partners in Health, which has worked in central Haiti since 1987, began publicly berating the W.H.O. for not moving faster.

    The vaccine is now used in Haiti, and has been deployed in outbreaks in Iraq, South Sudan and elsewhere. A second version, Euvichol, from South Korea, was approved in 2015.

    And later this year, Bangladesh — where it all began — hopes to begin wiping out its persistent cholera. A local company has begun making a domestic version of the vaccine, called Vaxchol. Dr. Firdausi Qadri, a leading ICDDR,B researcher, estimated last year that success there would require almost 200 million doses.

    10
    An infant cholera patient with his mother in the general hospital ward at the ICDDR,B.

    The world finally has a vaccine that, with routine administration, could end one of history’s great scourges. But what will happen is still hazy.

    With 1.4 billion people at risk, the potential cost of vaccination in cholera-endemic countries is enormous. And the disease tends to move, surging and vanishing among the many causes of diarrhea.

    Even Bill Gates, who paid for much of the research, has asked: “We actually have a cholera vaccine, but where should it be used?”

    Looking back on his long struggle to prove the vaccine’s value, and then to win acceptance, Dr. Clemens offered an explanation that blended wistfulness and cynicism. “We’re probably not bad scientists,” he said, “but we were lousy advocates.

    “If this disease had been in American kids, there would have been trials as fast as the Sabin polio vaccine.”

    See the full article here .

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  • richardmitnick 4:29 pm on February 6, 2017 Permalink | Reply
    Tags: , , Medicine, , UW joins elite effort for better cancer tests in primary care   

    From U Washington: “UW joins elite effort for better cancer tests in primary care” 

    U Washington

    University of Washington

    01.31.2017
    Brian Donohue

    1
    Dr. Eunice Chen examines a patient at the UW Neighborhood Olympia Clinic. Clare McLean

    Primary-care doctors make first-line decisions about which patients – say, with an abnormal mole or a gastric complaint – should be referred out for cancer tests that are often expensive, invasive or difficult to schedule quickly.

    “That uncertainty is part of our everyday work as family doctors,” said Dr. Matthew Thompson, director of family medicine at the University of Washington School of Medicine and a practitioner at the UW Neighborhood Northgate Clinic in Seattle.

    3
    Dr. Matthew Thompson directs the family medicine program in the UW School of Medicine.

    So he’s jazzed about his department’s inclusion in an international effort that aspires to get better cancer diagnostics into primary-care doctors’ hands – to recognize cancers faster and reduce unwarranted referrals that wring patients’ emotions and wallets.

    “These technologies will take investment and development and testing, and I think primary care doctors will welcome that, as will our patients,” Thompson said.

    “CanTest,” a $6 million project funded by Cancer Research UK, makes UW Medicine a partner of the University of Cambridge and a handful of other elite research schools around the world; UW Family Medicine will direct its small share into the Primary Care Innovation Lab.

    “When the right test and technology comes up, we want to see which clinics in our WWAMI-based Practice & Research Network would be good sites for further studies,” Thompson said, referring to a group of 60 clinics across Washington, Wyoming, Alaska, Montana and Idaho.

    “Some of this is sharing; maybe there’s something that works in Australia or Denmark that we could be using here. How can we learn from each other across countries with the same kind of cancer issues?”

    4
    Technology aiming to screen for lung cancer with an exhalation is an example of a diagnostic pursued by this research grant. Owlstone Inc

    Over a five-year span of the grant, Cancer Research UK will train and support scientists to develop and share new screenings.

    “We want to nurture a new generation of researchers from a variety of backgrounds to work in primary-care cancer diagnostics, creating an educational melting pot to rapidly expand the field internationally,” said Dr. Fiona Walter, co- lead investigator at Cambridge.

    Dr. Willie Hamilton, co-lead researcher from the University of Exeter, said: “As a GP (general practitioner) myself, I know it can be frustrating to wait weeks for results before making any decisions for my patients. We’re trying to reduce this time by assessing ways that GPs could carry out these tests by themselves, as long as it’s safe and sensible to do so.”

    “We’re open to assessing many different tests, and we’re excited to hear from potential collaborators.”

    In addition to Hamilton, Walter and Thompson, the project’s senior faculty include Richard Neal, Yoryos Lyratzopoulos, Jon Emery, Hardeep Singh and Peter Vedsted. The Baylor College of Medicine in Houston is the only other U.S. site.

    See the full article here .

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    The University of Washington is one of the world’s preeminent public universities. Our impact on individuals, on our region, and on the world is profound — whether we are launching young people into a boundless future or confronting the grand challenges of our time through undaunted research and scholarship. Ranked number 10 in the world in Shanghai Jiao Tong University rankings and educating more than 54,000 students annually, our students and faculty work together to turn ideas into impact and in the process transform lives and our world. For more about our impact on the world, every day.

    So what defines us — the students, faculty and community members at the University of Washington? Above all, it’s our belief in possibility and our unshakable optimism. It’s a connection to others, both near and far. It’s a hunger that pushes us to tackle challenges and pursue progress. It’s the conviction that together we can create a world of good. Join us on the journey.

     
  • richardmitnick 11:25 am on February 6, 2017 Permalink | Reply
    Tags: , , , Medicine, Mullerian Inhibiting Substance (MIS), Ovarian Chemo Shield?   

    From HMS: “Ovarian Chemo Shield?” 

    Harvard University

    Harvard University

    Harvard Medical School

    Harvard Medical School

    January 30, 2017
    SUE MCGREEVEY

    A hormone that plays a role in fetal development may help protect the ovaries from chemo damage.

    1
    Scientists report that a naturally occurring hormone that plays a role in fetal development may help protect the ovaries from chemo damage. Photo credit: Magicmine/Getty Images.

    A naturally occurring hormone that plays an important role in fetal development may be the basis for a new type of reversible contraceptive that can protect ovaries from the damage caused by chemotherapy drugs.

    In their report receiving online publication in PNAS, a team from the Pediatric Surgical Research Laboratories in the Harvard-affiliated Massachusetts General Hospital (MGH) Department of Surgery describes using Mullerian Inhibiting Substance (MIS) to halt, in a mouse model, the early development of the ovarian follicles in which oocytes mature, an accomplishment that protects these primordial follicles from chemotherapy-induced damage.

    “MIS has long been suspected as an inhibitor of the initial stages of follicular development, but the complete blockade of the process was unexpected and opened up a number of new applications for the hormone,” said corresponding author David Pepin, an assistant professor of Surgery at Harvard Medical School (HMS).

    “Because most of what we know about female reproduction is focused on the late stages of follicle maturation, our current therapies – including contraceptive drugs – are all targeted at those processes.

    The ability to target earlier stages and potentially maintain the larger pool of quiescent oocytes called the ovarian reserve not only could maintain fertility during chemotherapy but also could be applied to modern fertility treatments,” he said.

    During embryonic development, MIS is secreted by the testes of male embryos to prevent the maturation of structures that would give rise to female reproductive organs.

    Patricia Donahoe, director of the Pediatric Surgical Research Laboratories and a co-author of the PNAS paper, has been investigating the potential use of MIS to treat ovarian cancer and other reproductive tumors for several years.

    As part of that continuing work, Pepin made the surprising observation that overexpression of MIS in female animals completely blocked the maturation of follicles, keeping them at the inactive, primordial stage and rendering the animals infertile.

    Chemotherapy’s anti-cancer effects depend on its ability to damage rapidly growing cells, including cells in maturing ovarian follicles. But chemotherapy is also believed to accelerate the activation of primordial follicles, essentially using up the ovarian reserve over a matter of months instead of years.

    The idea that ovarian suppression could preserve fertility in women undergoing chemotherapy is not new, but the ability to halt activation of primordial follicles during chemotherapy was not previously possible.

    Current hormonal contraceptives act at later stages, after the follicle has been committed to either grow or perish, so the unique action of MIS in maintaining follicles at the primordial stage offered intriguing new possibilities.

    In a series of experiments with female mice, the research team first showed that increasing MIS levels either by twice-daily injection of the purified protein or by gene therapy led to a gradual but significant decrease in the number of growing follicles, leading after several weeks to an almost complete lack of growing follicles but maintaining a consistent level of primordial follicles.

    Halting MIS treatment, either by discontinuing the injections or by transplanting follicle-depleted ovarian tissues from gene-therapy treated mice into untreated control animals, led to resumption of follicle development in as little as 12 days, indicating that the effect is reversible.

    Mice in which MIS levels were elevated by gene therapy gradually lost their fertility, and those with higher MIS levels were completely infertile after six weeks.

    Both methods of MIS administration were able to protect the ovarian reserve from the effects of common chemotherapy drugs, resulting in primordial follicle counts from 1.4 to nearly 3 times higher than in mice not receiving MIS during chemotherapy, with counts depending on the particular chemotherapy drug used and the route of MIS administration.

    “We have just begun to scratch the surface of the implications of MIS for reproductive and overall health,” Pepin said.

    “Its unique mechanism of action means it could be useful in treating many conditions that cause primary ovarian insufficiency or premature menopause. Long-term contraceptive use would probably require replacement of hormones such as estrogen to prevent the side effects of ovarian shutdown, which would be less of a concern for short-term treatment during chemotherapy. Gene therapy with MIS could also offer a nonsurgical alternative to veterinary sterilization procedures,” Pepin said.

    Pepin’s team is now investigating the quality of the oocytes preserved by MIS treatment after chemotherapy, along with elucidating the molecular mechanisms by which MIS inhibits follicle activation, which may lead to the development of small-molecule oral alternatives.

    The researchers have also formed a company, Provulis LLC, to develop clinical applications of MIS treatment and are planning clinical trials.

    See the full article here .

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    Established in 1782, Harvard Medical School began with a handful of students and a faculty of three. The first classes were held in Harvard Hall in Cambridge, long before the school’s iconic quadrangle was built in Boston. With each passing decade, the school’s faculty and trainees amassed knowledge and influence, shaping medicine in the United States and beyond. Some community members—and their accomplishments—have assumed the status of legend. We invite you to access the following resources to explore Harvard Medical School’s rich history.

    Harvard University campus

    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.

     
  • richardmitnick 3:19 pm on February 4, 2017 Permalink | Reply
    Tags: , , Coxsackievirus B1, Enteroviruses, Medicine, , Wyss Institute’s human gut-on-a-chip goes viral   

    From Wyss: “Wyss Institute’s human gut-on-a-chip goes viral” 

    Harvard bloc tiny
    Wyss Institute bloc
    Wyss Institute

    February 1, 2017
    No writer credit found

    Enteroviruses enter the human body through the digestive or respiratory tract and from there spread to other sites in the body where they can cause a variety of serious health threats including meningitis, pancreatitis, myocarditis, the death of motor neurons, and perhaps even help trigger diabetes. However, they remain a challenge to study because they cannot be grown in conventional human cell cultures. Yet, understanding how enteroviruses invade gastrointestinal cells, multiply within them, and are released to other sites in the body could be key to ending the present dearth of specific anti-viral therapies and vaccines.

    1
    As shown in these immunofluorescence images, the research team recapitulated the typical epithelial microvilli architecture of the human gut in a microchannel of a microfluidic chip with cell nuclei shown in blue and the cytoskeleton that enables each cell to assume and maintain its shape in the microvilli structure shown in red (left image). Upon infection with a clinical Coxsackievirus B1 strain (green), the epithelium produced and secreted additional viral particles that induced the break-down of the tissue’s normal architecture. Credit: Wyss Institute at Harvard University.

    Towards solving this problem, a multidisciplinary team of tissue engineers and biologists at Harvard’s Wyss Institute for Biologically Inspired Engineering working alongside scientists from the Molecular Virology Team at the U.S. Food and Drug Administration (FDA)’s Center for Food Safety and Applied Nutrition now have leveraged the Wyss Institute’s previously developed human gut-on-a-chip to mimic the entry, host cell-interaction and multiplication of a pathogenic clinical strain of Coxsackievirus using gut epithelium outside the human body. Their findings are reported in PLoS One.

    “We teamed up with FDA researchers to show for the first time that an enterovirus can be successfully cultured in a microfluidic human Gut Chip system. We were excited to find that the organ-on-a-chip approach offers a potential new way to study these viral pathogens under more physiologically relevant conditions in vitro,” said the Wyss Institute Founding Director Donald Ingber, M.D., Ph.D., who led the team. Ingber also is the Judah Folkman Professor of Vascular Biology at Boston Children’s Hospital and Harvard Medical School, and Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS).

    “Now that we have a functional minimal system in place that replicates typical host-pathogen interactions, we can start to vary the type of intestinal cells, include immune cells that may contribute to the host response to infection, or create tissues using human stem cell-derived intestinal cells to tease out virus specificities and requirements for infection,” said Ingber.

    First developed in 2012, the Wyss Institute’s human gut-on-a-chip is a transparent, hollow-channeled microfluidic device the size of a computer memory stick that recapitulates the gut microenvironment. Human intestinal epithelial cells are cultured in a microchannel on a porous membrane that separates them from a parallel microchannel that mimics a neighboring capillary blood vessel. Fluid with or without viruses is flowed through both channels and exchanged through the pores of the membrane. Suction forces are also applied to parallel hollow channels, which produce cyclic deformations in the tissue that mimic intestinal peristalsis-like motions. This culture approach results in the growth of a fully differentiated gut epithelium that exhibits three-dimensional finger-like villus structures and that harbors all of the relevant cell types of the small intestine. In 2015, the team added more complexity to their biomimicking device by co-culturing a capillary endothelium on the lower surface of the membrane as well as a bacterial gut microbiome on the lumen of the epithelial channel to model aspects of human intestinal inflammation.

    “We were able to recapitulate how Coxsackievirus B1 enters the epithelium lining the intestinal villi from the gut lumen, and show that the virus replicates inside the cells and exits them again via a specific route to go on to infect cells downstream in the channel,” said Remi Villenave, Ph.D., the study’s first author who did the work when he was a postdoctoral fellow working with Ingber. “Also inflammatory cytokines that likely contribute to intestinal tissue injury in the chip were preferentially secreted into the lumen of the intestinal channel rather than into the media transporting channel, paralleling what is seen in acute infections in people.”

    Besides Villenave and Ingber, the article is also authored by FDA researchers Samantha Wales, Efstathia Papafragkou, Christopher Elkins and Michael Kulka. Additional authors are Tiama Hamkins-Indik, James Weaver, Thomas Ferrante and Anthony Bahinski, who at the time of the study were affiliated with the Wyss Institute.

    See the full article here .

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    The Wyss (pronounced “Veese”) Institute for Biologically Inspired Engineering uses Nature’s design principles to develop bioinspired materials and devices that will transform medicine and create a more sustainable world.

    Working as an alliance among Harvard’s Schools of Medicine, Engineering, and Arts & Sciences, and in partnership with Beth Israel Deaconess Medical Center, Boston Children’s Hospital, Brigham and Women’s Hospital, Dana Farber Cancer Institute, Massachusetts General Hospital, the University of Massachusetts Medical School, Spaulding Rehabilitation Hospital, Tufts University, and Boston University, the Institute crosses disciplinary and institutional barriers to engage in high-risk research that leads to transformative technological breakthroughs.

     
  • richardmitnick 4:47 pm on February 2, 2017 Permalink | Reply
    Tags: , , Medicine, , Yale scientists identify key defect in brain tumor cells   

    From Yale: “Yale scientists identify key defect in brain tumor cells” 

    Yale University bloc

    Yale University

    February 1, 2017

    Ziba Kashef
    ziba.kashef@yale.edu
    203-436-9317

    1
    © stock.adobe.com

    In a new study, Yale researchers identified a novel genetic defect that prevents brain tumor cells from repairing damaged DNA. They found that the defect is highly sensitive to an existing FDA-approved drug used to treat ovarian cancer — a discovery that challenges current practice for treatment of brain tumors and other cancers with the same genetic defect, said the scientists.

    The study was published on Feb. 1 by Science Translational Medicine.

    Certain malignant brain tumors and leukemias have mutations in genes known as IDH1 and IDH2. The mutations render the cancers sensitive to treatment with radiation therapy or chemotherapy, significantly increasing the survival time for patients with the mutations. To better understand this sensitivity, a cross-disciplinary team of researchers led by Yale created models of the mutation in cell cultures.

    The researchers tested several existing cancer drugs on the mutated cell lines. They found that tumor cells with the mutant genes were particularly sensitive to a drug, olaparib, recently approved for the treatment of hereditary ovarian cancer. The drug caused a 50-fold increase in brain tumor cell death.

    Known as a PARP inhibitor, the drug acts on a defect in the DNA repair mechanism in the brain tumor cells, they said.

    These findings run counter to current practices in oncology. “Our work at Yale has practice-changing implications, as our data suggest an entirely new group of tumors can be targeted effectively with DNA repair inhibitors, and that possibly these patients currently are not being treated with the most optimal approaches,” said senior author Dr. Ranjit Bindra, assistant professor of therapeutic radiology and of experimental pathology.

    Co-senior author Dr. Peter Glazer, professor of therapeutic radiology and of genetics, noted, “Our work raises serious caution regarding current therapeutic strategies that are aimed at blocking mutant IDH1 and IDH2 protein function, as we believe the DNA repair defect should be exploited rather than blocked.”

    Based on these studies, the authors are designing a clinical trial to test whether DNA repair inhibitors, such as olaparib, are active against IDH1- and IDH2-mutant tumors. They anticipate that this trial will be open for enrollment later in 2017.

    “The opportunity to translate Yale science directly into the clinic is just so exciting, as it shows our ability to pivot seamlessly between the bench and the bedside, which is a key mission of our cancer center,” says Bindra.

    Co-first authors are Parker Sulkowski and Chris Corso. Additional authors are Nathaniel Robinson, Susan Scanlon, Karin Purshouse, Hanwen Bai, Yanfeng Liu, Ranjini Sundaram, Denise Hegan, Nathan Fons, Gregory Breuer, Yuanbin Song, Ketu Mishra-Gorur, Henk de Feyter, Robin de Graaf, Yulia Surovtseva, and Maureen Kachman. Bindra and Glazer are inventors on a related patent application.

    This research was supported by the National Institutes of Health (NIH), the American Cancer Society, the Cure Search for Children’s Cancer Research Foundation, and the Connecticut Department of Public Health.

    See the full article here .

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    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 2:26 pm on February 2, 2017 Permalink | Reply
    Tags: , , , Medicine,   

    From Caltech: “Protein Chaperone Takes Its Job Seriously” 

    Caltech Logo

    Caltech

    02/02/2017

    Whitney Clavin
    (626) 395-1856
    wclavin@caltech.edu

    1
    Structural rendering of a ribosomal protein (yellow and red) bound to its chaperone (blue). By capturing an atomic-resolution snapshot of the pair of proteins interacting with each other, Ferdinand Huber, a graduate student in the lab of André Hoelz revealed that chaperones can protect their ribosomal proteins by tightly packaging them up. The red region illustrates where the dramatic shape alterations occur when the ribosomal protein is released from the chaperone during ribosome assembly. Credit: Huber and Hoelz/Caltech

    2
    A diagram of the cell showing the process by which chaperone proteins (red) transport ribosomal proteins (beige) to the nucleus. The chaperones bind to the ribosomal proteins and usher them into the nucleus, while also protecting the proteins from liquidation machinery. Once a ribosomal protein reaches a growing ribosome (green and purple), the chaperone releases it. The nearly complete ribosome units exit the nucleus where they undergo final assembly. Credit: Huber and Hoelz/Caltech

    For proteins, this would be the equivalent of the red-carpet treatment: each protein belonging to the complex machinery of ribosomes—components of the cell that produce proteins—has its own chaperone to guide it to the right place at the right time and protect it from harm.

    In a new Caltech study, researchers are learning more about how ribosome chaperones work, showing that one particular chaperone binds to its protein client in a very specific, tight manner, almost like a glove fitting a hand. The researchers used X-ray crystallography to solve the atomic structure of the ribosomal protein bound to its chaperone.

    “Making ribosomes is a bit like baking a cake. The individual ingredients come in protective packaging that specifically fits their size and shape until they are unwrapped and blended into a batter,” says André Hoelz, professor of chemistry at Caltech, a Heritage Medical Research Institute (HMRI) Investigator, and Howard Hughes Medical Institute (HHMI) Faculty Scholar.” What we have done is figure out how the protective packaging fits one ribosomal protein, and how it comes unwrapped.” Hoelz is the principal investigator behind the study published February 2, 2017, in the journal Nature Communications. The finding has potential applications in the development of new cancer drugs designed specifically to disable ribosome assembly.

    In all cells, genetic information is stored as DNA and transcribed into mRNAs that code for proteins. Ribosomes translate the mRNAs into amino acids, linking them together into polypeptide chains that fold into proteins. More than a million ribosomes are produced per day in an animal cell.

    Building ribosomes is a formidable undertaking for the cell, involving about 80 proteins that make up the ribosome itself, strings of ribosomal RNA, and more than 200 additional proteins that guide and regulate the process. “Ribosome assembly is a dynamic process, where everything happens in a certain order. We are only now beginning to elucidate the many steps involved,” says Hoelz.

    To make matters more complex, the proteins making up a ribosome are first synthesized outside the nucleus of a cell, in the cytoplasm, before being transported into the nucleus where the initial stages of ribosome assembly take place.

    Chaperone proteins help transport ribosomal proteins to the nucleus while also protecting them from being chopped up by a cell’s protein shredding machinery. The components that specifically aim this machinery at unprotected ribosomal proteins, recently identified by Raymond Deshaies, professor of biology at Caltech and an HHMI Investigator, ensures that equal numbers of the various ribosomal proteins are available for building the massive structure of a ribosome.

    3
    Structural rendering of a chaperone called Acl4 bound to ribosomal protein L4

    Previously, Hoelz and his team, in collaboration with the laboratory of Ed Hurt at the University of Heidelberg, discovered that a ribosomal protein called L4 is bound by a chaperone called “Assembly chaperone of RpL4,” or Acl4. The chaperone ushers L4 through the nucleus, protecting it from harm, and delivers it to a developing ribosome at a precise time and location. In the new study, the team used X-ray crystallography, a process that involves exposing protein crystals to high-energy X-rays, to solve the structure of the bound pair. The technique was performed at Caltech’s Molecular Observatory beamline at the Stanford Synchrotron Radiation Lightsource.

    “This was not an easy structure to solve,” says Ferdinand Huber, a graduate student at Caltech in the Hoelz lab and first author of the new study. “Solving the structure was incredibly exciting because you could see with your eyes, for the very first time, how the chaperone embraces the ribosomal protein to protect it.”

    Hoelz says that the structure was a surprise because it was not known previously that chaperones hold on to their ribosomal proteins so tightly. He says they want to study other chaperones in the future to see if they function in a similar fashion to tightly guard ribosomal proteins. The results may lead to the development of new drugs for cancer therapy by preventing cancer cells from supplying the large numbers of ribosomes required for tumor growth.

    The study, called “Molecular Basis for Protection of Ribosomal Protein L4 from Cellular Degradation,” was funded by a PhD fellowship of the Boehringer Ingelheim Fonds, a Faculty Scholar Award of the Howard Hughes Medical Research Institute, a Heritage Medical Research Institute Principal Investigatorship, a Kimmel Scholar Award of the Sidney Kimmel Foundation for Cancer Research, a Teacher-Scholar Award of the Camille & Henry Dreyfus Foundation, and Caltech startup funds.

    See the full article here .

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    The California Institute of Technology (commonly referred to as Caltech) is a private research university located in Pasadena, California, United States. Caltech has six academic divisions with strong emphases on science and engineering. Its 124-acre (50 ha) primary campus is located approximately 11 mi (18 km) northeast of downtown Los Angeles. “The mission of the California Institute of Technology is to expand human knowledge and benefit society through research integrated with education. We investigate the most challenging, fundamental problems in science and technology in a singularly collegial, interdisciplinary atmosphere, while educating outstanding students to become creative members of society.”
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