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  • richardmitnick 3:04 pm on October 20, 2014 Permalink | Reply
    Tags: , , , Medicine   

    From LLNL: “Supercomputers link proteins to drug side effects” 


    Lawrence Livermore National Laboratory

    10/20/2014
    Kenneth K Ma, LLNL, (925) 423-7602, ma28@llnl.gov

    New medications created by pharmaceutical companies have helped millions of Americans alleviate pain and suffering from their medical conditions. However, the drug creation process often misses many side effects that kill at least 100,000 patients a year, according to the journal Nature.

    Lawrence Livermore National Laboratory researchers have discovered a high-tech method of using supercomputers to identify proteins that cause medications to have certain adverse drug reactions (ADR) or side effects. They are using high-performance computers (HPC) to process proteins and drug compounds in an algorithm that produces reliable data outside of a laboratory setting for drug discovery.

    The team recently published its findings in the journal PLOS ONE, titled Adverse Drug Reaction Prediction Using Scores Produced by Large-Scale Drug-Protein Target Docking on High-Performance Computer Machines.

    “We need to do something to identify these side effects earlier in the drug development cycle to save lives and reduce costs,” said Monte LaBute, a researcher from LLNL’s Computational Engineering Division and the paper’s lead author.

    It takes pharmaceutical companies roughly 15 years to bring a new drug to the market, at an average cost of $2 billion. A new drug compound entering Phase I (early stage) testing is estimated to have an 8 percent chance of reaching the market, according to the Food and Drug Administration (FDA).

    A typical drug discovery process begins with identifying which proteins are associated with a specific disease. Candidate drug compounds are combined with target proteins in a process known as binding to determine the drug’s effectiveness (efficacy) and/or harmful side effects (toxicity). Target proteins are proteins known to bind with drug compounds in order for the pharmaceutical to work.

    While this method is able to identify side effects with many target proteins, there are myriad unknown “off-target” proteins that may bind to the candidate drug and could cause unanticipated side effects.

    Because it is cost prohibitive to experimentally test a drug candidate against a potentially large set of proteins — and the list of possible off-targets is not known ahead of time — pharmaceutical companies usually only test a minimal set of off-target proteins during the early stages of drug discovery. This results in ADRs remaining undetected through the later stages of drug development, such as clinical trials, and possibly making it to the marketplace.

    There have been several highly publicized medications with off-target protein side effects that have reached the marketplace. For example, Avandia, an anti-diabetic drug, caused heart attacks in some patients; and Vioxx, an anti-inflammatory medication, caused heart attacks and strokes among certain patient populations. Both therapeutics were recalled because of their side effects.

    “There were no indications of side effects of these medications in early testing or clinical trials,” LaBute said. “We need a way to determine the safety of such therapeutics before they reach patients. Our work can help direct such drugs to patients who will benefit the most from them with the least amount of side effects.”

    LaBute and the LLNL research team tackled the problem by using supercomputers and information from public databases of drug compounds and proteins. The latter included protein databases of DrugBank, UniProt and Protein Data Bank (PDB), along with drug databases from the FDA and SIDER, which contain FDA-approved drugs with ADRs.

    The team examined 4,020 off-target proteins from DrugBank and UniProt. Those proteins were indexed against the PDB, which whittled the number down to 409 off-proteins that have high-quality 3D crystallographic X-ray diffraction structures essential for analysis in a computational setting.

    mp

    The 409 off-target proteins were fed into a Livermore HPC software known as VinaLC along with 906 FDA-approved drug compounds. VinaLC used a molecular docking matrix that bound the drugs to the proteins. A score was given to each combination to assess whether effective binding occurred.

    The binding scores were fed into another computer program and combined with 560 FDA-approved drugs with known side effects. An algorithm was used to determine which proteins were associated with certain side effects.

    The Lab team showed that in two categories of disorders — vascular disorders and neoplasms — their computational model of predicting side effects in the early stages of drug discovery using off-target proteins was more predictive than current statistical methods that do not include binding scores.

    In addition to LLNL ADR prediction methods performing better than current prediction methods, the team’s calculations also predicted new potential side effects. For example, they predicted a connection between a protein normally associated with cancer metastasis to vascular disorders like aneurysms. Their ADR predictions were validated by a thorough review of existing scientific data.

    “We have discovered a very viable way to find off-target proteins that are important for side effects,” LaBute said. “This approach using HPC and molecular docking to find ADRs never really existed before.”

    The team’s findings provide drug companies with a cost-effective and reliable method to screen for side effects, according to LaBute. Their goal is to expand their computational pharmaceutical research to include more off-target proteins for testing and eventually screen every protein in the body.

    “If we can do that, the drugs of tomorrow will have less side effects that can potentially lead to fatalities,” Labute said. “Optimistically, we could be a decade away from our ultimate goal. However, we need help from pharmaceutical companies, health care providers and the FDA to provide us with patient and therapeutic data.”

    two
    LLNL researchers Monte LaBute (left) and Felice Lightstone (right) were part of a Lab team that recently published an article in PLOS ONE detailing the use of supercomputers to link proteins to drug side effects. Photo by Julie Russell/LLNL

    The LLNL team also includes Felice Lightstone, Xiaohua Zhang, Jason Lenderman, Brian Bennion and Sergio Wong.

    See the full article here.

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  • richardmitnick 2:46 pm on October 17, 2014 Permalink | Reply
    Tags: , Medicine,   

    From NOVA: “Insulin-Producing Stem Cells Could Provide Lasting Diabetes Treatments” 

    PBS NOVA

    NOVA

    Fri, 17 Oct 2014
    Sarah Schwartz

    Researchers have crafted what may be a powerful weapon in the fight against diabetes: A new line of insulin-producing cells that has been shown to reverse diabetes in mice within forty days. Scientists hope that these cells may someday do the same in humans.

    The new cells, called “Stage 7” or “S7” for their seven-step production process, are the product of a study by researchers at the University of British Columbia and the pharmaceutical company Janssen. S7 cells are made to mimic human beta cells, which are damaged or destroyed in patients with diabetes. Healthy beta cells produce insulin and help regulate blood sugar; S7 cells are grown from human embryonic stem cells and are programmed to do the same.

    cells
    A microscopic view of beta cells derived from stem cells

    “The advance that they have made is that they’ve got better cells in the test tube, cells that have more insulin and can secrete insulin in response to glucose,” said Dr. Gordon Weir, a physician and researcher at Joslin Diabetes Center and Harvard Medical School. “People haven’t been able to do that before.”

    Human embryonic stem cells, like those used to produce the S7 line, show great promise for producing beta cell replacements. Just last week, another team of researchers led by Dr. Douglas Melton at Harvard University announced their own line of insulin-producing cells, also produced from human embryonic stem cells. Like S7 cells, the Harvard team’s cells produce insulin in response to high blood sugar and can reverse diabetes symptoms in mice.

    The hope is that cells like these could be injected into diabetic patients, restoring normal beta cell function. Timothy Kieffer, head of the diabetes research group at University of British Columbia and a co-author of the S7 cell study, said that treatment with these cells could be curative, though other researchers caution that additional work has to be done before that’s the case.

    Cellular transplantation has already been shown to effectively combat diabetes. Since the late 1980s, beta cells extracted from cadaver pancreases have been used to normalize blood sugar in diabetics. But these treatments are not an option for many patients. In addition to the challenges of establishing a treatment program, Weir said, “there aren’t enough pancreatic donors to even scratch the surface.” These transplanted cells also tend to stop working over time, said Dr. David Nathan, the director of the Diabetes Center and Clinical Research Center at Massachusetts General Hospital. Whole organ pancreatic transplants usually last longer and have been increasingly successful in recent years, Nathan says. But both organ and cell transplants from cadavers require immunosuppressive treatments, which can cause tumors, skin cancers, and weakened immune systems.

    Beta cells grown from stem cells could solve some of these problems. It is possible that stem cells could be developed to reduce or eliminate the need for immunosuppression, Nathan said. Plus, their supply is theoretically unlimited. “If you can make them in a test tube, in a dish, whatever—well, that gets rid of the problem of donor pancreases,” Nathan said. While S7 cells are most efficient when made from human embryonic stem cells, they can also be made using induced pluripotent stem cells, which are reprogrammed adult cells. This, Weir noted, could eliminate “ethical issues” involved with embryonic stem cell use.

    Kieffer believes that a stem cell-based treatment would also be superior to insulin supplementation, the current standard of treatment for type 1 diabetes. In type 1 diabetes, which Kieffer’s research targets, beta cells are destroyed by an autoimmune attack, and patients require external insulin to survive. Even with advanced treatment options like insulin pumps, Weir said, it is challenging to keep blood sugar in a normal range. “And if you push hard enough to drive the blood sugar down, you end up getting into trouble with insulin reactions,” Weir said. “The blood sugar goes too low and that’s dangerous.”

    But S7 cells have some challenges to overcome before they can replace current treatments. For one, it can be difficult to control the development of stem cells, Nathan pointed out. Kieffer agreed that more research is needed to mature the cells, which are still not identical to human beta cells because they react more slowly to sugar and don’t release as much insulin. Kieffer’s collaborators are also working to scale up production of the S7 line. Meanwhile, the Harvard study uses a protocol that already seems to allow relatively large-scale development of insulin-producing cells.

    There are also other challenges to treating type 1 diabetes with cells like S7 because of the autoimmune nature of the disease. If beta cell transplants are injected into type 1 diabetics, Weir said, “those cells are still going to be subject to the immune problem that killed the cells in the first place.” Kieffer said that the “next hurdle” for his team is to see if S7 cells will work inside devices that prevent immune attack.

    These “immunobarrier” devices are essentially capsules that contain implanted stem cells, allowing the exchange of nutrients and insulin while blocking attacking immune cells. Nathan and Weir expressed reservations about these devices. Nathan wondered if they can be designed to allow sufficient blood flow and nutrients to all the cells inside, while Weir questioned whether there could be a device large enough to hold the number of cells needed to control the disease. Still, in August, the company Viacyte started clinical trials with such a device, using a line of cells less developed than S7. “We’ll have to wait and see,” Weir said.

    Because of the autoimmunity problem inherent in type 1 diabetes, Weir says that it may be easier to use beta cell transplantations to treat type 2 diabetes instead. Up to 95% of diabetic patients have this form of the disease, which involves no autoimmunity. Instead, in type 2, beta cells “wear out” such that the body stops responding to insulin.

    “You can take a type 2 diabetic and give them insulin injections and normalize the sugar if you do it carefully,” Weir said. “So, a beta cell transplant is just the same thing as giving an insulin injection.” He feels the effects of such treatment could be profound. “You can put cells in and normalize the blood sugar for years,” he said. “So if you want to call that a cure, I’d go along with that.” Nathan disagrees: because type 2 diabetics have some pancreatic function, it can be simpler and easier to treat their symptoms. Because of this, he believes that cellular transplantations will mostly be useful to combat type 1 diabetes.

    Nathan doesn’t think that beta cell transplantations are an “appropriate clinical option”—yet. “The balance between risk and benefit isn’t quite right,” he says. Still, he hopes that someday, a cellular treatment will be advanced enough to safely and effectively treat this disease. “To cure type 1 diabetes would be a godsend,” he says. “To actually do a single procedure that essentially takes away the disease at low risk would be great.”

    Though several questions must be answered before they start curing patients, S7 cells are a promising step in the fight against a disease that affects 347 million people worldwide. The field is moving quickly towards its goal; as Kieffer writes, “I am very optimistic that we are narrowing down on a cure for diabetes.”

    See the full article here.

    NOVA is the highest rated science series on television and the most watched documentary series on public television. It is also one of television’s most acclaimed series, having won every major television award, most of them many times over.

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  • richardmitnick 8:38 am on October 17, 2014 Permalink | Reply
    Tags: , , Medicine, ,   

    From UC Berkeley: “New front in war on Alzheimer’s, other protein-folding diseases” 

    UC Berkeley

    UC Berkeley

    October 16, 2014
    Robert Sanders

    A surprise discovery that overturns decades of thinking about how the body fixes proteins that come unraveled greatly expands opportunities for therapies to prevent diseases such as Alzheimer’s and Parkinson’s, which have been linked to the accumulation of improperly folded proteins in the brain.

    “This finding provides a whole other outlook on protein-folding diseases; a new way to go after them,” said Andrew Dillin, the Thomas and Stacey Siebel Distinguished Chair of Stem Cell Research in the Department of Molecular and Cell Biology and Howard Hughes Medical Institute investigator at the University of California, Berkeley.

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    A cell suffering heat shock is like a country besieged, where attackers first sever lines of communications. The pat-10 gene helps repair communication to allow chaperones to treat misfolded proteins. (Andrew Dillin graphic)

    Dillin, UC Berkeley postdoctoral fellows Nathan A. Baird and Peter M. Douglas and their colleagues at the University of Michigan, The Scripps Research Institute and Genentech Inc., will publish their results in the Oct. 17 issue of the journal Science.

    Cells put a lot of effort into preventing proteins – which are like a string of beads arranged in a precise three-dimensional shape – from unraveling, since a protein’s activity as an enzyme or structural component depends on being properly shaped and folded. There are at least 350 separate molecular chaperones constantly patrolling the cell to refold misfolded proteins. Heat is one of the major threats to proteins, as can be demonstrated when frying an egg – the clear white albumen turns opaque as the proteins unfold and then tangle like spaghetti.

    Heat shock

    For 35 years, researchers have worked under the assumption that when cells undergo heat shock, as with a fever, they produce a protein that triggers a cascade of events that field even more chaperones to refold unraveling proteins that could kill the cell. The protein, HSF-1 (heat shock factor-1), does this by binding to promoters upstream of the 350-plus chaperone genes, upping the genes’ activity and launching the army of chaperones, which originally were called “heat shock proteins.”

    Injecting animals with HSF-1 has been shown not only to increase their tolerance of heat stress, but to increase lifespan.

    Because an accumulation of misfolded proteins has been implicated in aging and in neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s diseases, scientists have sought ways to artificially boost HSF-1 in order to reduce the protein plaques and tangles that eventually kill brain cells. To date, such boosters have extended lifespan in lab animals, including mice, but greatly increased the incidence of cancer.

    Dillin’s team found in experiments on the nematode worm C. elegans that HSF-1 does a whole lot more than trigger release of chaperones. An equal if not more important function is to stabilize the cell’s cytoskeleton, which is the highway that transports essential supplies – healing chaperones included – around the cell.

    “We are suggesting that, rather than making more of HSF-1 to prevent diseases like Huntington’s, we should be looking for ways to make the actin cytoskeleton better,” Dillin said. Such tactics might avoid the carcinogenic side effects of upping HSF-1.

    Dillin is codirector of the Paul F. Glenn Center for Aging Research, a new collaboration between UC Berkeley and UC San Francisco supported by the Glenn Foundation for Medical Research. Center investigators will study the many ways that proteins malfunction within cells, ideally paving the way for novel treatments for neurodegenerative diseases.

    A cell at war

    Dillin compares a cell experiencing heat shock to a country under attack. In a war, an aggressor first cuts off all communications, such as roads, train and bridges, which prevents the doctors from treating the wounded. Similarly, heat shock disrupts the cytoskeletal highway, preventing the chaperone “doctors” from reaching the patients, the misfolded proteins.

    chap
    Chaperones help newborn proteins (polypeptides) fold properly, but also fix misfolded proteins.

    “We think HSF-1 not only makes more chaperones, more doctors, but also insures that the roadways stay intact to keep everything functional and make sure the chaperones can get to the sick and wounded warriors,” he said.

    The researchers found specifically that HSF-1 up-regulates another gene, pat-10, that produces a protein that stabilizes actin, the building blocks of the cytoskeleton.

    By boosting pat-10 activity, they were able to cure worms that had been altered to express the Huntington’s disease gene, and also extend the lifespan of normal worms.

    Dillin suspects that HSF-1’s main function is, in fact, to protect the actin cytoskeleton. He and his team mutated HSF-1 so that it no longer boosted chaperones, demonstrating, he said, that “you can survive heat shock with the normal level of heat shock proteins, as long as you make your cytoskeleton work better.”

    He noted that the team’s results – that boosting chaperones is not essential to surviving heat stress – were so contradictory to current thinking that “I made my post-docs’ lives hell for three years” insisting on more experiments to rule out errors. Yet, when Dillin presented the results recently to members of the protein-folding community, he said the first reaction of many was, “That makes perfect sense.”

    Dillin’s colleagues include Milos S. Simic and Suzanne C. Wolff of UC Berkeley, Ana R. Grant of the University of Michigan in Ann Arbor, James J. Moresco and John R. Yates III of Scripps in La Jolla, Calif., and Gerard Manning of Genentech, South San Francisco, Calif. The work is funded by the Howard Hughes Medical Institute as well as by the National Institute of General Medical Sciences (8 P41 GM103533-17) and National Institute on Aging (R01AG027463-04) of the National Institutes of Health.

    See the full article here.

    Founded in the wake of the gold rush by leaders of the newly established 31st state, the University of California’s flagship campus at Berkeley has become one of the preeminent universities in the world. Its early guiding lights, charged with providing education (both “practical” and “classical”) for the state’s people, gradually established a distinguished faculty (with 22 Nobel laureates to date), a stellar research library, and more than 350 academic programs.

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  • richardmitnick 9:04 pm on October 16, 2014 Permalink | Reply
    Tags: , , , , Medicine   

    From LLNL: “Lab, UC Davis partner to personalize cancer medications” 


    Lawrence Livermore National Laboratory

    10/16/2014
    Stephen P Wampler, LLNL, (925) 423-3107, wampler1@llnl.gov

    Buoyed by several dramatic advances, Lawrence Livermore National Laboratory scientists think they can tackle biological science in a way that couldn’t be done before.

    Over the past two years, Lab researchers have expedited accelerator mass spectrometer sample preparation and analysis time from days to minutes and moved a complex scientific process requiring accelerator physicists into routine laboratory usage.

    Ken Turteltaub, the leader of the Lab’s Biosciences and Biotechnology Division, sees the bio AMS advances as allowing researchers to undertake quantitative assessments of complex biological pathways.

    “We are hopeful that we’ll be able to quantify the individual steps in a metabolic pathway and be able to measure indicators of disease processes and factors important to why people differ in responses to therapeutics, to diet and other factors,” Turteltaub said.

    Graham Bench, the director of the Lab’s Center for Accelerator Mass Spectrometry, anticipates the upgrades will enable Lab researchers “to produce high-density data sets and tackle novel biomedical problems that in the past couldn’t be addressed.”

    Ted Ognibene, a chemist who has worked on AMS for 15 years and who co-developed the technique that accommodates liquid samples, also envisions new scientific work coming forth.

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    Ted Ognibene (left), a chemist who co-developed the technique that accommodates liquid samples for accelerator mass spectrometry, peers with biomedical scientist Mike Malfatti at the new biological AMS instrument that has been installed in the Laboratory’s biomedical building. Photo by George Kitrinos

    “We previously had the capability to detect metabolites, but now with the ability to see our results almost immediately for a fraction of the cost, it’s going to enable a lot more fundamental and new science to be done,” Ognibene said.

    Biological AMS is a technique in which carbon-14 is used as a tag to study with extreme precision and sensitivity complex biological processes, such as cancer, molecular damage, drug and toxin behavior, nutrition and other areas.

    Among the biomedical studies that will be funded through the five-year, $7.8 million National Institutes of Health grant for biological AMS work is one to try to develop a test to predict how people will respond to chemotherapeutic drugs.

    Another research project seeks to create an assay that is so sensitive that it can detect one cancer cell among one million healthy cells. If this work is successful, it could be possible to evaluate the metastasis potential of different primary human cancer cells.

    Lab biomedical scientist Mike Malfatti and two researchers - Paul Henderson, an associate professor, and Chong-Xian Pan, a medical oncologist — from the University of California, Davis Comprehensive Cancer Center, are using the AMS in a human trial with 50 patients to see how cancer patients respond or don’t respond to the chemotherapeutic drug carboplatin. This drug kills cancer cells by binding to DNA, and is toxic to rapidly dividing cells.

    The three researchers have the patients take a microdose of carboplatin — about 1/100th of a therapeutic dose — that has no toxicity or therapeutic value to evaluate how effectively the drug will bind to a person’s DNA during full dose treatment.

    Within a few days of patients receiving the microdose, the degree of drug binding is checked by blood sample, in which the DNA is isolated from white blood cells, or by tumor biopsy, in which the DNA is isolated from the tumor cells.

    The carboplatin dose is prepared with a carbon-14 tag. The DNA sample is analyzed using AMS and the instrument quantifies the carbon-14 level, with a high level of carbon-14 indicating a high level of drug binding to the DNA.

    “A high degree of binding indicates that you have a high probability of a favorable response to the drug,” Malfatti said. “Conversely, a low degree of binding means it is likely the person’s body won’t respond to the treatment.

    “If we can identify which people will respond to which chemotherapeutic drug, we can tailor the treatment to the individual.

    “There are many negative side effects associated with chemotherapy, such as nausea, loss of appetite, loss of hair and even death. We don’t want someone to receive chemotherapy that’s not going to help them, yet leave them with these negative side effects,” he added.

    Malfatti, Henderson and Pan also are using the AMS in pre-clinical studies to investigate the resistance or receptivity of other commonly used chemotherapeutic agents such as cisplatin, oxaliplatin and gemcitabine.

    Another team of researchers, led by Gaby Loots, a Lab biomedical scientist and an associate professor at the University of California, Merced, wants to use AMS to measure cancer cells labeled with carbon-14 to study the cancer cells’ migration to healthy tissues to determine how likely they are to form metastatic tumors.

    While today’s standard methods can detect tumors that are comprised of thousands of cells, the team would like to develop an assay with a thousand-fold better resolution – to detect one cancer cell among one million healthy ones.

    “The sensitivity of AMS allows us to develop more accurate, quantitative assays with single-cell resolution. Is the cancer completely gone, or do we see one cell worth of cancer DNA?” Loots noted.

    Some of the questions the team would like to answer are: 1) why certain cells metastasize? 2) how do cells metastasize? 3) what new methods can be developed to prevent metastasis?

    “Tumors shed cells all the time that enter our circulation. We would like to find ways to prevent the circulating tumor cells from forming metastatic tumors,” Loots continued.

    As a part of their research, the team members hope to determine whether cancer cells with stem-cell-like properties form more aggressive tumors.

    “We’re going to separate the cancer cells into stem-cell-like and non-stem-cell-like populations and seek to determine if they behave differently,” said Loots, who is working with fellow Lab biomedical scientists Nick Hum and Nicole Collette.

    See the full article here.

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  • richardmitnick 6:09 pm on October 16, 2014 Permalink | Reply
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    From Johns Hopkins: “Chemical derived from broccoli sprouts shows promise in treating autism” 

    Johns Hopkins
    Johns Hopkins University

    October 13, 2014
    Catherine Kolf

    Many trial participants who received daily dose of sulforaphane show improvements in social interaction, verbal communication, researchers say

    Results of a small clinical trial suggest that a chemical derived from broccoli sprouts—and best known for claims that it can help prevent certain cancers—may ease classic behavioral symptoms in those with autism spectrum disorders.

    bro

    The study, a joint effort by scientists at MassGeneral Hospital for Children and the Johns Hopkins University School of Medicine, involved 40 teenage boys and young men, ages 13 to 27, with moderate to severe autism.

    In a report published online in the journal Proceedings of the National Academy of Sciences, the researchers say that many of those who received a daily dose of the chemical sulforaphane experienced substantial improvements in their social interaction and verbal communication, along with decreases in repetitive, ritualistic behaviors, compared to those who received a placebo.

    “We believe that this may be preliminary evidence for the first treatment for autism that improves symptoms by apparently correcting some of the underlying cellular problems,” says Paul Talalay, a professor of pharmacology and molecular sciences at the Johns Hopkins University School of Medicine who has researched these vegetable compounds for the past 25 years.

    “We are far from being able to declare a victory over autism, but this gives us important insights into what might help,” says co-investigator Andrew Zimmerman, a professor of pediatric neurology at UMass Memorial Medical Center.

    Autism experts estimate that the group of disorders affects 1 to 2 percent of the world’s population, with a much higher incidence in boys than in girls. Its behavioral symptoms, such as poor social interaction and verbal communication, are well known and were first described 70 years ago by Leo Kanner, the founder of pediatric psychiatry at Johns Hopkins University.

    Unfortunately, the root causes of autism remain elusive, though progress has been made, Talalay says, in describing some of the biochemical and molecular abnormalities that tend to accompany the disorders. Many of these are related to the efficiency of energy generation in cells. He says that studies show that the cells of those on the autism spectrum often have high levels of oxidative stress, the buildup of harmful, unintended byproducts from the cell’s use of oxygen that can cause inflammation, damage DNA, and lead to cancer and other chronic diseases.

    In 1992, Talalay’s research group discovered that sulforaphane has some ability to bolster the body’s natural defenses against oxidative stress, inflammation, and DNA damage. In addition, the chemical later turned out to improve the body’s heat-shock response—a cascade of events used to protect cells from the stress caused by high temperatures, including those experienced when people have fever.

    Intriguingly, he says, about 50% of parents report that their children’s autistic behavior improves noticeably when they have a fever, then reverts back when the fever is gone. In 2007, Zimmerman, a principal collaborator in the current study, tested this anecdotal trend clinically and found it to be true, though a mechanism for the fever effect was not identified.

    Because fevers, like sulforaphane, initiate the body’s heat-shock response, Zimmerman and Talalay wondered if sulforaphane could cause the same temporary improvement in autism that fevers do. The current study was designed to find out.

    Before the start of the trial, the patients’ caregivers and physicians filled out three standard behavioral assessments: the Aberrant Behavior Checklist (ABC), the Social Responsiveness Scale (SRS), and the Clinical Global Impressions-Improvement scale (CGI-I). The assessments measure sensory sensitivities, ability to relate to others, verbal communication skills, social interactions, and other behaviors related to autism.

    Twenty-six of the subjects were randomly selected to receive, based on their weight, 9 to 27 milligrams of sulforaphane daily, and 14 received placebos. Behavioral assessments were again completed at four, 10, and 18 weeks while treatment continued. A final assessment was completed for most of the participants four weeks after the treatment had stopped.

    Most of those who responded to sulforaphane showed significant improvements by the first measurement at four weeks and continued to improve during the rest of the treatment. After 18 weeks of treatment, the average ABC and SRS scores of those who received sulforaphane had decreased 34 and 17 percent, respectively, with improvements in bouts of irritability, lethargy, repetitive movements, hyperactivity, awareness, communication, motivation, and mannerisms.

    After 18 weeks of treatment, according to the CGI-I scale, sulforaphane recipients experienced noticeable improvements in social interaction (46%), aberrant behaviors (54%), and verbal communication (42%).

    Talalay notes that the scores of those who took sulforaphane trended back toward their original values after they stopped taking the chemical, just like what happens to those who experience improvements during a fever. “It seems like sulforaphane is temporarily helping cells to cope with their handicaps,” he says.

    Zimmerman adds that before they learned which subjects got the sulforaphane or placebo, the impressions of the clinical team—including parents—were that 13 of the participants noticeably improved. For example, some treated subjects looked them in the eye and shook their hands, which they had not done before. They found out later that all 13—half of the treatment group—had been taking sulforaphane.

    Talalay cautions that the levels of sulforaphane precursors present in different varieties of broccoli are highly variable. Furthermore, the capacity of individuals to convert these precursors to active sulforaphane also varies greatly. It would be very difficult to achieve the levels of sulforaphane used in this study by eating large amounts of broccoli or other cruciferous vegetables, he notes.

    See the full article here.

    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.

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  • richardmitnick 4:00 pm on October 10, 2014 Permalink | Reply
    Tags: , , , Medicine   

    From Caltech: “Sensors to Simplify Diabetes Management” 

    Caltech Logo
    Caltech

    10/10/2014
    Jessica Stoller-Conrad

    For many patients diagnosed with diabetes, treating the disease can mean a burdensome and uncomfortable lifelong routine of monitoring blood sugar levels and injecting the insulin that their bodies don’t naturally produce. But, as part of their Summer Undergraduate Research Fellowship (SURF) projects at Caltech, several engineering students have contributed to the development of tiny biosensors that could one day eliminate the need for these manual blood sugar tests.

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    From left to right: Sagar Vaidyanathan, a visiting undergraduate researcher from UCLA, and Caltech sophomore Sophia Chen. Chen spent her summer in the laboratory of Hyuck Choo, assistant professor of electrical engineering, studying new ways to power tiny health-monitoring sensors and devices.
    Credit: Lance Hayashida/Caltech Marketing and Communications

    Because certain patients with diabetes are unable to make their own insulin—a hormone that helps transfer glucose, or sugar, from the blood into muscle and other tissues—they need to monitor frequently their blood glucose, manually injecting insulin when sugar levels surge after a meal. Most glucose monitors require that patients prick their fingertips to collect a drop of blood, sometimes up to 10 times a day for the rest of their lives.

    In their SURF projects, the students, all from Caltech’s Division of Engineering and Applied Science, looked for different ways to do these same tests but painlessly and automatically.

    man
    Senior applied physics major Mehmet Sencan has approached the problem with a tiny chip that can be implanted under the skin. The sensor, a square just 1.4 millimeters on each side, is designed to detect glucose levels from the interstitial fluid (fluid found in the spaces between cells) that is just under the skin. The glucose levels in this fluid directly relate to the blood glucose concentration.

    Sencan has been involved in optimizing the electrochemical method that the chip will use to detect glucose levels. Much like a traditional finger-stick glucose meter, the chip uses glucose oxidase, an enzyme that reacts in the presence of glucose, to create an electrical current. Higher levels of glucose result in a stronger current, allowing the device to measure glucose levels based on the charge that passes through the fluid.

    Once the glucose level is detected, the information is wirelessly transmitted via a radio wave frequency to a reader that uses the same frequency to power the device itself. Ultimately an external display will let the patient know if their levels are within range.

    Sencan, who works in the laboratory of Axel Scherer, the Bernard Neches Professor of Electrical Engineering, Applied Physics, and Physics, and who is co-mentored by postdoctoral researcher Muhammad Mujeeb-U-Rahman, started this project three years ago during his very first SURF.

    “When I started, we were just thinking about what kind of chemistry the sensor would use, and now we have a sensor that is actually designed to do that,” he says. Over the summer, he implanted the sensors in rat models, and he will continue the study over the fall and spring terms using both rat and mouse models—a first step in determining if the design is a clinically viable option.

    jun
    Junior electrical engineering major Sith Domrongkitchaiporn from the Scherer laboratory, also co-mentored by Mujeeb-U-Rahman, took a different approach to glucose detection, making tiny biosensors that are inconspicuously wearable on the surface of a contact lens. “It’s an interesting concept because instead of having to do a procedure to place something under the skin, you can use a less invasive method, placing a sensor on the eye to get the same information,” he says.

    He used the method optimized by Mehmet to determine blood glucose levels from interstitial fluid and adapted the chemistry to measure glucose in the eyes’ tears. This summer, he will be attempting to fabricate the lens itself and improve upon the process whereby radio waves are used to power the sensor and then transmit data from the sensor to an external computer.

    girl
    SURF student and sophomore electrical engineering major Jennifer Chih-Wen Lin wanted to incorporate a different kind of glucose sensor into a contact lens. “The concept—determining glucose readings from tears—is very similar to Sith’s, but the method is very different,” she says.

    Instead of determining the glucose level based on the amount of electrical current that passes through a sample, Lin, who works in the laboratory of Hyuck Choo, assistant professor of electrical engineering, worked on a sensor that detects glucose levels from the interaction between light and molecules.

    In her SURF project, she began optimizing the characterization of glucose molecules in a sample of glucose solution using a technique called Raman spectroscopy. When molecules encounter light, they vibrate differently based on their symmetry and the types of bonds that hold their atoms together. This vibrational information provides a unique fingerprint for each type of molecule, which is represented as peaks on the Raman spectrum—and the intensity of these peaks correlates to the concentration of that molecule within the sample.

    “This step is important because once I can determine the relationship between peak intensities and glucose concentrations, our sensor can just compare that known spectrum to the reading from a sample of tears to determine the amount of glucose in the sample,” she says.

    Lin’s project is in the very beginning stages, but if it is successful, it could provide a more accurate glucose measurement, and from a smaller volume of liquid, than is possible with the finger-stick method. Perhaps more importantly for patients, it can provide that measurement painlessly.

    girl12
    Also in Choo’s laboratory, sophomore electrical engineering major Sophia Chen’s SURF project involves a new way to power devices like these tiny sensors and other medical implants, using the vibrations from a patient’s vocal cords. These vibrations produce the sound of our voice, and also create vibrations in the skull.

    “We’re using these devices called energy harvesters that can extract energy from vibrations at specific frequencies. When the vibrations go from the vocal folds to the skull, a structure in the energy harvester vibrates at the same frequency, generating energy—energy that can be used to power batteries or charge things,” Chen says.

    Chen’s goal is to determine the frequency of these vibrations—and if the energy that they produce is actually enough to power a tiny device. The hope is that one day these vibrations could power, or at least supplement the power of, medical devices that need to be implanted near the head and that presently run on batteries with finite lifetimes.

    Chen and the other students acknowledge that health-monitoring sensors powered by the human body might be years away from entering the clinic. However, this opportunity to apply classroom knowledge to a real-life challenge—such as diabetes treatment—is an important part of their training as tomorrow’s scientists and engineers.

    See the full article here.

    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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  • richardmitnick 3:41 pm on October 8, 2014 Permalink | Reply
    Tags: , , Medicine   

    From ALMA: “ALMA, a natural laboratory for high-altitude medicine” 

    ESO ALMA Array
    ALMA

    Wednesday, 01 October 2014
    Valeria Foncea
    Education and Public Outreach Officer
    Joint ALMA Observatory
    Santiago, Chile
    Tel: +56 2 467 6258
    Cell: +56 9 75871963
    Email: vfoncea@alma.cl

    Health experts took part in an important multidisciplinary meeting at the ALMA Observatory facilities, where they shared experiences and research on medicine at high geographic altitude, with a particular focus on a condition known as intermittent hypoxia –lack of oxygen– which has only been studied among mountain climbers.

    About 50 people participated in the seminar, which was held on September 23-25 at the Operation Support Facility (OSF, at 2,900 meters altitude). Those attending included the Latin America Health Manager for Barrick Gold Corporation; the Health Superintendent at Toromocho mine in Peru; representatives of Carabineros de Chile (the uniformed police); the Chilean Safety Association; the APEX Observatory; executives from Indura, Correa Ingeniería, ESACHS and Medicina de Altura; and medical specialists from the University of Calgary in Canada, Universidad Católica del Norte, Universidad de Chile and Tocopilla Hospital.

    team
    Fig. 1: Medical team observing eye fundus and monitoring heart with a telemedicine machine that can be controlled from all over the world through an internet connection. Credit: ALMA(ESO/NAOJ/NRAO), Carlos Padilla

    “ALMA offers a unique opportunity to study physiological adaptation and human action at high geographic altitude,” said Marc Poulin, a doctor from the University of Calgary. “In addition to its location at high altitude, people from all over the world work at ALMA. Therefore, it’s an interdisciplinary and multicultural environment where specialists like us hope to advance the knowledge frontier in terms of what the human body can do.”

    Members of communities that have historically lived at high geographic altitude have succeeded in adapting to lower oxygen levels by changing habits such as diet in order to enjoy a better quality of life. This acclimation, however, is not so easy for those who work in shifts at high altitudes –such as at astronomical observatories or mines–but who live closer to sea level.

    “The Chilean model is different from the rest of the world because the ocean and the mountains are so close together,” said Daniel Jiménez, a doctor who led a legal reform effort that has placed Chile at the forefront of this area. “The result is that thousands of people travel from the coast to high altitudes, especially due to mining work scheduled in weekly shifts.” Jiménez explained that this special phenomenon has been of interest for diverse areas of medicine, with the study of the resulting disorders.

    two
    Fig. 2: ALMA staff drawing the Complex Rey-Osterrieth Figure at 5.000 meters above sea level in a pressurized room. Credit: ALMA(ESO/NAOJ/NRAO), Carlos Padilla |

    ALMA is unique because its employees work at an altitude of 2,900 meters–where its offices, laboratories and camp are located–but they sometimes also work at 5,000 meters, where its antennas are located. Rapid, intermittent exposure to low oxygen levels –known as chronic intermittent hypobaric hypoxia– can cause various illnesses that must be prevented, such as acute mountain sickness (known in Chile as puna), polyglobulia (excess production of red blood cells), brain swelling, acute pulmonary edema and sleep disorders.

    “Sleep disorders are defined as sleeping less than 6 hours per day due to sleep fragmentation and insomnia, which produces sleepiness the following day and also fatigue that has impacts on work. This is especially dangerous for drivers. The new Chilean law is aimed at preventing these illnesses,” said Dr. Jiménez.

    To empirically experience variation in oxygen levels, the conference members participated in an exercise at the Array Operations Site (AOS), more than 5.000 meters above sea level, that consisted of memorizing an image and then drawing it twice. The first drawing was done with an oxygen supplement and then, 15 minutes later, without extra oxygen. The results were conclusive (see drawings below).

    dwg
    Fig. 3: Rey-Osterrieth Complex Figure

    To reduce the risk associated with hypoxia, the specialists recommended changing habits, mainly through a diet that is lower in calories and contains more liquids, and ensuring good sleep habits, such as going to bed early. In a joint project with Chilean universities, ALMA is also studying the effects of working at high altitude on target groups such as smokers.

    See the full article here.

    The Atacama Large Millimeter/submillimeter Array (ALMA), an international astronomy facility, is a partnership of Europe, North America and East Asia in cooperation with the Republic of Chile. ALMA is funded in Europe by the European Organization for Astronomical Research in the Southern Hemisphere (ESO), in North America by the U.S. National Science Foundation (NSF) in cooperation with the National Research Council of Canada (NRC) and the National Science Council of Taiwan (NSC) and in East Asia by the National Institutes of Natural Sciences (NINS) of Japan in cooperation with the Academia Sinica (AS) in Taiwan.

    ALMA construction and operations are led on behalf of Europe by ESO, on behalf of North America by the National Radio Astronomy Observatory (NRAO), which is managed by Associated Universities, Inc. (AUI) and on behalf of East Asia by the National Astronomical Observatory of Japan (NAOJ). The Joint ALMA Observatory (JAO) provides the unified leadership and management of the construction, commissioning and operation of ALMA.

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  • richardmitnick 7:04 pm on September 29, 2014 Permalink | Reply
    Tags: , Medicine,   

    From MIT: “Modeling shockwaves through the brain” 


    MIT News

    September 29, 2014
    Jennifer Chu | MIT News Office

    New scaling law helps estimate humans’ risk of blast-induced traumatic brain injury.

    Since the start of the military conflicts in Iraq and Afghanistan, more than 300,000 soldiers have returned to the United States with traumatic brain injury (TBI) caused by exposure to bomb blasts — and in particular, exposure to improvised explosive devices, or IEDs. Symptoms of traumatic brain injury can range from the mild, such as lingering headaches and nausea, to more severe impairments in memory and cognition.

    brain
    Jose-Luis Olivares/MIT

    Since 2007, the U.S. Department of Defense has recognized the critical importance and complexity of this problem, and has made significant investments in traumatic brain injury research. Nevertheless, there remain many gaps in scientists’ understanding of the effects of blasts on the human brain; most new knowledge has come from experiments with animals.

    br
    MIT researchers have developed a model of the human head for use in simulations to predict the risk for blast-induced traumatic brain injury. Relevant tissue structures include the skull (green), brain (red), and flesh (blue). Courtesy of the researchers

    Now MIT researchers have developed a scaling law that predicts a human’s risk of brain injury, based on previous studies of blasts’ effects on animal brains. The method may help the military develop more protective helmets, as well as aid clinicians in diagnosing traumatic brain injury — often referred to as the “invisible wounds” of battle.

    “We’re really focusing on mild traumatic brain injury, where we know the least, but the problem is the largest,” says Raul Radovitzky, a professor of aeronautics and astronautics and associate director of the MIT Institute for Soldier Nanotechnologies (ISN). “It often remains undetected. And there’s wide consensus that this is clearly a big issue.”

    While previous scaling laws predicted that humans’ brains would be more resilient to blasts than animals’, Radovitzky’s team found the opposite: that in fact, humans are much more vulnerable, as they have thinner skulls to protect much larger brains.

    A group of ISN researchers led by Aurélie Jean, a postdoc in Radovitzky’s group, developed simulations of human, pig, and rat heads, and exposed each to blasts of different intensities. Their simulations predicted the effects of the blasts’ shockwaves as they propagated through the skulls and brains of each species. Based on the resulting differences in intracranial pressure, the team developed an equation, or scaling law, to estimate the risk of brain injury for each species.

    “The great thing about doing this on the computer is that it allows you to reduce and possibly eventually eliminate animal experiments,” Radovitzky says.

    The MIT team and co-author James Q. Zheng, chief scientist at the U.S. Army’s soldier protection and individual equipment program, detail their results this week in the Proceedings of the National Academy of Sciences.

    Air (through the) head

    A blast wave is the shockwave, or wall of compressed air, that rushes outward from the epicenter of an explosion. Aside from the physical fallout of shrapnel and other chemical elements, the blast wave alone can cause severe injuries to the lungs and brain. In the brain, a shockwave can slam through soft tissue, with potentially devastating effects.

    In 2010, Radovitzky’s group, working in concert with the Defense and Veterans Brain Injury Center, a part of the U.S. military health system, developed a highly sophisticated, image-based computational model of the human head that illustrates the ways in which pressurized air moves through its soft tissues. With this model, the researchers showed how the energy from a blast wave can easily reach the brain through openings such as the eyes and sinuses — and also how covering the face with a mask can prevent such injuries. Since then, the team has developed similar models for pigs and rats, capturing the mechanical response of brain tissue to shockwaves.

    In their current work, the researchers calculated the vulnerability of each species to brain injury by establishing a mathematical relationship between properties of the skull, brain, and surrounding flesh, and the propagation of incoming shockwaves. The group considered each brain structure’s volume, density, and celerity — how fast stress waves propagate through a tissue. They then simulated the brain’s response to blasts of different intensities.

    “What the simulation allows you to do is take what happens outside, which is the same across species, and look at how strong was the effect of the blast inside the brain,” Jean says.

    In general, they found that an animal’s skull and other fleshy structures act as a shield, blunting the effects of a blast wave: The thicker these structures are, the less vulnerable an animal is to injury. Compared with the more prominent skulls of rats and pigs, a human’s thinner skull increases the risk for traumatic brain injury.

    Shifting the problem

    This finding runs counter to previous theories, which held that an animal’s vulnerability to blasts depends on its overall mass, but which ignored the role of protective physical structures. According to these theories, humans, being more massive than pigs or rats, would be better protected against blast waves.

    Radovitzky says this reasoning stems from studies of “blast lung” — blast-induced injuries such as tearing, hemorrhaging, and swelling of the lungs, where it was found that mass matters: The larger an animal is, the more resilient it may be to lung damage. Informed by such studies, the military has since developed bulletproof vests that have dramatically decreased the number of blast-induced lung injuries in recent years.

    “There have essentially been no reported cases of blast lung in the last 10 years in Iraq or Afghanistan,” Radovitzky notes. “Now we’ve shifted that problem to traumatic brain injury.”

    In collaboration with Army colleagues, Radovitzky and his group are performing basic research to help the Army develop helmets that better protect soldiers. To this end, the team is extending the simulation approach they used for blast to other types of threats.

    His group is also collaborating with audiologists at Massachusetts General Hospital, where victims of the Boston Marathon bombing are being treated for ruptured eardrums.

    “They have an exact map of where each victim was, relative to the blast,” Radovitzky says. “In principle, we could simulate the event, find out the level of exposure of each of those victims, put it in our scaling law, and we could estimate their risk of developing a traumatic brain injury that may not be detected in an MRI.”

    Joe Rosen, a professor of surgery at Dartmouth Medical School, sees the group’s scaling law as a promising window into identifying a long-sought mechanism for blast-induced traumatic brain injury.

    “Eighty percent of the injuries coming off the battlefield are blast-induced, and mild TBIs may not have any evidence of injury, but they end up the rest of their lives impaired,” says Rosen, who was not involved in the research. “Maybe we can realize they’re getting doses of these blasts, and that a cumulative dose is what causes [TBI], and before that point, we can pull them off the field. I think this work will be important, because it puts a stake in the ground so we can start making some progress.”

    This work was supported by the U.S. Army through ISN.

    See the full article here.

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  • richardmitnick 8:54 pm on September 28, 2014 Permalink | Reply
    Tags: , , , Medicine,   

    From MIT: “Biologists find an early sign of cancer” 


    MIT News

    September 28, 2014
    Anne Trafton | MIT News Office

    Patients show boost in certain amino acids years before diagnosis of pancreatic cancer.

    Years before they show any other signs of disease, pancreatic cancer patients have very high levels of certain amino acids in their bloodstream, according to a new study from MIT, Dana-Farber Cancer Institute, and the Broad Institute.

    cancer
    Christine Daniloff/MIT

    This finding, which suggests that muscle tissue is broken down in the disease’s earliest stages, could offer new insights into developing early diagnostics for pancreatic cancer, which kills about 40,000 Americans every year and is usually not caught until it is too late to treat.

    The study, which appears today in the journal Nature Medicine, is based on an analysis of blood samples from 1,500 people participating in long-term health studies. The researchers compared samples from people who were eventually diagnosed with pancreatic cancer and samples from those who were not. The findings were dramatic: People with a surge in amino acids known as branched chain amino acids were far more likely to be diagnosed with pancreatic cancer within one to 10 years.

    “Pancreatic cancer, even at its very earliest stages, causes breakdown of body protein and deregulated metabolism. What that means for the tumor, and what that means for the health of the patient — those are long-term questions still to be answered,” says Matthew Vander Heiden, an associate professor of biology, a member of MIT’s Koch Institute for Integrative Cancer Research, and one of the paper’s senior authors.

    The paper’s other senior author is Brian Wolpin, an assistant professor of medical oncology at Dana-Farber. Wolpin, a clinical epidemiologist, assembled the patient sample from several large public-health studies. All patients had their blood drawn when they began participating in the studies and subsequently filled out annual health questionnaires.

    Working with researchers at the Broad Institute, the team analyzed blood samples for more than 100 different metabolites — molecules, such as proteins and sugars, produced as the byproducts of metabolic processes.

    “What we found was that this really interesting signature fell out as predicting pancreatic cancer diagnosis, which was elevation in these three branched chain amino acids: leucine, isoleucine, and valine,” Vander Heiden says. These are among the 20 amino acids — the building blocks for proteins — normally found in the human body.

    Some of the patients in the study were diagnosed with pancreatic cancer just one year after their blood samples were taken, while others were diagnosed two, five, or even 10 years later.

    “We found that higher levels of branched chain amino acids were present in people who went on to develop pancreatic cancer compared to those who did not develop the disease,” Wolpin says. “These findings led us to hypothesize that the increase in branched chain amino acids is due to the presence of an early pancreatic tumor.”

    Early protein breakdown

    Vander Heiden’s lab tested this hypothesis by studying mice that are genetically programmed to develop pancreatic cancer. “Using those mouse models, we found that we could perfectly recapitulate these exact metabolic changes during the earliest stages of cancer,” Vander Heiden says. “What happens is, as people or mice develop pancreatic cancer, at the very earliest stages, it causes the body to enter this altered metabolic state where it starts breaking down protein in distant tissues.”

    “This is a finding of fundamental importance in the biology of pancreatic cancer,” says David Tuveson, a professor at the Cancer Center at Cold Spring Harbor Laboratory who was not involved in the work. “It really opens a window of possibility for labs to try to determine the mechanism of this metabolic breakdown.”

    The researchers are now investigating why this protein breakdown, which has not been seen in other types of cancer, occurs in the early stages of pancreatic cancer. They suspect that pancreatic tumors may be trying to feed their own appetite for amino acids that they need to build cancerous cells. The researchers are also exploring possible links between this early protein breakdown and the wasting disease known as cachexia, which often occurs in the late stages of pancreatic cancer.

    Also to be answered is the question of whether this signature could be used for early detection. The findings need to be validated with more data, and it may be difficult to develop a reliable diagnostic based on this signature alone, Vander Heiden says. However, he believes that studying this metabolic dysfunction further may reveal additional markers, such as misregulated hormones, that could be combined to generate a more accurate test.

    The findings may also allow scientists to pursue new treatments that would work by targeting tumor metabolism and cutting off a tumor’s nutrient supply, Vander Heiden says.

    MIT’s contribution to this research was funded by the Lustgarten Foundation, the National Institutes of Health, the Burroughs Wellcome Fund, and the Damon Runyon Cancer Research Foundation.

    See the full article here.

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  • richardmitnick 3:24 pm on September 23, 2014 Permalink | Reply
    Tags: , , , Medicine,   

    From Sandia Lab: “Sandia researchers find clues to superbug evolution” 


    Sandia Lab

    September 23, 2014
    Patti Koning, pkoning@sandia.gov, (925) 294-4911

    Imagine going to the hospital with one disease and coming home with something much worse, or not coming home at all.

    With the emergence and spread of antibiotic-resistance pathogens, healthcare-associated infections have become a serious threat. On any given day about one in 25 hospital patients has at least one such infection and as many as one in nine die as a result, according to the Centers for Disease Control and Prevention.

    Consider Klebsiella pneumoniae, not typically a ferocious pathogen, but now armed with resistance to virtually all antibiotics in current clinical use. It is the most common species of carbapenem-resistant Enterobacteriaceae (CRE) in the United States. As carbapenems are considered the antibiotic of last resort, CREs are a triple threat for their resistance to nearly all antibiotics, high mortality rates and ability to spread their resistance to other bacteria.

    But there is hope. A team of Sandia National Laboratories microbiologists for the first time recently sequenced the entire genome of a Klebsiella pneumoniae strain, encoding New Delhi Metallo-beta-lactamase (NDM-1). They presented their findings in a paper published in PLOS One, Resistance Determinants and Mobile Genetic Elements of an NDM-1 Encoding Klebsiella pneumoniae Strain.

    image
    Sandia National Laboratories’ researchers Kelly Williams, left, and Corey Hudson look at the mosaic pattern of one of the Klebsiella pneumoniae plasmids and discuss mechanisms that mobilize resistance genes. (Photo by Dino Vournas)

    The Sandia team of Corey Hudson, Zach Bent, Robert Meagher and Kelly Williams is beginning to understand the bacteria’s multifaceted mechanisms for resistance. To do this, they developed several new bioinformatics tools for identifying mechanisms of genetic movement, tools that also might be effective at detecting bioengineering.

    “Once we had the entire genome sequenced, it was a real eye opener to see the concentration of so many antibiotic resistant genes and so many different mechanisms for accumulating them,” explained Williams, a bioinformaticist. “Just sequencing this genome unlocked a vault of information about how genes move between bacteria and how DNA moves within the chromosome.”

    Meagher first worked last year with Klebsiella pneumoniae ATCC BAA-2146 (Kpn2146), the first U.S. isolate found to encode NDM-1. Along with E.coli, it was used to test an automatic sequencing library preparation platform for the RapTOR Grand Challenge, a Sandia project that developed techniques to allow discovery of pathogens in clinical samples.

    “I’ve been interested in multi-drug-resistant organisms for some time. The NDM-1 drug resistance trait is spreading rapidly worldwide, so there is a great need for diagnostic tools,” said Meagher. “This particular strain of Klebsiella pneumoniae is fascinating and terrifying because it’s resistant to practically everything. Some of that you can explain on the basis on NDM-1, but it’s also resistant to other classes of antibiotics that NDM-1 has no bearing on.”

    Unlocking Klebsiella pneumoniae

    Assembling an entire genome is like putting together a puzzle. Klebsiella pneumoniae turned out to have one large chromosome and four plasmids, small DNA molecules physically separate from and able to replicate independently of the bacterial cell’s chromosomal DNA. Plasmids often carry antibiotic resistant genes and other defense mechanisms.

    The researchers discovered their Klebsiella pneumoniae bacteria encoded 34 separate enzymes of antibiotic resistance, as well as efflux pumps that move compounds out of cells, and mutations in chromosomal genes that are expected to confer resistance. They also identified several mechanisms that allow cells to mobilize resistance genes, both within a single cell and between cells.

    “Each one of those genes has a story: how it got into this bacteria, where it has been, and how it has evolved,” said Williams.

    Necessity leads to development of new tools

    Klebsiella pneumoniae uses established mechanisms to move genes, such as “jumping genes” known as transposons, and genomic islands, mobile DNA elements that enable horizontal gene transfer between organisms. However, the organism has so many tricks and weapons that the research team had to go beyond existing bioinformatics tools and develop new ways of identifying mechanisms of genetic movement.

    Williams and Hudson detected circular forms of transposons in movement, which has never been shown this way, and discovered sites within the genome undergoing homologous recombination, another gene mobilization mechanism. By applying two existing bioinformatics methods for detecting genomic islands, they found a third class of islands that neither method alone could have detected.

    “To some extent, every extra piece of DNA that a bacteria acquires comes at some cost, so the bacteria doesn’t usually hang onto traits it doesn’t need,” said Hudson. “The further we dug down into the genome, the more stories we found about movement within the organism and from other organisms and the history of insults, like antibiotics, that it has faced. This particular bacteria is just getting nastier over time.”

    Applying findings to future work

    The findings are being applied to a Laboratory Directed Research and Development project led by Sandia microbiologist Eric Carnes, who is examining alternative approaches for treating drug-resistant organisms. “Instead of traditional antibiotics, we use a sequence-based approach to silence expression of drug-resistant genes,” said Meagher.

    The researchers also are applying their understanding of Klebsiella pneumoniae’s mechanisms of resistance and their new bioinformatics tools to developing diagnostic tools to detect bioengineering. Looking across 10 related but distinct strains of Klebsiella pneumoniae, they pinpointed regions that were new to their strain, and so indicate genetic movement.

    “By studying the pattern of movement, we can better characterize a natural genomic island,” said Hudson. “This leads down the path of what does an unnatural island look like, which is an indication of bioengineering. We hope to apply the knowledge we gained from sequencing Klebsiella pneumoniae to developing diagnostic tools that could detect bioengineering.”

    See the full article here.

    Sandia National Laboratories is a multiprogram laboratory operated by Sandia Corporation, a wholly owned subsidiary of Lockheed Martin Corporation, for the U.S. Department of Energy’s National Nuclear Security Administration. With main facilities in Albuquerque, N.M., and Livermore, Calif., Sandia has major R&D responsibilities in national security, energy and environmental technologies, and economic competitiveness.
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