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  • richardmitnick 12:45 pm on January 17, 2017 Permalink | Reply
    Tags: , , , Vanderbilt U   

    From Vanderbilt: “Softening tumor tissue could aid cancer treatments” 

    Vanderbilt U Bloc

    Vanderbilt University

    Jan. 16, 2017
    Liz Entman

    Softening tumors’ blood vessels may help more chemo reach the cancer

    Normally, the glue that holds cells together in the human body – what scientists call the extracellular matrix – is soft and pliable. But when a metastatic tumor forms it causes the matrix surrounding it to stiffen.

    According to a new study, this mechanical effect produces changes in the blood vessels that feed the tumor in a way that can reduce the effectiveness of chemotherapeutics and radiation treatments. The finding suggests that softening this protective layer could make existing cancer treatments more effective.

    2
    Cynthia Reinhart-King (Steve Green/Vanderbilt)

    The study was published Dec. 22 in the Proceedings of the National Academy of Sciences, by a team of researchers led by Vanderbilt Professor of Biomedical Engineering Cynthia Reinhart-King, which includes postdoctoral researcher François Bordeleau in the Reinhart-King group along with collaborators from Cornell University. The report is titled Matrix Stiffening Promotes a Tumor Vasculature Phenotype.

    For years, the idea has been that the way to treat tumors was to starve them by killing off their blood vessels. While that works in some cases, in others it only serves to make the tumor more aggressive, Reinhart-King said, adding: “There are ways tumors can grow in the absence of those nutrients, and they get more aggressive. At the same time, they may also stop responding to some chemotherapeutics and radiation treatments.”

    A metastatic tumor’s blood vessels tend to be malformed and more permeable than blood vessels in healthy tissue. For this reason, fluid tends to leak from the vessels, building up pressure inside the tumor that prevents drugs from getting to their target.

    “Basically, as fluid leaks out of the blood vessels, it causes high pressures to build up in the tumor. These high pressures can cause blood flow to stall or even reverse and vessels tocollapse,” Reinhart-King said. “So fluid, including the drugs, cannot reach the tumor tissue.”

    3
    Image of a mammary tumor stained for cell nuclei (in blue), blood vessels (in green) and the protein beta-catenin that causes cells to stick together (in red) (Reinhart-King Lab / Vanderbilt)

    Unlike in previous work in this area, Reinhart-King and Bordeleau see the vascular breakdown as a product of the stiffening of the tumor and its matrix, which triggers proteins in cells to alter vascular growth and integrity. Previous work has targeted chemical factors, in particular vascular endothelial growth factor.

    “The idea that you would want to restore barrier integrity and help blood vessels is not a new one,” Reinhart-King said. “The idea that we discovered is that it’s controlled through matrix stiffness.” This, in turn, suggests that promoting healthy vasculature through a softening of the extracellular matrix would use the tumor itself as a conduit for delivering cancer-killing drugs.

    “What we show,” Reinhart-King said, “is that we can drive a lot of the same behaviors that are typically thought to occur due to chemical changes, by changing the mechanical properties of the tumor.”

    This work was supported by National Institutes of Health grants R01-HL127499 and R01-CA163255 and National Science Foundation awards 1055502 and 435755.

    See the full article here .

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  • richardmitnick 9:30 am on December 28, 2016 Permalink | Reply
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    From Vanderbilt: “Investigational new drug for Alzheimer’s scheduled for first study in humans” 

    Vanderbilt U Bloc

    Vanderbilt University

    Dec. 27, 2016
    Bill Snyder

    Vanderbilt University scientists have received notification from the U.S. Food and Drug Administration (FDA) that testing in humans may proceed for an investigational new drug for Alzheimer’s disease after more than 10 years of research by scientists at Vanderbilt University and Vanderbilt University Medical Center.

    It is relatively uncharted territory for an academic drug discovery group to take a molecule from the laboratory setting to the clinical trials stage.

    “The movement to the clinical phase of the research is the result of tireless colleagues reaching across disciplines in pursuit of the shared goal of hoping to someday improve the lives of individuals with Alzheimer’s disease and possibly other brain disorders, such as schizophrenia,” said Provost and Vice Chancellor for Academic Affairs Susan R. Wente, Ph.D. “This work exactly illustrates the critical role that basic science conducted in partnership with a world-class medical center can play in advancing knowledge in an attempt to fight a devastating disease.”

    For Alzheimer’s disease, the aim is for the investigational drug to target major pathologies of the disease and selectively activate a key receptor in the brain. The Vanderbilt researchers believe that the current standard of care for Alzheimer’s disease, cholinesterase inhibitors, has a different mechanism of action. They are hoping to establish through future clinical testing that the molecule is broadly effective across a number of cognitive and neuropsychiatric disorders, including schizophrenia.

    1
    P. Jeffrey Conn, Ph.D.

    “This is the first instance I am aware of where an academic drug discovery group moved a molecule designed to hopefully treat a chronic brain disorder all the way from early discovery to human trials without there being, at some point along the way, a pharmaceutical partner,” said P. Jeffrey Conn, Ph.D., Lee E. Limbird Professor of Pharmacology in the Vanderbilt University School of Medicine and director of the Vanderbilt Center for Neuroscience Drug Discovery (VCNDD).

    “And that really is crossing what people refer to all of the time as the ‘Valley of Death,’ where good research discoveries have a hard time moving into the clinical testing phase due to lack of funding,” he said. “Importantly, at this early stage, the FDA has only granted permission to assess potential safety of this investigational new drug in healthy volunteers” said Conn. “We cannot predict the outcome, but if these studies are successful in demonstrating that the investigational drug can be safely administered to humans, this would pave the way to allow filing of additional applications with the FDA to seek permission to advance to testing for efficacy in improving cognitive function in patients suffering from Alzheimer’s disease, and possibly schizophrenia or other brain disorders. While we cannot predict the outcome of any future safety or efficacy studies, this decision by FDA allowing clinical research to begin represents a major milestone in allowing us to hopefully provide answers to those critical questions in the future.”

    2
    Craig W. Lindsley, Ph.D.

    VCNDD Co-Director Craig W. Lindsley, Ph.D., director of Medicinal Chemistry and William K. Warren, Jr. Professor of Medicine, said Phase I testing will assess drug safety and tolerability in healthy volunteer participants, a process that could take a year. If successful, the Phase II and III studies would include efficacy assessments in patients with Alzheimer’s disease and could take three to five years to complete.

    “We are hoping to address what we see as an unmet medical need,” Lindsley said. “For Alzheimer’s patients, the standard of care for symptomatic treatment remains cholinesterase inhibitors, which are 25 years old at this point. There hasn’t been any real scientific advancement in this field in a long time.”

    Lindsley and Conn credit The William K. Warren Foundation for its philanthropic investments along the way to make clinical trials for this investigational drug a reality.

    “One of the most challenging things about doing this in an academic environment is funding,” Lindsley said. “Every step requires funding and if there is a delay or break in funding, then everything sits idle and potentially innovative approaches for patient care do not advance.”

    “Being matched with the Warrens happened serendipitously. They have invested so much in our programs, and it is wonderful to show them progress on their investments,” he said. “Without the financial support from the Warrens, this investigational drug would not be poised to enter human clinical trials.”

    The William K. Warren Foundation Chief Executive Officer John-Kelly Warren said he is gratified that FDA has allowed for the investigational drug to proceed to testing in human beings.

    “Although this is an important sequential milestone, the only milestone that matters to us is the hope that one day we will learn that this investigational new drug has positively and safely changed the life of a patient suffering from a brain disorder such as schizophrenia or Alzheimer’s disease,” Warren said.

    “That day will warrant a celebration felt in the heavens. Until then, we are prepared to support the VCNDD research team until they can deliver the necessary results,” he said.

    A NIH National Cooperative Drug Discovery/Development grant funded the early basic science and discovery of this investigational drug and the Alzheimer’s Drug Discovery Foundation and Harrington Discovery Institute helped support some of the key toxicity studies that FDA required, Conn said.

    “The investigational new drug has the potential to improve cognitive functions with fewer unwanted side effects. This could someday be an important advance for the treatment of cognitive deficits in psychiatric disorders and Alzheimer’s disease,” said Joshua Gordon, M.D., Ph.D., director of the National Institute of Mental Health, which co-funded the research.

    Conn and Lindsley said Vanderbilt’s “team science” approach included contributions from the director of Translational Pharmacology and Development for the VCNDD and Assistant Professor Carrie K. Jones, Ph.D., who coordinated the IND drafting, submission, and subsequent development into Phase I, director of Molecular Pharmacology for the VCNDD and Research Associate Professor of Pharmacology Colleen Niswender, Ph.D., for the molecular pharmacology; Research Assistant Professor of Pharmacology Jerri Rook, Ph.D., for the behavioral studies; and Research Assistant Professor of Pharmacology Thomas Bridges, Ph.D., and Research Assistant Professor of Pharmacology Anna Blobaum, Ph.D., for drug metabolism and pharmacokinetic profiling.

    Paul Newhouse, M.D., director of the Center for Cognitive Medicine at VUMC and Jim Turner Professor in Cognitive Disorders, is expected to lead the upcoming clinical study funded in part by the Alzheimer’s Association and Alzheimer’s Drug Discovery Foundation.

    See the full article here .

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  • richardmitnick 5:52 am on September 10, 2016 Permalink | Reply
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    From Vanderbilt: “In search of new cancer targets” 

    Vanderbilt U Bloc

    Vanderbilt University

    Sep. 9, 2016
    Leigh MacMillan

    Molecularly heterogeneous cancers such as triple-negative breast cancer are challenging to treat, because they often lack the “driver” mutations that are targeted by the newest cancer therapies. These cancers exhibit genomic instability, resulting in chromosomal rearrangements and gene fusions, and identifying these alterations is technically difficult.

    Timothy Shaver and Brian Lehmann, Ph.D., working with Jennifer Pietenpol, Ph.D., developed a new algorithm, Segmental Transcript Analysis (STA), to predict gene rearrangements.

    Using STA, they identified multiple known and novel gene rearrangements in triple-negative breast cancer and then expanded their analysis to other malignancies using a cohort from The Cancer Genome Atlas.

    Two of the gene rearrangements that the team characterized in triple-negative breast cancer involve molecular targets for therapies already in clinical investigation or development.

    The findings, reported Aug. 15 in Cancer Research, provide evidence that STA is an effective prediction tool for gene rearrangements and highlight the need to advance gene fusion detection for molecularly heterogeneous cancers.

    This research was supported by grants from the National Institutes of Health (CA183531, GM008554, CA098131, CA105436, CA068485) and from the Susan G. Komen Foundation.

    See the full article here .

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  • richardmitnick 9:57 am on September 9, 2016 Permalink | Reply
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    From Vanderbilt: “Investigators create ‘Trojan Horse’ to fight Ebola” 

    Vanderbilt U Bloc

    Vanderbilt University

    Sep. 8, 2016
    Bill Snyder
    william.snyder@Vanderbilt.Edu
    (615) 322-4747

    A multi-center research team including scientists from the Vanderbilt Vaccine Center has come up with a clever “Trojan Horse” strategy for thwarting the highly lethal Ebola virus.

    Using “bispecific” antibodies — two monoclonal antibodies combined into a single package — they first tricked the virus into revealing a normally hidden binding site required for infection. Then in a mouse model, they blocked the site, fully protecting the animals from Ebola infection.

    Their findings, reported in this week’s Science magazine, suggest that this two-step, “deliver-and-block” strategy can provide broad protection against Ebola and other members of its hemorrhagic filovirus family, including the Marburg virus.

    We were intrigued to find this remarkable antibody that has the capacity to inhibit both Marburg and Ebola viruses,” said James Crowe Jr., M.D., Ann Scott Carell Professor in the Vanderbilt University School of Medicine and director of the Vanderbilt Vaccine Center at Vanderbilt University Medical Center.

    “The team’s feat of delivering the antibody into cells using creative engineering tricks so that it can kill Ebola inside cells is very exciting,” Crowe said.

    This advance is only the latest in a string of fundamental discoveries made during the past decade by a far-flung group of researchers including Crowe and four other corresponding authors of the paper.

    The four are Kartik Chandran, Ph.D., and Jonathan Lai, Ph.D., of Albert Einstein College of Medicine in New York, John Dye, Ph.D., of the U.S. Army Medical Research Institute of Infectious Diseases in Fort Detrick, Maryland, and Javad Aman, Ph.D., of Integrated Biotherapeutics in Gaithersburg, Maryland.

    Like other viruses, Ebola must “hijack” factors in the cells it infects to make copies of itself. As a first step, the virus enters a vesicle called an endosome inside the cell. There it commandeers two cellular enzymes called proteases to cut a sugar-bearing glycoprotein on its surface in two.

    Cleavage of the glycoprotein reveals a previously hidden receptor-binding site that attaches to another cellular factor, a cholesterol transporter protein called Niemann–Pick C1 or NPC1. This step is essential for infection to occur.

    Mutations in the NPC1 gene result in an abnormal protein that causes the rare lipid storage disorder Niemann-Pick type C disease. While patients with this disease are often quite ill, their abnormal NPC1 protein also renders them resistant to infection by Ebola and the related Marburg virus.

    Last year, Crowe, Vanderbilt graduate student Andrew Flyak and colleagues at The Scripps Research Institute in La Jolla, California, reported that a human survivor of a severe Marburg infection had neutralizing antibodies that recognized and blocked the NPC1 binding site in Marburg virus

    These antibodies also could bind to the Ebola virus, but only to the form of the virus inside cells.

    Crowe and Flyak followed up that finding by generating a “monoclonal” antibody, called MR72, which specifically recognized and could block the NPC1 binding site. To actually prevent Ebola virus infection, however, they’d have to get the antibody into the endosome inside the cell where the action is taking place.

    To do that, the researchers fused MR72 to another antibody, called FVM09, which recognizes and attaches to the Ebola glycoprotein before it is cut in two. The result was an immunological “Trojan horse.” Once the virus brought its antibody cargo into the endosome, MR72 went to work, and blocked infection.

    “This Trojan horse bispecific antibody approach may also find utility against other viral pathogens known to use intracellular receptors,” they concluded.

    Other contributors to the current study were Erica Ollmann Saphire, Ph.D., at Scripps and Zachary Bornholdt, Ph.D., now at Mapp Pharmaceutical in San Diego. The study was supported in part by National Institutes of Health grants AI109762, AI088027 and AI122403.

    See the full article here .

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  • richardmitnick 8:33 am on September 9, 2016 Permalink | Reply
    Tags: , , Myocardial infarction, Vanderbilt U   

    From Vanderbilt: “Going after the heart attack Gremlin” 

    Vanderbilt U Bloc

    Vanderbilt University

    Sep. 8, 2016
    Sanjay Mishra

    Myocardial infarction (MI) or heart attack is the major cause of death in men and women in the United States. Because it interrupts the heart’s oxygen supply, MI causes irreversible tissue damage that can lead to heart failure.

    1
    Blausen Medical Communications, Inc.
    A protein called Gremlin 2 (Grem2), which is required for early cardiac development, also is strongly induced in the heart after experimental MI. However, little is known about the function of Grem2 after cardiac injury.

    Now, in a paper published recently in the journal Circulation Research, Antonis Hatzopoulos, Ph.D., and colleagues show that Grem2 provides a molecular barrier that controls the magnitude and extent of inflammation after MI.

    They show that Grem2 suppresses the signaling of bone morphogenetic protein (BMP). BMP signaling plays an important role in heart development but its activation following ischemic injury regulates the inflammatory response.

    Their findings suggest a new strategy to limit the adverse effects of excessive inflammation following MI.

    This research was supported by grants from the National Institutes of Health (HL083958, HL100398, GM114640) and by institutional support from Vanderbilt University Medical Center.

    See the full article here .

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  • richardmitnick 8:05 am on September 1, 2016 Permalink | Reply
    Tags: , , , Neuroblastoma, Vanderbilt U   

    From Vanderbilt: “Proliferative capacity of neuroblastoma” 

    Vanderbilt U Bloc

    Vanderbilt University

    Aug. 31, 2016
    Sanjay Mishra

    Neuroblastoma is a neural crest cell-derived extracranial solid cancer that affects infants and young children. The most vigorous of these cancers spreads through self-renewing cancer stem cells. Knowing the nature of these cells is essential to understanding the progression of neuroblastoma and devising the right treatment strategy.

    Reporting in the journal Biochemical and Biophysical Research Communications, Dai Chung, M.D., and colleagues use a technique called “limiting dilution analysis” to show that the frequency with which neuroblastoma stem cells form spheres in suspension cultures accurately quantifies their stemness, or ability to “self-renew.”

    Cell lines formed spheres more frequently when the MYCN oncogene was overactive. Retinoic acid, used clinically to induce differentiation of residual disease after chemotherapy and radiation, almost blocked sphere formation entirely, while fibroblast growth factor (FGF) promoted sphere formation.

    Limiting dilution analysis is an accurate method of quantifying sphere-forming frequency, and should be adopted as an effective way to assess the stemness or proliferative capacity of neuroblastoma stem cells, they conclude.

    This research was supported by a grant from the National Institutes of Health (DK061470) and by a Rally Foundation for Cancer Research Pediatric Oncology Fellowship Award.

    See the full article here .

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  • richardmitnick 4:18 pm on May 6, 2016 Permalink | Reply
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    From Vanderbilt: “Current cancer drug discovery method flawed: VUMC study” 

    Vanderbilt U Bloc

    Vanderbilt University

    May 5, 2016
    Leigh MacMillan

    The primary method used to test compounds for anti-cancer activity in cells is flawed, Vanderbilt University researchers reported* May 2 in Nature Methods. The findings cast doubt on methods used by the entire scientific enterprise and pharmaceutical industry to discover new cancer drugs.

    “More than 90 percent of candidate cancer drugs fail in late-stage clinical trials, costing hundreds of millions of dollars,” said Vito Quaranta, M.D., director of the Quantitative Systems Biology Center at Vanderbilt. “The flawed in vitro drug discovery metric may not be the only responsible factor, but it may be worth pursuing an estimate of its impact.”

    Quaranta and his colleagues have developed a new metric to evaluate a compound’s effect on cell proliferation — called the DIP (drug-induced proliferation) rate — that overcomes the flawed bias in the traditional method.

    For more than 30 years, scientists have evaluated the ability of a compound to kill cells by adding the compound to cells and counting how many cells are alive after 72 hours. But these “proliferation assays” that measure cell number at a single time point don’t take into account the bias introduced by exponential cell proliferation, even in the presence of the drug, said Darren Tyson, Ph.D., co-author and research assistant professor of Cancer Biology.

    “Cells are not uniform; they all proliferate exponentially, but at different rates,” said Quaranta, professor of Cancer Biology. “At 72 hours, some cells will have doubled three times and others will not have doubled at all.”

    In addition, he noted, drugs don’t all behave the same way on every cell line — for example, a drug might have an immediate effect on one cell line and a delayed effect on another.

    In a close collaboration with computational biologist Carlos Lopez, Ph.D., assistant professor of Cancer Biology, Quaranta’s team used a systems biology approach — a mixture of experimentation and mathematical modeling — to demonstrate the time-dependent bias in static proliferation assays and to develop the time-independent DIP rate metric.

    “Systems biology is what really makes the difference here,” Lopez said. “It’s about understanding cells — and life — as dynamic systems.”

    Tyson, an experimentalist, conceived the method with Leonard Harris, Ph.D., a systems biology postdoctoral fellow and co-first author Peter Frick, Ph.D., a recent Vanderbilt graduate.

    The findings have particular importance in light of recent international efforts to generate data sets that include the responses of “thousands of cell lines to hundreds of compounds,” Quaranta said. The Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC) databases include drug response data along with genomic and proteomic data that detail each cell line’s molecular makeup.

    “The idea is to look for statistical correlations — these particular cell lines with this particular makeup are sensitive to these types of compounds — to use these large databases as discovery tools for new therapeutic targets in cancer,” Quaranta said. “If the metric by which you’ve evaluated the drug sensitivity of the cells is wrong, your statistical correlations are basically no good.”

    The researchers evaluated the responses of four different melanoma cell lines to the drug vemurafenib, currently used to treat melanoma, with the standard metric – used for the CCLE and GDSC databases — and with the DIP rate. In one cell line, they found a stark disagreement between the two metrics.

    “The static metric says that the cell line is very sensitive to vemurafenib. However, our analysis shows this is not the case,” Harris said. “A brief period of drug sensitivity, quickly followed by rebound, fools the static metric, but not the DIP rate.”

    The findings “suggest we should expect melanoma tumors treated with this drug to come back, and that’s what has happened, puzzling investigators,” Quaranta added. “DIP rate analyses may help solve this conundrum, leading to better treatment strategies.”

    The DIP rate metric offers another advantage — it can reveal which drugs are truly cytotoxic (cell-killing), rather than merely cytostatic (cell growth-inhibiting). Although cytostatic drugs may initially have promising therapeutic effects, they may leave tumor cells alive that then have the potential to cause the cancer to recur.

    Quaranta noted that using the DIP rate is possible because of advances in automation, robotics, microscopy and image processing.

    His team has developed a software package that will be available to other researchers through a hyperlink in the Nature Methods paper. Quaranta is working with the Vanderbilt Center for Technology Transfer and Commercialization to identify commercial entities that can further refine the software and make it widely available to the research community to inform drug discovery.

    Other contributors to the research included Shawn Garbett in Biostatistics, and Keisha Hardeman and Bishal Paudel, graduate students in the Quaranta laboratory. This research was supported by grants from Uniting Against Lung Cancer, the Vanderbilt Breast Cancer SPORE, the National Institutes of Health (CA113007, CA174706, TR000445), and by a National Library of Medicine Fellowship.

    *Science paper:
    An unbiased metric of antiproliferative drug effect in vitro

    See the full article here .

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  • richardmitnick 7:08 am on March 18, 2016 Permalink | Reply
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    From Vandy: “Study suggests cancer’s ‘clock’ can be rewound” 

    Vanderbilt U Bloc

    Vanderbilt University

    Mar. 17, 2016
    Bill Snyder

    Researchers at Vanderbilt University Medical Center have “turned back the clock” in a mouse model of metaplasia — precancerous stomach lesions — raising hopes that gastric cancer, a worldwide scourge that’s rising in the United States, can be prevented.

    “This was totally unexpected,” said James Goldenring, M.D., Ph.D., the Paul W. Sanger Professor of Experimental Surgery and Co-Director of the Epithelial Biology Center. “I would never have believed it a year and a half ago.”

    The “clock” is abnormal activation of Ras, a signaling protein that regulates cell growth and survival. Ras mutations are found in up to one-third of all human cancers. Ras activation, possibly triggered by other signaling molecules, recently was identified in a large percentage of gastric cancers.

    Goldenring and Steven Leach, M.D., a former Vanderbilt faculty member now at the Memorial Sloan Kettering Cancer Center in New York, found that Ras activation in gastric chief cells, which secrete digestive enzymes, was involved in the “full spectrum” of transitions leading to precancerous metaplasia in mice.

    The surprise came when the animals were given selumetinib, a drug now in clinical trials that blocks MEK, an enzyme downstream of Ras activation. Not only was metaplasia halted, but normal stomach cells repopulated the stomach, turning it “back to normal,” they reported recently in the journal Gastroenterology.

    Eunyoung Choi, Ph.D., research instructor in Surgery at Vanderbilt, was the paper’s first author.

    It appears that underneath all the abnormal metaplastic cells hides a lineage of normal progenitor cells which can regenerate the normal mucosal layer of the stomach, Goldenring said. When Ras activation was blocked, the normal cells actually pushed the abnormal tissue right out of the mucosa, he said.

    The researchers are extending their studies in gerbils, another animal model, and with colleagues at Yonsei University in Seoul, South Korea, they are preparing to test MEK inhibition in patients who have had local endoscopic removal of a stage 1 gastric cancer.

    Koreans have one of the highest incidences of gastric cancer in the world. Most cases of gastric cancer are triggered by Helicobacter pylori, a bacterium that infects the stomach lining.

    But other factors must play a role, Goldenring said.

    Metaplasia persists, despite antibiotic treatment to clear the infection. Even after endoscopic resection to remove early gastric cancer, patients still have a 2 to 5 percent annual risk of a second cancer occurring elsewhere in the stomach.

    If short-term treatment with selumetinib is successful in reversing metaplasia in patients in Korea, it could be tried as a form of chemoprevention for patients with metaplasia in other countries in Asia and South America that have high gastric cancer rates.

    “It makes a lot more sense to me to treat a precancerous lesion than to try to treat a big cancer,” Goldenring said.

    The research was supported by the U.S. Department of Veterans Affairs, the National Institutes of Health, and the T.J. Martell Foundation.

    See the full article here .

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  • richardmitnick 2:07 am on January 23, 2016 Permalink | Reply
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    From Vanderbilt: “Faulty building blocks in DNA” 

    Vanderbilt U Bloc

    Vanderbilt University

    Jan. 22, 2016
    Bill Snyder

    Temp 1
    (iStock)

    Enzymes called DNA polymerases assemble DNA from 2´-deoxyribonucleoside triphosphate building blocks in the cell. Normally they can distinguish DNA building blocks from the ribonucleotides that make up RNA, but sometimes they misinsert ribonucleotides into DNA, generating “DNA lesions.”

    Yan Su, Ph.D., Martin Egli, Ph.D., and F. Peter Guengerich, Ph.D., have provided an important glimpse into how this happens. They studied human DNA polymerase eta (hpol-eta), which is directly related to a human genetic disorder, xeroderma pigmentosum, associated with an increased risk of skin and other cancers.

    In a paper published online this month by the Journal of Biological Chemistry, they show that hpol-eta can incorporate ribonucleotides into DNA with relatively high selectivity but low efficiency. They also crystallized the enzyme and obtained what appears to be the first crystal structure of an incoming ribonucleotide opposite a DNA lesion within a DNA polymerase. Based on these findings, “it is highly possible that hpol-eta inserts a considerable amount of ribonucleotides into DNA,” they conclude.

    This work was supported by National Institutes of Health.

    See the full article here .

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  • richardmitnick 10:39 am on September 4, 2015 Permalink | Reply
    Tags: , , Palaeoecology, Vanderbilt U   

    From Vanderbilt: “Evidence that Earth’s first mass extinction was caused by critters, not catastrophe” 

    Vanderbilt U Bloc

    Vanderbilt University

    Sep. 2, 2015
    David Salisbury

    1
    Fossil of frond-like Ediacaran species found in Namibia. (Sarah Tweedt, Smithsonian Institution)

    In the popular mind, mass extinctions are associated with catastrophic events, like giant meteorite impacts and volcanic super-eruptions.

    But the world’s first known mass extinction, which took place about 540 million years ago, now appears to have had a more subtle cause: evolution itself.

    “People have been slow to recognize that biological organisms can also drive mass extinction,” said Simon Darroch, assistant professor of earth and environmental sciences at Vanderbilt University. “But our comparative study of several communities of Ediacarans, the world’s first multicellular organisms, strongly supports the hypothesis that it was the appearance of complex animals capable of altering their environments, which we define as ‘ecosystem engineers,’ that resulted in the Ediacaran’s disappearance.”

    The study is described in the paper Biotic replacement and mass extinction of the Ediacara biota published Sept. 2 in the journal Proceedings of the Royal Society B.

    “There is a powerful analogy between the Earth’s first mass extinction and what is happening today,” Darroch observed. “The end-Ediacaran extinction shows that the evolution of new behaviors can fundamentally change the entire planet, and we are the most powerful ‘ecosystem engineers’ ever known.”

    The earliest life on Earth consisted of microbes – various types of single-celled microorganisms. They ruled the Earth for more than 3 billion years. Then some of these microorganisms [cyanobacteria] discovered how to capture the energy in sunlight.

    3
    Cyanobacteria

    The photosynthetic process that they developed had a toxic byproduct: oxygen. Oxygen was poisonous to most microbes that had evolved in an oxygen-free environment, making it the world’s first pollutant.

    But for the microorganisms that developed methods for protecting themselves, oxygen served as a powerful new energy source. Among a number of other things, it gave them the added energy they needed to adopt multicellular forms. Thus, the Ediacarans arose about 600 million years ago during a warm period following a long interval of extensive glaciation.

    “We don’t know very much about the Ediacarans because they did not produce shells or skeletons. As a result, almost all we know about them comes from imprints of their shapes preserved in sand or ash,” said Darroch.

    2
    Simon Darroch (Steve Green / Vanderbilt)

    What scientists do know is that, in their heyday, Ediacarans spread throughout the planet. They were a largely immobile form of marine life shaped like discs and tubes, fronds and quilted mattresses. The majority were extremely passive, remaining attached in one spot for their entire lives. Many fed by absorbing chemicals from the water through their outer membranes, rather than actively gathering nutrients.

    Paleontologists have coined the term “Garden of Ediacara” to convey the peace and tranquility that must have prevailed during this period. But there was a lot of churning going on beneath that apparently serene surface.

    After 60 million years, evolution gave birth to another major innovation: animals. All animals share the characteristics that they can move spontaneously and independently, at least during some point in their lives, and sustain themselves by eating other organisms or what they produce. Animals burst onto the scene in a frenzy of diversification that paleontologists have labeled the Cambrian explosion, a 25-million-year period when most of the modern animal families – vertebrates, molluscs, arthropods, annelids, sponges and jellyfish – came into being.

    “These new species were ‘ecological engineers’ who changed the environment in ways that made it more and more difficult for the Ediacarans to survive,” said Darroch.

    3
    Ediacaran fossil found in the Swartput Farm site. (Sarah Tweedt / Smithsonian Institution)

    He and his colleagues performed an extensive paleoecological and geochemical analysis of the youngest known Ediacaran community exposed in hillside strata in southern Namibia. The site, called Farm Swartpunt, is dated at 545 million years ago, in the waning one to two million years of the Ediacaran reign.

    “We found that the diversity of species at this site was much lower, and there was evidence of greater ecological stress, than at comparable sites that are 10 million to 15 million years older,” Darroch reported. Rocks of this age also preserve an increasing diversity of burrows and tracks made by the earliest complex animals, presenting a plausible link between their evolution and extinction of the Ediacarans.

    The older sites were Mistaken Point in Newfoundland, dating from 579 to 565 million years ago; Nilpena in South Australia, dating from 555 to 550 million years ago; and the White Sea in Russia, dating also from 555 to 550 million years ago million years ago.

    Darroch and his colleagues made extensive efforts to ensure that the differences they recorded were not due to some external factor.

    For example, they ruled out the possibility that the Swartpunt site might have been lacking in some vital nutrients by closely comparing the geochemistry of the sites.

    It is a basic maxim in paleontology that the more effort that is made in investigating a given site, the greater the diversity of fossils that will be found there. So the researchers used statistical methods to compensate for the variation in the differences in the amount of effort that had been spent studying the different sites.

    4
    Simon Darroch in Namibia searching for fossils. (Sarah Tweedt, Smithsonian Institution)

    Having ruled out any extraneous factors, Darroch and his collaborators concluded that “this study provides the first quantitative palaeoecological evidence to suggest that evolutionary innovation, ecosystem engineering and biological interactions may have ultimately caused the first mass extinction of complex life.”

    Marc Laflamme, Thomas Boag and Sara Mason from the University of Toronto; Douglas Erwin and Sarah Tweedt from the Smithsonian Institution, Erik Sperling from Stanford University, Alex Morgan and Donald Johnston from Harvard University; Rachel Racicot from Yale University; and Paul Myrow from Colorado College collaborated in the study.

    The project was supported by grants from the Connaught Foundation, National Science and Engineering Research Council of Canada, NASA Astrobiology Institute, National Geographic Society and National Science Foundation grant EAR 1324095.

    See the full article here .

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