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  • richardmitnick 1:34 pm on December 15, 2015 Permalink | Reply
    Tags: , Wash U St. Louis   

    From Wash U: “Study uncovers hard-to-detect cancer mutations” 

    Wash U Bloc

    Washington University in St.Louis

    December 14, 2015
    Julia Evangelou Strait

    Findings could help identify patients who would benefit from existing drugs

    1
    A new study led by Li Ding, PhD, describes a way to identify a complex type of mutation in cancer genomes that is systematically missed by current genetic sequencing tools. The analysis may expand the number of cancer patients who can benefit from existing drugs.

    New research shows that current approaches to genome analysis systematically miss detecting a certain type of complex mutation in cancer patients’ tumors. Further, a significant percentage of these complex mutations are found in well-known cancer genes that could be targeted by existing drugs, potentially expanding the number of cancer patients who may benefit.

    The study, from Washington University School of Medicine in St. Louis, appears Dec. 14 in the journal Nature Medicine.

    “The idea of not catching a targetable mutation in a patient’s tumor is devastating,” said senior author Li Ding, PhD, associate professor of medicine and assistant director of the McDonnell Genome Institute at Washington University. “We developed a software tool for finding a certain type of genetic error that has been consistently missed by cancer genome studies. We identified a large number of such events in critical cancer genes. The ability to discover such events is crucial for cancer research and for clinical practice.”

    Mutations in the genome happen in a variety of ways. Perhaps the simplest is a change in a single “letter” of the DNA code. Among the more complex types of mutations are those that involve deleting or inserting a few letters. In the new study of 8,000 cancer cases, the investigators focused on mutations involving letters that are inserted at the same time that other letters are deleted.​​​​​​​​​​​​​

    “We call this type of mutation a complex indel because insertion and deletion is happening at the same time, in the same genomic location,” said Ding, who also is a research member of the Siteman Cancer Center at the School of Medicine and Barnes-Jewish Hospital​. “It is very difficult to capture such events because conventional approaches were designed to catch one or the other, not both types at the same time and place.”

    To find the complex indels, the researchers developed specialized computer software and verified its accuracy in genome sequences into which they purposely introduced these complex mutations.

    Then, the researchers looked at cancer genomes that already had been sequenced and found 285 complex indels in genes known to be associated with cancer. About 81 percent of these complex indel events had been missed on the first analysis using conventional approaches. And another 18 percent had been misidentified as some other type of mutation.

    Ding emphasized the importance of developing special tools to find these complex indels, as the data suggest they go almost completely undetected by existing tools and appear to cluster in important cancer genes more often than can be attributed to random chance. This information is particularly valuable when indels are found in genes that already have drugs designed to counter the effects of mutation.

    In particular, the researchers identified complex indels in the gene EGFR, which is implicated in lung cancer. If such an indel is found in this gene, Ding and her colleagues suggest a patient may benefit from an EFGR inhibitor, such as erlotinib, regardless of the tumor type. The investigators also found complex indels in a gene called KIT, which appears to play a role in melanoma. The analysis suggests that patients with complex indels in KIT would benefit from drugs such as imatinib, sunitnib and sorafenib, which target mutations in this gene.

    The new software the investigators developed specifically to find complex indels is called Pindel-C. It was built on top of existing software called Pindel, which was published in 2009 by the study’s first author, Kai Ye, PhD, assistant professor of genetics. Both versions of the software are freely available online for download.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Wash U campus

    Washington University’s mission is to discover and disseminate knowledge, and protect the freedom of inquiry through research, teaching, and learning.

    Washington University creates an environment to encourage and support an ethos of wide-ranging exploration. Washington University’s faculty and staff strive to enhance the lives and livelihoods of students, the people of the greater St. Louis community, the country, and the world.

     
  • richardmitnick 2:48 pm on September 14, 2015 Permalink | Reply
    Tags: , , , Staph infection, Wash U St. Louis   

    From Wash U: “Combo of 3 antibiotics can kill deadly staph infections​​​” 

    Wash U Bloc

    Washington University in St.Louis

    September 14, 2015
    Jim Dryden

    1
    Using three antibiotic drugs thought to be useless against MRSA infection — piperacillin and tazobactam (bottle on left) and meropenem — Washington University researchers, led by Gautam Dantas, PhD, have killed the deadly staph infection in culture and in laboratory mice.
    Robert Boston

    2
    Scanning electron micrograph of a human neutrophil ingesting MRSA

    Three antibiotics that, individually, are not effective against a drug-resistant staph infection can kill the deadly pathogen when combined as a trio, according to new research.

    The researchers, at Washington University School of Medicine in St. Louis, have killed the bug — <a href="http://“>methicillin-resistant Staphylococcus aureus (MRSA) — in test tubes and laboratory mice, and believe the same three-drug strategy may work in people.

    “MRSA infections kill 11,000 people each year in the United States, and the pathogen is considered one of the world’s worst drug-resistant microbes,” said principal investigator Gautam Dantas, PhD, an associate professor of pathology and immunology. “Using the drug combination to treat people has the potential to begin quickly because all three antibiotics are approved by the FDA.”

    The study is published online Sept. 14 in the journal Nature Chemical Biology.

    The three drugs — meropenem, piperacillin and tazobactam — are from a class of antibiotics called beta-lactams that has not been effective against MRSA for decades.​​​​​​​​​​​​​​

    2
    Shown are clumps of MRSA bacteria magnified more than 2,300 times by an electron microscope.

    Working with collaborators in the microbiology laboratory at Barnes-Jewish Hospital​ in St. Louis, Dantas’ team tested and genetically analyzed 73 different variants of the MRSA microbe to represent a range of hospital-acquired and community-acquired forms of the pathogen. The researchers treated the various MRSA bugs with the three-drug combination and found that the treatments worked in every case.

    Then, in experiments conducted by collaborators at the University of Notre Dame, the team found that the drug combination cured MRSA-infected mice and was as effective against the pathogen as one of the strongest antibiotics on the market.

    “Without treatment, these MRSA-infected mice tend to live less than a day, but the three-drug combination cured the mice,” Dantas said. “After the treatment, the mice were thriving.”

    Dantas explained that the drugs, which attack the cell wall of bacteria, work in a synergistic manner, meaning they are more effective combined than each alone.

    The researchers also found that the drugs didn’t produce resistance in MRSA bacteria — an important finding since more and more bacteria are developing resistance to available drugs.

    “This three-drug combination appears to prevent MRSA from becoming resistant to it,” Dantas said. “We know all bacteria eventually develop resistance to antibiotics, but this trio buys us some time, potentially a significant amount of time.”

    Dantas’ team also is investigating other antibiotics thought to be ineffective against various bacterial pathogens to see if they, too, may work if used in combination with other drugs.

    “We started with MRSA because it’s such a difficult bug to treat,” he said. “But we are optimistic the same type of approach may work against other deadly pathogens, such as Pseudomonas and certain virulent forms of E. coli.”

    Funding for this research comes from the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of General Medical Sciences, and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH). Additional funding comes from an NIH Director’s New Innovator Award and a Ruth Kirschstein National Research Service Award from NIH.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Wash U campus

    Washington University’s mission is to discover and disseminate knowledge, and protect the freedom of inquiry through research, teaching, and learning.

    Washington University creates an environment to encourage and support an ethos of wide-ranging exploration. Washington University’s faculty and staff strive to enhance the lives and livelihoods of students, the people of the greater St. Louis community, the country, and the world.

     
  • richardmitnick 8:13 am on August 12, 2015 Permalink | Reply
    Tags: Anxiety, , , Wash U St. Louis   

    From Wash U: “Exploring the brain’s role in stress-induced anxiety​​​” 

    Wash U Bloc

    Washington University in St.Louis

    July 23, 2015
    Jim Dryden

    1
    Neurons in the mouse brain appear green as they produce a substance that makes them sensitive to light. The red marks the presence of norepinephrine, which surges under stress. Bruchas laboratory

    Calming a neural circuit in the brain can alleviate stress in mice, according to new research that could lay the foundation for understanding stress and anxiety in people.

    Using cutting-edge techniques, the researchers at Washington University School of Medicine in St. Louis also showed they could shine a light into the brain to activate the stress response in mice that had not been exposed to stressful situations.

    The study is published online July 23 in the journal Neuron.

    “We now have a much better idea of the neural circuit involved in producing anxiety following stress,” said first author Jordan G. McCall, PhD, a former graduate student in the laboratory of principal investigator Michael R. Bruchas, PhD, associate professor of anesthesiology and neurobiology. “You can imagine that this same response also may be important to longer-term stress-related problems such as post-traumatic stress disorder (PTSD) or anxiety disorder.”

    The work may lead to the development of new treatments for such disorders, as well as for depression and alcohol and drug abuse.

    Neuroscientists already knew that a small structure in the brain called the locus coeruleus (LC) plays a key role in stress and anxiety. Neurons in that region secrete the hormone norepinephrine, which surges when a person is under stress. But using techniques called optogenetics and chemogenetics, the researchers showed they could selectively control the firing of LC neurons, lower norepinephrine levels and prevent the anxiety that normally follows stressful events.

    In these techniques, researchers genetically engineer mice with brain cells that have special receptors. Those receptors can be activated by light (optogenetics) or synthetic chemicals (chemogenetics). Those light or chemical signals either trigger or block neuronal activity, giving researchers a way to control the brain circuits in an animal and, thus, the behavior.

    As part of the research, the scientists observed mice moving through mazes and roaming freely in an open box.

    “Mice usually move toward the wall and try to stay out of the open area, just like a mouse in your house,” Bruchas explained. “Anxious mice rarely venture into the center of the box, whereas mice that feel less anxious roam into the middle more often.”

    Mice that experienced stressful events were more likely to stay near the edges of the box. But when mice were treated with stress-lowering drugs — either beta blockers or alpha 1 blockers, which are used to treat high blood pressure and stress in people — the animals were more likely to venture into the middle of the box, even if they had experienced stressful events.

    The researchers also found that activating LC neurons with light made mice in the mazes behave as if they were stressed, even when they had not been exposed to a stressful event.

    “With this study, we now understand how a bunch of puzzle pieces fit together in a network that we’ve demonstrated is critical to stress-induced anxiety,” Bruchas said.

    Funding for this research comes from the National Institute on Drug Abuse (NIDA) and the National Institute of Mental Health (NIMH) of the National Institutes of Health (NIH), grant numbers R21 DA035144, R01 DA035821, F31 MH101956 and K99 DA038725; the McDonnell Center for Systems Neuroscience; and the Washington University Division of Biology and Biological Sciences.

    McCall JG, Al-Hasani R, Suida ER, Hong DY, Norris AJ, Ford CP, Bruchas MR. CRH engagement of the locus coeruleus noradrenergic system mediates stress-induced anxiety. Neuron, published online July 23, 2015.

    Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

    See the full article here.

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Wash U campus

    Washington University’s mission is to discover and disseminate knowledge, and protect the freedom of inquiry through research, teaching, and learning.

    Washington University creates an environment to encourage and support an ethos of wide-ranging exploration. Washington University’s faculty and staff strive to enhance the lives and livelihoods of students, the people of the greater St. Louis community, the country, and the world.

     
  • richardmitnick 12:57 pm on May 6, 2015 Permalink | Reply
    Tags: , , Wash U St. Louis   

    From Wash U: “Scientists find new link between diabetes and Alzheimer’s” 

    Wash U Bloc

    Washington University in St.Louis

    May 4, 2015
    Michael C. Purdy

    1
    Shannon Macauley, PhD, and David Holtzman, MD, neurology researchers at Washington University School of Medicine in St. Louis, have found a new link between Alzheimer’s disease and diabetes. Their research, in mice, suggests elevated blood sugar can harm brain function.

    Researchers have uncovered a unique connection between diabetes and Alzheimer’s disease, providing further evidence that a disease that robs people of their memories may be affected by elevated blood sugar, according to scientists at Washington University School of Medicine in St. Louis.

    While many earlier studies have pointed to diabetes as a possible contributor to Alzheimer’s, the new study – in mice – shows that elevated glucose in the blood can rapidly increase levels of amyloid beta, a key component of brain plaques in Alzheimer’s patients. The buildup of plaques is thought to be an early driver of the complex set of changes that Alzheimer’s causes in the brain.

    The research is published May 4 in The Journal of Clinical Investigation.

    “Our results suggest that diabetes, or other conditions that make it hard to control blood sugar levels, can have harmful effects on brain function and exacerbate neurological conditions such as Alzheimer’s disease,” said lead author Shannon Macauley, PhD, a postdoctoral research scholar. “The link we’ve discovered could lead us to future treatment targets that reduce these effects.”

    People with diabetes can’t control the levels of glucose in their blood, which can spike after meals. Instead, many patients rely on insulin or other medications to keep blood sugar levels in check.

    To understand how elevated blood sugar might affect Alzheimer’s disease risk, the researchers infused glucose into the bloodstreams of mice bred to develop an Alzheimer’s-like condition.

    In young mice without amyloid plaques in their brains, doubling glucose levels in the blood increased amyloid beta levels in the brain by 20 percent.

    When the scientists repeated the experiment in older mice that already had developed brain plaques, amyloid beta levels rose by 40 percent.

    Looking more closely, the researchers showed that spikes in blood glucose increased the activity of neurons in the brain, which promoted production of amyloid beta. One way the firing of such neurons is influenced is through openings called KATP channels on the surface of brain cells. In the brain, elevated glucose causes these channels to close, which excites the brain cells, making them more likely to fire.

    Normal firing is how a brain cell encodes and transmits information. But excessive firing in particular parts of the brain can increase amyloid beta production, which ultimately can lead to more amyloid plaques and foster the development of Alzheimer’s disease.

    To show that KATP channels are responsible for the changes in amyloid beta in the brain when blood sugar is elevated, the scientists gave the mice diazoxide, a glucose-elevating drug commonly used to treat low blood sugar. To bypass the blood-brain barrier, the drug was injected directly into the brain.

    The drug forced the KATP channels to stay open even as glucose levels rose. Production of amyloid beta remained constant, contrary to what the researchers typically observed during a spike in blood sugar, providing evidence that the KATP channels directly link glucose, neuronal activity and amyloid beta levels.

    Macauley and her colleagues in the laboratory of David M. Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology, are using diabetes drugs in mice with conditions similar to Alzheimer’s to further explore this connection.

    “Given that KATP channels are the way by which the pancreas secretes insulin in response to high blood sugar levels, it is interesting that we see a link between the activity of these channels in the brain and amyloid beta production,” Macauley said. “This observation opens up a new avenue of exploration for how Alzheimer’s disease develops in the brain as well as offers a new therapeutic target for the treatment of this devastating neurologic disorder.”

    The researchers also are investigating how changes caused by increased glucose levels affect the ability of brain regions to network with each other and complete cognitive tasks.
    ___________________________________________________________________________________________
    The research was supported by the National Institutes of Health (NIH); the National Science Foundation (NSF); and the JPB Foundation.

    Macauley SL, Stanley M, Caesar EE, Yamada SA, Raichle ME, Perez R, Mahan TE, Sutphen CL, Holtzman DM. Hyperglycemia modulates extracellular amyloid beta concentrations and neuronal activity in vivo. The Journal of Clinical Investigation, online May 4, 2015.

    See the full article here.

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Wash U campus

    Washington University’s mission is to discover and disseminate knowledge, and protect the freedom of inquiry through research, teaching, and learning.

    Washington University creates an environment to encourage and support an ethos of wide-ranging exploration. Washington University’s faculty and staff strive to enhance the lives and livelihoods of students, the people of the greater St. Louis community, the country, and the world.

     
  • richardmitnick 4:59 pm on January 22, 2015 Permalink | Reply
    Tags: , , Wash U St. Louis   

    From Wash U.: “Scientists find gene vital to central nervous system development” 

    Wash U Bloc

    Washington University in St.Louis

    January 21, 2015
    Julia Evangelou Strait

    2
    Using Washington University’s zebrafish facility, graduate student Sarah Ackerman (left) and senior author Kelly Monk, PhD, identified a gene that regulates how well the wiring of the central nervous system is insulated.

    Scientists have identified a gene that helps regulate how well nerves of the central nervous system are insulated, researchers at Washington University School of Medicine in St. Louis report.

    Healthy insulation is vital for the speedy propagation of nerve cell signals. The finding, in zebrafish and mice, may have implications for human diseases like multiple sclerosis, in which this insulation is lost.

    The study appears Jan. 21 in Nature Communications.

    Nerve cells send electrical signals along lengthy projections called axons. These signals travel much faster when the axon is wrapped in myelin, an insulating layer of fats and proteins. In the central nervous system, the cells responsible for insulating axons are called oligodendrocytes.

    The research focused on a gene called Gpr56, which manufactures a protein of the same name. Previous work indicated that this gene likely was involved in central nervous system development, but its specific roles were unclear.

    In the new study, the researchers found that when the protein Gpr56 is disabled, there are too few oligodendrocytes to provide insulation for all of the axons. Still, the axons looked normal. And in the relatively few axons that were insulated, the myelin also looked normal. But the researchers observed many axons that were simply bare, not wrapped in any myelin at all.

    Without Gpr56, the cells responsible for applying the insulation failed to reproduce themselves sufficiently, according to the study’s senior author, Kelly R. Monk, PhD, assistant professor of developmental biology. These cells actually matured too early instead of continuing to replicate as they should have. Consequently, in adulthood, there were not enough mature cells, leaving many axons without insulation.

    Monk and her team study zebrafish because they are excellent models of the vertebrate nervous system. Their embryos are transparent and mature outside the body, making them useful for observing developmental processes.

    “We first saw this defect in the developing zebrafish embryo,” said first author Sarah D. Ackerman, a graduate student in Monk’s lab. “But it’s not simply a temporary defect that only results in delayed myelination. When I looked at fish that were six months old, I still saw this problem of undermyelinated axons.”

    In a companion paper in the same issue of Nature Communications, senior author Xianhua Piao, MD, PhD, of Harvard University, and her co-authors, including Monk, showed similar defects in mice without Gpr56. In past work, Piao also has shown evidence that human defects in Gpr56 lead to brain malformations related to a lack of myelin.

    “These are nice studies that arrived at the same conclusion independently,” said Monk, who is also with the Hope Center for Neurological Disorders at Washington University. “Our Harvard colleagues used mouse models while we used fish models. And Dr. Piao’s research in human patients suggests that similar mechanisms are at work in people.”

    Monk also said that Gpr56 belongs to a large class of cell receptors that are common targets for many commercially available drugs, making the protein attractive for further research. The investigators pointed out its possible relevance in treating diseases associated with a lack of myelin, with particular interest in multiple sclerosis.

    “In the case of MS, there are areas where the central nervous system has lost its myelin,” Monk said. “At least part of the problem is that the precursor myelin-producing cells are recruited to that area, but they fail to become adult cells capable of producing nerve cell insulation. Now, we have evidence that Gpr56 modulates the switch from precursor to adult cell.”

    In theory, if the precursor cells can be pushed to mature into adulthood, they may become capable of producing myelin. According to Monk and Ackerman, possible future work includes using the zebrafish model system as a drug-screening tool to search for small molecules that may flip that switch.

    The work led by Washington University was supported by predoctoral fellowships from the National Institutes of Health (NIH), and from the Edward J. Mallinckrodt Foundation.

    Ackerman SD, Garcia C, Piao X, Gutmann DH, Monk KR. The adhesion-GPCR Gpr56 regulates oligodendrocyte development via interactions with G-alpha12/13 and RhoA. Nature Communications. January 21, 2015.

    The work led by Harvard University was supported by grants from the NIH, and by the William Randolph Hearst Fund, the Leonard and Isabelle Goldenson Research Fellowship and the Cerebral Palsy International Research Foundation.

    Giera S, Deng Y, Luo R, Ackerman SD, Mogha A, Monk KR, Ying Y, Jeong SJ, Makinodan M, Bialis A, Chang B, Stevens B, Corfas G, Piao X. The adhesion G protein-coupled receptor GPR56 is a cell autonomous regulator of oligodendrocyte development. Nature Communications. January 21, 2015.

    See the full article here.

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Wash U campus

    Washington University’s mission is to discover and disseminate knowledge, and protect the freedom of inquiry through research, teaching, and learning.

    Washington University creates an environment to encourage and support an ethos of wide-ranging exploration. Washington University’s faculty and staff strive to enhance the lives and livelihoods of students, the people of the greater St. Louis community, the country, and the world.

     
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