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  • richardmitnick 1:21 pm on January 30, 2017 Permalink | Reply
    Tags: , , , Wash U St. Louis   

    From Wash U: “Study unveils new way to starve tumors to death” 

    Wash U Bloc

    Washington University in St.Louis

    January 24, 2017
    Julia Evangelou Strait

    1
    Unlike a healthy cell, a sarcoma cell (above) relies on environmental sources of arginine, an important protein building block. Remove environmental arginine and the cell must begin a process called autophagy, or “self-eating,” to survive. A second hit to its survival pathways then kills the cell, according to a new study at Washington University School of Medicine in St. Louis. Areas of autophagy are shown in green and the cell nucleus in blue. (Image: Jeff Kremer)

    For decades, scientists have tried to halt cancer by blocking nutrients from reaching tumor cells, in essence starving tumor cells of the fuel needed to grow and proliferate. Such attempts often have disappointed because cancer cells are nimble, relying on numerous backup routes to continue growing.

    Now, scientists at Washington University School of Medicine in St. Louis have exploited a common weak point in cancer cell metabolism, forcing tumor cells to reveal the backup fuel supply routes they rely on when this weak point is compromised. Mapping these secondary routes, the researchers also identified drugs that block them. They now are planning a small clinical trial in cancer patients to evaluate this treatment strategy.

    The research is published Jan. 24 in Cell Reports [link is below].

    Studying human cancer cells and mice implanted with patients’ tumor samples, the researchers demonstrate that a double hit — knocking out the weak point and one of the tumor cells’ backup routes — shows promise against many hard-to-treat cancers. Though present in multiple cancer types, the weak point is particularly common in sarcomas — rare cancers of fat, muscle, bone, cartilage and connective tissues. Doctors treat sarcomas primarily with traditional surgery, radiation and chemotherapy, but such treatments often are not effective.

    “We have determined that this metabolic defect is present in 90 percent of sarcomas,” said senior author Brian A. Van Tine, MD, PhD, an associate professor of medicine. “Healthy cells don’t have this weakness. We have been trying to create a therapy that takes advantage of the metabolic defect because, in theory, it should target only the tumor. Basically, the defect allows us to force the tumor cells to starve.”

    To grow and proliferate, tumor cells must have basic building materials. The researchers’ strategy relies on the fact that the vast majority of sarcomas have lost the ability to manufacture their own arginine, a protein building block that cells need to make more of themselves. Lacking this ability, the cells must harvest arginine from the surrounding environment. The supply of arginine in the blood is abundant, and cancer cells have no trouble scavenging it. But remove this environmental supply of arginine and the cells have a problem.

    “When we use a drug to deplete arginine in the blood, the cancer cells panic because they’ve lost their fuel supply,” Van Tine said. “So they rewire themselves to try to survive. In this study, we used that rewiring to identify drugs that block the secondary routes.”

    Unlike most cancer therapies, depleting arginine in the blood does not affect healthy cells. Normal cells don’t rely on external sources of arginine because they don’t have the cancer’s metabolic defect. They continue to make their own arginine, so there is no induced starvation in normal cells even when there is no arginine in the blood. Van Tine said this strategy is based on the properties of a tumor — it shuts down tumor metabolism specifically and nothing else.

    Unable to make or obtain external arginine, the tumor cells’ fuel supply routes are forced inward. The cells must begin to metabolize their internal supply of arginine in a process called autophagy, or “self-eating.” In the case of sarcomas, this state slows or pauses cancer growth but does not kill the cell. During this period, tumor cells appear to be buying time to find yet another internal work-around.

    “Cancer doesn’t die when you halt its primary fuel supply,” Van Tine said. “Instead, it turns on all these salvage pathways. In this paper, we identified the salvage pathways. Then we showed that when you drug them, too, you kill cells. Our study showed that tumors actually shrink under these conditions. This is the first time tumors have been shown to shrink using just metabolism drugs and no other anti-cancer strategies.”

    The arginine-depleting drug is currently in clinical trials investigating its safety and effectiveness against liver, lung, pancreatic, breast and other cancers. But so far, it has been ineffective likely because it has activated the salvage pathways allowing cancer growth to continue. The researchers said the drug may yet become a vital metabolic therapy for cancer as long as it is used in combination with other drugs targeting the backup pathways.

    Van Tine and the study’s first author, Jeff C. Kremer, a PhD student in Van Tine’s lab, explained that when cancer cells with this metabolic defect are deprived of environmental arginine, they are forced to shift from a system that burns glucose to a system that burns a different fuel called glutamine. They showed that adding a glutamine inhibitor to the arginine-depleting drug is lethal to the cells. Eliminating arginine from the blood also rewires serine biology, another backup fuel, so adding serine inhibitors also causes cell death.

    This strategy could be applied beyond rare sarcoma tumors because the metabolic defect is often present in other cancers, including certain types of breast, colon, lung, brain and bone tumors, the researchers said. The new study includes data showing similar anti-tumor responses in cell lines from these cancer types. Van Tine also pointed out that all of the drugs used in the study are either already approved by the U.S. Food and Drug Administration for other conditions or in ongoing clinical trials investigating cancer drugs.

    Based on this study and related research, Van Tine and his colleagues at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine are planning a clinical trial of the arginine-depleting drug in patients with sarcomas.

    “We will start with a baseline trial testing the arginine-depleting drug against sarcomas with this defect, and then we can begin layering additional drugs on top of that therapy,” Van Tine said. “Unlike breast cancer, for example, sarcomas currently have no targeted therapies. If this strategy is effective, it could transform the treatment of 90 percent of sarcoma tumors.”
    This work was supported by grants from CJ’s Journey; The Sarcoma Foundation of America; a Sarcoma Alliance for Research and Collaboration Career Development Award; and Polaris Pharmaceuticals. Polaris Pharmaceuticals provided funding and the arginine-depleting drug, ADI-PEG20 (pegylated arginine deiminase).

    Kremer JC, Prudner BC, Lange SES, Bean GR, Schultze MB, Brashears CB, Radyk MD, Redlich N, Tzeng S, Kami K, Shelton L, Li A, Morgan Z, Bomalaski JS, Tsukamoto T, McConathy J, Michel LS, Held JM, Van Tine BA. Arginine deprivation inhibits the Warburg effect and upregulates glutamine anaplerosis and serine biosynthesis in ASS1-deficient cancers. Cell Reports. Jan. 24, 2017.

    See the full article here .

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    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 3:02 pm on January 25, 2017 Permalink | Reply
    Tags: , Leishmania, , Persistent infection keeps immune memory sharp leading to long-term protection, Wash U St. Louis   

    From Wash U: “Persistent infection keeps immune memory sharp, leading to long-term protection” 

    Wash U Bloc

    Washington University in St.Louis

    January 16, 2017
    Tamara Bhandari

    1
    For many infectious diseases, a single bout of the illness protects a person against contracting it again. In some cases, the infecting microbe persists in the body long after symptoms resolve, and can cause disease later in life. Now, researchers studying the tropical parasite Leishmania have found a clue to explain the link between long-term immunity and long-term infection: The parasite (shown in green) is constantly multiplying and being killed by immune cells (pink and blue), keeping the immune system alert and prepared for any new encounters with the parasite. (Image: M.A. Mandell and S.M. Beverley)

    Many infectious diseases are one and done; people get sick once and then they are protected from another bout of the same illness. For some of these infections – chickenpox, for example – a small number of microbes persist in the body long after the symptoms have gone away. Often, such microbes can reactivate when the person’s immunity has waned with age or illness, and cause disease again.

    Now, researchers at Washington University School of Medicine in St. Louis studying leishmaniasis, a tropical disease that kills tens of thousands of people every year, believe they have found an explanation for the seemingly paradoxical connection between long-term infection and long-term immunity. By constantly reminding the immune system what the parasite that causes leishmaniasis looks like, a persistent infection keeps the immune system on alert against new encounters, even while it carries the risk of causing disease later in life, the researchers found.

    Understanding how persistent infection leads to long-term immunity could help researchers design vaccines and treatments for persistent pathogens.

    The research is published the week of Jan. 16 in Proceedings of the National Academy of Sciences.

    “People had been thinking of the role of the immune system in persistent infection in terms of mowing down any pathogens that reactivate in order to protect the body from disease,” said Stephen Beverley, the Marvin A. Brennecke Professor of Molecular Microbiology and the study’s senior author. “What was often overlooked was that in the process of doing this, the immune system is constantly being stimulated, which potentially promotes protection against future illness.”

    In a persistent infection, a small population of microbes remains in the body long after the patient’s symptoms are gone. In addition to the parasite that causes leishmaniasis, many kinds of microbes can cause persistent infections, including bacteria responsible for tuberculosis and viruses that lead to herpes and chickenpox.

    “A lot of pathogens cause persistent infections, but the process was something of a black box,” said Michael Mandell, the first author on the study. Mandell, who conducted the research for the study as a graduate student, is now an assistant professor at the University of New Mexico. “Nobody really knew what was going on during persistent infection and why it was associated with immunity.”

    To find out, Mandell and Beverley studied Leishmania, a group of parasites that cause ulcers on the skin and can infect internal organs. An estimated 250 million people worldwide are infected with the parasite – found in tropical areas – and 12 million have active disease. The disease can be disfiguring or even fatal, but once a person is infected, he or she is protected from getting sick a second time. In other words, infection confers long-term immunity.

    People are thought to continue to harbor the parasite at low numbers for years after they recover from the disease, including some people treated with anti-leishmania drugs. This persistence may be to the benefit of their human hosts; studies in mice have shown that completely clearing the parasite often makes the animals susceptible to another bout of disease if they encounter the parasite again.

    Studying mice, the researchers used fluorescent markers to distinguish different types of mouse cells, and found that most of the parasites live in immune cells capable of killing the parasites. Yet, despite their dangerous homes, the parasites appeared normal in shape and size.

    Further, most of the parasites continued to multiply, yet the total number of parasites stayed the same over time.

    “Mike Mandell called it the ‘Jimmy Hoffa effect’ because we couldn’t locate the body,” Beverley said. “We were unable to show directly that the parasites were being killed. But some of them must have been dying because the numbers weren’t going up.”

    The immune cells that housed the parasites are responsible for killing pathogens and activating a more robust immune response. It is this process – the ongoing multiplication and killing of parasites – that the researchers believe underlies the long-term immunity associated with persistent infection, and thus explains why people typically can’t get sick with the same pathogen twice.

    “It seems that our immunologic memory needs reminding sometimes,” Mandell said. “As the persistent parasites replicate and get killed, they are continually stimulating the immune system, keeping it primed and ready for any new encounters with the parasite.”

    These findings suggest that there are benefits as well as dangers to persistent infection, and, for some organisms at least, developing a vaccine that elicits life-long immunity might require a live vaccine that has the ability to persist without sickening people.

    “Usually scientists design vaccines to get sterilizing immunity. They’re trying to just kill all the bugs,” Beverley said. “But what you really need is protection against the pathologic consequences of the disease, not necessarily sterilizing immunity. For some of these organisms, solid, long-term protection may come at the price of persistent infection.”

    See the full article here .

    Please help promote STEM in your local schools.

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    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 12:17 pm on January 19, 2017 Permalink | Reply
    Tags: , , , TREM2, Wash U St. Louis   

    From Wash U: “Study details molecular roots of Alzheimer’s” 

    Wash U Bloc

    Washington University in St.Louis

    December 20, 2016 [Don’t know where this was hiding.]
    Julia Evangelou Strait
    straitj@wustl.edu

    1

    A new study at Washington University School of Medicine in St. Louis details the structure of TREM2, a protein involved in Alzheimer’s disease and other neurodegenerative disorders. Researchers found that mutations associated with Alzheimer’s alter the surface of the protein, while mutations linked to another brain disorder disrupt the protein’s interior. Such alterations may impair TREM2’s normal role in cleaning up cellular waste via a process called phagocytosis. (Image: Daniel L. Kober)

    Scientists at Washington University School of Medicine in St. Louis have detailed the structure of a molecule that has been implicated in Alzheimer’s disease. Knowing the shape of the molecule — and how that shape may be disrupted by certain genetic mutations — can help in understanding how Alzheimer’s and other neurodegenerative diseases develop and how to prevent and treat them.

    The study is published Dec. 20 in the journal eLife.

    The idea that the molecule TREM2 is involved in cognitive decline — the hallmark of neurodegenerative diseases, including Alzheimer’s — has gained considerable support in recent years. Past studies have demonstrated that certain mutations that alter the structure of TREM2 are associated with an increased risk of developing late-onset Alzheimer’s, frontal temporal dementia, Parkinson’s disease and sporadic amyotrophic lateral sclerosis (ALS). Other TREM2 mutations are linked to Nasu-Hakola disease, a rare inherited condition that causes progressive dementia and death in most patients by age 50.

    “We don’t know exactly what dysfunctional TREM2 does to contribute to neurodegeneration, but we know inflammation is the common thread in all these conditions,” said senior author Thomas J. Brett, PhD, an assistant professor of medicine. “Our study looked at these mutations in TREM2 and asked what they do to the structure of the protein itself, and how that might impact its function. If we can understand that, we can begin to look for ways to correct it.”

    The analysis of TREM2 structure, completed by first author, Daniel L. Kober, a doctoral student in Brett’s lab, revealed that the mutations associated with Alzheimer’s alter the surface of the protein, while those linked to Nasu-Hakola influence the “guts” of the protein. The difference in location could explain the severity of Nasu-Hakula, in which signs of dementia begin in young adulthood. The internal mutations totally disrupt the structure of TREM2, resulting in fewer TREM2 molecules. The surface mutations, in contrast, leave TREM2 intact but likely make it harder for the molecule to connect to proteins or send signals as normal TREM2 molecules would.

    TREM2 lies on the surface of immune cells called microglia, which are thought to be important “housekeeping” cells. Via a process called phagocytosis, such cells are responsible for engulfing and cleaning up cellular waste, including the amyloid beta that is known to accumulate in Alzheimer’s disease. If the microglia lack TREM2, or the TREM2 that is present doesn’t function properly, the cellular housekeepers can’t perform their cleanup tasks.

    “Exactly what TREM2 does is still an open question,” Brett said. “We know mice without TREM2 have defects in microglia, which are important in maintaining healthy brain biology. Now that we have these structures, we can study how TREM2 works, or doesn’t work, in these neurodegenerative diseases.”

    TREM2 also has been implicated in other inflammatory conditions, including chronic obstructive pulmonary disease and stroke, making the structure of TREM2 important for understanding chronic and degenerative diseases throughout the body, he added.

    This work was supported by the National Institutes of Health (NIH), grant numbers R01-HL119813, R01-AG044546, R01-AG051485, R01-HL120153, R01-HL121791, K01-AG046374, T32-GM007067, K08-HL121168, and P50-AG005681-30.1; the Burroughs-Wellcome Fund; the Alzheimer’s Association, grant number AARG-16-441560; and the American Heart Association, grant number PRE22110004. Results were derived from work performed at Argonne National Laboratory (ANL) Structural Biology Center. ANL is operated by U. Chicago Argonne, LLC, for the U.S. DOE, Office of Biological and Environmental Research, supported by grant number DE-AC02-06CH11357.

    Kober DL, Alexander-Brett JM, Karch CM, Cruchaga C, Colonna M, Holtzman MJ, Brett TJ. Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms. eLife. Dec. 20, 2016.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

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    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 7:52 am on July 7, 2016 Permalink | Reply
    Tags: "Light-Speed" Camera, , , Wash U St. Louis   

    From SA: “Light-Speed Camera Captures Split-Second Action” 

    Scientific American

    Scientific American

    July 5, 2016
    Larry Greenemeier

    The enhanced ultrafast camera is three billion times faster than the one on an iPhone, the researchers say

    1
    Washington University in Saint Louis researchers demonstrated their upgraded camera by pointing laser light onto a printout of a toy car to create a movie of the light reaching different portions of the car at different times. Credit: Courtesy of Liren Zhu, Jinyang Liang and Lihong V. Wang, Washington University in St. Louis

    A new approach to high-speed photography could help capture the clearest-ever footage of light pulses, explosions or neurons firing in the brain, according to a team of ultrafast camera developers. The technique involves shooting 100 billion frames per second in a single exposure without an external light source. That means, for example, there would be no need to set off multiple explosions just to gather enough data to create a video reconstructing exactly how chemicals react to create the blast.

    A team of Washington University in Saint Louis researchers introduced their “single-shot compressed ultrafast photography” camera two years ago. Last week they published a study in Optica describing improvements to their original camera that allow it to reconstruct images with finer spatial resolution, higher contrast and a cleaner background—qualities crucial to detailed observations of high-speed events. The camera is three billion times faster than one on a typical iPhone, says Lihong Wang, a professor of biomedical engineering at Washington University and a co-author of the study.

    The sharper images come from adding a second integrated circuit—a type of sensor called a charge-coupled device, or CCD—and an enhanced data reconstruction algorithm to the team’s original setup. The algorithm gathers data from both CCDs to deliver higher-quality images. The researchers demonstrated the upgrades by making a movie of a picosecond laser pulse traveling through the air. (One picosecond is equal to one trillionth of a second.)

    One area where such a camera could someday prove useful is in capturing information about how the brain’s neural networks operate—not just how they are connected—Wang says. He uses the following analogy: If the neural network is represented as city streets, current imaging technology enables scientists to see only the layout of those streets. New technologies are needed to see the traffic coursing through the streets and understand how the whole system functions. Wang hopes his work will ultimately be useful to the White House BRAIN Initiative, a project launched in 2013 that seeks to better understand brain function through the development and use of new technologies.

    Another advantage of the new ultrafast technique is that it does not need a laser or other external light source. “If you require external illumination then you have to sync it with the camera,” Wang says. “In some cases you don’t want to or can’t do this—you want to image the native emission of some object such as an explosion, for example.” When people study events like that now, they use a “pump-probe” method, which requires them to repeat the event many times and piece together the data into a single video. “Our camera can be used for real-time imaging of a single event, capturing it all in one shot at extremely high speeds,” Wang adds.

    The single-shot compressed ultrafast photography camera is useful for imaging brightly fluorescent objects but does not currently have the sensitivity needed to capture detailed images of neurons, says Keisuke Goda, a University of Tokyo physical chemistry professor and part of a group of researchers who in 2014 built a “sequentially timed all-optical mapping photography” camera that can snap pictures at 4.4 trillion frames per second. But unlike the device Wang and his colleagues developed, the Japanese camera requires a light flash—albeit one lasting just a femtosecond, or one-quadrillionth of a second—to illuminate its subject.

    Goda, who was not involved in the team’s research, says the Washington University camera also lacks the speed needed to take clear pictures of chemical reactions that take place on the order of femtoseconds. Wang counters that the speed is more than enough and that the sensitivity was theoretically estimated to be sufficient, although it has not been tested yet. “We are seeking funding to conduct [that] experiment,” Wang says.

    Given the amount of money the government is throwing at its BRAIN project—$85 million in fiscal 2015 alone—Wang and his team might not have to wait too long.

    3
    Using the improved version of their compressed ultrafast photography, or CUP, camera (right), the researchers captured a high quality movie showing laser light reaching different portions of a printout of a toy car at different times. The left image shows the image quality they achievable prior to the CUP upgrades. Courtesy of Liren Zhu, Jinyang Liang and Lihong V. Wang, Washington University in St. Louis

    See the full article here .

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    Scientific American, the oldest continuously published magazine in the U.S., has been bringing its readers unique insights about developments in science and technology for more than 160 years.

     
  • richardmitnick 5:49 pm on January 12, 2016 Permalink | Reply
    Tags: , , Atherosclerosis Alzheimer’s and Parkinson's diseases related, , Wash U St. Louis   

    From Wash U: “Atherosclerosis is Alzheimer’s disease of blood vessels, study suggests” 

    Wash U Bloc

    Washington University in St.Louis

    January 11, 2016
    Julia Evangelou Strait

    1
    A new study suggests that plaque forming in arteries has much in common with the progression of Alzheimer’s disease. The image shows a cross section of a mouse aorta, the main artery in the body, with a large plaque. Red lines near the top are the wall of the aorta. The plaque contains a dysfunctional buildup of immune cells called macrophages (pink) and protein waste (green). I. Sergin

    In atherosclerosis, plaque builds up on the inner walls of arteries that deliver blood to the body. Studying mice and tissue samples from the arteries of patients, researchers at Washington University School of Medicine​ in St. Louis suggest this accumulation is driven, at least in part, by processes similar to the plaque formation implicated in brain diseases such as Alzheimer’s and Parkinson’s.

    The study is published in the journal Science Signaling.

    A look behind the scenes in the process of plaque accumulating in arteries, the new study is the first to show that another buildup is taking place. Immune cells attempting to counteract plaque formation begin to accumulate misshapen proteins. This buildup of protein junk inside the cells interferes with their ability to do their jobs.

    Protein buildup is widely studied in the brain — accumulation of proteins such as amyloid beta and tau are hallmarks of Alzheimer’s, Parkinson’s and other degenerative neurological disorders. But until now, the process of misshapen protein buildup within cells has not been implicated in atherosclerosis.

    “In an attempt to fix the damage characteristic of atherosclerosis, immune cells called macrophages go into the lining of the arteries,” said senior author Babak Razani, MD, PhD, assistant professor of medicine. “The macrophage is like a firefighter going into a burning building. But in this case, the firefighter is overcome by the conditions. So another firefighter goes in to save the first and is likewise overcome. And another goes in, and the process continues to build on itself and worsen.”

    The researchers showed that this protein buildup inside macrophages results from problems with the waste-disposal functions of the cell. They identified a protein called p62 that is responsible for sequestering waste and delivering it to cellular incinerators called lysosomes. To mimic atherosclerosis, the researchers exposed the cells to types of fats known to lead to the condition. The researchers noted that during atherosclerosis, the macrophages’ incinerators become dysfunctional. And when cells stop being able to dispose of waste, p62 builds up. In a surprise finding, when p62 is missing and no longer gathers the waste in one place, atherosclerosis in mice becomes even worse.

    Razani and his colleagues, including the study’s first author, Ismail Sergin, PhD, a postdoctoral research fellow, also found these protein aggregates and high amounts of p62 in atherosclerotic plaque samples taken from patients, suggesting these processes are at work in people with plaque building up in the arteries.

    “That p62 sequesters waste in brain cells was known, and its buildup is a marker for a dysfunctional waste-disposal system,” Razani said. “But this is the first evidence that its function in macrophages is playing a role in atherosclerosis.”

    The study demonstrates that p62’s role in gathering up the misfolded proteins is protective against atherosclerosis, even if the cell can’t actually dispose of the waste it gathers.

    “If p62 is missing, the proteins don’t aggregate,” Razani said. “It’s tempting to think this might be good for the cell, but we showed this is actually worse. It causes more damage than if the waste were corralled into a large ‘trash bin.’ You can imagine a situation where lots of trash is being generated and see that it would be better to keep it all in one place, rather than have it strewn across the floor. You might have difficulty removing the trash to the dumpster, but at least it’s contained.”

    In atherosclerosis, and perhaps in the brain disorders characterized by protein accumulation, such evidence suggests it would be better to focus on ways to fix the cells’ waste-disposal system for getting rid of the large protein aggregates, rather than on ways to stop the aggregates from forming.

    This work was supported by the National Institutes of Health (NIH), grant numbers 5K08HL098559, 1R01HL125838 and 1R01AG037120; the Foundation for Barnes-Jewish Hospital; and the Washington University Diabetic Cardiovascular Disease Center.

    Sergin I, Bhattacharya S, Emanuel R, Esen E, Stokes CJ, Evans TD, Arif B, Curci JA, Razani B. Inclusion bodies enriched for p62 and polyubiquitinated proteins in macrophages protect against atherosclerosis. Science Signaling. Jan. 5, 2016.

    See the full article here .

    Please help promote STEM in your local schools.

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    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 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

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    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 .

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    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.

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    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.

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    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

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    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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