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  • LJI scientists harness ‘helper’ T cells to treat tumors

    LJI scientists harness ‘helper’ T cells to treat tumors

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    Newswise — LA JOLLA, CA—Scientists are on the hunt for a unique set of mutations, called “neoantigens,” that let the immune system distinguish tumor cells from normal cells. Their goal is to help the immune system react to neoantigens and target tumor cells for destruction.

    This area of research has led to life-saving antibody therapeutics, such as immune checkpoint inhibitors, which rely on antibodies to help immune cells kill tumors. Unfortunately, antibody-based cancer immunotherapies don’t work for all patients.

    At La Jolla Institute for Immunology (LJI), Professor Stephen Schoenberger, Ph.D., and his colleagues are looking beyond antibodies. Schoenberger’s lab leads pioneering research into how the immune system’s CD4+ “helper” T cells detect neoantigens.

    Now Schoenberger and his colleagues have published a pair of studies that show how we might harness CD4+ T cells while boosting the cancer-fighting power of CD8+ “killer” T cells. In fact, the researchers demonstrate a new kind of vaccine design that recruits both types of T cells to destroy large tumors.

    “Therapeutic cancer vaccines can work,” says Schoenberger, who serves as a member of the LJI Center for Cancer Immunotherapy. “But they should leverage the natural synergy of CD4+ and CD8+ T cells.”

    Researchers help CD4+ T cells detect tumors

    As Schoenberger points out, CD4+ and CD8+ T cells already work together when fighting viruses and bacteria. “Why not learn from the immune system’s natural way of keeping us protected and turn that against cancer?” he says.

    In a paper published recently in Nature Immunology, Schoenberger worked closely with LJI Professor Bjoern Peters, Ph.D,. to demonstrate the essential role of CD4+ T cells in recognizing tumor cells. Their strategy depends on an innovative way to predict which tumor neoantigens will spark a strong CD4+ T cell response. 

    As Schoenberger explains, tumor cells arise from normal cells in the body. This means the body has a harder time recognizing tumor cells as dangerous. Other threats, such as viruses, tend to carry around very un-human looking peptide sequences. “With prompting from CD4+ T cells, immune cells called dendritic cells can capture these peptide sequences and show them to CD8+ T cells—sending the immune system into red alert. “CD8+ T cells execute the tumor,” says Schoenberger, “but they require the cooperation of CD4+ T cells to do so efficiently.”

    But tumor cells share most of their peptide sequences with normal cells, and are therefore harder for the immune system to “see.” To get around this problem, Schoenberger and Peters have devised computational tools to identify the genetic mutations and specific peptides that serve as neoantigens to distinguish tumor cells from their neighbors.

    The Nature Immunology study shows that CD4+ T cells that recognize a single target mutation can  drive a diverse CD8+ T cell response that eradicates large established tumors . The researchers tested T cells recognizing this target mutation for “avidity,” which is how strongly their antigen receptors bind to the neoantigen. Their surprising results showed that neoantigen-specific CD4+ T cells can mediate their effect across a range of affinities.

    “This is brand new because no one has ever studied the neoantigen-specific CD4+ repertoire at the level of T cell receptors,” says Schoenberger.

    The researchers also found that the most effective responses happened when the transferred CD4+ T cells were induced to develop into stem cell memory-like CD4+ T cells. This type of T cell are endowed with special properties of longevity and the ability to generate powerful effector cells. As Schoenberger’s research spans the lab to the clinic, these findings will be translated to clinical trials in the near future.

    New vaccine brings T cells together

    In a second study, published recently in the Journal of Clinical Investigation, Schoenberger and his colleagues showed how a new vaccine strategy can induce CD4+ T cells and CD8+ T cells to work together to destroy large, aggressive tumors in a mouse model.

    For the study, Schoenberger collaborated with Joseph Dolina, Ph.D., a senior scientist at Pfizer Inc., and former member of the Schoenberger Lab (Pfizer has no financial disclosures to this specific study).

    The team began with an aggressive squamous cell tumor that contained a low number of mutations, as many human cancers do. The researchers identified 270 mutations that make this tumor stand out from normal cells, and they performed in-depth studies on 39 of these mutations. They narrowed that group down to five mutations that were recognized by the natural anti-tumor T cell response—with some mutations targeted by CD4+ T cells and others by CD8+ T cells. Remarkably, only mutations targeted by both CD4+ and CD8+ T cells were capable of triggering protective or therapeutic responses against the tumor.

    “These neoantigens had to be physically linked to mediate therapy,” says Schoenberger. “We could make large tumors go away so long as the vaccine activated both CD4+ and CD8+ T cells via the same antigen-presenting cell.”

    Going forward, Schoenberger plans to work with his clinical colleagues at the UC San Diego Moores Cancer Center to study whether this type of linked vaccine is effective in human patients. He hopes a future clinical trial can give hope to patients with especially aggressive tumors.

    “The other message here is that we think we can greatly increase the number of patients who could benefit from checkpoint blockade immunotherapy if we combine it with a personalized cancer vaccine,” says Schoenberger.

    Additional authors of the Nature Immunology study, “Neoantigen-specific stem cell memory-like CD4+ T cells mediate CD8+ T cell-dependent immunotherapy of MHC class II-negative solid tumors,” include Spencer E. Brightman (first author), Angelica Becker, Rukman R. Thota, Martin S. Naradikian, Leila Chihab, Karla Soria Zavala, Ryan Q. Griswold, Joseph S. Dolina, Ezra E. W. Cohen and Aaron M. Miller.

    This study was supported by the National Institutes of Health (grant UO1 DE028227), the San Diego Center for Precision Immunotherapy, and the Sandor and Rebecca Shapery Family.

    Nature Immunology DOI: https://doi.org/10.1038/s41590-023-01543-9

    Additional authors of the Journal of Clinical Investigation study, “Linked CD4+/CD8+ T cell neoantigen vaccination overcomes immune checkpoint blockade resistance and enables tumor regression,” include Joey Lee, Spencer E. Brightman, Sara McArdle, Samantha M. Hall, Rukman R. Thota, Karla S. Zavala, Manasa Lanka, Ashmitaa Logandha Ramamoorthy Premlal, Jason A. Greenbaum, Ezra E.W. Cohen and Bjoern Peters.

    This study was supported by the National Institutes of Health (grants U01 DE028227, P30CA23100, S10 RR027366 and S10 OD016262), the San Diego Center for Precision Immunotherapy, and the Sandor and Rebecca Shapery Family.

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    La Jolla Institute for Immunology

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  • Short-Term Use of Immunosuppressants Not Linked to Cancer Risk

    Short-Term Use of Immunosuppressants Not Linked to Cancer Risk

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    Newswise — Relatively short-term use of immunosuppressant medications to control an inflammatory disease was not associated with an increased risk of later developing cancer, according to new research led by scientists at the University of Pittsburgh and Mass Eye and Ear, a member of the Mass General Brigham health care system, and published today in the journal BMJ Oncology.

    The findings should provide reassurance to patients and clinicians who may hesitate to prescribe the medications because they are known to increase the risk of cancer in people who take them over many years or a lifetime to prevent dire consequences, such as organ rejection in transplant recipients.

    “When we got these results, I was reassured, and I hope patients will be, too,” said lead author Jeanine Buchanich, Ph.D., associate dean for research and associate professor of biostatistics at Pitt’s School of Public Health. “Immunosuppressants are widely used and transformative for care of patients with inflammatory diseases, but the potential concern that they carry a cancer risk has forced people to make difficult decisions without enough information. Alleviating that concern with use for inflammatory diseases will help people make the treatment decision that’s right for them.”

    The  new findings were from the Systemic Immunosuppressive Therapy for Eye Diseases (SITE) Cohort, which began two decades ago when principal investigator John Kempen, M.D., Ph.D., senior scientist and director of epidemiology for ophthalmology at Mass Eye and Ear and professor of ophthalmology at Harvard Medical School, approached Buchanich, who directs Pitt Public Health’s Center for Occupational Biostatistics and Epidemiology, to partner in evaluating cancer risk for people with non-infectious ocular inflammatory diseases taking immunosuppressants. These eye diseases are caused by immune dysfunction and do not themselves cause cancer but can be very serious, with blindness as a possible outcome.

    The diseases are commonly treated with immunosuppressive medications, which patients generally take for several months to several years.

    This new research adds evidence to the limited cancer risk associated with immunosuppressant treatments uncovered by the SITE study consortium. In a study published last month in Ophthalmology, the researchers found no increased risk in cancer-related and overall mortality in individuals taking commonly used immunosuppressants. The study included 15,938 SITE participants who were tracked for an average of 10 years.

    The BMJ Oncology study included 10,872 participants, ultimately encompassing 84% of the enrolled SITE participants who lived in one of the 12 states from which the research team obtained data linking participants to each state’s cancer registries. Though most states track cancer incidence, there is no centralized federal cancer registry, and different states require different permissions and use different interfaces to share data. For this reason, it is difficult to do large-scale epidemiological cancer studies in the U.S., making this study incorporating years of data from multiple states a rarity.

    The research team tracked each participant for an average of 10 years after they took immunosuppressant medications, or for a similar amount of time for those not taking immunosuppression, to see if they ever developed cancer. Four different categories of immunosuppressants – TNF-inhibitors, antimetabolites, alkylating agents and calcineurin inhibitors – were covered by the study, with some patients taking more than one type. Patients were on the medications for a median of one year.

    Across all four classes of immunosuppressant medications the scientists found no evidence of excess risk of cancer in patients who took them on a short-term basis, regardless of medication dose.

    While the study only looked at people with noninfectious eye diseases and the researchers caution that the results aren’t generalizable to everyone taking immunosuppressants, the results probably are generalizable to patients with inflammatory diseases, Kempen said.

    “The patients in our study actually tended to have a lower incidence of cancer than non-immunosuppressed patients, suggesting that an increased risk of overall cancer from commonly used immunosuppressants given for the short- to medium-term is very unlikely,” said Kempen. “This result is foundational for a large number of patients with inflammatory eye conditions and a broad range of patients with other inflammatory diseases.”

    Additional researchers on this study are Craig Newcomb, M.S., Nirali Bhatt, M.D., Tonetta Fitzgerald, Ebenezer Daniel, Ph.D., and Naira Khachatryan, M.D., Dr.P.H., all of the University of Pennsylvania (Penn); Terri Washington, of Pitt; C. Stephen Foster, M.D., of the Massachusetts Eye Research and Surgery Institution (MERSI) and Harvard Medical School; Lucia Sobrin, M.D., of Mass Eye and Ear and Harvard Medical School; Jennifer Thorne, M.D., Ph.D., Douglas Jabs, M.D., M.B.A., Kurt Dreger, Hosne Begum and Kathy Helzlsouer, M.D., all of Johns Hopkins University; Eric Suhler, M.D., M.P.H., James Rosenbaum, M.D., and Teresa Liesegang, all of the Oregon Health & Science University; H. Nida Sen, M.D., of George Washington University; Grace Levy-Clarke, M.D., of West Virginia University; the late Robert Nussenblatt, M.D., of the National Eye Institute; Careen Lowder, M.D., Ph.D., of the Cleveland Clinic; Debra Goldstein, M.D., of Northwestern University; Yannek Leiderman, M.D., Ph.D., of the University of Illinois, Chicago; Nisha Acharya, M.D., of the University of California San Francisco; Gary Holland, M.D., of the University of California Los Angeles; Russel Read, M.D., Ph.D., of the University of Alabama at Birmingham; James Dunn, M.D., of the Wills Eye Hospital; Pichaporn Artornsombudh, M.D., of Somdech Phra Pinkloa Hospital, Thailand; Srishti Kothari, of Penn and MERSI; Abhishek Payal, M.D., of Mahatme EyeBank Eye Hospital, India; Sapna Gangaputra, M.D., of Vanderbilt University Medical Center; R. Oktay Kacmaz, M.D., of Santen Pharmaceutical Co Ltd; Siddharth Pujari, M.D., of Siddharth Netralaya Superspecialty Eye Hospital, India; Armin Maghsoudlou, M.D., of Northwell Health; Hilkiah Suga, M.D., Myungsung Christian Medical Center (MCM), Ethiopia; and Clara Pak, of MCM and University of Rochester.

    This research was supported by National Institutes of Health (NIH) grants R01 EY14943 and R21 EY02617, NIH University of Pennsylvania Core Grant for Vision Research 2P30EYEY001583, the Massachusetts Eye and Ear Global Surgery Program, Sight for Souls and Research to Prevent Blindness.

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    About the University of Pittsburgh School of Public Health

    Founded in 1948, the University of Pittsburgh School of Public Health is a top-ranked institution of seven academic departments partnering with stakeholders locally and globally to create, implement and disseminate innovative public health research and practice. With hands-on and high-tech instruction, Pitt Public Health trains a diverse community of students to become public health leaders who counter persistent population health problems and inequities. 

    About Mass Eye and Ear

    Massachusetts Eye and Ear, founded in 1824, is an international center for treatment and research and a teaching hospital of Harvard Medical School. A member of Mass General Brigham, Mass Eye and Ear specializes in ophthalmology (eye care) and otolaryngology–head and neck surgery (ear, nose and throat care). Mass Eye and Ear clinicians provide care ranging from the routine to the very complex. Also home to the world’s largest community of hearing and vision researchers, Mass Eye and Ear scientists are driven by a mission to discover the basic biology underlying conditions affecting the eyes, ears, nose, throat, head and neck and to develop new treatments and cures. In the 2022–2023 “Best Hospitals Survey,” U.S. News & World Report ranked Mass Eye and Ear #4 in the nation for eye care and #4 for ear, nose and throat care. For more information about life-changing care and research at Mass Eye and Ear, visit our blog, Focus, and follow us on Instagram, Twitter and Facebook.

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    University of Pittsburgh

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  • Transcription Factors Contribute to Subtypes of Colorectal Cancers

    Transcription Factors Contribute to Subtypes of Colorectal Cancers

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    Newswise — New research in colorectal cancers directed by investigators at the Johns Hopkins Kimmel Cancer Center suggests that expression of transcription factors — proteins that help turn specific genes on or off by binding to nearby DNA — may play a central role in the degree of DNA methylation across the genome, contributing to the development of different subtypes of these cancers. Methylation is a process in which certain chemical groups attach to areas of DNA that guide genes’ on/off switches. Studying the expression of these transcription factors in patients with colorectal cancers could reveal biomarkers to help determine overall survival in people with a subgroup of colorectal cancers who generally have better survival rates and, importantly, respond better to immune checkpoint therapy — a type of immunotherapy that releases restraints that cancer cells place on the immune response — and other treatments. Similar patterns of transcription factor expression could be seen by the researchers even in precancerous polyps, and could potentially be used by physicians to determine which patients need closer follow-up to prevent cancer development.

    A description of the work was published online July 24 in the journal Proceedings of the National Academy of Sciences.

    Aberrant DNA methylation is a well-known phenomenon occurring in cancers, explains senior study author Hariharan Easwaran, Ph.D., M.Sc., an associate professor of oncology at the Johns Hopkins Kimmel Cancer Center, but the degree of DNA methylation varies in cancers of the same tissue type. Some colon and other cancers have a very high degree of DNA methylation gains while others have much lower frequency of DNA methylation gains, he says. Traditionally, these have been described in an area of the genome known as a promoter region, which helps launch the transcription process. The exact mechanisms underlying these changes have not been clear.

    In a series of laboratory studies of genetic material taken from tubular adenomas (precancerous polyps in the colon) and colon tumors, the researchers linked cancer-specific transcription factor expression alterations to methylation alterations in colorectal cancers and their premalignant precursor lesions, which provided insights into the origins and evolution of different molecular subtypes of colorectal cancers.

    Specifically, researchers observed that some regions of the genome undergoing increased methylation tend to have binding sites for transcription factors that are downregulated, or have low expression. In some types of colon cancer, based on the types of genetic alterations associated with the cancer, transcription factors are upregulated or have higher expression.

    The findings suggest that cancer-specific methylation differences potentially evolve due to perturbation in the activity or expression of transcription factors. Similar changes in DNA methylation patterns were observed in precancerous polyps.

    “These studies highlight that the transcription factor expression changes and corresponding DNA methylation changes are early events during tumor development,” says lead study author Yuba Bhandari, Ph.D., a research associate at the Johns Hopkins Kimmel Cancer Center. “As polyps do not carry all of the key genetic changes typically found in full-blown cancer cells, the transcription factor changes may represent the earliest molecular regulators of precancerous cells, with profound impact on the genome-wide DNA methylation changes.”

    The specific set of transcription factors identified in the study may help in stratifying colorectal cancer prognosis, Easwaran adds.

    “This is particularly important, because multiple studies have shown that a certain subtype of colorectal cancers responds best to immune checkpoint blockade therapies, while others may not fare as well,” he says. “Expression profiling of relevant transcription factors may help develop better therapeutic strategies across subtypes of colorectal cancers.”

    Additional study co-authors included Rachael Powers, Sehej Parmar, Sara-Jayne Thursby, Ekta Gupta, Ozlem Kulak, Kurtis Bachman and Stephen Baylin of Johns Hopkins. Additional investigators from Janssen Research and Development in Pennsylvania and in Belgium contributed.

    The work was supported by the National Institutes of Health grants R01CA230995 and R01CA229240; National Institute of Environmental Health Sciences grant R01ES011858; National Cancer Institute grant R21CA212495; Sam Waxman Research Foundation and National Institute on Aging grant U01AG066101; Janssen Initiative; Commonwealth Grant; and Grollman Glick Scholarship.

    Baylin consults for MDxHealth. Methylation-specific PCR is licensed to MDxHealth in agreement with The Johns Hopkins University. Baylin and JHU are entitled to royalty shares received from sales. These arrangements have been reviewed and approved by The Johns Hopkins University in accordance with its conflict-of-interest policies.

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    Johns Hopkins Medicine

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  • This sugar kills honeybees—it could also help fight cancer

    This sugar kills honeybees—it could also help fight cancer

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    Newswise — LA JOLLA, CALIF. – July 18, 2023 – Research from Sanford Burnham Prebys and the Osaka International Cancer Institute has shed new light on the anti-cancer properties of mannose, a sugar that is crucial to many physiological processes in humans and is also known to inhibit the growth of cancer cells. The findings, published in the journal eLife, suggest that mannose could be a helpful secondary treatment for cancer.

    “This sugar could give cancer an extra punch alongside other treatments,” says study co-author Hudson Freeze, Ph.D., director of the Human Genetics Program at Sanford Burnham Prebys. “And because mannose is found throughout the body naturally, it could improve cancer treatment without any undesirable side effects.”

    Mannose is a sugar that the body adds to proteins to stabilize their structure and help them interact with other molecules. This process, called glycosylation, is essential for life; and malfunctions in glycosylation are associated with rare, but often life-threatening, human diseases.

    “Until now, the most promising therapeutic use for mannose was to treat congenital disorders of glycosylation, diseases that can cause a wide range of severe symptoms throughout the body,” says Freeze. “But we believe that there may be ways to leverage mannose against cancer and other diseases as well.”

    Mannose has already been shown to inhibit the growth of several types of cancer in the lab, but scientists don’t fully understand why this happens. To learn more, the research team turned their attention to an unusual property of mannose observed in an unlikely subject: honeybees. 

    “It’s been known for more than a century that mannose is lethal to honeybees because they can’t process it like humans do—it’s known as ‘honeybee syndrome,’” says Freeze. “We wanted to see if there is any relationship between honeybee syndrome and the anti-cancer properties of mannose, which could lead to an entirely new approach to combat cancer.” 

    Using genetically engineered human cancer cells from fibrosarcoma—a rare cancer that affects connective tissue—the research team re-created honeybee syndrome and discovered that without the enzyme needed to metabolize mannose, cells replicate slowly and are significantly more vulnerable to chemotherapy. 

    “We found that triggering honeybee syndrome in these cancer cells made them unable to synthesize the building blocks of DNA and replicate normally,” says Freeze. “This helps explain the anti-cancer effects of mannose that have we’ve observed in the lab.” 

    While leveraging honeybee syndrome could be a promising supplemental cancer treatment, the researchers caution that because the effect is dependent on vital metabolic processes, more research is needed to determine which types of cancer would be most vulnerable to mannose.

    “If we can find cancers that have a low activity of the enzyme that processes mannose, treating them with mannose could give just enough of a nudge to make chemotherapy more effective,” says Freeze. “Many people assume that you always discover treatments in response to the disease, but sometimes you find biology that could be useful for treatment and then have to find the disease to match it.”

    In the meantime, the study speaks to the broader potential of glycosylating sugars for cancer treatment, which is still an emerging area of research. 

    “The glycobiology of sugar metabolism within cancer cells is still an unexplored frontier, and it could be an untapped treasure trove of potential treatments just waiting to be discovered,” adds Freeze. 

    ###

    Additional authors on the study include Yoichiro Harada, Yu Mizote, Toru Hiratsuka, Yusuke Imagawa, Kento Maeda, Yuki Ohkawa, Shigeki Higashiyama, Hideaki Tahara and Naoyuki Taniguchi, Osaka International Cancer Institute; Takehiro Suzuki and Naoshi Dohmae, RIKEN Center for Sustainable Resource Science; Akiyoshi Hirayama, Satsuki Ikeda and Junko Murai, Keio University; Mikako Nishida and Heiichiro Udono, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences; and Ayaka Ueda and Eiji Miyoshi, Osaka University. 

    The study was supported by the Takeda Science Foundation, JSPS KAKENHI (JP23K06645), the Rocket Fund, and the National Institutes of Health (R01DK99551).

    The study’s DOI is 10.7554/eLife.83870.

    About Sanford Burnham Prebys

    Sanford Burnham Prebys is an independent biomedical research institute dedicated to understanding human biology and disease and advancing scientific discoveries to profoundly impact human health. For more than 45 years, our research has produced breakthroughs in cancer, neuroscience, immunology and children’s diseases, and is anchored by our NCI-designated Cancer Center and advanced drug discovery capabilities. For more information, visit us at SBPdiscovery.org or on Facebook facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.

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  • Virginia Tech awarded grant to study lingering Lyme disease symptoms

    Virginia Tech awarded grant to study lingering Lyme disease symptoms

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    Newswise — An estimated 1,200 Americans, on average, are diagnosed with Lyme disease each day. Some of those patients continue to experience negative effects, even after treatment.

    Lyme disease researcher Brandon Jutras, associate professor in the College of Agriculture and Life Sciences and affiliated faculty of the Fralin Life Sciences Institute, recently received a $2.7 million grant from the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, to study what causes the disease to linger long after treatment.

    “Using a series of sophisticated molecular techniques, in combination with both bacterial and host genetics, we’re working to understand why and how some patients respond to therapy, while others do not,” said Jutras, the lead investigator in the Department of Biochemistry and an affiliate faculty member in the Center for Emerging, Zoonotic, and Arthropod-borne Pathogens. “Our two-pronged approach looks at this problem from both sides: What unique chemical features of the bacterium’s cell wall are responsible for causing symptoms and what genetic factors from the host-response side play a role in sustained pathology”.

    Previously, Jutras discovered that:

    This research builds upon the previous discoveries and will determine what about the cell wall makes patients sick and define new strategies, such as monoclonal antibody therapy, to improve Lyme disease patient health when previous treatments have failed.

    “We recognize this is an issue and that patients have these long-term symptoms, but we don’t know why,” said Mecaila McClune, who is a key member of the research team and a graduate student in the Jutras lab. “This is what my research is trying to determine what’s going on and how we can treat the persistent effects of the disease, which will improve quality of life going forward.”

    These new studies were facilitated by earlier support from the Global Lyme Alliance and Bay Area Lyme Foundation and continue an active collaboration with GlycoMIP, and both the University of Virginia and the Medical College of Wisconsin.

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    Virginia Tech

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  • Blood test aids in predicting lung cancer mortality risk

    Blood test aids in predicting lung cancer mortality risk

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    Newswise — HOUSTON ― A blood-based test developed by researchers at The University of Texas MD Anderson Cancer Center can predict an individual’s risk of dying from lung cancer when combined with a personalized risk model.

    According to new data published today in the Journal of Clinical Oncology, a blood-based four-protein panel (4MP), when combined with a lung cancer risk model (PLCOm2012), can better identify those at high risk of dying from lung cancer than the current U.S. Preventive Services Task Force (USPSTF) criteria.

    These findings build upon previous MD Anderson research demonstrating the combination test more accurately determined who is likely to benefit from lung cancer screening than the USPSTF criteria.

    “This simple blood test has the potential to save lives by determining the need for lung cancer screening on a personalized basis,” said co-corresponding author Samir Hanash, M.D., Ph.D., professor of Clinical Cancer Prevention. “Given the challenges associated with CT as a frontline screening method for lung cancer and the fact that most individuals diagnosed with the disease do not meet current guidelines, there is an urgent demand for an alternative approach.”

    For this study, MD Anderson researchers analyzed pre-diagnostic blood samples from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, including 552 individuals who later developed lung cancer and 2,193 who did not. Of the 552 individuals diagnosed during the six-year study period, 70% (387) died from lung cancer.

    Using hazard ratios, the researchers assessed the relationship between the risk scores generated by the combination model (4MP + PLCOm2012) and the incidence of lung cancer death. The combination showed improved sensitivity, specificity and positive predictive value compared to the 2013 and 2021 USPSTF criteria for predicting lung cancer-specific mortality among individuals who smoked at least 10 pack-years (PYs).

    The USPSTF recommends that adults at elevated risk for lung cancer receive a low-dose CT scan each year, which was shown to reduce lung cancer deaths in the 2011 National Lung Screening Trial (NLST). The 2021 USPSTF criteria applies to adults aged 50 to 80 who have at least a 20 PY smoking history and currently smoke or have quit within the past 15 years.

    “For individuals who currently are not eligible for lung cancer screening, a positive test may help to identify those possibly at risk for lung cancer death,” said co-corresponding author Edwin Ostrin, M.D., Ph.D., assistant professor of General Internal Medicine. “We envision this as a tool that could be deployed worldwide, as the future of early detection of this disease.”

    Lung cancer causes an estimated 25% of cancer deaths. Early detection improves prospects of survival, but most countries do not screen for it. Fewer than half of all U.S. cases are among people who are eligible under USPSTF guidelines.

    While the blood test could be implemented as a lab-developed test in the near future, Food and Drug Administration (FDA) approval likely would require evaluation through a prospective clinical trial.

    Hanash is an inventor on a patent application related to the blood test. A complete list of co-authors and their disclosures is included in the paper.

    This study was supported by the National Institutes of Health and National Cancer Institute (U01CA194733, U01CA213285, U01CA200468, U24CA086368), the Cancer Prevention & Research Institute of Texas, Lyda Hill Philanthropies, and the Lung Cancer Moon Shot®, part of MD Anderson’s Moon Shots Program®.

    Read the full release on the MD Anderson Newsroom. 

     

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    University of Texas MD Anderson Cancer Center

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  • Metformin reduces long COVID risk

    Metformin reduces long COVID risk

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    Newswise — MINNEAPOLIS/ST. PAUL (06/09/2023) — In a new study published in The Lancet Infectious Diseases, University of Minnesota researchers found that metformin, a drug commonly used to treat diabetes, prevents the development of long COVID. 

    The study, called COVID-OUT, investigated if early outpatient COVID-19 treatment with metformin, ivermectin or fluvoxamine could prevent long COVID. Long COVID is a chronic illness that can affect up to 10% of people who have had COVID-19. 

    “The results of this study are important because long COVID can have a significant impact on people’s lives,” said Carolyn Bramante, MD, principal investigator and an assistant professor at the U of M Medical School. “Metformin is an inexpensive, safe and widely available drug, and its use as a preventive measure could have significant public health implications.”

    This was a large, placebo-controlled randomized clinical trial which enrolled volunteers across the United States. The study found: 

    • Those who received metformin were more than 40% less likely to develop long COVID than those who received an identical looking placebo. 
    • For participants who started metformin less than four days after their COVID symptoms started, metformin decreased the risk of long COVID by 63%. 
    • The effect was consistent across different demographic populations of volunteers who participated and across multiple viral variants, including the Omicron variant. 
    • Ivermectin and fluvoxamine did not prevent long COVID.

    The study included more than 1,200 participants who were randomly chosen to receive either metformin or placebo, and an additional subset received ivermectin, fluvoxamine or their placebos. Participants were between 30 and 85 years old who qualified as overweight or obese. Over 1,100 of the participants reported on their symptoms for up to 10 months after their initial COVID-19 diagnosis. 

    “This long-term outcome from a randomized trial is high-quality evidence that metformin prevents harm from the SARS-CoV-2 virus,” said Dr. Bramante, who is also an internist and pediatrician with M Health Fairview. “While half of our trial had been vaccinated, none had been previously infected with the COVID-19 virus. Further research could show whether it is also effective in those with previous infection or in adults with lower body mass index.” 

    Metformin’s ability to stop the virus was predicted by a simulator developed by U of M Medical School and College of Science and Engineering Biomedical Engineering faculty. The model has been highly accurate to date, successfully predicting, among others, the failure of hydroxychloroquine and the success of remdesivir before the results of clinical trials testing these therapies were announced.

    Funding was provided by the Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants and the United Health Foundation.This research was also supported by the National Institutes of Health’s National Center for Advancing Translational Sciences under award number [UL1TR002494, KL2TR002492, and UM1TR004406]. 

    -30-

    The University of Minnesota Medical School, School of Public Health, College of Science and Engineering and M Health Fairview served as the lead site. The trial was also conducted at Northwestern University; University of Colorado, Denver; Olive View – UCLA Education & Research Institute in Los Angeles; Optum Health, and with scientific collaboration from partners at the University of North Carolina at Chapel Hill, Vanderbilt University, and Emory University School of Medicine. 

    The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health’s National Center for Advancing Translational Sciences.

    About the University of Minnesota Medical School
    The University of Minnesota Medical School is at the forefront of learning and discovery, transforming medical care and educating the next generation of physicians. Our graduates and faculty produce high-impact biomedical research and advance the practice of medicine. We acknowledge that the U of M Medical School, both the Twin Cities campus and Duluth campus, is located on traditional, ancestral and contemporary lands of the Dakota and the Ojibwe, and scores of other Indigenous people, and we affirm our commitment to tribal communities and their sovereignty as we seek to improve and strengthen our relations with tribal nations. For more information about the U of M Medical School, please visit med.umn.edu.

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    University of Minnesota Medical School

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  • UNC Researchers Receive NIH Grant to Study Drug-Resistant Malaria in Ethiopia

    UNC Researchers Receive NIH Grant to Study Drug-Resistant Malaria in Ethiopia

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    Newswise — CHAPEL HILL, NC – Ethiopia is Africa’s second most-populated country with an estimated 60% of its population at risk for malaria exposure. Plasmodium falciparum infection accounts for the majority of malaria deaths and approximately 70% of all cases. Artemisinin-based combination therapies (ACTs) have been critical to the success in reducing the global burden of falciparum malaria between 2000 and 2015. But the emergence and spread of artemisinin-resistant falciparum malaria has become a major threat to global elimination.

    “Ethiopia has made meaningful gains in the fight against malaria. However, the malaria parasite has a long history of evolving to survive, and it appears to be doing just that,” said Jonathan Parr, MD, MPH, assistant professor of medicine in infectious diseases at the UNC School of Medicine.

    The project “Epidemiology and Determinants of Emerging Artemisinin-Resistant Malaria in Ethiopia,” has been awarded 3.6 million in NIH R01 funding, building upon UNC-Chapel Hill’s strong partnership with the Ethiopian Public Health Institute (EPHI), the technical arm of the Ethiopia Federal Ministry of Health. The project also includes partners at Brown University, University of Notre Dame, and Imperial College London. Parr described the study as an exciting opportunity to use cutting-edge, multidisciplinary science in the fight against malaria.

    “We will be sequencing parasites from a network of sites across the country, conducting laboratory experiments, and performing predictive modeling to understand how dangerous new strains of malaria emerge and spread,” he said.

    Ashenafi Assefa, PhD, who trained as a UNC postdoctoral researcher in Dr. Parr’s group and has years of experience conducting translational malaria research, will lead study activities in Ethiopia, training personnel and running assays while overseeing protocol implementation and data collection. Assefa said the research outcomes will contribute to the advancement of scientific knowledge in the field.

    “This study is expected to generate critical evidence about the rise and expansion of drug-resistant parasites in the region,” said Assefa. “The results will be readily consumed by policymakers and advance malaria elimination efforts in Ethiopia and beyond.”

    Collaborating with EPHI, researchers will conduct surveys of people presenting to health facilities with falciparum malaria across Ethiopia to characterize resistant parasites. These results will be integrated into a point-of-care clinical tool for identifying individuals with drug-resistant falciparum malaria. The results will also guide the development of a model to predict the future spread of resistance mutations.

    Jon Juliano, MD, MSPH, heads the Infectious Disease Epidemiology and Ecology Lab at UNC, an interdisciplinary research collaboration that explores how pathogens interact with human hosts, with a focus on malaria.

    “We are entering a period of great concern about the effectiveness of antimalarial drugs in East Africa,” Juliano said. “The emergence of partial artemisinin resistance in multiple countries in the Rift Valley raises concerns about the long-term utility of these first line agents. This project represents a significant extension of studies to understand the emergence and spread of these mutations that the University of North Carolina is either leading or supporting in Rwanda, Uganda, Tanzania, the Democratic Republic of the Congo and now Ethiopia.”

    The UNC Institute for Global Health and Infectious Diseases (IGHID) at the UNC School of Medicine is an engine for global health research and pan-university collaboration, transforming health in North Carolina and around the world. IGHID facilitates research excellence while providing opportunities for investigators to nurture emerging scientists through training and service, to achieve positive patient care outcomes and practice.

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  • Sylvester study identifies ‘marked disparities’ in federal cancer research funding

    Sylvester study identifies ‘marked disparities’ in federal cancer research funding

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    Newswise — MIAMI, FLORIDA (EMBARGOED UNTIL JUNE 8, 2023) – A research team at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine compiled and analyzed statistics from federal cancer research funding sources and found that funds tend to be allocated more heavily toward cancers that occur more often in non-Hispanic white people than in other racial and ethnic groups.

    The study found that funding across cancer sites is not concordant with lethality and that cancers with high incidence among racial/ethnic minorities receive lower funding, but the study’s authors say addressing these inequities could make a difference in cancer research disparities within a short time.

    “The results of this study are immediately actionable,” said Dr. Shria Kumar, a Sylvester gastroenterologist and the senior author of a paper in the June 8 Journal of the National Cancer Institute. “Agencies can evaluate their own recent funding distributions and those for upcoming cycles, then they can prioritize funding for cancers that disproportionately impact minorities to mitigate disparities and reduce cancer burden.”

    The authors analyzed federal funding data to determine correlations between funding directed to cancer incidence and funding aimed at cancer mortality. They focused on National Cancer Institute funding for the 19 most common cancers, considering their respective “public health burdens,” a term that includes the incidence rate of the disease, the mortality rate, and person-years of life lost.

    Although previous studies of funding distribution have evaluated these three factors separately, the Sylvester team evaluated funding using a validated measure – funding-to-lethality (FTL) scores – that incorporates all three metrics and provides a composite, objective perspective on disease burden.

    “We were very surprised that correlation was stronger for incidence than mortality. It shows how complex and multifaceted funding allocation is, but it really underlines the need to look at it objectively, as we did here, and use it as a tool to mitigate cancer disparities, a common goal,” Kumar said.

    Breast and prostate cancer had the highest and second-highest FTL scores, while esophagus and stomach cancer ranked 18th and 19th. Kumar and colleagues noted that breast cancer research received approximately 50 times more funding than stomach cancer in 2018, even though estimated breast cancer deaths were only four times those of stomach cancer deaths.

    The authors also cited previously published statistics showing that cancers more frequently affecting non-Hispanic white people – such as breast cancer, leukemia and lymphoma – receive more funding than cancers with high incidence rates among racial and ethnic minorities – such as stomach, uterine and liver cancers.

    “In my research and in clinical practice, disparities in cancer are an unfortunate but well-known entity. I’m a gastroenterologist, and disparities are of paramount concern in my areas of expertise – stomach and colorectal cancer,” Kumar said. “Racial and ethnic disparities are well documented across the spectrum of cancer types, and this is of utmost importance. The White House’s Cancer Moonshot initiative has a focus on mitigating cancer disparities, and the NCI is very attuned to the impact that disparities have on our quest to improve cancer burden.”

    Specifics from the study:

    • There was a stronger correlation between FTL scores and race/ethnicity-specific cancer incidence, rather than mortality.
    • There was strong correlation between a cancer’s incidence among non-Hispanic white people and its FTL score, but this was not the case for other racial/ethnic groups, where there was only a weak to moderate correlation.
    • There was a moderate to strong correlation between a cancer’s mortality among non-Hispanic white people and its FTL score, but there was only a weak correlation for all other racial/ethnic groups.

    For the study, Kumar and her team obtained data from the NCI’s Surveillance, Epidemiology and End Results (SEER) database, the United States Cancer Statistics (USCS) database, and Funding Statistics between 2014 and 2018. For each year, they identified the incidence rate and mortality rate – both overall and by race/ethnicity – per 100,000 people for the 19 most common cancer sites, as well as NCI funding for each cancer.

    “Despite initiatives to bolster cancer research funding and to mitigate disparities in cancer outcomes, there are marked disparities in federally funded cancer research that do not correlate with lethality,” the authors said. “Our paper identifies discrepancies in funding by demographic groups and highlights the need to ensure that federal funds are equitably distributed. This is especially important given the discrepancies in cancer outcomes for minorities, particularly in the more underfunded cancers.”

    Additional authors: Dr. Shida Haghighat is the study’s first and corresponding author. Co-authors include Dr. Chunsu Jiang, Dr. Wael El-Rifai, Alexander Zaika, and Dr. David S. Goldberg. All authors are affiliated with the University of Miami Miller School of Medicine or Sylvester Comprehensive Cancer Center and the University of Miami Health System.

    Funding: Dr. Haghighat is supported by a National Institutes of Health training grant, T32 DK 116678-05.

    Disclosures: The authors declare no personal, professional or financial conflicts of interest.

    Journal: Journal of the National Cancer Institute: Urgent Need to Mitigate Disparities in Federal Funding for Cancer Research.

    DOI: https://doi.org/10.1093/jnci/djad097

    # # #

    PHOTO CAPTION/CREDIT:

    “Racial and ethnic disparities are well documented across the spectrum of cancer types, and this is of utmost importance,” said Dr. Shria Kumar. “The White House’s Cancer Moonshot initiative has a focus on mitigating cancer disparities, and the NCI is very attuned to the impact that disparities have on our quest to improve cancer burden.” Photo by Sylvester

    # # #

    MEDIA CONTACT:
    Sandy Van
    [email protected]
    808.206.4576

     

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  • Scientists Use Machine Learning to ‘See’ How the Brain Adapts to Different Environments

    Scientists Use Machine Learning to ‘See’ How the Brain Adapts to Different Environments

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    Newswise — Johns Hopkins scientists have developed a method involving artificial intelligence to visualize and track changes in the strength of synapses — the connection points through which nerve cells in the brain communicate — in live animals. The technique, described in Nature Methods, should lead, the scientists say, to a better understanding of how such connections in human brains change with learning, aging, injury and disease.

    “If you want to learn more about how an orchestra plays, you have to watch individual players over time, and this new method does that for synapses in the brains of living animals,” says Dwight Bergles, Ph.D., the Diana Sylvestre and Charles Homcy Professor in the Solomon H. Snyder Department of Neuroscience at the Johns Hopkins University (JHU) School of Medicine.

    Bergles co-authored the study with colleagues Adam Charles, Ph.D., M.E., and Jeremias Sulam, Ph.D., both assistant professors in the biomedical engineering department, and Richard Huganir, Ph.D., Bloomberg Distinguished Professor at JHU and Director of the Solomon H. Snyder Department of Neuroscience. All four researchers are members of Johns Hopkins’ Kavli Neuroscience Discovery Institute.

    Nerve cells transfer information from one cell to another by exchanging chemical messages at synapses (“junctions”). In the brain, the authors explain, different life experiences, such as exposure to new environments and learning skills, are thought to induce changes at synapses, strengthening or weakening these connections to allow learning and memory. Understanding how these minute changes occur across the trillions of synapses in our brains is a daunting challenge, but it is central to uncovering how the brain works when healthy and how it is altered by disease.

    To determine which synapses change during a particular life event, scientists have long sought better ways to visualize the shifting chemistry of synaptic messaging, necessitated by the high density of synapses in the brain and their small size — traits that make them extremely hard to visualize even with new state-of-the-art microscopes.

    “We needed to go from challenging, blurry, noisy imaging data to extract the signal portions we need to see,” Charles says.

    To do so, Bergles, Sulam, Charles, Huganir and their colleagues turned to machine learning, a computational framework that allows flexible development of automatic data processing tools. Machine learning has been successfully applied to many domains across biomedical imaging, and in this case, the scientists leveraged the approach to enhance the quality of images composed of thousands of synapses. Although it can be a powerful tool for automated detection, greatly surpassing human speeds, the system must first be “trained,” teaching the algorithm what high quality images of synapses should look like.

    In these experiments, the researchers worked with genetically altered mice in which glutamate receptors — the chemical sensors at synapses — glowed green (fluoresced) when exposed to light. Because each receptor emits the same amount of light, the amount of fluorescence generated by a synapse in these mice is an indication of the number of synapses, and therefore its strength.

    As expected, imaging in the intact brain produced low quality pictures in which individual clusters of glutamate receptors at synapses were difficult to see clearly, let alone to be individually detected and tracked over time. To convert these into higher quality images, the scientists trained a machine learning algorithm with images taken of brain slices (ex vivo) derived from the same type of genetically altered mice. Because these images weren’t from living animals, it was possible to produce much higher quality images using a different microscopy technique, as well as low quality images — similar to those taken in live animals — of the same views.

    This cross-modality data collection framework enabled the team to develop an enhancement algorithm that can produce higher resolution images from low quality ones, similar to the images collected from living mice. In this way, data collected from the intact brain can be significantly enhanced and able to detect and track individual synapses (in the thousands) during multiday experiments. 

    To follow changes in receptors over time in living mice, the researchers then used microscopy to take repeated images of the same synapses in mice over several weeks. After capturing baseline images, the team placed the animals in a chamber with new sights, smells and tactile stimulation for a single five-minute period. They then imaged the same area of the brain every other day to see if and how the new stimuli had affected the number of glutamate receptors at synapses.

    Although the focus of the work was on developing a set of methods to analyze synapse level changes in many different contexts, the researchers found that this simple change in environment caused a spectrum of alterations in fluorescence across synapses in the cerebral cortex, indicating connections where the strength increased and others where it decreased, with a bias toward strengthening in animals exposed to the novel environment.

    The studies were enabled through close collaboration among scientists with distinct expertise, ranging from molecular biology to artificial intelligence, who don’t normally work closely together. But such collaboration, is encouraged at the cross disciplinary Kavli Neuroscience Discovery Institute, Bergles says. The researchers are now using this machine learning approach to study synaptic changes in animal models of Alzheimer’s disease, and they believe the method could shed new light on synaptic changes that occur in other disease and injury contexts.

    “We are really excited to see how and where the rest of the scientific community will take this,” Sulam says.

    The experiments in this study were conducted by Yu Kang Xu (a Ph.D. student and Kavli Neuroscience Discovery Institute fellow at JHU), Austin Graves, Ph.D. (assistant research professor in biomedical engineering at JHU) and Gabrielle Coste (neuroscience Ph.D. student at JHU). This research was funded by the National Institutes of Health (RO1 RF1MH121539).

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  • Lung infection may be less transmissible than thought

    Lung infection may be less transmissible than thought

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    Newswise — A little-known bacterium — a distant cousin of the microbes that cause tuberculosis and leprosy — is emerging as a public health threat capable of causing severe lung infections among vulnerable populations, those with compromised immunity or reduced lung function.

    Recent research found that various strains of the bacterium, Mycobacterium abscessus, were genetically similar, stoking fears that it was spreading from person to person.

    But a new study by Harvard Medical School researchers published May 22 in PNAS, calls those findings into question, offering an alternative explanation behind the genetic similarity of clinical clusters. This suggests that the pathogen may not be that prone to person-to-person transmission after all.

    “Our findings make a strong case for a different explanation behind the observed genetic similarities across strains,” said study senior author Maha Farhat, the Gilbert S. Omenn Associate Professor of Biomedical Informatics at HMS and a pulmonary disease expert at Massachusetts General Hospital. Farhat conducted the work in collaboration with Eric Rubin’s lab at the Harvard T.H. Chan School of Public Health.

    The results, Farhat added, argue against direct person-to-person transmission in clinical settings and instead point to M. abscessus infections being acquired from the home or other environmental exposures.

    In addition to having implications for the precautions that hospitals take to prevent outbreaks, it’s an important new clue into the behavior of a relatively unknown pathogen that poses serious risks for vulnerable populations.

    The research not only contributes to the understanding of M. abscessus transmission, but also suggests scientists should be cautious about assuming human transmission when they see genetic similarities in pathogens more generally, said study first author Nicoletta Commins, who conducted the research as a doctoral candidate at HMS and is now a postdoctoral fellow at the Broad Institute.

    “Our results certainly do not refute the possibility of person-to-person transmission of Mycobacterium abscessus in some cases, and more research is needed to inform best clinical practice for vulnerable patients,” she said. “However, our work supports a model in which person-to-person transmission may not be as common as it is sometimes suggested to be.”

    M. abscessus is a hardy microbe highly resistant to antibiotics and can infect the lungs of immunocompromised people. While it doesn’t pose a threat to most healthy individuals, it can cause severe infection in those with suppressed immunity or people with compromised lung function such as patients with cystic fibrosis, a genetic condition marked by recurrent lung infections and lung scarring. Notably, patients with CF who become infected with this organism become ineligible for lifesaving lung transplants.

    The earlier study that sounded the alarm about person-to-person transmission was based on genetic sequencing of M. abscessus samples obtained from cystic fibrosis patients at clinics in the United States, Australia, and Europe, including the United Kingdom. Researchers found few genetic mutations across the samples — a possible sign that the pathogen was spreading directly between humans.

    For many pathogens such as TB, for example, recent person-to-person transmission leads to only a few or no mutations between any pair of samples simply because the pathogen does not have much time to acquire genetic mutations, Farhat explained.

    “Understandably, observing the genetic similarity between M. abscessus samples caused a great deal of anxiety and fear around how these organisms could be transmitting,” she said.

    Clinicians, especially in clinics that treat cystic fibrosis patients, began taking extra precautions to avert transmission. However, follow-up investigations failed to find supporting evidence that human-to-human transmission was happening, raising questions about other possible explanations for the genetic similarities across samples.

    Farhat’s team set out to investigate a hypothesis that the samples appeared genetically similar because the pathogen was evolving at a very slow rate.

    “We thought, yeah, you observed a small number of mutations, but we don’t know how quickly these mutations are acquired, she explained. “It may be slower than we think, and links between samples that appear recent may not be.’”

    The scientists first used a large dataset of M. abscessus genomes to create a “tree of life,” a kind of genetic family tree for the bacterium.

    They looked at branches of the tree with clusters of genetically similar strains, then tried to calculate their evolutionary rate. They found that these genetically similar clusters were evolving around 10 times more slowly than typical M. abscessus strains.

    Next, they used computer modeling to determine whether the genetic similarities could be explained by the relatively small population size of these bacteria. But even when they simulated extreme population sizes, the result didn’t change. This was an indicator that the high genetic similarity is best explained by a slower evolutionary rate.

    Finally, researchers conducted experiments to see how fast different strains of M. abscessus evolved to develop resistance when exposed to antibiotics in the lab. They found that the genetically similar strains evolved much more slowly than other strains.

    “These are three separate lines of evidence supporting this idea that these clustered isolates of Mycobacterium abscessus are evolving at a slower rate,” Farhat said.

    In addition to reducing concern about person-to-person transmission, the findings provide new insight into a poorly understood pathogen.

    In particular, the results offer clues about how a bug found primarily in the environment adapts and changes after it enters the human body — information that could help scientists eventually understand how to prevent and treat infections.

    Farhat is now planning follow-up studies that would compare bacteria in the environment with samples taken from patients, to better understand why certain patients become infected.

    Authorship, funding, disclosures

    Additional authors included Mark R. Sullivan, Kerry McGowen

    Evan Koch, and Eric Rubin. The work was partly supported by the Damon Runyon Cancer Research Foundation, DRG-2415-20, with additional support from the Orchestra High Performance Compute Cluster at Harvard Medical School, funded by the NIH NCRR 1S10RR028832-01.

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    Harvard Medical School

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  • UCLA-led research suggests no difference in health outcomes, care costs for patients treated by traditional MDs or osteopaths

    UCLA-led research suggests no difference in health outcomes, care costs for patients treated by traditional MDs or osteopaths

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    EMBARGOED FOR USE UNTIL 5 P.M. (EDT) ON MAY 29, 2023

    Newswise — New UCLA-led research suggests that patient mortality rates, readmissions, length of stay, and health care spending were virtually identical for elderly hospitalized patients who were treated by physicians with Doctor of Medicine (MD) or Doctor of Osteopathic Medicine (DO) degrees.

    While both traditional, or allopathic, medical schools and osteopathic medical schools provide the same rigorous health education, osteopathic training adds a more holistic, hands-on component involving manipulation of the musculoskeletal system – for instance, the use of stretching and massage to reduce pain or improve mobility.

    “These findings offer reassurance to patients by demonstrating that they can expect high-quality care regardless of whether their physicians received their training from allopathic or osteopathic medical schools,” said senior author Dr. Yusuke Tsugawa, associate professor of medicine in the division of general internal medicine and health services research at the David Geffen School of Medicine at UCLA and associate professor of health policy and management at the UCLA Fielding School of Public Health.

    The study will be published May 30 in the peer-reviewed Annals of Internal Medicine.

    Both types of physicians are licensed to practice medicine in every state. Currently about 90% of practicing physicians hold MD degrees and 10% have DO degrees. But the latter group is rapidly growing due to an increasing number of osteopathic medical schools, with their numbers having swelled by 72% between 2010 and 2020 compared with a 16% increase in MDs during the same period, and their ranks are expected to continue expanding.

    In addition, osteopathic physicians are more likely than their MD counterparts to serve patients in rural and underserved areas.

    The researchers relied on four data sources: a 20% sample of Medicare fee-for-service beneficiaries, amounting to about 329,500 people aged 65 years and older who were hospitalized between Jan. 1, 2016 and Dec. 31 2019; Medicare Data on Provider Practice and Specialty; a comprehensive physician database assembled by Doximity, and the American Hospital Association’s annual survey on hospital characteristics. Of the patients, 77% were treated by MDs and 23% were treated by DOs.

    The researchers found that patient mortality rates were 9.4% among MDs vs. 9.5% among DOs, patient readmission rates were 15.7% vs. 15.6% respectively, healthcare spending was $1004 vs. $1003, and lengths of stay were 4.5 days for both.

    The results are similar because both types of medical schools deliver rigorous, standardized medical education and comply with comparable accreditation standards, including four-year curriculums mixing science and clinical rotations, Tsugawa said.

    The study does have some limitations, the researchers write, primarily the fact that they focused on elderly Medicare beneficiaries who were hospitalized with medical conditions, so the results may not apply to other population groups. In addition, they limited outcomes to specific measures of care quality and resource use, so these findings may not generalize to other outcomes.

    But the findings “should be reassuring for policymakers, medical educators, and patients because they suggest that any differences between allopathic and osteopathic medical schools, either in terms of educational approach or students who enroll, are not associated with differences in quality or costs of care, at least in the inpatient setting,” the researchers write.

    Additional study authors are Dr. Atsushi Miyawaki of UCLA and the University of Tokyo; Dr. Anupam Jena of Harvard University, Massachusetts General Hospital and the National Bureau of Economic Research; and Dr. Nate Gross of Doximity.

    The study was funded by the National Institutes of Health’s National Institute on Aging (R01AG068633) and the Social Science Research Council.

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    University of California, Los Angeles (UCLA), Health Sciences

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  • Pan-cancer T cell atlas reveals new details of tumor microenvironment

    Pan-cancer T cell atlas reveals new details of tumor microenvironment

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    Newswise — HOUSTON ― A new study led by researchers at The University of Texas MD Anderson Cancer Center, published today in Nature Medicine, provides a deeper understanding of the vast diversity of T cell states as well as their relationships and roles within the complex tumor microenvironment, bringing a fresh perspective to understanding immunotherapy efficacy in cancer.

    Recent studies have shown that the phenotypic states of T cells, as well as their relative proportions, play a crucial role in determining the effectiveness of immunotherapy and the likelihood of potential adverse effects. This new pan-cancer single-cell T cell atlas integrates 27 single-cell RNA sequencing datasets, including nine unique datasets from MD Anderson, covering 16 cancer types. It is the most detailed picture to date of the heterogeneity of T cells present within the tumor microenvironment.

    “This kind of large dataset and comprehensive pan-cancer analysis provides the opportunity to see things that aren’t visible when studying a single type of cancer or even a handful of cancer types,” said corresponding author Linghua Wang, M.D., Ph.D. associate professor of Genomic Medicine. “We hope these high-resolution maps, including the thoroughly characterized T cell states, are valuable resources for facilitating future T cell studies and biomarker discovery.”

    One notable discovery from this study is the previously undescribed T cell stress response state, or TSTR. In prior single-cell studies, these T cells often were overlooked or considered to be artifacts related to tissue dissociation. However, with the extensive data available, the researchers were able to identify these cells as a clearly unique group, distinct from other CD4+ or CD8+ T cell subsets, and to validate their existence in situ using multiple spatial profiling methods.

    TSTR cells can be thought of as ‘stressed out’ T cells and, just like a stressed person might be less effective at their job, they seem to be less effective at fighting cancer. While both TSTR cells and exhausted T cells may be dysfunctional, TSTR cells appear to follow a unique differentiation path, distinct from the trajectory of exhausted T cells.

    TSTR cells are characterized by high heat shock gene expression and, importantly, are seen at significantly higher fractions in both CD4+ and CD8+ T cells following immune checkpoint blockade therapy, particularly in non-responders. This suggests TSTR cells may play a role in resistance to immunotherapy. This new T cell state adds an additional layer to our understanding of the intricate biology of cancer and provides a potential target for future therapies.

    “The fact that these TSTR cells are found in many different types of tumors opens up a whole new world of possibilities that could have high translational potential,” Wang said. “Investigating the mechanistic causes of stress response in T cells, understanding how these stressed T cells are induced in the tumor microenvironment, and learning how to stop or reverse this TSTR state could catalyze the development of more effective therapeutic strategies that may bring the benefit of immunotherapy to more cancer patients.”

    This work also underscores the value of large, integrative datasets in oncology. This pan-cancer T cell atlas exemplifies the power of big data to unravel the complex landscape of T cells within tumors. The researchers described a total of 32 T cell states in this study, and further identified seven subpopulations within the CD4+ regulatory subset, five within the CD4+ follicular helper T cell population, and eight states among proliferating T cells.

    These findings all highlight the extensive heterogeneity of T cell states within the tumor microenvironment and the need to further understand how these states contribute to disease progression and immunotherapy response.

    “There are still many questions left to answer,” Wang said. “One of the limitations of this study is we don’t have the corresponding T cell receptor data for most of the datasets analyzed. We are not sure what triggers the TSTR state, and we don’t know from which T cell subset(s) they originate. It also is unclear whether these TSTR cells are specific to tumor cells and how they communicate with and influence other cells within the tumor microenvironment.”

    The research team has shared their T cell atlas with the wider research community through the Single-Cell Research Portal, a user-friendly, interactive web portal. This portal, developed by the team, allows both internal and external users to visualize and query the atlas without the need for bioinformatics skills.

    The team has also developed a tool named TCellMap, which enables researchers to automatically annotate T cells from their datasets by aligning with the high-resolution T cell maps generated by this study. Wang expressed her hope that these resources will prove valuable to scientists aiming to perform an in-depth analysis of T cells, leading to further discoveries and ultimately enhancing strategies for T cell therapy.

    Dr. Yanshuo Chu, Ph.D., from the Wang laboratory led the data analysis. This research was supported by MD Anderson, the National Institutes of Health/National Cancer Institute (R01CA266280, U01CA264583, P50CA016672, T32CA217789), the Cancer Prevention and Research Institute of Texas (CPRIT) and the U.S. Department of Defense. A full list of collaborating authors and their disclosures can be found with the full paper here.

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    University of Texas MD Anderson Cancer Center

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  • Epigenetic landscape modulates pioneer transcription factor binding

    Epigenetic landscape modulates pioneer transcription factor binding

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    Newswise — Memphis, Tenn.—May 24, 2023) Like thread tightly wrapped around a spool, DNA is wrapped around histones and packaged into structures called nucleosomes. Scientists at St. Jude Children’s Research Hospital are exploring how a type of transcription factor called a pioneer transcription factor accesses DNA even when it is tightly wound. Their work revealed how the epigenetic landscape influences transcription factor binding. Problems with transcription have been implicated in numerous cancers, so this more detailed understanding of the process may aid in developing future therapeutics. The study was published today in Nature.  

    The nucleosome packaging of DNA can physically block transcription factors that regulate gene expression from accessing their binding sites. Restricting access to DNA is an integral part of how transcription is regulated. However, pioneer transcription factors can bind to their target piece of DNA even within compacted chromatin and are also known to promote the binding of other transcription factors. 

    Among pioneer transcription factors are the so-called Yamanaka factors which include Oct4 and are used to induce pluripotency (the ability to give rise to different cell types). How pioneer transcription factors access tightly wound DNA was unclear. To better understand the process, scientists at St. Jude used cryo-electron microscopy (cryo-EM) and biochemistry to investigate how Oct4 interacts with nucleosomes.  

    “Building on prior work to understand the dynamic behavior of nucleosomes, we wanted to understand how other factors might utilize those dynamic changes to access chromatin,” said corresponding author Mario Halic, Ph.D., St. Jude Department of Structural Biology. “Oct4 did not bind where we anticipated it might — rather than binding inside the nucleosome, we found that it bound a little bit outside.” 

    “One of the main findings is that epigenetic modifications can affect transcription factor binding and cooperativity,” Halic added. “The existing epigenetic state of chromatin can determine how transcription factors will cooperatively bind to chromatin.” 

    The epigenetic impact 

    Results show that the first Oct4 molecule binding “fixes” the nucleosome in a position that increases the exposure of other binding sites, thus promoting the binding of additional transcription factors and explaining transcription factor cooperativity. They also found that Oct4 contacts histones, and these interactions promote chromatin opening and influence cooperativity. Their work also showed that modifications at histone H3K27 affect the positioning of DNA by Oct4. These findings explain how the epigenetic landscape can regulate Oct4 activity to ensure proper cell programming.  

    Notably, the researchers used endogenous human DNA sequences instead of artificial sequences to assemble their nucleosomes. This allowed them to study the dynamic nature of the nucleosome, despite it being more challenging to work with.  

    “In this work, we used real genomic DNA sequences to study transcription factors in the context of where they function,” said first author Kalyan Sinha, Ph.D., St. Jude Department of Structural Biology. “This strategy allowed us to discover that the first binding event of Oct4 positions the nucleosomal DNA in a manner that allows cooperative binding of additional Oct4 molecules to internal sites. In addition, we observed exciting interactions with histone tails and have seen that histone modifications can alter those interactions. Together, these findings provide new insights into the pioneering activity of Oct4.” 

    “Histone modifications affect how DNA is positioned and how transcription factors can bind cooperatively,” Sinha added, “which means in cells, if you have the same DNA sequence, different epigenetic modifications can result in different, combinatorial effects on transcription factor binding.” 

    Authors and funding 

    The study’s other authors are Silvija Bilokapic, Yongming Du and Deepshikha Malik of St. Jude. 

    The study was supported by the National Institutes of Health (1R01GM135599-01 and 1R01GM141694-01) and ALSAC, the fundraising and awareness organization of St. Jude.  

     

      

    St. Jude Children’s Research Hospital 

    St. Jude Children’s Research Hospital is leading the way the world understands, treats and cures childhood cancer, sickle cell disease and other life-threatening disorders. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 60 years ago. St. Jude shares the breakthroughs it makes to help doctors and researchers at local hospitals and cancer centers around the world improve the quality of treatment and care for even more children. To learn more, visit stjude.org, read St. Jude Progress blog, and follow St. Jude on social media at @stjuderesearch. 

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  • Biomarkers may help ID treatment of acute kidney injury

    Biomarkers may help ID treatment of acute kidney injury

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    Newswise — Hospital inpatients who develop an acute kidney injury (AKI) generally fare poorly after being discharged, and have few options for effective treatment.  

    A UW Medicine-led study published recently in American Journal of Kidney Diseases suggests that new tests might improve this narrative.

    In the study, “about 30% of the patients that came into the hospital developed AKI, which means in a matter of hours or days, their kidneys might be failing because of reaction to drugs or contracting sepsis,” said lead author Dr. Pavan Bhatraju, an assistant professor of pulmonary and critical care medicine at the University of Washington School of Medicine.

    Causes of AKI vary. For instance, sepsis, medication and inadequate blood supply in someone who is undergoing cardiac bypass are all potential causes of kidney injury. It’s also the case that, within the kidneys, different cell types can be injured in the process of AKI, said Dr. Jonathan Himmelfarb, a professor of nephrology at the UW School of Medicine and the study’s senior author.

    “The way that we diagnose acute kidney injury today relies on a simple blood test of kidney function or a change in urine output,” Himmelfarb said. “These relatively crude diagnostic tools don’t detect the specific cause of injury or predict which individuals will be more likely to respond to a treatment or recover kidney function.”

    Unfortunately, effective medical therapies do not exist for this population of patients, Bhatraju said. In their paper, the investigators proposed a way to classify subpopulations of AKI patients with the aim of identifying therapies specific patient populations.  

    In much the same way that distinct biomarkers inform treatments of subgroups of patients with cancer or asthma, so, too, could blood- and urine-based biomarkers help identify subgroups of patients with AKI, leading to new ideas for treatments, the authors said.

    In the study, the researchers retrospectively analyzed 769 patients with AKI and 769 without the condition, and followed them for five years after hospital discharge. The researchers found two molecularly distinct AKI subgroups, or sub-phenotypes, that were associated with differing risk profiles and long-term outcomes.

    Patients in one group had higher rates of congestive heart failure, while another group had higher rates of chronic kidney disease and sepsis, Bhatraju said. The patients in the second group also had a 40% higher risk for major adverse kidney events five years later, compared with the first group, he said.

    Interestingly, Bhatraju added, age, sex, diabetes rate or major surgical procedure as the cause of AKI was not different across AKI subgroups. This finding suggests that commonly measured clinical factors may not predict the AKI subgroups, and that identification requires measurement of blood and urine biomarkers, he said.

    “We’re attempting to better understand the clinical factors and molecular drivers of acute kidney injury so that, in the long run, we can better treat the different ways that people experience this disease process,” Himmelfarb added. “We want to better understand the individual characteristics of people who get acute kidney injury so we can establish common characteristics of subgroup populations of these patients to know whose risk is relatively higher or lower, and work toward treatments specific to their needs.

    “Our paper is one step on the path to tailoring clinical trials of new therapies to the people who are most likely to respond to those therapies,” Himmelfarb said.  

    This study was supported by the supplemental American Recovery and Reinvestment Act funds through the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health (grants U01DK082223, U01DK082185, U01DK082192, U01DK082183, U01DK084012 and R01DK098233) and by the NIH (K23DK116967, R01DK133177, U2CDK114886, UG3TR002158, and U01DK099923).

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  • Artificial Intelligence Catalyzes Gene Activation Research and Uncovers Rare DNA Sequences

    Artificial Intelligence Catalyzes Gene Activation Research and Uncovers Rare DNA Sequences

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    BYLINE: Mario Aguilera

    Newswise — Artificial intelligence has exploded across our news feeds, with ChatGPT and related AI technologies becoming the focus of broad public scrutiny. Beyond popular chatbots, biologists are finding ways to leverage AI to probe the core functions of our genes.

    Previously, University of California San Diego researchers who investigate DNA sequences that switch genes on used artificial intelligence to identify an enigmatic puzzle piece tied to gene activation, a fundamental process involved in growth, development and disease. Using machine learning, a type of artificial intelligence, School of Biological Sciences Professor James T. Kadonaga and his colleagues discovered the downstream core promoter region (DPR), a “gateway” DNA activation code that’s involved in the operation of up to a third of our genes.

    Building from this discovery, Kadonaga and researchers Long Vo ngoc and Torrey E. Rhyne have now used machine learning to identify “synthetic extreme” DNA sequences with specifically designed functions in gene activation. Publishing in the journal Genes & Development, the researchers tested millions of different DNA sequences through machine learning (AI) by comparing the DPR gene activation element in humans versus fruit flies (Drosophila). By using AI, they were able to find rare, custom-tailored DPR sequences that are active in humans but not fruit flies and vice versa. More generally, this approach could now be used to identify synthetic DNA sequences with activities that could be useful in biotechnology and medicine.

    “In the future, this strategy could be used to identify synthetic extreme DNA sequences with practical and useful applications. Instead of comparing humans (condition X) versus fruit flies (condition Y) we could test the ability of drug A (condition X) but not drug B (condition Y) to activate a gene,” said Kadonaga, a distinguished professor in the Department of Molecular Biology. “This method could also be used to find custom-tailored DNA sequences that activate a gene in tissue 1 (condition X) but not in tissue 2 (condition Y). There are countless practical applications of this AI-based approach. The synthetic extreme DNA sequences might be very rare, perhaps one-in-a-million—if they exist they could be found by using AI.”

    Machine learning is a branch of AI in which computer systems continually improve and learn based on data and experience. In the new research, Kadonaga, Vo ngoc (a former UC San Diego postdoctoral researcher now at Velia Therapeutics) and Rhyne (a staff research associate) used a method known as support vector regression to “train” machine learning models with 200,000 established DNA sequences based on data from real-world laboratory experiments. These were the targets presented as examples for the machine learning system. They then “fed” 50 million test DNA sequences into the machine learning systems for humans and fruit flies and asked them to compare the sequences and identify unique sequences within the two enormous data sets.

    While the machine learning systems showed that human and fruit fly sequences largely overlapped, the researchers focused on the core question of whether the AI models could identify rare instances where gene activation is highly active in humans but not in fruit flies. The answer was a resounding “yes.” The machine learning models succeeded in identifying human-specific (and fruit fly-specific) DNA sequences. Importantly, the AI-predicted functions of the extreme sequences were verified in Kadonaga’s laboratory by using conventional (wet lab) testing methods.

    “Before embarking on this work, we didn’t know if the AI models were ‘intelligent’ enough to predict the activities of 50 million sequences, particularly outlier ‘extreme’ sequences with unusual activities. So, it’s very impressive and quite remarkable that the AI models could predict the activities of the rare one-in-a-million extreme sequences,” said Kadonaga, who added that it would be essentially impossible to conduct the comparable 100 million wet lab experiments that the machine learning technology analyzed since each wet lab experiment would take nearly three weeks to complete.

    The rare sequences identified by the machine learning system serve as a successful demonstration and set the stage for other uses of machine learning and other AI technologies in biology.

    “In everyday life, people are finding new applications for AI tools such as ChatGPT. Here, we’ve demonstrated the use of AI for the design of customized DNA elements in gene activation. This method should have practical applications in biotechnology and biomedical research,” said Kadonaga. “More broadly, biologists are probably at the very beginning of tapping into the power of AI technology.”

    Funding from the National Institutes of Health (R35 GM118060) supported the research.

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  • New algorithm can predict diabetic kidney disease

    New algorithm can predict diabetic kidney disease

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    Newswise — LA JOLLA, CALIF. – May 15, 2023 – Researchers from Sanford Burnham Prebys and the Chinese University of Hong Kong have developed a computational approach to predict whether a person with type 2 diabetes will develop kidney disease, a frequent and dangerous complication of diabetes. Their results, published in Nature Communications, could help doctors prevent or better manage kidney disease in people with type 2 diabetes.

    “This study provides a glimpse into the powerful future of predictive diagnostics,” says co-senior author Kevin Yip, Ph.D., a professor and director of Bioinformatics at Sanford Burnham Prebys. “Our team has demonstrated that by combining clinical data with cutting-edge technology, it’s possible to develop computational models to help clinicians optimize the treatment of type 2 diabetes to prevent kidney disease.”

    Diabetes is the leading cause of kidney failure worldwide. In the United States, 44% of cases of end-stage kidney disease and dialysis are due to diabetes. In Asia, this number is 50%.

    “There has been significant progress developing treatments for kidney disease in people with diabetes,” says co-senior author Ronald Ma, MB BChir, FRCP, a professor in the Department of Medicine and Therapeutics at the Chinese University of Hong Kong. “However, it can be difficult to assess an individual patient’s risk for developing kidney disease based on clinical factors alone, so determining who is at greatest risk of developing diabetic kidney disease is an important clinical need.”

    The new algorithm depends on measurements of a process called DNA methylation, which occurs when subtle changes accumulate in our DNA. DNA methylation can encode important information about which genes are being turned on and off, and it can be easily measured through blood tests.

    “Our computational model can use methylation markers from a blood sample to predict both current kidney function and how the kidneys will function years in the future, which means it could be easily implemented alongside current methods for evaluating a patient’s risk for kidney disease,” says Yip.

    The researchers developed their model using detailed data from more than 1,200 patients with type 2 diabetes in the Hong Kong Diabetes Register. They also tested their model on a separate group of 326 Native Americans with type 2 diabetes, which helped ensure that their approach could predict kidney disease in different populations.

    “This study highlights the unique strength of the Hong Kong Diabetes Register and its huge potential to fuel further discoveries to improve our understanding of diabetes and its complications,” says study co-author Juliana Chan, M.D., FRCP, a professor in the Department of Medicine and Therapeutics at the Chinese University of Hong Kong, who established the Hong Kong Diabetes Register more than two decades ago.

    “The Hong Kong Diabetes Register is a scientific treasure,” adds first author Kelly Yichen Li, Ph.D., a postdoctoral scientist at Sanford Burnham Prebys. “They follow up with patients for many years, which gives us a full picture of how human health can change over decades in people with diabetes.”

    The researchers are currently working to further refine their model. They are also expanding the application of their approach to look at other questions about human health and disease—such as determining why some people with cancer don’t respond well to certain treatments.

    “The science is still evolving, but we are working on incorporating additional information into our model to further empower precision medicine in diabetes,” adds Ma.

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    Additional authors on the study include Claudia Ha Ting Tam, Cadmon King Poo Lim, Wing Yee So, Chuiguo Huang, Guozhi Jiang, Mai Shi, Hueng Man Lee, Hui-yao Lan and Cheuk-Chun Szeto, Chinese University of Hong Kong; Hongbo Liu, Katalin Susztak, University of Pennsylvania; Samantha Day, Robert L. Hanson and Robert G. Nelson, National Institute of Diabetes and Digestive and Kidney Diseases.

    The study was supported by grants from The Hong Kong Research Grants Council Theme-based Research Scheme (T12-402/13N) and Research Impact Fund (R4012-18), with additional support from the Research Grants Council (C4015-20E, C4045-18W, C4057-18E, C7044-19G, 14107420 and 14203119), National Institutes of Health (P30 CA030199-41, U54 AG079758-01, R21 AG075483-01S1, R01 DK087635, DK076077 and DK105821) and support from the Croucher Foundation and the Chinese University of Hong Kong.

    The study’s DOI is 10.1038/s41467-023-37837-7

    About Sanford Burnham Prebys

    Sanford Burnham Prebys is an independent biomedical research institute dedicated to understanding human biology and disease and advancing scientific discoveries to profoundly impact human health. For more than 45 years, our research has produced breakthroughs in cancer, neuroscience, immunology and children’s diseases, and is anchored by our NCI-designated Cancer Center and advanced drug discovery capabilities. For more information, visit us at SBPdiscovery.org or on Facebook facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.

    About the Faculty of Medicine, The Chinese University of Hong Kong (CU Medicine)

    CU Medicine was set up to meet the needs of society by providing graduates with the professional development and knowledge that equips them to be caring and competent medical practitioners. As a young medical school established in 1981, the Faculty ranks top 3 in Asia and 32nd globally in the QS World University Rankings by Subject 2023.

    We have a team of over 1,200 full-time teaching and research staff from 19 departments/schools covering the entire range of research and clinical disciplines. We encourage collaborative working between scientists and clinicians across disciplines and specialties, and remain at the forefront of the translational medicine revolution. Our Faculty members excel in tackling challenging health problems, making a memorable impact on patients’ lives and the wider society.

    CU Medicine has won an internationally renowned research reputation for its encouraging environment for the effective pursuit of world-class research as well as remarkable contributions from team members.

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  • Task-specific modulation of corticospinal neuron activity during motor learning in mice (Nature Communications)

    Task-specific modulation of corticospinal neuron activity during motor learning in mice (Nature Communications)

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    Newswise — Learning motor skills depends on the brain’s ability to change, or be plastic. Specifically, the primary motor cortex of the brain can change as a person learns new motor tasks. When someone learns a complex task that involves fine motor control, like grasping an object, their brain undergoes large changes in the representation of the body part that controls the fine movements. In contrast, simpler tasks do not lead to such changes.

    In this study, researchers at Burke Neurological Institute investigated the role of a specific group of neurons, called corticospinal neurons, in learning and performing different motor tasks. Corticospinal neurons provide output from the brain directly to the spinal cord. The researchers used calcium imaging to measure activity in these neurons in mice as they learned to perform two different tasks: one that required precise movements of the forelimb, and another that was simpler and did not require as much precision.

    The researchers found that the activity of corticospinal neurons was different depending on the task the mice were performing. Specifically, the neurons showed patterns of activity that were associated with the timing of the precise movements required for the more complex task, but not for the simpler task. Further experiments showed that corticospinal neuron activity was necessary for performing the complex task, but not the simpler one.

    Overall, these findings suggest that the corticospinal network in the brain plays an important role in learning and executing precise motor movements. This research was supported by the Burke Foundation, the New York State Department of Health Spinal Cord Injury Research Board, the Craig H. Neilsen Foundation, and the National Institutes of Health.

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  • Van Andel Institute, Washington University School of Medicine in St. Louis to lead genome center under $140M NIH initiative

    Van Andel Institute, Washington University School of Medicine in St. Louis to lead genome center under $140M NIH initiative

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    Newswise — GRAND RAPIDS, Mich. (May 11, 2023) — Van Andel Institute’s Hui Shen, Ph.D., and Washington University School of Medicine in St. Louis’s Ting Wang, Ph.D., will co-lead a collaborative project supported by the Somatic Mosaicism across Human Tissues (SMaHT) Network, a new $140 million National Institutes of Health-led effort to better understand the genetic differences between individual cells and tissues in the body.

    Somatic mosaicism occurs when DNA, which houses the genetic code, accumulates slight changes throughout a person’s lifetime.

    Some variations may impede cells’ ability to function. Somatic mosaicism is a key contributor to cancer, but its role in other diseases is not well understood.

    SMaHT aims to identify and catalog these somatic variants in different individuals and enable new research into development, aging and a host of disorders.

    Together, Van Andel Institute and Washington University will serve as one of five SMaHT-supported Genome Characterization Centers, which will conduct leading-edge genomic analysis for the network.

    Wang will serve as the project’s director; Shen will serve as co-director. The project is supported by a $15 million grant from the NIH Common Fund as part of SMaHT.

    “We all carry such genetic mosaicism in our bodies, but the extent and implications of these variations remain unclear. Establishing an accurate picture of its role in the body is a massive undertaking that only can be achieved through collaboration,” Shen said. “I am thrilled to partner with Dr. Wang and the SMaHT Network, and look forward to contributing to a fuller understanding of this important and yet very much uncharted aspect of our cells.”

    In total, the NIH Common Fund issued 22 awards to establish the SMaHT Network. The project is akin to other large-scale NIH-supported projects such as the Human Genome Project, a 13-year endeavor that resulted in the first full blueprint of the human genome. 

    Shen is an internationally recognized expert in bioinformatics and epigenetics, the study of changes to DNA that do not alter the DNA sequence itself. She was a long-time member of The Cancer Genome Atlas (TCGA), an NIH-led collaborative effort to molecularly map 33 different cancer types. TCGA ended in 2018 with the publication of its Pan-Cancer Atlas, a comprehensive resource for scientists seeking to understand how and why cancer develops. Shen is a current member of the National Cancer Institute’s Genome Data Analysis Network (GDAN), a successor to TCGA that develops new tools to assist in the analysis of data.

    Research reported in this publication is supported by the NIH Common Fund under award no. UM1DA058219. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

     

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    ABOUT VAN ANDEL INSTITUTE Van Andel Institute (VAI) is committed to improving the health and enhancing the lives of current and future generations through cutting-edge biomedical research and innovative educational offerings. Established in Grand Rapids, Michigan, in 1996 by the Van Andel family, VAI is now home to more than 500 scientists, educators and support staff, who work with a growing number of national and international collaborators to foster discovery. The Institute’s scientists study the origins of cancer, Parkinson’s and other diseases and translate their findings into breakthrough prevention and treatment strategies. Our educators develop inquiry-based approaches for K-12 education to help students and teachers prepare the next generation of problem-solvers, while our Graduate School offers a rigorous, research-intensive Ph.D. program in molecular and cellular biology. Learn more at vai.org.

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  • فهم سرعة اتصال الدماغ

    فهم سرعة اتصال الدماغ

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    Newswise — مدينة روتشستر، ولاية مينيسوتا — في الغالب كان يُعتقد أن سرعة المعلومات المنقولة ما بين مناطق الدماغ تستقر في بداية المراهقة. لقد وجدت دراسة جديدة في مجلة نيتشر نيوروسينس أجراها باحثو مايو كلينك وزملاؤهم من هولندا أن سرعات نقل المعلومات تستمر في الزيادة حتى بداية البلوغ.

    نظرًا لأن مشاكل مثل: القلق والاكتئاب واضطرابات ثنائي القطب، يمكن أن تظهر في أواخر مرحلة المراهقة وبداية مرحلة البلوغ، فإن تحسين فهمنا لنمو الدماغ قد يساعد الأطباء على تقديم علاجات لهذه الاضطرابات.

    تقول دورا هيرميس، الحاصلة على الدكتوراه، مهندسة الطب الحيوي في مايو كلينك وكبيرة مؤلفي الدراسة: “قد يساعد الفهم الأساسي لمسار تطور دوائر الدماغ في تحديد فترات النمو الحساسة حيث يمكن للأطباء تقديم علاجات لمرضاهم”.

    يتطور النظام الهيكلي للمسارات العصبية في الدماغ أو الجهاز العصبي، الذي يُسمى الشبكة العصبية البشرية، مع تقدم الناس في السن. لكننا لا نملك وصفًا جيدًا لكيف تُؤثر التغييرات الهيكلية على سرعة الإشارات العصبية.

    توضح الدكتورة هيرميس قائلةً: “مثلما يعتمد وقت عبور الشاحنة على هيكل الطريق، فإن سرعة إرسال الإشارات بين مناطق الدماغ تعتمد على بنية المسارات العصبية. تنضج الشبكة العصبية البشرية خلال النمو والتقدم في العمر، ويمكن أن تتأثر بالمرض. قد تؤثر كل هذه العمليات على سرعة تدفق المعلومات إلى الدماغ. “في الدراسة، قامت الدكتورة هيرميس وزملاؤها بتحفيز أزواج من الأقطاب الكهربائية بنبضة كهربائية قصيرة لقياس الوقت الذي تستغرقه الإشارات للانتقال بين مناطق الدماغ لدى 74 مشاركًا في البحث تتراوح أعمارهم ما بين 4 و51 عامًا. تم إجراء قياسات داخل الجمجمة على مجموعة صغيرة من المرضى الذين لديهم مسارات كهربائية مزروعة لمراقبة الصرع في المركز الطبي الجامعي أوترخت، هولندا.

    أظهرت فترات تأخر الاستجابة في مناطق الدماغ المتصلة أن سرعات نقل المعلومات في الدماغ البشري تزداد طوال فترة الطفولة وحتى في بداية مرحلة البلوغ. وتكون الذروة في العمر من 30 إلى 40 عامًا تقريبًا.

    تشير بيانات الفريق إلى أن سرعات نقل البيانات لدى البالغين كانت أسرع مرتين تقريبًا مقارنة بالتي لدى الأطفال عادةً. كانت سرعات نقل المعلومات عادةً أسرع لدى الأشخاص ما بين 30 أو 40 عامًا مقارنةً بالمراهقين.

    تُقاس سرعة نقل المعلومات في الدماغ بالميلي ثانية، وهي وحدة زمنية تساوي واحدًا من الألف من الثانية. على سبيل المثال، وجد الباحثون أن قياس السرعة العصبية لمريض يبلغ من العمر 4 سنوات هو 45 مللي ثانية لإشارة واحدة لتنتقل من المناطق الأمامية إلى المناطق الجدارية في الدماغ. ولدى مريض يبلغ من العمر 38 عامًا، تم قياس نفس المسار فبلغ القياس 20 مللي ثانية. فقط للمقارنة، فإن طرفة العين تستغرق حوالي 100 إلى 400 مللي ثانية.

    ويعمل الباحثون على توصيف الاتصال الذي يبدؤه التحفيز الكهربائي في دماغ الإنسان. من الخطوات التالية هي فهم كيفية تغير سرعات نتقل الملعومات مع الأمراض العصبية بشكل أفضل. يتعاون الفريق مع جراحي أعصاب الأطفال وأطباء الأعصاب لفهم كيف تغيّر الأمراض من سرعات نتقل المعلومات بالمقارنة مع ما يمكن اعتباره ضمن النطاق الطبيعي لفئة عمرية معينة.

    تلقى البحث الدعم من المعهد الوطني للصحة العقلية التابع للمعاهد الوطنية للصحة (R01MH122258). لم يذكر الكاتبون أي إفصاحات ذات صلة. توجد قائمة كاملة بالمؤلفين والمؤسسات التي ينتمون إليها في مقال البحث.

    لمزيد من المعلومات، يرجى زيارة ديسكافريز إيدج.

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    نبذة عن مايو كلينك
    مايو كلينك هي مؤسسة غير ربحية تلتزم بالابتكار في الممارسات السريرية والتعليم والبحث وتوفير التعاطف والخبرة لكل مَن يحتاج إلى الاستشفاء والرد على استفساراته. لمعرفة المزيد من أخبار مايو كلينك، تفضَّل بزيارة شبكة مايو كلينك الإخبارية.

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