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Tag: National Institute on Aging (NIA)

  • Transcription Factors Contribute to Subtypes of Colorectal Cancers

    Transcription Factors Contribute to Subtypes of Colorectal Cancers

    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.

    Johns Hopkins Medicine

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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

    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.

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

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  • Study Finds Relationship Between Discrimination and Frailty in Black Cancer Survivors

    Study Finds Relationship Between Discrimination and Frailty in Black Cancer Survivors

    Newswise — WASHINGTON — Discrimination experienced by Black people can affect their health and increase their frailty, which can be particularly impactful for cancer survivors, according to a new study by researchers at Georgetown University’s Lombardi Comprehensive Cancer Center and colleagues at the Barbara Ann Karmanos Cancer Institute in Detroit. The researchers assessed frailty by a number of factors, including whether a participant had several chronic diseases, poor muscle strength and difficulty performing activities of daily living.

    The findings appeared March 20, 2023, in Cancer.

    “Discrimination can act as a chronic stressor which can throw the body off balance, resulting in increases in blood pressure, heart rate, metabolism, inflammation, and numerous other factors. These stressors can also increase rates of aging, leading to greater risk of frailty,” says the study’s lead investigator, Jeanne Mandelblatt, MD, MPH, director of the Georgetown Lombardi Institute for Cancer and Aging Research. “We hypothesize that discrimination can lead to an older biological age than a person’s actual chronological age. This is important to understand as there have been virtually no studies of the relationships between discrimination and aging in the setting of cancer survivorship.”

    The investigators looked at associations between discrimination and frailty among 2,232 Black breast, lung, prostate and colorectal cancer survivors who were within five years of their diagnoses and were no longer actively being treated for their cancers. Survivors were 62 years of age on average (with ages ranging from 23 to 84) at the time of the study, but they may have experienced discrimination over many decades of their lives. All participants were part of the Detroit Research on Cancer Survivors (ROCS), which is the largest U.S. study of Black cancer survivors.

    The researchers surveyed the participants, via phone, in writing, or online about any aging-related diseases they had, their ability to maintain a healthy lifestyle, and most importantly, about major discrimination events they may have experienced over their lifetimes, specifically targeting seven areas:

    • being unfairly fired or denied a promotion in their job;
    • not being hired for a job;
    • being unfairly stopped, searched, questioned, physically threatened or abused by police officers;
    • being unfairly discouraged by a teacher or advisor from continuing their education;
    • unfairly receiving worse medical care than other people;
    • being prevented from moving into a neighborhood because a landlord or realtor refused to sell or rent them a house or an apartment; and/or
    • moved into a neighborhood where neighbors made life difficult.

    Based on the survey results, the majority of cancer survivors were classified as either prefrail (42.7%), meaning they had some health difficulties, or frail (32.9%). Only 24.4% of those surveyed had few or no signs of frailty. When queried about the seven discrimination areas, 63.2% of the participants reported experiencing major discrimination, with an average respondent reporting 2.4 types of discrimination.

    “For those cancer survivors who reported four to seven types of discrimination events, we observed a large, clinically meaningful increase in frailty scores compared to survivors with fewer discrimination events,” explains Mandelblatt, also a professor of oncology and medicine at the Georgetown University School of Medicine. “Significantly, this pattern of discrimination affecting frailty was consistent across the four types of cancer surveyed, indicating that discrimination is an important factor to study and understand in Black cancer survivors in order to improve their quality and length of life.”

    “Our results indicate that after considering the effects of traditional factors on poor health, such as income, education and types of cancer treatment, discrimination was a significant factor explaining frailty and it acted independently of the other variables,” says  Ann Schwartz, PhD, MPH, co-lead author on the paper and co-principal investigator of the Detroit ROCS. “Regardless of whether you were rich or poor, if you experienced more discrimination then you had greater frailty.” Schwartz is also professor and associate chair of oncology at Wayne State University School of Medicine, and deputy center director and executive vice president for research and academic affairs at Karmanos.

    For their next steps, the researchers are hoping to study the relationships between major discrimination, other chronic life stressors and markers of biological aging and test how cancer and its treatment further contributes to biological aging among racial and ethnic minorities. 

    “We have long since recognized the impact of discrimination on health and well-being in Black communities,” says study co-author Lucile Adams-Campbell, PhD, a professor of oncology and associate director for Minority Health and Health Disparities Research at Georgetown Lombardi. “We hope that this study leads to more discussions between providers and their patients about the types of discrimination they have experienced and gives providers a greater understanding of how discrimination impacts frailty.”

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    Additional authors include Xingtao Zhou and Traci Bethea at Georgetown Lombardi; Julie Ruterbusch, Hayley Thompson and Kristen Purrington at Wayne State University School of Medicine and Karmanos Cancer Institute.

    The authors report having no personal financial interests related to the study.

    This research was supported by National Cancer Institute grants U01 CA199240, R01CA129769,  R35CA197289 and K01CA212056 and a National Institute on Aging grant R21AG07500. This work was supported by the Epidemiology Research Core and the National Cancer Institute Center Grant (P30CA022453) awarded to the Karmanos Cancer Institute at Wayne State University.

    About Georgetown University’s Lombardi Comprehensive Cancer Center
    Georgetown’s Lombardi Comprehensive Cancer Center is designated by the National Cancer Institute (NCI) as a comprehensive cancer center. A part of Georgetown University Medical Center, Georgetown Lombardi is the only comprehensive cancer center in the Washington D.C. area. It serves as the research engine for MedStar Health, Georgetown University’s clinical partner. Georgetown Lombardi is also an NCI recognized consortium with John Theurer Cancer Center/Hackensack Meridian Health in Bergen County, New Jersey. The consortium reflects an integrated cancer research enterprise with scientists and physician-researchers from both locations. Georgetown Lombardi seeks to improve the diagnosis, treatment, and prevention of cancer through innovative basic, translational and clinical research, patient care, community education and outreach to service communities throughout the Washington region, while its consortium member John Theurer Cancer Center/Hackensack Meridian Health serves communities in northern New Jersey. Georgetown Lombardi is a member of the NCI Community Oncology Research Program (UG1CA239758). Georgetown Lombardi is supported in part by a National Cancer Institute Cancer Center Support Grant (P30CA051008). Connect with Georgetown Lombardi on Facebook (Facebook.com/GeorgetownLombardi) and Twitter (@LombardiCancer).

    Lombardi Comprehensive Cancer Center at Georgetown University

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  • Review strengthens evidence that repetitive head impacts can cause CTE

    Review strengthens evidence that repetitive head impacts can cause CTE

    Newswise — (Boston)—During the past 17 years, there has been a remarkable increase in scientific research concerning chronic traumatic encephalopathy (CTE) with researchers at the BU CTE Center at the forefront. While some sports organizations like the National Hockey League and World Rugby still claim their sports do not cause CTE, a new review of the evidence by the world’s leading CTE expert strengthens the case that repetitive head impact (RHI) exposure is the chief risk factor for the condition.

    CTE became national news in the United States in 2007, but it wasn’t until 2016 that the National Institute of Neurological Disorders and Stroke/National Institute of Biomedical Imaging and Bioengineering (NINDS-NIBIB) criteria for the neuropathological diagnosis of CTE were published, and they were refined in 2021. Rare, isolated case studies reporting aberrant findings or using non-accepted diagnostic criteria have been disproportionately emphasized to cast doubt on the connection between RHI and CTE.

    In a review article in the journal Acta Neuropathologica, Ann McKee, MD, chief of neuropathology at VA Boston Healthcare System and director of the BU CTE Center, stresses that now over 600 CTE cases have been published in the literature from multiple international research groups. And of those over 600 cases, 97 percent have confirmed exposure to RHI, primarily through contact and collision sports. CTE has been diagnosed in amateur and professional athletes, including athletes from American, Canadian, and Australian football, rugby union, rugby league, soccer, ice hockey, bull-riding, wrestling, mixed-martial arts, and boxing.

    What’s more, 82 percent (14 of the 17) of the purported CTE cases that occurred in the absence of RHI, where up-to-date criteria were used, the study authors disclosed that families were never asked what sports the decedent played. 

    According to the researchers, despite global efforts to find CTE in the absence of contact sport participation or RHI exposure, it appears to be extraordinarily rare, if it exists at all. “In studies of community brain banks, CTE has been seen in 0 to 3 percent of cases, and where the information is available, positive cases were exposed to brain injuries or RHI. In contrast, CTE is the most common neurodegenerative disease diagnosis in contact and collision sport athletes in brain banks around the world. A strong dose response relationship is perhaps the strongest evidence that RHI is causing CTE in athletes,” she added.

    “The review presents the timeline for the development of neuropathological criteria for the diagnosis of CTE which was begun nearly 100 years ago by pathologist Harrison Martland who introduced the term “punch-drunk” to describe a neurological condition in prizefighters,” explained McKee, corresponding author of the study. The review chronologically describes the multiple studies conducted by independent, international groups investigating different populations that found CTE pathology in individuals with a history of RHI from various sources.”

    CTE is characterized by a distinctive molecular structural configuration of p-tau fibrils that is unlike the changes observed with aging, Alzheimer’s disease, or any other diseases caused by tau protein.

    Funding for this research was provided by the National Institute of Neurological Disorders and Stroke (U54NS115266; R01NS119651; U01 NS 086659), National Institute on Aging (P30AG13846; U19AG06875; R01AG062348; RF1AG057902; K01AG070326), Department of Veterans Affairs (101BX002466, 101BX004613, BX004349), the Nick and Lynn Buoniconti Foundation, Andlinger Foundation, National Football League (NFL) and World Wrestling Entertainment (WWE) through unrestricted gifts, the Mac Parkman Foundation, and the National Operating Committee on Safety for Sports Equipment (NOCSEA).

    Boston University School of Medicine

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