Bioprocessing

Aging (Aging-US)

Dr. May Beydoun from the Laboratory of Epidemiology and Population Sciences, NIA/NIH/IRP, in Baltimore, MD, discusses a research paper she co-authored that was published by Aging (Aging-US) as the cover for Volume 14, Issue 13, entitled, “Epigenetic clocks and their association with trajectories in perceived discrimination and depressive symptoms among US middle-aged and older adults.”

DOI - https://doi.org/10.18632/aging.204150

Corresponding author - May A. Beydoun - baydounm@mail.nih.gov

Abstract

Background: Perceived discrimination may be associated with accelerated aging later in life, with depressive symptoms acting as potential mediator.

Methods: A nationally representative sample of older adults was used [Health and Retirement Study 2010–2016, Age: 50–100 y in 2016, N = 2,806, 55.6% female, 82.3% Non-Hispanic White (NHW)] to evaluate associations of perceived discrimination measures [Experience of discrimination or EOD; and Reasons for Perceived discrimination or RPD) and depressive symptoms (DEP)] with 13 DNAm-based measures of epigenetic aging. Group-based trajectory and four-way mediation analyses were used.

Results: Overall, and mostly among female and NHW participants, greater RPD in 2010–2012 had a significant adverse total effect on epigenetic aging [2016: DNAm GrimAge, DunedinPoAm38 (MPOA), Levine (PhenoAge) and Horvath 2], with 20–50% of this effect being explained by a pure indirect effect through DEP in 2014–2016. Among females, sustained elevated DEP (2010–2016) was associated with greater LIN DNAm age (β ± SE: +1.506 ± 0.559, p = 0.009, reduced model), patterns observed for elevated DEP (high vs. low) for GrimAge and MPOA DNAm markers. Overall and in White adults, the relationship of the Levine clock with perceived discrimination in general (both EOD and RPD) was mediated through elevated DEP.

Conclusions: Sustained elevations in DEP and RPD were associated with select biological aging measures, consistently among women and White adults, with DEP acting as mediator in several RPD-EPICLOCK associations.

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Press release - https://www.aging-us.com/news_room/epigenetic-clocks-and-their-association-with-perceived-discrimination-and-depressive-symptoms

Keywords - aging, DNA methylation, epigenetic clocks, biological age, perceived discrimination, depressive symptoms

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

Please visit our website at https://www.Aging-US.com​​ and connect with us:

SoundCloud - https://soundcloud.com/Aging-Us
Facebook - https://www.facebook.com/AgingUS/
Twitter - https://twitter.com/AgingJrnl
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YouTube - https://www.youtube.com/agingus​
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Behind the Study: Epigenetic Clocks Association with Perceived Discrimination, Depressive Symptoms

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In the fourth episode of the Longevity & Aging Series, Dr. Carly Bobak from Dartmouth College, Dr. Cristian Coarfa from Baylor College of Medicine, and Dr. Andrew DiNardo from Baylor College of Medicine, discuss a research paper they co-authored that was published in Volume 14, Issue 5 of Aging (Aging-US), entitled, “Increased DNA methylation, cellular senescence and premature epigenetic aging in guinea pigs and humans with tuberculosis.”

DOI - https://doi.org/10.18632/aging.203936

Corresponding Authors - Carly A. Bobak - carlybobak@dartmouth.edu, Cristian Coarfa - coarfa@bcm.edu, and Andrew R. DiNardo - andrew.dinardo@bcm.edu

Abstract

Background: Tuberculosis (TB) is the archetypical chronic infection, with patients having months of symptoms before diagnosis. In the two years after successful therapy, survivors of TB have a three-fold increased risk of death.

Methods: Guinea pigs were infected with Mycobacterium tuberculosis (Mtb) for 45 days, followed by RRBS DNA methylation analysis. In humans, network analysis of differentially expressed genes across three TB cohorts were visualized at the pathway-level. Serum levels of inflammation were measured by ELISA. Horvath (DNA methylation) and RNA-seq biological clocks were used to investigate shifts in chronological age among humans with TB.

Results: Guinea pigs with TB demonstrated DNA hypermethylation and showed system-level similarity to humans with TB (p-value = 0.002). The transcriptome in TB in multiple cohorts was enriched for DNA methylation and cellular senescence. Senescence associated proteins CXCL9, CXCL10, and TNF were elevated in TB patients compared to healthy controls. Humans with TB demonstrate 12.7 years (95% CI: 7.5, 21.9) and 14.38 years (95% CI: 10.23–18.53) of cellular aging as measured by epigenetic and gene expression based cellular clocks, respectively.

Conclusions: In both guinea pigs and humans, TB perturbs epigenetic processes, promoting premature cellular aging and inflammation, a plausible means to explain the long-term detrimental health outcomes after TB.

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Keywords - aging, tuberculosis, multi-cohort analysis, network analysis, DNA methylation, senescence, Cavia porcellus, DNA hypermethylation, epigenetic aging
About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

Please visit our website at https://www.Aging-US.com​​ and connect with us:

SoundCloud - https://soundcloud.com/Aging-Us
Facebook - https://www.facebook.com/AgingUS/
Twitter - https://twitter.com/AgingJrnl
Instagram - https://www.instagram.com/agingjrnl/
YouTube - https://www.youtube.com/agingus​
LinkedIn - https://www.linkedin.com/company/aging/
Pinterest - https://www.pinterest.com/AgingUS/

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Longevity & Aging Series (EP 4): Drs. Carly Bobak, Cristian Coarfa, Andrew DiNardo

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Oncotarget

Oncotarget published this research paper on August 16, 2022 in Volume 13, entitled, "Combined epigenetic and immunotherapy for blastic and classical mantle cell lymphoma" by researchers from Department of Medicine, Pennsylvania State University College of Medicine and Penn State Hershey Cancer Institute, Hershey, PA; Department of Hematology/Oncology, Penn State Hershey Cancer Institute, Hershey, PA; BayCare Medical Group, Cassidy Cancer Center, Winter Haven, FL; Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY; Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD; Department of Pharmacology, University of Virginia, Charlottesville, VA; Department of Public Health Sciences, The Pennsylvania State University College of Medicine, Hershey, PA; Department of Medicine/Hematology-Oncology, UVA Cancer Center, Charlottesville, VA; Department of Anatomic Pathology, Pennsylvania State University College of Medicine, Hershey, PA; Department of Medicine and Cancer Center, University of Arizona College of Medicine, Tucson, AZ; Department of Medicine, Oregon Health and Science University, Portland, OR; Beverly Hills Cancer Center, Beverly Hills, CA.

DOI - https://www.oncotarget.com/article/28258/text/

Correspondence to - Francis R. LeBlanc - francis.leblanc@cchmc.org

Abstract

Classical MCL (cMCL) constitutes 6–8% of all B cell NHL. Despite recent advances, MCL is incurable except with allogeneic stem cell transplant. Blastic mantle cell lymphoma (bMCL) is a rarer subtype of cMCL associated with an aggressive clinical course and poor treatment response, frequent relapse and poor outcomes. We treated 13 bMCL patients with combined epigenetic and immunotherapy treatment consisting of vorinostat, cladribine and rituximab (SCR). We report an increased OS greater than 40 months with several patients maintaining durable remissions without relapse for longer than 5 years. This is remarkably better then current treatment regimens which in bMCL range from 14.5-24 months with conventional chemotherapy regimens. We demonstrate that the G/A870 CCND1 polymorphism is predictive of blastic disease, nuclear localization of cyclinD1 and response to SCR therapy. The major resistance mechanisms to SCR therapy are loss of CD20 expression and evasion of treatment by sanctuary in the CNS. These data indicate that administration of epigenetic agents improves efficacy of anti-CD20 immunotherapies. This approach is promising in the treatment of MCL and potentially other previously treated refractory cancers.

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Keywords - epigenetics, blastic mantle cell lymphoma, cladribine

About Oncotarget

Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed.

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Combined Epigenetic and Immunotherapy for Mantle Cell Lymphoma

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Oncotarget published this research paper on August 3, 2022 in Volume 13, entitled, "Glypican-3 (GPC3) is associated with MCPyV-negative status and impaired outcome in Merkel cell carcinoma" by researchers from SOTIO Biotech Inc., Cambridge, MA; Department of Dermatology, University Hospital of Tours, France.

DOI - https://doi.org/10.18632/oncotarget.28260

Correspondence to - Glen J. Weiss - weiss@sotio.com, and Mahtab Samimi - mahtab.samimi@univ-tours.fr
Abstract

Introduction: Merkel cell carcinoma (MCC) is an aggressive skin cancer, related to the Merkel Cell Polyomavirus (MCPyV) in 80% of cases. Immune checkpoint inhibitors provide sustained benefit in about 50% of MCC patients with advanced disease. Glypican-3 (GPC3) is an oncofetal tumor antigen that is an attractive target for chimeric antigen receptor T cell therapy due to its highly restricted expression on normal tissue and high prevalence in several solid tumors. GPC3 is known to be expressed in MCC but its association with tumor characteristics or prognosis has not been reported. We investigated MCC GPC3 expression by immunohistochemistry (IHC) and its association with tumor characteristics, MCPyV status, and patient outcome.

Methods: The GC33 antibody clone was validated for GPC3 IHC staining of tumor specimens in comparison to an established GPC3 IHC antibody. An MCC tissue microarray was stained for GPC3 by IHC using GC33 antibody. Association of GPC3+ IHC with baseline characteristics, MCPyV status (qPCR) and outcome (death from MCC/recurrence) were assessed.

Results: Forty-two of 62 samples (67.7%) were GPC3+. GPC3 expression was more frequently observed in females (p = 0.048) and MCPyV-negative tumors (p = 0.021). By multivariate analysis, GPC3 expression was associated with increased death from disease (CSS) (hazard ratio [HR] 4.05, 95% CI 1.06–15.43), together with advanced age (HR 4.85, 95% CI 1.39–16.9) and male gender (HR 4.64, 95% CI 1.31–16.41).

Conclusions: GPC3 expression is frequent in MCC tumors, especially MCPyV-negative cases, and is associated with increased risk of death. High prevalence of surface GPC3 makes it a putative drug target.

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Press release - https://www.oncotarget.com/news/pr/oncotarget-glypican-gpc-is-associated-with-mcpyv-negative-status-and-impaired-outcome-in-merkel-cell-carcinoma/

Keywords - Merkel cell carcinoma, glypican-3, Merkel cell polyomavirus, outcome

About Oncotarget

Oncotarget is a peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

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Trending With Impact: GPC3 Associated With MCPyV-negative Status and Impaired Outcome in Merkel Cell Carcinoma

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