bims-minfam 2024-05-05 papers

Issue of 2024–05–05
ten papers selected by
Ayesh Seneviratne, Western University

J Am Coll Cardiol. 2024 May 07. pii: S0735-1097(24)06688-9. [Epub ahead of print]83(18): 1728-1730

Clonal Hematopoiesis Among Patients With Asymptomatic Carotid Stenosis Compounds Risk of Cardiovascular Death.

Keywords: aging; carotid atherosclerosis; clonality; inflammation; prognosis; risk prediction

DOI: https://doi.org/10.1016/j.jacc.2024.03.389

Blood. 2024 Apr 29. pii: blood.2023021985. [Epub ahead of print]

Kinase-inactivated CDK6 preserves the long-term functionality of adult hematopoietic stem cells.

Hematopoietic stem cells (HSCs) are characterized by the ability to self-renew and to replenish the hematopoietic system. The cell-cycle kinase cyclin dependent-kinase 6 (CDK6) regulates transcription, whereby it has both kinase-dependent and kinase-independent functions. We here describe the complex role of CDK6, balancing quiescence, proliferation, self-renewal and differentiation in activated HSCs. Mouse HSCs expressing kinase-inactivated CDK6 show enhanced long-term repopulation and homing, whereas HSCs lacking CDK6 have impaired functionality. The transcriptomes of basal and serially transplanted HSCs expressing kinase-inactivated CDK6 exhibit an expression pattern dominated by HSC quiescence and self-renewal, proposing a concept where MAZ and NFY-A are critical CDK6 interactors. Pharmacologic kinase inhibition with a clinically used CDK4/6 inhibitor in murine and human HSCs validated our findings and resulted in increased repopulation capability and enhanced stemness. Our findings highlight a kinase-independent role of CDK6 in long-term HSC functionality. CDK6 kinase inhibition represents a possible strategy to improve HSC fitness.

DOI: https://doi.org/10.1182/blood.2023021985

Sci Immunol. 2024 May 03. 9(95): eadq0013

The Benjamin Button effect on stem cells: Reversing the clock on aging immunity.

Luciana Conde, Carolina Lucas.

Antibody-based therapy depletes myeloid-biased hematopoietic stem cells (my-HSCs) to rejuvenate the immune system and improve immune responses in aged mice.

DOI: https://doi.org/10.1126/sciimmunol.adq0013

Cold Spring Harb Perspect Med. 2024 May 01. pii: a041534. [Epub ahead of print]

Mitochondria and Cancer.

Timothy C Kenny, Kıvanç Birsoy.

Mitochondria are semiautonomous organelles with diverse metabolic and cellular functions including anabolism and energy production through oxidative phosphorylation. Following the pioneering observations of Otto Warburg nearly a century ago, an immense body of work has examined the role of mitochondria in cancer pathogenesis and progression. Here, we summarize the current state of the field, which has coalesced around the position that functional mitochondria are required for cancer cell proliferation. In this review, we discuss how mitochondria influence tumorigenesis by impacting anabolism, intracellular signaling, and the tumor microenvironment. Consistent with their critical functions in tumor formation, mitochondria have become an attractive target for cancer therapy. We provide a comprehensive update on the numerous therapeutic modalities targeting the mitochondria of cancer cells making their way through clinical trials.

DOI: https://doi.org/10.1101/cshperspect.a041534

Aging Cell. 2024 Apr 30. e14162

Cellular senescence is a double-edged sword in regulating aged immune responses to influenza.

Blake L Torrance, Andreia N Cadar, Hunter A Panier, Dominique E Martin, Erica C Lorenzo, Evan R Jellison, Jenna M Bartley, Laura Haynes.

Clearance of senescent cells has demonstrated therapeutic potential in the context of chronic age-related diseases. Little is known, however, how clearing senescent cells affects the ability to respond to an acute infection and form quality immunological memory. We aimed to probe the effects of clearing senescent cells in aged mice on the immune response to influenza (flu) infection. We utilized a p16 trimodality reporter mouse model (p16-3MR) to allow for identification and selective clearance of p16-expressing cells upon administration of ganciclovir (GCV). While p16-expressing cells may exacerbate dysfunctional responses to a primary infection, our data suggest they may play a role in fostering memory cell generation. We demonstrate that although clearance of p16-expressing cells enhanced viral clearance, this also severely limited antibody production in the lungs of flu-infected aged mice. 30 days later, there were fewer flu-specific CD8 memory T cells and lower levels of flu-specific antibodies in the lungs of GCV-treated mice. Furthermore, GCV-treated mice were unable to mount an optimal memory response and demonstrated increased viral load following heterosubtypic challenge. These results suggest that targeting senescent cells may potentiate primary responses while limiting the ability to form durable and protective immune memory with age.

Keywords: T cells; aging; influenza; memory; p16; senescence

DOI: https://doi.org/10.1111/acel.14162

Public Health Nutr. 2024 Apr 29. 1-20

Inflammatory potential of diet and mortality in Australian adults.

Azam Majidi, Maria Celia B Hughes, Imogen K Webb, Kyoko Miura, Jolieke C van der Pols.

OBJECTIVE: Inflammation is implicated in chronic diseases including cancer and cardiovascular diseases (CVD), which are major causes of mortality. Diet can influence inflammation status. We therefore examined whether the inflammatory potential of a person's diet is associated with mortality.
DESIGN: Inflammatory potential of usual diet was assessed by calculating dietary inflammatory index (DII) scores from repeated food frequency (FFQ) data (collected in 1992, 1994, 1996), placing each participant's diet on a continuum from anti- to pro-inflammatory. DII scores were analysed as a continuous variable and as categories by creating quartile groups. Death registry data were used to ascertain all-cause mortality and separately mortality from CVD, cancers, and other causes between 1992-2022. Cox proportional hazards regression analysis was used to calculate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs), comparing higher vs. lowest quartile groups, or HR change per one DII-unit increase.
SETTING: Nambour, Australia.
PARTICIPANTS: A community-based sample of 1440 adults aged 25-75 years.
RESULTS: During follow-up, 488 participants died, including 188 from CVD, 151 from cancer, and 170 from other causes. Participants in the most pro-inflammatory diet group were at increased risk of all-cause mortality (HRQ4vsQ1 = 1.55; 95% CI 1.19, 2.03; P trend < 0.001), and other-cause mortality (HRQ4vsQ1 = 1.69; 95% CI 1.12, 2.54; P trend 0.01). A one-unit increase in DII-score was associated with a 36% increased risk of CVD among those younger than 55 years of age (HR for a one-unit increase in DII score: 1.36, 95% CI: 1.04-1.78). The risk of cancer mortality was also increased for those with a more pro-inflammatory diet in age ≤55yr: HR for a one-unit increase in DII score: 1.20, 95% CI: 1.02-1.40, and age 56-65yr: HR for a one-unit increase in DII score: 1.11, 95 % CI: 1.00-1.23).
CONCLUSIONS: A pro-inflammatory diet increases the risk of all-cause mortality. Our results support promotion of anti-inflammatory diets to help promote longevity.

Keywords: cancer; cardiovascular disease; diet; inflammation; mortality; prospective study

DOI: https://doi.org/10.1017/S1368980024000909

Cell Stem Cell. 2024 May 02. pii: S1934-5909(24)00131-0. [Epub ahead of print]31(5): 617-639

Hallmarks of cancer stemness.

Jia-Jian Loh, Stephanie Ma.

Cancer stemness is recognized as a key component of tumor development. Previously coined "cancer stem cells" (CSCs) and believed to be a rare population with rigid hierarchical organization, there is good evidence to suggest that these cells exhibit a plastic cellular state influenced by dynamic CSC-niche interplay. This revelation underscores the need to reevaluate the hallmarks of cancer stemness. Herein, we summarize the techniques used to identify and characterize the state of these cells and discuss their defining and emerging hallmarks, along with their enabling and associated features. We also highlight potential future directions in this field of research.

Keywords: cancer cell plasticity; cancer stem cells; cancer stemness; immunosuppression; metastasis; self-renewal; tumor microenvironment; tumor recurrence; tumor-initiating cells

DOI: https://doi.org/10.1016/j.stem.2024.04.004

J Clin Invest. 2024 May 01. pii: e180558. [Epub ahead of print]134(9):

A pipeline for senolytics.

Sundeep Khosla.

There is intense interest in identifying compounds that selectively kill senescent cells, termed senolytics, for ameliorating age-related comorbidities. However, screening for senolytic compounds currently relies on primary cells or cell lines where senescence is induced in vitro. Given the complexity of senescent cells across tissues and diseases, this approach may not target the senescent cells that develop under specific conditions in vivo. In this issue of the JCI, Lee et al. describe a pipeline for high-throughput drug screening of senolytic compounds where senescence was induced in vivo and identify the HSP90 inhibitor XL888 as a candidate senolytic to treat idiopathic pulmonary fibrosis.

DOI: https://doi.org/10.1172/JCI180558