bims-minfam 2022-06-12 papers

Issue of 2022–06–12
six papers selected by
Ayesh Seneviratne, Western University

J Immunother Precis Oncol. 2021 Aug;4(3): 160-167

Inflammation in Myeloid Malignancies: From Bench to Bedside.

Myeloid malignancies, stemming from a somatically mutated hematopoietic clone, can cause a wide variety of clinical consequences, including pancytopenia in myelodysplastic syndrome, overproduction of three myeloid lineages in myeloproliferative neoplasm, and the rapid growth of immature hematopoietic cells in acute myeloid leukemia (AML). It is becoming clear that inflammation is a hallmark feature of clonal myeloid conditions, ranging from clonal hematopoiesis of indeterminate potential to AML. Fundamental findings from laboratory research on inflammation in myeloid malignancies has potential implications for diagnosis, prognostication, and treatment in these diseases. In this review, we highlighted some pertinent basic science findings regarding the role of inflammation in myeloid malignancies and speculated how these findings could impact the clinical care of patients.

DOI: https://doi.org/10.36401/JIPO-21-3

Front Cell Dev Biol. 2022 ;10 882211

Modern Concepts in Cardiovascular Disease: Inflamm-Aging.

Yustina M Puspitasari, Stefano Ministrini, Lena Schwarz, Caroline Karch, Luca Liberale, Giovanni G Camici.

The improvements in healthcare services and quality of life result in a longer life expectancy and a higher number of aged individuals, who are inevitably affected by age-associated cardiovascular (CV) diseases. This challenging demographic shift calls for a greater effort to unravel the molecular mechanisms underlying age-related CV diseases to identify new therapeutic targets to cope with the ongoing aging "pandemic". Essential for protection against external pathogens and intrinsic degenerative processes, the inflammatory response becomes dysregulated with aging, leading to a persistent state of low-grade inflammation known as inflamm-aging. Of interest, inflammation has been recently recognized as a key factor in the pathogenesis of CV diseases, suggesting inflamm-aging as a possible driver of age-related CV afflictions and a plausible therapeutic target in this context. This review discusses the molecular pathways underlying inflamm-aging and their involvement in CV disease. Moreover, the potential of several anti-inflammatory approaches in this context is also reviewed.

Keywords: aging; cardiovascular disease; inflammaging; inflammation; senescence

DOI: https://doi.org/10.3389/fcell.2022.882211

Nat Cell Biol. 2022 Jun 06.

The metabolic enzyme hexokinase 2 localizes to the nucleus in AML and normal haematopoietic stem and progenitor cells to maintain stemness.

Mitochondrial metabolites regulate leukaemic and normal stem cells by affecting epigenetic marks. How mitochondrial enzymes localize to the nucleus to control stem cell function is less understood. We discovered that the mitochondrial metabolic enzyme hexokinase 2 (HK2) localizes to the nucleus in leukaemic and normal haematopoietic stem cells. Overexpression of nuclear HK2 increases leukaemic stem cell properties and decreases differentiation, whereas selective nuclear HK2 knockdown promotes differentiation and decreases stem cell function. Nuclear HK2 localization is phosphorylation-dependent, requires active import and export, and regulates differentiation independently of its enzymatic activity. HK2 interacts with nuclear proteins regulating chromatin openness, increasing chromatin accessibilities at leukaemic stem cell-positive signature and DNA-repair sites. Nuclear HK2 overexpression decreases double-strand breaks and confers chemoresistance, which may contribute to the mechanism by which leukaemic stem cells resist DNA-damaging agents. Thus, we describe a non-canonical mechanism by which mitochondrial enzymes influence stem cell function independently of their metabolic function.

DOI: https://doi.org/10.1038/s41556-022-00925-9

Can J Anaesth. 2022 Jun 10.

Applying the geriatric 5Ms in critical care: the ICU-5Ms.

Olivia Geen, Andrew Perrella, Bram Rochwerg, Xuyi Mimi Wang.

Keywords: critical care; delirium; frailty; geriatrics; polypharmacy

DOI: https://doi.org/10.1007/s12630-022-02270-9

Mol Oncol. 2022 Jun 08.

Targeting cellular senescence to combat cancer and aging.

Chen Wang, Xue Hao, Rugang Zhang.

Senescence is a complex cellular process that is implicated in various physiological and pathological processes. It is characterized by a stable state of cell growth arrest and by a secretome of diverse pro-inflammatory factors, chemokines and growth factors. In this review, we summarize the context-dependent role of cellular senescence in aging and in age-related diseases, such as cancer. We discuss current approaches to targeting senescence to develop therapeutic strategies to combat cancer and to promote healthy aging, and we outline our vision for future research directions for senescence-based interventions in these fields.

Keywords: aging; cancer; senescence; senolytics; senomorphics

DOI: https://doi.org/10.1002/1878-0261.13266

Mayo Clin Proc. 2022 Jun;pii: S0025-6196(22)00188-4. [Epub ahead of print]97(6): 1194-1208

Skeletal Aging.

Jad G Sfeir, Matthew T Drake, Sundeep Khosla, Joshua N Farr.

Aging represents the single greatest risk factor for chronic diseases, including osteoporosis, a skeletal fragility syndrome that increases fracture risk. Optimizing bone strength throughout life reduces fracture risk. Factors critical for bone strength include nutrition, physical activity, and vitamin D status, whereas unhealthy lifestyles, illnesses, and certain medications (eg, glucocorticoids) are detrimental. Hormonal status is another important determinant of skeletal health, with sex steroid concentrations, particularly estrogen, having major effects on bone remodeling. Aging exacerbates bone loss in both sexes and results in imbalanced bone resorption relative to formation; it is associated with increased marrow adiposity, osteoblast/osteocyte apoptosis, and accumulation of senescent cells. The mechanisms underlying skeletal aging are as diverse as the factors that determine the strength (and thus fragility) of bone. This review updates our current understanding of the epidemiology, pathophysiology, and treatment of osteoporosis and provides an overview of the underlying hallmark mechanisms that drive skeletal aging.

DOI: https://doi.org/10.1016/j.mayocp.2022.03.011