bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021‒07‒04
thirty-nine papers selected by
Ayesh Seneviratne
University of Toronto

  1. Cells. 2021 Jun 04. pii: 1386. [Epub ahead of print]10(6):
      All vertebrate blood cells descend from multipotent hematopoietic stem cells (HSCs), whose activity and differentiation depend on a complex and incompletely understood relationship with inflammatory signals. Although homeostatic levels of inflammatory signaling play an intricate role in HSC maintenance, activation, proliferation, and differentiation, acute or chronic exposure to inflammation can have deleterious effects on HSC function and self-renewal capacity, and bias their differentiation program. Increased levels of inflammatory signaling are observed during aging, affecting HSCs either directly or indirectly via the bone marrow niche and contributing to their loss of self-renewal capacity, diminished overall functionality, and myeloid differentiation skewing. These changes can have significant pathological consequences. Here, we provide an overview of the current literature on the complex interplay between HSCs and inflammatory signaling, and how this relationship contributes to age-related phenotypes. Understanding the mechanisms and outcomes of this interaction during different life stages will have significant implications in the modulation and restoration of the hematopoietic system in human disease, recovery from cancer and chemotherapeutic treatments, stem cell transplantation, and aging.
    Keywords:  aging; bone marrow niche; hematopoiesis; hematopoietic stem cells; inflammatory signaling; myelodysplasia; myeloid bias; regeneration
  2. Foods. 2021 Jun 02. pii: 1268. [Epub ahead of print]10(6):
      We aimed to assess the effects of the antioxidant-rich Mediterranean diet (MedDiet) on white blood cell count. Our study population included participants in the PREvención con DIeta MEDiterránea study (average age 67 years old, 58% women, high cardiovascular risk). We assessed whether a MedDiet intervention enriched in extra-virgin olive oil or nuts, versus a low-fat control diet, modified the incidence of leukocytosis (>11 × 109 leukocytes/L), mild leukopenia (<4.5 × 109 leukocytes/L), or severe leukopenia (<3.5 × 109 leukocytes/L) in individuals without the condition at baseline (n = 3190, n = 2925, and n = 3190, respectively). We also examined whether MedDiet modified the association between leukocyte count alterations and all-cause mortality. Both MedDiet interventions were associated with a lower risk of developing leukopenia (incidence rates: 5.06% in control diet, 3.29% in MedDiet groups combined; hazard ratio [95% confidence interval]: 0.54 [0.36-0.80]) and severe leukopenia (incidence rates: 1.26% in control diet, 0.46% in MedDiet groups combined; hazard ratio: 0.25 [0.10-0.60]). High cumulative adherence to a MedDiet was linked to lower risk of leukocytosis (incidence rates: 2.08% in quartile 1, 0.65% in quartile 4; HRQ4-Q1: 0.29 [0.085-0.99]) and attenuated the association between leukopenia and all-cause mortality (P-interaction = 0.032). In brief, MedDiet decreased the incidence of white blood cell count-related alterations in high cardiovascular risk individuals.
    Keywords:  Mediterranean diet; leukocytosis; leukopenia; prevention; randomized controlled trial; white blood cell count
  3. Cancers (Basel). 2021 Jun 25. pii: 3190. [Epub ahead of print]13(13):
      INTRODUCTION: Despite a 50% cure rate, relapse remains the main cause of death in patients with acute myeloid leukemia (AML) consolidated with autologous stem cell transplantation (ASCT) in first remission (CR1). Clonal hematopoiesis of indeterminate potential (CH) increases the risk for hematological and cardiovascular disorders and death. The impact of CH persisting after ASCT in AML patients is unclear.MATERIALS AND METHODS: We retrospectively investigated the prognostic value of persisting DNMT3A, TET2, or ASXL1 (DTA) mutations after ASCT. Patients underwent stratification depending on the presence of DTA mutations.
    RESULTS: We investigated 110 consecutive AML patients receiving ASCT in CR1 after two induction cycles at our center between 2007 and 2020. CH-related mutations were present in 31 patients (28.2%) after ASCT. The baseline characteristics were similar between patients with or without persisting DTA mutations after ASCT. The median progression free survival was 26.9 months in patients without DTA mutations and 16.7 months in patients with DTA mutations (HR 0.75 (0.42-1.33), p = 0.287), and the median overall survival was 80.9 and 54.4 months (HR 0.79 (0.41-1.51), p = 0.440), respectively.
    CONCLUSION: We suggest that DTA-CH after ASCT is not associated with an increased risk of relapse or death. The persistence of DTA mutations after induction should not prevent AML patients in CR1 from ASCT consolidation. Independent studies should confirm these data.
    Keywords:  acute myeloid leukemia (AML); autologous stem cell transplantation (ASCT); clonal hematopoiesis (CH); outcome; prognosis
  4. Biology (Basel). 2021 Jun 18. pii: 552. [Epub ahead of print]10(6):
      Autophagy, which literally means "eat yourself", is more than just a lysosomal degradation pathway. It is a well-known regulator of cellular metabolism and a mechanism implicated in tumor initiation/progression and therapeutic resistance in many cancers. However, whether autophagy acts as a tumor suppressor or promoter is still a matter of debate. In acute myeloid leukemia (AML), it is now proven that autophagy supports cell proliferation in vitro and leukemic progression in vivo. Mitophagy, the specific degradation of mitochondria through autophagy, was recently shown to be required for leukemic stem cell functions and survival, highlighting the prominent role of this selective autophagy in leukemia initiation and progression. Moreover, autophagy in AML sustains fatty acid oxidation through lipophagy to support mitochondrial oxidative phosphorylation (OxPHOS), a hallmark of chemotherapy-resistant cells. Nevertheless, in the context of therapy, in AML, as well as in other cancers, autophagy could be either cytoprotective or cytotoxic, depending on the drugs used. This review summarizes the recent findings that mechanistically show how autophagy favors leukemic transformation of normal hematopoietic stem cells, as well as AML progression and also recapitulates its ambivalent role in resistance to chemotherapies and targeted therapies.
    Keywords:  AML; autophagy; hematopoiesis; mitophagy; therapy
  5. Cells. 2021 Jun 14. pii: 1492. [Epub ahead of print]10(6):
      Accessibility of hematopoietic stem cells (HSCs) for the manipulation and repopulation of the blood and immune systems has placed them at the forefront of cell and gene therapy development. Recent advances in genome-editing tools, in particular for clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) and CRISPR/Cas-derived editing systems, have transformed the gene therapy landscape. Their versatility and the ability to edit genomic sequences and facilitate gene disruption, correction or insertion, have broadened the spectrum of potential gene therapy targets and accelerated the development of potential curative therapies for many rare diseases treatable by transplantation or modification of HSCs. Ongoing developments seek to address efficiency and precision of HSC modification, tolerability of treatment and the distribution and affordability of corresponding therapies. Here, we give an overview of recent progress in the field of HSC genome editing as treatment for inherited disorders and summarize the most significant findings from corresponding preclinical and clinical studies. With emphasis on HSC-based therapies, we also discuss technical hurdles that need to be overcome en route to clinical translation of genome editing and indicate advances that may facilitate routine application beyond the most common disorders.
    Keywords:  CRISPR/Cas; TALEN; ZFN; base editor; blood disorders; gene therapy (GT); genome editing; hematopoietic stem cell; monogenic disorder; prime editor
  6. Molecules. 2021 Jun 09. pii: 3506. [Epub ahead of print]26(12):
      Cardiovascular diseases (CVDs) are a global health burden that greatly impact patient quality of life and account for a huge number of deaths worldwide. Despite current therapies, several side effects have been reported that compromise patient adherence; thus, affecting therapeutic benefits. In this context, plant metabolites, namely volatile extracts and compounds, have emerged as promising therapeutic agents. Indeed, these compounds, in addition to having beneficial bioactivities, are generally more amenable and present less side effects, allowing better patient tolerance. The present review is an updated compilation of the studies carried out in the last 20 years on the beneficial potential of essential oils, and their compounds, against major risk factors of CVDs. Overall, these metabolites show beneficial potential through a direct effect on these risk factors, namely hypertension, dyslipidemia and diabetes, or by acting on related targets, or exerting general cellular protection. In general, monoterpenic compounds are the most studied regarding hypotensive and anti-dyslipidemic/antidiabetic properties, whereas phenylpropanoids are very effective at avoiding platelet aggregation. Despite the number of studies performed, clinical trials are sparse and several aspects related to essential oil's features, namely volatility and chemical variability, need to be considered in order to guarantee their efficacy in a clinical setting.
    Keywords:  cardiovascular; diabetes; dyslipidemia; essential oils; hypertension; risk factors
  7. Int J Mol Sci. 2021 Jun 29. pii: 7016. [Epub ahead of print]22(13):
      Immune functions decline as we age, while the incidence of cancer rises. The advent of immune checkpoint blockade (ICB) has not only revolutionized cancer therapy, but also spawned great interest in identifying predictive biomarkers, since only one third of patients show treatment response. The aging process extensively affects the adaptive immune system and thus T cells, which are the main target of ICB. In this review, we address age-related changes regarding the adaptive immune system with a focus on T cells and their implication on carcinogenesis and ICB. Differences between senescence, exhaustion, and anergy are defined and current knowledge, treatment strategies, and studies exploring T cell aging as a biomarker for ICB are discussed. Finally, novel approaches to improve immunotherapies and to identify biomarkers of response to ICB are presented and their potential is assessed in a comparative analysis.
    Keywords:  T cells; aging; biomarker; cancer; exhaustion; immune checkpoint inhibitors; senescence
  8. Cells. 2021 Jun 22. pii: 1568. [Epub ahead of print]10(7):
      Cancer incidence increases drastically with age. Of the many possible reasons for this, there is the accumulation of senescent cells in tissues and the loss of function and proliferation potential of immune cells, often referred to as immuno-senescence. Immune checkpoint inhibitors (ICI), by invigorating immune cells, have the potential to be a game-changers in the treatment of cancer. Yet, the variability in the efficacy of ICI across patients and cancer types suggests that several factors influence the success of such inhibitors. There is currently a lack of clinical studies measuring the impact of aging and senescence on ICI-based therapies. Here, we review how cellular senescence and aging, either by directly altering the immune system fitness or indirectly through the modification of the tumor environment, may influence the cancer-immune response.
    Keywords:  aging; cancer; immune checkpoint inhibitors; senescence; tumor
  9. Life (Basel). 2021 Jun 09. pii: 541. [Epub ahead of print]11(6):
      Sixty years ago (1961), Hayflick and Moorhead reported that primary cells terminate their growth and stop dividing after ~50 passages or one year in culture [...].
  10. Cells. 2021 Jun 11. pii: 1472. [Epub ahead of print]10(6):
      Phospholipids are suggested to drive tumorigenesis through their essential role in inflammation. Phospholipase A2 (PLA2) is a phospholipid metabolizing enzyme that releases free fatty acids, mostly arachidonic acid, and lysophospholipids, which contribute to the development of the tumor microenvironment (TME), promoting immune evasion, angiogenesis, tumor growth, and invasiveness. The mechanisms mediated by PLA2 are not fully understood, especially because an important inhibitory molecule, Annexin A1, is present in the TME but does not exert its action. Here, we will discuss how Annexin A1 in cancer does not inhibit PLA2 leading to both pro-inflammatory and pro-tumoral signaling pathways. Moreover, Annexin A1 promotes the release of cancer-derived exosomes, which also lead to the enrichment of PLA2 and COX-1 and COX-2 enzymes, contributing to TME formation. In this review, we aim to describe the role of PLA2 in the establishment of TME, focusing on cancer-derived exosomes, and modulatory activities of Annexin A1. Unraveling how these proteins interact in the cancer context can reveal new strategies for the treatment of different tumors. We will also describe the possible strategies to inhibit PLA2 and the approaches that could be used in order to resume the anti-PLA2 function of Annexin A1.
    Keywords:  Annexin A1; cancer aggressiveness; lipid metabolism; phospholipase A2; tumor microenvironment; tumorigenesis
  11. Antioxidants (Basel). 2021 Jun 29. pii: 1044. [Epub ahead of print]10(7):
      Oxidative stress and inflammation triggered by increased oxidative stress are the cause of many chronic diseases. The lack of anti-inflammatory drugs without side-effects has stimulated the search for new active substances. Plant-derived compounds provide new potential anti-inflammatory and antioxidant molecules. Natural products are structurally optimized by evolution to serve particular biological functions, including the regulation of endogenous defense mechanisms and interaction with other organisms. This property explains their relevance for infectious diseases and cancer. Recently, among the various natural substances, polyphenols from extra virgin olive oil (EVOO), an important element of the Mediterranean diet, have aroused growing interest. Extensive studies have shown the potent therapeutic effects of these bioactive molecules against a series of chronic diseases, such as cardiovascular diseases, diabetes, neurodegenerative disorders and cancer. This review begins from the chemical structure, abundance and bioavailability of the main EVOO polyphenols to highlight the effects and the possible molecular mechanism(s) of action of these compounds against inflammation and oxidation, in vitro and in vivo. In addition, the mechanisms of inhibition of molecular signaling pathways activated by oxidative stress by EVOO polyphenols are discussed, together with their possible roles in inflammation-mediated chronic disorders, also taking into account meta-analysis of population studies and clinical trials.
    Keywords:  EVOO polyphenols; inflammation; oxidative stress
  12. Aging (Albany NY). 2021 Jun 28. 13
      BACKGROUND: Stem cell aging, characterized by elevated p16INK4a expression, decreases cell repopulating and self-renewal abilities, which results in elevated inflammation and slow recovery against stress.METHODS: Biopsied muscles were analyzed at baseline and 24 h after squat exercise in 12 trained men (22 ± 2 y). Placebo (PLA) and immunostimulant Rg1 (5 mg) were supplemented 1 h before a squat exercise, using a double-blind counterbalanced crossover design.
    RESULTS: Perceived exertion at the end of resistance exercise session was significantly lowered after Rg1 supplementation. Exercise doubled endothelial progenitor cells (EPC) (p < 0.001) and decreased p16INK4a mRNA to 50% of baseline (d = 0.865, p < 0.05) in muscle tissues, despite p16INK4a+ cell and beta-galactosidase+ (ß-Gal+) cell counts being unaltered. Rg1 further lowered p16INK4a mRNA to 35% of baseline with greater effect size than the PLA level (d = 1.302, p < 0.01) and decreased myeloperoxidase (MPO) mRNA to 39% of baseline (p < 0.05). A strong correlation between MPO and p16INK4a expression in muscle tissues was observed (r = 0.84, p < 0.001).
    CONCLUSION: EPC in skeletal muscle doubled 1 d after an acute bout of resistance exercise. The exercised effects in lowering EPC aging and tissue inflammation were enhanced by immunostimulant Rg1, suggesting the involvement of immune stimulation on EPC rejuvenation.
    Keywords:  CD4; Rg1; cellular senescence; p16INK4a; resistance exercise; senolytic
  13. Front Aging Neurosci. 2021 ;13 700306
      Aging is a process that adversely affects brain functions such as cognition. Brain activity is highly energy consuming, with glucose serving as the main energy source under normal circumstances. Whether the dynamics of glucose metabolism change with aging is not well understood. This study sought to investigate the activity-dependent changes in glucose metabolism of the mouse hippocampus during aging. In brief, after 1 h of contextual exploration in an enriched environmental condition or 1 h in a familiar home cage condition, metabolites were measured from the hippocampus of both young adult and aged mice with metabolomic profiling. Compared to the home cage context, the enriched contextual exploration condition resulted in changes in the concentration of 11 glucose metabolism-related metabolites in the young adult hippocampus. In contrast, glucose metabolism-related metabolite changes were more apparent in the aged group altered by contextual exploration when compared to those in the home cage condition. Importantly, in the aged groups, several key metabolites involved in glycolysis, the TCA cycle, and ketone body metabolism accumulated, suggesting the less efficient metabolization of glucose-based energy resources. Altogether, the analyses revealed that in the aged mice altered by enriched contextual exploration, the glucose resource seems to be unable to provide enough energy for hippocampal function.
    Keywords:  aging; energy; enriched contextual exploration; glucose metabolism; hippocampus
  14. Leukemia. 2021 Jul 02.
      The accumulation of somatic mutations in hematopoietic stem cells during aging, leading to clonal expansion, is linked to a higher risk of cardiovascular mortality and hematologic malignancies. Clinically, clonal hematopoiesis is associated with a pro-inflammatory phenotype of hematopoietic cells and their progeny, inflammatory conditions and a poor outcome for patients with hematologic neoplasms and solid tumors. Here, we review the relevance and complications of clonal hematopoiesis for the treatment of hematologic malignancies with cell therapeutic approaches. In autologous and allogeneic hematopoietic stem cell transplantation native hematopoietic and immune effector cells of clonal origin are transferred, which may affect outcome of the procedure. In chimeric antigen receptor modified T-cell therapy, the effectiveness may be altered by preexisting somatic mutations in genetically modified effector cells or by unmodified bystander cells harboring clonal hematopoiesis. Registry studies and carefully designed prospective trials will be required to assess the relative roles of donor- and recipient-derived individual clonal events for autologous and allogeneic cell therapies and to incorporate novel insights into therapeutic strategies.
  15. Front Pharmacol. 2021 ;12 695687
      We have reported recently that the mitochondrial Na+/Ca2+ exchanger inhibitor CGP37157 extends lifespan in Caenorhabditis elegans by a mechanism involving mitochondria, the TOR pathway and the insulin/IGF1 pathway. Here we show that CGP37157 significantly improved the evolution with age of the sarcomeric regular structure, delaying development of sarcopenia in C. elegans body wall muscle and increasing the average and maximum speed of the worms. Similarly, CGP37157 favored the maintenance of a regular mitochondrial structure during aging. We have also investigated further the mechanism of the effect of CGP37157 by studying its effect in mutants of aak-1;aak-2/AMP-activated kinase, sir-2.1/sirtuin, rsks-1/S6 kinase and daf-16/FOXO. We found that this compound was still effective increasing lifespan in all these mutants, indicating that these pathways are not involved in the effect. We have then monitored pharynx cytosolic and mitochondrial Ca2+ signalling and our results suggest that CGP37157 is probably inhibiting not only the mitochondrial Na+/Ca2+ exchanger, but also Ca2+ entry through the plasma membrane. Finally, a transcriptomic study detected that CGP37157 induced changes in lipid metabolism enzymes and a four-fold increase in the expression of ncx-6, one of the C. elegans mitochondrial Na+/Ca2+ exchangers. In summary, CGP37157 increases both lifespan and healthspan by a mechanism involving changes in cytosolic and mitochondrial Ca2+ homeostasis. Thus, Ca2+ signalling could be a promising target to act on aging.
    Keywords:  C. elegans; CGP37157; endoplasmic reticulum; lifespan; mitochondria; sarcopenia
  16. J Nutr Health Aging. 2021 ;25(6): 795-801
      As life expectancy increases, frailty and cognitive impairment have become major factors influencing healthy aging in elderly individuals. Frailty is a complicated clinical condition characterized by decreased physiological reserve and multisystem abnormalities. Cognitive frailty is a subtype of frailty that has aroused widespread concern among the scientific community and public health organizations. We herein review the pathogenesis of cognitive frailty, such as chronic inflammatory response, immunological hypofunction, imbalanced oxidative stress, reduced regenerative function, endocrine dysfunction, and energy metabolism disorder. Although existing interventions show some therapeutic effects, they do not meet the current clinical needs. To date, studies using stem cell technology for treating age-related diseases have achieved remarkable success. This suggests the possibility of applying stem cell treatment to cognitive frailty. We analyzed stem cell-based strategies for targeting anti-inflammation, antioxidation, regeneration, and immunoregulation using mesenchymal stem cells, as well as potential therapeutic targets for cognitive frailty. Based on this investigation, we propose a highly effective and low-cost stem cell-based replacement strategy. However, there is a lack of comprehensive research on the prospect of stem cell transplantation for improving cognitive frailty. In this review, we aim to provide the scientific background and a theoretical basis for testing cell therapy in future research.
    Keywords:  Frailty; cognitive frailty; mesenchymal stem cell therapy
  17. Antioxidants (Basel). 2021 Jun 29. pii: 1047. [Epub ahead of print]10(7):
      Mitochondria act as hubs of numerous metabolic pathways. Mitochondrial dysfunctions contribute to altering the redox balance and predispose to aging and metabolic alterations. The sirtuin family is composed of seven members and three of them, SIRT3-5, are housed in mitochondria. They catalyze NAD+-dependent deacylation and the ADP-ribosylation of mitochondrial proteins, thereby modulating gene expression and activities of enzymes involved in oxidative metabolism and stress responses. In this context, mitochondrial sirtuins (mtSIRTs) act in synergistic or antagonistic manners to protect from aging and aging-related metabolic abnormalities. In this review, we focus on the role of mtSIRTs in the biological competence of reproductive cells, organs, and embryos. Most studies are focused on SIRT3 in female reproduction, providing evidence that SIRT3 improves the competence of oocytes in humans and animal models. Moreover, SIRT3 protects oocytes, early embryos, and ovaries against stress conditions. The relationship between derangement of SIRT3 signaling and the imbalance of ROS and antioxidant defenses in testes has also been demonstrated. Very little is known about SIRT4 and SIRT5 functions in the reproductive system. The final goal of this work is to understand whether sirtuin-based signaling may be taken into account as potential targets for therapeutic applications in female and male infertility.
    Keywords:  SIRT3; SIRT4; SIRT5; fertility; mitochondria; mitochondrial sirtuins (mtSIRTs); oocyte; ovary; sperm; testis
  18. Int J Mol Sci. 2021 Jun 29. pii: 7015. [Epub ahead of print]22(13):
      Adult human cardiomyocytes have an extremely limited proliferative capacity, which poses a great barrier to regenerative medicine and research. Human embryonic stem cells (hESCs) have been proposed as an alternative source to generate large numbers of clinical grade cardiomyocytes (CMs) that can have potential therapeutic applications to treat cardiac diseases. Previous studies have shown that bioactive lipids are involved in diverse cellular responses including cardiogenesis. In this study, we explored the novel function of the chemically synthesized bioactive lipid O-cyclic phytosphingosine-1-phosphate (cP1P) as an inducer of cardiac differentiation. Here, we identified cP1P as a novel factor that significantly enhances the differentiation potential of hESCs into cardiomyocytes. Treatment with cP1P augments the beating colony number and contracting area of CMs. Furthermore, we elucidated the molecular mechanism of cP1P regulating SMAD1/5/8 signaling via the ALK3/BMP receptor cascade during cardiac differentiation. Our result provides a new insight for cP1P usage to improve the quality of CM differentiation for regenerative therapies.
    Keywords:  bioactive lipids; biomolecules; cardiac differentiation; cardiac injury; cardiogenic transcription factors; cardiomyocyte differentiation
  19. Cancers (Basel). 2021 Jun 30. pii: 3296. [Epub ahead of print]13(13):
      Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal disorders caused by sequential accumulation of somatic driver mutations in hematopoietic stem and progenitor cells (HSPCs). MDS is characterized by ineffective hematopoiesis with cytopenia, dysplasia, inflammation, and a variable risk of transformation into secondary acute myeloid leukemia. The advent of next-generation sequencing has revolutionized our understanding of the genetic basis of the disease. Nevertheless, the biology of clonal evolution remains poorly understood, and the stochastic genetic drift with sequential accumulation of genetic hits in HSPCs is individual, highly dynamic and hardly predictable. These continuously moving genetic targets pose substantial challenges for the implementation of precision medicine, which aims to maximize efficacy with minimal toxicity of treatments. In the current postgenomic era, allogeneic hematopoietic stem cell transplantation remains the only curative option for younger and fit MDS patients. For all unfit patients, regeneration of HSPCs stays out of reach and all available therapies remain palliative, which will eventually lead to refractoriness and progression. In this review, we summarize the recent advances in our understanding of MDS pathophysiology and its impact on diagnosis, risk-assessment and disease monitoring. Moreover, we present ongoing clinical trials with targeting compounds and highlight future perspectives for precision medicine.
    Keywords:  future perspectives; myelodysplastic syndromes; postgenomic era; precision medicine; targeted therapies
  20. J Clin Med. 2021 Jun 24. pii: 2788. [Epub ahead of print]10(13):
      Myeloid malignancies arise from an altered hematopoietic stem cell and mainly comprise acute myeloid leukemia, myelodysplastic syndromes, myeloproliferative malignancies, and chronic myelomonocytic leukemia. Myeloid neoplastic leukemic cells may influence the growth and differentiation of other hematopoietic cell lineages in peripheral blood and bone marrow. Myeloid-derived suppressor cells (MDSCs) and mesenchymal stromal cells (MSCs) display immunoregulatory properties by controlling the innate and adaptive immune systems that may induce a tolerant and supportive microenvironment for neoplasm development. This review analyzes the main features of MDSCs and MSCs in myeloid malignancies. The number of MDSCs is elevated in myeloid malignancies exhibiting high immunosuppressive capacities, whereas MSCs, in addition to their immunosuppression contribution, regulate myeloid leukemia cell proliferation, apoptosis, and chemotherapy resistance. Moreover, MSCs may promote MDSC expansion, which may mutually contribute to the creation of an immuno-tolerant neoplasm microenvironment. Understanding the implication of MDSCs and MSCs in myeloid malignancies may favor their potential use in immunotherapeutic strategies.
    Keywords:  T-cell immunosuppression; immunotherapy; mesenchymal stem/stromal cells; myeloid malignancies/neoplasm; myeloid-derived suppressor cells
  21. J Am Coll Cardiol. 2021 Jul 06. pii: S0735-1097(21)04974-3. [Epub ahead of print]78(1): 53-55
    Keywords:  clonal hematopoiesis of indeterminate potential; heart failure; risk factor
  22. Cells. 2021 Jun 29. pii: 1625. [Epub ahead of print]10(7):
      The age of incidence of spinal cord injury (SCI) and the average age of people living with SCI is continuously increasing. However, SCI is extensively modeled in young adult animals, hampering translation of research to clinical applications. While there has been significant progress in manipulating axon growth after injury, the impact of aging is still unknown. Mitochondria are essential to successful neurite and axon growth, while aging is associated with a decline in mitochondrial functions. Using isolation and culture of adult cortical neurons, we analyzed mitochondrial changes in 2-, 6-, 12- and 18-month-old mice. We observed reduced neurite growth in older neurons. Older neurons also showed dysfunctional respiration, reduced membrane potential, and altered mitochondrial membrane transport proteins; however, mitochondrial DNA (mtDNA) abundance and cellular ATP were increased. Taken together, these data suggest that dysfunctional mitochondria in older neurons may be associated with the age-dependent reduction in neurite growth. Both normal aging and traumatic injury are associated with mitochondrial dysfunction, posing a challenge for an aging SCI population as the two elements can combine to worsen injury outcomes. The results of this study highlight this as an area of great interest in CNS trauma.
    Keywords:  CNS Injury; aging; dysfunction; mitochondria; mitochondrial respiration; neurite growth
  23. Semin Immunol. 2021 Jun 29. pii: S1044-5323(21)00010-5. [Epub ahead of print] 101479
      The opposing roles of innate and adaptive immune cells in suppressing or supporting cancer initiation, progression, metastasis and response to therapy has been long debated. The mechanisms by which different monocyte and T cell subtypes affect and modulate cancer have been extensively studied. However, the role of B cells and their subtypes have remained elusive, perhaps partially due to their heterogeneity and range of actions. B cells can produce a variety of cytokines and present tumor-derived antigens to T cells in combination with co-stimulatory or inhibitory ligands based on their phenotype. Unlike most T cells, B cells can be activated by innate immune stimuli, such as endotoxin. Furthermore, the isotype and specificity of the antibodies produced by plasma cells regulate distinct immune responses, including opsonization, antibody-mediated cellular cytotoxicity (ADCC) and complement activation. B cells are shaped by the tumor environment (TME), with the capability to regulate the TME in return. In this review, we will describe the mechanisms of B cell action, including cytokine production, antigen presentation, ADCC, opsonization, complement activation and how they affect tumor development and response to immunotherapy. We will also discuss how B cell fate within the TME is affected by tumor stroma, microbiome and metabolism.
    Keywords:  Anti-tumor immunity; B cells; Cancer; Humoral immunity; Immunotherapy; Plasma cells
  24. Onco Targets Ther. 2021 ;14 3803-3812
      Checkpoint-based immunotherapies, such as programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) inhibitors, have shown promising clinical outcomes in many types of cancers. Unfortunately, the response rate of immune checkpoint inhibitors is low. It is very important to discover novel therapeutic targets and prognostic biomarkers. Cholesterol metabolism has been demonstrated to be related to the occurrence and development of a variety of tumors and may provide a new breakthrough in the development of immunotherapy. First of all, cholesterol metabolism in the tumor microenvironment affects the function of tumor-infiltrating immune cells. In addition, intracellular cholesterol homeostasis is an important regulator of immune cell function. Furthermore, drugs that act on cholesterol metabolism affect the efficacy of immunotherapy. What is more, peripheral blood cholesterol level can be a biomarker to predict the efficacy of immunotherapy. In this review, we aimed to explore the potential role of cholesterol metabolism on immunotherapy. By summarizing the major findings of recent preclinical and clinical studies on cholesterol metabolism in immunotherapy, we suggested that cholesterol metabolism could be a potential therapeutic target and a prognostic biomarker for immunotherapy.
    Keywords:  biomarker; cholesterol metabolism; immune cell; immunotherapy; therapeutic target
  25. Aging (Albany NY). 2021 Jun 26.
    Keywords:  COVID-19; late sequelae; organ-enriched miRNAs; plasma miRNAs; universal screening test (UST)
  26. Comput Struct Biotechnol J. 2021 ;19 3319-3329
      Mitochondria, as the energy factory of cells, participate in metabolism processes and play a critical role in the maintenance of human life activities. Mitochondria belong to semi-automatic organelles, which have their own genome different from nuclear genome. Mitochondrial DNA (mtDNA) mutations can cause a series of diseases and threaten human health. However, an effective approach to edit mitochondrial DNA, though long-desired, is lacking. In recent years, gene editing technologies, represented by restriction endonucleases (RE) technology, zinc finger nuclease (ZFN) technology, transcription activator-like effector nuclease (TALEN) technology, CRISPR system and pAgo-based system have been comprehensively explored, but the application of these technologies in mitochondrial gene editing is still to be explored and optimized. The present study highlights the progress and limitations of current mitochondrial gene editing technologies and approaches, and provides insights for development of novel strategies for future attempts.
    Keywords:  Gene editing; Mitochondria; mtDNA
  27. Antioxidants (Basel). 2021 Jun 22. pii: 994. [Epub ahead of print]10(7):
      Dietary lipids have a major role in nutrition, not only for their fuel value, but also as essential and bioactive nutrients. This narrative review aims to describe the current evidence on nutrigenomic effects of dietary lipids. Firstly, the different chemical and biological properties of fatty acids contained both in plant- and animal-based food are illustrated. A description of lipid bioavailability, bioaccessibility, and lipotoxicity is provided, together with an overview of the modulatory role of lipids as pro- or anti-inflammatory agents. Current findings concerning the metabolic impact of lipids on gene expression, epigenome, and gut microbiome in animal and human studies are summarized. Finally, the effect of the individual's genetic make-up on lipid metabolism is described. The main goal is to provide an overview about the interaction between dietary lipids and the genome, by identifying and discussing recent scientific evidence, recognizing strengths and weaknesses, to address future investigations and fill the gaps in the current knowledge on metabolic impact of dietary fats on health.
    Keywords:  fatty acids; gut microbiota; inflammation; nutrigenomics; personalized nutrition
  28. Clin Lymphoma Myeloma Leuk. 2021 May 29. pii: S2152-2650(21)00203-2. [Epub ahead of print]
      With the Food and Drug Administration approval of 9 agents for different acute myeloid leukemia (AML) indications, the prognosis and management of AML is evolving rapidly. Herein, we review the important milestones in the history of AML research and therapy, discuss insights regarding prognostic assessment and prediction of treatment outcome, detail practical supportive care measures, and summarize the current treatment landscape and areas of evolving research.
    Keywords:  AML; Biology; Prognosis; Targeted therapy; Therapy
  29. J Am Heart Assoc. 2021 Jun 26. e021848
    Keywords:  Editorials; blood pressure; cognitive impairment; dementia
  30. J Clin Endocrinol Metab. 2021 Jun 29. pii: dgab468. [Epub ahead of print]
      CONTEXT: While adrenal adenomas have been linked with cardiovascular morbidity in convenience samples of patients from specialized referral centers, large-scale population-based data is lacking.OBJECTIVE: To determine the prevalence and incidence of cardiometabolic disease and assess mortality in a population-based cohort of patients with adrenal adenomas.
    DESIGN: Population-based cohort study.
    SETTING: Olmsted County, Minnesota.
    PATIENTS: Patients diagnosed with adrenal adenomas without overt hormone excess and age- and sex-matched referent subjects without adrenal adenomas.
    MAIN OUTCOME MEASURE: Prevalence, incidence of cardiometabolic outcomes, mortality.
    RESULTS: Adrenal adenomas were diagnosed in 1,004 patients (58% women, median age 63 years). At baseline, patients with adrenal adenomas were more likely to have hypertension (aOR 1.96, 95% CI 1.58-2.44), dysglycemia (aOR 1.63, 95% CI 1.33-2.00), peripheral vascular disease (aOR 1.59, 95% CI 1.32-2.06), heart failure (aOR 1.64, 95% CI 1.15-2.33), and myocardial infarction (aOR 1.50, 95% CI 1.02-2.22) compared to referent subjects. During median follow-up of 6.8 years, patients with adrenal adenomas were more likely than referent subjects to develop de novo chronic kidney disease(aHR 1.46, 95% CI 1.14-1.86), cardiac arrhythmia(aHR 1.31, 95% CI 1.08-1.58), peripheral vascular disease (aHR 1.28, 95% CI 1.05-1.55), cardiovascular events (aHR 1.33, 95% CI 1.01-1.73), and venous thromboembolic events (aHR 2.15, 95% CI 1.48-3.13). Adjusted mortality was similar between the two groups.
    CONCLUSION: Adrenal adenomas are associated with an increased prevalence and incidence of adverse cardiometabolic outcomes in a population-based cohort.
    Keywords:  adrenal incidentaloma; adrenal mass; cardiovascular events; cardiovascular outcomes; epidemiology; incidence; prevalence
  31. Ann Geriatr Med Res. 2021 Jun;25(2): 65-71
      South Korea became an aged society in 2017 and is predicted to become a super-aged society by 2025. Therefore, knowing the trends among older adults and identifying the geriatric burden are crucial for both healthcare professionals and policymakers. We previously summarized the general health and socioeconomic profiles of Korean older adults from the 2017 National Survey of Living Conditions and Welfare Needs of Older Koreans. In this update, we briefly summarized the results of the 2020 National Survey of Living Conditions and Welfare Needs of Older Koreans by categorizing them according to their general aging profile, socioeconomic status, lifestyle, and health status. In addition, we reviewed recent updates in the field of frailty and sarcopenia from population-based community cohorts in Korea. We hope this study will serve as a current reference for nationwide statistical data on common clinical and social parameters used in geriatrics and gerontology.
    Keywords:  Aged; Frail elderly; Health services for the aged; Residence characteristics
  32. Cells. 2021 Jun 17. pii: 1528. [Epub ahead of print]10(6):
      During past decades, survival rates in cancer patients have drastically improved due to the successful development of novel, promising chemical compounds and therapeutic schedules [...].
  33. Metabolites. 2021 Jun 26. pii: 422. [Epub ahead of print]11(7):
      The endoplasmic reticulum (ER) is a complex, multifunctional organelle of eukaryotic cells and responsible for the trafficking and processing of nearly 30% of all human proteins. Any disturbance to these processes can cause ER stress, which initiates an adaptive mechanism called unfolded protein response (UPR) to restore ER functions and homeostasis. Mitochondrial ATP production is necessary to meet the high energy demand of the UPR, while the molecular mechanisms of ER to mitochondria crosstalk under such stress conditions remain mainly enigmatic. Thus, better understanding the regulation of mitochondrial bioenergetics during ER stress is essential to combat many pathologies involving ER stress, the UPR, and mitochondria. This article investigates the role of Sigma-1 Receptor (S1R), an ER chaperone, has in enhancing mitochondrial bioenergetics during early ER stress using human neuroblastoma cell lines. Our results show that inducing ER stress with tunicamycin, a known ER stressor, greatly enhances mitochondrial bioenergetics in a time- and S1R-dependent manner. This is achieved by enhanced ER Ca2+ leak directed towards mitochondria by S1R during the early phase of ER stress. Our data point to the importance of S1R in promoting mitochondrial bioenergetics and maintaining balanced H2O2 metabolism during early ER stress.
    Keywords:  ER Ca2+ leak; ER stress; UPR; mitochondrial Ca2+; mitochondrial bioenergetics; mitochondrial metabolism; sigma-1 receptor
  34. Cells. 2021 Jun 19. pii: 1550. [Epub ahead of print]10(6):
      COVID-19 is an acute infectious disease of the respiratory system caused by infection with the SARS-CoV-2 virus (Severe Acute Respiratory Syndrome Coronavirus 2). Transmission of SARS-CoV-2 infections occurs through droplets and contaminated objects. A rapid and well-coordinated immune system response is the first line of defense in a viral infection. However, a disturbed and over-activated immune response may be counterproductive, causing damage to the body. Severely ill patients hospitalised with COVID-19 exhibit increased levels of many cytokines, including Interleukin (IL)-1β, IL-2, IL-6, IL-7, IL-8, IL-10, IL-17, granulocyte colony stimulating factor (G-CSF), monocyte chemoattractant protein 1 (MCP-1) and tumor necrosis factor (TNF). Increasing evidence suggests that Th17 cells play an important role in the pathogenesis of COVID-19, not only by activating cytokine cascade but also by inducing Th2 responses, inhibiting Th1 differentiation and suppressing Treg cells. This review focuses on a Th17 pathway in the course of the immune response in COVID-19, and explores plausible targets for therapeutic intervention.
    Keywords:  COVID-19 pneumonia; SARS-CoV-2; Th17 response; cytokines
  35. Mayo Clin Proc Innov Qual Outcomes. 2021 Jun;5(3): 645-653
      Objective: To highlight the current global trends in mortality for cardiovascular disease and cancer.Methods: The World Health Organization and the World Bank DataBank databases were used to analyze mortality rates for cancer and cardiovascular disease by calculating age-standardized mortality rates (ASRs) from 2000 to 2015 for high-income, upper-middle-income, and lower-middle-income countries. Data for cancer mortality and population for 43 countries representing 5 of the 7 continents (except Australia and Antarctica) were analyzed.
    Results: From 2000 to 2015, there was an increase in the ASR for cancer for both men and women irrespective of a country's income status, representing an overall 7% increase in cancer ASR (Pearson r, +0.99; P<.00001). We report a higher ASR for cancer in high-income countries than in upper-middle-income and lower-middle-income countries specifically; high-income countries saw a 3% increase in cancer ASR vs +31% for upper-middle-income and +19% for lower-middle-income countries (P<.01). There has been a decrease in the ASR for cardiovascular disease for the 15 years analyzed (P<.00001). In addition, high-income countries had a higher ASR for cardiovascular disease than upper-middle-income countries during the 15-year period (P<.05).
    Conclusion: We suspect that because of early detection and targeted interventions, cardiovascular disease mortality rates have decreased during the past decade. On the basis of our results, cancer mortality rates continue to rise, with the projection of surpassing cardiovascular disease mortality rates in the near future.
    Keywords:  ASR, age-standardized mortality rate; GBD, Global Burden of Disease; GNI, gross national income; WHO, World Health Organization
  36. Cancers (Basel). 2021 Jun 25. pii: 3183. [Epub ahead of print]13(13):
      Metabolic (bariatric) surgery (MBS) is recommended for individuals with a BMI > 40 kg/m2 or those with a BMI 35-40 kg/m2 who have one or more obesity related comorbidities. MBS leads to greater initial and sustained weight loss than nonsurgical weight loss approaches. MBS provides dramatic improvement in metabolic function, associated with a reduction in type 2 diabetes mellitus and cardiovascular risk. While the number of MBS procedures performed in the U.S. and worldwide continues to increase, they are still only performed on one percent of the affected population. MBS also appears to reduce the risk of certain obesity related cancers, although which cancers are favorably impacted vary by study, who benefits most is uncertain, and the mechanism(s) driving this risk reduction are mostly speculative. The goal of this manuscript is to highlight (1) emerging evidence that MBS influences cancer risk, and that the potential benefit appears to vary based on cancer, gender, surgical procedure, and likely other variables; (2) the role of the NIH in MBS research in T2DM and CV risk for many years, and more recently in cancer; and (3) the opportunity for research to understand the mechanism(s) by which MBS influences cancer. There is evidence that women benefit more from MBS than men, that MBS may actually increase the risk of colorectal cancer in both women and men, and there is speculation that the benefit in cancer risk reduction may vary according to which MBS procedure an individual undergoes. Herein, we review what is currently known, the historical role of government, especially the National Institutes of Health (NIH), in driving this research, and provide suggestions that we believe could lead to a better understanding of whether and how MBS impacts cancer risk, which cancers are impacted either favorably or unfavorably, the role of the NIH and other research agencies, and key questions to address that will help us to move the science forward.
    Keywords:  bariatric surgery; cancer mortality; cancer risk; metabolic surgery
  37. Psychiatr Serv. 2021 Jun 30. appips202100047
      OBJECTIVE: Evidence-based lifestyle interventions tailored to young adults with serious mental illness are needed to reduce their cardiometabolic risk. This study evaluated the effectiveness of a group lifestyle intervention ("PeerFIT") enhanced with mobile health (mHealth) compared with one-on-one mHealth coaching (basic education supported by activity tracking [BEAT]) for young adults with serious mental illness who were overweight or obese.METHODS: Participants were young adults ages 18-35 years with serious mental illness and a body mass index ≥25 kg/m2, who were randomly assigned to PeerFIT or BEAT. Research staff collected data at baseline and at 6 and 12 months. Main outcomes were clinically significant changes from baseline in weight (≥5% weight loss), cardiorespiratory fitness (CRF; increase of >50 m on the 6-minute walk test), and cardiovascular disease (CVD) risk reduction (clinically significant weight loss or CRF improvement).
    RESULTS: Participants were 150 young adults with a mean ± SD body mass index of 37.1±7.4. Intent-to-treat analyses revealed no significant between-group difference for weight-loss, CRF, or CVD outcomes at 6 and 12 months. Participants in both conditions achieved clinically significant CVD risk reduction, weight loss, and CRF from baseline to 6 and 12 months, and all these improvements were statistically significant (p<0.01).
    CONCLUSION: The PeerFIT group lifestyle intervention was not superior to one-on-one mHealth coaching in achieving clinically significant changes in weight, CRF, and CVD risk reduction. Although both interventions improved outcomes, low-intensity mHealth coaching may be a more scalable approach for addressing modifiable cardiometabolic risk factors among young adults with serious mental illness.
    Keywords:  Health coaching; Lifestyle intervention; Mobile health technology; Serious mental illness; Young adults
  38. Iran J Public Health. 2020 Dec;49(12): 2392-2399
      Background: Interests between pain and frailty have been increasing in aging or aged societies. This study aimed to identify the prevalence of pain and frailty and to find the influence of pain on frailty.Methods: Subjects were selected with aged 65 yr or older among pooled Korea Health Panel data from 2009 to 2013. The prevalence of pain was determined by combining some pain and extreme pain and also, frailty was defined when subjects had at least one of the following 6-domain frailty: physical inactivity, mobility reduction, dependence of daily life, depression, multimorbidity, and disability.
    Results: The prevalence of pain and frailty was 56.1% and 59.8%. It was significantly higher in female (66.1% and 65.2%) and the oldest-old (69.4% and 71.8%). After adjusting for gender, age group, spouse, illiteracy, and economic activity, odds ratios of frailty for some pain and extreme pain were 2.8 (95% CI 2.6-3.0) and 10.5 (95% CI 8.0-13.8) in total subjects. The odds ratios of each 6-domain frailty for some and extreme pain were also significant. Among them, mobility reduction was 5.1 (95% CI 4.5-5.8) and 16.5 (95% CI 13.6-20.1), and dependence of daily life was 3.9 (95% CI 3.5-4.5) and 12.4 (95% CI 10.2-15.1).
    Conclusion: Among the elderly, prevalence of frailty (59.8%) was somewhat higher than that of pain (56.1%). Female and oldest-old had higher prevalence of pain and frailty. In addition, some pain and extreme pain had a decisive influence on frailty and each 6-domain frailty. Therefore, pain control is essential to prevent or manage frailty.
    Keywords:  Elderly; Frailty; Odds ratio; Pain; Prevalence
  39. Brain Sci. 2021 Jun 08. pii: 760. [Epub ahead of print]11(6):
      The aim of this study was to describe the clinical evolution during 6 months of follow-up of adults recovered from COVID-19. We tried to determine how many met the definition of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). A total of 130 patients (51.0 ± 14 years, 34.6% female) were enrolled. Symptoms were common, participants reported a median number of 9 (IQR 5-14) symptoms. Fatigue was the most common symptom (61/130; 46.9%). Patients with fatigue were older 53.9 ± 13.5 years compared with 48.5 ± 13.3 years in those without fatigue (p = 0.02) and had a longer length of hospital stay, 17 ± 14 days vs. 13 ± 10 days (p = 0.04). There was no difference in other comorbidities between patients with fatigue and those without it, and no association between COVID-19 severity and fatigue. After multivariate adjustment of all baseline clinical features, only age 40 to 50 years old was positively associated with fatigue, OR 2.5 (95% CI 1.05-6.05) p = 0.03. In our survey, only 17 (13%) patients met the Institute of Medicine's criteria for "systemic exertion intolerance disease," the new name of ME/CFS. In conclusion, in some patients, the features of post-acute COVID-19 syndrome overlap with the clinical features of ME/CFS.
    Keywords:  Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; fatigue; symptoms of COVID-19