bims-minfam 2021-03-14 papers

bims-minfam

Biomed News

on Inflammation and metabolism in ageing and cancer

Issue of 2021–03–14
forty papers selected by
Ayesh Seneviratne, University of Toronto

Endocannabinoids and aging-Inflammation, neuroplasticity, mood and pain.
Senolytics: Potential for Alleviating Diabetes and Its Complications.
Sirtuins and the prevention of immunosenescence.
Fructose- and sucrose- but not glucose-sweetened beverages promote hepatic de novo lipogenesis: A randomized controlled trial.
Acetyl-CoA and Metabolite Fluxes Regulate White Adipose Tissue Expansion.
Clinical and molecular predictors of response and survival following venetoclax therapy in relapsed/refractory AML.
β cell aging and age-related diabetes.
Insulin and aging.
Using mitochondrial activity to select for potent human hematopoietic stem cells.
Arterial stiffness and cardiac dysfunction in Hutchinson-Gilford Progeria Syndrome corrected by inhibition of lysyl oxidase.
Intermittent fasting: from calories to time restriction.
Clonal haematopoiesis of emerging significance.
Consumption of High-Fructose Corn Syrup Compared with Sucrose Promotes Adiposity and Increased Triglyceridemia but Comparable NAFLD Severity in Juvenile Iberian Pigs.
Clinical Implications of Inflammation in Acute Myeloid Leukemia.
Multiple Myeloma Cells Alter Adipogenesis, Increase Senescence-Related and Inflammatory Gene Transcript Expression, and Alter Metabolism in Preadipocytes.
Identification and Development of Therapeutics for COVID-19.
How should we judge edible oils and fats? An umbrella review of the health effects of nutrient and bioactive components found in edible oils and fats.
Cancer Vaccines: Adjuvant Potency, Importance of Age, Lifestyle, and Treatments.
Cytokines and the immune response in obesity-related disorders.
Effect of tomato, lycopene and related products on blood pressure: A systematic review and network meta-analysis.
Systematic Review of Inclusion and Analysis of Older Adults in Randomized Controlled Trials of Medications Used to Treat Inflammatory Bowel Diseases.
Exploring the Role of ATP-Citrate Lyase in the Immune System.
Autophagy is dispensable for the maintenance of hematopoietic stem cells in neonates.
High fat high sucrose diet-induced dyslipidemia in guinea pigs.
Frailty and Quality of Life Among Community-Dwelling Older Adults.
Mitochondria's Role in the Maintenance of Cancer Stem Cells in Glioblastoma.
Benchside to the bedside of frailty and cardiovascular aging: Main shared cellular and molecular mechanisms.
Resistance to CART cell therapy: lessons learned from the treatment of hematological malignancies.
Cellular aging beyond cellular senescence: Markers of senescence prior to cell cycle arrest in vitro and in vivo.
How the lessons of previous epidemics helped successful countries fight covid-19.
Interleukin-6 Is a Biomarker for the Development of Fatal Severe Acute Respiratory Syndrome Coronavirus 2 Pneumonia.
Combining Machine Learning Predictive Algorithms With Behavioral Nudges to Increase Rates of Serious Illness Conversations in Patients With Cancer-Reply.
Aging and altruism: A meta-analysis.
Iron Metabolism in the Tumor Microenvironment: Contributions of Innate Immune Cells.
Covid-19: European countries suspend use of Oxford-AstraZeneca vaccine after reports of blood clots.
COVID-19 Death Reporting Inconsistencies and Working Lessons for Low- and Middle-Income Countries: Opinion.
Behind the scenes of the CRISPR story.
COVID-19 lessons for research.
Cholesterol alters mitophagy by impairing optineurin recruitment and lysosomal clearance in Alzheimer's disease.
Aging and pathological aging signatures of the brain: through the focusing lens of SIRT6.

Vitam Horm. 2021 ;pii: S0083-6729(20)30055-8. [Epub ahead of print]115 129-172

Endocannabinoids and aging-Inflammation, neuroplasticity, mood and pain.

Yongsoon Park, Bruce A Watkins.

  Aging is associated with changes in hormones, slowing of metabolism, diminished physiological processes, chronic inflammation and high exposure to oxidative stress factors, generally described as the biological cost of living. Lifestyle interventions of diet and exercise can improve the quality of life during aging and lower diet-related chronic disease. The endocannabinoid system (ECS) has important effects on systemic metabolism and physiological systems, including the central and peripheral nervous systems. Exercise can reduce the loss of muscle mass and improve strength, and increase the levels of endocannabinoids (eCB) in brain and blood. Although the ECS exerts controls on multiple systems throughout life it affords benefits to natural aging. The eCB are synthesized from polyunsaturated fatty acids (PUFA) and the primary ones are produced from arachidonic acid (n-6 PUFA) and others from the n-3 PUFA, namely eicosapentaenoic and docosahexaenoic acids. The eCB ligands bind to their receptors, CB1 and CB2, with effects on appetite stimulation, metabolism, immune functions, and brain physiology and neuroplasticity. Dietary families of PUFA are a primary factor that can influence the types and levels of eCB and as a consequence, the downstream actions when the ligands bind to their receptors. Furthermore, the association of eCB with the synthesis of oxylipins (OxL) is a connection between the physiological actions of eCB and the lipid derived immunological OxL mediators of inflammation. OxL are ubiquitous and influence neuroinflammation and inflammatory processes. The emerging actions of eCB on neuroplasticity, well-being and pain are important to aging. Herein, we present information about the ECS and its components, how exercise and diet affects specific eCB, their role in neuroplasticity, neuroinflammation, pain, mood, and relationship to OxL. Poor nutrition status and low nutrient intakes observed with many elderly are reasons to examine the role of dietary PUFA actions on the ECS to improve health.

Keywords:  Aging; Cannabinoid receptors; Endocannabinoids; Exercise; Neuroinflammation; Neuroplasticity; Oxylipins; Pain; Polyunsaturated fatty acids

DOI:  https://doi.org/10.1016/bs.vh.2020.12.007
Endocrinology. 2021 Mar 11. pii: bqab058. [Epub ahead of print]

Senolytics: Potential for Alleviating Diabetes and Its Complications.

Allyson K Palmer, Tamar Tchkonia, James L Kirkland.

  Therapeutics that target cellular senescence, including novel "senolytic" compounds, hold significant promise for treating or preventing obesity-induced metabolic dysfunction, type 2 diabetes, and the multiple complications of diabetes and obesity. Senolytics selectively clear senescent cells, which accumulate with aging and obesity and represent a fundamental mechanism of aging that contributes to metabolic dysfunction and diabetes pathogenesis. In addition to improving metabolic function, targeting senescent cells holds promise as a preventative strategy to reduce incidence and severity of diabetes complications. The intermittent administration schedule utilized for senolytic therapy may confer benefits in terms of improving adherence and limiting adverse effects. It is necessary to design effective clinical trials that will safely translate discoveries from preclinical models into human studies that may pave the way for a novel therapeutic class for treating obesity, diabetes, and their complications. In this review, we outline what is known regarding the role of cellular senescence in the pathogenesis of type 2 diabetes and its complications, present evidence from preclinical models that targeting cellular senescence is beneficial, review senolytic drugs, and outline the features of clinical trials investigating the role of targeting senescent cells for diabetes.

Keywords:  aging; cellular senescence; diabetes complications; diabetes mellitus

DOI:  https://doi.org/10.1210/endocr/bqab058
Vitam Horm. 2021 ;pii: S0083-6729(20)30059-5. [Epub ahead of print]115 221-264

Sirtuins and the prevention of immunosenescence.

Denise Lasigliè.

  Aging of hematopoietic stem cells (HSCs) has been largely described as one underlying cause of senescence of the immune-hematopoietic system (immunosenescence). A set of well-defined hallmarks characterizes aged HSCs contributing to unbalanced hematopoiesis and aging-associated functional alterations of both branches of the immune system. In this chapter, the contribution of sirtuins, a family of conserved NAD+ dependent deacetylases with key roles in metabolism, genome integrity, aging and lifespan, to immunosenescence, will be addressed. In particular, the role of SIRT6 will be deeply analyzed highlighting a multifaceted part of this deacetylase in HSCs aging as well as in the immunosenescence of dendritic cells (DCs). These and other emerging data are currently paving the way for future design and development of rejuvenation means aiming at rescuing age-related changes in immune function in the elderly and combating age-associated hematopoietic diseases.

Keywords:  Dendritic cells (DCs); Epigenetics; Hematopoiesis; Hematopoietic stem cells (HSCs); IGF-1; Immunosenescence; NAD(+) dependent deacetylases; Niche; Rejuvenation; SIRT6

DOI:  https://doi.org/10.1016/bs.vh.2020.12.011
J Hepatol. 2021 Mar 05. pii: S0168-8278(21)00161-6. [Epub ahead of print]

Fructose- and sucrose- but not glucose-sweetened beverages promote hepatic de novo lipogenesis: A randomized controlled trial.

Bettina Geidl-Flueck, Michel Hochuli, Ágota Németh, Anita Eberl, Nina Derron, Harald C Köfeler, Luc Tappy, Kaspar Berneis, Giatgen A Spinas, Philipp A Gerber.

   BACKGROUND & AIMS: Excessive fructose intake associates with increased de novo lipogenesis, blood triglycerides, and hepatic insulin resistance. Whether fructose-specific effects on lipid metabolism in healthy men exist independently from overfeeding needs clarification.
METHODS: 94 subjects were studied in this double-blind, randomized trial. They were assigned to daily consumption of sugar-sweetened beverages (SSB) containing moderate amounts of fructose, sucrose (fructose-glucose disaccharide) or glucose (80g/day) in addition to their usual diet or SSB abstinence (control group) for seven weeks. De novo fatty acid (FA) and triglyceride (TAG) synthesis, lipolysis and plasma free FA (FFA) oxidation were assessed by tracer methodology.
RESULTS: Daily intake of beverages sweetened with free fructose and fructose combined with glucose (sucrose) increased basal fractional secretion rates (FSR) of newly synthesized FA by the liver 2-fold compared to control (median FSR %/day: sucrose 20.8 (p=0.0015); fructose 19.7 (p=0.013); control 9.1). Conversely, the same amounts of glucose did not change FSR (median of FSR %/day 11.0 (ns)). Fructose intake did not change basal secretion of newly synthesized VLDL-TAG. It did neither alter rates of peripheral lipolysis nor total FA and plasma FFA oxidation. Total energy intake was similar across groups with SSB intake and controls.
CONCLUSIONS: Regular consumption of both fructose and sucrose sweetened beverages in moderate doses associated with stable caloric intake increases hepatic FA synthesis even in a basal state, whereas this effect is not observed after consumption of glucose. These findings support the hypothesis of an adaptative response of the liver to regular fructose exposure, i. e. habitual SSB consumption. The study has a trial registration number of NCT01733563 (www.clinicaltrials.gov).

Keywords:  carbohydrate; lipid metabolism; liver; stable isotopes; sugar

DOI:  https://doi.org/10.1016/j.jhep.2021.02.027
Trends Endocrinol Metab. 2021 Mar 09. pii: S1043-2760(21)00043-6. [Epub ahead of print]

Acetyl-CoA and Metabolite Fluxes Regulate White Adipose Tissue Expansion.

Jessica B Felix, Aaron R Cox, Sean M Hartig.

  White adipose tissue (WAT) depends on coordinated regulation of transcriptional and metabolic pathways to respond to whole-body energy demands. We highlight metabolites that contribute to biosynthetic reactions for WAT expansion. Recent studies have precisely defined how byproducts of carbohydrate and lipid metabolism affect physiological and endocrine functions in adipocytes. We emphasize the critical emerging roles of short-chain fatty acids (SCFAs) and tricarboxylic acid (TCA) cycle metabolites that connect lipogenesis to WAT energy balance and endocrine functions. These insights address how adipocytes use small molecules generated from central carbon metabolism to measure responses to nutritional stress.

Keywords:  adipose tissue; insulin; lipid metabolism; metabolite; microenvironment

DOI:  https://doi.org/10.1016/j.tem.2021.02.008
Blood Adv. 2021 Mar 09. 5(5): 1552-1564

Clinical and molecular predictors of response and survival following venetoclax therapy in relapsed/refractory AML.

Maximilian Stahl, Kamal Menghrajani, Andriy Derkach, Alexander Chan, Wenbin Xiao, Jacob Glass, Amber C King, Anthony F Daniyan, Christopher Famulare, Bernadette M Cuello, Troy Z Horvat, Omar Abdel-Wahab, Ross L Levine, Aaron D Viny, Eytan M Stein, Sheng F Cai, Mikhail Roshal, Martin S Tallman, Aaron D Goldberg.

Azacitidine + venetoclax, decitabine + venetoclax, and low-dose cytarabine + venetoclax are now standard treatments for newly diagnosed older or unfit patients with acute myeloid leukemia (AML). Although these combinations are also commonly used in relapsed or refractory AML (RR-AML), clinical and molecular predictors of response and survival in RR-AML are incompletely understood. We retrospectively analyzed clinical and molecular characteristics and outcomes for 86 patients with RR-AML who were treated with venetoclax combinations. The complete remission (CR) or CR with incomplete hematologic recovery (CRi) rate was 24%, and the overall response rate was 31% with the inclusion of a morphologic leukemia-free state. Azacitidine + venetoclax resulted in higher response rates compared with low-dose cytarabine + venetoclax (49% vs 15%; P = .008). Median overall survival (OS) was 6.1 months, but it was significantly longer with azacitidine + venetoclax compared with low-dose cytarabine + venetoclax (25 vs 3.9 months; P = .003). This survival advantage of azacitidine + venetoclax over low-dose cytarabine + venetoclax persisted when patients were censored for subsequent allogeneic stem cell transplantation (8.1 vs 3.9 months; P = .035). Mutations in NPM1 were associated with higher response rates, whereas adverse cytogenetics and mutations in TP53, KRAS/NRAS, and SF3B1 were associated with worse OS. Relapse was driven by diverse mechanisms, including acquisition of novel mutations and an increase in cytogenetic complexity. Venetoclax combination therapy is effective in many patients with RR-AML, and pretreatment molecular characteristics may predict outcomes. Trials that evaluate novel agents in combination with venetoclax therapy in patients with RR-AML that have adverse risk genomic features are warranted.

DOI: https://doi.org/10.1182/bloodadvances.2020003734
Aging (Albany NY). 2021 Mar 03. 13

β cell aging and age-related diabetes.

Min Zhu, Xiaohong Liu, Wen Liu, Yanrong Lu, Jingqiu Cheng, Younan Chen.

  Type 2 diabetes is characterized by insulin resistance and loss of β cell mass and function. Aging is considered as a major risk factor for development of type 2 diabetes. However, the roles of pancreatic β cell senescence and systemic aging in the pathogenesis of type 2 diabetes in elderly people remain poorly understood. In this review, we aimed to discuss the current findings and viewpoints focusing on β cell aging and the development of type 2 diabetes.

Keywords:  age-related diabetes; aging; type 2 diabetes (T2D); β cell function; β cell senescence

DOI:  https://doi.org/10.18632/aging.202593
Vitam Horm. 2021 ;pii: S0083-6729(20)30058-3. [Epub ahead of print]115 185-219

Insulin and aging.

Mirian Ayumi Kurauti, Gabriela Moreira Soares, Carine Marmentini, Gabriela Alves Bronczek, Renato Chaves Souto Branco, Antonio Carlos Boschero.

  Aging is characterized by a progressive loss of physiological function leading to increase in the vulnerability to death. This deterioration process occurs in all living organisms and is the primary risk factor for pathological conditions including obesity, type 2 diabetes mellitus, Alzheimer's disease and cardiovascular diseases. Most of the age-related diseases have been associated with impairment of action of an important hormone, namely insulin. It is well-known that this hormone is a critical mediator of metabolism, growth, proliferation and differentiation. Insulin action depends on two processes that determine its circulating levels, insulin secretion and clearance, and insulin sensitivity in its target tissues. Aging has deleterious effects on these three mechanisms, impairing insulin action, thereby increasing the risk for diseases and death. Thus, improving insulin action may be an important strategy to have a healthier and longer life.

Keywords:  Elderly; Health; Insulin action; Insulin clearance; Insulin resistance; Insulin secretion; Insulin sensitivity; Lifespan; Longevity; Old age

DOI:  https://doi.org/10.1016/bs.vh.2020.12.010
Blood Adv. 2021 Mar 23. 5(6): 1605-1616

Using mitochondrial activity to select for potent human hematopoietic stem cells.

Jiajing Qiu, Jana Gjini, Tasleem Arif, Kateri Moore, Miao Lin, Saghi Ghaffari.

Hematopoietic cell transplantation is a critical curative approach for many blood disorders. However, obtaining grafts with sufficient numbers of hematopoietic stem cells (HSCs) that maintain long-term engraftment remains challenging; this is due partly to metabolic modulations that restrict the potency of HSCs outside of their native environment. To address this, we focused on mitochondria. We found that human HSCs are heterogeneous in their mitochondrial activity as measured by mitochondrial membrane potential (MMP) even within the highly purified CD34+CD38-CD45RA-CD90+CD49f+ HSC population. We further found that the most potent HSCs exhibit the lowest mitochondrial activity in the population. We showed that the frequency of long-term culture initiating cells in MMP-low is significantly greater than in MMP-high CD34+CD38-CD45RA-CD90+ (CD90+) HSCs. Notably, these 2 populations were distinct in their long-term repopulating capacity when transplanted into immunodeficient mice. The level of chimerism 7 months posttransplantation was >50-fold higher in the blood of MMP-low relative to MMP-high CD90+ HSC recipients. Although more than 90% of both HSC subsets were in G0, MMP-low CD90+ HSCs exhibited delayed cell-cycle priming profile relative to MMP-high HSCs. These functional differences were associated with distinct mitochondrial morphology; MMP-low in contrast to MMP-high HSCs contained fragmented mitochondria. Our findings suggest that the lowest MMP level selects for the most potent, likely dormant, stem cells within the highly purified HSC population. These results identify a new approach for isolating highly potent human HSCs for further clinical applications. They also implicate mitochondria in the intrinsic regulation of human HSC quiescence and potency.

DOI: https://doi.org/10.1182/bloodadvances.2020003658
Life Sci Alliance. 2021 May;pii: e202000997. [Epub ahead of print]4(5):

Arterial stiffness and cardiac dysfunction in Hutchinson-Gilford Progeria Syndrome corrected by inhibition of lysyl oxidase.

Ryan von Kleeck, Emilia Roberts, Paola Castagnino, Kyle Bruun, Sonja A Brankovic, Elizabeth A Hawthorne, Tina Xu, John W Tobias, Richard K Assoian.

Arterial stiffening and cardiac dysfunction are hallmarks of premature aging in Hutchinson-Gilford Progeria Syndrome (HGPS), but the molecular regulators remain unknown. Here, we show that the LaminAG609G mouse model of HGPS recapitulates the premature arterial stiffening and early diastolic dysfunction seen in human HGPS. Lysyl oxidase (LOX) is up-regulated in the arteries of these mice, and treatment with the LOX inhibitor, β-aminopropionitrile, improves arterial mechanics and cardiac function. Genome-wide and mechanistic analysis revealed reduced expression of the LOX-regulator, miR-145, in HGPS arteries, and forced expression of miR-145 restores normal LOX gene expression in HGPS smooth muscle cells. LOX abundance is also increased in the carotid arteries of aged wild-type mice, but its spatial expression differs from HGPS and its up-regulation is independent of changes in miR-145 abundance. Our results show that miR-145 is selectively misregulated in HGPS and that the consequent up-regulation of LOX is causal for premature arterial stiffening and cardiac dysfunction.

DOI: https://doi.org/10.26508/lsa.202000997
Geroscience. 2021 Mar 09.

Intermittent fasting: from calories to time restriction.

Eleonora Duregon, Laura C D D Pomatto-Watson, Michel Bernier, Nathan L Price, Rafael de Cabo.

  The global human population has recently experienced an increase in life expectancy with a mounting concern about the steady rise in the incidence of age-associated chronic diseases and socio-economic burden. Calorie restriction (CR), the reduction of energy intake without malnutrition, is a dietary manipulation that can increase health and longevity in most model organisms. However, the practice of CR in day-to-day life is a challenging long-term goal for human intervention. Recently, daily fasting length and periodicity have emerged as potential drivers behind CR's beneficial health effects. Numerous strategies and eating patterns have been successfully developed to recapitulate many of CR's benefits without its austerity. These novel feeding protocols range from shortened meal timing designed to interact with our circadian system (e.g., daily time-restricted feeding) to more extended fasting regimens known as intermittent fasting. Here, we provide a glimpse of the current status of knowledge on different strategies to reap the benefits of CR on metabolic health in murine models and in humans, without the rigor of continuous reduction in caloric intake as presented at the USU State of the Science Symposium.

Keywords:  Calorie restriction; Calories; Fasting; Intermittent Fasting; Time Restricted Feeding

DOI:  https://doi.org/10.1007/s11357-021-00335-z
Pathology. 2021 Mar 05. pii: S0031-3025(21)00059-3. [Epub ahead of print]

Clonal haematopoiesis of emerging significance.

Danielle Hammond, Sanam Loghavi.

  Clonal haematopoiesis (CH) is a ubiquitous feature of aging and provides mechanistic insight into the inextricable relationship between chronic inflammation and age-related diseases. Although CH confers a cumulative risk of subsequent haematological malignancy, particularly myeloid neoplasms, that risk is heavily mutation- and context-specific. Individuals with mutations in DNA damage response pathway genes receiving select cytotoxic therapies for solid tumours are among the highest risk groups for subsequent development of myeloid neoplasms. Multiple lines of evidence suggest that TET2-mutated macrophages causally contribute to cardiometabolic disease through the generation of proinflammatory cytokines. It is speculated that such CH-related inflammation is a shared driver of several other chronic diseases. Whether we can intervene in individuals with CH to diminish the risk of subsequent haematological malignancy or non-haematological disease remains to be seen. However, precision anti-cytokine therapies are a rational starting point to break the feedforward loop between clonal myeloid expansion, inflammation, and end-organ damage.

Keywords:  Age-related; cardiometabolic; clonal haematopoiesis; inflammasome; myeloid

DOI:  https://doi.org/10.1016/j.pathol.2021.02.005
J Nutr. 2021 Mar 09. pii: nxaa441. [Epub ahead of print]

Consumption of High-Fructose Corn Syrup Compared with Sucrose Promotes Adiposity and Increased Triglyceridemia but Comparable NAFLD Severity in Juvenile Iberian Pigs.

Magdalena Maj, Brooke Harbottle, Payton A Thomas, Gabriella V Hernandez, Victoria A Smith, Mark S Edwards, Rob K Fanter, Hunter S Glanz, Chad Immoos, Douglas G Burrin, Tasha M Santiago-Rodriguez, Michael R La Frano, Rodrigo Manjarín.

   BACKGROUND: Fructose consumption has been linked to nonalcoholic fatty liver disease (NAFLD) in children. However, the effect of high-fructose corn syrup (HFCS) compared with sucrose in pediatric NAFLD has not been investigated.
OBJECTIVES: We tested whether the isocaloric substitution of dietary sucrose by HFCS would increase the severity of NAFLD in juvenile pigs, and whether this effect would be associated with changes in gut histology, SCFA production, and microbial diversity.
METHODS: Iberian pigs, 53-d-old and pair-housed in pens balanced for weight and sex, were randomly assigned to receive a mash diet top-dressed with increasing amounts of sucrose (SUC; n = 3 pens; 281.6-486.8 g/kg diet) or HFCS (n = 4; 444.3-724.8 g/kg diet) during 16 wk. Diets exceeded the animal's energy requirements by providing sugars in excess, but met the requirements for all other nutrients. Animals were killed at 165 d of age after blood sampling, and liver, muscle, and gut were collected for histology, metabolome, and microbiome analyses. Data were analyzed by multivariate and univariate statistics.
RESULTS: Compared with SUC, HFCS increased subcutaneous fat, triacylglycerides in plasma, and butyrate in colon (P ≤ 0.05). In addition, HFCS decreased UMP and short-chain acyl carnitines in liver, and urea nitrogen and creatinine in serum (P ≤ 0.05). Microbiome analysis showed a 24.8% average dissimilarity between HFCS and SUC associated with changes in SCFA-producing bacteria. Body weight gain, intramuscular fat, histological and serum markers of liver injury, and circulating hormones, glucose, and proinflammatory cytokines did not differ between diets.
CONCLUSIONS: Fructose consumption derived from HFCS promoted butyrate synthesis, triglyceridemia, and subcutaneous lipid deposition in juvenile Iberian pigs, but did not increase serum and histological markers of NAFLD compared with a sucrose-enriched diet. Longer studies could be needed to observe differences in liver injury among sugar types.

Keywords:  added sugar; dysbiosis; metabolomics; microbiome; pediatric

DOI:  https://doi.org/10.1093/jn/nxaa441
Front Oncol. 2021 ;11 623952

Clinical Implications of Inflammation in Acute Myeloid Leukemia.

Christian Récher.

  Recent advances in the description of the tumor microenvironment of acute myeloid leukemia, including the comprehensive analysis of the leukemic stem cell niche and clonal evolution, indicate that inflammation may play a major role in many aspects of acute myeloid leukemia (AML) such as disease progression, chemoresistance, and myelosuppression. Studies on the mechanisms of resistance to chemotherapy or tyrosine kinase inhibitors along with high-throughput drug screening have underpinned the potential role of glucocorticoids in this disease classically described as steroid-resistant in contrast to acute lymphoblastic leukemia. Moreover, some mutated oncogenes such as RUNX1, NPM1, or SRSF2 transcriptionally modulate cell state in a manner that primes leukemic cells for glucocorticoid sensitivity. In clinical practice, inflammatory markers such as serum ferritin or IL-6 have a strong prognostic impact and may directly affect disease progression, whereas interesting preliminary data suggested that dexamethasone may improve the outcome for AML patients with a high white blood cell count, which paves the way to develop prospective clinical trials that evaluate the role of glucocorticoids in AML.

Keywords:  FLT3; RUNX1; acute myeloid leukemia; chemoresistance; dexamethasone; glucocorticoids; inflammation; leukemic stem cells

DOI:  https://doi.org/10.3389/fonc.2021.623952
Front Oncol. 2020 ;10 584683

Multiple Myeloma Cells Alter Adipogenesis, Increase Senescence-Related and Inflammatory Gene Transcript Expression, and Alter Metabolism in Preadipocytes.

Heather Fairfield, Samantha Costa, Carolyne Falank, Mariah Farrell, Connor S Murphy, Anastasia D'Amico, Heather Driscoll, Michaela R Reagan.

  Within the bone marrow microenvironment, mesenchymal stromal cells (MSCs) are an essential precursor to bone marrow adipocytes and osteoblasts. The balance between this progenitor pool and mature cells (adipocytes and osteoblasts) is often skewed by disease and aging. In multiple myeloma (MM), a cancer of the plasma cell that predominantly grows within the bone marrow, as well as other cancers, MSCs, preadipocytes, and adipocytes have been shown to directly support tumor cell survival and proliferation. Increasing evidence supports the idea that MM-associated MSCs are distinct from healthy MSCs, and their gene expression profiles may be predictive of myeloma patient outcomes. Here we directly investigate how MM cells affect the differentiation capacity and gene expression profiles of preadipocytes and bone marrow MSCs. Our studies reveal that MM.1S cells cause a marked decrease in lipid accumulation in differentiating 3T3-L1 cells. Also, MM.1S cells or MM.1S-conditioned media altered gene expression profiles of both 3T3-L1 and mouse bone marrow MSCs. 3T3-L1 cells exposed to MM.1S cells before adipogenic differentiation displayed gene expression changes leading to significantly altered pathways involved in steroid biosynthesis, the cell cycle, and metabolism (oxidative phosphorylation and glycolysis) after adipogenesis. MM.1S cells induced a marked increase in 3T3-L1 expression of MM-supportive genes including Il-6 and Cxcl12 (SDF1), which was confirmed in mouse MSCs by qRT-PCR, suggesting a forward-feedback mechanism. In vitro experiments revealed that indirect MM exposure prior to differentiation drives a senescent-like phenotype in differentiating MSCs, and this trend was confirmed in MM-associated MSCs compared to MSCs from normal donors. In direct co-culture, human mesenchymal stem cells (hMSCs) exposed to MM.1S, RPMI-8226, and OPM-2 prior to and during differentiation, exhibited different levels of lipid accumulation as well as secreted cytokines. Combined, our results suggest that MM cells can inhibit adipogenic differentiation while stimulating expression of the senescence associated secretory phenotype (SASP) and other pro-myeloma molecules. This study provides insight into a novel way in which MM cells manipulate their microenvironment by altering the expression of supportive cytokines and skewing the cellular diversity of the marrow.

Keywords:  adipocytes; bone marrow; mesenchymal stromal cells (MSCs); microarray; myeloma; preadipocytes ; senescence

DOI:  https://doi.org/10.3389/fonc.2020.584683
ArXiv. 2021 Mar 03. pii: arXiv:2103.02723v1. [Epub ahead of print]

Identification and Development of Therapeutics for COVID-19.

Halie M Rando, Nils Wellhausen, Soumita Ghosh, Alexandra J Lee, Anna Ada Dattoli, Fengling Hu, James Brian Byrd, Diane N Rafizadeh, Yanjun Qi, Yuchen Sun, Jeffrey M Field, Marouen Ben Guebila, Nafisa M Jadavji, Ronan Lordan, Ashwin N Skelly, Bharath Ramsundar, Christian Brueffer, Jinhui Wang, Rishi Raj Goel, YoSon Park, Covid-Review Consortium, Simina M Boca, Anthony Gitter, Casey S Greene.

After emerging in China in late 2019, the novel Severe acute respiratory syndrome-like coronavirus 2 (SARS-CoV-2) spread worldwide and as of early 2021, continues to significantly impact most countries. Only a small number of coronaviruses are known to infect humans, and only two are associated with the severe outcomes associated with SARS-CoV-2: Severe acute respiratory syndrome-related coronavirus, a closely related species of SARS-CoV-2 that emerged in 2002, and Middle East respiratory syndrome-related coronavirus, which emerged in 2012. Both of these previous epidemics were controlled fairly rapidly through public health measures, and no vaccines or robust therapeutic interventions were identified. However, previous insights into the immune response to coronaviruses gained during the outbreaks of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) have proved beneficial to identifying approaches to the treatment and prophylaxis of novel coronavirus disease 2019 (COVID-19). A number of potential therapeutics against SARS-CoV-2 and the resultant COVID-19 illness were rapidly identified, leading to a large number of clinical trials investigating a variety of possible therapeutic approaches being initiated early on in the pandemic. As a result, a small number of therapeutics have already been authorized by regulatory agencies such as the Food and Drug Administration (FDA) in the United States, and many other therapeutics remain under investigation. Here, we describe a range of approaches for the treatment of COVID-19, along with their proposed mechanisms of action and the current status of clinical investigation into each candidate. The status of these investigations will continue to evolve, and this review will be updated as progress is made.
Crit Rev Food Sci Nutr. 2021 Mar 11. 1-15

How should we judge edible oils and fats? An umbrella review of the health effects of nutrient and bioactive components found in edible oils and fats.

Scott B Teasdale, Skye Marshall, Kylie Abbott, Tim Cassettari, Emily Duve, Flavia Fayet-Moore.

  Dietary guidelines for many Western countries base their edible oil and fat recommendations solely on saturated fatty acid content. This study aims to demonstrate which nutritional and bioactive components make up commonly consumed edible oils and fats; and explore the health effects and strength of evidence for key nutritional and bioactive components of edible oils. An umbrella review was conducted in several stages. Food composition databases of Australia and the United States of America, and studies were examined to profile nutrient and bioactive content of edible oils and fats. PUBMED and Cochrane databases were searched for umbrella reviews, systematic literature reviews of randomized controlled trials or cohort studies, individual randomized controlled trials, and individual cohort studies to examine the effect of the nutrient or bioactive on high-burden chronic diseases (cardiovascular disease, type 2 diabetes mellitus, obesity, cancer, mental illness, cognitive impairment). Substantial systematic literature review evidence was identified for fatty acid categories, tocopherols, biophenols, and phytosterols. Insufficient evidence was identified for squalene. The evidence supports high mono- and polyunsaturated fatty acid compositions, total biophenol content, phytosterols, and possibly high α-tocopherol content as having beneficial effects on high-burden health comes. Future dietary guidelines should use a more sophisticated approach to judge edible oils beyond saturated fatty acid content.

Keywords:  Guideline; fats; fatty acids; nutrition policy; phytosterols; plant oils; polyphenols; squalene; tocopherols

DOI:  https://doi.org/10.1080/10408398.2021.1882382
Front Immunol. 2020 ;11 615240

Cancer Vaccines: Adjuvant Potency, Importance of Age, Lifestyle, and Treatments.

Stefania Cuzzubbo, Sara Mangsbo, Divya Nagarajan, Kinana Habra, Alan Graham Pockley, Stephanie E B McArdle.

  Although the discovery and characterization of multiple tumor antigens have sparked the development of many antigen/derived cancer vaccines, many are poorly immunogenic and thus, lack clinical efficacy. Adjuvants are therefore incorporated into vaccine formulations to trigger strong and long-lasting immune responses. Adjuvants have generally been classified into two categories: those that 'depot' antigens (e.g. mineral salts such as aluminum hydroxide, emulsions, liposomes) and those that act as immunostimulants (Toll Like Receptor agonists, saponins, cytokines). In addition, several novel technologies using vector-based delivery of antigens have been used. Unfortunately, the immune system declines with age, a phenomenon known as immunosenescence, and this is characterized by functional changes in both innate and adaptive cellular immunity systems as well as in lymph node architecture. While many of the immune functions decline over time, others paradoxically increase. Indeed, aging is known to be associated with a low level of chronic inflammation-inflamm-aging. Given that the median age of cancer diagnosis is 66 years and that immunotherapeutic interventions such as cancer vaccines are currently given in combination with or after other forms of treatments which themselves have immune-modulating potential such as surgery, chemotherapy and radiotherapy, the choice of adjuvants requires careful consideration in order to achieve the maximum immune response in a compromised environment. In addition, more clinical trials need to be performed to carefully assess how less conventional form of immune adjuvants, such as exercise, diet and psychological care which have all be shown to influence immune responses can be incorporated to improve the efficacy of cancer vaccines. In this review, adjuvants will be discussed with respect to the above-mentioned important elements.

Keywords:  adjuvant; cancer vaccine; immunosenescence; immunotherapy; inflamm-aging; microbiota

DOI:  https://doi.org/10.3389/fimmu.2020.615240
Adv Clin Chem. 2021 ;pii: S0065-2423(20)30076-7. [Epub ahead of print]101 135-168

Cytokines and the immune response in obesity-related disorders.

Meysam Moghbeli, Hamed Khedmatgozar, Mehran Yadegari, Amir Avan, Gordon A Ferns, Majid Ghayour Mobarhan.

  The increasing prevalence of obesity and the associated morbidity and mortality are important public health problems globally. There is an important relationship between an unhealthy lifestyle and increased serum inflammatory cytokines. Adipocytes secrete several pro-inflammatory cytokines involved in the recruitment and activation of macrophages resulting in chronic low-grade inflammation. Increased cytokines in obese individual are related to the progression of several disorders including cardiovascular disease, hypertension, and insulin resistance. In present review we have summarized the crucial roles of cytokines and their inflammatory functions in obesity-related immune disorders.

Keywords:  Cytokine; Immune disorder; Inflammation; Obesity

DOI:  https://doi.org/10.1016/bs.acc.2020.06.004
Phytomedicine. 2021 Feb 16. pii: S0944-7113(21)00054-4. [Epub ahead of print] 153512

Effect of tomato, lycopene and related products on blood pressure: A systematic review and network meta-analysis.

Wipharak Rattanavipanon, Chonruepat Nithiphongwarakul, Pornsawan Sirisuwansith, Thanaputt Chaiyasothi, Ammarin Thakkinstian, Surakit Nathisuwan, Thanika Pathomwichaiwat.

   BACKGROUND: A number of randomized controlled trials (RCTs) have been conducted to evaluate the hypotensive effects of tomato, lycopene, and related products. However, the findings were conflicting, partly due to differences in the types of products investigated. Therefore, this study aimed to assess and compare the hypotensive effects of different tomato-related preparations through a network meta-analysis based on randomized controlled trials.
STUDY DESIGN: A systematic review and network meta-analysis.
METHODS: A network meta-analysis based on a systematic review of RCTs comparing the effect of various tomato, lycopene and related products versus placebo on blood pressure in adults was performed. PubMed, EMBASE, SCOPUS, and Clinicaltrial.gov databases were searched up to October 2020 without language restrictions. The primary outcomes were systolic and diastolic blood pressure. Mean differences (MDs) along with 95% confidence intervals (CIs) were estimated and pooled using a random-effects model. Heterogeneity was assessed using the global inconsistency test.
RESULTS: A total of 11 studies including six forms of tomato, lycopene and related products met the inclusion criteria. Among these trials, eight (N = 617) and seven trials (N = 501) were included in the analysis of systolic (SBP) and diastolic blood pressure (DBP) outcomes, respectively. The standardized tomato extract (STE) significantly decreased SBP compared to placebo, with a pooled MD (95% CI) of -5.89 (-9.13 to -2.64) mmHg. The effect on DBP was not significant, with a pooled MD (95% CI) of -3.51 (-7.39 to 0.38) mmHg. Subgroup analysis in hypertensive patients showed that STE significantly reduced both SBP and DBP with pooled MDs (95% CIs) of -8.09 (-11.52 to -4.67) and -4.25 (-6.97 to -1.53) mmHg, respectively, compared to placebo. Other forms of tomato, including other dose ranges of standardized tomato extract, tomato-containing diet, lycopene-free preparation, and synthetic lycopene, did not show consistent and significant effects on either SBP or DBP in all analyses.
CONCLUSION: Standardized tomato extract (STE) significantly decreased SBP compared to placebo in a mixed population of healthy volunteers and hypertensive patients. The BP-lowering effect was more pronounced among hypertensive patients. No significant BP effects were seen with other forms of tomato, lycopene and related products in the overall population or any subgroup of the population.

Keywords:  Cardiovascular disease; Hypertension; Lycopene; Network meta-analysis; Tomato

DOI:  https://doi.org/10.1016/j.phymed.2021.153512
Inflamm Bowel Dis. 2021 Mar 11. pii: izab052. [Epub ahead of print]

Systematic Review of Inclusion and Analysis of Older Adults in Randomized Controlled Trials of Medications Used to Treat Inflammatory Bowel Diseases.

Bharati Kochar, Lakshman Kalasapudi, Nneka N Ufere, Ryan D Nipp, Ashwin N Ananthakrishnan, Christine S Ritchie.



Keywords:  Crohn’s disease; aging; clinical trials; treatment; ulcerative colitis

DOI:  https://doi.org/10.1093/ibd/izab052
Front Immunol. 2021 ;12 632526

Exploring the Role of ATP-Citrate Lyase in the Immune System.

Monica Dominguez, Bernhard Brüne, Dmitry Namgaladze.

  Studies over the past decade have revealed that metabolism profoundly influences immune responses. In particular, metabolism causes epigenetic regulation of gene expression, as a growing number of metabolic intermediates are substrates for histone post-translational modifications altering chromatin structure. One of these substrates is acetyl-coenzyme A (CoA), which donates an acetyl group for histone acetylation. Cytosolic acetyl-CoA is also a critical substrate for de novo synthesis of fatty acids and sterols necessary for rapid cellular growth. One of the main enzymes catalyzing cytosolic acetyl-CoA formation is ATP-citrate lyase (ACLY). In addition to its classical function in the provision of acetyl-CoA for de novo lipogenesis, ACLY contributes to epigenetic regulation through histone acetylation, which is increasingly appreciated. In this review we explore the current knowledge of ACLY and acetyl-CoA in mediating innate and adaptive immune responses. We focus on the role of ACLY in supporting de novo lipogenesis in immune cells as well as on its impact on epigenetic alterations. Moreover, we summarize alternative sources of acetyl-CoA and their contribution to metabolic and epigenetic regulation in cells of the immune system.

Keywords:  ATP-citrate lyase; acetyl-CoA; histone acetylation; macrophage; metabolism

DOI:  https://doi.org/10.3389/fimmu.2021.632526
Blood Adv. 2021 Mar 23. 5(6): 1594-1604

Autophagy is dispensable for the maintenance of hematopoietic stem cells in neonates.

Michihiro Hashimoto, Terumasa Umemoto, Ayako Nakamura-Ishizu, Takayoshi Matsumura, Tomomasa Yokomizo, Maiko Sezaki, Hitoshi Takizawa, Toshio Suda.

Hematopoietic stem cells (HSCs) undergo self-renewal or differentiation to sustain lifelong hematopoiesis. HSCs are preserved in quiescence with low mitochondrial activity. Recent studies indicate that autophagy contributes to HSC quiescence through suppressing mitochondrial metabolism. However, it remains unclear whether autophagy is involved in the regulation of neonatal HSCs, which proliferate actively. In this study, we clarified the role of autophagy in neonatal HSCs using 2 types of autophagy-related gene 7 (Atg7)-conditional knockout mice: Mx1-Cre inducible system and Vav-Cre system. Atg7-deficient HSCs exhibited excess cell divisions with enhanced mitochondrial metabolism, leading to bone marrow failure at adult stage. However, Atg7 deficiency minimally affected hematopoiesis and metabolic state in HSCs at neonatal stage. In addition, Atg7-deficient neonatal HSCs exhibited long-term reconstructing activity, equivalent to wild-type neonatal HSCs. Taken together, autophagy is dispensable for stem cell function and hematopoietic homeostasis in neonates and provide a novel aspect into the role of autophagy in the HSC regulation.

DOI: https://doi.org/10.1182/bloodadvances.2020002410
J Appl Physiol (1985). 2021 Mar 11.

High fat high sucrose diet-induced dyslipidemia in guinea pigs.

Cynthia Rodrigues Muller, Alexander T Williams, Allyn M Eaker, Fernando Dos Santos, Andre F Palmer, Pedro Cabrales.

  Easy access to high-calorie and fat-dense fast food has resulted in unhealthy dietary and lifestyle changes worldwide, which affects both developed and developing economies. This predisposes populations to a considerable number of metabolic and inflammatory conditions, such as diabetes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular disease (CVD). Guinea pigs have been proposed as a model to study high fat diet-induced metabolic disease due to their similar antioxidant metabolism and lipid profile to humans, and their susceptibility to atherosclerosis and endothelial disease. This study aims to evaluate cardiovascular and metabolic disorders induced by high-fat high-sucrose diet (HFHSD) in guinea pigs. 2-3-week-old male guinea pigs were fed a normal diet (ND) or HFHSD for 12 weeks. Guinea pigs fed a HFHSD developed glucose intolerance, dyslipidemia, and liver, cardiac, and kidney damage. However, hypertension, dysautonomia, endothelial disease, and obesity were absent in these HFHSD guinea pigs. Taken together, these results show that guinea pigs fed a HFHSD are a non-obese model of metabolic disorders, resulting in important cardiac damage. Moreover, our findings suggest that NAFLD may be an important risk factor for diet induced CVD.

Keywords:  Cardiovascular disease; Dyslipidemia; Guinea pigs

DOI:  https://doi.org/10.1152/japplphysiol.00013.2021
Cureus. 2021 Feb 01. 13(2): e13049

Frailty and Quality of Life Among Community-Dwelling Older Adults.

Ioanna V Papathanasiou, Anna Rammogianni, Dimitrios Papagiannis, Foteini Malli, Dimitrios C Mantzaris, Konstantinos Tsaras, Lamprini Kontopoulou, Evridiki Kaba, Martha Kelesi, Evangelos C Fradelos.

  Older people often feel weak and have limited physical activity and walking capacity, without energy. These characteristics meet the conditions for the onset of the frailty syndrome. The effect that frailty syndrome can have on the elderly's quality of life (QOL) status has not been sufficiently explored, especially in the Greek population. This study aims to investigate the correlation between frailty and QOL in a community population of elderly people with independent living. A descriptive cross-sectional study was performed. The study sample consisted of 257 elderly people from three Open Care Centers for the Elderly Population of the Municipality of Grevena, Greece. The Tilburg Frailty Indicator was used to measure frailty in elderly people and the World Health Organization QOL-BREF was used to assess the health-related QOL of older people. The majority of elderly people showed relatively low overall frailty score (mean: 5.44). The elderly people had relatively high QoL assessment values and general satisfaction with their health condition. The obtained results show a statistically significant negative relationship between (i) physical frailty, psychological frailty, and all dimensions of QOL, (ii) social frailty and social relationships, and (iii) total frailty and all dimensions of QOL. Consequently, despite an average age of 75.12 years and higher female participation, the study population was not very frail and were satisfied with their QOL. Frailty has a negative effect in all QOL domains.

Keywords:  aging; community healthcare; elderly people; frailty; health aging.; quality of life

DOI:  https://doi.org/10.7759/cureus.13049
Front Oncol. 2021 ;11 582694

Mitochondria's Role in the Maintenance of Cancer Stem Cells in Glioblastoma.

Yasaman Iranmanesh, Biao Jiang, Okoye C Favour, Zhangqi Dou, Jiawei Wu, Jinfan Li, Chongran Sun.

  Glioblastoma (GBM), one of the deadliest primary brain malignancies, is characterized by a high recurrence rate due to its limited response to existing therapeutic strategies such as chemotherapy, radiation therapy, and surgery. Several mechanisms and pathways have been identified to be responsible for GBM therapeutic resistance. Glioblastoma stem cells (GSCs) are known culprits of GBM resistance to therapy. GSCs are characterized by their unique self-renewal, differentiating capacity, and proliferative potential. They form a heterogeneous population of cancer stem cells within the tumor and are further divided into different subpopulations. Their distinct molecular, genetic, dynamic, and metabolic features distinguish them from neural stem cells (NSCs) and differentiated GBM cells. Novel therapeutic strategies targeting GSCs could effectively reduce the tumor-initiating potential, hence, a thorough understanding of mechanisms involved in maintaining GSCs' stemness cannot be overemphasized. The mitochondrion, a regulator of cellular physiological processes such as autophagy, cellular respiration, reactive oxygen species (ROS) generation, apoptosis, DNA repair, and cell cycle control, has been implicated in various malignancies (for instance, breast, lung, and prostate cancer). Besides, the role of mitochondria in GBM has been extensively studied. For example, when stressors, such as irradiation and hypoxia are present, GSCs utilize specific cytoprotective mechanisms like the activation of mitochondrial stress pathways to survive the harsh environment. Proliferating GBM cells exhibit increased cytoplasmic glycolysis in comparison to terminally differentiated GBM cells and quiescent GSCs that rely more on oxidative phosphorylation (OXPHOS). Furthermore, the Warburg effect, which is characterized by increased tumor cell glycolysis and decreased mitochondrial metabolism in the presence of oxygen, has been observed in GBM. Herein, we highlight the importance of mitochondria in the maintenance of GSCs.

Keywords:  GSC; glioblastoma; metabolism; mitochondria; quiescence; stem cell; stemness

DOI:  https://doi.org/10.3389/fonc.2021.582694
Exp Gerontol. 2021 Mar 03. pii: S0531-5565(21)00077-2. [Epub ahead of print]148 111302

Benchside to the bedside of frailty and cardiovascular aging: Main shared cellular and molecular mechanisms.

Sandra Maria Barbalho, Ricardo José Tofano, Eduardo Federigui Baisi Chagas, Cláudia Rucco Penteado Detregiachi, Ricardo de Alvares Goulart, Uri Arian Princ Flato.

  Due to the impact that frailty and cardiac aging have on society and health systems, the mechanisms surrounding these conditions must be known. If the frailty and cardiovascular complications are due to numerous controllable factors or not, different strategies must be considered to improve the elderly patient's prognosis and improve their quality of life. This review aimed to investigate the main shared mechanisms of cardiac aging and frailty. MEDLINE-PubMed, Cohrane and EMBASE databases were searched to perform this review. The mesh-terms used for this search was frailty, cardiovascular disease, cardiovascular aging, or heart failure (HF). Frailty frequently coexists with heart conditions since they share predisposing pathophysiological alterations, the aging process, and elevated comorbidity burden, contributing to fast functional decline and sarcopenia. Mitochondrial dysfunctions and decreased protein synthesis lead to protein degradation, denervation, atrophy, impairment in the fatty acid oxidation, resulting in cardiomyopathy. The homeostasis of muscle metabolism deteriorates with aging, leading to a reduction in muscle quality and quantity. The installation of a low-grade and chronic inflammatory process adds to an impairment in glucose, protein and lipid metabolism, endothelial dysfunction, cardiovascular conditions, sarcopenia, and HF. The exacerbated rise in inflammatory biomarkers and impaired insulin resistance leads to worsening of the patient's general condition. The good news is that frailty is a dynamic syndrome, fluctuating between different states of seriousness but still has potential for reversibility based on physical activity, cognitive training, nutrition intervention, and a plethora of other approaches that can be performed by a multi-disciplinary team.

Keywords:  Aging; Cardiovascular diseases; Cellular mechanisms; Frailty; Heart failure; Molecular mechanisms

DOI:  https://doi.org/10.1016/j.exger.2021.111302
Leuk Lymphoma. 2021 Mar 08. 1-18

Resistance to CART cell therapy: lessons learned from the treatment of hematological malignancies.

Reona Sakemura, Michelle J Cox, Mehrdad Hefazi, Elizabeth L Siegler, Saad S Kenderian.

  Chimeric antigen receptor T (CART) cell immunotherapy has yielded significant clinical success in treating certain hematological malignancies. However, despite high initial response rates, most patients eventually relapse. Resistance to CART cell therapy can stem from tumor cell mutations, T cell defects, and tumor microenvironment (TME) immunosuppression. Tumor cells can downregulate target antigen expression to evade CART cell detection or mutate death receptor pathways to resist CART cell cytotoxicity. Patient T cells can be intrinsically defective, and CART cells often undergo exhaustion. The TME is abundant with immunosuppressive cells and factors which contribute to suboptimal CART cell activity. Collectively, issues originating in tumor cells, T cells, and the TME present significant hurdles to long-term remission after CART cell therapy. Various strategies to combat CART cell resistance have shown promise in preclinical studies and early clinical trials and are crucial to achieving durable responses.

Keywords:  CART; drug resistance; mechanism; treatment

DOI:  https://doi.org/10.1080/10428194.2021.1894648
Aging Cell. 2021 Mar 12. e13338

Cellular aging beyond cellular senescence: Markers of senescence prior to cell cycle arrest in vitro and in vivo.

Mikolaj Ogrodnik.

  The field of research on cellular senescence experienced a rapid expansion from being primarily focused on in vitro aspects of aging to the vast territories of animal and clinical research. Cellular senescence is defined by a set of markers, many of which are present and accumulate in a gradual manner prior to senescence induction or are found outside of the context of cellular senescence. These markers are now used to measure the impact of cellular senescence on aging and disease as well as outcomes of anti-senescence interventions, many of which are at the stage of clinical trials. It is thus of primary importance to discuss their specificity as well as their role in the establishment of senescence. Here, the presence and role of senescence markers are described in cells prior to cell cycle arrest, especially in the context of replicative aging and in vivo conditions. Specifically, this review article seeks to describe the process of "cellular aging": the progression of internal changes occurring in primary cells leading to the induction of cellular senescence and culminating in cell death. Phenotypic changes associated with aging prior to senescence induction will be characterized, as well as their effect on the induction of cell senescence and the final fate of cells reviewed. Using published datasets on assessments of senescence markers in vivo, it will be described how disparities between quantifications can be explained by the concept of cellular aging. Finally, throughout the article the applicational value of broadening cellular senescence paradigm will be discussed.

Keywords:  aging; cellular senescence; evolutionary biology; molecular biology of aging; molecular damage; theories of aging; wound healing

DOI:  https://doi.org/10.1111/acel.13338
BMJ. 2021 Mar 11. 372 n486

How the lessons of previous epidemics helped successful countries fight covid-19.

Alvin Qijia Chua, Bandar Al Knawy, Ben Grant, Helena Legido-Quigley, Wui-Chiang Lee, Gabriel M Leung, Mun-Keat Looi, Sebastian Maurer-Stroh.

DOI: https://doi.org/10.1136/bmj.n486
Front Immunol. 2021 ;12 613422

Interleukin-6 Is a Biomarker for the Development of Fatal Severe Acute Respiratory Syndrome Coronavirus 2 Pneumonia.

André Santa Cruz, Ana Mendes-Frias, Ana Isabel Oliveira, Luís Dias, Ana Rita Matos, Alexandre Carvalho, Carlos Capela, Jorge Pedrosa, António Gil Castro, Ricardo Silvestre.

  Hyper-inflammatory responses induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are a major cause of disease severity and death. Predictive prognosis biomarkers to guide therapeutics are critically lacking. Several studies have indicated a "cytokine storm" with the release of interleukin-1 (IL-1), IL-6, and IL-8, along with tumor necrosis factor alpha (TNFα) and other inflammatory mediators. Here, we proposed to assess the relationship between IL-6 and outcomes of patients with coronavirus disease 2019 (COVID-19). Our cohort consisted of 46 adult patients with PCR-proven SARS-CoV-2 infection admitted in a COVID-19 ward of the Hospital de Braga (HB) from April 7 to May 7, 2020, whose IL-6 levels were followed over time. We found that IL-6 levels were significantly different between the disease stages. Also, we found a significant negative correlation between IL-6 levels during stages IIb and III, peripheral oxygen saturation (SpO2), and partial pressure of oxygen in arterial blood (PaO2), showing that IL-6 correlates with respiratory failure. Compared to the inflammatory markers available in the clinic routine, we found a positive correlation between IL-6 and C-reactive protein (CRP). However, when we assessed the predictive value of these two markers, IL-6 behaves as a better predictor of disease progression. In a binary logistic regression, IL-6 level was the most significant predictor of the non-survivors group, when compared to age and CRP. Herein, we present IL-6 as a relevant tool for prognostic evaluation, mainly as a predictor of outcome.

Keywords:  COVID-19; IL-6; SARS-CoV-2; biomarker; fatal pneumonia

DOI:  https://doi.org/10.3389/fimmu.2021.613422
JAMA Oncol. 2021 Mar 11.

Combining Machine Learning Predictive Algorithms With Behavioral Nudges to Increase Rates of Serious Illness Conversations in Patients With Cancer-Reply.

Christopher R Manz, Ravi B Parikh, Mitesh S Patel.

DOI: https://doi.org/10.1001/jamaoncol.2020.8499
Psychol Aging. 2021 Feb;36(1): 49-56

Aging and altruism: A meta-analysis.

Erika P Sparrow, Liyana T Swirsky, Farrah Kudus, Julia Spaniol.

Life span theories postulate that altruistic tendencies increase in adult development, but the mechanisms and moderators of age-related differences in altruism are poorly understood. In particular, it is unclear to what extent age differences in altruism reflect age differences in altruistic motivation, in resources such as education and income, or in socially desirable responding. This meta-analysis combined 16 studies assessing altruism in younger and older adults (N = 1,581). As expected, results revealed an age-related difference in altruism (Mg = 0.61, p < .001), with older adults showing greater altruism than younger adults. Demographic moderators (income, education, sex distribution) did not significantly moderate this effect, nor did aspects of the study methodology that may drive socially desirable responding. However, the age effect was moderated by the average age of the older sample, such that studies with young-old samples showed a larger age effect than studies with old-old samples. These findings are consistent with the theoretical prediction of age-related increases in altruistic motivation, but they also suggest a role for resources (e.g., physical, cognitive, social) that may decline in advanced old age. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

DOI: https://doi.org/10.1037/pag0000447
Front Immunol. 2020 ;11 626812

Iron Metabolism in the Tumor Microenvironment: Contributions of Innate Immune Cells.

Wei Liang, Napoleone Ferrara.

  Cells of the innate immune system are a major component of the tumor microenvironment. They play complex and multifaceted roles in the regulation of cancer initiation, growth, metastasis and responses to therapeutics. Innate immune cells like neutrophils and macrophages are recruited to cancerous tissues by chemotactic molecules released by cancer cells and cancer-associated stromal cells. Once they reach the tumor, they can be instructed by a network of proteins, nucleic acids and metabolites to exert protumoral or antitumoral functions. Altered iron metabolism is a feature of cancer. Epidemiological studies suggest that increased presence of iron and/or iron binding proteins is associated with increased risks of cancer development. It has been shown that iron metabolism is involved in shaping the immune landscapes in inflammatory/infectious diseases and cancer-associated inflammation. In this article, we will dissect the contribution of macrophages and neutrophils to dysregulated iron metabolism in malignant cells and its impact on cancer growth and metastasis. The mechanisms involved in regulating the actions of macrophages and neutrophils will also be discussed. Moreover, we will examine the effects of iron metabolism on the phenotypes of innate immune cells. Both iron chelating and overloading agents are being explored in cancer treatment. This review highlights alternative strategies for management of iron content in cancer cells by targeting the iron donation and modulation properties of macrophages and neutrophils in the tumor microenvironment.

Keywords:  cancer; iron; macrophage; metastasis; neutrophils

DOI:  https://doi.org/10.3389/fimmu.2020.626812
BMJ. 2021 Mar 11. 372 n699

Covid-19: European countries suspend use of Oxford-AstraZeneca vaccine after reports of blood clots.

Jacqui Wise.

DOI: https://doi.org/10.1136/bmj.n699
Front Med (Lausanne). 2021 ;8 595787

COVID-19 Death Reporting Inconsistencies and Working Lessons for Low- and Middle-Income Countries: Opinion.

Garumma Tolu Feyissa, Lemi Belay Tolu, Alex Ezeh.



Keywords:  COVID-19; SARS CoV-2; corona-virus 2; excess mortality; mortality; severe acute respiratory coronavirus 2

DOI:  https://doi.org/10.3389/fmed.2021.595787
Science. 2021 Mar 11. pii: eabh4256. [Epub ahead of print]

Behind the scenes of the CRISPR story.

H Holden Thorp.

DOI: https://doi.org/10.1126/science.abh4256
Science. 2021 Mar 12. 371(6534): 1081

COVID-19 lessons for research.

Francis S Collins.

DOI: https://doi.org/10.1126/science.abh3996
Mol Neurodegener. 2021 03 08. 16(1): 15

Cholesterol alters mitophagy by impairing optineurin recruitment and lysosomal clearance in Alzheimer's disease.

Vicente Roca-Agujetas, Elisabet Barbero-Camps, Cristina de Dios, Petar Podlesniy, Xenia Abadin, Albert Morales, Montserrat Marí, Ramon Trullàs, Anna Colell.

   BACKGROUND: Emerging evidence indicates that impaired mitophagy-mediated clearance of defective mitochondria is a critical event in Alzheimer's disease (AD) pathogenesis. Amyloid-beta (Aβ) metabolism and the microtubule-associated protein tau have been reported to regulate key components of the mitophagy machinery. However, the mechanisms that lead to mitophagy dysfunction in AD are not fully deciphered. We have previously shown that intraneuronal cholesterol accumulation can disrupt the autophagy flux, resulting in low Aβ clearance. In this study, we examine the impact of neuronal cholesterol changes on mitochondrial removal by autophagy.
METHODS: Regulation of PINK1-parkin-mediated mitophagy was investigated in conditions of acute (in vitro) and chronic (in vivo) high cholesterol loading using cholesterol-enriched SH-SY5Y cells, cultured primary neurons from transgenic mice overexpressing active SREBF2 (sterol regulatory element binding factor 2), and mice of increasing age that express the amyloid precursor protein with the familial Alzheimer Swedish mutation (Mo/HuAPP695swe) and mutant presenilin 1 (PS1-dE9) together with active SREBF2.
RESULTS: In cholesterol-enriched SH-SY5Y cells and cultured primary neurons, high intracellular cholesterol levels stimulated mitochondrial PINK1 accumulation and mitophagosomes formation triggered by Aβ while impairing lysosomal-mediated clearance. Antioxidant recovery of cholesterol-induced mitochondrial glutathione (GSH) depletion prevented mitophagosomes formation indicating mitochondrial ROS involvement. Interestingly, when brain cholesterol accumulated chronically in aged APP-PSEN1-SREBF2 mice the mitophagy flux was affected at the early steps of the pathway, with defective recruitment of the key autophagy receptor optineurin (OPTN). Sustained cholesterol-induced alterations in APP-PSEN1-SREBF2 mice promoted an age-dependent accumulation of OPTN into HDAC6-positive aggresomes, which disappeared after in vivo treatment with GSH ethyl ester (GSHee). The analyses in post-mortem brain tissues from individuals with AD confirmed these findings, showing OPTN in aggresome-like structures that correlated with high mitochondrial cholesterol levels in late AD stages.
CONCLUSIONS: Our data demonstrate that accumulation of intracellular cholesterol reduces the clearance of defective mitochondria and suggest recovery of the cholesterol homeostasis and the mitochondrial scavenging of ROS as potential therapeutic targets for AD.

Keywords:  APP-PSEN1 mice; Aggressomes; Glutathione; Mitochondria; Optineurin; Oxidative stress; PINK1; Parkin

DOI:  https://doi.org/10.1186/s13024-021-00435-6
Aging (Albany NY). 2021 Mar 09. 13

Aging and pathological aging signatures of the brain: through the focusing lens of SIRT6.

Daniel Stein, Amir Mizrahi, Anastasia Golova, Adam Saretzky, Alfredo Garcia Venzor, Zeev Slobodnik, Shai Kaluski, Monica Einav, Ekaterina Khrameeva, Debra Toiber.

  Brain-specific SIRT6-KO mice present increased DNA damage, learning impairments, and neurodegenerative phenotypes, placing SIRT6 as a key protein in preventing neurodegeneration. In the aging brain, SIRT6 levels/activity decline, which is accentuated in Alzheimer's patients. To understand SIRT6 roles in transcript pattern changes, we analyzed transcriptomes of young WT, old WT and young SIRT6-KO mice brains, and found changes in gene expression related to healthy and pathological aging. In addition, we traced these differences in human and mouse samples of Alzheimer's and Parkinson's diseases, healthy aging and calorie restriction (CR). Our results define four gene expression categories that change with age in a pathological or non-pathological manner, which are either reversed or not by CR. We found that each of these gene expression categories is associated with specific transcription factors, thus serving as potential candidates for their category-specific regulation. One of these candidates is YY1, which we found to act together with SIRT6 regulating specific processes. We thus argue that SIRT6 has a pivotal role in preventing age-related transcriptional changes in brains. Therefore, reduced SIRT6 activity may drive pathological age-related gene expression signatures in the brain.

Keywords:  SIRT6; YY1; aging; neurodegeneration; transcription regulation

DOI:  https://doi.org/10.18632/aging.202755