bims-minfam 2021-02-21 papers

bims-minfam

Biomed News

on Inflammation and metabolism in ageing and cancer

Issue of 2021‒02‒21
28 papers selected by
Ayesh Seneviratne
University of Toronto

Role for Leptin and Leptin Receptors in Stem Cells During Health and Diseases.
Feed-forward regulation between cellular senescence and immunosuppression promotes the aging process and age-related diseases.
Inflammation-driven deaminase deregulation fuels human pre-leukemia stem cell evolution.
Aspirin in the Prevention of Cardiovascular Disease and Cancer.
Putative metabolites involved in the beneficial effects of wholegrain cereal: Nontargeted metabolite profiling approach.
Conflicting metabolic alterations in cancer stem cells and regulation by the stromal niche.
Lysophospholipid acylation modulates plasma membrane lipid organization and insulin sensitivity in skeletal muscle.
Inhibition of ATM induces hypersensitivity to proton irradiation by upregulating toxic end joining.
Cross-talk between ANGPTL4 gene SNP Rs1044250 and weight management is a risk factor of metabolic syndrome.
Diagnosis, grading and management of toxicities from immunotherapies in children, adolescents and young adults with cancer.
Inherited Disorders of Complex Lipid Metabolism: A Clinical Review.
A lipid lover's guide to novel therapeutics for lipid and cardiovascular risk reduction.
Maintenance Therapy in AML.
Alternative diets among adolescents: facts or fads?
Long-term weight loss strategies for obesity.
mTOR Signaling as a Regulator of Hematopoietic Stem Cell Fate.
Kmt2c mutations enhance HSC self-renewal capacity and convey a selective advantage after chemotherapy.
The efficacy of bone marrow mononuclear stem cell transplantation in patients with non-ischemic dilated cardiomyopathy-a meta analysis.
Dietary low ratio of n-6/n-3 polyunsaturated fatty acids improve type 2 diabetes mellitus via activating brown adipose tissue in male mice.
Consumption of High-Oleic Soybean Oil Improves Lipid and Lipoprotein Profile in Humans Compared to a Palm Oil Blend: A Randomized Controlled Trial.
Lipid metabolism and cancer.
Cell-to-cell variation in gene expression and the aging process.
Will allogeneic CAR T cells for CD19+ malignancies take autologous CAR T cells 'off the shelf'?
Changes in peripheral blood biomarkers with aging and neurodegenerative disorders.
The future of healthy aging: translation of geroscience discoveries to public health practice.
Late-career unemployment and risk of frailty among older adults in Taiwan: An 8-year population-based cohort study.
A vaccine to prevent initial loss of cognition and eventual Alzheimer's disease in elderly persons.
LIGHT/LTβR signaling regulates self-renewal and differentiation of hematopoietic and leukemia stem cells.

Stem Cell Rev Rep. 2021 Feb 17.

Role for Leptin and Leptin Receptors in Stem Cells During Health and Diseases.

Thao Trinh, Hal E Broxmeyer.

  Hematopoietic stem cells (HSCs) give rise to all blood and immune cells in the body. These rare cells reside in the hypoxic niche of the bone marrow (BM) where they are subjected to a complex network of regulatory factors including cellular and molecular components. To sustain hematopoiesis over the lifetime of an individual, HSCs maintain distinctive metabolic programs, and in recent years nutritional factors have been increasingly recognized as critical regulators of HSC numbers and functions. Leptin (LEP), a neuroendocrine messenger, and its receptor (LEPR) are well-known for their immunomodulatory and energy balancing effects; yet, how LEP/LEPR signaling plays a role in hematopoiesis is under-appreciated. In this review, we summarize and highlight recent work that demonstrated involvement of LEP/LEPR in hematopoiesis under steady state or stress-associated situations as well as in pathological conditions such as cardiovascular diseases and malignancies. Although the field is only in its infancy, these studies suggest evidence of potential clinical applications and proof-of-principle for more in-depth future research. Under steady state, only a minor subset of long-term hematopoietic stem cells (HSCs) express LEPR. Upon irradiation, LEPR+HSCs exhibited robust repopulating capacity in long-term engraftment studies that outcompeted LEPR-HSCs. LEPR+ stromal cells secrete critical niche factors including stem cell factor (SCF) and pleiotrophin (PTN) to support HSCs and progenitor cells. LEPR signaling mediated protective effects of fasting in ALL but not AML leukemias.

Keywords:  Hematopoiesis; Hematopoietic stem cells; Leptin; Leptin receptor; Malignancy

DOI:  https://doi.org/10.1007/s12015-021-10132-y
Ageing Res Rev. 2021 Feb 10. pii: S1568-1637(21)00027-1. [Epub ahead of print]67 101280

Feed-forward regulation between cellular senescence and immunosuppression promotes the aging process and age-related diseases.

Antero Salminen.

  Aging is a progressive degenerative process involving a chronic low-grade inflammation and the accumulation of senescent cells. One major issue is to reveal the mechanisms which promote the deposition of pro-inflammatory senescent cells within tissues. The accumulation involves mechanisms which increase cellular senescence as well as those inhibiting the clearance of senescent cells from tissues. It is known that a persistent inflammatory state evokes a compensatory immunosuppression which inhibits pro-inflammatory processes by impairing the functions of effector immune cells, e.g., macrophages, T cells and natural killer (NK) cells. Unfortunately, these cells are indispensable for immune surveillance and the subsequent clearance of senescent cells, i.e., the inflammation-induced counteracting immunosuppression prevents the cleansing of host tissues. Moreover, senescent cells can also repress their own clearance by expressing inhibitors of immune surveillance and releasing the ligands of NKG2D receptors which impair their surveillance by NK and cytotoxic CD8+ T cells. It seems that cellular senescence and immunosuppression establish a feed-forward process which promotes the aging process and age-related diseases. I will examine in detail the immunosuppressive mechanisms which impair the surveillance and clearance of pro-inflammatory senescent cells with aging. In addition, I will discuss several therapeutic strategies to halt the degenerative feed-forward circuit associated with the aging process and age-related diseases.

Keywords:  Ageing; Alzheimer’s; Anti-inflammatory; Immunometabolism; Immunosenescence; Inflammaging; SASP

DOI:  https://doi.org/10.1016/j.arr.2021.101280
Cell Rep. 2021 Jan 26. pii: S2211-1247(20)31659-4. [Epub ahead of print]34(4): 108670

Inflammation-driven deaminase deregulation fuels human pre-leukemia stem cell evolution.

Qingfei Jiang, Jane Isquith, Luisa Ladel, Adam Mark, Frida Holm, Cayla Mason, Yudou He, Phoebe Mondala, Isabelle Oliver, Jessica Pham, Wenxue Ma, Eduardo Reynoso, Shawn Ali, Isabella Jamieson Morris, Raymond Diep, Chanond Nasamran, Guorong Xu, Roman Sasik, Sara Brin Rosenthal, Amanda Birmingham, Sanja Coso, Gabriel Pineda, Leslie Crews, Mary E Donohoe, J Craig Venter, Thomas Whisenant, Ruben A Mesa, Ludmil B Alexandrov, Kathleen M Fisch, Catriona Jamieson.

  Inflammation-dependent base deaminases promote therapeutic resistance in many malignancies. However, their roles in human pre-leukemia stem cell (pre-LSC) evolution to acute myeloid leukemia stem cells (LSCs) had not been elucidated. Comparative whole-genome and whole-transcriptome sequencing analyses of FACS-purified pre-LSCs from myeloproliferative neoplasm (MPN) patients reveal APOBEC3C upregulation, an increased C-to-T mutational burden, and hematopoietic stem and progenitor cell (HSPC) proliferation during progression, which can be recapitulated by lentiviral APOBEC3C overexpression. In pre-LSCs, inflammatory splice isoform overexpression coincides with APOBEC3C upregulation and ADAR1p150-induced A-to-I RNA hyper-editing. Pre-LSC evolution to LSCs is marked by STAT3 editing, STAT3β isoform switching, elevated phospho-STAT3, and increased ADAR1p150 expression, which can be prevented by JAK2/STAT3 inhibition with ruxolitinib or fedratinib or lentiviral ADAR1 shRNA knockdown. Conversely, lentiviral ADAR1p150 expression enhances pre-LSC replating and STAT3 splice isoform switching. Thus, pre-LSC evolution to LSCs is fueled by primate-specific APOBEC3C-induced pre-LSC proliferation and ADAR1-mediated splicing deregulation.

Keywords:  Enter keywords here

DOI:  https://doi.org/10.1016/j.celrep.2020.108670
Annu Rev Med. 2021 Jan 27. 72 473-495

Aspirin in the Prevention of Cardiovascular Disease and Cancer.

Emanuela Ricciotti, Garret A FitzGerald.

  More than a century after its synthesis, daily aspirin, given at a low dose, is a milestone treatment for the secondary prevention of cardiovascular disease (CVD). Its role in primary prevention of CVD is still debated. Older randomized controlled trials showed that aspirin reduced the low incidence of myocardial infarction but correspondingly increased the low incidence of serious gastrointestinal bleeds without altering mortality. More recent trials see the benefit attenuated, perhaps obscured by other cardioprotective practices, while the bleeding risk remains, especially in older patients. Indirect evidence, both preclinical and clinical, suggests that aspirin may protect against sporadic colorectal cancer and perhaps other cancers. However, further studies are still necessary to warrant the consumption of aspirin for primary prevention of CVD and cancer by apparently healthy individuals.

Keywords:  aspirin; cancer; cardiovascular disease; prevention

DOI:  https://doi.org/10.1146/annurev-med-051019-102940
Nutr Metab Cardiovasc Dis. 2020 Dec 30. pii: S0939-4753(20)30548-2. [Epub ahead of print]

Putative metabolites involved in the beneficial effects of wholegrain cereal: Nontargeted metabolite profiling approach.

Marilena Vitale, Kati Hanhineva, Ville Koistinen, Seppo Auriola, Jussi Paananen, Giuseppina Costabile, Giuseppe Della Pepa, Angela A Rivellese, Gabriele Riccardi, Rosalba Giacco.

  BACKGROUND AND AIMS: Wholegrain cereals have been implicated in the reduction of lifestyle-related chronic diseases risk including cardiovascular diseases and type 2 diabetes. Molecular mechanisms responsible for the beneficial health effects are not entirely understood. The aims of this study were 1) to identify new potential plasma biomarker candidate metabolites of wholegrain cereal foods intake and 2) to examine whether some putative metabolites associated with wholegrain foods intake may play a role in the improvement of cardiometabolic risk factors.METHODS AND RESULTS: Analysis have been conducted in 54 individuals with metabolic syndrome of both genders, age 40-65 years, randomly assigned to 2 dietary interventions lasting 12-week: 1) wholegrain enriched diet (n = 28), and 2) refined-wheat cereals diet (control diet) (n = 26). Nontargeted metabolite profiling analysis was performed on fasting plasma samples collected at baseline and at the end of the experimental diets. Our data show that, at the end of the intervention, a higher intake of wholegrain (tertile 3) was significantly associated with a marked increase in several lipid compounds, as PC (20:4/16:1), LPC (20:4), LPC (22:6), LPC (18:3), LPC (22:5), and a phenolic compound (P < .05 for all). In the wholegrain group, higher concentrations of these metabolites (tertile 3 vs tertile 1 of each metabolite) were significantly associated with lower postprandial insulin and triglyceride responses (P < .05) by 29% and 37%, respectively.
CONCLUSION: These observations suggest a possible role of lipid and polyphenol metabolites in the postprandial metabolic benefits of wholegrains in subjects at high risk of cardiovascular disease. In addition, they provide insight into the role of these metabolites as potential candidate biomarkers of wholegrain foods. The study was registered on ClinicalTrials.gov (identifier: NCT00945854).

Keywords:  Dietary biomarker; Metabolic effect; Metabolomics; Nontargeted metabolite profiling; Wholegrain cereals

DOI:  https://doi.org/10.1016/j.numecd.2020.12.022
Regen Ther. 2021 Jun;17 8-12

Conflicting metabolic alterations in cancer stem cells and regulation by the stromal niche.

Tadahito Yasuda, Takatsugu Ishimoto, Hideo Baba.

  Recent studies have revealed that cancer stem cells (CSCs) undergo metabolic alterations that differentiate them from non-CSCs. Inhibition of specific metabolic pathways in CSCs has been conducted to eliminate the CSC population in many types of cancer. However, there is conflicting evidence about whether CSCs depend on glycolysis or mitochondrial oxidative phosphorylation (OXPHOS) to maintain their stem cell properties. This review summarizes the latest knowledge regarding CSC-specific metabolic alterations and offers recent evidence that the surrounding microenvironments may play an important role in the maintenance of CSC properties.

Keywords:  ALDH, aldehyde dehydrogenase; ATP, adenosine triphosphate; CD44v, CD44 variant isoform; CSCs; CSCs, cancer stem cells; EMT, epithelial–mesenchymal transition; EVs, extracellular vesicles; FAO, fatty acid oxidation; FBP1, fructose-1,6-biphosphatase 1; GLUT1, glucose transporter 1; GP6, glucose-6-phosphate; Glycolysis; HCC, hepatocellular carcinoma; HIF1a, hypoxia inducible factor 1a; IMP2, insulin-like growth factor 2; IncRNAs, long noncoding RNAs; LSCs, leukemia stem cells; Mitochondrial OXPHOS; NRF2, nuclear factor erythroid 2–related factor 2; OXPHOS, oxidative phosphorylation; PDK1, pyruvate dehydrogenase kinase 1; PPP, pentose phosphate pathway; ROS; ROS, reactive oxygen species; SOD2, superoxide dismutase 2; Stromal niche; TCA, tricarboxylic acid; TICs, tumor initiating stem-like cells; mTORC1, mammalian target of rapamycin complex 1

DOI:  https://doi.org/10.1016/j.reth.2021.01.005
J Clin Invest. 2021 Feb 16. pii: 135963. [Epub ahead of print]

Lysophospholipid acylation modulates plasma membrane lipid organization and insulin sensitivity in skeletal muscle.

Patrick J Ferrara, Xin Rong, J Alan Maschek, Anthony Rp Verkerke, Piyarat Siripoksup, Haowei Song, Thomas D Green, Karthickeyan C Krishnan, Jordan M Johnson, John Turk, Joseph A Houmard, Aldons J Lusis, Micah J Drummond, Joseph M McClung, James E Cox, Saame R Shaikh, Peter Tontonoz, William L Holland, Katsuhiko Funai.

  Aberrant lipid metabolism promotes the development of skeletal muscle insulin resistance, but the exact identity of lipid-mediated mechanisms relevant to human obesity remains unclear. A comprehensive lipidomic analysis of primary myocytes from lean insulin-sensitive (LN) and obese insulin-resistant (OB) individuals revealed several species of lysophospholipids (lyso-PL) that were differentially-abundant. These changes coincided with greater expression of lysophosphatidylcholine acyltransferase 3 (LPCAT3), an enzyme involved in phospholipid transacylation (Lands cycle). Strikingly, mice with skeletal muscle-specific knockout of LPCAT3 (LPCAT3-MKO) exhibited greater muscle lyso-PC/PC, concomitant with improved skeletal muscle insulin sensitivity. Conversely, skeletal muscle-specific overexpression of LPCAT3 (LPCAT3-MKI) promoted glucose intolerance. The absence of LPCAT3 reduced phospholipid packing of cellular membranes and increased plasma membrane lipid clustering, suggesting that LPCAT3 affects insulin receptor phosphorylation by modulating plasma membrane lipid organization. In conclusion, obesity accelerates the skeletal muscle Lands cycle, whose consequence might induce the disruption of plasma membrane organization that suppresses muscle insulin action.

Keywords:  Insulin signaling; Metabolism; Muscle Biology; Skeletal muscle

DOI:  https://doi.org/10.1172/JCI135963
Cancer Res. 2021 Feb 17. pii: canres.CAN-20-2960-A.2020. [Epub ahead of print]

Inhibition of ATM induces hypersensitivity to proton irradiation by upregulating toxic end joining.

Qin Zhou, Michelle E Howard, Xinyi Tu, Qian Zhu, Janet M Denbeigh, Nicholas B Remmes, Michael G Herman, Chris J Beltran, Jian Yuan, Patricia T Greipp, Judy C Boughey, Liewei Wang, Neil Johnson, Matthew P Goetz, Jann N Sarkaria, Zhenkun Lou, Robert W Mutter.

Proton Bragg peak irradiation has a higher ionizing density than conventional photon irradiation or the entrance of the proton beam profile. Whether targeting the DNA damage response could enhance vulnerability to the distinct pattern of damage induced by proton Bragg peak irradiation is currently unknown. Here we performed genetic or pharmacologic manipulation of key DNA damage response elements and evaluated DNA damage signaling, DNA repair, and tumor control in cell lines and xenografts treated with the same physical dose across a radiotherapy linear energy transfer spectrum. Radiotherapy consisted of 6 MV photons and the entrance beam or Bragg peak of a 76.8 MeV spot scanning proton beam. More complex DNA double strand breaks induced by Bragg peak proton irradiation preferentially underwent resection and engaged homologous recombination (HR) machinery. Unexpectedly, the ATM inhibitor AZD0156 but not an inhibitor of ATR rendered cells hypersensitive to more densely ionizing proton Bragg peak irradiation. ATM inhibition blocked resection and shunted more double strand breaks to processing by toxic ligation through nonhomologous end-joining, whereas loss of DNA ligation via XRCC4 or Lig4 knockdown rescued resection and abolished the enhanced Bragg peak cell killing. Proton Bragg peak monotherapy selectively sensitized cell lines and tumor xenografts with inherent HR defects, and the repair defect induced by ATM inhibitor co-administration showed enhanced efficacy in HR proficient models. In summary, inherent defects in HR or administration of an ATM inhibitor in HR proficient tumors selectively enhance the relative biological effectiveness of proton Bragg peak irradiation.

DOI: https://doi.org/10.1158/0008-5472.CAN-20-2960
J Transl Med. 2021 Feb 16. 19(1): 72

Cross-talk between ANGPTL4 gene SNP Rs1044250 and weight management is a risk factor of metabolic syndrome.

Zhoujie Tong, Jie Peng, Hongtao Lan, Wenwen Sai, Yulin Li, Jiaying Xie, Yanmin Tan, Wei Zhang, Ming Zhong, Zhihao Wang.

  BACKGROUND: The prevalence of metabolic syndrome (Mets) is closely related to an increased incidence of cardiovascular events. Angiopoietin-like protein 4 (ANGPTL4) is contributory to the regulation of lipid metabolism, herein, may provide a target for gene-aimed therapy of Mets. This observational case control study was designed to elucidate the relationship between ANGPTL4 gene single nucleotide polymorphism (SNP) rs1044250 and the onset of Mets, and to explore the interaction between SNP rs1044250 and weight management on Mets.METHODS: We have recruited 1018 Mets cases and 1029 controls in this study. The SNP rs1044250 was genotyped with blood samples, base-line information and Mets-related indicators were collected. A 5-year follow-up survey was carried out to track the lifestyle interventions and changes in Mets-related indicators.
RESULTS: ANGPTL4 gene SNP rs1044250 is an independent risk factor for increased waist circumference (OR 1.618, 95% CI [1.119-2.340]; p = 0.011), elevated blood pressure (OR 1.323, 95% CI [1.002-1.747]; p = 0.048), and Mets (OR 1.875, 95% CI [1.363-2.580]; p < 0.001). The follow-up survey shows that rs1044250 CC genotype patients with weight gain have an increased number of Mets components (M [Q1, Q3]: CC 1 (0, 1), CT + TT 0 [- 1, 1]; p = 0.021); The interaction between SNP rs1044250 and weight management is a risk factor for increased systolic blood pressure (β = 0.075, p < 0.001) and increased diastolic blood pressure (β = 0.097, p < 0.001), the synergistic effect of weight management and SNP rs1044250 is negative (S < 1).
CONCLUSION: ANGPTL4 gene SNP rs1044250 is an independent risk factor for increased waist circumference and elevated blood pressure, therefore, for Mets. However, patients with wild type SNP 1044250 are more likely to have Mets when the body weight is increased, mainly due to elevated blood pressure.

Keywords:  ANGPTL4; Metabolic syndrome; Single nucleotide polymorphism; Weight management

DOI:  https://doi.org/10.1186/s12967-021-02739-z
Nat Rev Clin Oncol. 2021 Feb 19.

Diagnosis, grading and management of toxicities from immunotherapies in children, adolescents and young adults with cancer.

Dristhi Ragoonanan, Sajad J Khazal, Hisham Abdel-Azim, David McCall, Branko Cuglievan, Francesco Paolo Tambaro, Ali Haider Ahmad, Courtney M Rowan, Cristina Gutierrez, Keri Schadler, Shulin Li, Matteo Di Nardo, Linda Chi, Alison M Gulbis, Basirat Shoberu, Maria E Mireles, Jennifer McArthur, Neena Kapoor, Jeffrey Miller, Julie C Fitzgerald, Priti Tewari, Demetrios Petropoulos, Jonathan B Gill, Christine N Duncun, Leslie E Lehmann, Sangeeta Hingorani, Joseph R Angelo, Rita D Swinford, Marie E Steiner, Fiorela N Hernandez Tejada, Paul L Martin, Jeffery Auletta, Sung Won Choi, Rajinder Bajwa, Natalie Dailey Garnes, Partow Kebriaei, Katayoun Rezvani, William G Wierda, Sattva S Neelapu, Elizabeth J Shpall, Selim Corbacioglu, Kris M Mahadeo.

Cancer immunotherapies are associated with remarkable therapeutic response rates but also with unique and severe toxicities, which potentially result in rapid deterioration in health. The number of clinical applications for novel immune effector-cell therapies, including chimeric antigen receptor (CAR)-expressing cells, and other immunotherapies, such as immune-checkpoint inhibitors, is increasing. In this Consensus Statement, members of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network Hematopoietic Cell Transplantation-Cancer Immunotherapy (HCT-CI) Subgroup, Paediatric Diseases Working Party (PDWP) of the European Society of Blood and Marrow Transplantation (EBMT), Supportive Care Committee of the Pediatric Transplantation and Cellular Therapy Consortium (PTCTC) and MD Anderson Cancer Center CAR T Cell Therapy-Associated Toxicity (CARTOX) Program collaborated to provide updated comprehensive recommendations for the care of children, adolescents and young adults receiving cancer immunotherapies. With these recommendations, we address emerging toxicity mitigation strategies, we advocate for the characterization of baseline organ function according to age and discipline-specific criteria, we recommend early critical care assessment when indicated, with consideration of reversibility of underlying pathology (instead of organ failure scores) to guide critical care interventions, and we call for researchers, regulatory agencies and sponsors to support and facilitate early inclusion of young patients with cancer in well-designed clinical trials.

DOI: https://doi.org/10.1038/s41571-021-00474-4
J Inherit Metab Dis. 2021 Feb 16.

Inherited Disorders of Complex Lipid Metabolism: A Clinical Review.

Changrui Xiao, Francis Rossignol, Frédéric M Vaz, Carlos R Ferreira.

  Over 80 human diseases have been attributed to defects in complex lipid metabolism. A majority of them have been reported recently in the setting of rapid advances in genomic technology and their increased use in clinical settings. Lipids are ubiquitous in human biology and play roles in many cellular and intercellular processes. While inborn errors in lipid metabolism can affect every organ system with many examples of genetic heterogeneity and pleiotropy, the clinical manifestations of many of these disorders can be explained based on the disruption of the metabolic pathway involved. In this review, we will discuss the physiological function of major pathways in complex lipid metabolism, including non-lysosomal sphingolipid metabolism, acylceramide metabolism, de novo phospholipid synthesis, phospholipid remodeling, phosphatidylinositol metabolism, mitochondrial cardiolipin synthesis and remodeling, and ether lipid metabolism as well as common clinical phenotypes associated with each. Corresponding author name: Carlos R. Ferreira, carlos.ferreira@nih.gov This article is protected by copyright. All rights reserved.

Keywords:  Complex Lipids; Mitochondrial Membrane Biogenesis; Phosphoinositides; Phospholipids; Sphingolipids

DOI:  https://doi.org/10.1002/jimd.12369
Future Cardiol. 2021 Feb 18.

A lipid lover's guide to novel therapeutics for lipid and cardiovascular risk reduction.

Rama Hritani, Aliza Hussain, Anum Saeed, Anandita Agarwala.

  Lipids and lipoproteins are the target of many novel therapeutics and are an area with great potential for the prevention and treatment of cardiovascular disease (CVD). Reduction of low-density lipoprotein cholesterol has been the mainstay of reducing the burden of CVD, however, several other atherogenic particles have more recently come into the spotlight as potential avenues for primary and/or secondary prevention of CVD. These include triglycerides, high sensitivity C-reactive protein, apolipoprotein A, apolipoprotein C3 and lipoprotein(a). In this review, we showcase novel therapeutics to target lipid and cardiovascular risk reduction that are either in development or that have recently been approved for use. We discuss the mechanisms of action, data from clinical trials and expected effects of each therapy based on the current body of literature.

Keywords:  ANGPTL3-LRx; Apo(a)-LRx; bempedoic acid; cardiovascular disease; eicosapentanoic acid; evinacumab; inclisiran; low-density lipoprotein cholesterol; pemafibrate; triglycerides; volanosorsen

DOI:  https://doi.org/10.2217/fca-2020-0216
Front Oncol. 2020 ;10 619085

Maintenance Therapy in AML.

Patrick K Reville, Tapan M Kadia.

  Recent advances in therapeutics coupled with steady improvements in supportive care for patients with acute myeloid leukemia (AML) have led to improved outcomes. Despite these advances, even in patients that achieve a complete remission with initial therapy high rates of relapse remain a clinical dilemma. For decades, investigators have attempted strategies of maintenance therapy to prolong both remission duration and overall survival in patients with AML. These approaches have included cytotoxic chemotherapy, immunotherapy, hypomethylating agents, and targeted small molecule therapy. Overall, the evidence in favor of maintenance therapy is limited. Recent strategies, especially with hypomethylating agents have begun to show promise as maintenance therapy in improving clinical outcomes. Ongoing and future studies will continue to elucidate the true role for maintenance therapy options in patients with AML. In this review we summarize prior and ongoing maintenance therapy approaches in AML and highlight some of the most promising strategies.

Keywords:  acute myeloid leukemia; cancer; chemotherapy; immunotherapy; maintenance therapy; targeted therapy

DOI:  https://doi.org/10.3389/fonc.2020.619085
Curr Opin Pediatr. 2021 Feb 16.

Alternative diets among adolescents: facts or fads?

Christian E Athanasian, Bojan Lazarevic, Elana R Kriegel, Ruth L Milanaik.

PURPOSE OF REVIEW: With rising rates of chronic noninfectious diseases across the United States thought to be associated with the average American diet, many have adopted alternative diets. Most of these diets promise weight reduction via adherence to strict dietary guidelines, often removing certain types of food. With access to a plethora of information online, it is easy for adolescents to become confused when making dietary decisions. Although these diets promise benefits, it is important to understand common shortcomings and how to overcome them for safe implementation among adolescents.RECENT FINDINGS: This review discusses the theory, implementation, and risks associated with intermittent fasting as well as vegetarian, vegan, ketogenic, Atkins, Paleolithic, and Mediterranean diets. These considerations are further modified for pediatric populations with a focus on the social influences on dieting.
SUMMARY: Although these diets may be promising, successful adherence to them requires addressing possible shortcomings associated with a certain diet. Pediatricians should be aware of how these dietary strategies may be properly implemented in order to prevent any harm to the patient. Empowering the patient and their families through informational resources is recommended. Pediatricians should also discuss motivations underlying their patient's dietary changes in order to determine whether these motivations are healthy.

DOI: https://doi.org/10.1097/MOP.0000000000001005
J Clin Endocrinol Metab. 2021 Feb 17. pii: dgab091. [Epub ahead of print]

Long-term weight loss strategies for obesity.

Karim Kheniser, David R Saxon, Sangeeta R Kashyap.

  CONTEXT: Obesity is a chronic disease that is difficult to manage without holistic therapy. The therapeutic armamentarium for obesity primarily consists of four forms of therapy: lifestyle modification (i.e., diet and exercise), cognitive behavioral therapy, pharmacotherapy, and bariatric surgery.EVIDENCE ACQUISITION: Evidence was consolidated from randomized controlled trials, observational studies, and meta-analyses.
EVIDENCE SYNTHESIS: After two years, lifestyle interventions can facilitate weight loss that equates to ~5%. Even though lifestyle interventions are plagued by weight regain, they can have substantial effects on type 2 diabetes and cardiovascular disease risk. Although 10-year percent excess weight loss can surpass 50% after bariatric surgery, weight regain is likely. To mitigate weight regain, instituting a multifactorial maintenance program is imperative. Such a program can integrate diet, exercise, and pharmacotherapy. Moreover, behavioral therapy can complement a maintenance program well.
CONCLUSIONS: Obesity is best managed by a multidisciplinary clinical team that integrates diet, exercise, and pharmacotherapy. Bariatric surgery is needed to manage T2D and obesity in select patients.

Keywords:  : obesity; bariatric surgery; diet; exercise; pharmacotherapy

DOI:  https://doi.org/10.1210/clinem/dgab091
Stem Cell Rev Rep. 2021 Feb 14.

mTOR Signaling as a Regulator of Hematopoietic Stem Cell Fate.

Hélia Fernandes, João Moura, Eugénia Carvalho.

  Blood is generated throughout life by continued proliferation and differentiation of hematopoietic progenitors, while at the top of the hierarchy, hematopoietic stem cells (HSCs) remain largely quiescent. This way HSCs avoid senescence and preserve their capacity to repopulate the hematopoietic system. But HSCs are not always quiescent, proliferating extensively in conditions such as those found in the fetal liver. Understanding the elusive mechanisms that regulate HSC fate would enable us to comprehend a crucial piece of HSC biology and pave the way for ex-vivo HSC expansion with clear clinical benefit. Here we review how metabolism, endoplasmic reticulum stress and oxidative stress condition impact HSCs decision to self-renew or differentiate and how these signals integrate into the mammalian target of rapamycin (mTOR) pathway. We argue that the bone marrow microenvironment continuously favors differentiation through the activation of the mTOR complex (mTORC)1 signaling, while the fetal liver microenvironment favors self-renewal through the inverse mechanism. In addition, we also postulate that strategies that have successfully achieved HSC expansion, directly or indirectly, lead to the inactivation of mTORC1. Finally, we propose a mechanism by which mTOR signaling, during cell division, conditions HSC fate. This mechanism has already been demonstrated in mature hematopoietic cells (T-cells), that face a similar decision after activation, either undergoing clonal expansion or differentiation.

Keywords:  Bone marrow microenvironment; Fate decision mechanism; HSC expansion; Hematopoietic stem cell; mTOR

DOI:  https://doi.org/10.1007/s12015-021-10131-z
Cell Rep. 2021 Feb 16. pii: S2211-1247(21)00064-4. [Epub ahead of print]34(7): 108751

Kmt2c mutations enhance HSC self-renewal capacity and convey a selective advantage after chemotherapy.

Ran Chen, Theresa Okeyo-Owuor, Riddhi M Patel, Emily B Casey, Andrew S Cluster, Wei Yang, Jeffrey A Magee.

  The myeloid tumor suppressor KMT2C is recurrently deleted in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), particularly therapy-related MDS/AML (t-MDS/t-AML), as part of larger chromosome 7 deletions. Here, we show that KMT2C deletions convey a selective advantage to hematopoietic stem cells (HSCs) after chemotherapy treatment that may precipitate t-MDS/t-AML. Kmt2c deletions markedly enhance murine HSC self-renewal capacity without altering proliferation rates. Haploid Kmt2c deletions convey a selective advantage only when HSCs are driven into cycle by a strong proliferative stimulus, such as chemotherapy. Cycling Kmt2c-deficient HSCs fail to differentiate appropriately, particularly in response to interleukin-1. Kmt2c deletions mitigate histone methylation/acetylation changes that accrue as HSCs cycle after chemotherapy, and they impair enhancer recruitment during HSC differentiation. These findings help explain why Kmt2c deletions are more common in t-MDS/t-AML than in de novo AML or clonal hematopoiesis: they selectively protect cycling HSCs from differentiation without inducing HSC proliferation themselves.

Keywords:  HSC exhaustion; Kmt2c; MLL3; hematopoietic stem cell; interleukin-1; self-renewal; therapy-related leukemia

DOI:  https://doi.org/10.1016/j.celrep.2021.108751
Heart Fail Rev. 2021 Feb 15.

The efficacy of bone marrow mononuclear stem cell transplantation in patients with non-ischemic dilated cardiomyopathy-a meta analysis.

Nso Nso, Kaveh Rezaei Bookani, Sostanie Takota Enoru, Farshid Radparvar, Robert Gordon.

  Cardiomyopathy refers to a wide spectrum of heart pathologies that interfere with normal heart function. Management options of patients with cardiomyopathy depended mainly on the severity of the condition. Lifestyle modifications and regular exercise together with a healthy diet is compatible for mild conditions. Severe conditions, however, rely on medications or surgery. Here, we aim to investigate the efficacy of bone marrow mononuclear stem cell transplantation in patients with dilated cardiomyopathy. We searched PubMed, Scopus, and Cochrane CENTRAL for relevant clinical trials and excluded observational studies. We performed the quality assessment of this study following GRADE guidelines. The assessment of the risk of bias was performed by the Cochrane's risk of bias tool. We present an analysis of the following outcomes: left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), and six minutes walking test. Data were pooled as mean differences (MD) and relative confidence intervals (CI). The analysis of 667 patients from 11 studies receiving autologous bone marrow cell therapy for non-ischemic dilated cardiomyopathy is presented. A total of 338 patients were allocated to the treatment group, and 329 participants entered the control group. The mean age of the patients in the treatment group is 52.4 ± 4.3 years, while that of the control is 53.7 ± 3.7 years. Seven studies (14.18-23) reported transplantation through the intracoronary route. Table 1 shows a summary of the baseline characteristics of the included studies and participants, the number of injected cells, and the type of injected cells in each trial. Table 2 summarizes and illustrates the previous treatment history of included patients in each trial, as well as the baseline values of different scores used as outcome measures in this analysis. We found that bone marrow mononuclear stem cell therapy leads to significantly increased LVEF (MD = 4.54%, 95% CI [3.52, 5.56], P < 0.0001). Patients in the transplant group experienced less left ventricular end-diastolic diameter (millimeter) than the control arm (MD = -1.86 mm, 95% CI [-4.01, 0.29], P = 0.09). Additionally, Patients in the transplant group could walk 28.53 m more than the controls (MD = 28.53 m, 95% CI [2.51, 54.55], P = 0.03). Transplantation of bone marrow stem cells yields acceptable results regarding left ventricular ejection fraction and lowers the left ventricular end-diastolic diameter. Additionally, the six minutes walking test is improved in the transplant group. Table 1 Demographic data about the included participants Study Year Sample size Age, years Males, n (%) Diabetics, n (%) Route of administration Number of injected cells Type of injected cells TTT Control TTT Control TTT Control TTT Control Bartolucci 2015 12 11 58 ± 14 57 ± 11 8 (66.7) 9 (81.8) 2 (16.7) 1 (9.1) Intracoronary 1.94 × 10^6 CD34 + Bocchi 2010 8 15 51 ± 15 NR NR NR NR Intracoronary NR NR Frljak 2018 30 30 56 ± 9 54 ± 11 27 (90) 26 (87) 3 (10) 2 (6) Trans-endocardial NR CD34 + Hamshere 2015 15 14 57.67 ± 12.32 56.79 ± 9.8 10 12 9(59.9%) 8(57.1%) Intracoronary 4.91 × 10^6 CD34 + Hu 2011 31 29 56.61 ± 9.72 58.27 ± 8.86 NR NR NR NR NR NR NR Matrino 2015 82 78 51 ± 11.1 49.6 ± 11.1 73.1 68.3 NR NR Intracoronary 10^8 TTT, CD45, CD105, and CD133 Sant'Anna 2014 20 10 48.3 ± 8.71 51.6 ± 7.79 13(65) 5 (50%) NR NR Intra-myocardial 1.06 × 108 CD3, CD4, CD14, CD34, CD38, and CD45 Seth 2010 41 40 45 ± 15 49 ± 9 33 35 NR NR NR 168 × 10^6 Bone marrow mononuclear cells Vrtovec 2011 28 27 52 ± 8 54 ± 7 26 (93) 23 (85) NR NR Intracoronary 123 × 10^6 CD34 + Vrtovec 2013 55 55 53 ± 8 55 ± 7 45 (82) 44 (80) NR NR Intracoronary NR NR Xiao 2017 16 20 49.5 ± 11.6 54.4 ± 11.6 9 (56.3) 14 (70.0) 6 (37.5) 5 (29.4) Intracoronary infusion (4.9 ± 1.7) × 108 (CD29, CD34, CD44, CD45, and CD166) Data are reported as mean ± SD or n (%) unless proved otherwise TTT treatment group, NR not reported Table 2 Previous history of treatment and drug intake by the patients Study Year Medical therapy, n (%) Baseline scores, mean (SD) Beta blockers ACE inhibitors Digoxin Diuretics LVEF, % LVEDD, mm Six minutes-walk test* TTT Control TTT Control TTT Control TTT Control TTT Control TTT Control TTT Control Bartolucci 2015 10 (83.3) 8 (72.7) NR NR 3 (25) 3 (27.3) 11 (91.6) 10 (90.9) 26.8 ± 4.9 30.3 ± 6.3 NR NR NR NR Bocchi 2010 NR NR NR NR NR NR NR NR 21.8 ± 3.8 30.6 ± 7.3 79 (10) 78 (12) NR NR Frljak 2018 30 (100) 30 (100) 31 (100) 32 (100) 2 (7) 3 (10) 32 (100) 33 (100) 32.2 ± 9.3 31.1 ± 7.8 NR NR NR NR Hamshere 2015 13 14 15 13 6 2 9 8 32.93 ± 16.46 29.75 ± 9.2 NR NR NR NR Hu* 2011 NR NR NR NR NR NR NR NR NR NR NR NR 466 (402, 495) 448 (383, 497) Matrino 2015 9 (11) 8 (10.2) 53 (64.1) 48 (61.1) 63 (77) 62 (79) 74 (89.7) 69 (88.9) 23.8 ± 7.2 24.7 ± 7.0 NR NR 347.3(146.7) 349.8(139.7) Sant'Anna 2014 NR NR NR NR NR NR NR NR NR NR NR NR 358.5 (88.69) 353 (86.67) Seth 2010 29 (70) 29 (72) 41 (100) 40 (100) NR NR NR NR NR NR NR NR NR NR Vrtovec 2011 21 (75) 22 (81) NR NR 5 (18) 6 (22) 26 (93) 24 (88) 25.6 ± 5.1 26.7 ± 3.9 69 ± 10 70 ± 7 NR NR Vrtovec 2013 43 (79) 46 (84) 51 (93) 54 (98) 9 (16) 11 (20) 51 (93) 20 (91) 24.3 ± 6.5 25.7 ± 4.1 69 ± 10 70 ± 7 NR NR Xiao 2017 16 (100) 20 (100) 16 (100) 19 (95) 4 (25.0) 8 (40.0) 5 (31.3) 6 (30.0) 33.1 ± 3.9 33.7 ± 4.0 NR NR 355.0 ± 91.2 323.3 ± 89.4 Data are reported as mean ± SD or n (%) unless proved otherwise TTT treatment group, NR not reported *Data are reported as median (IQR).

Keywords:  Bone marrow transplant; Cardiac treatment; Cardiomyopathy; Non-ischemic disease; Stem cell

DOI:  https://doi.org/10.1007/s10741-021-10082-0
J Food Sci. 2021 Feb 16.

Dietary low ratio of n-6/n-3 polyunsaturated fatty acids improve type 2 diabetes mellitus via activating brown adipose tissue in male mice.

Hao Yue, Wei Liu, Wenlong Zhang, Min Jia, Fenghong Huang, Fangling Du, Tongcheng Xu.

  The ratio n-6/n-3 polyunsaturated fatty acids (PUFA) has been caused widespread discussion. However, the best ratio and mechanism of n-6/n-3 PUFA in type 2 diabetes mellitus (T2DM) are largely unknown. This study investigated the effects of different ratio of n-6/n-3 PUFA diets on brown adipose tissue (BAT) and T2DM in mice. Results showed that compared with high ratio of n-6/n-3 PUFA (50:1) diet, lower ratio of n-6/n-3 PUFA (1:1 and 5:1) diets significantly increased BAT mass by 67.55% and 60.49%, decreased the fasting blood glucose (24.87% and 20.64%), total cholesterol (32.9% and 23.84%), triglyceride (33.51% and 29.62%), low-density lipoprotein cholesterol (19.23% and 17.38%), and increased glucose tolerance by 21.99% and 15.52%. Further, qRT-PCR analyses indicated that lower ratio of n-6/n-3 PUFA diets activated BAT, increased the expression of Ucp1, β-3AR, PPAR-γ, cAMP, GLU1, HSL, LPL, and PGC-1α, further improved lipid and glucose metabolism in T2DM mice. In conclusion, this study substantiated that the lower ratio of n-6/n-3 PUFA (1:1 and 5:1) improve symptoms associated with T2DM via activating BAT. PRACTICAL APPLICATION: Dietary ratio of n-6/n-3 polyunsaturated fatty acids is essential for the improvement of chronic diseases. Our current study showed that 1:1 or 5:1 ratio of n-6/n-3 polyunsaturated fatty acids had better efficiency for type 2 diabetes mellitus via activating brown adipose tissue when compared with 1:50. This finding provided useful guidance for the daily diet of patients with diabetes.

Keywords:  brown adipose tissue; glucose metabolism; lipid metabolism; n-6/n-3 polyunsaturated fatty acids; type 2 diabetes mellitus

DOI:  https://doi.org/10.1111/1750-3841.15645
Lipids. 2021 Feb 17.

Consumption of High-Oleic Soybean Oil Improves Lipid and Lipoprotein Profile in Humans Compared to a Palm Oil Blend: A Randomized Controlled Trial.

David J Baer, Theresa Henderson, Sarah K Gebauer.

  Partially hydrogenated oils (PHO) have been removed from the food supply due to adverse effects on risk for coronary heart disease (CHD). High-oleic soybean oils (HOSBO) are alternatives that provide functionality for different food applications. The objective of this study was to determine how consumption of diets containing HOSBO compared to other alternative oils, with similar functional properties, modifies LDL cholesterol (LDLc) and other risk factors and biomarkers of CHD. A triple-blind, crossover, randomized controlled trial was conducted in humans (n = 60) with four highly-controlled diets containing (1) HOSBO, (2) 80:20 blend of HOSBO and fully hydrogenated soybean oil (HOSBO+FHSBO), (3) soybean oil (SBO), and (4) 50:50 blend of palm oil and palm kernel oil (PO + PKO). Before and after 29 days of feeding, lipids/lipoproteins, blood pressure, body composition, and markers of inflammation, oxidation, and hemostasis were measured. LDLc, apolipoprotein B (apoB), NonHDL-cholesterol (HDLc), ratios of total cholesterol (TC)-to-HDLc and LDLc-to-HDL cholesterol, and LDL particle number and small LDL particles concentration were lower after HOSBO and HOSBO+FHSBO compared to PO (specific comparisons p < 0.05). Other than TC:HDL, there were no differences in lipid/lipoprotein markers when comparing HOSBO+FHSBO with HOSBO. LDLc and apoB were higher after HOSBO compared to SBO (p < 0.05). PO + PKO increased HDLc (p < 0.001) and apolipoprotein AI (p < 0.03) compared to HOSBO and HOSBO+FHSBO. With the exception of lipid hydroperoxides, dietary treatments did not affect other CHD markers. HOSBO, and blends thereof, is a PHO replacement that results in more favorable lipid/lipoprotein profiles compared to PO + PKO (an alternative fat with similar functional properties).

Keywords:  Body composition; Coronary heart disease; High-oleic soybean oil; LDL cholesterol; Palm oil; Soybean oil

DOI:  https://doi.org/10.1002/lipd.12298
J Exp Med. 2021 Jan 04. pii: e20201606. [Epub ahead of print]218(1):

Lipid metabolism and cancer.

Xueli Bian, Rui Liu, Ying Meng, Dongming Xing, Daqian Xu, Zhimin Lu.

Dysregulation in lipid metabolism is among the most prominent metabolic alterations in cancer. Cancer cells harness lipid metabolism to obtain energy, components for biological membranes, and signaling molecules needed for proliferation, survival, invasion, metastasis, and response to the tumor microenvironment impact and cancer therapy. Here, we summarize and discuss current knowledge about the advances made in understanding the regulation of lipid metabolism in cancer cells and introduce different approaches that have been clinically used to disrupt lipid metabolism in cancer therapy.

DOI: https://doi.org/10.1084/jem.20201606
Geroscience. 2021 Feb 17.

Cell-to-cell variation in gene expression and the aging process.

Alexander R Mendenhall, George M Martin, Matt Kaeberlein, Rozalyn M Anderson.

  There is tremendous variationin biological traits, and much of it is not accounted for by variation in DNA sequence, including human diseases and lifespan. Emerging evidence points to differences in the execution of the genetic program as a key source of variation, be it stochastic variation or programmed variation. Here we discuss variation in gene expression as an intrinsic property and how it could contribute to variation in traits, including the rate of aging. The review is divided into sections describing the historical context and evidence to date for nongenetic variation, the different approaches that may be used to detect nongenetic variation, and recent findings showing that the amount of variation in gene expression can be both genetically programmed and epigenetically controlled. Finally, we present evidence that changes in cell-to-cell variation in gene expression emerge as part of the aging process and may be linked to disease vulnerability as a function of age. These emerging concepts are likely to be important across the spectrum of biomedical research and may well underpin what we understand as biological aging.

Keywords:  Aging; Cell-to-cell; Epigenetics; Gene expression; Heterogeneity; Lifespan; Nongenetic; Stochastic; Systems biology

DOI:  https://doi.org/10.1007/s11357-021-00339-9
Nat Rev Clin Oncol. 2021 Feb 19.

Will allogeneic CAR T cells for CD19+ malignancies take autologous CAR T cells 'off the shelf'?

Amanda M DiNofia, Stephan A Grupp.

DOI: https://doi.org/10.1038/s41571-021-00485-1
Curr Aging Sci. 2021 Jan 26.

Changes in peripheral blood biomarkers with aging and neurodegenerative disorders.

Marcela Lima, Cezar Pestana.

  BACKGROUND: Aging is associated with most neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. Determination of peripheral blood biomarkers represents a low invasive approach for tracking early changes in body metabolism during aging.OBJECTIVES: This study addresses a cross-sectional analysis to identity changes in lipid, minerals and antioxidant capacity as potential biomarkers to the onset of neurodegenerative diseases during aging.
METHODS: A retrospective analysis was performed to determine age-related biomarkers from a clinical sample database. Next, one hundred volunteers between 20-59 (adult) and over 60 years (elderly) were submitted to motor and cognitive tests according to Unified Parkinson's Disease Rating Scale (UPDRS) and Mini Mental State Examination (MMSE) respectively. Peripheral blood samples were also collected to determine circulating lipids, minerals and antioxidant capacity.
RESULTS: Lipid profile revealed an increase in Triglycerides, Total and VLDL Cholesterol. Among elderly, HDL was lower than adult group, particularly in volunteers with severe cognitive decline. Minerals involved in antioxidant defense such as Iron, Selenium and Manganese were lower in elderly compared to adults. Catalase activity was also reduced among elderly with mild cognitive impairment.
CONCLUSION: Here we show changes in key serum biomarkers correlates with aging and clinical cognitive decline among elderly. These findings may contribute to the understanding how biomarkers can be useful for early diagnosis and treatment of aging-related diseases.

Keywords:  Neurodegeneration; aging; antioxidants. ; biomarkers; hypercholesterolemia

DOI:  https://doi.org/10.2174/1874609814666210127090100
Eur J Public Health. 2021 Feb 16. pii: ckaa212. [Epub ahead of print]

The future of healthy aging: translation of geroscience discoveries to public health practice.

Zoltan Ungvari, Roza Adany.

DOI: https://doi.org/10.1093/eurpub/ckaa212
Geriatr Gerontol Int. 2021 Feb 15.

Late-career unemployment and risk of frailty among older adults in Taiwan: An 8-year population-based cohort study.

Wei-Min Chu, Hsin-En Ho, Chih-Jung Yeh, Yu-Tse Tsan, Shu-Hsin Lee, Meng-Chih Lee.

  AIM: To evaluate whether late-career unemployment is associated with increased physical frailty among older adults in Taiwan by the design of a population-based cohort study.METHODS: Data were retrieved from the Taiwan Longitudinal Study on Aging. The study examined data from the period 1999 to 2007. A total of 652 subjects were included in the final analysis, and they were categorized as normally employed or unemployed depending on their employment status in 1999. Frailty was defined using the Fried criteria. Multiple confounding factors were adjusted in a multilevel analysis.
RESULTS: The average age of the participants in 1999 was 59.0 years. A total of 491 participants were normally employed, and 161 participants were unemployed. After adjustment for gender, age, level of education, income, marital status, and number of chronic diseases, late-career unemployment was associated with increased frailty [odds ratio (OR) = 1.61; 95% confidence interval (CI) = 1.00-2.59]. The risk of developing frailty was higher for participants who were unemployed during late career and had poor self-rated health [OR = 3.54; 95% CI = 1.37-9.20].
CONCLUSIONS: Late-career unemployment is associated with increased frailty, especially for those who also have poor self-rated health. Older adults should be encouraged to maintain normal employment during the later stages of their career before retirement. Employers should apply strategies to prevent possible late-career unemployment, and the government should provide resources and help to unemployed older workers so that they can minimize poor health outcomes in late life. Geriatr Gerontol Int 2021; ••: ••-••.

Keywords:  elderly; frailty; late-career; unemployment

DOI:  https://doi.org/10.1111/ggi.14136
Alzheimers Dement (N Y). 2021 ;7(1): e12126

A vaccine to prevent initial loss of cognition and eventual Alzheimer's disease in elderly persons.

Jeffrey Fessel.

  Prevention is better than cure and prevention of Alzheimer's disease (AD) may be possible. In elderly persons who are cognitively normal, synaptic hypometabolism as shown by reduced cerebral uptake of fluorodeoxyglucose (18F-FDG), provides a premonitory signal of potential, future loss of cognition if those individuals also have present evidence of amyloid deposition seen in the Pittsburgh compound B positron emission tomography (PIB-PET) scan for amyloid. Those are the persons who should be targeted if one aims to prevent AD. The synaptic hypometabolism implies that the brain's availability of adenosine triphosphate (ATP) is inadequate for performance of all required synaptic functions. This review first describes the basis for asserting that reduced cerebral uptake of 18F-FDG accurately reflects synaptic hypometabolism; second, explains the basis for asserting that hypometabolism implies inadequate ATP; third, shows that amyloid beta (Aβ) itself, Aβ modified by pyroglutamate to become a molecule termed pE(3)Aβ, and cyclophilin-D, in concert are the main contributors to inadequate synaptic ATP and that, therefore, reducing all of their levels would neutralize their combined effect and correct the hypometabolism. pE(3)Aβ is more neurotoxic than unmodified Aβ; and cyclophilin D inhibits ATP synthase and reduces ATP formation. Finally, this review describes an mRNA self-replicating vaccine that will raise brain levels of ATP by reducing Aβ, pyroglutamate-modified Aβ, and cyclophilin-D, and thereby-in cognitively normal elderly persons who have synaptic hypometabolism-prevent initiation of the process that terminates in AD.

Keywords:  ATP‐synthase; Abeta; cyclophilin‐D; inadequate ATP level; mRNA vaccine to prevent original cognitive loss; normal cognition; prevent Alzheimer's disease; prevent cognitive loss; pyroglutamate‐modified Abeta; synaptic hypometabolism

DOI:  https://doi.org/10.1002/trc2.12126
Nat Commun. 2021 02 16. 12(1): 1065

LIGHT/LTβR signaling regulates self-renewal and differentiation of hematopoietic and leukemia stem cells.

S S Höpner, Ana Raykova, R Radpour, M A Amrein, D Koller, G M Baerlocher, C Riether, A F Ochsenbein.

The production of blood cells during steady-state and increased demand depends on the regulation of hematopoietic stem cell (HSC) self-renewal and differentiation. Similarly, the balance between self-renewal and differentiation of leukemia stem cells (LSCs) is crucial in the pathogenesis of leukemia. Here, we document that the TNF receptor superfamily member lymphotoxin-β receptor (LTβR) and its ligand LIGHT regulate quiescence and self-renewal of murine and human HSCs and LSCs. Cell-autonomous LIGHT/LTβR signaling on HSCs reduces cell cycling, promotes symmetric cell division and prevents primitive HSCs from exhaustion in serial re-transplantation experiments and genotoxic stress. LTβR deficiency reduces the numbers of LSCs and prolongs survival in a murine chronic myeloid leukemia (CML) model. Similarly, LIGHT/LTβR signaling in human G-CSF mobilized HSCs and human LSCs results in increased colony forming capacity in vitro. Thus, our results define LIGHT/LTβR signaling as an important pathway in the regulation of the self-renewal of HSCs and LSCs.

DOI: https://doi.org/10.1038/s41467-021-21317-x