bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021–07–25
seventeen papers selected by
Ayesh Seneviratne, University of Toronto
  1. Venetoclax enhances T cell-mediated antileukemic activity by increasing ROS production.
  2. Nuclear NAD+ homeostasis governed by NMNAT1 prevents apoptosis of acute myeloid leukemia stem cells.
  3. Clonal hematopoiesis of indeterminate potential (CHIP): Linking somatic mutations, hematopoiesis, chronic inflammation and cardiovascular disease.
  4. Nicotinamide phosphoribosyltransferase inhibitors selectively induce apoptosis of AML stem cells by disrupting lipid homeostasis.
  5. Mitochondria as extracellular vesicle cargo in aging.
  6. The Impact of Sedentary Lifestyle, High-fat Diet, Tobacco Smoke, and Alcohol Intake on the Hematopoietic Stem Cell Niches.
  7. Role of Lysophospholipid Metabolism in Chronic Myelogenous Leukemia Stem Cells.
  8. Emerging roles of angiopoietin-like proteins in inflammation: Mechanisms and potential as pharmacological targets.
  9. EGR1 dysregulation defines an inflammatory and leukemic program in cell trajectory of human-aged hematopoietic stem cells (HSC).
  10. Neutralization of oxidized phospholipids attenuates age-associated bone loss in mice.
  11. The Jackson Laboratory Nathan Shock Center: impact of genetic diversity on aging.
  12. Caloric restriction inhibits renal artery ageing by reducing endothelin-1 expression.
  13. Efficacy of Venetoclax Combined with Decitabine-Based Treatment for Heavily Pre-Treated Relapsed or Refractory AML Patients in a Real-World Setting.
  14. Research into ageing and frailty.
  15. Targeting intracellular WT1 in AML with a novel RMF-peptide-MHC specific T-cell bispecific antibody.
  16. Eat like an athlete: insights of sports nutrition science to support active aging in healthy older adults.
  17. Inflammation and ROS in arthritis: management by Ayurvedic medicinal plants.
  1. Blood. 2021 Jul 22. 138(3): 234-245
    Venetoclax enhances T cell-mediated antileukemic activity by increasing ROS production.
    Jong Bok Lee, Dilshad H Khan, Rose Hurren, Mingjing Xu, Yoosu Na, Hyeonjeong Kang, Sara Mirali, Xiaoming Wang, Marcela Gronda, Yulia Jitkova, Neil MacLean, Andrea Arruda, Zoe Alaniz, Marina Y Konopleva, Michael Andreeff, Mark D Minden, Li Zhang, Aaron D Schimmer.
      Venetoclax, a Bcl-2 inhibitor, in combination with the hypomethylating agent azacytidine, achieves complete remission with or without count recovery in ∼70% of treatment-naive elderly patients unfit for conventional intensive chemotherapy. However, the mechanism of action of this drug combination is not fully understood. We discovered that venetoclax directly activated T cells to increase their cytotoxicity against acute myeloid leukemia (AML) in vitro and in vivo. Venetoclax enhanced T-cell effector function by increasing reactive oxygen species generation through inhibition of respiratory chain supercomplexes formation. In addition, azacytidine induced a viral mimicry response in AML cells by activating the STING/cGAS pathway, thereby rendering the AML cells more susceptible to T cell-mediated cytotoxicity. Similar findings were seen in patients treated with venetoclax, as this treatment increased reactive oxygen species generation and activated T cells. Collectively, this study presents a new immune-mediated mechanism of action for venetoclax and azacytidine in the treatment of AML and highlights a potential combination of venetoclax and adoptive cell therapy for patients with AML.
    DOI:  https://doi.org/10.1182/blood.2020009081
  2. Sci Adv. 2021 Jul;pii: eabf3895. [Epub ahead of print]7(30):
    Nuclear NAD+ homeostasis governed by NMNAT1 prevents apoptosis of acute myeloid leukemia stem cells.
    Xiangguo Shi, Yajian Jiang, Ayumi Kitano, Tianyuan Hu, Rebecca L Murdaugh, Yuan Li, Kevin A Hoegenauer, Rui Chen, Koichi Takahashi, Daisuke Nakada.
      Metabolic dysregulation underlies malignant phenotypes attributed to cancer stem cells, such as unlimited proliferation and differentiation blockade. Here, we demonstrate that NAD+ metabolism enables acute myeloid leukemia (AML) to evade apoptosis, another hallmark of cancer stem cells. We integrated whole-genome CRISPR screening and pan-cancer genetic dependency mapping to identify NAMPT and NMNAT1 as AML dependencies governing NAD+ biosynthesis. While both NAMPT and NMNAT1 were required for AML, the presence of NAD+ precursors bypassed the dependence of AML on NAMPT but not NMNAT1, pointing to NMNAT1 as a gatekeeper of NAD+ biosynthesis. Deletion of NMNAT1 reduced nuclear NAD+, activated p53, and increased venetoclax sensitivity. Conversely, increased NAD+ biosynthesis promoted venetoclax resistance. Unlike leukemia stem cells (LSCs) in both murine and human AML xenograft models, NMNAT1 was dispensable for hematopoietic stem cells and hematopoiesis. Our findings identify NMNAT1 as a previously unidentified therapeutic target that maintains NAD+ for AML progression and chemoresistance.
    DOI:  https://doi.org/10.1126/sciadv.abf3895
  3. J Mol Cell Cardiol. 2021 Jul 20. pii: S0022-2828(21)00145-0. [Epub ahead of print]
    Clonal hematopoiesis of indeterminate potential (CHIP): Linking somatic mutations, hematopoiesis, chronic inflammation and cardiovascular disease.
    ChristopherS Marnell, Alexander Bick, Pradeep Natarajan.
      Clonal hematopoiesis of indeterminate potential (CHIP) is the presence of a clonally expanded hematopoietic stem cell caused by a leukemogenic mutation in individuals without evidence of hematologic malignancy, dysplasia, or cytopenia. CHIP is associated with a 0.5-1.0% risk per year of leukemia. Remarkably, it confers a two-fold increase in cardiovascular risk independent of traditional risk factors. Roughly 80% of patients with CHIP have mutations in epigenetic regulators DNMT3A, TET2, ASXL1, DNA damage repair genes PPM1D, TP53, the regulatory tyrosine kinase JAK2, or mRNA spliceosome components SF3B1, and SRSF2. CHIP is associated with a pro-inflammatory state that has been linked to coronary artery disease, myocardial infarction, and venous thromboembolic disease, as well as prognosis among those with aortic stenosis and heart failure. Heritable and acquired risk factors are associated with increased CHIP prevalence, including germline variation, age, unhealthy lifestyle behaviors (i.e. smoking, obesity), inflammatory conditions, premature menopause, HIV and exposure to cancer therapies. This review aims to summarize emerging research on CHIP, the mechanisms underlying its important role in propagating inflammation and accelerating cardiovascular disease, and new studies detailing the role of associated risk factors and co-morbidities that increase CHIP prevalence.
    Keywords:  ASCVD; Aortic stenosis; CHIP; Cardio-oncology; Heart failure; Inflammation
    DOI:  https://doi.org/10.1016/j.yjmcc.2021.07.004
  4. Cell Stem Cell. 2021 Jul 12. pii: S1934-5909(21)00274-5. [Epub ahead of print]
    Nicotinamide phosphoribosyltransferase inhibitors selectively induce apoptosis of AML stem cells by disrupting lipid homeostasis.
    Amit Subedi, Qiang Liu, Dhanoop M Ayyathan, David Sharon, Severine Cathelin, Mohsen Hosseini, Changjiang Xu, Veronique Voisin, Gary D Bader, Angelo D'Alessandro, Eric R Lechman, John E Dick, Mark D Minden, Jean C Y Wang, Steven M Chan.
      Current treatments for acute myeloid leukemia (AML) are often ineffective in eliminating leukemic stem cells (LSCs), which perpetuate the disease. Here, we performed a metabolic drug screen to identify LSC-specific vulnerabilities and found that nicotinamide phosphoribosyltransferase (NAMPT) inhibitors selectively killed LSCs, while sparing normal hematopoietic stem and progenitor cells. Treatment with KPT-9274, a NAMPT inhibitor, suppressed the conversion of saturated fatty acids to monounsaturated fatty acids, a reaction catalyzed by the stearoyl-CoA desaturase (SCD) enzyme, resulting in apoptosis of AML cells. Transcriptomic analysis of LSCs treated with KPT-9274 revealed an upregulation of sterol regulatory-element binding protein (SREBP)-regulated genes, including SCD, which conferred partial protection against NAMPT inhibitors. Inhibition of SREBP signaling with dipyridamole enhanced the cytotoxicity of KPT-9274 on LSCs in vivo. Our work demonstrates that altered lipid homeostasis plays a key role in NAMPT inhibitor-induced apoptosis and identifies NAMPT inhibition as a therapeutic strategy for targeting LSCs in AML.
    Keywords:  NAD metabolism; NAMPT; SREBP signaling; acute myeloid leukemia; dipyridamole; drug screen; fatty acid; leukemic stem cells; lipotoxicity; metabolism
    DOI:  https://doi.org/10.1016/j.stem.2021.06.004
  5. Aging (Albany NY). 2021 07 20. undefined(undefined):
    Mitochondria as extracellular vesicle cargo in aging.
    Nicole Noren Hooten, Michele K Evans.
      
    Keywords:  aging; biomarker; circulating cell-free mitochondrial DNA; exosomes; extracellular vesicles; microvesicles; mitochondria; mitochondrial DNA
    DOI:  https://doi.org/10.18632/aging.203358
  6. Hemasphere. 2021 Aug;5(8): e615
    The Impact of Sedentary Lifestyle, High-fat Diet, Tobacco Smoke, and Alcohol Intake on the Hematopoietic Stem Cell Niches.
    Katja Kaastrup, Kirsten Grønbæk.
      Hematopoietic stem and progenitor cells maintain hematopoiesis throughout life by generating all major blood cell lineages through the process of self-renewal and differentiation. In adult mammals, hematopoietic stem cells (HSCs) primarily reside in the bone marrow (BM) at special microenvironments called "niches." Niches are thought to extrinsically orchestrate the HSC fate including their quiescence and proliferation. Insight into the HSC niches mainly comes from studies in mice using surface marker identification and imaging to visualize HSC localization and association with niche cells. The advantage of mouse models is the possibility to study the 3-dimensional BM architecture and cell interactions in an intact traceable system. However, this may not be directly translational to human BM. Sedentary lifestyle, unhealthy diet, excessive alcohol intake, and smoking are all known risk factors for various diseases including hematological disorders and cancer, but how do lifestyle factors impact hematopoiesis and the associated niches? Here, we review current knowledge about the HSC niches and how unhealthy lifestyle may affect it. In addition, we summarize epidemiological data concerning the influence of lifestyle factors on hematological disorders and malignancies.
    DOI:  https://doi.org/10.1097/HS9.0000000000000615
  7. Cancers (Basel). 2021 Jul 08. pii: 3434. [Epub ahead of print]13(14):
    Role of Lysophospholipid Metabolism in Chronic Myelogenous Leukemia Stem Cells.
    Kazuhito Naka.
      It is well known that mature chronic myelogenous leukemia (CML) cells proliferate in response to oncogenic BCR-ABL1-dependent signaling, but how CML stem cells are able to survive in an oncogene-independent manner and cause disease relapse has long been elusive. Here, I put into the context of the broader literature our recent finding that lysophospholipid metabolism is essential for the maintenance of CML stem cells. I describe the fundamentals of lysophospholipid metabolism and discuss how one of its key enzymes, Glycerophosphodiester Phosphodiesterase Domain Containing 3 (Gdpd3), is responsible for maintaining the unique characteristics of CML stem cells. I also explore how this knowledge may be exploited to devise novel therapies for CML patients.
    Keywords:  CML stemness; Foxo3a; Gdpd3; lysophospholipid
    DOI:  https://doi.org/10.3390/cancers13143434
  8. J Cell Physiol. 2021 Jul 21.
    Emerging roles of angiopoietin-like proteins in inflammation: Mechanisms and potential as pharmacological targets.
    Jing Yang, Qiu-Yi Song, Shu-Xuan Niu, Hui-Jing Chen, Robert B Petersen, Yu Zhang, Kun Huang.
      Angiopoietin-like proteins (ANGPTLs), a family of eight secreted glycoproteins termed ANGTPL1-8, are involved in angiogenesis, lipid metabolism, cancer progression, and inflammation. Their roles in regulating lipid metabolism have been intensively studied, as some ANGPTLs are promising pharmacological targets for hypertriglyceridemia and associated cardiovascular disease. Recently, the emerging roles of ANGPTLs in inflammation have attracted great attention. First, elevated levels of multiple circulating ANGPTLs in inflammatory diseases make them potential disease biomarkers. Second, multiple ANGPTLs regulate acute or chronic inflammation via various mechanisms, including triggering inflammatory signaling through their action as ligands for integrin or forming homo- /hetero-oligomers to regulate signal transduction via extra- or intracellular mechanisms. As dysregulation of the inflammatory response is a critical trigger in many diseases, understanding the roles of ANGPTLs in inflammation will aid in drug/therapy development. Here, we summarize the roles, mechanisms, and potential therapeutic values for ANGPTLs in inflammation and inflammatory diseases.
    Keywords:  ANGPTLs; drug development; inflammation; integrin; metabolism; oligomerization
    DOI:  https://doi.org/10.1002/jcp.30534
  9. Stem Cell Res Ther. 2021 Jul 22. 12(1): 419
    EGR1 dysregulation defines an inflammatory and leukemic program in cell trajectory of human-aged hematopoietic stem cells (HSC).
    Christophe Desterke, Annelise Bennaceur-Griscelli, Ali G Turhan.
       BACKGROUND: During aging, hematopoietic stem cells (HSC) lose progressively both their self-renewal and differentiation potential. The precise molecular mechanisms of this phenomenon are not well established. To uncover the molecular events underlying this event, we have performed a bioinformatics analysis of 650 single-cell transcriptomes.
    METHODS: Single-cell transcriptome analyses of expression heterogeneity, cell cycle, and cell trajectory in human cell compartment enriched in hematopoietic stem cell compartment were investigated in the bone marrow according to the age of the donors. Identification of aging-related nodules was identified by weighted correlation network analysis in this primitive compartment.
    RESULTS: The analysis of single-cell transcriptomes allowed to uncover a major upregulation of EGR1 in human-aged lineage-CD34+CD38- cells which present cell cycle dysregulation with reduction of G2/M phase according to less expression of CCND2 during S phase. EGR1 upregulation in aging hematopoietic stem cells was found to be independent of cell cycle phases and gender. EGR1 expression trajectory in aged HSC highlighted a signature enriched in hematopoietic and immune disorders with the best induction of AP-1 complex and quiescence regulators such as EGR1, BTG2, JUNB, and NR41A. Sonic Hedgehog-related TMEM107 transmembrane molecule followed also EGR1 cell trajectory. EGR1-dependent gene weighted network analysis in human HSC-associated IER2 target protein-specific regulators of PP2A activity, IL1B, TNFSF10 ligands, and CD69, SELP membrane molecules in old HSC module with immune and leukemogenic signature. In contrast, for young HSC which were found with different cell cycle phase progression, its specific module highlighted upregulation of HIF1A hypoxic factor, PDE4B immune marker, DRAK2 (STK17B) T cell apoptosis regulator, and MYADM myeloid-associated marker.
    CONCLUSION: EGR1 was found to be connected to the aging of human HSC and highlighted a specific cell trajectory contributing to the dysregulation of an inflammatory and leukemia-related transcriptional program in aged human HSCs. EGR1 and its program were found to be connected to the aging of human HSC with dissociation of quiescence property and cell cycle phase progression in this primitive hematopoietic compartment.
    Keywords:  Aging; EGR1; Hematopoietic stem cell; Inflammation; Leukemia; Single cell
    DOI:  https://doi.org/10.1186/s13287-021-02498-0
  10. Aging Cell. 2021 Jul 19. e13442
    Neutralization of oxidized phospholipids attenuates age-associated bone loss in mice.
    Michela Palmieri, Maria Almeida, Intawat Nookaew, Horacio Gomez-Acevedo, Teenamol E Joseph, Xuchu Que, Sotirios Tsimikas, Xiaoli Sun, Stavros C Manolagas, Joseph L Witztum, Elena Ambrogini.
      Oxidized phospholipids (OxPLs) are pro-inflammatory molecules that affect bone remodeling under physiological conditions. Transgenic expression of a single-chain variable fragment (scFv) of the antigen-binding domain of E06, an IgM natural antibody that recognizes the phosphocholine (PC) moiety of OxPLs, increases trabecular and cortical bone in adult male and female mice by increasing bone formation. OxPLs increase with age, while natural antibodies decrease. Age-related bone loss is associated with increased oxidative stress and lipid peroxidation and is characterized by a decline in osteoblast number and bone formation, raising the possibility that increased OxPLs, together with the decline of natural antibodies, contribute to age-related bone loss. We show here that transgenic expression of E06-scFv attenuated the age-associated loss of spinal, femoral, and total bone mineral density in both female and male mice aged up to 22 and 24 months, respectively. E06-scFv attenuated the age-associated decline in trabecular bone, but not cortical bone, and this effect was associated with an increase in osteoblasts and a decrease in osteoclasts. Furthermore, RNA-seq analysis showed that E06-scFv increased Wnt10b expression in vertebral bone in aged mice, indicating that blocking OxPLs increases Wnt signaling. Unlike age-related bone loss, E06-scFv did not attenuate the bone loss caused by estrogen deficiency or unloading in adult mice. These results demonstrate that OxPLs contribute to age-associated bone loss. Neutralization of OxPLs, therefore, is a promising therapeutic target for senile osteoporosis, as well as atherosclerosis and non-alcoholic steatohepatitis (NASH), two other conditions shown to be attenuated by E06-scFv in mice.
    Keywords:  Wnt signaling; aging and bone; osteoblasts; oxidized phospholipids
    DOI:  https://doi.org/10.1111/acel.13442
  11. Geroscience. 2021 Jul 23.
    The Jackson Laboratory Nathan Shock Center: impact of genetic diversity on aging.
    Ron Korstanje, Luanne L Peters, Laura L Robinson, Stephen D Krasinski, Gary A Churchill.
      Healthspan is a complex trait, influenced by many genes and environmental factors that accelerate or delay aging, reduce or increase disease risk, and extend or reduce lifespan. Thus, assessing the role of genetic variation in aging requires an experimental strategy capable of modeling the genetic and biological complexity of human populations. The goal of the The Jackson Laboratory Nathan Shock Center (JAX NSC) is to provide research resources and training for geroscience investigators that seek to understand the role of genetics and genetic diversity on the fundamental process of aging and diseases of human aging using the laboratory mouse as a model system. The JAX NSC has available novel, deeply characterized populations of aged mice, performs state-of-the-art phenotyping of age-relevant traits, provides systems genetics analysis of complex data sets, and provides all of these resources to the geroscience community. The aged animal resources, phenotyping capacity, and genetic expertise available through the JAX NSC benefit the geroscience community by fostering cutting-edge, novel lines of research that otherwise would not be possible. Over the past 15 years, the JAX NSC has transformed aging research across the geroscience community, providing aging mouse resources and tissues to researchers. All JAX NSC data and tools are publicly disseminated on the Mouse Phenome Database and the JAX NSC website, thus ensuring that the resources generated and expertise acquired through the Center are readily available to the aging research community. The JAX NSC will continue to enhance its ability to perform innovative research using a mammalian model to illuminate novel genotype-phenotype relationships and provide a rational basis for designing effective risk assessments and therapeutic interventions to boost longevity and disease-free healthspan.
    Keywords:  Complex trait; Diversity outbred mice; Genetic diversity; Healthspan; Lifespan
    DOI:  https://doi.org/10.1007/s11357-021-00421-2
  12. Ann Transl Med. 2021 Jun;9(12): 979
    Caloric restriction inhibits renal artery ageing by reducing endothelin-1 expression.
    Xiao-Hua Wang, Qiang-Guo Ao, Qing-Li Cheng.
       Background: The renal artery plays a central role in renal perfusion and is critical for proper renal function. Ageing is an independent risk factor for both impaired renal function and vascular disorders, and associated with an increase in the expression of the vasoconstrictor endothelin-1 (ET-1), and caloric restriction (CR) without malnutrition has been shown to be an effective inhibitor of renal dysfunction induced by ageing. The objective of this study was to determine whether CR-mediated alleviation of renal dysfunction is mediated by ET-1 expression.
    Methods: The young (2 months, 2 M) and old (12 months, 12 M) Sprague-Dawley male rats were used and fed ad libitum. The 12-month-old rats were further divided into 12 M and 12 M-caloric restriction (CR) (30% calorie restriction). After 8 weeks, the renal tissues were showed by PAS staining, and age-related metabolic parameters and renal functions were detected in each group of rats. The inflammatory cytokines of interleukin (IL)-6, IL-1β, tumor necrosis factor alpha (TNF-α), and transforming growth factor beta 1 (TGF-β1) were analyzed using ELISA. The mRNA and protein expression in the renal artery were analysis by qRT-PCR and Immunoblot analysis.
    Results: Ageing was associated with significant increases in 24 h urine protein content and serum triglyceride and cholesterol in 12 M rats, both of which were significantly inhibited in 12 M-CR. The mRNA expression and the secretion of IL-6, IL-1β, TNF-α, and TGF-β1 in the renal artery was significantly increased with ageing and inhibited by CR. CR also inhibited ageing-induced Edn1 (encoding ET-1) mRNA and protein expression in the renal artery. In addition, CR could regulate ET-1 expression by inhibiting the activation of NF-κB signaling and activation and induction in the expression of NF-E2-related factor 2 (Nrf2) and histone deacetylase and gene repressor sirtuin 1 (SIRT1), both of which play a central role in mitigating oxidative stress in young rats.
    Conclusions: Moderate CR can reverse the ageing related kidney dysfunction by reducing the ET-1 expression. CR might be used as an alternative to prevent the ageing induced renal artery dysfunction.
    Keywords:  Caloric restriction (CR); NF-κB signaling; ageing; endothelin-1 (ET-1); renal artery
    DOI:  https://doi.org/10.21037/atm-21-2218
  13. Cancer Manag Res. 2021 ;13 5613-5621
    Efficacy of Venetoclax Combined with Decitabine-Based Treatment for Heavily Pre-Treated Relapsed or Refractory AML Patients in a Real-World Setting.
    Juan Tong, Na Zhao, Xing Hu, Wen Yao, Yaxin Cheng, Li Zhou, Huilan Liu, Liangquan Geng, Zimin Sun, Changcheng Zheng.
       Purpose: We report the efficacy and safety of venetoclax plus decitabine-based treatment in heavily pre-treated relapsed or refractory acute myeloid leukaemia (RR-AML) in a real-world setting.
    Patients and Methods: There were 22 patients in this study and the median age was 47.5 (12-84) years old, including 11 males and 11 females. Among them, 8 patients were relapsed AML including 2 patients relapsed after HSCT and 14 patients with primary refractory AML including 4 secondary AML. The median number of cycles of previous chemotherapy was 4 (range, 2-10).
    Results: After a course of venetoclax plus decitabine-based treatment, 9 patients achieved complete remission (CR) and 1 patient achieved complete remission with incomplete haematological recovery (CRi). The overall response rate (ORR) was 45.5% and the CR rate was 40.9%, and the median time to reach CR/CRi was 21 (13-46) days. Four of the 10 CR/CRi patients relapsed again, and the median time of relapse was 5 (1.0-24) months. The one-year overall survival rate was 31.8%, and the median survival time was 6 months (95% CI, 1-9 months). The one-year overall survival rate of 10 CR/CRi patients was 59.1%, and the 12 NR patients was 10.4% (p=0.001). Nausea and vomiting occurred in 11 patients (50.0%). All patients had grade IV neutropenia and IV thrombocytopenia (100%). Pneumonia occurred in 14 patients (63.6%) and septicaemia occurred in 2 patients (9.0%). The cause of death in all patients was primary disease progression, and no patients died due to the side effects.
    Conclusion: The efficacy of venetoclax plus decitabine-based treatment in the real-world treatment of heavily pre-treated RR-AML is similar to that in clinical trials, and the side effects are controllable.
    Keywords:  acute myeloid leukaemia; hypomethylating agents; venetoclax
    DOI:  https://doi.org/10.2147/CMAR.S316561
  14. Future Healthc J. 2021 Jul;8(2): e237-e242
    Research into ageing and frailty.
    Adam L Gordon, Miles D Witham, Emily J Henderson, Rowan H Harwood, Tahir Masud.
      Research into ageing covers opportunities and challenges posed by an older population, and research to understand the ageing processes across the lifespan. The evidence base for Comprehensive Geriatric Assessment (CGA) is well established and efforts should now shift to understanding how to implement its principles across different healthcare contexts. Research around syndromes common in older people has progressed with variable success; while effective therapies for falls and cognitive impairment have been identified, older people with advanced frailty have commonly been excluded from Parkinson's disease and continence research. Research to understand the mechanisms of ageing has potential to mitigate against or treat emerging sarcopenia and cognitive impairment, and thus modify frailty trajectories. Pharmacogenetics could individualise therapeutics to reduce polypharmacy. These issues can only be addressed with development of infrastructure, capacity and expertise in ageing research. Commonly used research methodologies must be adapted to take account of frailty, cognitive impairment and functional dependency.
    Keywords:  ageing; cognitive impairment; frailty; research; sarcopenia
    DOI:  https://doi.org/10.7861/fhj.2021-0088
  15. Blood. 2021 Jul 19. pii: blood.2020010477. [Epub ahead of print]
    Targeting intracellular WT1 in AML with a novel RMF-peptide-MHC specific T-cell bispecific antibody.
    Christian Augsberger, Gerulf Hänel, Wei Xu, Vesna Pulko, Lydia Jasmin Hanisch, Angelique Augustin, John Challier, Katharina Hunt, Binje Vick, Pier Edoardo Rovatti, Christina Krupka, Maurine Rothe, Anne Schönle, Johannes Sam, Emmanuelle Lezan, Axel Ducret, Daniela Ortiz-Franyuti, Antje-Christine Walz, Jörg Benz, Alexander Bujotzek, Felix S Lichtenegger, Christian Gassner, Alejandro Carpy, Victor Lyamichev, Jigar Patel, Nikola P Konstandin, Antje Tunger, Marc Schmitz, Michael von Bergwelt-Baildon, Karsten Spiekermann, Luca Vago, Irmela Jeremias, Estelle Marrer-Berger, Pablo Umaña, Christian Klein, Marion Subklewe.
      Antibody-based immunotherapy is a promising strategy for targeting chemo-resistant leukemic cells. However, classical antibody-based approaches are restricted to targeting lineage-specific cell-surface antigens. By targeting intracellular antigens, a large number of other leukemia-associated targets would become accessible. In this study, we evaluated a novel T-cell bispecific (TCB) antibody, generated using CrossMab and knob-into-holes technology, containing a bivalent T-cell receptor-like binding domain that recognizes the RMFPNAPYL peptide derived from the intracellular tumor antigen Wilms' tumor 1 (WT1) in the context of human leukocyte antigen (HLA) A*02. Binding to CD3ε recruits T cells irrespective of their T-cell receptor specificity. WT1-TCB elicited antibody-mediated T-cell cytotoxicity against AML cell lines in a WT1- and HLA-restricted manner. Specific lysis of primary AML cells was mediated in ex vivo long-term co-cultures utilizing allogenic (mean specific lysis: 67±6% after 13-14 days; ±SEM; n=18) or autologous, patient-derived T cells (mean specific lysis: 54±12% after 11-14 days; ±SEM; n=8). WT1-TCB-treated T cells exhibited higher cytotoxicity against primary AML cells than an HLA-A*02 RMF-specific T-cell clone. Combining WT1-TCB with the immunomodulatory drug lenalidomide further enhanced antibody-mediated T-cell cytotoxicity against primary AML cells (mean specific lysis on day 3-4: 45.4±9.0% vs 70.8±8.3%; p=0.015; ±SEM; n=9-10). In vivo, WT1-TCB-treated humanized mice bearing SKM-1 tumors showed a significant and dose-dependent reduction in tumor growth. In summary, we show that WT1-TCB facilitates potent in vitro, ex vivo and in vivo killing of AML cell lines and primary AML cells; these results led to the initiation of a phase I trial in patients with r/r AML (NCT04580121).
    DOI:  https://doi.org/10.1182/blood.2020010477
  16. Geroscience. 2021 Jul 20.
    Eat like an athlete: insights of sports nutrition science to support active aging in healthy older adults.
    Sara Y Oikawa, Tristin D Brisbois, Luc J C van Loon, Ian Rollo.
      Skeletal muscle mass losses with age are associated with negative health consequences, including an increased risk of developing metabolic disease and the loss of independence. Athletes adopt numerous nutritional strategies to maximize the benefits of exercise training and enhance recovery in pursuit of improving skeletal muscle quality, mass, or function. Importantly, many of the principles applied to enhance skeletal muscle health in athletes may be applicable to support active aging and prevent sarcopenia in the healthy (non-clinical) aging population. Here, we discuss the anabolic properties of protein supplementation in addition to ingredients that may enhance the anabolic effects of protein (e.g. omega 3 s, creatine, inorganic nitrate) in older persons. We conclude that nutritional strategies used in pursuit of performance enhancement in athletes are often applicable to improve skeletal muscle health in the healthy older population when implemented as part of a healthy active lifestyle. Further research is required to elucidate the mechanisms by which these nutrients may induce favourable changes in skeletal muscle and to determine the appropriate dosing and timing of nutrient intakes to support active aging.
    Keywords:  Carbohydrate periodization; Creatine; Protein; Skeletal muscle; n-3PUFA
    DOI:  https://doi.org/10.1007/s11357-021-00419-w
  17. Food Funct. 2021 Jul 24.
    Inflammation and ROS in arthritis: management by Ayurvedic medicinal plants.
    Sahdeo Prasad, Alok Kulshreshtha, Rajiv Lall, Subash C Gupta.
      Chronic joint inflammatory disorders like osteoarthritis and rheumatoid arthritis, which are manifested by joint dysfunction, show an upsurge in inflammation and oxidative stress. Although conventional anti-arthritic drugs are being used to relieve pain from arthritic symptoms, they usually cause severe side effects. Traditionally used Ayurvedic medicinal plants are a promising alternative for the management of arthritic symptoms, as they are safe and effective. Ayurvedic medicinal plants improve arthritic symptoms by reducing joint tenderness, joint pain, swelling, bone and cartilage damage, and increasing knee flexion, walking distance and sports activities. These beneficial effects of Ayurvedic medicinal plants on arthritis are mediated through various cellular mechanisms including inhibition of the inflammatory markers NF-κB, cytokines, adipokines, PGE2, NO, iNOS, COX-2, and MMPs and induction of antioxidant status by decreasing free radicals, lipid peroxidation, and myeloperoxidase, and increasing antioxidant enzymes, Nrf2, and HO-1. Thus, a strategy requires using these Ayurvedic medicinal plants to treat arthritis. This article describes the status of inflammation and oxidative stress in arthritic conditions. We also provide evidence that Ayurvedic medicinal plants and their bioactive components are highly effective in improving arthritic symptoms.
    DOI:  https://doi.org/10.1039/d1fo01078f
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