bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021–08–01
nineteen papers selected by
Ayesh Seneviratne, University of Toronto
  1. Clonal hematopoiesis and associated diseases: A review of recent findings.
  2. CD70-specific CAR T cells have potent activity against acute myeloid leukemia without HSC toxicity.
  3. Germline Stem and Progenitor Cell Aging in C. elegans.
  4. Trends in Natural Nutrients for Oxidative Stress and Cell Senescence.
  5. Donepezil Protects Against Doxorubicin-Induced Chemobrain in Rats via Attenuation of Inflammation and Oxidative Stress Without Interfering With Doxorubicin Efficacy.
  6. Multimorbidity networks associated with frailty among middle aged and older people with HIV.
  7. Aging increases senescence, calcium signaling, and extracellular matrix deposition in human airway smooth muscle.
  8. Ten Simple Dietary Steps to Strengthen Your Immune System - A Guide for Elderly Individuals at Risk of COVID-19.
  9. Anti-cachexia therapy should target metabolism, inflammatory cytokines, and androgens in hormone-independent cancers.
  10. Statins: a repurposed drug to fight cancer.
  11. Hematopoietic Stem Cells in Type 1 Diabetes.
  12. Anterograde regulation of mitochondrial genes and FGF21 signaling by hepatic LSD1.
  13. Plant-based diets, pescatarian diets and COVID-19 severity: a population-based case-control study in six countries.
  14. MK2206 attenuates atherosclerosis by inhibiting lipid accumulation, cell migration, proliferation, and inflammation.
  15. Hepatic mTORC1 signaling activates ATF4 as part of its metabolic response to feeding and insulin.
  16. Venetoclax plus low-dose cytarabine in Japanese patients with untreated acute myeloid leukaemia ineligible for intensive chemotherapy.
  17. Lipid metabolism, inflammation, and foam cell formation in health and metabolic disorders: targeting mTORC1.
  18. Lipid metabolism in cancer: A systematic review.
  19. Fragility of randomized trials supporting cancer drug approvals stratified by approval pathway and review designations.
  1. Cancer Sci. 2021 Jul 30.
    Clonal hematopoiesis and associated diseases: A review of recent findings.
    Shuhei Asada, Toshio Kitamura.
      Recent genome-wide studies have revealed that aging or chronic inflammation can cause clonal expansion of cells in normal tissues. Clonal hematopoiesis has been the most intensively studied form of clonal expansion in the last decade. Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related phenomenon observed in elderly individuals with no history of hematological malignancy. The most frequently mutated genes in CHIP are DNMT3A, TET2, and ASXL1, which are associated with initiation of leukemia. Importantly, CHIP has been the focus of a number of studies because it is an independent risk factor for myeloid malignancy, cardiovascular disease (CVD), and all-cause mortality. Animal models recapitulating human CHIP revealed that CHIP-associated mutations alter the number and function of hematopoietic stem and progenitor cells (HSPCs) and promote leukemic transformation. Moreover, chronic inflammation caused by infection or aging confers a fitness advantage to the CHIP-associated mutant HSPCs. Myeloid cells, such as macrophages with a CHIP-associated mutation, accelerate chronic inflammation and are associated with increased levels of inflammatory cytokines. This positive feedback loop between CHIP and chronic inflammation promotes development of atherosclerosis and chronic heart failure and thereby increases the risk for CVD. Notably, HSPCs with a CHIP-associated mutation may alter not only innate but also acquired immune cells. This suggests that CHIP is involved in the development of solid cancers or immune disorders, such as aplastic anemia. In this review, we provide an overview of recent findings on CHIP. We also discuss potential interventions for treating CHIP and preventing myeloid transformation and CVD progression.
    DOI:  https://doi.org/10.1111/cas.15094
  2. Blood. 2021 Jul 29. 138(4): 318-330
    CD70-specific CAR T cells have potent activity against acute myeloid leukemia without HSC toxicity.
    Tim Sauer, Kathan Parikh, Sandhya Sharma, Bilal Omer, David Sedloev, Qian Chen, Linus Angenendt, Christoph Schliemann, Michael Schmitt, Carsten Müller-Tidow, Stephen Gottschalk, Cliona M Rooney.
      The prognosis of patients with acute myeloid leukemia (AML) remains dismal, highlighting the need for novel innovative treatment strategies. The application of chimeric antigen receptor (CAR) T-cell therapy to patients with AML has been limited, in particular by the lack of a tumor-specific target antigen. CD70 is a promising antigen to target AML, as it is expressed on most leukemic blasts, whereas little or no expression is detectable in normal bone marrow samples. To target CD70 on AML cells, we generated a panel of CD70-CAR T cells that contained a common single-chain variable fragment (scFv) for antigen detection, but differed in size and flexibility of the extracellular spacer and in the transmembrane and the costimulatory domains. These CD70scFv CAR T cells were compared with a CAR construct that contained human CD27, the ligand of CD70 fused to the CD3ζ chain (CD27z). The structural composition of the CAR strongly influenced expression levels, viability, expansion, and cytotoxic capacities of CD70scFv-based CAR T cells, but CD27z-CAR T cells demonstrated superior proliferation and antitumor activity in vitro and in vivo, compared with all CD70scFv-CAR T cells. Although CD70-CAR T cells recognized activated virus-specific T cells (VSTs) that expressed CD70, they did not prevent colony formation by normal hematopoietic stem cells. Thus, CD70-targeted immunotherapy is a promising new treatment strategy for patients with CD70-positive AML that does not affect normal hematopoiesis but will require monitoring of virus-specific T-cell responses.
    DOI:  https://doi.org/10.1182/blood.2020008221
  3. Front Cell Dev Biol. 2021 ;9 699671
    Germline Stem and Progenitor Cell Aging in C. elegans.
    Theadora Tolkin, E Jane Albert Hubbard.
      Like many animals and humans, reproduction in the nematode C. elegans declines with age. This decline is the cumulative result of age-related changes in several steps of germline function, many of which are highly accessible for experimental investigation in this short-lived model organism. Here we review recent work showing that a very early and major contributing step to reproductive decline is the depletion of the germline stem and progenitor cell pool. Since many cellular and molecular aspects of stem cell biology and aging are conserved across animals, understanding mechanisms of age-related decline of germline stem and progenitor cells in C. elegans has broad implications for aging stem cells, germline stem cells, and reproductive aging.
    Keywords:  Notch pathway; germline flux; insulin/IGF-like signal transduction pathway; reproductive aging; stem cell aging
    DOI:  https://doi.org/10.3389/fcell.2021.699671
  4. Oxid Med Cell Longev. 2021 ;2021 7501424
    Trends in Natural Nutrients for Oxidative Stress and Cell Senescence.
    Navid Omidifar, Mohsen Moghadami, Seyyed Mojtaba Mousavi, Seyyed Alireza Hashemi, Ahmad Gholami, Mansoureh Shokripour, Zahra Sohrabi.
      Due to the increase in the aged population and increased life expectancy, the underlying mechanisms involved in the aging process and cell senescence and the ways for modulating these processes in age-related diseases become important. One of the main mechanisms involved in aging and cell senescence, especially in the diseases related to aging, is the oxidative stress process and the following inflammation. Hence, the effects of antioxidants are highlighted in the literature due to their beneficial impacts on inhibiting telomere shortening or DNA damage and other processes related to aging and cell senescence in age-related diseases. Dietary components, foods, and dietary patterns rich in antioxidants can modulate the aging process and delay the progression of some chronic diseases such as cardiovascular diseases, diabetes, and Alzheimer's disease. Foods high in polyphenols, vitamin C, or carotenoids, olive oil, seeds, nuts, legumes, dietary supplements such as CoQ10, and some other dietary factors are the most important nutritional sources that have high antioxidant contents which can positively affect cell senescence and disease progression. Plant dietary patterns including Mediterranean diets can also inhibit telomere shortening following oxidative damages, and this can delay cell aging and senescence in age-related diseases. Further, olive oil can inhibit protein aggregation in Alzheimer's disease. It can be concluded that nutrition can delay the process of cell senescence in age-related diseases via inhibiting oxidative and inflammatory pathways. However, more studies are needed to better clarify the underlying mechanisms of nutrition and dietary components on cell senescence, aging, and disease progression, especially those related to age.
    DOI:  https://doi.org/10.1155/2021/7501424
  5. Neurotherapeutics. 2021 Jul 26.
    Donepezil Protects Against Doxorubicin-Induced Chemobrain in Rats via Attenuation of Inflammation and Oxidative Stress Without Interfering With Doxorubicin Efficacy.
    Benjamin Ongnok, Thawatchai Khuanjing, Titikorn Chunchai, Patcharapong Pantiya, Sasiwan Kerdphoo, Busarin Arunsak, Wichwara Nawara, Thidarat Jaiwongkam, Nattayaporn Apaijai, Nipon Chattipakorn, Siriporn C Chattipakorn.
      Although doxorubicin (Dox) is an effective chemotherapy medication used extensively in the treatment of breast cancer, it frequently causes debilitating neurological deficits known as chemobrain. Donepezil (DPZ), an acetylcholinesterase inhibitor, provides therapeutic benefits in various neuropathological conditions. However, comprehensive mechanistic insights regarding the neuroprotection of DPZ on cognition and brain pathologies in a Dox-induced chemobrain model remain obscure. Here, we demonstrated that Dox-treated rats manifested conspicuous cognitive deficits and developed chemobrain pathologies as indicated by brain inflammatory and oxidative insults, glial activation, defective mitochondrial homeostasis, increased potential lesions associated with Alzheimer's disease, disrupted neurogenesis, loss of dendritic spines, and ultimately neuronal death through both apoptosis and necroptosis. Intervention with DPZ co-treatment completely restored cognitive function by attenuating these pathological conditions induced by DOX. We also confirmed that DPZ treatment does not affect the anti-cancer efficacy of Dox in breast cancer cells. Together, our findings suggest that DPZ treatment confers potential neuroprotection against Dox-induced chemobrain.
    Keywords:  Acetylcholinesterase inhibitor; Chemobrain; Chemotherapy; Donepezil; Doxorubicin; Neurotoxicity
    DOI:  https://doi.org/10.1007/s13311-021-01092-9
  6. AIDS. 2021 Jul 28.
    Multimorbidity networks associated with frailty among middle aged and older people with HIV.
    David R Lorenz, Shibani S Mukerji, Vikas Misra, Hajime Uno, Benjamin B Gelman, David J Moore, Elyse J Singer, Susan Morgello, Dana Gabuzda.
       OBJECTIVE: People with human immunodeficiency virus (HIV) (PWH) have increased prevalence of multimorbidity and frailty at younger ages compared to the general population. This study investigated individual and combinatorial effects of neuropsychiatric and medical comorbidities as predictors of frailty in PWH.
    DESIGN: Analysis of data from the National NeuroAIDS Tissue Consortium, a longitudinal observational cohort.
    METHODS: 524 PWH over age 40 were classified using Fried's Frailty criteria. Twelve comorbidities were documented from longitudinal data and associations between individual and co-occurring comorbidities with frailty were assessed using weighted network and logistic regression analyses.
    RESULTS: At frailty assessment between 2015-2020, median age was 61 years, 76% were male, 94% were on ART, 73% had two or more comorbidities, 24% were frail, and 52% were prefrail. Among individual comorbidities, highest odds of frailty were in participants with depressive symptoms (adjusted odds ratio [aOR], 95% confidence interval [CI] 3.48 [2.22-5.46]]), followed by bone disease and COPD (2.47 [1.28-4.72] and 2.13 [1.36-3.34], respectively). Among co-occurring comorbidities, highest odds of frailty were in participants having depressive symptoms with diabetes, hypertension, or obesity (aORs [95% CIs] 5.29 [2.32-12.08], 5.21 [2.65-10.40], 4.85 [2.39-9.95], respectively), cognitive impairment with diabetes or renal disease, (2.81 [1.38-5.68] and 2.53 [1.26-5.03], respectively), renal disease with cardiovascular disease (2.81 [1.32-6.01]), and diabetes with obesity (2.76 [1.39-5.45]).
    CONCLUSIONS: Co-occurrence of depressive symptoms, cognitive impairment, diabetes, or renal disease with other medical conditions substantially increases odds of frailty in older PWH. Identifying and treating these comorbidities may help to reduce functional decline with aging in PWH.
    DOI:  https://doi.org/10.1097/QAD.0000000000003040
  7. PLoS One. 2021 ;16(7): e0254710
    Aging increases senescence, calcium signaling, and extracellular matrix deposition in human airway smooth muscle.
    Sarah A Wicher, Benjamin B Roos, Jacob J Teske, Yun Hua Fang, Christina Pabelick, Y S Prakash.
      Lung function declines as people age and their lungs become stiffer. With an increasing elderly population, understanding mechanisms that contribute to these structural and functional changes in the aging lung is important. Part of the aging process is characterized by thicker, more fibrotic airways, and senile emphysema caused by changes in lung parenchyma. There is also senescence, which occurs throughout the body with aging. Here, using human airway smooth muscle (ASM) cells from patients in different age groups, we explored senescence pathways and changes in intracellular calcium signaling and extracellular matrix (ECM) deposition to elucidate potential mechanisms by which aging leads to thicker and stiffer lungs. Senescent markers p21, γH2AX, and β-gal, and some senescence-associated secretory proteins (SASP) increased with aging, as shown by staining and biochemical analyses. Agonist-induced intracellular Ca2+ responses, measured using fura-2 loaded cells and fluorescence imaging, increased with age. However, biochemical analysis showed that expression of the following markers decreased with age: M3 muscarinic receptor, TRPC3, Orai1, STIM1, SERCA2, MMP2 and MMP9. In contrast, collagen III, and fibronectin deposition increased with age. These data show that senescence increases in the aging airways that is associated with a stiffer but surprisingly greater intracellular calcium signaling as a marker for contractility. ASM senescence may enhance fibrosis in a feed forward loop promoting remodeling and altered calcium storage and buffering.
    DOI:  https://doi.org/10.1371/journal.pone.0254710
  8. Arch Phys Med Rehabil. 2021 Jul 27. pii: S0003-9993(21)00329-4. [Epub ahead of print]
    Ten Simple Dietary Steps to Strengthen Your Immune System - A Guide for Elderly Individuals at Risk of COVID-19.
    Elena Philippou, Ahmed Negm, Patricia C Heyn.
      
    DOI:  https://doi.org/10.1016/j.apmr.2021.04.002
  9. J Cachexia Sarcopenia Muscle. 2021 Jul 28.
    Anti-cachexia therapy should target metabolism, inflammatory cytokines, and androgens in hormone-independent cancers.
    Charles Paul Lambert.
      
    DOI:  https://doi.org/10.1002/jcsm.12762
  10. J Exp Clin Cancer Res. 2021 Jul 24. 40(1): 241
    Statins: a repurposed drug to fight cancer.
    Wen Jiang, Jin-Wei Hu, Xu-Ran He, Wei-Lin Jin, Xin-Yang He.
      As competitive HMG-CoA reductase (HMGCR) inhibitors, statins not only reduce cholesterol and improve cardiovascular risk, but also exhibit pleiotropic effects that are independent of their lipid-lowering effects. Among them, the anti-cancer properties of statins have attracted much attention and indicated the potential of statins as repurposed drugs for the treatment of cancer. A large number of clinical and epidemiological studies have described the anticancer properties of statins, but the evidence for anticancer effectiveness of statins is inconsistent. It may be that certain molecular subtypes of cancer are more vulnerable to statin therapy than others. Whether statins have clinical anticancer effects is still an active area of research. Statins appear to enhance the efficacy and address the shortcomings associated with conventional cancer treatments, suggesting that statins should be considered in the context of combined therapies for cancer. Here, we present a comprehensive review of the potential of statins in anti-cancer treatments. We discuss the current understanding of the mechanisms underlying the anti-cancer properties of statins and their effects on different malignancies. We also provide recommendations for the design of future well-designed clinical trials of the anti-cancer efficacy of statins.
    Keywords:  Drug repurposing; Mevalonate pathway; Statins; Synergistic antitumor; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13046-021-02041-2
  11. Front Immunol. 2021 ;12 694118
    Hematopoietic Stem Cells in Type 1 Diabetes.
    Ida Pastore, Emma Assi, Moufida Ben Nasr, Andrea Mario Bolla, Anna Maestroni, Vera Usuelli, Cristian Loretelli, Andy Joe Seelam, Ahmed Abdelsalam, Gian Vincenzo Zuccotti, Francesca D'Addio, Paolo Fiorina.
      Despite the increasing knowledge of pathophysiological mechanisms underlying the onset of type 1 diabetes (T1D), the quest for therapeutic options capable of delaying/reverting the diseases is still ongoing. Among all strategies currently tested in T1D, the use of hematopoietic stem cell (HSC)-based approaches and of teplizumab, showed the most encouraging results. Few clinical trials have already demonstrated the beneficial effects of HSCs in T1D, while the durability of the effect is yet to be established. Investigators are also trying to understand whether the use of selected and better-characterized HSCs subsets may provide more benefits with less risks. Interestingly, ex vivo manipulated HSCs showed promising results in murine models and the recent introduction of the humanized mouse models accelerated the translational potentials of such studies and their final road to clinic. Indeed, immunomodulatory as well as trafficking abilities can be enhanced in genetically modulated HSCs and genetically engineered HSCs may be viewed as a novel "biologic" therapy, to be further tested and explored in T1D and in other autoimmune/immune-related disorders.
    Keywords:  NOD mouse model; autoimmune response; genetic modulation; hematopoietic stem cells; type 1 diabetes
    DOI:  https://doi.org/10.3389/fimmu.2021.694118
  12. JCI Insight. 2021 Jul 27. pii: 147692. [Epub ahead of print]
    Anterograde regulation of mitochondrial genes and FGF21 signaling by hepatic LSD1.
    Yang Cao, Lingyi Tang, Kang Du, Kitt Paraiso, Qiushi Sun, Zhengxia Liu, Xiaolong Ye, Yuan Fang, Fang Yuan, Yu-Han Chen, Yumay Chen, Xiaorong Wang, Clinton Yu, Ira L Blitz, Ping H Wang, Lan Huang, Haibo Cheng, Xiang Lu, Ken Wy Cho, Marcus Seldin, Zhuyuan Fang, Qin Yang.
      Mitochondrial biogenesis and function are controlled by anterograde regulatory pathways involving more than one thousand nuclear-encoded proteins. Transcriptional networks controlling the nuclear-encoded mitochondrial genes remain to be fully elucidated. Here we show that histone demethylase LSD1 knockout from adult mouse liver (LSD1-LKO) reduces the expression of one-third of all nuclear-encoded mitochondrial genes and decreases mitochondrial biogenesis and function. LSD1-modulated histone methylation epigenetically regulates nuclear-encoded mitochondrial genes. Furthermore, LSD1 regulates gene expression and protein methylation of nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), which controls the final step of NAD+ synthesis and limits NAD+ availability in nucleus. Lsd1 knockout reduces NAD+-dependent SIRT1 and SIRT7 deacetylase activity, leading to hyperacetylation and hypofunctioning of GABPβ and PGC-1α, the major transcriptional factor/cofactor for nuclear-encoded mitochondrial genes. Despite the reduced mitochondrial function in liver, LSD1-LKO mice are protected from diet-induced hepatic steatosis and glucose intolerance, partially due to induction of hepatokine FGF21. Thus, LSD1 orchestrates a core regulatory network involving epigenetic modifications and NAD+ synthesis to control mitochondrial function and hepatokine production.
    Keywords:  Diabetes; Endocrinology; Obesity
    DOI:  https://doi.org/10.1172/jci.insight.147692
  13. BMJ Nutr Prev Health. 2021 ;4(1): 257-266
    Plant-based diets, pescatarian diets and COVID-19 severity: a population-based case-control study in six countries.
    Hyunju Kim, Casey M Rebholz, Sheila Hegde, Christine LaFiura, Madhunika Raghavan, John F Lloyd, Susan Cheng, Sara B Seidelmann.
       Background: Several studies have hypothesised that dietary habits may play an important role in COVID-19 infection, severity of symptoms, and duration of illness. However, no previous studies have investigated the association between dietary patterns and COVID-19.
    Methods: Healthcare workers (HCWs) from six countries (France, Germany, Italy, Spain, UK, USA) with substantial exposure to COVID-19 patients completed a web-based survey from 17 July to 25 September 2020. Participants provided information on demographic characteristics, dietary information, and COVID-19 outcomes. We used multivariable logistic regression models to evaluate the association between self-reported diets and COVID-19 infection, severity, and duration.
    Results: There were 568 COVID-19 cases and 2316 controls. Among the 568 cases, 138 individuals had moderate-to-severe COVID-19 severity whereas 430 individuals had very mild to mild COVID-19 severity. After adjusting for important confounders, participants who reported following 'plant-based diets' and 'plant-based diets or pescatarian diets' had 73% (OR 0.27, 95% CI 0.10 to 0.81) and 59% (OR 0.41, 95% CI 0.17 to 0.99) lower odds of moderate-to-severe COVID-19 severity, respectively, compared with participants who did not follow these diets. Compared with participants who reported following 'plant-based diets', those who reported following 'low carbohydrate, high protein diets' had greater odds of moderate-to-severe COVID-19 (OR 3.86, 95% CI 1.13 to 13.24). No association was observed between self-reported diets and COVID-19 infection or duration.
    Conclusion: In six countries, plant-based diets or pescatarian diets were associated with lower odds of moderate-to-severe COVID-19. These dietary patterns may be considered for protection against severe COVID-19.
    Keywords:  COVID-19; dietary patterns
    DOI:  https://doi.org/10.1136/bmjnph-2021-000272
  14. Acta Pharmacol Sin. 2021 Jul 27.
    MK2206 attenuates atherosclerosis by inhibiting lipid accumulation, cell migration, proliferation, and inflammation.
    Ya-Qin Tang, Zhi-Wei Li, Yu-Fan Feng, Hong-Qin Yang, Cui-Liu Hou, Chi Geng, Pei-Ran Yang, Hong-Mei Zhao, Jing Wang.
      Cardiovascular disease is a common comorbidity in patients with cancer, and the main leading cause of noncancer-related deaths in cancer survivors. Considering that current antitumor drugs usually induce cardiovascular injury, the quest for developing new antitumor drugs, especially those with cardiovascular protection, is crucial for improving cancer prognosis. MK2206 is a phase II clinical anticancer drug and the role of this drug in cardiovascular disease is still unclear. Here, we revealed that MK2206 significantly reduced vascular inflammation, atherosclerotic lesions, and inhibited proliferation of vascular smooth muscle cell in ApoE-/- mice in vivo. We demonstrated that MK2206 reduced lipid accumulation by promoting cholesterol efflux but did not affect lipid uptake and decreased inflammatory response by modulating inflammation-related mRNA stability in macrophages. In addition, we revealed that MK2206 suppressed migration, proliferation, and inflammation in vascular smooth muscle cells. Moreover, MK2206 inhibited proliferation and inflammation of endothelial cells. The present results suggest that MK2206, as a promising drug in clinical antitumor therapy, exhibits anti-inflammatory and antiatherosclerotic potential. This report provides a novel strategy for the prevention of cardiovascular comorbidities in cancer survivors.
    Keywords:  Akt; MK2206; atherosclerosis; cholesterol efflux; inflammation
    DOI:  https://doi.org/10.1038/s41401-021-00729-x
  15. Mol Metab. 2021 Jul 22. pii: S2212-8778(21)00156-3. [Epub ahead of print] 101309
    Hepatic mTORC1 signaling activates ATF4 as part of its metabolic response to feeding and insulin.
    Vanessa Byles, Yann Cormerais, Krystle Kalafut, Victor Barrera, James E Hughes Hallett, Shannan Ho Sui, John M Asara, Christopher M Adams, Gerta Hoxhaj, Issam Ben-Sahra, Brendan D Manning.
       OBJECTIVE: The mechanistic target of rapamycin complex 1 (mTORC1) is dynamically regulated by fasting and feeding cycles in the liver to promote protein and lipid synthesis while suppressing autophagy. However, beyond these functions, the metabolic response of the liver to feeding and insulin signaling orchestrated by mTORC1 remains poorly defined. Here, we determine whether ATF4, a stress responsive transcription factor recently found to be independently regulated by mTORC1 signaling in proliferating cells, is responsive to hepatic mTORC1 signaling to alter hepatocyte metabolism.
    METHODS: ATF4 protein levels and expression of canonical gene targets were analyzed in the liver following fasting and physiological feeding in the presence or absence of the mTORC1 inhibitor rapamycin. Primary hepatocytes from wild-type or liver-specific Atf4 knockout (LAtf4KO) mice were used to characterize the effects of insulin-stimulated mTORC1-ATF4 function on hepatocyte gene expression and metabolism. Both unbiased steady-state metabolomics and stable-isotope tracing methods were employed to define mTORC1 and ATF4-dependent metabolic changes. RNA-sequencing was used to determine global changes in feeding-induced transcripts in the livers of wild-type versus LAtf4KO mice.
    RESULTS: We demonstrate that ATF4 and its metabolic gene targets are stimulated by mTORC1 signaling in the liver in response to feeding and in a hepatocyte-intrinsic manner by insulin. While we demonstrate that de novo purine and pyrimidine synthesis is stimulated by insulin through mTORC1 signaling in primary hepatocytes, this regulation was independent of ATF4. Metabolomics and metabolite tracing studies revealed that insulin-mTORC1-ATF4 signaling stimulates pathways of non-essential amino acid synthesis in primary hepatocytes, including those of alanine, aspartate, methionine, and cysteine, but not serine.
    CONCLUSION: The results demonstrate that ATF4 is a novel metabolic effector of mTORC1 in liver, extending the molecular consequences of feeding and insulin-induced mTORC1 signaling in this key metabolic tissue to the control of amino acid metabolism.
    Keywords:  ATF4; feeding; insulin; liver; mTORC1; methionine metabolism
    DOI:  https://doi.org/10.1016/j.molmet.2021.101309
  16. Jpn J Clin Oncol. 2021 Jul 29. pii: hyab112. [Epub ahead of print]
    Venetoclax plus low-dose cytarabine in Japanese patients with untreated acute myeloid leukaemia ineligible for intensive chemotherapy.
    Takahiro Yamauchi, Chikashi Yoshida, Kensuke Usuki, Satoru Takada, Itaru Matsumura, Nobuaki Dobashi, Yasushi Miyazaki, Toshihiro Miyamoto, Hiroatsu Iida, Norio Asou, Junya Kuroda, Satoshi Ichikawa, Norio Komatsu, Wellington Mendes, Hideyuki Honda, Sumiko Okubo, Misaki Kurokawa, Qi Jiang, Andrew Wei, Kenichi Ishizawa.
       BACKGROUND: In a multinational phase 3 trial (VIALE-C), venetoclax plus low-dose cytarabine prolonged overall survival vs placebo plus low-dose cytarabine in patients with newly diagnosed acute myeloid leukaemia ineligible for intensive chemotherapy, although it was not statistically significant. Herein, we assess the benefit of venetoclax plus low-dose cytarabine in the Japanese subgroup of VIALE-C patients (n = 27).
    METHODS: VIALE-C, a randomized (2:1), double-blind study (NCT03069352), enrolled untreated patients (≥18 years) with acute myeloid leukaemia. Patients received venetoclax (600 mg days 1-28, 4-day ramp-up in cycle 1) or placebo in 28-day cycles with low-dose cytarabine (20 mg/m2 days 1-10). The primary endpoint was median overall survival.
    RESULTS: In the Japanese subgroup, at a 6-month follow-up from the primary analysis, median overall survival for venetoclax (n = 18) and placebo (n = 9), plus low-dose cytarabine, was 4.7 and 8.1 months, respectively (hazard ratio, 0.928, 95% confidence intervals : 0.399, 2.156). The rate of complete remission plus complete remission with incomplete blood count recovery was higher with venetoclax plus low-dose cytarabine (44.4%) vs placebo plus low-dose cytarabine (11.1%). All patients experienced at least 1 adverse event. The most common grade ≥3 adverse events with venetoclax or placebo, plus low-dose cytarabine, were febrile neutropenia (50.0% vs 44.4%, respectively) and thrombocytopenia (27.8% vs 44.4%, respectively). Serious adverse events were reported in 50.0 and 33.3% of patients in the venetoclax and placebo, plus low-dose cytarabine arms, respectively; pneumonia was the most common (22.2% each).
    CONCLUSIONS: Limited survival benefit in the Japanese subgroup can be attributed to small patient numbers and to baseline imbalances observed between treatment arms, with more patients in the venetoclax plus low-dose cytarabine arm presenting poor prognostic factors. Venetoclax plus low-dose cytarabine was well tolerated in Japanese patients with acute myeloid leukaemia ineligible for intensive chemotherapy.
    Keywords:  Japan; VIALE-C; acute myeloid leukaemia; low-dose cytarabine; venetoclax
    DOI:  https://doi.org/10.1093/jjco/hyab112
  17. J Mol Med (Berl). 2021 Jul 26.
    Lipid metabolism, inflammation, and foam cell formation in health and metabolic disorders: targeting mTORC1.
    So Yeong Cheon, KyoungJoo Cho.
      Metabolic homeostasis is important for maintaining a healthy lifespan. Lipid metabolism is particularly necessary for the maintenance of metabolic energy sources and their storage, and the structure and function of cell membranes, as well as for the regulation of nutrition through lipogenesis, lipolysis, and lipophagy. Dysfunctional lipid metabolism leads to the development of metabolic disorders, such as atherosclerosis, diabetes mellitus, and non-alcoholic fatty liver disease (NAFLD). Furthermore, dyslipidaemia causes inflammatory responses and foam cell formation. Mechanistic target of rapamycin (mTOR) signalling is a key regulator of diverse cellular processes, including cell metabolism and cell fate. mTOR complex 1 (mTORC1) is involved in lipid metabolism and immune responses in the body. Therefore, the mTORC1 signalling pathway has been suggested as a potential therapeutic target for the treatment of metabolic disorders. In this review, we focus on the roles of mTORC1 in lipid metabolism and inflammation, and present current evidence on its involvement in the development and progression of metabolic disorders.
    Keywords:  Foam cells; Inflammation; Lipid metabolism; Mechanistic target of rapamycin (mTOR); Metabolic disorders
    DOI:  https://doi.org/10.1007/s00109-021-02117-8
  18. J Carcinog. 2021 ;20 4
    Lipid metabolism in cancer: A systematic review.
    Wafa Khan, Dominic Augustine, Roopa S Rao, Shankargouda Patil, Kamran Habib Awan, Samudrala Venkatesiah Sowmya, Vanishri C Haragannavar, Kavitha Prasad.
      Preclinical studies and clinical trials have emphasized the decisive role of lipid metabolism in tumor proliferation and metastasis. This systematic review aimed to explore the existing literature to evaluate the role and significance of the genes and pathways most commonly involved in the regulation of lipid metabolism in cancer. The literature search was performed as per Preferred Reporting Items for Systematic Reviews and Meta-analyses. Approximately 2396 research articles were initially selected, of which 215 were identified as potentially relevant for abstract review. Upon further scrutiny, 62 of the 215 studies were reviews, seminars, or presentations, and 44 were original study articles and were thus included in the systematic review. The predominant gene involved in lipid metabolism in cancer was stearoyl-coenzyme A desaturase 1 (SCD1), followed by fatty acid synthase (FASN). The pathway most commonly involved in lipid metabolism in cancer was the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway, followed by the mitogen activated protein kinase (MAPK) pathway. SCD1 and FASN play significant roles in the initiation and progression of cancer and represent attractive targets for potentially effective anti-cancer treatment strategies. The regulation of cancer metabolism by the Akt kinases will be an interesting topic of future study.
    Keywords:  Akt; PI3K; fatty acid synthase; lipid metabolism; oral cancer; signaling pathways; stearoyl-coenzyme A desaturase
    DOI:  https://doi.org/10.4103/jcar.JCar_15_20
  19. Cancer Med. 2021 Jul 28.
    Fragility of randomized trials supporting cancer drug approvals stratified by approval pathway and review designations.
    Brooke E Wilson, Alexandra Desnoyers, Michelle B Nadler, Ariadna Tibau, Eitan Amir.
       BACKGROUND: It has been suggested that the results from fragile trials are less likely to translate into benefit in routine clinical practice.
    METHODS: We searched the Food and Drug Administration (FDA) archives to identify drug approvals for solid organ malignancies between 2010 and 2019. We calculated the Fragility Index (FI) supporting each approval, using methods to account for time-to-event. We compared FI and trial and approval characteristics using Mann-Whitney U and Kruskal-Wallis test. Using logistic regression, we examined study characteristics associated with withdrawal of consent or lost to follow-up (WCLFU) exceeding the calculated FI.
    RESULTS: The median FI among 125 included studies was 23 (range 1-322). The FI was ≤10 in 35 studies (28%), 11-20 in 21 (17%), and >20 in 69 (55%). The median FI/Nexp was 7.7% (range 0.1-51.7%). The median FI was significantly lower among approvals processed through the accelerated vs regular pathway (5.5 vs 25, p = 0.001), but there was no difference in median FI/Nexp. The WCLFU exceeded FI in 42% of studies. Overall survival endpoints were more likely to have a WCLFU exceeding FI (OR 3.16, p = 0.003). WCLFU exceeding FI was also associated with a lesser magnitude of effect (median HR 0.69 vs 0.55, p < 0.001). In a sensitivity analysis including only studies with 1:1 randomization, 51% of studies had WCLFU >FI.
    CONCLUSION: The median FI among all trials was 23, and WCLFU exceeded FI in 42%. Comparative trials in solid tumors supporting approval through the accelerated pathway are more fragile compared to trials approved through the regular pathway, an observation likely explained by a lower sample size in the experimental arm.
    Keywords:  FDA approvals; accelerated approvals; fragility index; trial robustness
    DOI:  https://doi.org/10.1002/cam4.4029
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