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Purpose Lung cancer, mainly lung adenocarcinoma, lung squamous cell carcinoma and small cell lung cancer, has the highest incidence and cancer-related mortality worldwide. Platinum-based chemotherapy plays an important role in the treatment of various lung cancer subtypes, but not all patients benefit from this treatment regimen; thus, it is worth identifying lung cancer patients who are resistant or sensitive to platinum-based therapy. Methods The drug response and sequencing data of 170 lung cancer cell lines were downloaded from the Genomics of Drug Sensitivity in Cancer (GDSC) database, and support vector machines (SVMs) and beam search were used to select an optimal gene panel that can predict the sensitivity of cell lines to cisplatin. Then, we used available cell line data to explore the potential mechanisms. Results In this work, the drug response and sequencing data of 170 lung cancer cell lines were downloaded from the GDSC database, and SVMs and beam search were used to screen a panel of genes related to lung cancer cell line resistance to cisplatin. A final panel of nine genes (PLXNC1, KIAA0649, SPTBN4, SLC14A2, F13A1, COL5A1, SCN2A, PLEC, and ALMS1) was identified, and achieved an area under the curve (AUC) of 0.873 ± 0.004. The natural logarithm of the half maximal inhibitory concentration (lnIC50) values of the mutant-type (panel-MT) group was significantly higher than that of the wild-type (panel-WT) group, regardless of the lung cancer subtype. The differentially expressed pathways between the two groups may explain this difference. Conclusion In this study, we found that a panel of nine genes can accurately predict sensitivity to cisplatin, which may provide individualized treatment recommendations to improve the prognosis of patients with lung cancer., Graphical Abstract

To systematically summarize the existing evidence regarding the effects of exercise interventions on physical and psychological outcomes in frail older adults and appraise the quality and strength of the evidence.An overview protocol.A literature search of PubMed, Embase, Web of Science, CINAHL and Cochrane Database of Systematic Reviews will be conducted to identify relevant systematic reviews with or without meta-analysis on exercise interventions for frail older adults. Two independent reviewers will select articles, extract data and appraise the quality of included reviews. Physical and psychological outcomes will be synthesized using narrative summaries. The methodological quality of included reviews and the quality of evidence will also be assessed.This overview will present the evidence on the effects of exercise interventions on physical and psychological outcomes for frail older adults, contributing to the implementation of exercise interventions to improve health outcomes for this population.

Cognitive frailty can increase the risk of adverse health outcomes in older adults. Estimates of the prevalence of cognitive frailty among older adults with diabetes varied widely in literature. This study aimed to conduct a systematic review and meta-analysis to assess the pooled prevalence of cognitive frailty and risk factors in community-dwelling older adults with diabetes, providing evidence for healthcare professionals to better understand the status of cognitive frailty and help develop effective interventions.Databases of PubMed, Web of Science, Cochrane Library, Embase, Cumulative Index of Nursing and Allied Health, Proquest, China National Knowledge Infrastructure and China Biology Medicine were searched from inception to February 10th, 2022. The reviewers independently selected studies, extracted data and assessed the quality of studies. Pooled prevalence of cognitive frailty and risk factors were estimated. Subgroup analysis, meta-regression analysis, sensitivity analysis and publication bias were also conducted.A total of 15 studies with 6391 participants were included in this review. The pooled prevalence of cognitive frailty was 11% (95%CI = 7.9-14%) in community-dwelling older adults with diabetes. Pooled estimates showed that increasing age, higher level of HbA1c, shorter night sleep duration and depression were risk factors, and regular exercise was the protective factor of cognitive frailty in community-dwelling older adults with diabetes.Cognitive frailty was common in community-dwelling older adults with diabetes. Routine screening of cognitive frailty and effective interventions should be implemented for this population in community settings.PROSPERO ID CRD42021276973.

Background Old age is associated with a significantly increased mortality in COVID-19 patients exposed to long-term controlled mechanical ventilation (CMV) and suggested to be due to the hyperinflammatory response associated with the viral infection. However, our understanding of age-related differences in the response to CMV in the absence of a viral infection remains insufficient. Methods Young (7–8 months) and old (28–32 months) F344 BN hybrid rats were exposed to the ICU condition for 5 days, i.e., complete immobilization, mechanical ventilation, and extensive monitoring. Transcriptomic (RNA-Seq) and proteomics (Proximity Extension Assay) analyses of the diaphragm and proteomics analysis of plasma were conducted to investigate the molecular differences between young and old rats exposed to the ICU condition. Results According to multi-omics analyses, significant differences were observed in the diaphragm between young and old rats in response to 5 days CMV and immobilization. In young rats, metabolic pathways were primarily downregulated in response to immobilization (post-synaptic blockade of neuromuscular transmission). In old rats, on the other hand, dramatic immune and inflammatory responses were observed, i.e., an upregulation of specific related pathways such as “IL-17 signaling pathway”, along with a higher level of inflammatory factors and cytokine/chemokine in plasma. Conclusions The dramatically increased mortality in old ICU patients with COVID-19-associated hyperinflammation and cytokine storm need not only reflect the viral infection but may also be associated with the ventilator induced diaphragm dysfunction (VIDD) and hyperinflammatory responses induced by long-term CMV per se. Although mechanical ventilation is a life-saving intervention in COVID-19 ICU patients, CMV should be cautiously used especially in old age and other means of respiratory support may be considered, such as negative pressure ventilation.

Based on the precipitation data observed by stations and data simulated by 23 CMIP5 models, the features and future changes of summer (Jun-Jul-Aug) extreme precipitation events in Sichuan Province of China were analysed. We found that the total precipitation (RSum), extreme precipitation threshold (Threshold90), extreme precipitation (TR90), extreme precipitation percentage (TR90pct) and extreme precipitation intensity (TR90str) decreased from the southeast to the northwest in Sichuan Province, reflecting the differences between eastern Sichuan (ESC, basins) and western Sichuan (WSC, mountains). Compared with the observations, most of the CMIP5 models showed that there were wet biases in WSC and an unclear bias pattern in ESC for the RSum, Threshold90, TR90, and TR90str. However, the extreme precipitation days (ND90) and TR90pct values simulated by the models were generally overestimated and underestimated, respectively. Compared with the historical period, most models showed obvious increases in the TR90 and TR90pct in the 21 century, while the characteristics of Rsum, ND90, and TR90str were inconspicuous. Compared with the mid-21st century, the extreme precipitation in the late-21st century exhibited a certain degree of increase. Even during the same period, the results of RCP8.5 were higher than those of RCP4.5, especially for the ND90, TR90, and TR90pct.

Sarcopenia seriously affects the quality of life of the elderly, but its molecular mechanism is still unclear. Degeneration in muscle innervation is related to age-related movement disorders and muscle atrophy. The expression of CHRNA1 is increased in the skeletal muscle of the elderly, and in aging rodents. Therefore, we investigated whether CHRNA1 induces the occurrence and development of sarcopenia. Compared with the control group, local injection of AAV9-CHRNA1 into the hindlimb muscles decreased the percentage of muscle innervation. At the same time, the skeletal muscle mass decreased, as manifested by a decrease in the gastrocnemius mass index and the cross-sectional area of the muscle fibers. The function of skeletal muscle also decreased, which was manifested by decreases of compound muscle action potential and muscle contractility. Therefore, we concluded that upregulation of CHRNA1 can induce and aggravate sarcopenia.

Background: Examine the association of serum Lp(a) with sarcopenia in Chinese elderly.Methods: We conducted this study using 2015–2020 data from hospitalized Chinese people 60 years old and older. Total body fat percentage and appendicular skeletal muscle mass were assessed with a dual-energy X-ray absorptiometry scan. We classified the participants into four sarcopenia/obesity groups based on both total body fat percentage and appendicular skeletal muscle mass.Results: The analysis included data of 528 participants. the LP(a) level of sarcopenia was significantly higher than no sarcopenia, compared with obese or no obese groups. Furthermore, In the sarcopenic obesity group, the LP(a) level was highest. Correlation analysis showed that ASM/height2 was negatively correlated with LP(a). Logistic regression analysis showed that sarcopenia was positively associated with LP(a).Conclusions: Our study shows that sarcopenia appeared to be significantly associated with Lp(a) no matter the subjects had obesity or not.

Sarcopenia and obese sarcopenia are increasingly prevalent chronic diseases with multifactorial pathogenesis, and no approved therapeutic drug to date. In the established sarcopenic mice models, muscle weakness, ectopic lipid deposition, and inflammatory responses in both serum and gastrocnemius muscle were observed, which were even deteriorated in obese sarcopenic models. With metformin intervention for 5 months, metformin exhibited benefits and restoring effects on gastrocnemius muscle of sarcopenic mice, but less effective on that of obese sarcopenic mice, as reflected in the increased percentage of muscle mass and enlarged fiber cross-sectional area, enhanced grip strength and exercise capacities, as well as the ameliorated ectopic lipid deposition and partially restored level of TNF-α, IL-1β, IL-6, MCP-1 and IL-1α, which may be via the activation of phospho-AMPKα (Thr172). The significant up-regulated mRNA and protein level of lipolysis related proteins like hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) may contribute to the ameliorated ectopic lipid deposition with metformin intervention. The uptake of free fatty acid may be also inhibited in obese sarcopenic mice with metformin administration, as reflected in down-regulated mRNA and protein level of fatty acid transporter CD36. Furthermore, NF-κB signaling pathway was involved in the anti-inflammatory effect of metformin. These findings suggest that metformin treatment may be conducive to the prevention of age-related sarcopenia by regulating lipid metabolism in skeletal muscle, i.e. enhanced lipolysis and attenuated hyper-inflammatory responses, which may be AMPK-dependent processes. Moreover, high-fat diet would aggravate the damage to ageing in skeletal muscles and reduced their reactivity to metformin.

Observational studies suggest a link between depression and osteoporosis, but these may be subject to confounding and reverse causality. In this two-sample Mendelian randomization analysis, we included the large meta-analysis of genome-wide association studies for depression among 807,553 individuals (246,363 cases and 561,190 controls) of European descent, the large meta-analysis to identify genetic variants associated with femoral neck bone mineral density (FN-BMD), forearm BMD (FA-BMD) and lumbar spine BMD (LS-BMD) among 53,236 individuals of European ancestry, and the GWAS summary data of heel BMD (HE-BMD) and fracture among 426,824 individuals of European ancestry. The results revealed that genetic predisposition towards depression showed no causal effect on FA-BMD (beta-estimate: 0.091, 95% confidence interval [CI] − 0.088 to 0.269, SE:0.091, P value = 0.320), FN-BMD (beta-estimate: 0.066, 95% CI − 0.016 to 0.148, SE:0.042, P value = 0.113), LS-BMD (beta-estimate: 0.074, 95% CI − 0.029 to 0.177, SE:0.052, P value = 0.159), HE-BMD (beta-estimate: 0.009, 95% CI − 0.043 to 0.061, SE:0.027, P value = 0.727), or fracture (beta-estimate: 0.008, 95% CI − 0.071 to 0.087, SE:0.041, P value = 0.844). These results were also confirmed by multiple sensitivity analyses. Contrary to the findings of observational studies, our results do not reveal a causal role of depression in osteoporosis or fracture.

Age is a potential predictive marker for the prognosis of cancer patients treated with immune checkpoint inhibitors (ICIs), but the appropriate age cutoff point is still controversial. We aimed to explore the influence of different age cutoff points on the prediction of prognosis for patients receiving ICIs and explore the mechanism underlying the appropriate age cutoff point from the aspects of gene mutation and expression, immune cell infiltration and so on. We applied cutoff points of 50, 55, 60, 65, 70, and 75 years old to divide 1660 patients from the Memorial Sloan-Kettering Cancer Center (MSKCC) immunotherapy cohort into older and younger groups and performed survival analysis of the six subgroups. The results showed that older patients had better survival than younger patients in accordance with the cutoff point of 50 years old [median overall survival (OS) (95% CI): 13.0 (10.5-15.5) months vs. 20.0 (16.7-23.3) months; p=0.002; unadjusted hazard ratio (HR) (95% CI): 0.77 (0.65-0.91)], whereas no significant difference was observed with other cutoff points. Further analysis of The Cancer Genome Atlas (TCGA) database and the MSKCC immunotherapy cohort data showed that the tumor mutation burden (TMB), neoantigen load (NAL), DNA damage response and repair (DDR) pathway mutation status, mutation frequencies of most genes (except IDH1, BRAF and ATRX), the expression of most immune-related genes and the degree of infiltration of most immune cells (such as CD8+ T cells and M1 macrophages) were higher in the elderly group (aged ≥50 years).

To investigate the effect of β-arrestin1 gene on senescence of T-ALL cells and its possible mechanism.The bone marrow specimens of T-ALL patients and controls were collected, the expression of β-arrestin1 and β-arrestin1 in the T-ALL patients was detected by RT-PCR and Western blot, respectively, and the relation of β-arrestin1 expression with the clinical pathologic characteristics and the prognosis of T-ALL patients was analyzed statistically. The stable Jurkat cell line with knocked down or overexpressed β-arrestin1 was constructed, the CCK method was used to detect the Jurkat cell number, the β-gal staining was used to analyze the effect of β-arrestin1 on senescence of Jurkat cells, the cross analysis of RNA-Seg data and KEGG data was performed for screening the possible signaling pathway, and Western blot was performed for varifying the key sites of signaling pathway.The β-arrestin1 expression in specimens of T-ALL patients decreased (P＜0.01), moreover the β-arrestin1 expression negatively related with peripheral blood cell number (r=-0.601), the blasts in peripheral blood (r=-0.516) and extramedullary infiltration (r=-0.359), while positively related with the response to chemotherapy (r=0.393). The detection of stable Jurkat cell line with knocked-down and overexpressed β-arrestin1 found that the β-arrestin 1 could decrease the Jurkat cell number and accelarate the senescence of Jurkat cells (P＜0.05). The cross analysis of RNA-Seg data and KEGG data showed that the senescence of T-ALL cells may be regulated via RAS-P16-PRb-E2F1 by β-arrestin 1. Western bolt confirmed that β-arrestin1 promoted the expression of Ras and p16, and decreased the expression of pRB and E2F1 (P＜0.05).β-arrestin1 accelerates the senescence of Jurkat cells via Ras-p16-pRb-E2F1, and delays the progression in T-ALL, which may provide a new hypothesis for the pathogenesis of T-ALL.β-arrestin 1促进急性T淋巴细胞白血病Jurkat细胞衰老.探讨β-arrestin1对急性T淋巴细胞白血病（T-ALL）细胞衰老的作用及其可能机制.收集T-ALL患者骨髓样本和对照样本，应用RT-PCR和Western blot检测β-arrestin1在T-ALL患者中的表达，统计分析β-arrestin1的表达与T-ALL患者临床病理特征及预后的关系。构建稳定敲低或过表达β-arrestin1 Jurkat细胞株，应用CCK-8检测Jurkat细胞数，β-半乳糖苷酶染色（SA-β-gal）法检测β-arrestin1对Jurkat细胞衰老的作用，应用RNA-Seq与KEGG数据交叉分析筛选可能的信号通路，Western blot验证信号通路关键位点.β-arrestin1在T-ALL患者样本中表达降低 （P＜0.01），且β-arrestin1的表达与外周血白细胞数（r=-0.601）、外周血原始细胞数（r=-0.516） 和髓外浸润（r=-0.359）呈负相关，与化疗敏感性（r=0.393）呈正相关。利用敲低或过表达β-arrestin1的稳定Jurkat细胞株发现，β-arrestin1降低Jurkat细胞数（P＜0.05），促进Jurkat细胞衰老（P＜0.05）。RNA-Seq与KEGG数据交叉分析发现，T-ALL患者中β-arrestin1可能通过Ras-p16-pRb-E2F1调控细胞衰老。经Western blot验证发现，β-arrestin1促进Ras和p16的表达，抑制pRB和E2F1的表达 （P＜0.05）.β-arrestin1可能通过Ras-p16-pRb-E2F1促进T-ALL细胞衰老，延缓T-ALL疾病进程，这为阐释T-ALL新的发病机制提供理论依据.

Coexistence of frailty and chronic diseases including diabetes is related to a higher risk of adverse health outcomes. There is an increasing interest in the intersection of diabetes and frailty. Understanding the prevalence of frailty in older adults with diabetes is of great importance. However, estimates of the prevalence of frailty among this population varied widely in the relevant literature.To conduct a systematic review and meta-analysis to estimate the overall prevalence of frailty and prefrailty among community-dwelling older adults with diabetes, and examine the risk factors associated with frailty in this population.PubMed, Web of Science, Embase, Wiley Cochrane Library, and Cumulative Index of Nursing and Allied Health were searched from inception to May 30th, 2020. Investigators assessed eligibility, extracted data and evaluated methodological quality. The pooled prevalence of frailty and prefrailty was calculated using the random-effects model. Meta-regression analysis and subgroup analysis were conducted to explore sources of heterogeneity.A total of 32 studies met the inclusion criteria, involving 14,450 individuals. The pooled prevalence of frailty and prefrailty in older adults with diabetes was 20.1% (95% CI = 16.0-24.2%) and 49.1% (95%CI = 45.1-53.1%), respectively, with significant heterogeneity across the studies. Frailty was more prevalent in older adults with diabetes than those without diabetes (OR = 1.61, 95%CI = 1.47-1.77, p 0.001). The pooled prevalence of frailty was lower in studies using Frailty Phenotype to define frailty (16.3%) and conducted in Asia (14.3%). Female gender and unmarried status were risk factors of frailty among this population.Frailty and prefrailty are common in community-dwelling older adults with diabetes. Early screening of frailty and interventions should be integrated into diabetes care for older adults to prevent and reduce the negative effects of frailty at the community level. Better quality longitudinal research is required to examine the temporal relationship between diabetes and frailty.

Aims Although autophagy impairment is a well-established cause of muscle atrophy and P300 has recently been identified as an important regulator of autophagy, the effects of P300 on autophagy and muscle atrophy in type 2 diabetes (T2D) remain unexplored. We aimed at characterizing the role of P300 in diabetic muscle and its underlying mechanism. Main methods Protein levels of phosphorylated P300, total P300, acetylated histone H3, LC3, p62 and myosin heavy chain, and mRNA levels of Atrogin-1 and MuRF1 were analyzed in palmitic acid (PA)-treated myotubes and db/db mice. Autophagic flux was assessed using transmission electron microscopy, immunofluorescence and mRFP-GFP-LC3 lentivirus transfection in cells. Muscle weight, blood glucose and grip strength were measured in mice. Hematoxylin and eosin (H&E) staining was performed to determine changes in muscle fiber size. To investigate the effects of P300 on autophagy and myofiber remodeling, a P300 specific inhibitor, c646, was utilized. 3-Methyladenine (3-MA) was utilized to inhibit autophagosomes formation, and chloroquine (CQ) was used to block autophagic flux. Key findings Phosphorylation of P300 in response to PA enhanced its activity and subsequently suppressed autophagic flux, leading to atrophy-related morphological and molecular changes in myotubes. Inhibition of P300 reestablished autophagic flux and ameliorated PA-induced myotubes atrophy. However, this effect was largely abolished by co-treatment with the autophagy inhibitor CQ. In vivo results demonstrated that inhibition of P300 partially rescued muscle wasting in db/db mice, accompanied with autophagy reactivation. Significance The findings revealed that T2D-induced overactivation of P300 contributes to muscle atrophy by blocking autophagic flux.

Sarcopenia is an age-related syndrome characterized by a gradual loss of muscle mass and function, but its pathophysiological mechanism remains unclear. Skeletal muscle extracellular matrix (ECM) remodeling is an important pathological change in sarcopenia, and fibrosis is the most obvious manifestation of this change. We found that the expression of the immunoreceptor Toll-like receptor 9 (TLR9) is significantly increased in skeletal muscle in aged mice and is positively related to muscle fibrosis. Moreover, in previous reports, the longevity gene Sirt1 was reported to attenuate ECM deposition and improve muscle function. In this study, we hypothesized that TLR9 modulated skeletal muscle fibrosis via Sirt1. We used TLR9 knockout (TLR9 KO) mice and C57 mice, and grip strength and body composition were compared at different ages. We found that TLR9 knockout significantly attenuated skeletal muscle fibrosis and improved muscle function in aged mice. Furthermore, silent information regulator 1 (Sirt1) activity in mice was inhibited by Ex527, which is a specific inhibitor of Sirt1. Negative Sirt1 regulation via the activation of TLR9-related signaling pathways participated in skeletal muscle fibrosis in the sarcopenic mice, and this process might mediated by the Sirt1/Smad signaling pathway. Our findings revealed that fibrosis changes in the gastrocnemius muscle in sarcopenic mice are closely related to TLR9 activation, and TLR9 modulation could be a therapeutic strategy for combating sarcopenia during aging.