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• Research Paper Volume 14, Issue 2 pp 907-922

  A radiomics model predicts the response of patients with advanced gastric cancer to PD-1 inhibitor treatment

  Relevance score: 4.849018

  Zhiwen Liang, Ai Huang, Linfang Wang, Jianping Bi, Bohua Kuang, Yong Xiao, Dandan Yu, Ma Hong, Tao Zhang

  Keywords: gastric cancer, programmed cell death 1 inhitors, CT image, radiomics, immunotherapy

  Published in Aging on January 24, 2022

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  Programmed cell death 1 (PD1) inhibitors have shown promising treatment effects in advanced gastric cancer, the beneficiary population not definite. This study aimed to construct an individualized radiomics model to predict the treatment benefits of PD-1 inhibitors in gastric cancer. Patients with advanced gastric cancer treated with PD-1 inhibitors were randomly divided into a training set (n = 58) and a validation set (n = 29). CT imaging data were extracted from medical records, and an individual radiomics nomogram was generated based on the imaging features and clinicopathological risk factors. Discrimination performance was evaluated by Harrell’s c-index and receiver operator characteristic (ROC) curve analyses. The areas under the ROC curves (AUCs) were analyzed to predict anti-PD-1 efficacy and survival. We found that the radiomics nomogram could predict the response of gastric cancer to anti-PD-1 treatment. The AUC was 0.865 with a 95% CI of 0.812-0.828 in the training set, while the AUC was 0.778 with a 95% CI of 0.732–0.776 in the validation set. The diagnostic performance of the radiomics was significantly higher than that of the clinical factors (p < 0.01). Patients with a low risk of disease progression discriminated by the radiomics nomogram had longer progression-free survival than those with a high risk (6.5 vs. 3.2 months, HR 1.99, 95% CI: 1.19-3.31, p = 0.009). The radiomics nomogram based on CT imaging features and clinical risk factors could predict the treatment benefits of PD-1 inhibitors in advanced gastric cancer, enabling it to guide decision-making regarding clinical treatment.

• Research Paper Volume 13, Issue 18 pp 21975-21990

  Thymus hirtus sp. algeriensis Boiss. and Reut. volatile oil enhances TRAIL/Apo2L induced apoptosis and inhibits colon carcinogenesis through upregulation of death receptor pathway

  Relevance score: 4.92716

  Fatma Guesmi, Sahdeo Prasad, Manel Ben Ali, Ismail A. Ismail, Ahmed Landoulsi

  Keywords: thymus hirtus Sp. algeriensis, HCT116, TRAIL, death receptors, colon cell carcinoma

  Published in Aging on September 20, 2021

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  Background: The aim of the study is to determine the anticancer activity of Thymus algeriensis (TS) and its underlying mechanisms using in vitro and in animal models.

  Methods: HCT116 cells were treated with TS essential oil alone or with TRAIL, and then its anticancer effect was determined by using MTT assay, live dead assay, caspase activation and PARP cleavage. Further mechanisms of its anticancer effects was determined by analyzing expression of death receptor signaling pathway using Western blotting. A mouse model was also used to assess the antitumor potential of thyme essential oil.

  Results: TS oily fraction showed tumor growth inhibitory effect even at lower concentration. TS induces apoptotic cell death as indicated by cleavage of PARP, and activation of the initiator and effector caspases (caspase-3, -8 and -9). Further, results showed that TS increases the expression of death receptors (DRs) and reduces the expression of TRAIL decoy receptors (DcRs). In addition, upregulation of signaling molecules of MAPK pathway (p38 kinase, ERK, JNK), down-regulation of c-FLIP, and overexpression of SP1 and CHOP were observed by TS. Further in animal model, intragastric administration of TS (12.5 mg/ml and 50 mg/ml) prevented colorectal carcinogenesis by blocking multi-steps in carcinoma.

  Conclusion: Overall, these results indicate that thymus essential oil promotes apoptosis in HCT116 cells and impedes tumorigenesis in animal model. Moreover, thyme potentiates TRAIL-induced cell death through upregulation of DRs, CHOP and SP1 as well as downregulation of antiapoptotic proteins in HCT116 cells. However, therapeutic potential of TS needs to be further explored.

• Research Paper Volume 13, Issue 13 pp 17253-17273

  Association between mean platelet volume and pulmonary embolism: a systematic review and meta-analysis

  Relevance score: 4.121499

  Wenyi Lin, Yu Wu, Xuan Lu, Yu Hu

  Keywords: mean platelet volume, pulmonary embolism, early death, risk stratification, meta-analysis

  Published in Aging on July 2, 2021

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  Platelet activation plays an important role in the progression of pulmonary embolism (PE). Mean platelet volume (MPV) can serve as a marker of platelet activity in patients with PE. Many studies have reported different results regarding the relationship. Therefore, we aimed to perform a systematic review and meta-analysis to evaluate the relationship between MPV and PE. Two reviewers independently searched relevant articles in databases from inception to April 21, 2021 and identified all studies on MPV and PE as the outcomes of interest. Further, we selected studies meeting the criteria and extracted the data. Of the 2505 publications identified, we included 18 studies after screening. Results showed MPV was significantly higher in patients with PE (0.83 fL, 95% CI: 0.38-1.28, P<0.001) than in controls. The mean difference in MPV between those who died and survivors of PE was 1.23 fL (95% CI: 0.96-1.51, P<0.001). Hence, an increased MPV is associated with PE. MPV could be a useful tool to predict the occurrence and death risk of PE together with other risk factors.

• Research Paper Volume 13, Issue 9 pp 13061-13072

  Plasma hemoglobin and the risk of death in HIV/AIDS patients treated with antiretroviral therapy

  Relevance score: 4.5719237

  Dayong Wang, Xiangqing Hou, Xianghua Yu, Tao Wang, Zhenmiao Ye, Jushuang Li, Feifei Su, Chengnan Guo, Fang Peng, Shuzhen Zhao, Huihui Li, Jingjing Zuo, Dehua Su, Lina Zhao, Hemei Zhang, Xiangyang Chen, Ruoqiu Wang, Qipeng Xie, Chao Zheng, Guangyun Mao

  Keywords: HB, HIV/AIDS associated death, interaction, C-index, net discrimination

  Published in Aging on May 7, 2021

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  Background: Previous studies concerning the effect of plasma hemoglobin (HB) and other factors that may modify the risk of death in people living with HIV/AIDS (PLHIV) treated with antiretroviral therapy (ART) are limited.

  Results: Higher HB was independently linked to a lower death risk in PLHIV, with a decrease of 29% (13%, 43%) per standard deviation (SD) increment after adjusting for CD4, VL and other potential factors [hazard ratio (HR): 0.71, 95% confidence interval (CI): 0.57-0.87, P<0.001]. In addition, the addition of HB to the predictive model containing VL and CD4 significantly improved the C-index, by 0.69% (95% CI: 0.68%-0.71%), and net discrimination, by 0.5% (95% CI: 0.0%-1.6%, P=0.040), when predicting the death risk of PLHIV.

  Conclusions: A lower level of HB was an independent risk factor for HIV/AIDS-associated death in PLHIV. HB combined with VL and CD4 may be an appropriate predictive model of the death risk of PLHIV.

  Materials and methods: A propensity-score matching (PSM) approach was applied to select a total of 750 PLHIV (150 deceased and 600 living) from the AIDS prevention and control information system in the Wenzhou area from 2006 to 2018. Multivariable Cox proportional hazards regression models were formulated to estimate the effect of HB. The predictive performance improvement contributed by HB was evaluated using the C-index and net reclassification improvement.

• Research Paper Volume 13, Issue 9 pp 13006-13022

  A preclinical study: correlation between PD-L1 PET imaging and the prediction of therapy efficacy of MC38 tumor with ⁶⁸Ga-labeled PD-L1 targeted nanobody

  Relevance score: 4.233062

  Songbing Qin, Yang Yu, Hui Guan, Yanling Yang, Fenghao Sun, Yan Sun, Jiaxing Zhu, Ligang Xing, Jinming Yu, Xiaorong Sun

  Keywords: positron emission tomography (PET), immunotherapy, programmed death-ligand 1 (PD-L1), MC38 tumor

  Published in Aging on April 27, 2021

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  Although immunotherapy has achieved great clinical success in clinical outcomes, especially the anti-PD-1 or anti-PD-L1 antibodies, not all patients respond to anti-PD-1 immunotherapy. It is urgently required for a clinical diagnosis to develop non-invasive imaging meditated strategy for assessing the expression level of PD-L1 in tumors. In this work, a ⁶⁸Ga-labeled single-domain antibody tracer, ⁶⁸Ga-NOTA-Nb109, was designed for specific and noninvasive imaging of PD-L1 expression in an MC38 tumor-bearing mouse model. Comprehensive studies including Positron Emission Tomography (PET), biodistribution, blocking studies, immunohistochemistry, and immunotherapy, have been performed in differences PD-L1 expression tumor-bearing models. These results revealed that ⁶⁸Ga-NOTA-Nb109 specifically accumulated in the MC38-hPD-L1 tumor. The content of this nanobody in MC38 hPD-L1 tumor and MC38 Mixed tumor was 8.2 ± 1.3, 7.3 ± 1.2, 3.7 ± 1.5, 2.3 ± 1.2%ID/g and 7.5 ± 1.4, 3.6 ± 1.7, 1.7 ± 0.6, 1.2 ± 0.5%ID/g at 0.5, 1, 1.5, 2 hours post-injection, respectively. ⁶⁸Ga-NOTA-Nb109 has the potential to further noninvasive PET imaging and therapy effectiveness assessments based on the PD-L1 status in tumors. To explore the possible synergistic effects of immunotherapy combined with chemotherapy, MC38 xenografts with different sensitivity to PD-L1 blockade were established. In addition, we found that PD-1 blockade also had efficacy on the PD-L1 knockout tumors. RT-PCR and immunofluorescence analysis were used to detect the expression of PD-L1. It was observed that both mouse and human PD-L1 expressed among three types of MC38 tumors. These results suggest that PD-L1 on tumor cells affect the efficacy, but it on host myeloid cells might be essential for checkpoint blockade. Moreover, anti–PD-1 treatment activates tumor-reactive CD103⁺ CD39⁺ CD8+T cells (TILs) in tumor microenvironment.

• Research Paper Volume 13, Issue 7 pp 9225-9242

  Risk factors for systemic and venous thromboembolism, mortality and bleeding risks in 1125 patients with COVID-19: relationship with anticoagulation status

  Relevance score: 5.4843454

  Wencheng Li, Zhifeng Xu, Huiling Xiang, Chun Zhang, Yutao Guo, Jing Xiong

  Keywords: COVID-19, thromboembolism, bleeding, death

  Published in Aging on March 26, 2021

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  Aim: Coronavirus disease 2019 (COVID-19) has been associated with increased mortality and morbidity from thromboembolism, especially venous thromboembolism. There are more limited data for systemic thromboembolism. The present study aimed to investigate the prevalence of systemic and venous thromboembolism as well as major bleeding and mortality in relation to underlying risk factors and the impact of anticoagulation use in hospitalized patients with COVID-19.

  Methods and results: Patients with COVID-19 admitted to Union Hospital, Wuhan, Hubei, China between January 08, 2020 and April 7, 2020 were enrolled in this retrospective study. Cox proportional hazard models were utilized to determine associated risk factors for clinical events, adjusting for the severity of COVID-19 infection, drug therapies, comorbidities, surgery, and use of antithrombotic drugs.

  There were 1125 patients (49.9% male; mean age 58 years (standard deviation, SD, 15 years)) with a mean follow-up of 21 (SD 13) days. Approximately 25 (30%) patients with thromboembolism also suffered bleeding events.

  Age was an independent risk factor for thromboembolism, bleeding events, and death (all p<0.05). After adjusting for the severity of COVID-19 infection, comorbidities, surgery, antiviral drugs, immunomodulators, Chinese herbs, and antithrombotic drugs, low lymphocyte counts (hazard ratio, HR, 95% confidence interval (CI), 1.03, 1.01-1.05, p=0.01) and surgery (HR 2.80, 1.08-7.29, p=0.03) independently predicted the risk for major bleeding, whereas liver dysfunction (HR 4.13, 1.30-13.1, p=0.02) was an independent risk factor for patients with both thromboembolism and bleeding events.

  Conclusions: Patients with COVID-19 were at high risk for thromboembolic and bleeding events as well as mortality. The use of anticoagulants, especially parenteral anticoagulants, significantly reduced the risk for composite outcomes of thromboembolism, bleeding events, and death. The presence of AF was a contributor to systemic thromboembolism in COVID-19 patients.

• Research Paper Volume 13, Issue 3 pp 3239-3253

  Uncovering molecular mechanisms of regulated cell death in the naked mole rat

  Relevance score: 4.7871304

  Alexei Evdokimov, Alexei Popov, Elena Ryabchikova, Olga Koval, Svetlana Romanenko, Vladimir Trifonov, Irina Petruseva, Inna Lavrik, Olga Lavrik

  Keywords: regulated cell death, naked mole rat, apoptosis, necrosis, DNA damage

  Published in Aging on January 28, 2021

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  The naked mole rat (NMR), Heterocephalus glaber, is the longest-living rodent species, and is extraordinarily resistant to cancer and aging-related diseases. The molecular basis for these unique phenotypic traits of the NMR is under extensive research. However, the role of regulated cell death (RCD) in the longevity and the protection from cancer in the NMR is still largely unknown. RCD is a mechanism restricting the proliferation of damaged or premalignant cells, which counteracts aging and oncotransformation. In this study, DNA damage-induced cell death in NMR fibroblasts was investigated in comparison to RCD in fibroblasts from Mus musculus. The effects of methyl methanesulfonate, 5-fluorouracil, and etoposide in both cell types were examined using contemporary cell death analyses. Skin fibroblasts from Heterocephalus glaber were found to be more resistant to the action of DNA damaging agents compared to fibroblasts from Mus musculus. Strikingly, our results revealed that NMR cells also exhibit a limited apoptotic response and seem to undergo regulated necrosis. Taken together, this study provides new insights into the mechanisms of cell death in NMR expanding our understanding of longevity, and it paves the way towards the development of innovative therapeutic approaches.

• Research Paper Volume 13, Issue 2 pp 1591-1607

  Coagulation dysfunction in ICU patients with coronavirus disease 2019 in Wuhan, China: a retrospective observational study of 75 fatal cases

  Relevance score: 4.121499

  Jiaran Shi, Wang Zhang, Ling Sang, Zhaohui Qu, Ming Zhong, Li jiang, Bin Song, Liang Kang, Yun Zhang, Xingxiang Wang, Dingyu Zhang, Xia Zheng

  Keywords: coronavirus disease 2019, COVID-19, death, coagulation dysfunction, inflammation, cardiac injury

  Published in Aging on December 9, 2020

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  Coagulation dysfunction in critically ill patients with coronavirus disease 2019 (COVID-19) has not been well described, and the efficacy of anticoagulant therapy is unclear. In this study, we retrospectively reviewed 75 fatal COVID-19 cases who were admitted to the intensive care unit at Jinyintan Hospital (Wuhan, China). The median age of the cases was 67 (62–74) years, and 47 (62.7%) were male. Fifty patients (66.7%) were diagnosed with disseminated intra-vascular coagulation. Approximately 90% of patients had elevated D-dimer and fibrinogen degradation products, which decreased continuously after anticoagulant treatment and was accompanied by elevated albumin (all P<0.05). The median survival time of patients treated with anticoagulant was 9.0 (6.0–14.0) days compared with 7.0 (3.0–10.0) days in patients without anticoagulant therapy (P=0.008). After anticoagulation treatment, C-reactive protein levels decreased (P=0.004), as did high-sensitivity troponin (P=0.018), lactate dehydrogenase (P<0.001), and hydroxybutyrate dehydrogenase (P<0.001). In conclusion, coagulation disorders were widespread among fatal COVID-19 cases. Anticoagulant treatment partially improved hypercoagulability, prolonged median survival time, and may have postponed inflammatory processes and cardiac injury.

• Research Paper Volume 12, Issue 23 pp 24301-24317

  Cigarette smoke extract induces airway epithelial cell death via repressing PRMT6/AKT signaling

  Relevance score: 4.779053

  Tiao Li, Kristen V. Fanning, Toru Nyunoya, Yan Chen, Chunbin Zou

  Keywords: cigarette smoke, cell death, lung epithelia, PRMT6, PI3K/AKT

  Published in Aging on December 1, 2020

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  Chronic obstructive pulmonary disease (COPD) is a severe public health threat world-wide. Cigarette smoke (CS)-induced airway epithelial cell death is a major pathway of pathogenesis in emphysema, a subtype of COPD. Protein arginine methyltransferase 6 (PRMT6) is a type I PRMT that catalyzes mono- and di-methylation on arginine residues within histone and non-histone proteins to modulate a variety of life processes, such as apoptosis. However, its role in CS-induced lung epithelial death has not been fully elucidated. Here we report that PRMT6 was decreased in mouse lung tissues from a cigarette smoke extract (CSE)-mediated experimental emphysematous model and in CSE treated or cigarette smoke exposed lung epithelial cells. Depletion of PRMT6 increased the protein levels of phosphatase PTEN and PI3K regulatory subunit p85 but decreased a downstream kinase PDK1, resulting in AKT dephosphorylation and thereafter, lung epithelial cell death. Knockout of PRMT6 inhibited epithelial survival and promoted CSE-mediated epithelial cell death, while ectopic expression of PRMT6 protein partially reversed epithelial cell death via PI3K/AKT-mediated cell survival signaling in CSE cellular models. These findings demonstrate that PRMT6 plays a crucial role in CS-induced bronchial epithelial cell death that may be a potential therapeutic target against the airway cell death in CS-induced COPD.

• Research Paper Volume 12, Issue 22 pp 22927-22948

  Cause of death among patients with colorectal cancer: a population-based study in the United States

  Relevance score: 4.4937253

  Jiayuan Chen, Yongqiang Zheng, Haihong Wang, Dejun Zhang, Lei Zhao, Dandan Yu, Zhenyu Lin, Tao Zhang

  Keywords: colorectal cancer, cancer survivorship, cause of death, surveillance, epidemiology

  Published in Aging on November 28, 2020

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  CRC (Colorectal cancer) is one of the most common causes of death worldwide and in the US (United States). In this study, we aim to perform a population-based analysis on the cause of death among patients with CRC in the US. A total of 834,510 CRC patients diagnosed between 1975 and 2016 in the US were selected from the SEER (Surveillance, Epidemiology, and End Results) program. Causes of death among CRC patients were characterized and SMRs (standardized mortality ratios) of death from non-cancer causes were calculated. Among all CRC patients included in this study, a total of 531,507 deaths were recorded, of which 51.3% were due to CRC, 10.3% were due to other cancers, and 38.4% were due to non-cancer causes. Recently, there has been a relative decrease in index-cancer deaths and an increase in non-cancer causes among CRC patients. The mortality risk from non-cancer rises with accumulating age and longer follow-up time. Cardiovascular diseases are the most prevalent non-cancer causes, accounting for 20.3% of all deaths among CRC patients. Compared with the general population, the mortality rate of non-cancer deaths among CRC patients is doubled (SMR, 2.02; 95% confidence interval, 2.01-2.03).

• Research Paper Volume 12, Issue 24 pp 24579-24595

  Characteristics of mortal COVID-19 cases compared to the survivors

  Relevance score: 3.95759

  Xianghui Zhou, Zhipeng Cheng, Dan Shu, Wenyi Lin, Zhangyin Ming, Wei Chen, Yu Hu

  Keywords: coronavirus disease 2019, COVID-19, SARS-CoV-2, death cases, survival cases

  Published in Aging on November 21, 2020

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  The outbreak of coronavirus disease 2019 (COVID-19) initially occurred in December 2019 and triggered a public health emergency. The increasing number of deaths due to this disease was of great concern. Therefore, our study aimed to explore risk factors associated with COVID-19 deaths.

  After having searched the PubMed, EMBASE, and CNKI for studies published as of August 10, 2020, we selected articles and extracted data. The meta-analysis was performed using Stata 16.0 software.

  Nineteen studies were used in our meta-analysis. The proportions of comorbidities such as diabetes, hypertension, malignancies, chronic obstructive pulmonary disease, cardio-cerebrovascular disease, and chronic liver disease were statistically significantly higher in mortal COVID-19 cases. Coagulation and inflammatory markers, such as platelet count, D-dimer, prothrombin time, C-reactive protein, procalcitonin, and interleukin 6, predicted the deterioration of the disease. In addition, extracorporeal membrane oxygenation and mechanical ventilation predicted the poor prognosis during its progression.

  The COVID-19 pandemic is still evolving, placing a huge burden on healthcare facilities. Certain coagulation indicators, inflammatory indicators, and comorbidities contribute to the prognosis of patients. Our study results may help clinicians optimize the treatment and ultimately reduce the mortality rate.

• Research Paper Volume 12, Issue 22 pp 22405-22412

  Clinical characteristics of the first known cases of death caused by COVID-19 pneumonia

  Relevance score: 4.9398613

  Fan-Zhen Kong, Yi Wang, Mei-Xia Wang, Qing-Zhang Cheng, Robert Logan, Guan-Hui Wu, Si-Ming Hu

  Keywords: clinical characteristics, death cases, COVID-19, pneumonia

  Published in Aging on November 20, 2020

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  Severe pneumonia caused by COVID-19 has resulted in many deaths worldwide. Here, we analyzed the clinical characteristics of the first 17 reported cases of death due to COVID-19 pneumonia in Wuhan, China. Demographics, initial symptoms, complications, chest computerized tomography (CT) images, treatments, and prognoses were collected and analyzed from the National Health Committee of China data. The first 17 reported deaths from COVID-19 were predominately in older men; 82.35% of patients were older than 65 years, and 76.47% were males. The most common initial symptoms were fever or fatigue (14 cases, 82.35%), respiratory symptoms, such as cough (12 cases, 70.59%), and neurological symptoms, such as headache (3 cases, 17.65%). The most common finding of chest CT was viral pneumonia (5 cases, 29.41%). Anti-infectives (11 cases, 64.71%) and mechanical ventilation (9 cases, 52.94%) were commonly used for treatment. Most of the patients (16 cases, 94.12%) died of acute respiratory distress syndrome (ARDS). Our findings show that advanced age and male gender are effective predictors of COVID-19 mortality, and suggest that early interventions to reduce the incidence of ARDS may improve prognosis of COVID-19 pneumonia patients.

• Research Paper Volume 12, Issue 22 pp 23129-23145

  Cognitive frailty in relation to adverse health outcomes independent of multimorbidity: results from the China health and retirement longitudinal study

  Relevance score: 5.8163943

  Chen Chen, JuYoung Park, Chenkai Wu, QianLi Xue, George Agogo, Ling Han, Emiel O. Hoogendijk, Zuyun Liu, Zunyou Wu

  Keywords: older adults, cognitive frailty, disability, death, multimorbidity

  Published in Aging on November 18, 2020

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  Our objectives were to evaluate: 1) the associations of cognitive frailty with various health outcomes including disability, hospitalization, and death; 2) whether the associations differed by multimorbidity. We included data of 5113 Chinese older adults (aged 60+ years) who had baseline cognition and physical frailty assessments (2011 wave) and follow-up for 4 years. About 16.0% (n=820) had cognitive impairment; 6.7% (n=342) had physical frailty; and 1.6% (n=82) met criteria for cognitive frailty. Both cognitive impairment (odds ratios (ORs) range: 1.41 to 2.11) and physical frailty (ORs range: 1.51 to 2.43) were independently associated with basic activities of daily living (BADL), instrumental ADL (IADL), mobility disability, hospitalization, and death among participants without that corresponding outcome at baseline, even after accounting for covariates. Relative to participants who had normal cognition and were nonfrail, those with cognitive frailty had the highest risk for IADL disability (OR=3.40, 95% CI, 1.23–9.40) and death (OR=3.89, 95% CI, 2.25–6.47). We did not find significant interaction effects between cognitive frailty and multimorbidity (P_interactions>0.05). Overall, cognitive frailty was associated with disability and death, independent of multimorbidity. This highlights the importance of assessing cognitive frailty in the community to promote primary and secondary preventions for healthy aging.

• Research Paper Volume 12, Issue 14 pp 13869-13881

  Risk of death by age and gender from CoVID-19 in Peru, March-May, 2020

  Relevance score: 4.121499

  Cesar Munayco, Gerardo Chowell, Amna Tariq, Eduardo A. Undurraga, Kenji Mizumoto

  Keywords: COVID-19, Peru, risk of death, time-delay adjusted CFR, 2020

  Published in Aging on July 21, 2020

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  Peru implemented strict social distancing measures during the early phase of the epidemic and is now experiencing one of the largest CoVID-19 epidemics in Latin America. Estimates of disease severity are an essential indicator to inform policy decisions about the intensity and duration of interventions needed to mitigate the outbreak. Here we derive delay-adjusted case fatality risks (aCFR) of CoVID-19 in a middle-income country in South America.

  We utilize government-reported time series of CoVID-19 cases and deaths in Peru stratified by age group and gender.

  As of May 25, 2020, we estimate the aCFR for men and women at 10.8% (95%CrI: 10.5-11.1%) and 6.5% (95%CrI: 6.2-6.8%), respectively, whereas the overall aCFR was estimated at 9.1% (95%CrI: 8.9-9.3%). Our results show that senior individuals have been the most severely affected by CoVID-19, particularly men, with an aCFR of nearly 60% for those aged 80- years. We also found that men have a significantly higher cumulative morbidity ratio across most age groups (proportion test, p-value< 0.001), with the exception of those aged 0-9 years.

  The ongoing CoVID-19 pandemic is generating a substantial mortality burden in Peru. Senior individuals, especially those older than 70 years, are being disproportionately affected by the CoVID-19 pandemic.

  

  Epidemiological characterization of CoVID-19 in Peru, as of May 25, 2020. (A) Age distribution of reported cases by gender, (B) Age distribution of reported deaths by gender. (C) Gender proportion of CoVID-19 cases by age group, (D) Gender proportion of CoVID-19 deaths by age group, (E) Cumulative morbidity risk by gender and age group, (F) Mortality directly caused by CoVID-19 by gender and age group.

  
  
  

  

  Temporal distribution of cases and deaths by age group due to CoVID-19, March-May 2020, Peru. Top: Male, cumulative cases, Second top: Male, cumulative cases, Second bottom: Female, cumulative cases, Bottom: Female cumulative deaths (A) aged 0-9, (B) aged 10-19, (C) aged 20-29, (D) aged 30-39, (E) aged 40-49, (F) aged 50-59, (G) aged 60-69, (H) aged 70-79, (I) aged 80- and (J) Overall (all age groups). Day 1 corresponds to March 1^st in 2020.

  
  
  

  

  Temporal variation of male and female risk of death by age group caused by CoVID-19, March-May 2020, Peru. Upper two rows; Male risk of deaths, Lower two rows; Female risk of deaths. Observed and posterior estimated of crude case fatality risk of (A) aged 0-9, (B) aged 10-19, (C) aged 20-29, (D) aged 30-39, (E) aged 40-49, (F) aged 50-59, (G) aged 60-69, (H) aged 70-79, (I) aged 80-, (J) all age groups and time-delay adjusted case fatality risk of (K) aged 0-9, (L) aged 10-19, (M) aged 20-29, (N) aged 30-39, (O) aged 40-49, (P) aged 50-59, (Q) aged 60-69, (R) aged 70-79, (S) aged 80-, (T) all age groups. Day 1 corresponds to March 1^st in 2020. Black dots show crude case fatality risk, and light and dark indicates 95% and 50% credible intervals for posterior estimates, respectively.

  
  
  

  

  Most recent estimates of time-delay adjusted risk of death caused by CoVID-19 by age group and gender, March-May 2020, Peru. Distribution of time-delay adjusted risk of death from the latest estimates (May 25, 2020) is presented. Top to bottom: female aged 0-9, female aged 10-19, female aged 20-29, female aged 30-39, female aged 40-49, female aged 50-59, female aged 60-69, female aged 70-79, female aged 80 and over, female overall.

  
  
  

• Editorial Volume 12, Issue 12 pp 11163-11164

  PANoptosis components, regulation, and implications

  Relevance score: 5.0058413

  R.K. Subbarao Malireddi, Rebecca E. Tweedell, Thirumala-Devi Kanneganti

  Keywords: PANoptosis, ZBP1, pyroptosis, apoptosis, necroptosis, inflammatory cell death

  Published in Aging on June 19, 2020

  

  PANoptosis and potential disease associations. This figure depicts some of the major classes of inflammatory diseases where PANoptosis may contribute to the onset or progression of the disease.

  
  
  

• Research Paper Volume 12, Issue 11 pp 11025-11041

  LncRNA ADAMTS9-AS2 inhibits gastric cancer (GC) development and sensitizes chemoresistant GC cells to cisplatin by regulating miR-223-3p/NLRP3 axis

  Relevance score: 4.233062

  Niansheng Ren, Tao Jiang, Chengbo Wang, Shilin Xie, Yanwei Xing, Daxun Piao, Tiemin Zhang, Yuekun Zhu

  Keywords: gastric cancer, pyroptotic cell death, lncRNA ADAMTS9-AS2, miR-223-3p, NLRP3 inflammasome

  Published in Aging on June 9, 2020

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  The role of LncRNA ADAMTS9-AS2 in the regulation of chemoresistance of gastric cancer (GC) is largely unknown. Here we found that LncRNA ADAMTS9-AS2 was low-expressed in GC tissues and cells compared to their normal counterparts. In addition, LncRNA ADAMTS9-AS2 inhibited miR-223-3p expressions in GC cells by acting as competing endogenous RNA, and the levels of LncRNA ADAMTS9-AS2 and miR-223-3p showed negative correlations in GC tissues. Of note, overexpression of LncRNA ADAMTS9-AS2 inhibited GC cell viability and motility by sponging miR-223-3p. In addition, the levels of LncRNA ADAMTS9-AS2 were lower, and miR-223-3p was higher in cisplatin-resistant GC (CR-GC) cells than their parental cisplatin-sensitive GC (CS-GC) cells. LncRNA ADAMTS9-AS2 overexpression enhanced the cytotoxic effects of cisplatin on CR-GC cells, which were reversed by overexpressing miR-223-3p. Furthermore, LncRNA ADAMTS9-AS2 increased NLRP3 expressions by targeting miR-223-3p, and upregulation of LncRNA ADAMTS9-AS2 triggered pyroptotic cell death in cisplatin treated CR-GC cells by activating NLRP3 inflammasome through downregulating miR-223-3p. Finally, the promoting effects of LncRNA ADAMTS9-AS2 overexpression on CR-GC cell death were abrogated by pyroptosis inhibitor Necrosulfonamide (NSA). Collectively, LncRNA ADAMTS9-AS2 acted as a tumor suppressor and enhanced cisplatin sensitivity in GC cells by activating NLRP3 mediated pyroptotic cell death through sponging miR-223-3p.

  

  The expression status of LncRNA ADAMTS9-AS2 and miR-223-3p in GC clinical specimens and cell lines. Real-Time qPCR was used to examine the levels of (A) LncRNA ADAMTS9-AS2 and (B) miR-223-3p in cancer tissues and adjacent normal tissues collected from GC patients. (C) Pearson correlation analysis was conducted to analyze the correlation of LncRNA ADAMTS9-AS2 and miR-223-3p in GC tissues. (D) Pan-cancer analysis was performed to analyze the correlation of LncRNA ADAMTS9-AS2 and miR-223-3p for 372 specimens from the patients with stomach adenocarcinoma (STAD). (E, F) Kaplan-Meier survival analysis was performed to determine prognosis of GC patients with differential LncRNA ADAMTS9-AS2 and miR-223-3p expressions. Real-Time qPCR was used to measure the levels of (G) LncRNA ADAMTS9-AS2 and (H) miR-223-3p in GES-1 cells and GC cells. Each experiment repeated at least 3 times. **P < 0.01.

  
  
  

  

  LncRNA ADAMTS9-AS2 acted as a RNA sponge to regulate miR-223-3p in GC cells. (A) The targeting sites of LncRNA ADAMTS9-AS2 and miR-223-3p were predicted by using the online starBase software (http://starbase.sysu.edu.cn). Dual-luciferase reporter gene system was used to verify the binding sites in (B) SGC7901 cells and (C) BGC-823 cells, respectively. (D) RIP was performed to measure the binding abilities of LncRNA ADAMTS9-AS2 and miR-223-3p. Real-Time qPCR was used to examine the expression levels of (E) LncRNA ADAMTS9-AS2 and (F) miR-223-3p in GC cells. Each experiment repeated at least 3 times. “NS” represented “no statistical significance”, *P < 0.05, **P < 0.01.

  
  
  

  

  LncRNA ADAMTS9-AS2 regulated GC cell proliferation, viability, mobility and EMT by targeting miR-223-3p. CCK-8 assay was used to measure cell proliferation in (A) SGC7901 cells and (C) BGC-823 cells. Cell counting assay by trypan blue staining method was performed to determine cell viability in (B) SGC7901 cells and (D) BGC-823 cells. (E, F) Transwell assay was conducted to measure cell migration in GC cells. Western Blot was employed to examine the expressions of EMT associated proteins (N-cadherin, E-cadherin and Vimentin) in (G, H) SGC7901 cells and (I, J) BGC-823 cells. Each experiment repeated at least 3 times. “NS” represented “no statistical significance”, *P < 0.05, **P < 0.01.

  
  
  

  

  The expression patterns of LncRNA ADAMTS9-AS2 and miR-223-3p were changed by long-term cisplatin stimulation in GC cells. Real-Time qPCR was used to examine the expression levels of (A) LncRNA ADAMTS9-AS2 and (B) miR-223-3p in CS-GC and CR-GC cells. (C) The schematic diagram for the production of ACR-GC cells involved in this study. (D) Trypan blue staining assay was performed to evaluate cell viability in CS-GC cells and ACR-GC cells. Real-Time qPCR was conducted to examine the expression levels of (E) LncRNA ADAMTS9-AS2 and (F) miR-223-3p in GC cells treated with continuous low-dose cisplatin stimulation. Each experiment repeated at least 3 times. “NS” represented “no statistical significance”, *P < 0.05, **P < 0.01.

  
  
  

  

  LncRNA ADAMTS9-AS2 regulated chemoresistance of GC cells to cisplatin by modulating cell pyroptosis. CCK-8 assay was performed to determine cell proliferation abilities in (A) CR-GC cells and (C) ACR-GC cells. Trypan blue staining assay was conducted to measure cell viability in (B) CR-GC cells and (D) ACR-GC cells. (E, F) Colony formation assay was used to detect colony formation abilities of CR-SGC7901 cells and CR-BGC-823 cells. Cell viability in (G) CR-GC cells and (H) ACR-GC cells were detected by trypan blue staining assay. (I) FCM assay (Related to Supplementary Figure 1) were performed to determine cell apoptosis ratio in CR-GC cells. (“OE-A” represented “overexpressed LncRNA ADAMTS9-AS2”, “OE-miR” represented “overexpressed miR-223-3p”, “Mic” represented “miR-223-3p mimic”). Each experiment repeated at least 3 times. “NS” represented “no statistical significance”, *P < 0.05, **P < 0.01.

  
  
  

  

  LncRNA ADAMTS9-AS2 regulated NLRP3 inflammasome in GC cells by sponging miR-223-3p. (A) The targeting sites of miR-223-3p and NLRP3 mRNA were predicted by the online starBase software (http://starbase.sysu.edu.cn). Dual-luciferase reporter gene system was employed to validate the binding sites of miR-223-3p and NLRP3 mRNA in (B) SGC7901 cells and (C) BGC-823 cells. (D) RIP assay was used to evaluate the binding ability of miR-223-3p and 3’ UTR regions of NLRP3 mRNA. (E–H) Western Blot was performed to detect the expression levels of NLRP3 in SGC7901 and BGC-823 cells. (“Mic” represented “miR-223-3p mimic” and “Inhi” represented “miR-223-3p inhibitor”). Each experiment repeated at least 3 times. “NS” represented “no statistical significance”, *P < 0.05, **P < 0.01.

  
  
  

  

  The role of LncRNA ADAMTS9/miR-223-3p axis in the regulation of pyroptotic cell death in cisplatin treated CR-GC cells in vitro and in vivo. Western Blot was used to detect the expression levels of NLRP3 and ASC in (A, B) CR-SGC7901 cells and (C, D) CR-BGC-823 cells. (E) The activity of Caspase-1 was determined in CR-GC cells. ELISA was employed to examine (F) IL-1β and (G) IL-18 expressions in the supernatants. (H) LDH release was measured to evaluate the formation of pores in the cell membrane. (I) LDH release was measured in mice cancer tissues. (J, K) The expressions of NLRP3 and ASC were determined by Western Blot in mice cancer tissues. (L) ELISA was used to measure IL-1β and IL-18 expressions in mice serum. (M) Caspase-1 activity was measured in mice cancer tissues. Each experiment repeated at least 3 times. “NS” represented “no statistical significance”, *P < 0.05, **P < 0.01.

  
  
  

  

  The graphical abstract of this study. Briefly, long-term cisplatin stimulation inhibited LncRNA ADAMTS9 and increased miR-223-3p levels in GC cells, which inhibited pyroptotic cell death by inactivating NLRP3 inflammasome. Therefore, the GC cells with aberrant gene expressions were resistant to cisplatin.

  
  
  

• Research Paper Volume 12, Issue 3 pp 2545-2583

  Global burden of larynx cancer, 1990-2017: estimates from the global burden of disease 2017 study

  Relevance score: 4.7319465

  Yujiao Deng, Meng Wang, Linghui Zhou, Yi Zheng, Na Li, Tian Tian, Zhen Zhai, Si Yang, Qian Hao, Ying Wu, Dingli Song, Dai Zhang, Jun Lyu, Zhijun Dai

  Keywords: larynx cancer, global burden of disease, incidence, death, disability adjusted life-years

  Published in Aging on February 8, 2020

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  Larynx cancer is one of the most common cancers in head and neck. This study aimed to investigate the health burden of larynx cancer at global, regional, and national levels. We collected data of larynx cancer between 1990 and 2017 from the Global Burden of Disease study, including incidence, mortality, and disability adjusted life-years (DALYs). Estimated annual percentage changes (EAPCs) were calculated to assess the changes in age-standardized rate (ASR) of larynx cancer. From 1990 to 2017, LC incident cases increased by 58.67%; however, age-standardized incidence rate (ASIR) decreased, with an EAPC of -0.99. Additionally, the incident cases and ASIR of LC were 6-fold higher for male than those for female in 2017. Over the past 28 years, deaths and DALYs of larynx cancer increased by 33.84% and 25%. Contrarily, age-standardized death and DALY rate showed a downward trend. Incidence, death, and DALYs of larynx cancer were always the highest in people aged 50-69 years. Overall, all the ASRs showed downward trends globally. The majority of larynx cancer burden was observed in men, especially among male aged 50-69 years. South and East Asia carried the heaviest burden of larynx cancer worldwide.

  

  The global incidence burden of larynx cancer in 195 countries. (A) The ASIR of larynx cancer in 2017; (B) The relative change in incident cases of larynx cancer between 1990 and 2017; (C) The EAPC of larynx cancer ASIR from 1990 to 2017. Countries with an extreme number of cases/evolution were annotated. ASIR, age-standardized incidence rate; EAPC, estimated annual percentage change.

  
  
  

  

  The EAPC of larynx cancer ASR from 1990 to 2017, by sex and region. (A) The EAPC of ASIR; (B) The EAPC of ASDR; (C) The EAPC of age-standardized DALY rate. ASR: age-standardized rate; ASDR: age standardized death rate; ASIR: age standardized incidence rate; EAPC, estimated annual percentage change; DALY: disability adjusted life-year.

  
  
  

  

  The change trends of age standardized rate among different SDI quintiles and gender from 1990 to 2017. (A) ASIR: age standardized incidence rate; (B) ASDR: age standardized death rate; (C) age-standardized DALY rate. DALY, disability adjusted life-year.

  
  
  

  

  The correlation between EAPC and larynx cancer ASR in 1990 as well as SDI in 2017. The circles represent countries that were available on SDI data. The size of circle is increased with the cases of larynx cancer. The ρ indices and P values presented were derived from Pearson correlation analysis. (A) EAPC and SDI in incidence; (B) EAPC and ASIR; (C) EAPC and SDI in death; (D) EAPC and ASDR; (E) EAPC and SDI in DALYs; (F) EAPC and age-standardized DALY rate. ASIR, age standardized incidence rate; ASDR: age standardized death rate; EAPC, estimated annual percentage change; SDI, socio-demographic index; DALY: disability adjusted life-year.

  
  
  

  

  The proportion of different age groups in larynx cancer by years. (A) incidence, (B) death, (C) DALY. DALY: disability adjusted life-year.

  
  
  

  

  The rate of larynx cancer among gender and age in 1990 and 2017. (A) incidence rate; (B) death rate; (C) DALY rate. DALY, disability adjusted life-year.

  
  
  

• Research Paper Volume 11, Issue 23 pp 11686-11721

  Cytological and genetic consequences for the progeny of a mitotic catastrophe provoked by Topoisomerase II deficiency

  Relevance score: 5.0058413

  Cristina Ramos-Pérez, Margaret Dominska, Laura Anaissi-Afonso, Sara Cazorla-Rivero, Oliver Quevedo, Isabel Lorenzo-Castrillejo, Thomas D. Petes, Félix Machín

  Keywords: mitotic catastrophe, Top2, senescence, cell death, genomic instability

  Published in Aging on December 8, 2019

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  Topoisomerase II (Top2) removes topological linkages between replicated chromosomes. Top2 inhibition leads to mitotic catastrophe (MC) when cells unsuccessfully try to split their genetic material between the two daughter cells. Herein, we have characterized the fate of these daughter cells in the budding yeast. Clonogenic and microcolony experiments, in combination with vital and apoptotic stains, showed that 75% of daughter cells become senescent in the short term; they are unable to divide but remain alive. Decline in cell vitality then occurred, yet slowly, uncoordinatedly when comparing pairs of daughters, and independently of the cell death mediator Mca1/Yca1. Furthermore, we showed that senescence can be modulated by ploidy, suggesting that gross chromosome imbalances during segregation may account for this phenotype. Indeed, we found that diploid long-term survivors of the MC are prone to genomic imbalances such as trisomies, uniparental disomies and terminal loss of heterozygosity (LOH), the latter affecting the longest chromosome arms.

  

  Most progeny coming from a Top2-mediated mitotic catastrophe is inviable. (A) Haploid TOP2 (WT) or top2-5 cells were grown at 25 °C and spread on YPD agar plates. Unbudded cells (G₁/G₀) were identified and photographed again after 6 h at 37 °C. Number of cell bodies (buds) coming from these G₁/G₀ cells were then counted and plotted as indicated. (B) The same analysis as in panel A but including data coming from independent experiments as well as after 24 h incubation at 37 °C (mean ± s.e.m., n=3). (C) The principle of the solid medium-based clonogenic assay. Unlike the liquid medium-based clonogenic assay, cells are spread on the Petri dish before the condition that challenges survivability is transiently triggered (Top2 inactivation in our study). In the solid medium-based assay, the colony forming unit (CFU) reading after the challenge is binary, irrespective of how far cells keep on dividing during the challenge: “0” if all clonal cells are inviable (grey); “1” if at least one cell from the clone stays viable (yellowish orange). (D) Time course of clonogenic survivability. Asynchronous top2-5 cultures growing at 25 °C were spread onto several YPD plates. The plates were incubated at 37 °C for different periods before transferring them 25 °C. Four days after the initial plating, visible colonies (macrocolonies) were counted and normalized to a control plate which was never incubated at 37 °C (0h). (E) Analysis of the origin of macrocolonies after the 6 h x 37 °C regime as determined after microscanning plates at the time of seeding (N=33 macrocolonies; 2:1 unbudded:budded ratio at seeding).

  
  
  

  

  Most daughter cells coming from a Top2-mediated mitotic catastrophe are unable to divide again. (A) Haploid top2-5 cells were spread at high cell density on two Petri dishes. At the time of seeding, 0h (25 °C), several fields were photomicrographed before incubating the plates at 37 °C during either 6 h or 24 h. After the 37 °C incubations, the same fields were localized, photomicrographed again, and further incubated 16-24 h at 25 °C. An example of a microscope field of a 37 °C x 24 h experiment. Three representative unbudded cells at 0h (25 °C) are highlighted. In red, two cells that budded just once during the 37 °C x 24 h incubation (“2” cell bodies); one of them able to re-bud again a few times after the 25 °C downshift (“m”) and the second one that remained stuck as “2”. In green, a cell that reached “3” bodies at 37° C and remained so after the final 25 °C x 24 h incubation. Scale bar corresponds to 50 μm. (B) Analysis of how far the top2-5 MC progeny can go based on the microcolony approach shown in panel A. Only unbudded (G₁/G₀) cells at 0h (25 °C) were considered. The inner circle in the sunburst chart depicts proportions of cell bodies after the 37 °C incubation. The outer circle depicts the situation after the final 25 °C incubations (see supplemental information for a detailed description). On the left are results from a 37 °C x 6 h regime; on the right are results from a 37 °C x 24 h regime. Numbers point to the number of cell bodies; “m” means microcolonies of 5 or more bodies. (C) Capability of the top2-5 progeny to split apart and relationship with overall survivability. Unbudded cells were micromanipulated and arranged at defined plate positions before incubating them for 6 h at 37 °C. Then, those cells able to re-bud at least once were subjected to an attempt to physically separate the cell bodies. The inner circle in the sunburst depicts the number of cell bodies after the 37 °C incubation. The middle circle depicts the result of the separation attempt (“Y” or “N”, successful or unsuccessful, respectively). The outer circle indicates if any of the bodies was able to raise a macrocolony (Yes or No) after 4 d incubation at 25 °C. (D) Progression of the size (volume) of the original G₁/G₀ cells (mother) after the top2-5 mitotic catastrophe with and without the osmotic stabilizer Sorbitol (Sorb, 1.2 M). (E) Time course of clonogenic survivability in the presence of 1.2 M Sorbitol. The experiment was conducted as in Figure 1D. (F) Sunbursts of microcolony analyses in the presence of 1.2 M Sorbitol (Srb) at the 6 h and 24 h x 37 °C regimes. Interpretation as in panel B. In sunburst charts, N indicates number of original unbudded cells which were followed; blue sectors depict G₁/G₀ cells that remained unbudded during the 37 °C incubations; red sectors, cells that budded once at 37 °C; green sectors, cells that reached 3 bodies at 37 °C; orange sectors, cells that reached 4 bodies at 37 °C; cyan sectors, cells that reached 5 or more bodies at 37 °C.

  
  
  

  

  Cell vitality remain high for several hours after the top2 mitotic catastrophe and is not modulated by Yca1. (A) Morphological patterns of cell and nuclear sickness after the top2 MC. Haploid top2-5 HTA2-GFP cells were seeded onto agarose patches and the same fields visualized under the fluorescence microscope at 0 h, 6 h and 24 h after the 37 °C temperature upshift. White filled triangles point to darkened inclusion bodies, asterisks (*) swelled cells, open circles (○) cells that has lost their rounded shape, and hash (#) points to cells that have largely lost the H2A-GFP signal. BF, bright field. Scale bar corresponds to 20 μm. (B) Time course of cell vitality decline as reporter by methylene blue (MB) negative staining. Asynchronous cultures of the top2-5 and top2-5yca1Δ strains were grown at 25 °C before shifting the temperature to 37 °C. At the indicated time points (0, 2, 4, 6, 24 & 48 h), samples were taken and stained with the vital dye MB. (C) Cell vitality decline as reported by metabolic competence, intrinsic ROS generation, and loss of plasma membrane impermeability. Cells were treated as in B and stained at the indicated time points with the vital dye FUN1, the death marker propidium iodide (PI), and/or the ROS reporter DCFH-DA (mean ± s.e.m., n=3). (D) Clonogenic survival profile of top2-5 yca1Δ as determined on the low-density plates (mean ± s.e.m., n=3). The experimental procedure is described in Figure 1D. (E) Ability to re-bud of the top2-5 yca1Δ MC progeny as determined on the high-density plates. The experimental procedure is described in Figure 2.

  
  
  

  

  Mitotic catastrophe in top2-5 diploids leads to progeny with a greater capacity for cell division than observed in the haploid. Isogenic homozygous top2-5 diploid cells were grown and spread at either low or high cell density on Petri dishes. In addition, G₁/G₀ cells were micromanipulated, arrayed and treated as described in Figure 2C. (A) Ability to re-bud after transient (6 h or 24 h) incubations at 37 °C of the high-density plates. The experimental procedure is described in Figure 2. (B) Clonogenic survival profile as determined on the low-density plates (mean ± s.e.m., n=3). The experimental procedure is described in Figure 1D. (C) Capability of the progeny to split apart and relationship with overall survivability. The experimental procedure is described in Figure 2C.

  
  
  

  

  Mitotic catastrophe in top2-5 heterozygous diploids leads to survivors with specific genetic instability footprints. (A) Schematic of the engineered chromosome V (cV) from the hybrid highly heterozygous (~55,000 SNPs) diploids used in this study. As explained in the text, the genetic modifications applied in cV allowed for selection of chromosome rearrangements. (B) G₁/G₀ cells from the hybrid highly heterozygous top2-5 diploid FM1873 strain were micromanipulated, arrayed and treated as described in Figure 2C. The capability of the immediate progeny to split apart and its relationship with overall survivability is shown in the sunburst chart. (C) Clonogenic survival profile of FM1873 as determined on low-density plates (mean ± s.e.m., n=3). The experimental procedure is described in Figure 1D. (D) Percentage of red or sectored (either white:red or pink:red) colonies in the surviving clones. Both outcomes often reflect genetic alterations on cV as described in the text. (E) Results of SNP microarray analysis of colonies derived from FM1873 or MD684. Microarray patterns showing specific chromosome rearrangements are shown on the left side, and diagrams of the putative events producing these patterns are shown on the right side. The number of specific events out of 118 total events is indicated. For the microarray patterns, hybridization to SNPs specific to homologs derived from W303-1A are shown in red, and hybridizations to SNPs specific to YJM789 are shown in blue. The X-axis shows SGD coordinates for the chromosome, and the Y-axis shows the ratio of hybridization normalized to a heterozygous diploid strain. The representative examples correspond to (1) a T-LOH event on chromosome IV (MD684.1.1 (E1) in Table 1); (2) a I-LOH event (marked with a green arrow) plus T-LOH event on chromosome IV (FM1873-15c (C2) in Table 1); (3) a Trisomy for chromosome XIV (MD684.1.1 (E1) in Table 1); and (4) a UPD for chromosome V (This isolate has two copies of the W303-1A-derived and no copies of the YJM789-derived chromosome).

  
  
  

  

  Summary of the top2-mediated mitotic catastrophe and the fate of the immediate progeny. After inactivation of Top2, cells cannot resolve sister chromatids in anaphase, leading to an anaphase bridge between the mother (M) and its daughter (D1). These bridges are quickly severed (at least in the top2-5 mutant [25]). The immediate progeny coming from the top2 mitotic catastrophes (MCs) is largely unable to enter a new cell cycle (do not re-bud) despite remaining metabolically active for many hours; hence, these cells become senescent. Only ~25% of the original mothers re-bud once (D2) after the top2 MC. The long-term fate of most daughter cells is death. They will eventually die through accidental cell death (ACD), as deduced from both the asynchrony and asymmetry of death events and the lack of regulation by the death modulator Yca1(Mca1). The inability to enter a new cell cycle is likely a consequence of both the massive DNA damage as a consequence of bridge severing, and the misdistribution of essential genetic material coded on the chromosome arms between the daughter cells. A small proportion of the progeny, especially those cell that underwent a milder top2 MC (e.g., already in S/G₂ at the time of Top2 inactivation) survives to yield a population of cells with characteristic footprints of genomic instability. Two of these footprints, terminal loss of heterozygosity (T-LOH) and uniparental disomy (UPD) are expected outcomes from anaphase bridges.

  
  
  

• Priority Research Paper Volume 11, Issue 11 pp 3418-3431

  α-Ketoglutarate inhibits autophagy

  Relevance score: 5.370254

  Elisa Elena Baracco, Francesca Castoldi, Sylvère Durand, David P. Enot, Jelena Tadic, Katharina Kainz, Frank Madeo, Alexis Chery, Valentina Izzo, Maria Chiara Maiuri, Federico Pietrocola, Guido Kroemer

  Keywords: acetyl CoA, aging, cell death, Krebs cycle, metabolomics, mitochondria

  Published in Aging on June 7, 2019

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  The metabolite α-ketoglutarate is membrane-impermeable, meaning that it is usually added to cells in the form of esters such as dimethyl −ketoglutarate (DMKG), trifluoromethylbenzyl α-ketoglutarate (TFMKG) and octyl α-ketoglutarate (O-KG). Once these compounds cross the plasma membrane, they are hydrolyzed by esterases to generate α-ketoglutarate, which remains trapped within cells. Here, we systematically compared DMKG, TFMKG and O-KG for their metabolic and functional effects. All three compounds similarly increased the intracellular levels of α−ketoglutarate, yet each of them had multiple effects on other metabolites that were not shared among the three agents, as determined by mass spectrometric metabolomics. While all three compounds reduced autophagy induced by culture in nutrient-free conditions, TFMKG and O-KG (but not DMKG) caused an increase in baseline autophagy in cells cultured in complete medium. O-KG (but neither DMKG nor TFMK) inhibited oxidative phosphorylation and exhibited cellular toxicity. Altogether, these results support the idea that intracellular α-ketoglutarate inhibits starvation-induced autophagy and that it has no direct respiration-inhibitory effect.

  

  Metabolic effects of α-ketoglutarate precursors. (A, B) Unsupervised hierarchical clustering of intracellular metabolites in U2OS cells treated with the α-ketoglutarate precursors dimethyl α-ketoglutarate (DMKG), trifluoromethylbenzyl α-ketoglutarate (TFMKG) and octyl α-ketoglutarate (O-KG) in complete (CM) (A) or nutrient free (NF) medium (B) for 4 h at the concentrations indicated in the Experimental Procedure section. Heat maps depict log₂ fold changes to the control of metabolite signals found altered (False Discovery Rate [FDR]< 0.1) upon incubation with α-ketoglutarate precursors. (C-E) Impact of α-ketoglutarate precursors on intracellular levels of α-ketoglutarate (C) and the energy related metabolites AcetylCoA (D) and ATP (E). Data represent averaged log₂ fold change ± S.E.M. to the controls (CM or NF). *** p < 0.001; ** p< 0.01 (unpaired t test).

  
  
  

  

  Modulation of autophagy by α-ketoglutarate precursors. (A) Inhibition of starvation-induced autophagy by DMKG, TFMKG and O-KG. U2OS cells stably expressing the autophagic markers GFP-LC3 were incubated in HBSS medium (NF) and left untreated or incubated with α-ketoglutarate precursors for 4h. Co-treatment with bafilomycin A1 (BafA1) was used to assess autophagic flux. Representative pictures (in presence of BafA1) (right panel) and quantification (left panel) are shown. Data represent mean ± S.D. (one representative experiment, n=3). *** p < 0.001 (compared to Control); ### p < 0.001 (compared to NF) (unpaired t test). Scale bar 10 μm. (B) Induction of autophagy by TFMKG and O-KG, but not DMKG, in complete medium. *** p < 0.001 (compared to Control); (unpaired t test). Scale bar 10 μm. (C, D) Immunoblotting showing the conversion of LC3I to LC3II in U2OS cells treated with α-ketoglutarate precursors in NF (C) or complete medium (D) in presence or absence of BafA1 to monitor autophagic flux (one representative experiment, n=3).

  
  
  

  

  Influence of α-ketoglutarate precursors on mitochondrial metabolism (A-D) O-KG, but not DMKG and TFMKG, inhibits mitochondrial respiration. U2OS cells were incubated for 6 h in presence or absence of DMKG (A, B), TFMKG (C, D), O-KG and octanol (A-D); after pre-incubation with distinct α-ketoglutarate precursors, oxygen consumption rate (OCR) was monitored in a Seahorse XF analyzer upon injection of the complex V inhibitor oligomycin (Oligo), the uncoupler carbonyl cyanide 3-chlorophenylhydrazone (CCCP) and the complex I inhibitor rotenone at the concentrations indicated in the Experimental Procedure section. Mitochondrial function was evaluated as basal respiration (B, D, left panel), ATP production (B, D, middle panel) and maximal respiratory capacity (B, D, right panel). Data are depicted as mean ± S.D. (one representative experiment, n=3). *** p < 0.001 (compared to Control) (unpaired t test)

  
  
  

  

  Impact of α-ketoglutarate precursors on cell viability. (A-B) Cytofluorimetric assessment of cell death elicited upon administration of distinct α-ketoglutarate precursors to U2OS cells in complete (A) or nutrient free medium (NF) (B) for 4 h. PI⁺ = dead cells; PI^-/DiOC₆(3) low cells = dying cells. Data (depicted as percentage of cells) represent mean ± S.D. (one representative experiment, n=3). *** p < 0.001 (compared to Control); * p < 0.05 (compared to NF) (unpaired t test). (C). Survival rates of treated (200 µM) and control cells were analyzed at indicated timepoints via clonogenicity assay. (D) Plasma membrane integrity via PI staining of treated (200 µM) versus control yeast cells was monitored at indicated timepoints during chronological aging. Data represent mean ± S.E.M of at least 3 independent experiments. ** p < 0.01; * π < 0.05 (Compared to O-KG vehicle); (two-way Anova).

  
  
  

• Research Paper Volume 10, Issue 6 pp 1523-1533

  Linc00472 suppresses proliferation and promotes apoptosis through elevating PDCD4 expression by sponging miR-196a in colorectal cancer

  Relevance score: 5.0055227

  Yafei Ye, Shengnan Yang, Yanping Han, Jingjing Sun, Lijuan Xv, Lina Wu, Yongfeng Wang, Liang Ming

  Keywords: Colorectal cancer, Linc00472, miR-196a, programmed cell death 4

  Published in Aging on June 21, 2018

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  Long intergenic non-coding RNA Linc00472 has been considered as a tumor suppressor in some cancers. However, the function and mechanism of Linc00472 in colorectal cancer has not been well elucidated. In this study, we found that Linc00472 was down-regulated in colorectal cancer tissues and cells. Elevated Linc00472 expression suppressed proliferation and induced apoptosis in colorectal cancer cells. Moreover, Linc00472 acted as a competing endogenous RNA (ceRNA) of miR-196a to release programmed cell death 4 (PDCD4). Furthermore, miR-196a overexpression or PDCD4 knockdown reversed Linc00472-mediated proliferation inhibition and apoptosis induction in colorectal cancer cells. Ectopic Linc00472 expression hindered tumor growth in vivo. Our study demonstrated that Linc00472 suppressed proliferation and induced apoptosis through up-regulating PDCD4 by decoying miR-196a, which may be an effective therapeutic target for colorectal cancer.

  

  Linc00472 was decreased in CRC tissues and cells. (A) The expression levels of Linc00472 in CRC tumor tissues and adjacent normal tissues were determined by qRT-PCR assays. (B) Linc00472 expression was analyzed in TCGA colon adenocarcinoma (COAD) cohort. (C) qRT-PCR analysis was performed to detect Linc00472 expression in immortalized human colonic epithelial cell line NCM460 and four CRC cell lines (SW480, SW620, HT-29 and HCT-116). (D) Kaplan-Meier curve was employed to assess the overall survival outcome in CRC patients with high or low Linc00472 expression in TCGA dataset. *P < 0.05, ***P < 0.001.

  
  
  

  

  Linc00472 overexpression inhibited proliferation and induced apoptosis in CRC cells. HT-29 and HCT-116 cells were transfected with pcDNA3.1 vector (Vector) or pcDNA-Linc00472 (Linc00472). (A) The Linc00472 expression level was detected using qRT-PCR assays. (B and C) Cell proliferation was measured with CCK-8 assays. (D and E) Cell clone numbers were evaluated by colony formation assay. (F and G) Cell apoptosis was determined by flow cytometry analysis. *P < 0.05.

  
  
  

  

  Linc00472 directly inhibited miR-1496a expression. (A) The predicted binding sites between Linc00472 and miR-141 were shown. (B) The luciferase activity was detected in 293T cells. (C) qRT-PCR analysis miR-196a expression in HT-29 and HCT-116 cells transfected with pcDNA3.1 vector (Vector) or pcDNA-Linc00472 (Linc00472). (D) qRT-PCR assay was performed to detect miR-196a expression in CRC tumor tissues and adjacent normal tissues. (E) Linc00472 expression was analyzed in TCGA COAD cohort. (F) Correlation analysis between Linc00472 and miR-196a in CRC tissues from TCGA COAD dataset. *P < 0.05, ***P < 0.001.

  
  
  

  

  PDCD4 was a target of miR-196a. (A) The putative binding sites between PDCD4 and miR-196a by miRanda software. (B) The luciferase activity of wide-type or mutant-type PDCD4 was determined in 293T cells. (C) PDCD4 protein level in HT-29 and HCT-116 cells was detected using western blot analysis. (D) qRT-PCR assay analyzed PDCD4 mRNA levels in CRC tumor tissues and adjacent normal tissues. (E) PDCD4 mRNA levels were analyzed in TCGA COAD cohort. (F) Correlation analysis between Linc00472 and PDCD4 in CRC tissues from TCGA COAD dataset. *P < 0.05, ***P < 0.001.

  
  
  

  

  Linc00472 inhibited proliferation and enhanced apoptosis by modulating miR-196a/PDCD4 axis in CRC cells. HT-29 cells were transfected with Vector+miR-con, Linc00472+miR-con, Vector+miR-196a or Linc00472+miR-196a, and HCT-116 cells were transfected with Vector+si-con, Linc00472+si-con, Vector+si-PDCD4 or Linc00472+si-PDCD4. The PDCD4 protein levels were measured by western blot assays (A and B), the cell proliferation was evaluated by CCK-8 assays (C and D), the cell clone numbers were estimated by colony formation assays (E and F), and the cell apoptosis was determined with flow cytometry (G and H). *P < 0.05.

  
  
  

  

  Linc00472 suppressed tumor growthin vivo. (A) The tumor volume curve of null mice was analyzed. (B) The tumor weight of null mice was measured. (C) The miR-196a expression and PDCD4 mRNA levels in tumors of null mice were detected by qRT-PCR. (D) Western blot analysis was performed to determine PDCD4 and Ki-67 protein levels. *P < 0.05.