Citations

Abstract The liver is organized into tightly regulated zones with distinct metabolic functions but zonation erodes with age. Cellular senescence contributes to aging and liver diseases, however, its impact on aging biology is ill-defined. As part of The Cellular Senescence Network Consortium, we used multiple spatial transcriptomics approaches (GeoMx, Visium, CosMx) with snRNA-seq to profile senescence signatures, zonation markers, and metabolic pathways in livers from wild-type (WT) mice of multiple ages. We observed a loss of canonical zone signatures in aged mouse livers characterized by “expansion” of midlobular (zone 2) marker gene expression, accompanied by diminished expression of zone 3 marker genes by middle-age (18 months), indicative of loss of cell identity. Multiple analytic approaches identified distinct age-, zone- and sex-specific senescence signatures, which were significantly associated with zonation markers changes. This was recapitulated in Ercc1 mutant models of accelerated senescence, supporting a causal role of senescent cells in liver aging. A “no-zone” hepatocyte-like cluster expanded with age and with the strongest Senescence-Associated Secretory Phenotype (SASP) profile. Gene expression profiles from senescent hepatocytes implicate decreased WNT signaling and increased BMP as contributing to age-related loss of zonation. Together, these data elucidate the role of senescent cells in driving aging biology in non-diseased liver through disruption of cell:cell signaling and the loss of metabolic and cell identity gene expression necessary for hepatocyte function.

BACKGROUND: Small, randomized trials of patients with cervical artery dissection showed conflicting results regarding optimal stroke prevention strategies. We aimed to compare outcomes in patients with cervical artery dissection treated with antiplatelets versus anticoagulation. METHODS: This is a multicenter observational retrospective international study (16 countries, 63 sites) that included patients with cervical artery dissection without major trauma. The exposure was antithrombotic treatment type (anticoagulation versus antiplatelets), and outcomes were subsequent ischemic stroke and major hemorrhage (intracranial or extracranial hemorrhage). We used adjusted Cox regression with inverse probability of treatment weighting to determine associations between anticoagulation and study outcomes within 30 and 180 days. The main analysis used an as-treated crossover approach and only included outcomes occurring with the above treatments. RESULTS: The study included 3636 patients (402 [11.1%] received exclusively anticoagulation and 2453 [67.5%] received exclusively antiplatelets). By day 180, there were 162 new ischemic strokes (4.4%) and 28 major hemorrhages (0.8%); 87.0% of ischemic strokes occurred by day 30. In adjusted Cox regression with inverse probability of treatment weighting, compared with antiplatelet therapy, anticoagulation was associated with a nonsignificantly lower risk of subsequent ischemic stroke by day 30 (adjusted hazard ratio [HR], 0.71 [95% CI, 0.45–1.12]; P =0.145) and by day 180 (adjusted HR, 0.80 [95% CI, 0.28–2.24]; P =0.670). Anticoagulation therapy was not associated with a higher risk of major hemorrhage by day 30 (adjusted HR, 1.39 [95% CI, 0.35–5.45]; P =0.637) but was by day 180 (adjusted HR, 5.56 [95% CI, 1.53–20.13]; P =0.009). In interaction analyses, patients with occlusive dissection had significantly lower ischemic stroke risk with anticoagulation (adjusted HR, 0.40 [95% CI, 0.18–0.88]; P interaction =0.009). CONCLUSIONS: Our study does not rule out the benefit of anticoagulation in reducing ischemic stroke risk, particularly in patients with occlusive dissection. If anticoagulation is chosen, it seems reasonable to switch to antiplatelet therapy before 180 days to lower the risk of major bleeding. Large prospective studies are needed to validate our findings.

BACKGROUND: Patients presenting with cervical artery dissection (CAD) are at risk for subsequent ischemic events. We aimed to identify characteristics that are associated with increased risk of ischemic stroke after initial presentation of CAD and to evaluate the differential impact of anticoagulant versus antiplatelet therapy in these high-risk individuals. METHODS: This was a preplanned secondary analysis of the STOP-CAD study (Antithrombotic Treatment for Stroke Prevention in Cervical Artery Dissection), a multicenter international retrospective observational study (63 sites from 16 countries in North America, South America, Europe, Asia, and Africa) that included patients with CAD predominantly between January 2015 and June 2022. The primary outcome was subsequent ischemic stroke by day 180 after diagnosis. Clinical and imaging variables were compared between those with versus without subsequent ischemic stroke. Significant factors associated with subsequent stroke risk were identified using stepwise Cox regression. Associations between subsequent ischemic stroke risk and antithrombotic therapy type (anticoagulation versus antiplatelets) among patients with identified risk factors were explored using adjusted Cox regression. RESULTS: In all, 4023 patients (mean age was 47.4 years; 44.5% were women) were included. By day 180, subsequent ischemic stroke occurred in 5.3% of the cohort. In adjusted Cox regression, factors associated with increased risk of subsequent ischemic stroke were prior history of ischemic stroke (adjusted hazard ratio [aHR], 7.31 [95% CI, 1.61–33.13]; P =0.010), presentation within 7 days from first symptoms (aHR, 3.04 [95% CI, 1.04–8.91]; P =0.043), infarct on baseline imaging (aHR, 9.85 [95% CI, 3.65–26.58]; P <0.001), and occlusive dissection (aHR, 2.34 [95% CI, 1.03–5.34]; P =0.043). Only patients with occlusive dissection demonstrated a reduced risk of subsequent ischemic stroke when treated with anticoagulation versus antiplatelets (aHR, 0.36 [95% CI, 0.16–0.80]; P =0.01). CONCLUSIONS: In this post hoc analysis of the STOP-CAD study, several factors associated with subsequent ischemic stroke were identified among patients with CAD. Furthermore, we identified a potential benefit of anticoagulation in patients with CAD with occlusive dissection. These findings require validation by meta-analyses of prior studies to formulate optimal treatment strategies for specific high-risk CAD subgroups.

AbstractBackgroundAppropriate time for ejection fraction (EF) reassessment after revascularization in patients with left ventricular dysfunction has not been investigated comprehensively, although 3 months after revascularization is recommended to stratify the risk of sudden cardiac death (SCD).HypothesisEF reassessed within different timeframe after revascularization may have incosistent contribution for risk stratification of SCD.MethodsPatients who had EF ≤ 40% before revascularization and had EF reassessment at least once during follow‐up were included. The role of early (<3 months) versus late (3–12 months) EF measurements in prediction of all‐cause mortality and SCD were compared.ResultsA total of 1589 patients were identified. EF reassessed <3 months was lower than EF reassessed within 3–12 months (42.1 ± 9.7% vs. 45.8 ± 10.8%; p < .01). Among 1069 patients who had EF reassessed <3 months, EF ≤ 35% was associated with a higher risk of all‐cause mortality (hazard ratio [HR], 1.67; 95% confidence interval [CI], 1.22–2.29; p < .01), but had no association with the risk of SCD (HR, 1.44; 95% CI, 0.84–2.48; p = .18). By contrast, among 595 patients who had EF reassessed within 3–12 months, EF ≤ 35% was associated with higher risks of both all‐cause death (HR, 1.81; 95% CI, 1.06–3.10; p = .03) and SCD (HR, 2.71; 95% CI, 1.31–5.61; p < .01). The relative contribution of SCD to all‐cause death was higher in patients with EF ≤ 35% than patients with EF > 35% when EF was reassessed within 3–12 months (p = .04). However, when EF was reassessed <3 months, the mode of death was similar in patients with EF ≤ 35% versus >35% (p = .85).Conclusions3 to 12 months after revascularization may be appropriate for cardiac function reassessment and SCD risk stratification.

Radiation-induced brain injury (RIBI) is a debilitating sequela after radiotherapy to treat head and neck cancer, and 20 to 30% of patients with RIBI fail to respond to or have contraindications to the first-line treatments of bevacizumab and corticosteroids. Here, we reported a Simon’s minmax two-stage, single-arm, phase 2 clinical trial (NCT03208413) to assess the efficacy of thalidomide in patients with RIBI who were unresponsive to or had contraindications to bevacizumab and corticosteroid therapies. The trial met its primary endpoint, with 27 of 58 patients enrolled showing ≥25% reduction in the volume of cerebral edema on fluid-attenuated inversion recovery–magnetic resonance imaging (FLAIR-MRI) after treatment (overall response rate, 46.6%; 95% CI, 33.3 to 60.1%). Twenty-five (43.1%) patients demonstrated a clinical improvement based on the Late Effects Normal Tissues–Subjective, Objective, Management, Analytic (LENT/SOMA) scale, and 36 (62.1%) experienced cognitive improvement based on the Montreal Cognitive Assessment (MoCA) scores. In a mouse model of RIBI, thalidomide restored the blood-brain barrier and cerebral perfusion, which were attributed to the functional rescue of pericytes secondary to elevation of platelet-derived growth factor receptor β (PDGFRβ) expression by thalidomide. Our data thus demonstrate the therapeutic potential of thalidomide for the treatment of radiation-induced cerebral vasculature impairment.

Abstract While epoxyeicosatrienoic acids (EETs) have been implicated in breast cancer growth and progression, less is known about their effects on oncogene transcription. We have previously found that the oncogenic regioisomer (±)14,15-EET drives mitochondrial respiration, ATP synthesis, and proliferation of ER+/HER2- breast cancer cells [Cell Chem Biol. 2017 Oct 19;24(10):1259-1275]. RNAseq analysis was performed (5 replicates per condition) on serum starved (16 hours) MCF-7 cells which were then treated with (±)14,15-EET or vehicle (2 hours; serum and phenol red free medium without estradiol). Using gene set enrichment analysis (GSEA), we found that (±)14,15-EET activated an estrogen receptor alpha (ER) hallmark early response gene set and synchronously activated a MYC hallmark gene set. With activation of the MYC hallmark gene set, c-Myc gene expression was also induced at 2 hours (3.99-fold; P=2.3 x 10-17; FDR=2.8 x 10-14). These data suggest an alternative pathway for activation of estrogen and MYC regulated genes in the absence of estradiol. The 15 genes most transcriptionally activated by (±)14,15-EET at 2 hours were: VMP1, ZFP36, JUNB, FOS, IER3, EGR1, IER5L, ELF3, JUN, NR4A1, HES1, DUSP1, MYC, TOB1, and CITED2 [fold change range: 3.25 (CITED2) to 90.5 (FOS); all P&lt; 2.86 x 10-17; all FDR &lt; 3.03 x 10-14]. The ER regulated genes most transcriptionally activated (&gt;1.5 fold) were: IER3, TOB1, AREG, CISH, KCNMB3, and PDK4 (fold change range: 1.77 to 4.35; P= 1.74 x 10-18 to 1.35 x 10-5; FDR=5.54 x 10-15 to 6.4 x 10-4). The MYC regulated genes most transcriptionally activated (&gt; 1.5-fold change) were EIF4A1 (fold change= 2.37; P=1.0 x 10-7; FDR=1.33 x 10-5), IRF9 (fold change=1.58; P=0.0044; FDR= 0.026), and FOSL1 (fold change=1.51; P=0.008; FDR=0.04). Supporting the hypothesis of (±)14,15-EET activation of ER-regulated transcription, (±)14,15-EET promoted nuclear translocation of ER at 1 hour measured by DAPI normalized immunofluorescence [MCF-7 nuclear ER increase of 1.66-fold (P=0.031); ZR75-1 nuclear ER increase of 1.77-fold (P=0.015)]. Supporting the hypothesis of (±)14,15-EET activation of MYC-regulated transcription, (±)14,15-EET treatment promoted nuclear translocation of c-Myc with MCF-7 cells exhibiting a 1.22-fold increase at 2 hours (P=0.002). (±)14,15-EET also promoted nuclear translocation of FITC-70 kDa dextran with MCF-7 cells exhibiting an increase of 1.35-fold at 1 hour (P=0.029). These data suggest that (±)14,15-EET can induce an estradiol-like immediate early gene response in ER+/HER2- breast cancer cells correlating with c-Myc activation. In summary, while the effect of (±)14,15-EET on nuclear translocation may be partially cargo agnostic, (±)14,15-EET promotes ER and c-Myc nuclear translocation and associated transcription, mimicking a tandem hormonal and growth factor response. Citation Format: Jianxun Lei, Zhijun Guo, Julissa Molina-Vega, Paloma Cervantes, Swaathi Jayaraman, John R. Hawse, Carlos Perez, Juan Abrahante, Xiaojia Tang, Krishna Kalari, Jinhua Wang, John R. Falck, Carol Lange, Matthew P. Goetz, David Potter. (±) 14,15-epoxyeicosatrienoic acid induces hallmark ER and MYC gene expression and associated ER and c-Myc nuclear translocation in ER+/HER2- breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB564.

Objectives To observe the weight change in Chinese youth during a 4-month COVID-19 lockdown, and the association between weight change and mental health, physical activity and sedentary time changes, and dietary habits. Design A retrospective observational study. Settings Two universities located in Zhejiang and Hunan provinces, China. Participants This study enrolled 12 889 college students whose body weight was measured before the lockdown (1 December 2019–20 January 2020) at the two universities, and reported their weight measured at home or community after the end of the lockdown (1–23 May 2020) via an online follow-up questionnaire. Primary and secondary outcome measures The primary outcome was the weight change in Chinese youth during a 4-month lockdown resulting from the COVID-19 pandemic. The secondary outcomes were the relationships of weight change to COVID-19-related stress, depression, anxiety, physical activity and sedentary time changes, and dietary habits. Results Participants’ ages ranged from 17 to 27 years ( M =19, SD=1) with 80.2% identified as female. The average absolute and relative changes in body weight were 2.6 (95% CI 2.0 to 3.2)) kg and 4.2% (95% CI 4.0% to 4.3%) for men, and 2.1 (1.9 to 2.4) kg and 4.2% (95% CI 3.9% to 4.4%) for women. An increase in overweight and obese individuals according to Asian cut-off points as a demographic percentage by 4.5% and 2.7% and 4.8% and 3.4% in men and women, respectively ( P <0.001), was observed. Weight gain was significantly associated with increased sedentary time and an increase in COVID-19-related stress and depression score. Conclusion The present study’s results suggest that the risk of weight gain in Chinese youth during the lockdown increased and that strategies to decrease sedentary time and improve mental health may be warranted to mitigate weight gain during and after the COVID-19 pandemic.

Background The COVID-19 pandemic has led to a spike in deleterious mental health. This dual-center retrospective cross-sectional study assessed the prevalence of depression in young adults during this pandemic and explored its association with various physical fitness measures. Methods This study enrolled 12,889 (80% female) young adults (mean age 20 ± 1) who performed a National Student Physical Fitness battery from December 1st, 2019, to January 20th, 2020, and completed a questionnaire including Beck’s Depression Inventory in May 2020. Independent associations between prior physical fitness and depression during the pandemic were assessed using multivariable linear and binary logistic regressions accordingly, covariates including age, dwelling location, economic level, smoking, alcohol, living status, weight change, and exercise volume during the pandemic. Sex- and baseline stress-stratified analyses were performed. Results Of the study population 13.9% of men and 15.0% of women sampled qualified for a diagnosis of depression. After multivariable adjustment, anaerobic (mean change 95% CI −3.3 [−4.8 to 1.8]) aerobic (−1.5 [−2.64 to −0.5]), explosive (−1.64 [−2.7 to −0.6]) and muscular (−1.7 [−3.0 to −0.5]) fitness were independently and inversely associated with depression for the overall population. These remained consistent after sex- and baseline stress-stratification. In binary logistic regression, the combined participants with moderate, high or excellent fitness also showed a much lower risk compared to those least fit in anaerobic (odd ratio (OR) 95% CI 0.68 [0.55–0.82]), aerobic (0.80 [0.68–0.91]), explosive (0.72 [0.61–0.82]), and muscular (0.66 [0.57–0.75]) fitness. Conclusions These findings suggest that prior physical fitness may be inversely associated with depression in young adults during a pandemic.

Abstract Background: The coronavirus disease-2019 (COVID-19) has resulted in nationwide lockdowns, cessation of school and work, and social distancing. Reducing the negative impacts, such as weight-gain, has garnered global attention.Methods: In this dual-center retrospective observational study of 12,889 students (aged 18-20), who performed a national student physical fitness battery between December 1, 2019, to January 20, 2020, and completed a follow-up online questionnaire beginning on May 1, 2020, and ending on May 23, 2020, and examined the associations between weight-gain and COVID-19 induced stress, depression and self-reported physical activity, dietary habits and sedentary time. Results: Participants gained an average of 2.6 kg (95% CI: 2.0 to 3.2 kg) for males and 2.1 kg (1.9 to 2.4 kg) for females. An increase in overweight and obese individuals according to Asian cut-off points as a demographic percentage by 4.5% and 2.7% and 4.8% and 3.4% in males and females respectively (P<0.001). Weight change was associated with sedentary time, COVID-19 induced stress, and depression score. Conclusion: These findings suggest that limiting sedentary time during lockdowns and strategies aimed t improve lifestyle habits and psychological health may be warranted to mitigate weight-gain during the pandemic.Registration: Registered with ChiCTR, registration no.: ChiCTR2000033514