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Background: Circular RNAs (circRNAs) play important roles in regulating the radioresistance of esophageal squamous cell carcinoma (ESCC). This study aimed to determine the role of hsa_circRNA_100367 in regulating radioresistance of ESCC. Results: Higher expression and potency of endothelial to mesenchymal transformation (EMT) was found in radioresistant ESCC cells (KYSE-150R) than in ESCC cells (KYSE-150). Silencing circRNA_100367 inhibited the proliferation and migration of KYSE-150R cells, and decreased the expression of β-catenin (an important molecule in Wnt pathway) in KYSE-150R cells. Additionally, circRNA_100367 bound to miR-217, and miR-217 targeted Wnt3. Low Wnt3 expression was associated with the short survival time in patients with ESCC and Wnt3 knockdown inhibited the proliferation and migration of KYSE-150R cells. CircRNA_100367 enhanced the radioresistance of KYSE-150R cells through miR-217/Wnt3 pathway. In vivo, circRNA_100367 silence reduced the growth of KYSE-150R cells under radiation. Conclusion: Our results revealed that circRNA_100367 attenuated radioresistance of ESCC through miR-217/Wnt3 pathway. Methods: CircRNAs related with the radioresistance of ESCC were analyzed by hierarchical cluster analysis. The relationship between circRNA_100367 and miR-217, Wnt3 was detected by RNA immunoprecipitation (RIP), RNA pull-down and luciferase reporte assays. The proliferation and migration ESCC cells were detected by MTT, Transwell and colony formation assays.

IntroductionPulmonary arterial hypertension (PAH) is a life-limiting condition characterized by progressive vascular obliteration leading to right heart failure and ultimately death. Recent research has highlighted altered cellular and systemic metabolism as a key feature promoting pulmonary vascular disease and right heart BACKGROUND. Pulmonary arterial hypertension (PAH) is a deadly disease of the small pulmonary vasculature with an increased prevalence of insulin resistance (IR). Insulin regulates both glucose and lipid homeostasis. We sought to quantify glucose-and lipid-related IR in human PAH, testing the hypothesis that lipoprotein indices are more sensitive indices of IR in PAH. METHODS.Oral glucose tolerance testing in PAH patients and triglyceride-matched (TG-matched) controls and proteomic, metabolomics, and lipoprotein analyses were performed in PAH and controls. Results were validated in an external cohort and in explanted human PAH lungs. RESULTS. PAH patients were similarly glucose intolerant or IR by glucose homeostasis metrics compared with control patients when matched for the metabolic syndrome. Using the insulinsensitive lipoprotein index, TG/HDL ratio, PAH patients were more commonly IR than controls. Proteomic and metabolomic analysis demonstrated separation between PAH and controls, driven by differences in lipid species. We observed a significant increase in long-chain acylcarnitines, phosphatidylcholines, insulin metabolism-related proteins, and in oxidized LDL receptor 1 (OLR1) in PAH plasma in both a discovery and validation cohort. PAH patients had higher lipoprotein axis-related IR and lipoprotein-based inflammation scores compared with controls. PAH patient lung tissue showed enhanced OLR1 immunostaining within plexiform lesions and oxidized LDL accumulation within macrophages.CONCLUSIONS. IR in PAH is characterized by alterations in lipid and lipoprotein homeostasis axes, manifest by elevated TG/HDL ratio, and elevated circulating medium-and long-chain acylcarnitines and lipoproteins. Oxidized LDL and its receptor OLR1 may play a role in a proinflammatory phenotype in PAH.

IMPORTANCEAgents targeting programmed cell death 1 (PD-1)/PD ligand 1 (PD-L1) improve long-term survival across many advanced cancers and are now used as adjuvant therapy for resected stage III and IV melanomas. The incidence and spectrum of chronic immune-related adverse events (irAEs) have not been well defined.OBJECTIVE To determine the incidence, time course, spectrum, and associations of chronic irAEs arising from adjuvant anti-PD-1 therapy. DESIGN, SETTING, AND PARTICIPANTSThis retrospective multicenter cohort study was conducted between 2015 and 2020 across 8 academic medical centers in the United States and Australia. Patients with stage III to IV melanomas treated with anti-PD-1 in the adjuvant setting were included.MAIN OUTCOMES AND MEASURES Incidence, types, and time course of chronic irAEs (defined as irAEs persisting at least 12 weeks after therapy cessation). RESULTS Among 387 patients, the median (range) age was 63 (17-88) years, and 235 (60.7%) were male. Of these patients, 267 (69.0%) had any acute irAE, defined as those arising during treatment with anti-PD-1, including 52 (19.5%) with grades 3 through 5 events; 1 patient each had fatal myocarditis and neurotoxicity. Chronic irAEs, defined as those that persisted beyond 12 weeks of anti-PD-1 discontinuation, developed in 167 (43.2%) patients, of which most (n = 161; 96.4%) were mild (grade 1 or 2) and most persisted until last available follow-up (n = 143; 85.6%). Endocrinopathies (73 of 88; 83.0%), arthritis (22 of 45; 48.9%), xerostomia (9 of 17; 52.9%), neurotoxicities (11 of 15; 73.3%), and ocular events (5 of 8; 62.5%) were particularly likely to become chronic. In contrast, irAEs affecting visceral organs (liver, colon, lungs, kidneys) had much lower rates of becoming chronic irAEs; for example, colitis became chronic in 6 of 44 (13.6%) cases, of which 4 of 6 (66.7%) resolved with prolonged follow-up. Age, gender, time of onset, and need for steroids were not associated with the likelihood of chronicity of irAEs. CONCLUSION AND RELEVANCEIn this multicenter cohort study, chronic irAEs associated with anti-PD-1 therapy appear to be more common than previously recognized and frequently persisted even with prolonged follow-up, although most were low grade. The risks of chronic irAEs should be integrated into treatment decision-making.

HOTAIR promoted cervical cancer cell growth by modulating BCL2 via miR-143-3p, hinting a novel regulatory mechanism and potential therapeutic target in cervical cancer.