Non‐small‐cell lung cancer (NSCLC) has been recognized as a highly heterogeneous disease with phenotypic and genotypic diversity in each subgroup. While never‐smoker patients with NSCLC have been well studied through next generation sequencing, we have yet to recognize the potentially unique molecular features of young never‐smoker patients with NSCLC. In this study, we conducted whole genome sequencing (WGS) to characterize the genomic alterations of 36 never‐smoker Chinese patients, who were diagnosed with lung adenocarcinoma (LUAD) at 45 years or younger. Besides the well‐known gene mutations (e.g., TP53 and EGFR), our study identified several potential lung cancer‐associated gene mutations that were rarely reported (e.g., HOXA4 and MST1). The lung cancer‐related copy number variations (e.g., EGFR and CDKN2A) were enriched in our cohort (41.7%, 15/36) and the lung cancer‐related structural variations (e.g., EML4‐ALK and KIF5B‐RET) were commonly observed (22.2%, 8/36). Notably, new fusion partners of ALK (SMG6‐ALK) and RET (JMJD1C‐RET) were found. Furthermore, we observed a high prevalence (63.9%, 23/36) of potentially targetable genomic alterations in our cohort. Finally, we identified germline mutations in BPIFB1 (rs6141383, p.V284M), CHD4 (rs74790047, p.D140E), PARP1 (rs3219145, p.K940R), NUDT1 (rs4866, p.V83M), RAD52 (rs4987207, p.S346*), and MFI2 (rs17129219, p.A559T) were significantly enriched in the young never‐smoker patients with LUAD when compared with the in‐house noncancer database (p < 0.05). Our study provides a detailed mutational portrait of LUAD occurring in young never‐smokers and gives insights into the molecular pathogenesis of this distinct subgroup of NSCLC.

PD-1/PD-L1 inhibitors are generally safer and better tolerated than chemotherapy for patients with NSCLC with regard to summary toxic events, detailed toxic symptoms and hematologic toxicities. However, PD-1/PD-L1 inhibitors can generate a unique spectrum of irAEs, and several of them can be severe and even life-threatening. Clinicians should be aware of the risk of these AEs, as they may have a potentially negative impact on the patients' quality of life and survival outcome.

Investigations using Drosophila melanogaster have shown that the circadian clock gene period can influence behavioral responses to cocaine, and the mouse homologues, mPer1 and mPer2, modulate cocaine sensitization and reward. In the present study, we applied DNAzyme targeting mPer1 to interfere the expression of mPer1 in CNS in mice and studied the role of mPer1 on morphine dependence. We found that the DNAzyme could attenuate the expression of mPer1 in CNS in mice. Mice treated with DNAzyme and morphine synchronously did not show preference to the morphinetrained side, whereas the control group did. In contrast, mice treated with DNAzyme after morphine showed preference to the morphine-trained side as well as the control group did. These results indicate that drug dependence seems to be influenced at least partially by mPer1, but mPer1 cannot affect morphine dependence that has been formed. Keywords drug dependence; DNAzyme; learning and memory; circadian; i.c.v.Circadian clocks are molecular time-keeping mechanisms that reside in a diverse range of cell types in a variety of organisms. The primary role of these cell-autonomous clocks is to maintain their own approximately 24 h molecular rhythm and to drive the rhythmic expression of genes involved in physiology, metabolism and behavior. Components of the endogenous master clock were first identified in the fruit fly Drosophila melanogaster. The Period (Per) encodes one of the essential elements involved in the transcription/translation-based auto-regular loop of the endogenous master clock (Reppert and Weaver, 2001). Three homologues of Drosophila Per genes were subsequently identified in mice (mPer1, mPer2, and mPer3) (Albrecht, 2002), leading to great progress in elucidation of the molecular mechanism underlying circadian rhythm in the CNS.It has been shown that repeated administration of methamphetamine caused behavioral sensitization as well as sensitized expression of mPer1 (Nikaido et al., 2001). Some studies implicate a role for Per genes in drug-induced behavioral sensitization processes. This suggestion is supported by investigations using Drosophila flies. Flies mutant in the Per gene did not sensitize after repeated exposure to volatilized free-base cocaine (Andretic et al., 1999;Hirsh, 2001). In mice, the mPer1 and mPer2 genes influence cocaine-induced sensitization and reward in an opposite manner. The lack or dysfunction of the mPer1 gene *Corresponding author. Tel: +86-28-8550-2051; fax: +86-28-8550-3204. E-mail address: wangzhengrong@126.com (Z. Wang). abolishes cocaine sensitization and reward whereas the dysfunction of the mPer2 gene induces a hypersensitized response to cocaine (Abarca et al., 2002). NIH Public AccessDNAzyme is a suitable tool for studying gene function. The typical DNAzyme, known as the "10-23" model, is capable of cleaving single-stranded RNA at specific sites. The "10-23" model of DNAzymes has a catalytic domain of 15 highly conserved deoxyribonucleotides, flanked by two substrate-recognition domains, which can cl...

Aim To investigate whether conicity index, abdominal volume index, body adiposity index, body roundness index, cardiometabolic index and lipid accumulation product compared with waist circumference could predict future diabetes in a 15-year prospective study.Methods The data were collected in 1992 and recollected in 2007 from the same group of 687 individuals. Anthropometric indices and biochemical data were obtained. Cox's proportional hazards regression models were used to estimate the hazard ratios of anthropometric measures. The discriminatory power of anthropometric measures for incident diabetes were assessed by Harrell's C-statistic.Results During follow-up, 74 participants were newly diagnosed with diabetes. In multivariable Cox regression analysis after adjusting potential for confounders, log 10 -conicity index [HR: 1.67 (95% CI: 1.31-2.11) per SD; P < 0.0001], log 10 -abdominal volume index [HR: 1.95 (95% CI: 1.50-2.55) per SD; P < 0.0001], log 10 -body adiposity index [HR: 1.82 (95% CI: 1.33-2.50) per SD; P < 0.0001], log 10 -body roundness index [HR: 2.16 (95% CI: 1.63-2.88) per SD; P < 0.0001], log 10 -cardiometabolic index [HR: 1.70 (95% CI: 1.39-2.09) per SD; P < 0.0001], log 10 -lipid accumulation product [HR: 2.06 (95% CI: 1.56-2.73) per SD; P < 0.0001] and log 10 -waist circumference [HR: 1.99 (95% CI: 1.51-2.46) per SD; P < 0.0001] were significantly associated with incident diabetes. Additionally, lipid accumulation product had the highest Harrell's C-statistic at 0.715 (95% CI: 0.656-0.775), followed by body roundness index at 0.714 (95% CI: 0.658-0.770) and cardiometabolic index at 0.704 (95% CI: 0.643-0.764) then by waist circumference at 0.701 (95% CI: 0.644-0.759).Conclusions Conicity index, abdominal volume index, body adiposity index, body roundness index, cardiometabolic index and lipid accumulation product were independent predictors of future diabetes. The discriminatory power of body roundness index, cardiometabolic index and lipid accumulation product for diabetes prediction were higher than that of waist circumference.

Primary pulmonary lymphoepithelioma-like carcinoma (pLELC) is a rare non-small cell lung cancer (NSCLC) subtype. Clinical features have been described in our previous report, but molecular characteristics remain unclear. Herein, pLELC genomic features were explored. Among 41,574 lung cancers, 128 pLELCs and 162 non-pLELC NSCLCs were enrolled. Programmed cell death ligand 1 (PD-L1) and protein 53 (p53) expression was detected in 47 surgically resected pLELC samples by immunohistochemical assays. Multiomics genomic analyses, including whole-genome sequencing (WGS), RNA whole-transcriptome sequencing (RNA-seq), and Epstein-Barr virus (EBV) integration analyses, were performed on eight frozen pLELC tissues and compared with 50 lung adenocarcinomas (LUADs) and 50 lung squamous cell carcinomas (LUSCs) from The Cancer Genome Atlas (TCGA) and another 26 EBV-positive nasopharynx cancers (EBV+-NPCs). Progression-free survival (PFS) and overall survival (OS) of pLELC patients were better than those of non-pLELC patients. High PD-L1 or p53 expression was associated with extended disease-free survival (DFS). pLELC had 14 frequently mutated genes (FMGs). Somatically mutated genes and enrichment of genetic lesions were found, which differed from observations in LUAD, LUSC, and EBV+-nasopharyngeal carcinoma (NPC). Three tumor-associated genes, zinc finger and BTB domain-containing 16 (ZBTB16), peroxisome proliferator activated receptor gamma (PPARG), and transforming growth factor beta receptor 2 (TGFBR2), were downregulated with copy number variation (CNV) loss. EBV was prone to integrating into intergenic and intronic regions with two upregulated miR-BamH1-A rightward transcripts (BARTs), BART5-3P and BART20-3P. Our findings reveal that pLELC has a distinct genomic signature. Three tumor-associated genes with CNV loss and two miR-BARTs might be involved in pLELC tumorigenesis.