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Although epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) show efficacy in lung adenocarcinoma (LUAD) patients, TKI resistance inevitably develops, limiting long-term results. Thus, there is an urgent need to address drug resistance in LUAD. Long non-coding RNA (lncRNA) HIF1A-AS2 could be a critical mediator in the progression of various tumor types. We examined the function of HIF1A-AS2 in modifying tumor aggravation and osimertinib resistance in lung adenocarcinoma. Using clinical samples, we showed that HIF1A-AS2 was upregulated in LUAD specimens, predicting poorer overall survival and disease-free survival. HIF1A-AS2 silencing inhibited the proliferation, migration, and tumorigenesis of LUAD cells and therapeutic efficacy of osimertinib against tumor cells in vitro and in vivo. RNA precipitation assays, western blotting, luciferase assays, and rescue experiments demonstrated that HIF1A-AS2 sponged microRNA-146b-5p (miR-146b-5p), promoting interleukin-6 (IL-6) expression, activating the IL-6/STAT3 pathway, and leading to LUAD progression. miR-146b-5p and IL-6 levels were correlated with the prognosis of LUAD patients. Our results indicated that HIF1A-AS2 functions as an oncogenic factor in adenocarcinoma cells by targeting the miR-146b-5p/IL-6/STAT3 axis and may be a prognostic indicator of survival. Moreover, it can be a potential therapeutic target to enhance the efficacy of osimertinib in LUAD patients., Graphical abstract, EGFR-TKIs have exhibited notable therapeutic efficacy in lung adenocarcinoma (LUAD) patients. However, TKIs resistance inevitably develops. The study indicates that HIF1A-AS2 functions as an oncogenic factor by targeting the miR-146b-5p/IL-6/STAT3 axis and may be a potential therapeutic target to enhance the efficacy of osimertinib in LUAD patients.

Background The associations between blood lipids and DNA methylation have been investigated in epigenome-wide association studies mainly among European ancestry populations. Several studies have explored the direction of the association using cross-sectional data, while evidence of longitudinal data is still lacking. Results We tested the associations between peripheral blood leukocytes DNA methylation and four lipid measures from Illumina 450 K or EPIC arrays in 1084 participants from the Chinese National Twin Registry and replicated the result in 988 participants from the China Kadoorie Biobank. A total of 23 associations of 19 CpG sites were identified, with 4 CpG sites located in or adjacent to 3 genes (TMEM49, SNX5/SNORD17 and CCDC7) being novel. Among the validated associations, we conducted a cross-lagged analysis to explore the temporal sequence and found temporal associations of methylation levels of 2 CpG sites with triglyceride and 2 CpG sites with high-density lipoprotein-cholesterol (HDL-C) in all twins. In addition, methylation levels of cg11024682 located in SREBF1 at baseline were temporally associated with triglyceride at follow-up in only monozygotic twins. We then performed a mediation analysis with the longitudinal data and the result showed that the association between body mass index and HDL-C was partially mediated by the methylation level of cg06500161 (ABCG1), with a mediation proportion of 10.1%. Conclusions Our study indicated that the DNA methylation levels of ABCG1, AKAP1 and SREBF1 may be involved in lipid metabolism and provided evidence for elucidating the regulatory mechanism of lipid homeostasis.

Epidermal growth factor receptor tyrosine kinase inhibitors therapy, such as gefitinib, have proven to be effective for lung adenocarcinoma with epidermal growth factor receptor-sensitive mutations. However, drug resistance remains inevitable and the underlying mechanisms are still elusive and poorly understood. In order to explore the mechanisms underlying tyrosine kinase inhibitors resistance, we used long non-coding RNA microarray analysis and found that long non-coding RNA H19 was highly expressed in gefitinib-resistant cell lines. In addition, knockdown of long non-coding RNA H19 was found to be able to decrease cell proliferation, half maximal inhibitory concentration (IC50) of gefitinib, migration and invasion. Mechanistically, we demonstrated that long non-coding RNA H19 positively regulated dimethylarginine dimethylaminohydrolase-1 expression via sponging miR-148b-3p. Furthermore, overexpression or inactivation of miR-148b-3p could enhance or reverse the inhibitory effect of long non-coding RNA H19 inhibition in lung adenocarcinoma cells, respectively. High expression of either long non-coding RNA H19 or dimethylarginine dimethylaminohydrolase-1 was associated with poorer overall survival in patients with lung adenocarcinoma, while high expression of miR-148b was associated with better overall survival. Overall, our data revealed that long non-coding RNA H19 confers resistance to gefitinib via miR-148b/dimethylarginine dimethylaminohydrolase-1 axis in lung adenocarcinoma, which offers a new insight into the epidermal growth factor receptor tyrosine kinase inhibitors therapy resistance.

Objectives: Epidermal growth factor receptor-tyrosine kinase inhibitors are widely used for lung epidermal growth factor receptor-positive lung adenocarcinomas, but acquired resistance is inevitable. Although non-coding RNAs, such as circular RNA and microRNA, are known to play vital roles in epidermal growth factor receptor-tyrosine kinase inhibitor resistance, comprehensive analysis is lacking. Thus, this study aimed to explore the circular RNA-microRNA-messenger RNA regulatory network involved in epidermal growth factor receptor-tyrosine kinase inhibitor resistance. Methods: To identify differentially expressed genes between the epidermal growth factor receptor-tyrosine kinase inhibitor sensitive cell line PC9 and resistant cell line PC9/ epidermal growth factor receptor-tyrosine kinase inhibitor resistance(PC9/ER), circular RNA, microRNA and messenger RNA microarrays were performed. Candidates were then identified to construct a circular RNA-microRNA-messenger RNA network using bioinformatics. Additionally, Gene Oncology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were conducted to evaluate the network messenger RNA, setting up a protein-protein interaction network for hub-gene identification. Afterwards, RNA immunoprecipitation was performed to enrich microRNA, and quantitative real-time PCR was used to estimated gene expression levels. Results: In total, 603, 377, and 1863 differentially expressed circular RNA, microRNA, messenger RNAs, respectively, were identified using microarray analysis, constructing a circular RNA-microRNA-messenger RNA network containing 18 circular RNAs, 17 microRNAs and 175 messenger RNAs. Moreover, Gene Oncology and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that the most enriched biological process terms and pathways were related to epidermal growth factor receptor-tyrosine kinase inhibitor resistance, including Wnt and Hippo signaling pathways. Based on the competing endogenous RNA and protein-protein interaction network, circ-0007312 was showed to interact with miR-764 and both circ-0003748 and circ-0001398 were shown to interact with miR-628; both these microRNAs targeted MAPK1. Furthermore, circ-0007312, circ-0003748, circ-0001398, and MAPK1 were up-regulated, whereas miR-764 and miR-628 were downregulated in PC9/ER cells as compared to parental PC9 cells. We also found that circ-0007312 and miR-764 were positively expressed in plasma. Conclusions: Our original study associated with mechanism of target therapy in lung cancer provided a systematic and comprehensive regulation of circular RNA, microRNA and messenger RNA in epidermal growth factor receptor-tyrosine kinase inhibitor resistance. It was found that circ-0007312- miR-764-MAPK1, circ-0003748-miR-628-MAPK1, and circ-0001398-miR-628-MAPK1 axis may play key roles in epidermal growth factor receptor-tyrosine kinase inhibitor resistance.

Zekai Huang,1,* Shaolei Li,1,* Xin Yang,2 Fangliang Lu,1 Miao Huang,1 Shanyuan Zhang,1 Ying Xiong,1 Panpan Zhang,1 Jiahui Si,1 Yuanyuan Ma,1 Yue Yang1 1Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing 100142, China; 2Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing 100142, China *These authors contributed equally to this work Purpose: The role of neoadjuvant chemotherapy and subsequent adjuvant therapy in the treatment of patients with locally advanced esophageal squamous cell carcinomas (ESCC) is not well established.Patients and methods: We retrospectively reviewed 228 patients with locally advanced ESCC receiving esophagectomy following neoadjuvant chemotherapy from January 2007 through December 2016. The probabilities of disease-free survival (DFS) and overall survival (OS) were estimated by means of the Kaplan–Meier method and were compared with the use of the log-rank test. Univariate and multivariate analyses of predictors of DFS and OS were performed using a Cox proportional-hazards model. Propensity score matching analysis was performed for further analysis regarding the benefit of adjuvant therapy.Results: The pathological complete response of neoadjuvant chemotherapy was achieved in 13 of 228 patients (5.7%). With a median follow-up of 59.6 months, the median DFS and OS were 35.4 and 45.4 months, respectively. The multivariate Cox model determined chemotherapy regimens (P=0.003) and ypT category (P=0.006) were significant independent predictors of DFS; and chemotherapy regimens (P=0.001), ypT category (P

The study sought to explore novel genetic aberration driving squamous cell lung carcinoma (LUSC). The whole exome (WES), whole genome (WGS) and target region (TS) sequencings and CRISPR-Cas9 genome editing techniques were integrated to explore and validate novel targeting candidates from LUSC primary tumors and corresponding patient-derived xenografts (PDXs). Seven genes (FGFR2, GRM1,PIK3CG, PIK3CA,ZFHX4, CSMD3, GRM8) with high frequencies of both single nucleotide variants (SNVs) and copy number variants (CNVs), and two genes (CLDN1 and RIT1) only with CNVs were identified by bioinformatics analysis. The functions of these candidates were validated through CRISPR-Cas9 system in primary PDX cells. Furthermore, we focused on the genetic and functional analysis of Metabotropic glutamate receptor 8 (GRM8), whose transcriptional activation was elucidated to promote the survival of LUSC tumor cell through inhibiting cAMP pathway and activating MAPK pathway. The SNV identified in GRM8, A112G, activated downstream signaling pathway and induced cell proliferation, which could be reversed by cAMP stimulator and MEK inhibitor. In conclusion, the components of GRM8 signaling pathway could serve as potential targets of squamous cell lung cancer carrying GRM8 activating variants.

Adherence to healthy lifestyles is associated with reduced risk of coronary heart disease (CHD), but uncertainty persists about the underlying lipid pathway. In a case–control study of 4681 participants nested in the prospective China Kadoorie Biobank, 61 lipidomic markers in baseline plasma were measured by targeted nuclear magnetic resonance spectroscopy. Baseline lifestyles included smoking, alcohol consumption, dietary habit, physical activity, and adiposity levels. Genetic instrument was used to mimic the lipid-lowering effect of statins. We found that 35 lipid metabolites showed statistically significant mediation effects in the pathway from healthy lifestyles to CHD reduction, including very low-density lipoprotein (VLDL) particles and their cholesterol, large-sized high-density lipoprotein (HDL) particle and its cholesterol, and triglyceride in almost all lipoprotein subfractions. The statins genetic score was associated with reduced intermediate- and low-density lipoprotein, but weak or no association with VLDL and HDL. Lifestyle interventions and statins may improve different components of the lipid profile.

ObjectiveThe size distribution of circulating aneuploid cells (CACs) and its clinical significance were investigated in resectable non-small cell lung cancer (NSCLC).Patients and MethodsA total of 50 patients with resectable NSCLC were enrolled in this study. Blood samples (50 pre-surgery and 35 post-surgery) were collected and used for the detection of CAC chromosome 8 heteroploidy through the subtraction enrichment and immunostaining fluorescence in situ hybridization (SE-iFISH) method.ResultsLess than 20% small cell size and more than 80% large cell size CACs were detected. Karyotypes, including triploid, tetraploid, and multiploid, had varying distributions. The triploid subtype accounted for the majority of small cell size CACs, whereas the multiploid subtype accounted for the majority of large cell size CACs. We found that total small cell size and triploid small cell size CACs, but not large cell size CACs, derived from pre-surgery samples, were associated with shorter disease-free survival. Moreover, total small cell size and triploid small cell size CACs were associated with higher TNM stage and recurrence. Nevertheless, the variation between pre- and post-surgery CACs was not related to survival among patients with resectable NSCLC.ConclusionsPre-surgery small cell size CACs, especially the triploid subtype, could be regarded as a potential prognostic biomarker for patients with resectable NSCLC.

Additional file 1: Table S1. QRT-PCR primer sequences. Table S2. EGFR mutations in lung adenocarcinoma patients. Table S3. EGFR mutations in lung adenocarcinoma cells. Table S4. mTOR signaling pathway enrichment in the PC9 cells with shisa3 knock-down. Table S5. Cell cycle signaling pathway enrichment in the PC9 cells with shisa3 knock-down. Figure S1. PC9/ER cells resistant to EGFR-TKIs induce CSC phenotype. Figure S2. Shisa3 decreases EGFR-TKI resistance and inhibits the CSC phenotype. Figure S3. EGFR-TKI inhibits tumor growth derived from PC9 cells in vivo.

Background Existing evidence remains inconclusive as to the association between chronic hepatitis B virus (HBV) infection and the risk of chronic kidney disease (CKD). We prospectively examined the association between chronic HBV infection and CKD risk, and the joint associations of HBV infection with established risk factors of several lifestyle factors and prevalent diseases on CKD risk. Methods Participants from the China Kadoorie Biobank were enrolled during 2004–2008 and followed up until 31 December 2015. After excluding participants with previously diagnosed CKD, cancer, heart disease, and stroke at baseline, the present study included 469,459 participants. Hepatitis B surface antigen (HBsAg) was qualitatively tested at baseline. Incident CKD cases were identified mainly through the health insurance system and disease and death registries. Results During a median follow-up of 9.1 years (4.2 million person-years), we documented 4555 incident cases of CKD. Cox regression yielded multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Compared with HBsAg-negative participants, the multivariable-adjusted HR (95% CI) for CKD was 1.37 (1.18, 1.60) for HBsAg-positive participants. The association was stronger in men (HR = 1.77; 95% CI: 1.43, 2.20) than in women (HR = 1.10; 95% CI: 0.88, 1.36). HBsAg-positive participants, with or without hepatitis or cirrhosis, whether or not under treatment, all showed increased risk of developing CKD. We observed positive additive interactions of HBsAg positivity with smoking, physical inactivity, or diabetes on CKD risk. Compared with HBsAg-negative participants who were nonsmokers, more physically active, or did not have diabetes at baseline, the greatest CKD risk for HBsAg-positive participants was for those who were smokers (HR = 1.85; 95% CI: 1.44, 2.38), physically inactive (HR = 1.91; 95% CI: 1.52, 2.40), or diabetic (HR = 6.11; 95% CI: 4.47, 8.36). Conclusions In countries with a high endemicity of HBV infection, kidney damage associated with chronic HBV infection should be a non-negligible concern. Our findings also highlight the importance of health advice on quitting smoking, increasing physical activity, improving glucose control, and early screening for CKD in people with chronic HBV infection. Electronic supplementary material The online version of this article (10.1186/s12916-018-1084-9) contains supplementary material, which is available to authorized users.

ObjectiveTo examine the associations between egg consumption and cardiovascular disease (CVD), ischaemic heart disease (IHD), major coronary events (MCE), haemorrhagic stroke as well as ischaemic stroke.MethodsDuring 2004–2008, over 0.5 million adults aged 30–79 years were recruited from 10 diverse survey sites in China. Participants were asked about the frequency of egg consumption and were followed up via linkages to multiple registries and active investigation. Among 461 213 participants free of prior cancer, CVD and diabetes, a total of 83 977 CVD incident cases and 9985 CVD deaths were documented, as well as 5103 MCE. Stratified Cox regression was performed to yield adjusted hazard ratios for CVD endpoints associated with egg consumption.ResultsAt baseline, 13.1% of participants reported daily consumption (usual amount 0.76 egg/day) and 9.1% reported never or very rare consumption (usual amount 0.29 egg/day). Compared with non-consumers, daily egg consumption was associated with lower risk of CVD (HR 0.89, 95% CI 0.87 to 0.92). Corresponding multivariate-adjusted HRs (95% CI) for IHD, MCE, haemorrhagic stroke and ischaemic stroke were 0.88 (0.84 to 0.93), 0.86 (0.76 to 0.97), 0.74 (0.67 to 0.82) and 0.90 (0.85 to 0.95), respectively. There were significant dose-response relationships of egg consumption with morbidity of all CVD endpoints (P for linear trend ConclusionAmong Chinese adults, a moderate level of egg consumption (up to

Activation of c-Met plays a critical role in tumorigenesis, migration and invasion in lung cancer. Here, we explored the therapeutic efficacy of a novel small-molecule c-Met inhibitor (BPI-9016M) in lung adenocarcinoma and investigated the underlying molecular mechanisms. Method: BPI-9016M, a c-Met tyrosine kinase receptor inhibitor, was used to treat patient-derived xenografts (PDX) from lung adenocarcinoma in NOD/SCID mice. Immunohistochemistry and Western blot analysis were used to determine the expression of c-Met and its downstream signaling molecules. CCK8, wound healing, and trans-well assays were used to analyze cell proliferation, spreading, migration and invasion. RNA sequencing and quantitative real-time PCR (qPCR) was used to screen and validate the expression of downstream genes in lung adenocarcinoma cells treated with BPI-9016M. Luciferase reporter assay was used to detect the interaction between miRNA and the targeted gene. Results: BPI-9016M significantly suppressed growth in three out of four lung adenocarcinoma PDX models, particularly in the tumors with high expression of c-Met. In lung adenocarcinoma cell lines, BPI-9016M treatment resulted in increased miR203, which reduced migration and invasion and also repressed Dickkopf-related protein 1 (DKK1) expression. Forced overexpression of DKK1 or down-regulation of miR203 reversed the inhibitory effect of BPI-9016M on migration and invasion. C-Met was verified to positively and negatively associate with DKK1 and miR203, respectively. High expression of c-Met/DKK1 or low expression of miR203 related to poor outcome of lung adenocarcinoma patients. Furthermore, we observed significantly enhanced tumor cell growth inhibition upon combining BPI-9016M treatment with miR203 mimics or DKK1 siRNA. Conclusion: Our data indicated that BPI-9016M is an effective agent against lung adenocarcinoma, particularly in tumors with c-Met activation, and likely functions through upregulation of miR203 leading to reduced DKK1 expression.

ObjectiveTo comprehensively examine the potential impacts of prenatal experience of the Chinese Great Famine on chronic disease risks in the middle age.MethodsThis study included 92 284 participants aged 39–51 years from China Kadoorie Biobank born around the famine period and without major chronic diseases at baseline. We categorised participants into non-famine births (born between 1 October 1956 and 30 September 1958, and 1 October 1962 and 30 September 1964) and famine births (born between 1 October 1959 and 30 September 1961). The outcomes were incident cardiovascular disease, cancer and respiratory system disease. Cox regression was used to estimate adjusted HR and 95% CI for famine exposure. Subgroup analyses were performed according to baseline characteristics.ResultsDuring a median 10.1 years of follow-up, we identified 4626 incident ischaemic heart disease (IHD) cases, 7332 cerebrovascular disease cases, 3111 cancer cases and 16 081 respiratory system disease cases. In the whole population, prenatal famine exposure was not statistically associated with the risks of developing any chronic diseases in adulthood. However, for urban participants, compared with non-famine births, famine births had a higher risk of cerebrovascular disease (HR 1.18; 95% CI 1.09 to 1.28); such association was not shown for rural participants (p for interaction ConclusionOur findings indicate that prenatal exposure to the Chinese famine might be associated with an increased cardiovascular risk and such risk may be modified by adult lifestyle.

BackgroundLung function is a heritable complex phenotype with obesity being one of its important risk factors. However, knowledge of their shared genetic basis is limited. Most genome-wide association studies (GWASs) for lung function have been based on European populations, limiting the generalisability across populations. Large-scale lung function GWASs in other populations are lacking.MethodsWe included 100 285 subjects from the China Kadoorie Biobank (CKB). To identify novel loci for lung function, single-trait GWAS analyses were performed on forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC in the CKB. We then performed genome-wide cross-trait analysis between lung function and obesity traits (body mass index (BMI), BMI-adjusted waist-to-hip ratio and BMI-adjusted waist circumference) to investigate the shared genetic effects in the CKB. Finally, polygenic risk scores (PRSs) of lung function were developed in the CKB and their interaction with BMI's association on lung function were examined. We also conducted cross-trait analysis in parallel with the CKB using up to 457 756 subjects from the UK Biobank (UKB) for replication and investigation of ancestry-specific effects.ResultsWe identified nine genome-wide significant novel loci for FEV1, six for FVC and three for FEV1/FVC in the CKB. FEV1 and FVC showed significant negative genetic correlation with obesity traits in both the CKB and UKB. Genetic loci shared between lung function and obesity traits highlighted important biological pathways, including cell proliferation, embryo, skeletal and tissue development, and regulation of gene expression. Mendelian randomisation analysis suggested significant negative causal effects of BMI on FEV1 and on FVC in both the CKB and UKB. Lung function PRSs significantly modified the effect of change in BMI on change in lung function during an average follow-up of 8 years.ConclusionThis large-scale GWAS of lung function identified novel loci and shared genetic aetiology between lung function and obesity. Change in BMI might affect change in lung function differently according to a subject's polygenic background. These findings may open new avenues for the development of molecular-targeted therapies for obesity and lung function improvement.

BACKGROUND The immune checkpoint of programmed cell death ligand 1 (PD-L1) commonly expressed in solid cancers, and the blockade of this molecule show promising results in advanced cancers, including lung cancer. The relevance of PD-L1 to patient-derived xenograft (PDX) formation and clinicopathological characteristics in early stage lung cancer have not been fully elucidated. MATERIAL AND METHODS Cell counting kit-8 and flow cytometry were carried out to examine proliferation and apoptosis in PC9 and H520 cells transfected with siRNAs. Nod-scid mice were used to establish PDX. Immunohistochemistry was done to investigate PD-L1 expression in tumor tissues. RESULTS PD-L1 was detected in lung cancer cell lines and 45.45% of primary tumor tissues from a cohort of 209 lung cancer patients. Cell growth was restrained and apoptosis was induced when PD-L1 was inhibited in PC9 and H520 cells. In addition, we successfully established 16 PDX models from tissues from 43 cases of primary lung cancer. Higher PD-L1 expression rates (75%) was observed in primary tumors with PDX formation compared to protein expression rate (44.44%) in tumors without PDX formation. Consistently, a 1.9-fold increase of PDX formation frequency was identified in the PD-L1 positive tumors than in the PD-L1 negative tumors. Moreover, PD-L1 was found to be related to smoking, histological type, and pathological stage. Importantly, PD-L1 overexpression was associated with shorter overall survival (OS) of lung cancer patients. CONCLUSIONS This study suggests that overexpression of PD-L1 could induce PDX formation and is related to poor outcome for the lung cancer patients.

Acquired resistance to standard chemotherapy causes treatment failure in patients with local advanced and advanced non-small lung cancer (NSCLC). Cancer stem cells (CSCs) are a small subpopulation within cancer that is thought to be resistant to conventional chemotherapy. The Notch pathway is one of the most intensively studied for putative therapeutic targets of CSCs in solid tumors. In our study, suppression of Notch3 decreased colony and sphere formation of stem-like property in lung cancer cells. In addition, Notch3 expression was demonstrated to be upregulated in the patients with chemoresistance and related to poor prognosis of NSCLC patients. Our results also showed that CSC markers ALDH1A1 and CD44 were highly expressed in NSCLC patients with chemoresistance and these two markers were positively correlated with Notch3 expression in lung cancer specimens from TCGA database. Furthermore, the lung cancer cells with drug resistance were shown to be associated with activation of autophagy. All the data support a crucial role of Notch3 in the increase of stem-like property in NSCLC cells that might be associated with upregulation of ALDH1A1 and CD44 and activation of autophagy.

Aims/hypothesis Season of birth as a surrogate for potential environmental exposure during fetal development and early postnatal life has shown an inconsistent association with adult type 2 diabetes in white populations living in high-latitude regions. The present study aimed to examine the association between birth seasonality and risk of adult type 2 diabetes in Chinese individuals living across wide regions of low latitude and lower to middle latitude. Methods Participants from the China Kadoorie Biobank were enrolled during 2004–2008 and followed up until 31 December 2013. After excluding participants with cancer, heart disease, stroke and diabetes at baseline, the present study included 189,153 men and 272,058 women aged 30–79 years. We used multivariable Cox proportional hazards model to estimate the HR and 95% CI. Results During a median follow-up of 7.2 years (3.3 million person-years), we documented 8784 incident cases of type 2 diabetes. In the whole cohort, compared with summer-born participants, the adjusted HRs (95% CIs) were 1.09 (1.02, 1.16), 1.08 (1.02, 1.15) and 1.09 (1.02, 1.15) for those who were born in Spring, Autumn and Winter, respectively. The association was consistent in both men and women and across subgroups defined by residence and lifestyle factors later in life. Conclusions/interpretation In this large prospective study, participants born in summer had a lower risk of adult type 2 diabetes compared with other seasons of birth, suggesting exposures in early life with some degree of seasonal variation might influence the risk of adult diabetes. Electronic supplementary material The online version of this article (doi:10.1007/s00125-016-4200-4) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Background Considering neoadjuvant chemotherapy (NAC) prior to surgery could shrink and reduce the primary tumor and distant micro-metastases to reduce the high relapses rates, NAC has been an accepted therapeutic management for patients with non-small cell lung cancer (NSCLC). CMTM1_v17 is highly expressed in human testis tissues and solid tumor tissues but relatively low expression was obtained in the corresponding normal tissues. This study aims to investigate the significance of CMTM1_v17 in NSCLC and its association with platinum-based NAC efficacy. Methods 31 pairs of tumor tissues before and after NAC and 78 resected tumor tissues after NAC were utilized for immunohistochemistry (IHC) staining of CMTM1_v17 protein. The correlation between CMTM1_v17 expression and chemotherapy efficacy was analyzed. The prognostic value of CMTM1_v17 index for disease-free survival (DFS) and overall survival (OS) was analyzed using Kaplan-Meier survival and multivariable Cox regression. Results CMTM1_v17 expression was related to treatment effect and outcome in tumor tissues after NAC not before NAC from 31 cases of NSCLC. We identified that high CMTM1_v17 expression was associated with low objective remission rate (ORR) (P = 0.008) and poor prognosis (the median OS: 35.1 months vs 65.6 months, P = 0.0045; the median DFS: 17.27 months vs 35.54 months, P = 0.0207) in the 31 patients. Next, we detected CMTM1_v17 expression to confirm correlation between this protein status and clinical characteristics in 78 NSCLC patients with NAC treatment. The upregulation of CMTM1_v17 had a higher SD rate (P = 0.007) and worse outcome (the median OS: 41.0 months vs 80.6 months, P = 0.0028; the median DFS: 33.4 vs 64.8 months, P = 0.0032). COX multivariate analysis indicated that CMTM1_v17 is an independent prognostic risk factor on patients who have received NAC (OS: HR = 3.642, P = 0.002; DFS:HR = 3.094, P = 0.002). Conclusions CMTM1_v17 expression is significantly associated with chemoresistance and poor prognosis of the early stage NSCLC patients who have received NAC.

ObjectivesChronic hepatitis B virus (HBV) infection is associated with a higher risk of liver diseases. Substantial uncertainty remains, however, about the associations of HBV infection with mortality from extrahepatic causes, especially from subtypes of cardiovascular diseases. We prospectively examined the association of chronic HBV infection with total and cause-specific mortality.DesignPopulation-based prospective cohort study.SettingChina Kadoorie Biobank in which participants from 10 geographically diverse areas across China were enrolled between 2004 and 2008.Participants475 801 participants 30–79 years of age without reporting major chronic diseases at baseline were enrolled. Hepatitis B surface antigen (HBsAg) was tested using an on-site rapid test strip at baseline.Primary and secondary outcome measuresTotal and cause-specific mortality.ResultsA total of 35 822 deaths were recorded during ~10 years of follow-up. In multivariable-adjusted analyses, compared with HBsAg-negative participants, HBsAg-positive participants had an increased risk of total mortality (HR=2.01, 95% CI: 1.91 to 2.12), which was higher in men (HR=2.16, 95% CI: 2.01 to 2.31) than in women (HR=1.74, 95% CI: 1.60 to 1.90). Presence of HBsAg was associated with increased mortality from liver cancer (1339 deaths, HR=13.95, 95% CI: 12.46 to 15.62), infections (410 deaths, HR=10.30, 95% CI: 8.21 to 12.94), digestive diseases (688 deaths, HR=6.83, 95% CI: 5.49 to 8.50), intracerebral haemorrhage (4077 deaths, HR=1.38, 95% CI: 1.14 to 1.68) and ischaemic heart diseases (4624 deaths, HR=1.31, 95% CI: 1.09 to 1.58). The positive association between HBsAg status and risk of death was stronger in participants younger than 50 years, smokers, physically active or non-hypertensive participants.ConclusionsAmong Chinese adults, chronic HBV infection was associated with increased mortality from a range of hepatic and extrahepatic diseases.

Objective To prospectively examine the association between tea consumption and the risk of ischaemic heart disease (IHD). Methods Prospective study using the China Kadoorie Biobank; participants from 10 areas across China were enrolled during 2004–2008 and followed up until 31 December 2013. After excluding participants with cancer, heart disease and stroke at baseline, the present study included 199 293 men and 288 082 women aged 30–79 years at baseline. Information on IHD incidence was collected through disease registries and the new national health insurance databases. Results During a median follow-up of 7.2 years, we documented 24 665 (7.19 cases/1000 person-years) incident IHD cases and 3959 (1.13 cases/1000 personyears) major coronary events (MCEs). Tea consumption was associated with reduced risk of IHD and MCE. In the whole cohort, compared with participants who never consumed tea during the past 12 months, the multivariable-adjusted HRs and 95% CIs for less than daily and daily tea consumers were 0.97 (0.94 to 1.00) and 0.92 (0.88 to 0.95) for IHD, 0.92 (0.85 to 1.00) and 0.90 (0.82 to 0.99) for MCE. No linear trends in the HRs across the amount of tea were observed in daily consumers for IHD and MCE (PLinear >0.05). The inverse association between tea consumption and IHD was stronger in rural (PInteraction 0.006 for IHD, Conclusions In this large prospective study, daily tea consumption was associated with a reduced risk of IHD.

Table. Association between HBsAg status and risk of chronic kidney disease by potential baseline risk factors for 469,459 participants. (DOCX 19 kb)

Table. HRs (95% CIs) for incident chronic kidney disease according to HBsAg status and presence of chronic hepatitis or cirrhosis and its duration for 469,459 participants. (DOCX 17 kb)

Text. Members of the China Kadoorie Biobank collaborative group. (DOCX 17 kb)

Table. HRs (95% CIs) for incident chronic kidney disease according to HBsAg status and presence of chronic hepatitis or cirrhosis and its duration for 469,459 participants. (DOCX 17 kb)

Table. Association between HBsAg status and risk of chronic kidney disease by potential baseline risk factors for 469,459 participants. (DOCX 19 kb)