Background Checkpoint-blockade immunotherapy targeting programmed cell death protein 1 (PD-1) has recently shown promising efficacy in hepatocellular carcinoma (HCC). However, the factors affecting and predicting the response to anti-PD-1 immunotherapy in HCC are still unclear. Herein, we report the dynamic variation characteristics and specificities of the gut microbiome during anti-PD-1 immunotherapy in HCC using metagenomic sequencing. Results Fecal samples from patients responding to immunotherapy showed higher taxa richness and more gene counts than those of non-responders. For dynamic analysis during anti-PD-1 immunotherapy, the dissimilarity of beta diversity became prominent across patients as early as Week 6. In non-responders, Proteobacteria increased from Week 3, and became predominant at Week 12. Twenty responder-enriched species, including Akkermansia muciniphila and Ruminococcaceae spp., were further identified. The related functional genes and metabolic pathway analysis, such as carbohydrate metabolism and methanogenesis, verified the potential bioactivities of responder-enriched species. Conclusions Gut microbiome may have a critical impact on the responses of HCC patients treated with anti-PD-1 immunotherapy. The dynamic variation characteristics of the gut microbiome may provide early predictions of the outcomes of immunotherapy in HCC, which is critical for disease-monitoring and treatment decision-making. Electronic supplementary material The online version of this article (10.1186/s40425-019-0650-9) contains supplementary material, which is available to authorized users.
BPA was positively associated with generalized obesity, abdominal obesity, and insulin resistance in middle-aged and elderly Chinese adults.
The associations between PSI and the lower prevalence of diabetes and a better metabolic profile in rural Chinese need to be confirmed in other populations. If confirmed, the protecting effect of helminth infection could be reconsidered in terms of therapeutic strategies for the treatment of diabetes and metabolic diseases.
BackgroundP73 antisense RNA 1 T (non-protein coding), also known as TP73-AS1, is a long non-coding RNA (lncRNA) which is involved in cell proliferation and the development of tumors. However, the exact effects and molecular mechanisms of TP73-AS1 in hepatocellular carcinoma (HCC) progression are still unknown. The present study is aimed to investigate the detailed functions and the mechanism of TP73-AS1 in regulation of HCC cell proliferation.MethodsTP73-AS1 expression in HCC tissues and cell lines was determined using real-time PCR assays; the correlation of TP73-AS1 expression with clinicopathological features of HCC was analyzed. The functions of TP73-AS1 in regulation of HCC cell proliferation was evaluated using MTT and BrdU assays. The candidate upstream miRNAs of HMGB1 were screened using miRcode, miRWalk, miRanda and Target scan, verified using real-time PCR assays. The interaction between TP73-AS1 and miR-200a was confirmed using Luciferase report gene assays. The proten levels of HMGB1 signaling-related factors in response to co-processing TP73-AS1 knockdown and miR-200a inhibition were determined using Western blot assays and ELISA. Further, miR-200a, HMGB1 mRNA and RAGE mRNA and their correlations in HCC tissues were determined.ResultsTP73-AS1 was upregulated in HCC tissues and cell lines. High TP73-AS1 expression was correlated with worse clinicopathological features, poorer prognosis and shorter survival. Knockdown of TP73-AS1 inhibited the HCC proliferation and the expression levels of HMGB1, RAGE and NF-κB in HCC cells. By using online tools, we screened out several candidate upstream miRNAs of HMGB1, among which miR-200a overexpression inhibited HMGB1 mRNA expression the most significantly. By using luciferase assays, we confirmed that miR-200a could directly bind to TP73-AS1 and the 3’UTR of HMGB1; TP73-AS1 competed with HMGB1 for miR-200a binding. MiR-200a inhibition could up-regulate HMGB1, RAGE, NF-κB expression as well as NF-κB regulated cytokines levels, which could be partially restored by si-TP73-AS1. In HCC tissues, miR-200a was down-regulated while HMGB1 and RAGE were up-regulated; TP73-AS1 was inversely correlated with miR-200a, while positively correlated with HMGB1 and RAGE, respectively.ConclusionOur data indicated that TP73-AS1 might be an oncogenic lncRNA that promoted proliferation of HCC and could be regarded as a therapeutic target in human HCC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-017-0519-z) contains supplementary material, which is available to authorized users.
Papillary thyroid carcinoma susceptibility candidate 3 (PTCSC3) is a newly identified non-coding RNA, which is highly thyroid-specific. Dramatic downregulation in thyroid cancers suggests its potential roles in the occurrence and development of thyroid tumors. The present study aimed to investigate the effects of PTCSC3 on the biological features of thyroid cancer cells and to explore its possible function as a competing endogenous RNA to bind with miRNAs. Constructs containing the long non-coding RNA, PTCSC3, were transfected into various thyroid cancer cell lines (BCPAP, FTC133 and 8505C). Cell growth, cell cycle transition and apoptosis were measured by MTT assay and flow cytometry. In silico analysis was performed to identify the binding site of PTCSC3 for target miRNAs. Additionally, detection of putative miRNA by quantitative reverse transcription-polymerase chain reaction (RT-PCR) in thyroid cancer cells transfected with PTCSC3 was determined to confirm the interaction. Following transfection with PTCSC3, all three thyroid cancer cells originating from various pathological types of thyroid cancers demonstrated significant growth inhibition, cell cycle arrest and increased apoptosis. The top 20 miRNAs to have a potential interaction with PTCSC3 were identified, out of which miR-574-5p was selected to further confirm the inverse correlation with PTCSC3 in thyroid cancer cells in vitro. In the present study, PTCSC3 as a tumor suppressor was investigated as a competing endogenous RNA for miR-574-5p.
These findings do not confirm a previously reported association between urinary bisphenol A levels and self-reported type 2 diabetes.
BackgroundMany susceptible loci for type 2 diabetes mellitus (T2DM) have recently been identified from Caucasians through genome wide association studies (GWAS). We aimed to determine the association of 11 known loci with T2DM and impaired glucose regulation (IGR), individually and in combination, in Chinese.Methods/Principal FindingsSubjects were enrolled in: (1) a case-control study including 1825 subjects with T2DM, 1487 with IGR and 2200 with normal glucose regulation; and (2) a prospective cohort with 734 non-diabetic subjects at baseline. The latter was followed up for 3.5 years, in which 67 subjects developed T2DM. Nineteen single nucleotide polymorphisms (SNPs) were selected to replicate in both studies. We found that CDKAL1 (rs7756992), SLC30A8 (rs13266634, rs2466293), CDKN2A/2B (rs10811661) and KCNQ1 (rs2237892) were associated with T2DM with odds ratio from 1.21 to 1.35. In the prospective study, the fourth quartile of risk scores based on the combined effects of the risk alleles had 3.05 folds (95% CI, 1.31–7.12) higher risk for incident T2DM as compared with the first quartile, after adjustment for age, gender, body mass index and diabetes family history. This combined effect was confirmed in the case-control study after the same adjustments. The addition of the risk scores to the model of clinical risk factors modestly improved discrimination for T2DM by 1.6% in the case-control study and 2.9% in the prospective study.Conclusions/SignificanceOur study provided further evidence for these GWAS derived SNPs as the genetic susceptible loci for T2DM in Chinese and extended this association to IGR.
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