Dynamics and correlations in multiplex immune profiling reveal persistent immune inflammation in male drug users after withdrawal.

Drug withdrawal elicits immune responses that contribute to the development of withdrawal symptoms and relapse. The understanding of the immunologic dynamics after drug withdrawal is limited, precluding the finding of promising immune intervention measures. Here, we performed cytokine and multiplex immune profiling in heroin, methamphetamine (METH) and ephedrine users after withdrawal and identified the correlation between cytokines and other immune parameters. We showed that broad and strong inflammatory responses occurred at the early stage after drug withdrawal, and the inflammatory responses showed a downtrend with the extension of withdrawal time. Notably, immune dysregulation remained through and may last longer than 12 months after withdrawal in heroin and METH users. Our findings suggest that cytokines, immune cells, complement and immunoglobulin form a complex immune network that regulates immune responses after withdrawal. These data provide a reference for future scientific research and drug research and development.

Long noncoding RNA XIST regulates the EGF receptor to promote TGF-ß1-induced epithelial-mesenchymal transition in pancreatic cancer.

BACKGROUND: This study focuses on the lncRNA XIST (X inactive-specific transcript), an lncRNA involved in multiple human cancers, and investigates the functional significance of XIST and the molecular mechanisms underlying the epithelial-mesenchymal transition (EMT) in pancreatic cancer (PC). METHODS: Clinical specimens from 25 patients as well as 5 human PC cell lines were analyzed for XIST, YAP, and microRNA(miR)-34a by quantitative real-time PCR (qRT-PCR) and immunohistochemistry. To investigate how XIST influences cell proliferation, invasiveness, and apoptosis in PC, we performed the CCK-8 assays, Transwell assays, and flow cytometry. Luciferase reporter assays, qRT-PCR, and Western blot were applied to prove that miR-34a directly binds to XIST. RESULTS: Up-regulation of XIST and Yes associated protein (YAP) and down-regulation of miR-34a were consistently observed in the clinical specimens and PC cell lines. Silencing XIST reduced the expression of YAP and suppressed transforming growth factor (TGF)-ß1-induced EMT, while over-expression of XIST increased the expression of YAP and promoted EMT. In addition, inhibition of epidermal growth factor receptor (EGFR) hampered the XIST-promoted EMT. The results from the luciferase reporter assays confirmed that miR-34a directly targets XIST and suggested that XIST regulates cell proliferation, invasiveness, and apoptosis in PC by sponging miR-34a. CONCLUSIONS: XIST promotes TGF-ß1-induced EMT by regulating the miR-34a-YAP-EGFR axis in PC.

Draft genome sequence analysis of a high carbapenem-resistant Klebsiella quasipneumoniae subsp. quasipneumoniae strain isolated from an HIV-positive patient with pneumonia.

OBJECTIVES: The rapid spread of Klebsiella spp. is recognised as a major threat to public health owing to a rise in the number both of healthcare- and community-acquired infections. Here we report the draft genome sequence of a high carbapenem-resistant Klebsiella quasipneumoniae subsp. quasipneumoniae strain (Cln185) isolated from a human immunodeficiency virus (HIV)-positive patient with pneumonia. METHODS: Classical microbiological methods were applied to isolate and identify the strain. Genomic DNA was sequenced using an Illumina HiSeq platform and the reads were de novo assembled into contigs using CLC Genomics Workbench. The assembled contigs was annotated and whole-genome sequencing (WGS) was performed. RESULTS: WGS analysis revealed that the genome comprised a circular chromosome of 5 406 774bp with a GC content of 57.73%. Three important antimicrobial resistance genes (blaIMP-38, blaOKP-B-6 and blaDHA-1) were detected. In addition, genes conferring resistance to aminoglycosides, ß-lactams, fluoroquinolones and tetracycline were also identified. CONCLUSION: The draft genome sequence reported here will lay the foundation for future research on antimicrobial resistance and pathogenic mechanisms in K. quasipneumoniae subsp. quasipneumoniae and also will promote comparative analysis with genomic features among different sources of clinically important multidrug-resistant strains.

Relationship Between Human mutL Homolog 1 (hMLH1) Hypermethylation and Colorectal Cancer: A Meta-Analysis.

BACKGROUND Hypermethylation of CpG islands in gene promoter regions is an important mechanism of gene inactivation in cancers. Promoter hypermethylation of human mutL homolog 1 (hMLH1) has been implicated in a subset of colorectal cancers that show microsatellite instability (MSI), while the connection of the epigenetic inactivation of hMLH1 in colorectal cancers remains unknown. The aim of this study was to evaluate the relationship between the promoter hypermethylation of hMLH1 and colorectal cancers by performing a meta-analysis. MATERIAL AND METHODS Eligible studies were identified through searching PubMed, Cochrane Library, Web of Science, and Google Scholar databases. R Software including meta packages was used to calculate the pooled and odds ratios (ORs) with corresponding confidence intervals (CIs). Funnel plots were also performed to evaluate publication bias. RESULTS This meta-analysis obtained 45 articles, including 4096 colorectal cancer patients, and identified a significant association between hMLH1 hypermethylation and colorectal cancer risk using the fixed-effects model (OR=8.3820; 95% CI, 6.9202~10.1527; z=21.7431; P<0.0001) and random effects model pooled (OR=10.0963; 95% CI, 6.1919~16.4626; z=9.2688; P<0.0001). The significant relationship was found in subgroup analyses. CONCLUSIONS The results of this meta-analysis show a significant association between hMLH1 hypermethylation and colorectal cancer risk.

Colorectal Cancer Genetic Heterogeneity Delineated by Multi-Region Sequencing.

Intratumor heterogeneity (ITH) leads to an underestimation of the mutational landscape portrayed by a single needle biopsy and consequently affects treatment precision. The extent of colorectal cancer (CRC) genetic ITH is not well understood in Chinese patients. Thus, we conducted deep sequencing by using the OncoGxOne™ Plus panel, targeting 333 cancer-specific genes in multi-region biopsies of primary and liver metastatic tumors from three Chinese CRC patients. We determined that the extent of ITH varied among the three cases. On average, 65% of all the mutations detected were common within individual tumors. KMT2C aberrations and the NCOR1 mutation were the only ubiquitous events. Subsequent phylogenetic analysis showed that the tumors evolved in a branched manner. Comparison of the primary and metastatic tumors revealed that PPP2R1A (E370X), SETD2 (I1608V), SMAD4 (G382T), and AR splicing site mutations may be specific to liver metastatic cancer. These mutations might contribute to the initiation and progression of distant metastasis. Collectively, our analysis identified a substantial level of genetic ITH in CRC, which should be considered for personalized therapeutic strategies.