A Systematic Pan-Cancer Analysis of MEIS1 in Human Tumors as Prognostic Biomarker and Immunotherapy Target.

BACKGROUND: We intended to explore the potential immunological functions and prognostic value of Myeloid Ecotropic Viral Integration Site 1 (MEIS1) across 33 cancer types. METHODS: The data were acquired from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx) and Gene expression omnibus (GEO) datasets. Bioinformatics was used to excavate the potential mechanisms of MEIS1 across different cancers. RESULTS: MEIS1 was downregulated in most tumors, and it was linked to the immune infiltration level of cancer patients. MEIS1 expression was different in various immune subtypes including C2 (IFN-gamma dominant), C5 (immunologically quiet), C3 (inflammatory), C4 (lymphocyte depleted), C6 (TGF-b dominant) and C1 (wound healing) in various cancers. MEIS1 expression was correlated with Macrophages_M2, CD8+T cells, Macrophages_M1, Macrophages_M0 and neutrophils in many cancers. MEIS1 expression was negatively related to tumor mutational burden (TMB), microsatellite instability (MSI) and neoantigen (NEO) in several cancers. Low MEIS1 expression predicts poor overall survival (OS) in adrenocortical carcinoma (ACC), head and neck squamous cell carcinoma (HNSC), and kidney renal clear cell carcinoma (KIRC) patients, while high MEIS1 expression predicts poor OS in colon adenocarcinoma (COAD) and low grade glioma (LGG) patients. CONCLUSION: Our findings revealed that MEIS1 is likely to be a potential new target for immuno-oncology.

Dihydroartemisinin ameliorates the liver steatosis in metabolic associated fatty liver disease mice by attenuating the inflammation and oxidative stress and promoting autophagy

Purpose: To explore the effect and potential mechanism of dihydroartemisinin (DHA) on metabolism-related fatty liver disease. Methods: A metabolic associated fatty liver disease (MAFLD) mice model was induced with continuous supplies of high-fat diet. DHA was intraperitoneally injected into mice. The weight of mice was monitored. The concentrations of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) in serum were detected by an automatic biochemical analyzer. The liver tissues were stained by hematoxylin and eosin and oil red O. The level of inflammation, oxidative stress, and autophagy was assessed by reverse transcription polymerase chain reaction, biochemical examination, Western blot and transmission electron microscope assays. Results: DHA treatment reduced theMAFLD-enhanced the level of weight gain, the concentrations of TC, TG, LDL and malonaldehyde, while increasedthe MAFLD-decreased the concentrations of HDL and superoxide dismutase. DHA ameliorated the MAFLD-aggravated pathological changes and the number of lipid droplets. Low dose of DHA declined the MAFLD-induced the enhancement of the expression of inflammatory factor. DHA treatment increased the MAFLD-enhanced the level of autophagy related protein, while decreased the MAFLD-reduced the protein level of p62. The increased level of autophagy was confirmed by transmission electron microscope. Conclusions: DHA can improve liver steatosis in MAFLD mice by inhibiting inflammation and oxidative stress and promoting autophagy.

The association of sex-biased ATRX mutation in female gastric cancer patients with enhanced immunotherapy-related anticancer immunity.

BACKGROUND: Genetic alterations have been proven to be the promising biomarkers for ICI response. However, sex biases in genetic alterations have been often ignored in the field of immunotherapy, which might specially influence the anticancer immunity and immunotherapy efficacy in male or female patients. Here, we have systematically evaluated the effect of the sex biases in somatic mutation of gastric cancer (GC) patients on the anticancer immunity and clinical benefit to immunotherapy. METHODS: Genomic and transcriptomic data of gastric cancer were downloaded from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC). We also obtained the genomic and clinical data of a MSKCC ICI-treated cohort from cbioportal database. GC male and female-derived tumor somatic mutation profiles were compared by maftools R package. Single sample gene set enrichment analysis (ssGSEA) was conducted to calculate the score of the anticancer immunity indicators including IFN-γ signaling, cytolytic activity (CYT) and antigen presenting machinery (APM). RESULTS: ATRX was found to mutate more frequently in female GC patients compared to male patients (FDR = 0.0108). Female GC patients with ATRX mutation manifested significantly more MSI-high subtypes, increased TMB and PDL1 expression as well as higher scores of IFN-γ signaling, CYT and APM. Gene set enrichment analysis (GSEA) has shown that ATRX mutation might enhance the immunogenicity and anticancer immunity through affecting DNA damage repair pathways. In the ICI-treated cohort from MSKCC, GC patients with ATRX mutation were associated with prolonged overall survival. When stratifying the entire ICI-treated cohort by sex, female patients with ATRX mutation obtained significantly better survival benefits than that of ATRX mutant male patients (Female patients, HR of ATRX MT vs WT = 0.636, 95%CI = 0.455-0.890, P = 0.023; Male patients, HR of ATRX MT vs WT = 0.929, 95%CI = 0.596-1.362, P = 0.712). CONCLUSIONS: ATRX mutation might serve as a potential predictive biomarker for favorable clinical benefit to ICI in female GC patients. ATRX mutation could be applied in combination with other biomarkers of ICI response to better identify the female GC patients who will derive greater benefits from ICI therapy.

The nationwide distribution and trends of hepatitis C virus genotypes in mainland China.

Comprehensive data on hepatitis C virus (HCV) genotypes distribution is critical for treatment regimen selection, vaccine design, and drug development. This study aimed to understand the dynamic distribution of HCV genotypes in Mainland China. Three hundred sixty-two studies published from January 1993 to December 2017 involving 64 891 samples (5133 injecting drug users, 2748 volunteer blood donors, 1509 former paid plasma donors, 160 sexually encounters, and 1992 human immunodeficiency virus (HIV)/HCV coinfection patients) were eligible for the quantitative synthesis estimation. Pooled proportion of HCV genotypes (and 95% confidence intervals [CIs]) was estimated through the Freeman-Tukey double arcsine transformation by period, region, and risk group. A sharp decline of the subtype 1b was observed in all regions except in northwestern and central regions. The genotypes 3 and 6 showed an obvious increase in southern and southwestern regions and have already spread nationwide. After 2010, subtype 1b was the most dominant variant in all regions and risk groups, accounting for 54.0% (95% CI, 51.9-56.1) of all national infections. Subtype 2a was the second most prevalent strain in all regions except in the south and southwest, with 15.4% (95% CI, 13.1-17.8) national infections. The subtype 6a in southern region and 3b and 3a in southwestern region had a higher proportion of infections than that in other regions. In addition, the genotypes 3 and 6 are already prevalent in almost all risk groups. The distribution of HCV genotypes were sharply shifting in China in the past three decades. The HCV subtype 1b posed a sharp decline, whereas genotypes 3 and 6 played an increasing role in the regional and populational HCV pandemic.

Clinical study of the use of gastroscopy as oral choledochoscopy.

Clinical value and safety of the use of gastroscopy as oral choledochoscopy in the treatment of biliary diseases was explored. Clinical data of 55 patients with biliary diseases who underwent gastroscopy were retrospectively analyzed. The types of gastroscopy, size of duodenal papilla incision, balloon dilatation, the success rate of gastroscopy entry, depth of gastroscopy entering into bile duct, endoscopic diagnosis and postoperative complications were recorded. Simple insertion-by-hand was performed, and insertion into common bile duct was successfully achieved in 53 cases, and the overall technical success rate was 96.4%. Residual bile duct stones in 25 patients (45.5%) after endoscopic retrograde cholangio-pancreatography (ERCP) were removed through endoscopy. Nine cases of benign stenosis and 2 cases of malignant stenosis were confirmed as 'cholangiocarcinoma' or 'duodenal papilla well-differentiated adenocarcinoma' by biopsy. Balloon oppression under intraoperative endoscopy was performed for 2 cases (3.6%) with biliary hemorrhage, and argon ion coagulation was successfully performed. No obvious abnormalities were found in 13 cases (23.6%) through gastroscopic biliary exploration. Complications occurred in 15 patients with a complication rate of 27.3%, including 2 cases of cholecystitis (3.6%), 8 cases of amyloidosis (14.6%) and 4 cases of acute pancreatitis (7.3%), and all those complications were cured. One case (1.8%) had perforation of biliary tract and was discharged after conservative treatment. The use of gastroscopy as oral choledochoscopy is safe as effective. However, this technique causes some rare and serious complications. Therefore, further studies are needed to improve this technique.

Submucosal Tunnel Endoscopic Resection for Esophageal Submucosal Tumors: A Multicenter Study.

BACKGROUND: Submucosal tumors (SMTs) are primarily benign tumors, but some may have a malignant potential. Endoscopic submucosal dissection that has been used for removing esophageal SMTs could cause perforation. Submucosal tunnel endoscopic resection (STER) is an improved and an effective technique for treating esophageal SMTs. AIMS: This study was conducted to evaluate the efficacy and safety of STER for treating esophageal SMTs. METHODS: A retrospective study design was adopted to analyze the baseline characteristics, clinical outcomes, and follow-up data of patients with esophageal SMTs, which originated from the muscularis propria layer and were treated with STER from September 2011 to May 2018. RESULTS: A total of 119 lesions were included from 115 patients who were successfully treated with STER. The mean age of the patients was 49.7 ± 10.7 years. The lesions were primarily located in the middle and lower esophagus. The mean size of the lesions was 19.4 ± 10.0 mm. The mean operation duration was 46.7 ± 25.6 min, and the mean duration of hospitalization was 5.9 ± 2.8 days. The total en bloc resection rate and the complete resection rate were 97.5% and 100%, respectively. Regarding complications, there were 9 (7.8%) cases of perforation, 2 (1.7%) cases of pneumothorax, and 9 (7.8%) cases of subcutaneous emphysema. Histopathological results revealed 113 (95.0%) cases of leiomyoma, 5 (4.2%) cases of gastrointestinal stromal tumors, and 1 (0.8%) case of a granular cell tumor. During the mean 15-month follow-up, there were no cases of recurrence and distant metastasis. CONCLUSIONS: STER is a safe and feasible technique for treating esophageal SMTs originating from the muscularis propria layer.

[Identification of differentially expressed genes in endometrium during the window of implantation using suppression substractive hybridization].

OBJECTIVE: To identify genes differentially expressed in the window of implantation and explore the molecular basis of the development of endometrial receptivity. METHODS: A subtracted cDNA library of the window of implantation was constructed by suppression subtractive hybridization (SSH) method. The screened clones of the subtracted library were sequenced and GenBank homology search was performed. The differential expression of ribosomal protein (RP) L7, RPL7 pseudogene (RPL7p), RPL19 and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta polypeptide (YWHAZ) were further confirmed by RT-PCR. RESULTS: After sequencing and GenBank homology search of 50 clones, 35 differentially expressed genes were detected in the window of implantation, of which 23 were known genes, and 12 were unknown genes. Some of the known genes have been proved to be associated with implantation, while others were firstly screened out by us. The results of RT-PCR confirmed that RPL7, RPL7p, RPL19 and YWHAZ were highly expressed in the window of implantation, 0.75 +/- 0.21, 1.72 +/- 0.30, 1.23 +/- 0.31, and 1.28 +/- 0.08, respectively. CONCLUSIONS: SSH is a useful technique to detect differential expression genes and an effective method to clone novel genes. It provides a new method to investigate the molecular basis of the development of endometrial receptivity.

Effects of galectin-3 inhibition on endometrial cell cycle and adhesion.

Galectin-3 (gal-3) and its ligands have been implicated in cell transformation and cancer metastasis. Gal-3 protein has been found in uterine epithelial cells adjacent to implanting blastocysts in different cell types. In order to investigate the role of gal-3 in the establishment of human endometrial receptivity, the expression of gal-3 in human endometrial cell line RL95-2 was silenced by RNA interference technology using gal-3 specific small RNA. The expression of gal-3 was detected by the reverse transcriptase-polymerase chain reaction and Western blot analysis. After the suppression of gal-3, cell cycle changes and the expression of integrin ß1 were detected by flow cytometry. The adhesive ability of RL95-2 cells was analyzed by the adhesion test. Gal-3 siRNA transfection efficiency reached 70%-90%. The expression of gal-3 mRNA and protein in RL95-2 cells was strongly inhibited by 70%-90% after RNA interference. Inhibition of gal-3 expression decreased S-phase but increased G1 phase cells. Integrin ß1 expression was down-regulated, and the adhesive ability of RL95-2 cells to fibronectin (FN) was significantly reduced. Gal-3 may be involved in the establishment of endometrial receptivity by regulating the proliferation and adhesion of endometrial cells. The influence on adhesion may be related with the integrin modulation.