Genetic variation in both innate and adaptive immune systems is associated with Crohn's disease (CD) susceptibility, but much of the heritability to CD remains unknown. We performed a genome-wide association study (GWAS) in 896 CD cases and 3204 healthy controls all of Caucasian origin as defined by multidimensional scaling. We found supportive evidence for 21 out of 40 CD loci identified in a recent CD GWAS meta-analysis, including two loci which had only nominally achieved replication (rs4807569, 19p13; rs991804, CCL2/CCL7). In addition, we identified associations with genes involved in tight junctions/epithelial integrity (ASHL, ARPC1A), innate immunity (EXOC2), dendritic cell biology [CADM1 (IGSF4)], macrophage development (MMD2), TGF-beta signaling (MAP3K7IP1) and FUT2 (a physiological trait that regulates gastrointestinal mucosal expression of blood group A and B antigens) (rs602662, P=3.4x10(-5)). Twenty percent of Caucasians are 'non-secretors' who do not express ABO antigens in saliva as a result of the FUT2 W134X allele. We demonstrated replication in an independent cohort of 1174 CD cases and 357 controls between the four primary FUT2 single nucleotide polymorphisms (SNPs) and CD (rs602662, combined P-value 4.90x10(-8)) and also association with FUT2 W143X (P=2.6x10(-5)). Further evidence of the relevance of this locus to CD pathogenesis was demonstrated by the association of the original four SNPs and CD in the recently published CD GWAS meta-analysis (rs602662, P=0.001). These findings strongly implicate this locus in CD susceptibility and highlight the role of the mucus layer in the development of CD.

In this study, 40 biopsy samples collected from cervical cancer patients at the First Affiliated Hospital of Xi'an Jiaotong University, China, were retrospectively assessed using immunohistochemistry for CD4 1 and CD8 1 tumor-infiltrating lymphocytes (TILs) and were analyzed for the expression of FOXP3, OX40, granzyme B (GrB) and perforin (Prf). The proliferating index of the TILs was determined by assessing Ki67 expression. We determined the prognostic value of low and high numbers of TILs on survival by performing KaplanMeier analysis using median values as the cut-off points. Except for the number of CD4 1 FOXP3 1 regulatory T cells (Tregs) and the CD4/ CD8 ratio, none of the CD4 1 , CD8 1 , OX40 1 , GrB 1 or Prf 1 TILs were associated with the overall 5-year survival rate. The 5-year survival rate was significantly lower in patients who had a high percentage of Tregs as compared with the those who had a lower percentage (35.3% versus 88.9%, P50.001), while the 5-year survival rate was significantly higher in patients with a high CD4/CD8 ratio as compared with patients who had a low CD4/CD8 ratio (82.4% versus 44.4%, P50.029). When we considered the deaths and surviving cases as separate groups, we found that both the number of CD4 1 T cells and the CD4/CD8 ratio were significantly lower in patients who died as compared with those who survived (26.33611.80 versus 47.79638.18, P50.023 and 0.6060.25 versus 1.1761.02, P50.019, respectively). In conclusion, decreased proportions of tumor-infiltrating CD4 1 T cells with high percentages of Tregs and reversed CD4/CD8 ratios were significantly associated with the clinical outcome of patients with cervical carcinoma.

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BackgroundLimited efficacy of immune checkpoint blockades was observed in clinical trials in colorectal (CRC) patients, especially in the microsatellite-stable patients. Interleukin-6 (IL-6) is critical in modeling immune responses in cancers. However, the effects of targeting IL-6 in combination with immune checkpoint blockades is unknown in CRC.Material/MethodsIn the present study, we investigated the profile of IL-6 expression in tumor tissues of CRC patient and we established CRC mouse models with various IL-6 expression levels using CT26 cells and MC38 cells. Effects of anti-IL-6 and anti-PD-L1 combination treatment were tested in these models.ResultsA total of 105 CRC patients were included in this study, with 41 (39%) females and 64 (61%) males. Sixty patients showed IL-6 high expression and 45 patients showed IL-6 low expression. The patients with IL-6 high expression tended to have shorter survival (median survival time of 25.5 months) than the patients with IL-6 low expression (median survival time of 46 months, P value=0.013). In the CRC mouse models, tumors with IL-6 overexpression tended to grow faster than the tumors with IL-6 knockout. The numbers of CD8+ T cells and CD4+ T cells were decreased in IL-6 overexpressed tumors. On the contrary, myeloid-derived suppressor cells and regulatory/suppressor T cells were more numerous in tumors with IL-6 overexpression. PD-L1 expression was upregulated in the tumors with IL-6 overexpression. Importantly, an IL-6 blockade reversed the anti-PD-L1 resistance and prolonged tumor-bearing mouse survival.ConclusionsOur study indicates that IL-6 induces strong immunosuppression in the CRC microenvironment by recruiting immunosuppression cells and impairing T cell infiltration. Inhibition of IL-6 enhanced the efficacy of anti-PD-L1 in CRC, providing a novel strategy to overcome anti-PD-L1 resistance in CRC.

Background/Aims: Doxorubicin (DOX) is a widely used chemotherapeutic agent for colorectal cancer (CRC). However, the acquirement of DOX resistance limits its clinical application for cancer therapy. Mounting evidence has suggested that aberrantly expressed lncRNAs contribute to drug resistance of various tumors. Our study aimed to explore the role and molecular mechanisms of lncRNA X-inactive specific transcript (XIST) in chemoresistance of CRC to DOX. Methods: The expressions of XIST, miR-124, serum and glucocorticoid-inducible kinase 1 (SGK1) mRNA in DOX-resistant CRC tissues and cells were detected by qRT-PCR or western blot analysis. DOX sensitivity was assessed by detecting IC50 value of DOX, the protein levels of P-glycoprotein (P-gp) and glutathione S-transferase-π (GST-π) and apoptosis. The interactions between XIST, miR-124 and SGK1 were confirmed by luciferase reporter assay, qRT-PCR and western blot. Xenograft tumor assay was used to verify the role of XIST in DOX resistance in CRC in vivo. Results: XIST expression was upregulated and miR-124 expression was downregulated in DOX-resistant CRC tissues and cells. Knockdown of XIST inhibited DOX resistance of CRC cells, as evidenced by the reduced IC50 value of DOX, decreased P-gp and GST-π levels and enhanced apoptosis in XIST-silenced DOX-resistant CRC cells. Additionally, XIST positively regulated SGK1 expression by interacting with miR-124 in DOX-resistant CRC cells. miR-124 suppression strikingly reversed XIST-knockdown-mediated repression on DOX resistance in DOX-resistant CRC cells. Moreover, SGK1-depletion-elicited decrease of DOX resistance was greatly restored by XIST overexpression or miR-124 inhibition in DOX-resistant CRC cells. Furthermore, XIST knockdown enhanced the anti-tumor effect of DOX in CRC in vivo. Conclusion: XIST exerted regulatory function in resistance of DOX possibly through miR-124/SGK1 axis, shedding new light on developing promising therapeutic strategy to overcome chemoresistance in CRC patients.

MiR-155 expression was highly elevated in EAM mice. An imbalance of Th17/Treg existed in EAM mice. MiR-155 inhibition in EAM attenuated disease severity and cardiac injury. MiR-155 inhibition suppressed Th17 immune response in EAM. MiR-155 inhibition reduced DC function of secreting Th17-polarizing cytokines in EAM.

Background Individual differences in subjective responses to alcohol (SR) are moderated by genetic variants and may be risk factors for the development of alcohol use disorders. Variation in the GABAA α2 receptor subunit gene (GABRA2) has been associated with alcohol dependence (AD). Therefore, we examined whether individual differences in SR, which reflect sensitivity to the effects of alcohol, are associated with variation in GABRA2. Methods Sixty-nine healthy subjects (21–30 yr) underwent a laboratory-based within-session, cumulative oral alcohol dosing procedure, achieving a mean peak blood alcohol level of 100.4 mg/dL (SE =2.5). Subjective assessments were obtained throughout the session, including ascending and descending limbs of the alcohol curve. We genotyped single nucleotide polymorphisms (SNPs) across the chromosome 4 region spanning GABRA2 and analyzed the effect of genotype and haplotypes on subjective responses to alcohol. Population substructure was characterized through the use of ancestry informative markers. Results Individual SNP analysis demonstrated that carriers of the minor alleles for SNPs rs279858, rs279844, rs279845, rs279826, rs279828 and rs279836 had lower “Negative” alcohol effects scores than individuals homozygous for the common allele at each SNP (p=0.0060, p=0.0035, p=0.0045, p=0.0043, p=0.0037, p=0.0061, respectively). Haplotype effects of block 1 showed concordant results with SNPs in this block (p=0.0492 and p=0.0150 for haplotypes 1 and 4, respectively). The minor alleles for several of these SNPs have previously been associated with AD. Conclusions Our findings provide further evidence that variation within GABRA2 is associated with attenuated negative responses to alcohol, a known risk factor for vulnerability to alcohol use disorders.

A recent large-scale meta-analysis of genome-wide studies has identified 95 loci, 59 of them novel, as statistically significant predictors of blood lipid traits; we tested whether the same loci explain the observed heterogeneity in response to lipid-lowering therapy with fenofibrate. Using data from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n = 861) we fit linear mixed models with the genetic markers as predictors and high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, total cholesterol, and triglyceride concentrations as outcomes. For all four traits, we analyzed both baseline levels and changes in response to treatment with fenofibrate. For the markers that were significantly associated with fenofibrate response, we fit additional models evaluating potential epistatic interactions. All models were adjusted for age, sex, and study center as fixed effects, and pedigree as a random effect. Statistically significant associations were observed between the rs964184 polymorphism near APOA1 (P-value≤0.0001) and fenofibrate response for HDL and triglycerides. The association was replicated in the Pharmacogenetics of Hypertriglyceridemia in Hispanics study (HyperTG, n = 267). Suggestive associations with fenofibrate response were observed for markers in or near PDE3A, MOSC1, FLJ36070, CETP, the APOE-APOC1-APOC4-APOC2, and CILP2. Finally, we present strong evidence for epistasis (P-value for interaction =  0.0006 in GOLDN, 0.05 in HyperTG) between rs10401969 near CILP2 and rs4420638 in the APOE-APOC1-APOC4-APOC2 cluster with total cholesterol response to fenofibrate. In conclusion, we present evidence linking several novel and biologically relevant genetic polymorphisms to lipid lowering drug response, as well as suggesting novel gene-gene interactions in fenofibrate pharmacogenetics.