Measles Virus Infection Fosters Dendritic Cell Motility in a 3D Environment to Enhance Transmission to Target Cells in the Respiratory Epithelium.

Transmission of measles virus (MV) from dendritic to airway epithelial cells is considered as crucial to viral spread late in infection. Therefore, pathways and effectors governing this process are promising targets for intervention. To identify these, we established a 3D respiratory tract model where MV transmission by infected dendritic cells (DCs) relied on the presence of nectin-4 on H358 lung epithelial cells. Access to recipient cells is an important prerequisite for transmission, and we therefore analyzed migration of MV-exposed DC cultures within the model. Surprisingly, enhanced motility toward the epithelial layer was observed for MV-infected DCs as compared to their uninfected siblings. This occurred independently of factors released from H358 cells indicating that MV infection triggered cytoskeletal remodeling associated with DC polarization enforced velocity. Accordingly, the latter was also observed for MV-infected DCs in collagen matrices and was particularly sensitive to ROCK inhibition indicating infected DCs preferentially employed the amoeboid migration mode. This was also implicated by loss of podosomes and reduced filopodial activity both of which were retained in MV-exposed uninfected DCs. Evidently, sphingosine kinase (SphK) and sphingosine-1-phosphate (S1P) as produced in response to virus-infection in DCs contributed to enhanced velocity because this was abrogated upon inhibition of sphingosine kinase activity. These findings indicate that MV infection promotes a push-and-squeeze fast amoeboid migration mode via the SphK/S1P system characterized by loss of filopodia and podosome dissolution. Consequently, this enables rapid trafficking of virus toward epithelial cells during viral exit.

Impact of a Missense Variation (p.S150R:AGC>AGG) in the XRCC2 Gene on Susceptibility to Colorectal Cancer.

BACKGROUND: The X-ray repair complementing defective repair in Chinese hamster cells 2 (XRCC2) is an important protein in response to DNA double-strand breaks (DSBs) in human cells. XRCC2, as a functional protein in the homologous recombination repair (HRR) process, has been identified to have several polymorphisms which might be associated with the risk of cancer. Therefore, we aimed to investigate a novel missense variation (AGC>AGG, p.Ser150Arg) in the XRCC2 gene for colorectal cancer susceptibility. METHODS: We studied 291 colorectal cancer (CRC) patients and 140 healthy individuals. ARMS PCR method was used to detect the AGC>AGG (p.Ser150Arg) variation in the XRCC2 gene. RESULTS: The results showed that there was a significant differential among CRC and controls in the genotypic and allelic frequencies (p < 0.001) of XRCC2; AGC>AGG, p.Ser150Arg. Our results demonstrated that the G allele of XRCC2; AGC>AGG, p.Ser150Arg was associated with increased CRC risk (odds ratio = 59.04, 95% confidence interval = 18.6 - 186). This variation also influenced CRC cancer susceptibility in smokers (p < 0.001). CONCLUSIONS: The G allele of XRCC2; AGC>AGG, p.Ser150Arg, may be a potential marker for CRC in Iranians and investigations in other populations are warranted for further universal application in CRC detection and prediction.

Association between TNF-α rs1799964 and RAF1 rs1051208 MicroRNA binding site SNP and gastric cancer susceptibility in an Iranian population.

AIM: The aim of this study was to find the relationship between rs1799964 in TNF-α gene as well as rs1051208 of RAF1 gene SNPs on GC in an Iranian population. BACKGROUND: Gastric cancer (GC) is the second leading cause of cancer-related death worldwide after lung cancer. Tumor necrosis factor (TNF) is one of the most important factors in the pathogenesis of this cancer. Single nucleotide polymorphisms have a principle role in gene expression of TNF-α and miRNAs which may lead to gastric cancer. METHODS: In a case-control study, we investigated the risk of GC in 198 Iranians. For this purpose, 5 mL of peripheral blood was collected in EDTA -containing tube and genomic DNA was isolated. Genotyping of SNPs was also performed by PCR-RFLP; to approve the outcome, 10% of genotyping results with RFLP were sequenced. RESULTS: The comparison between case and control groups revealed a significant association between the rs1051208 C allele of RAF1 gene and GC (P = 0.04). We did not observe any remarkable association between TNF-α -1031 in gastric cancer patients and the healthy control group. CONCLUSION: The results indicated that C allele in RAF1 gene plays a role in susceptibility to gastric cancer. Therefore, SNPs are among notable biomarkers for predicting susceptibility to dreadful diseases, especially cancers.

Interleukin-16 polymorphisms as new promising biomarkers for risk of gastric cancer.

Gastric cancer (GC) is the second cause of cancer-related death worldwide. Interleukin (IL)-16 has a vital role in the development and homeostasis of the immune system. In the present study, we evaluated an exon variant rs4072111 C/T polymorphism and 3' UTR variant rs1131445 C/T within the miRNA binding with gastric cancer susceptibility in Iranian population. Genomic DNA was isolated from peripheral blood samples according to phenol chloroform extraction. The genotypes of IL-16 polymorphisms rs1131445 T/C and rs4072111 T/C were determined by polymerase chain reaction-restriction fragment length polymorphism method. In this case control study, a total of 256 patients with gastric cancer (238 cases (92.9 %) non-cardia and 18 cases (7.1 %) cardia) and 300 healthy control subjects were evaluated. In the present study, we found a significant association between rs4072111 of IL-16 gene and risk of GC in Iranian population. Individuals with CT genotype showed a significant association with 1.79-fold increased risk of GC (P = 0.008; adjusted OR 1.792; 95 % CI 1.164-2.759). The significant association was also detected for T allele of rs4072111 and increased risk of GC (P < 0.001; adjusted OR 1.981; 95 % CI 1.354-2.900). We also observed statistically a significant relationship between rs1131445 of IL-16 CT genotype and GC risk. Carriers of IL-16 CT genotype compared with TT genotype had 1.44 times higher increased likelihood of GC (P = 0.048; adjusted OR 1.445; 95 % CI 1.003-2.084). After stratification according to gender, we observed that in rs1131445, CT and CC male carriers had a higher risk of GC than females (P = 0.08; adjusted OR 1.608; 95 % CI 0.945-2.737 and P = 0.08; adjusted OR 2.186; 95 % CI 0.897-5.325, respectively). We also observed that for male carriers with C allele in rs1131445, there was a 1.53-fold higher risk of GC risk than female subjects (P = 0.029; adjusted OR 1.53; 95 % CI 1.04.4-2.248). We found that the rs1131445 T/C and rs4072111 T/C variants of IL-16 were significantly associated with increased risk of GC in Iranian population.

Intronic polymorphisms of the SMAD7 gene in association with colorectal cancer.

Based on genome-wide association studies (GWAS) a linkage between several variants such as single nucleotide polymorphisms (SNPs) in intron 3 of SMAD7 (mothers against decapentaplegic homolog7) were, rs12953717, rs4464148 and rs4939827 has been noted for susceptibility to colorectal cancer (CRC). In this study we investigated the relationship of rs12953717 and rs4464148 with risk of CRC among 487 Iranian individuals based on a case- control study. Genotyping of SNPs was performed by PCR-RFLP and for confirming the outcomes, 10% of genotyping cases were sequenced with RFLP. Comparing the case and control group, we have found significant association between the rs4464148 SNP and lower risk of CRC. The AG genotype showed decreased risk with and odds ratio of 0.635 (adjusted OR=0.635, 95% CI: 0.417-0.967, p=0.034). There was no significant difference in the distribution of SMAD7 gene rs12953717 TT genotype between two groups of the population evaluated (adjusted OR=1.604, 95% CI: 0.978-2.633, p=0.061). On the other hand, rs12953717 T allele showed a statistically significant association with CRC risk (adjusted OR=1.339, 95% CI: 1.017-1.764, p=0.037). In conclusion, we found a significant association between CRC risk and the rs4464148 AG genotype. Furthermore, the rs12953717 T allele may act as a risk factor. This association may be caused by alternative splicing of pre mRNA. Although we observed a strong association with rs4464148 GG genotype in affected women, we did not detect the same association in CRC male patients.

A Study on Genetic Association of Interleukin-16 Single Nucleotide Polymorphism (rs1131445) With Chronic Hepatitis B Virus Infection in Iranian Patients.

BACKGROUND: Interleukin-16 (IL-16) is an immunomodulatory cytokine, which plays an important role in some inflammatory and autoimmune diseases such as hepatitis B, which is a major health concern worldwide. OBJECTIVES: In this study, we aimed to investigate the plausible association between IL-16 polymorphism and chronic HBV susceptibility in an Iranian population. PATIENTS AND METHODS: In a case-control study, we analyzed rs1131445 polymorphism in the microRNA binding site of the IL-16 gene in 262 patients with chronic hepatitis B and 269 healthy controls, using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and DNA sequencing technology to confirm our results. RESULTS: Altogether, in this investigation, a significant association was observed between the IL-16 TC genotype compared with the TT genotype (OR = 0.696, 95% CI: 0.485 - 0.997, P = 0.048), after adjustments for confounders including age and gender. CONCLUSIONS: These findings show that immunogenetic factors, such as single nucleotide polymorphism in IL-16, could be a risk factor for susceptibility to chronic HBV infection. However, further investigations are needed to verify these results.

Interleukin-16 gene polymorphisms are considerable host genetic factors for patients' susceptibility to chronic hepatitis B infection.

Host genetic background is known as an important factor in patients' susceptibility to infectious diseases such as viral hepatitis. The aim of this study was to determine the effect of genetic polymorphisms of interleukin-16 (IL-16) cytokine on susceptibility of hepatitis B virus (HBV) infected patients to develop chronic HBV infection. Genotyping was conducted using PCR followed by enzymatic digestion and RFLP (restriction fragment length polymorphism) analysis. We genotyped three single nucleotide polymorphisms (SNPs) in the Il-16 gene (rs11556218 T>G, rs4778889 T>C, and rs4072111 C>T) to test for relationship between variation at these loci and patients' susceptibility to chronic HBV infection. Allele frequency of Il-16 gene rs4072111 and rs11556218 was significantly different between chronic HBV patients and healthy blood donors. Genotype frequency of rs4778889 polymorphism of Il-16 gene was significantly different when chronic HBV patients and HBV clearance subjects were compared. Our results showed that Il-16 gene polymorphisms are considerable host genetic factors when we chase biomarkers for prognosis of HBV infected patients.