The influence of Interleukin-6, Interleukin-8, Interleukin-10, Interleukin-17, TNF-A, MIF, STAT3 on lung cancer risk in Moroccan population.

To date, several studies have reported that key cytokines in the inflammatory system have important roles in the pathogenesis of cancer, notably in lung cancer. The aim of this case-control study, conducted for the first time in Moroccan population, was to investigate and to analyze the association of the following inflammatory cytokine genes Interleukin (IL)-6, Interleukin (IL)-8, Interleukin (IL)-10, Interleukin (IL)-17, Tumor Necrosis Factor-Alpha (TNFA), Macrophage migration Inhibitory Factor (MIF) and Signal Transducer and Activator of Transcription 3 (STAT3) with lung cancer risk in our patients. Firstly, the mRNA expression was assessed by a quantitative real time PCR in the peripheral blood of lung cancer patients and healthy subjects. Secondly, polymorphisms in the genes encoding cytokines were assessed in 160 lung cancer patients and 150 healthy controls. Genotyping analysis was performed with a Real-Time polymerase chain reaction using TaqMan® genotyping assays on a 7500 FAST Real-Time PCR System and Restriction Fragment Length PolymorphismPCR. Our results revealed a significant difference in mRNA expression levels of IL-6, IL-8, IL-10, IL-17 and TNFA genes in lung cancer patients compared to healthy subjects (P < 0.05). Among the studied genes, we found a significant association between lung cancer risk in our patients and the following polymorphisms IL-6 (rs1800795, rs1800796), IL-8 (rs4075, rs2227306), IL-17F (rs763780, rs2397084) and MIF (rs755622). In conclusion, the results of our study suggest that IL-6, IL-8, IL-10, IL-17 and MIF cytokine genes may aggravate lung cancer risk in the Moroccan population. However, further investigations are required to confirm our findings.

Association of Variants in IL6-Related Genes with Lung Cancer Risk in Moroccan Population.

PURPOSE: Lung cancer is known to be a complex multifactorial disease, involving both genetic and environmental factors. The study of the different signaling pathways and the identification of the genes involved, will contribute to further understanding the pathogenesis of the disease, thus allowing the development of appropriate targeted treatments. Recently, the link between cancer and inflammation has become more evident and inflammation has been proposed as the seventh hallmark of cancer. Previous studies have suggested that key cytokines involved in inflammation may have an important role in the etiology of lung cancer. The aim of this study was to investigate whether common variants in inflammation-related genes: IL-6, IL6-R, and IL6-ST, influence lung cancer risk in Moroccan population. MATERIALS AND METHODS: Single nucleotide polymorphisms (SNPs) in IL-6, IL6-R, and IL6-ST genes were assessed in 120 controls and 120 patients with confirmed lung cancer diagnosis. Genotyping analysis was performed with the TaqMan® allelic discrimination technology. The results were analyzed using SPSS 24.0 software. RESULTS: Among the studied SNPs, we found a significant association for the IL-6 (rs2069840) (OR = 1.63; 95% confidence interval 1.08-2.47; p = 0.01). No significant association was observed for the remaining SNPs of IL-6R (rs2228145) and IL-6ST (rs2228044) genes. CONCLUSION: Our results suggest the IL-6 (rs2069840) polymorphism may influence the occurrence of lung cancer in Moroccan patients.

Peroxiredoxin-2 up-regulation in inflammatory bowel disease: Friend or foe?

BACKGROUND: Inflammatory bowel diseases (IBD) are chronic multi-factorial inflammatory disorders. Accumulating investigations have provided compelling evidence that describe the interplay of a complex genetic landscape and inappropriate inflammatory response to intestinal microbes in disease etiopathogenesis but still pose challenges in diagnostic practices. METHOD: In this study, comparative proteomic analysis was conducted to identify disease specific proteins underlying IBD pathogenetic mechanisms. Total blood proteins of the IBD patients and healthy subjects were analyzed with one-dimensional electrophoresis; differentially expressed bands were excised and subjected to matrix-assisted laser desorption ionization-time of flight mass spectrometry along with nanoflow liquid chromatography electrospray ionization-tandem mass spectrometry analysis. Presence of glycosylation, hydroxylation, and phosphorylation post-translational modifications was further investigated by immunoprecipitation. RESULTS: Peroxiredoxin-2 (PRDX2) and hemoglobin-subunits proteins, which are closely involved in the response to oxidative stress, were identified. PRDX2 was selected for further validation using western blot and reverse transcription-polymerase chain reaction. PRDX2 overexpression was restricted to the protein level within the membrane fraction. Immunoprecipitation identified PRDX2 to be post-translationally glycosylated and phosphorylated. CONCLUSION: Our findings demonstrate the implication of PRDX2 in IBD. Future studies are required to establish its functional role and to determine the clinical utility.

Genetic Polymorphisms of Multidrug Resistance Gene-1 (MDR1/ABCB1) and Glutathione S-Transferase Gene and the Risk of Inflammatory Bowel Disease among Moroccan Patients.

Inflammatory bowel diseases (IBD) are multifactorial disorders resulting from environmental and genetic factors. Polymorphisms in MDR1 and GSTs genes might explain individual differences in susceptibility to IBD. We carried out a case-control study to examine the association of MDR1 (C1236T and C3435T), GSTT1, and GSTM1 polymorphisms with the risk of IBD. Subjects were genotyped using PCR-RFLP for MDR1 gene and multiplex PCR for GSTT1 and GSTM1. Meta-analysis was performed to test the association of variant allele carriage with IBD risk. We report that GSTT1 null genotype is significantly associated with the risk of CD (OR: 2.5, CI: 1.2-5, P = 0.013) and UC (OR: 3.5, CI: 1.5-8.5, P = 0.004) and can influence Crohn's disease behavior. The interaction between GSTT1 and GSTM1 genes showed that the combined null genotypes were associated with the risk of UC (OR: 3.1, CI: 1.1-9, P = 0.049). Furthermore, when compared to combined 1236CC/CT genotypes, the 1236TT genotype of MDR1 gene was associated with the risk of UC (OR: 3.7, CI: 1.3-10.7, P = 0.03). Meta-analysis demonstrated significantly higher frequencies of 3435T carriage in IBD patients. Our results show that GSTT1 null and MDR1 polymorphisms could play a role in susceptibility to IBD.

Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms: New data and a meta-analysis.

BACKGROUND: The pathogenesis of inflammatory bowel disease (IBD) involves interactions between the host genetic susceptibility, intestinal microflora and mucosal immune responses through the pattern recognition receptor. Polymorphisms in toll-like receptor 4 (TLR4) induce an aberrant immune response to indigenous intestinal flora, which might favor IBD development. In this study, we aimed to determine whether TLR4 gene was associated with Crohn's disease (CD) and ulcerative colitis (UC) among Moroccan patients, and evaluated its correlation with clinical manifestation of the disease. METHODS: The study population comprised 117 patients with IBD and 112 healthy unrelated blood donors. TLR4 polymorphisms: Asp299Gly and Thr399Ile were genotyped by polymerase chain reaction-restriction fragment length polymorphism. PCR products were cleaved with Nco I for the Asp299Gly polymorphism and Hinf I for the Thr399Ile polymorphism. Meta-analysis was performed to test the association of 299Gly and 399Ileu carriage with CD, UC and the overall IBD risk. RESULTS: Our study revealed that the frequency of Asp299Gly and Thr399Ile did not differ significantly between patients and controls in the Moroccan population. However, meta-analysis demonstrated significantly higher frequencies of both Asp299Gly and Thr399Ile SNPs in IBD and CD and for 399Ileu carriage in UC patients. CONCLUSION: The meta-analysis provides evidence that TLR4 polymorphisms confer a significant increased risk for the overall IBD development.

Mutation and cell state compatibility is required and targetable in Ph+ acute lymphoblastic leukemia minimal residual disease.

Efforts to cure BCR::ABL1 B cell acute lymphoblastic leukemia (Ph+ ALL) solely through inhibition of ABL1 kinase activity have thus far been insufficient despite the availability of tyrosine kinase inhibitors (TKIs) with broad activity against resistance mutants. The mechanisms that drive persistence within minimal residual disease (MRD) remain poorly understood and therefore untargeted. Utilizing 13 patient-derived xenograft (PDX) models and clinical trial specimens of Ph+ ALL, we examined how genetic and transcriptional features co-evolve to drive progression during prolonged TKI response. Our work reveals a landscape of cooperative mutational and transcriptional escape mechanisms that differ from those causing resistance to first generation TKIs. By analyzing MRD during remission, we show that the same resistance mutation can either increase or decrease cellular fitness depending on transcriptional state. We further demonstrate that directly targeting transcriptional state-associated vulnerabilities at MRD can overcome BCR::ABL1 independence, suggesting a new paradigm for rationally eradicating MRD prior to relapse. Finally, we illustrate how cell mass measurements of leukemia cells can be used to rapidly monitor dominant transcriptional features of Ph+ ALL to help rationally guide therapeutic selection from low-input samples.

IL-1 and CD40/CD40L platelet complex: elements of induction of Crohn's disease and new therapeutic targets.

Ulcerative colitis (UC) and Crohn's disease (CD) are chronic and multifactorial diseases that affect the intestinal tract, both characterized by recurrent inflammation of the intestinal mucosa, resulting in abdominal pain, diarrhea, vomiting and, rectal bleeding. Inflammatory bowel diseases (IBD) regroup these two disorders. The exact pathological mechanism of IBD remains ambiguous and poorly known. In genetically predisposed patients, defects in intestinal mucosal barrier are due to an uncontrolled inflammatory response to normal flora. In addition to the genetic predisposition, these defects could be triggered by environmental factors or by a specific lifestyle which is widely accepted as etiological hypothesis. The involvement of the CD40/CD40L platelet complex in the development of IBD has been overwhelmingly demonstrated. CD40L is climacteric in cell signalling in innate and adaptive immunity, the CD40L expression on the platelet cell surface gives them an immunological competence. The IL-1, a major inflammation mediator could be involved in different ways in the development of IBD. Here, we provide a comprehensive review regarding the role of platelet CD40/CD40L in the pathophysiological effect of IL-1 in the development of Crohn's disease (CD). This review could potentially help future approaches aiming to target these two pathways for therapeutic purposes and elucidate the immunological mechanisms driving gut inflammation.

Coverage rate of ADME genes from commercial sequencing arrays.

Pharmacogenomics offers remarkable potential for the rapid translation of discoveries into changes in clinical practice. In the present work, we are interested in evaluating the ability of commercially available genome-wide association sequencing chips to cover genes that have high pharmacogenomics potential.We used a set of 2794 variations within 369 absorption, distribution, metabolism, and elimination (ADME) genes of interest, as previously defined in collaboration with the Pharma ADME consortium. We have compared the Illumina TrueSeq and both Agilent SureSelect and HaloPlex sequencing technologies. We have developed Python scripts to evaluate the coverage for each of these products. In particular, we considered a specific list of 155 allelic variants in 34 genes which present high pharmacogenomics potential. Both the theoretical and practical coverage was assessed.Given the need to have a good coverage to establish confidently the functionality of an enzyme, the observed rates are unlikely to provide sufficient evidence for pharmacogenomics studies. We assessed the coverage using enrichment technology for exome sequencing using the Illumina Trueseq exome, Agilent SureSelectXT1 V4 and V5, and Haloplex exome, which offer a coverage of 96.12%, 91.61%, and 88.38%, respectively.Although pharmacogenomic advances had been limited in the past due in part to the lack of coverage of commercial genotyping chips, it is anticipated that future studies that make use of new sequencing technologies should offer a greater potential for discovery.

The PTPN22 C1858T (R620W) functional polymorphism in inflammatory bowel disease.

OBJECTIVE: In view of the discrepant data regarding the association between the protein tyrosine phosphatase non-receptor 22 (PTPN22) rs2476601 (R620W, 1858C→T) polymorphism and susceptibility to autoimmune diseases including inflammatory bowel diseases (IBD), we investigated whether this functional single-nucleotide polymorphism influences IBD risk in a group of Moroccan patients. RESULTS: This is the first report on the prevalence of PTPN22 (R620W) variant in a Moroccan cohort. No evidence of statistically significant differences was observed when the PTPN22 (R620W) allele and genotype distribution among IBD, Crohn's disease (CD), ulcerative colitis (UC) patients and healthy controls were compared. The frequency of the variant allele in healthy subjects was 1.77% compared to 2.56% in the IBD patients and 1.85% in CD patients. Furthermore, the frequency of this allele was increased in UC patients compared to controls (4.17% vs. 1.77%, OR = 2.42, 95% CI 0.82-7.08; P = 0.09), but the difference was not statistically significant. Our data suggest a lack of association between PTPN22 R620W variant and IBD susceptibility in Moroccan patients.

Polymorphisms in oxidative pathway related genes and susceptibility to inflammatory bowel disease.

AIM: To investigate whether common variants in the oxidative pathway genes influence inflammatory bowel disease (IBD) risk among Moroccan patients. METHODS: The distribution of (TAAA)n_rs12720460 and (CCTTT)n _rs3833912 NOS2A microsatellite repeats, HIF-1A_rs11549467 and NFKB1-94ins/delATTG_rs28362491 was analyzed in 507 subjects grouped in 199 IBD and 308 healthy controls. Genotyping was performed with polymerase chain reaction-fluorescent method and the TaqMan® allelic discrimination technology. RESULTS: The allele and genotype frequencies of HIF1A_ rs11549467, NFKB1_rs28362491 and NOS2A_ (TAAA)n did not differ significantly between patients and controls. Analysis of NOS2A_ (CCTTT)n markers evidenced differences between patients and healthy controls. A preferential presence of the (CCTTT)8 (P = 0.02; OR = 1.71, 95%CI: 1.07-2.74), (CCTTT)14 (P = 0.02; OR = 1.71, 95%CI: 1.06-2.76) alleles in IBD, (CCTTT)8 (P = 0.008; OR = 1.95, 95%CI: 1.17-3.23) in CD and (CCTTT)7 (P = 0.009; OR = 7.61, 95%CI: 1.25-46.08), (CCTTT)11 (P = 0.05; OR = 0.51, 95%CI: 0.25-1.01), (CCTTT)14 (P = 0.02; OR = 2.05, 95%CI: 1.07-3.94), (CCTTT)15 (P = 0.01; OR = 2.25, 95%CI: 1.16-4.35) repeats in UC patients indicated its possible association with higher disease risk which need to be confirmed in a larger sample size. CONCLUSION: Our results suggest that the NOS2A_ (CCTTT)n gene variations may influence IBD susceptibility in the Moroccan population.

Paraphenylene diamine exacerbates platelet aggregation and thrombus formation in response to a low dose of collagen.

Paraphenylene daimine (PPD) is an aromatic amine that is widely used in several industrial products; however, its toxicity has been reported in several cases of cardiac arrests. As platelets play a key role in cardiovascular diseases, we aimed to determine the impact of PPD in vitro and in vivo on platelet function. Our findings demonstrated that platelet activation and aggregation were strongly enhanced by PPD. Treatment with PPD primed human platelets that became more reactive in response to low doses of collagen. Furthermore, PPD exacerbated thrombus formation in rats in comparison with those untreated. Our results suggest that PPD is an important platelet primer predisposing platelets to promote thrombus formation in response to vascular injury. This should prompt the authorities to consider controlling the marketing of this product.

The Contribution of CD40/CD40L Axis in Inflammatory Bowel Disease: An Update.

Inflammatory bowel disease (IBD) is a chronic and multifactorial disease of the gastrointestinal tract. The exact etiology of IBD remains complex and unclear involving an inadequately defined relationship between microbial insult, genetic predisposition, altered intestinal barrier permeability, oxidative stress components and abnormal immune responses. The role of the co-stimulatory system made up of cluster of differentiation 40 protein (CD40) and its ligand (CD40L) in the response of the immune system to pathogens is now widely accepted. The implication of CD40/CD40L axis in immune system disorders due to its important role as signal transduction pathway among immune cells is well documented. Several studies have suggested that CD40/CD40L interactions regulate oxidative stress; this can affect various signaling pathways leading to IBD development. Hence, CD40/CD40L signaling pathway may become a new target for IBD treatment. This review will cover the general contribution of the CD40/CD40L dyad in the development of IBD in order to facilitate future approaches aiming to elucidate the immunological mechanisms that control gut inflammation.

IL23R and ATG16L1 variants in Moroccan patients with inflammatory bowel disease.

BACKGROUND: Inflammatory bowel diseases (IBD) are chronic diseases of the gastrointestinal tract. Although their pathogenesis is unclear, the combination of genetic predisposition and environmental components are believed to be the main cause of these diseases. Recently, many variants in interleukin 23 receptor (IL23R) and autophagy-related 16-like 1 (ATG16L1) genes have been associated with the disease. Our objective was to assess the frequency of ATG16L1 (T300A) and IL23R (L310P) variants in Moroccan IBD (Crohn's disease and Ulcerative Colitis) patients and to evaluate a possible effect of these variants on disease's phenotype and clinical course. METHODS: 96 Moroccan IBD patients and 114 unrelated volunteers were genotyped for ATG16L1 (T300A) and IL23R (L310P) variants by PCR-restriction fragment length polymorphism. RESULTS: This is the first report on the prevalence of ATG16L1 (T300A) and IL23R (L310P) variants in a Moroccan group. We found that IL23R (L310P) variant conferred a protective effect for crohn's disease (CD) but not ulcerative colitis (UC) patients. The presence of ATG16L1 (T300A) mutated alleles was associated with CD type but not with disease onset. In addition, the carriage of T300A variant alleles conferred a protective effect in UC. CONCLUSION: Our results showed that the prevalence of ATG16L1 and IL23R variants was not significantly different between patients and controls. However a possible role of ATG16L1 (T300A) on CD phenotype was suggested.

Methylenetetrahydrofolate reductase C677T variant in Moroccan patients with inflammatory bowel disease.

BACKGROUND: The association of genetic polymorphisms related to metabolism of homocysteine and folate with inflammatory bowel disease has been evidenced. Several studies have identified genetic variants of MTHFR as significant susceptibility loci for Crohn's disease (CD) and ulcerative colitis (UC). The C677T genetic polymorphism in the MTHFR gene is found to be associated with a thermolabile variant enzyme that shows a reduced activity. Therefore, we investigated whether the C677T variant confers genetic susceptibility to CD or UC and evaluated the genotype-phenotype associations in the Moroccan population. METHODS: The present study included 96 inflammatory bowel disease patients (68 patients with CD and 28 with UC) and 182 healthy controls. DNA samples were genotyped for the MTHFR (C677T) mutation by the PCR-RFLP method. Statistical analyzes were performed using MedCalc software, Chi square test and Fisher test. RESULTS: The respective odds ratio for CD, UC and control group were, 1.55 (CI 95%: 0.53-4.53, P=0.52); 0.50 (CI 95%: 0.06-4.15, P=0.52) and 0.50 (CI 95%: 0.06-4.15, P=0.52). Thus, no statistically significant association with the disease was observed in frequency of the TT variant in comparison to healthy controls. Stratification of IBD patients on the basis of CD or UC showed that individuals carrying at least one T allele are not protected against Crohn's disease. Furthermore, clinical features of the disease did not show any significant association. CONCLUSION: In conclusion, the present study indicates that the genetic risk for IBD is not modulated by MTHFR C677T polymorphism in Moroccan population.