Humoral and cellular response of two different vaccines against SARS-CoV-2 in a group of healthcare workers: An observational study.

On March 13, 2021, Tunisia started a widespread immunization program against SARS-CoV-2 utilizing different vaccinations that had been given emergency approval. Herein, we followed prospectively a cohort of participant who received COVID-19 vaccine (Pfizer BioNTech and Sputnik-Gameleya V). The goal of this follow-up was to define the humoral and cellular immunological profile after immunization by assessing neutralizing antibodies and IFN- γ release. 26 vaccinated health care workers by Pfizer BioNTech (n=12) and Sputnik-Gameleya V (n=14) were enrolled from June to December 2021 in Military hospital of Tunis. All consenting participants were sampled for peripheral blood after three weeks of vaccination. The humoral response was investigated by the titer of anti-SARS-CoV-2 immunoglobulin G (IgG) antibodies to S1 protein. The CD4 and CD8 T cell responses were evaluated by the QuantiFERON® SARS-CoV-2 (Qiagen® Basel, Switzerland). Regardless the type of vaccine, the assessment of humoral and cellular response following vaccination showed a strong involvement of the later with expression of IFN-γ as compared to antibodies secretion. Moreover, we showed that people with past SARS-CoV-2 infection developed high levels of antibodies than those who are not previously infected. However, no significant difference was detected concerning interferon gamma (IFN-γ) expression by CD4 and CD8 T cells in health care worker (HCW) previously infection or not with COVID-19 infection. Analysis of immune response according to the type of vaccine, we found that Pfizer BioNTech induced high level of humoral response (91.66%) followed by Sputnik-Gameleya V (64.28%). However, adenovirus vaccine gave a better cellular response (57.14%) than mRNA vaccine (41.66%). Regarding the immune response following vaccine doses, we revealed a significant increase of neutralizing antibodies and IFN-γ release by T cells in patients fully vaccinated as compared to those who have received just one vaccine. Collectively, our data revealed a similar immune response between Pfizer BioNTech and Sputnik-Gameleya V vaccine with a slight increase of humoral response by mRNA vaccine and cellular response by adenovirus vaccine. It's evident that past SARS-CoV-2 infection was a factor that contributed to the vaccination's increased immunogenicity. However, the administration of full doses of vaccines (Pfizer BioNTech or Sputnik-Gameleya V) induces better humoral and cellular responses detectable even more than three months following vaccination.

sCXCL16 as a prognostic biomarker for COVID-19 outcome.

As elevated levels of the soluble CXCL16 (sCXCL16) chemokine have been reported in severe coronavirus disease 2019 (COVID-19) patients, this study examined whether sCXCL16 concentration on the first day of hospitalization predicted death in COVID-19 patients. A total of 76 patients with COVID-19 were admitted to the Military Hospital of Tunis, Tunisia, between October 2020 and April 2021, and later classified as survivors or nonsurvivors based on their outcomes. At admission, the groups were matched by age, gender, comorbidities, and the percentage of patients with moderate conditions. On the first day of admission, serum's sCXCL16 concentrations were measured using a magnetic-bead assay. There was an eightfold increase in serum sCXCL16 levels in the nonsurvivors' group (3661.51 ± 2464.87 pg/mL vs. 454.3 ± 338.07 pg/mL, p < 0.0001). For the optimal cutoff value of sCXCL16 at 2095 pg/mL, we found a 94.6% sensitivity and a 97.4% specificity, with an area under curve of 0.981 (p = 5.03E-08; 95% confidence interval [95% CI]: 0.951-1.0114). Considering the risk of death at a concentration above the threshold, the unadjusted odds ratio was 36 (p < 0.0001). The adjusted odd ratio was estimated at 1.003 (p < 0.0001; 95% CI: 1.002-1.004). Finally, there was a significant difference between survival and nonsurvival groups in leukocyte numbers (p = 0.006), lymphocytes (p = 0.001), polymorphonuclear neutrophils (p = 0.001), and C-reactive protein levels (p = 0.007), except for monocytes (p = 0.881). Based on these results, sCXCL16 level could be used for detecting nonsurvival COVID-19 patients. Therefore, we recommend assessing this marker in hospitalized COVID-19 patients.

Immune Cell Response during COVID-19 Infection and following SARS-CoV-2 Vaccination in Patients Admitted to Intensive Care Unit.

Background: Immune response plays a crucial role in virus clearance during COVID-19 infection and underpins vaccine efficacy. Herein, we aimed to assess the immune response during COVID-19 infection and following SARS-CoV-2 vaccination. Methods: In this retrospective study, 94 confirmed COVID-19 patients admitted to the intensive care unit were categorized into unvaccinated patients (n = 50), including 33 deceased and 17 discharged patients, and vaccinated group (n = 44) with 26 deceased and 18 discharged patients. Records of patients with severe COVID-19 admitted to the ICU between March, 2021 and March, 2022 were gathered and analyzed. Result: The assessment of immune cell counts revealed a large rise of neutrophils associated to decrease number of lymphocytes in patients with COVID-19 infection. In dead patients, we detected a significant correlation between neutrophils and inflammatory parameters such as IL-6 and CRP. Moreover, analysis of immune cell count following vaccination did not reveal any significant difference. However, the most substantial result, herein, detected is the decrease level of IL-6 in vaccinated patients as compared to unvaccinated. The reduce level of IL-6 following vaccination is observed in discharged patients as compared to deceased. Regarding the level of mortality after vaccination, we showed that all patients who received the first dose were died (46.1%, n = 12) as compared to those who have received two doses (34.6%, n = 9) and the third dose of vaccine (19.23%, n = 3) (p=0.0018). Strikingly, studying the inflammatory parameters after each vaccine dose, we revealed a significant decrease of IL-6 level after the booster dose (third dose), especially in vaccinated discharged patients. Conclusions: Neutrophils combined with IL-6 and CRP can be very useful markers to predict disease severity in patients admitted to ICU. The decrease level of IL-6 in vaccinated group pointed out the impact of vaccination to prevent inflammatory cytokine release.

Twice-Daily Oral Zinc in the Treatment of Patients With Coronavirus Disease 2019: A Randomized Double-Blind Controlled Trial.

BACKGROUND: Zinc supplementation has been considered a potential therapy for coronavirus disease 2019 (COVID-19). We aimed to examine zinc efficacy in adult patients with COVID-19 infection. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled multicenter trial. Patients who were tested positive for COVID-19 without end-organ failure were randomized to oral zinc (n = 231) or matching placebo (n = 239) for 15 days. The primary combined outcome was death due to COVID-19 or intensive care unit (ICU) admission ≤30 days after randomization. Secondary outcomes included length of hospital stay for inpatients and duration of COVID-19 symptoms with COVID-19-related hospitalization for outpatients. RESULTS: 190 patients (40.4%) were ambulatory and 280 patients (59.6%) were hospitalized. Mortality at 30 days was 6.5% in the zinc group and 9.2% in the placebo group (OR: .68; 95% CI .34-1.35); ICU admission rates were, respectively, 5.2% and 11.3% (OR: .43; 95% CI .21-.87). Combined outcome was lower in the zinc group versus the placebo group (OR: .58; 95% CI .33-.99). Consistent results were observed in prespecified subgroups of patients aged <65 years, those with comorbidity, and those who needed oxygen therapy at baseline. Length of hospital stay was shorter in the zinc group versus the placebo group (difference: 3.5 days; 95% CI 2.76-4.23) in the inpatient group; duration of COVID-19 symptoms decreased with zinc treatment versus placebo in outpatients (difference: 1.9 days; 95% CI .62-2.6). No severe adverse events were observed during the study. CONCLUSIONS: Our results showed that, in COVID-19 patients, oral zinc can decrease 30-day death, ICU admission rate and can shorten symptom duration. Clinical Trials Registration. ClinicalTrials.gov, NCT05212480.

COVID-19 prophylaxis with doxycycline and zinc in health care workers: a prospective, randomized, double-blind clinical trial.

OBJECTIVES: This study aims to assess the efficacy of a combination treatment of doxycycline and zinc in the primary prevention of COVID-19 infection in Tunisian health care workers compared with two control groups. METHODS: We conducted a prospective, randomized, double-blind clinical trial over 5 months to determine the efficacy of a preventive combination treatment dose of doxycycline (100 mg/day) and zinc (15 mg/day), compared with a single-dose treatment with doxycycline versus placebo. The effectiveness of preventive treatment was measured by the significant decline in the number of cases of COVID-19 infection and/or a decrease in the viral load as determined by SARS-CoV-2 cycle threshold value using reverse transcription polymerase chain reaction tests. RESULTS: We detected a significant decrease of SARS-CoV-2 infection in the group that received both doxycycline and zinc compared with other participants. We also demonstrated that COVID-19 infection was neither associated with diabetes (P = 0.51) nor associated with hypertension (P = 0.99), asthma (P = 0.52), and chronic obstructive pulmonary disease (P = 0.27). CONCLUSION: Our findings indicated that preventive therapy reduced the risk of SARS-CoV-2. These results suggest that the combination of doxycycline and zinc has a protective effect in patients with SARS-CoV-2 infection.

Immediate Psychological Responses, Stress Factors, and Coping Behaviors in Military Health-Care Professionals During the COVID-19 Pandemic in Tunisia.

Objective: The COVID-19 epidemic began in Tunisia in March 2020; health-care workers (HCWs) were suddenly confronted with a particularly stressful situation. The aim of this study was to assess the psychological responses of HCWs during the epidemic, determine the stressors and identify ways to cope. Methods: This cross-sectional study used an online questionnaire that included 62 questions. ANOVAs and t-tests were used to compare the responses between professional groups, age groups, and genders. Results: Questionnaires were completed by 368 HCWs. HCWs believed they had a social and professional obligation to continue working long hours (95.3%). They were anxious regarding their safety (93.7%) and the safety of their families (97.8%). Youthful age (p = 0.044) and female gender (ps <0.046) were identified as stressors. The availability of personal protective equipment (PPE; 99.7%) and good communication between colleagues (98.1%) and managers (91.6%) were important protective factors. Family and friend support (95.9%), following strict protective measures (99.4%), knowing more about COVID-19 (94.8%), adopting a positive attitude (89.6%), and engaging in leisure activities (96.1%) helped in dealing with this epidemic. Conclusion: This study highlights the importance of providing HCWs with infection control guidelines and adequate PPE. Communication and support within the team and maintaining family support help in coping with this stressful situation.

Involvement of IL17A, IL17F and IL23R Polymorphisms in Colorectal Cancer Therapy.

IL23/IL17 pathway plays an important role in the development of inflammatory bowel diseases (IBD). In general, the genes encoding the cytokines are genetically polymorphic and polymorphisms in genes IL23R and IL17 have been proved to be associated with its susceptibility to inflammatory diseases as well as cancer including colorectal cancer. Moreover, it has been shown that these interleukins are involved in anti-tumor or pro-tumor effects of various cancers. Previously, we showed that there is a significant association between IL17A, IL17F and IL23R polymorphisms as well as the occurrence of colorectal cancer and the clinical features of the disease. The purpose of the present work is to investigate an association between IL17A, IL17F and IL23R polymorphisms in 102 Tunisian patients with colorectal cancer treatment. The association was analyzed by statistical tools. We found that patients with mutated genotypes of IL17A G197A SNP could be a risk factor for the inefficiency of chemotherapy and radiotherapy. Unlike IL17F variant, patients with wild type genotypes require surgery and adjuvant chemotherapy. On the one hand, we found no evidence that supports a significant association between IL23R polymorphism and the combined genotypes of these three genes and the colorectal cancer treatment. On the other hand, we showed that there is an important interaction between IL17A/IL17F polymorphisms and the stage of the disease as well as its treatment. Finally, patients with IL17F wild type genotype highlighted that there is a valid longer OS without all treatments and with radiotherapy and a neoadjuvant chemotherapy. In contrast, we observed that there are no relationships between IL17A, IL23R and the survival of these patients neither with nor without the treatment. Our results suggest that polymorphisms in IL17A and IL17F genes may be a predictive source of colorectal cancer therapy type. Therefore, IL17F may serve as an independent prognostic factor for overall survival in patients with colorectal cancer.

Wild-type genotypes of BRCA1 gene SNPs combined with micro-RNA over-expression in mammary tissue leading to familial breast cancer with an increased risk of distant metastases' occurrence.

Germ line deleterious mutations of BRCA1 gene are not the unique factor that could inactivate BRCA1 protein which leads to familial breast cancer onset with distant metastases' occurrence. The present research explores the role that could be assigned to BRCA1 SNPs to inactivate BRCA1 protein and therefore to the occurrence of familial breast cancer with an increased risk of distant metastases' occurrence. The presence or the absence of BRCA1 protein was first analyzed by applying the immunohistochemistry technique to the tumors with sporadic and familial breast cancer. Then, a case-control study was conducted including 40 patients with familial breast cancer, 46 ones with sporadic breast cancer and 34 healthy controls based on the genotyping of nine BRCA1 SNPs (c.442.58delT, c.2082C>T, c.2311T>C, c.2612C>T, c.3113A>G, c.3119G>A, c.3548A>G, c.4308T>C and 4837A>G) via direct sequencing. Finally, the functional role that could be assigned to these SNPs was focused upon. miRbase site was used as a bioinformatics tool to predict potential micro-RNAs (miRs) targeting SNPs that are associated with familial breast cancer according to the results of this research. These predicted miRs were confirmed by Q-PCR analysis and correlated with BRCA1 protein expression among patients along with potential distant metastases. Clinical outcome showed that distant metastasis concerned 45 % of familial breast cancer patients and 19.5 % with sporadic breast cancer. Analysis of BRCA1 protein expression revealed a negative staining among 46.6 % of familial breast cancer patients and only 16.6 % within sporadic breast cancer ones. The association of four variants was identified within BRCA1 gene (c.442.58 delT, c.2311T>C, c.2612C>T and c.4308T>C) to familial breast cancer across their wild genotypes. miR-1179 was selected as potential miR that targets the region of BRCA1 mRNA containing the c.2311T>C variant within the TT genotype. The expression of miR-1179 was significantly associated with familial breast cancer patients without BRCA1 deleterious mutations compared to those with sporadic breast cancer according to TT genotype along with BRCA1 negative staining and according to the occurrence of distant metastases. Combination between TT genotype of c.2311T>C and miR-1179 over-expression could generate a lack of BRCA1 protein leading to a high risk of familial breast cancer with distant metastases.

Breast cancer in Tunisia: association of body mass index with histopathological aspects of tumors.

BACKGROUND: Previous studies have suggested a link between obesity and breast cancer (BC). However, there is no universal consensus, especially in population based studies. Because only few studies have been conducted on African women, we aimed here to assess the relationship between BMI at time of diagnosis and the BC histopathological features among Tunisian patients according to menopausal status using a hospital-based prospective cohort study. MATERIALS AND METHODS: Clinical and pathological data were collected from 262 patients stratified on four groups according to their BMI. The relationship between BMI and histopathological features at diagnosis was analysed using univariate and multivariate analysis. Receiver-operating characteristic (ROC) curves were used to evaluate the performance of BMI in predicting of high tumor grade, in comparison to ki-67 index of proliferation. RESULTS: Obesity was correlated with larger tumors, advanced grade and with ER-PR- Her2+ BC subtype. An association of BMI with tumor size and tumor grade was observed in both premenopausal and postmenopausal women. Additionally, a significant association between BMI and ER+, ER+PR+Her2+ and ER-PR-Her2+ status was revealed for premenopausal patients, while only ER+PR+Her2+ was associated with BMI for postmenopausal women. Finally, our results showed that compared to Ki67 proliferation index, BMI is a useful prognostic marker of high grade BC tumors. CONCLUSIONS: These data are the first to show that in Tunisia obese women suffering from BC have significantly larger tumors and advanced tumor grade and that higher BMI might influence tumor characteristics and behavior.

MicroRNAs 146a and 147b biomarkers for colorectal tumor's localization.

The recently identified class of microRNAs (miRs) provided a new insight into cancer research, since abnormalities of members of microRNAs family have been found in various types of cancer. However, the relationship between five miRNAs (miR146a, miR155, miR21, miR135a, and miR147b) and colorectal cancer remains unclear. In the present study, we examined expression of these miRNAs in 25 pair-matched colon cancer tissues and normal colon mucosa. The expression levels of miR146a, miR155, miR21, miR135a, and miR147b were quantified by real-time PCR. We found that miR21, miR146a, and miR135a were all expressed at higher levels in colon tumors. On the other hand, miR146a and miR147b expressions are significantly higher in left colon compared to right colon. These two miRs, especially miR146a, seemed to be markers for the left colon tumors. Moreover, significant proportional and inverse correlations were found between miR expressions in tumor and healthy tissue, and the correlations profiles were different depending on cancer localization. Taken together, these results lead us to suggest the presence of different mechanisms regulating miRs expression and consequently their target genes in left and right colon. So the pathway of colorectal carcinogenesis would be different according to the site of the tumor.

Significant association between interleukin-17A polymorphism and colorectal cancer.

Interleukin (IL) 17A is an inflammatory cytokine expressed by Th 17 cells and plays a role in tissue inflammation by inducing release of proinflammatory and neutrophil-mobilizing cytokines. We have investigated the association between colorectal cancer and polymorphisms of IL17A (rs2275913. G197A). The study was performed in 241 subjects (102 with colorectal cancer and 139 healthy controls). Genotypes were determined by fluorescent-based restriction fragment length polymorphism method. The association between the molecular features at the gene in relation to tumor and patient clinical characteristics was analyzed. There was a significant difference between the genotype frequencies of IL17A G197A of control subjects (GG 68.34 % and GA + AA 31.65 %) and patients with colorectal cancer (GG 47.05 % and GA + AA 52.94 %) (p = 0.001 with odds ratio (OR) 2.45 (1.43-4.11)). IL17A G197A polymorphism is particularly associated with colon cancer. Indeed, the IL17A GG genotype could be considered as a protective factor against colon cancer (p = 0.00001) with OR 3.77 (2.04-6.99). We have noted a significant association of IL17A G197A polymorphism not only with tumor localization (p = 0.003) but also with tumor differentiation (p = 0.0005) in CRC patients. We have also showed a significant association of G197A variant with an increased risk of advanced stage (p = 0.005). Our result suggests that the A allele of IL17A gene is involved in susceptibility to colorectal cancer and is associated with clinical features as tumor location, tumor differentiation, and TNM stage. IL17A polymorphism may serve as biomarker of disease location and progression.

3020insC NOD2/CARD15 polymorphism associated with treatment of colorectal cancer.

Chronic inflammation is closely linked to cancer. The risk of damage by colorectal cancer (CRC) may increase due to autoimmune disease and cryptogenic inflammation. Therefore, genetic factors implicated in the chronic irritation in inflammatory bowel disease such as NOD2/CARD15 may predispose to CRC. In this report, we shed the light on the possible contribution of the NOD2 3020insC variant to CRC risk in a series of 246 Tunisian subjects including 101 patients with CRC and 145 healthy controls. NOD2/CARD15 polymorphism was genotyped by sizing fluorescently labeled PCR products and automated sequencers. We analyzed the association between the molecular features at this gene in relation to tumor and patient characteristics and treatments. Through this qualitative analysis, we found that CRC patients with mutant allele of NOD2/CARD15 were suffering from Crohn's disease (CD) with canonic presentation. We also observed a positive association between 3020insC polymorphism and surgery and chemotherapy. We suppose that around 3% of colorectal cases which happen at an age older than 50 years are associated with the canonic form of CD along with the 3020insC mutation and that these patients are in need for chemotherapy.

Structural insight into the binding complex: ß-arrestin/CCR5 complex.

The chemokine receptor 5 (CCR5) belongs to the superfamily of serpentine G protein-coupled receptors (GPCRs). The DRY motif (Asp, Arg, Tyr) of the intracellular loop 2 (ICL2), which is highly conserved in the GPCRs has been shown to be essential for the stability of folding of CCR5 and the interaction with ß-arrestin. But the molecular mechanism by which it recognizes and interacts with ß-arrestin has not been elucidated. In the present study, we described the active state of the ß-arrestin structure using normal mode analysis and characterized the binding cleft of CCR5-ICL2 with ß-arrestin using SABRE© docking tool and molecular dynamics simulation. Based on our computational results, we proposed a mode of binding between the ICL2 loop of CCR5 and ß-arrestin structure, and modeled the energetically stable ß-arrestin/CCR5 complex. In view of CCR5's importance as a therapeutic target for the treatment of HIV, this observation provides novel insight into the ß-arrestin/CCR5 pathway. As a result, the current computational study of the detailed ß-arrestin/CCR5 binding complex could provide the rationale for the development of next generation of HIV peptide inhibitors as therapeutic agents.

Significant association between IL23R and IL17F polymorphisms and clinical features of colorectal cancer.

Th17cells are involved in inflammatory and autoimmune diseases. These cells may be involved in pathological processes mainly producing pro-inflammatory cytokines. Recently, it was shown that the IL23/IL17 pathway plays an important role in the development of inflammatory bowel disease. In general, genes encoding cytokines are genetically polymorphic and polymorphisms in genes IL23R el IL17F were shown associated with susceptibility to Crohn's disease and ulcerative colitis which in their turn are considered as risk factors for developing colorectal cancer (CRC). Our approach is to study IL17F and IL23R polymorphisms as risk factor associated with CRC in the Tunisian population in patients and healthy controls. Interesting, we noted a significant association between IL17F and IL23R polymorphisms and tumor location (p=0.0001 and p=0.049, respectively), tumor histology (p=0.007 and p=0.049, respectively) and tumor architecture (p=0.0000000001 and p=0.07, respectively) in CRC patients. We also showed a significant association of IL17F variant with an increased risk of TNM stage III/IV (p=0.007), showing an increased risk of advanced stage. Finally, we observed a positive link between IL17F polymorphism and CRC patients with lymph nodes (p=0.0000000001) and metastasis (p=0.00000009). However, we found no evidence to support a significant association between IL17F and IL23R polymorphisms and colorectal cancer susceptibility. Our findings suggest that IL17F and IL23R polymorphisms were significantly associated with clinical features variables. The IL17F cytokine appear to be involved in the control of tumor growth and invasion of gastrointestinal tumors. IL17 and IL23 polymorphisms or those of their receptors as important determinants of susceptibility to colorectal cancer are still subject to questioning.

Positive link between variant Toll-like receptor 4 (Asp299Gly and Thr399Ile) and colorectal cancer patients with advanced stage and lymph node metastasis.

Toll-like receptors (TLRs) are considered as major endotoxin-signaling receptor and as crucial sensors of innate immunity. TLRs recognize pathogen-associated molecular patterns; induce effectors genes involving inflammatory cytokines and therefore initiation of adaptative immune responses against pathogens. Recently, it has been shown that TLRs are involved in tumor progression. In fact, increased level of TLR4 is associated with progression of colon malignancies. Even, TLR4 polymorphism has been shown associated with susceptibility to have colorectal cancer. Our study aimed to investigate an association between TLR4 Asp299Gly (D299G) and Thr399Ile (T399I) polymorphisms in Tunisian patients with colorectal cancer. Using a primer extension method (SNaPshot), we genotyped two variants of TLR4 D299G and T399I in 100 patients with colorectal cancer and 140 healthy controls in Tunisian population. Interesting, we noted a significant association between T399I polymorphism and tumor differentiation (p = 0.027) and tumor architecture (p = 0.02) in colorectal cancer (CRC) patients. We also showed a significant association of D299G with an increased risk of advanced stage (p = 0.03). Finally, we observed a positive link between D299G and T399I polymorphisms and CRC patients with lymph node (p = 0.00024; p = 0.0005, respectively) and metastasis (p = 0.001; p = 0.002, respectively). However, we found no evidence to support a significant association between TLR4 D299G and T399I polymorphisms and colorectal cancer susceptibility. Our findings suggest that TLR4 D299G and T399I polymorphisms are significantly associated with clinical features variables. TLR4 polymorphisms may serve as biomarker of disease progression. Therefore, our results need confirmation in even larger studies.

Structural insight into a novel human CCR5-V130I variant associated with resistance to HIV-1 infection.

We report the identification of a novel CC chemokine receptor 5 (CCR5) variant that seems associated with resistance to HIV-1 infection. The V130I mutation of the CCR5 receptor is located in the intracellular loop ICL2 known as DRY box and described in the literature as a nonsynonymous mutation present in nonhuman primates group. Extensive molecular modeling and dynamics simulations were performed to elucidate the mechanism by which the V130I mutation may induce conformational change of the CCR5 folding protein and prevent the interaction with the ß-arrestin protein. Our study provides new mechanistic insight into how a specific mutation in the regulatory domain of CCR5 might alter the structural folding of the DRY box and the possible ICL2 loop binding with the ß-arrestin protein, as described in our previous computational study. The results from our large-scale simulations complement recent experimental results and clinical features and offer useful insights into the mechanism behind CCR5 protein folding and signal transduction. In order for HIV, the entry of the virus to the cells must fuse with the CCR5 receptor that sits on the surface of T-helper immune cells. The described V130I mutation in the gene encoding the CCR5 protein may results in a defective CCR5-Arrestin binding complex that blocks entry of the virus.

The effect of tobacco, XPC, ERCC2 and ERCC5 genetic variants in bladder cancer development.

BACKGROUND: In this work, we have conducted a case-control study in order to assess the effect of tobacco and three genetic polymorphisms in XPC, ERCC2 and ERCC5 genes (rs2228001, rs13181 and rs17655) in bladder cancer development in Tunisia. We have also tried to evaluate whether these variants affect the bladder tumor stage and grade. METHODS: The patients group was constituted of 193 newly diagnosed cases of bladder tumors. The controls group was constituted of non-related healthy subjects. The rs2228001, rs13181 and rs17655 polymorphisms were genotyped using a polymerase chain reaction-restriction fragment length polymorphism technique. RESULTS: Our data have reported that non smoker and light smoker patients (1-19PY) are protected against bladder cancer development. Moreover, light smokers have less risk for developing advanced tumors stage. When we investigated the effect of genetic polymorphisms in bladder cancer development we have found that ERCC2 and ERCC5 variants were not implicated in the bladder cancer occurrence. However, the mutated homozygous genotype for XPC gene was associated with 2.09-fold increased risk of developing bladder cancer compared to the control carrying the wild genotype (p = 0.03, OR = 2.09, CI 95% 1.09-3.99). Finally, we have found that the XPC, ERCC2 and ERCC5 variants don't affect the tumors stage and grade. CONCLUSION: These results suggest that the mutated homozygous genotype for XPC gene was associated with increased risk of developing bladder. However we have found no association between rs2228001, rs13181 and rs17655 polymorphisms and tumors stage and grade.

The impact of smoking and polymorphic enzymes of xenobiotic metabolism on the stage of bladder tumors: a generalized ordered logistic regression analysis.

Cigarette smoking is the predominant risk factor for bladder cancer in males and females. The tobacco carcinogens are metabolized by various xenobiotic metabolizing enzymes such as N-acetyltransferases (NAT) and glutathione S-transferases (GST). Polymorphisms in NAT and GST genes alter the ability of these enzymes to metabolize carcinogens. In this paper, we conduct a statistical analysis based on logistic regressions to assess the impact of smoking and metabolizing enzyme genotypes on the risk to develop bladder cancer using a case-control study from Tunisia. We also use the generalized ordered logistic model to investigate whether these factors do have an impact on the progression of bladder tumors.

Experimental and computational studies indicate specific binding of pVHL protein to Aurora-A kinase.

Overexpression of Aurora-A kinase is commonly detected in many cancers, whereas the von Hippel-Lindau protein (pVHL) is frequently mutated or absent in renal cell carcinoma and is involved in the Ub proteasome complex, an important degradation pathway. In order to establish a link between Aurora-A overexpression and lack of pVHL protein, we hypothesized that pVHL regulates Aurora-A expression through a physical interaction. We present the first evidence, from both biological assays and computational biology techniques, that human pVHL binds strongly to Aurora-A kinase. Extensive molecular modeling, docking, and dynamic simulations demonstrate that the structure of the pVHL protein would allow it to bind to the TPX2 binding region of Aurora-A. In view of Aurora-A's importance as a therapeutic target for the treatment of cancer, this observation provides novel insights into the Aurora-A/pVHL pathway. In addition, the detailed Aurora-A/pVHL binding structure obtained will be valuable for the design of future Aurora-A inhibitors as therapeutic agents.