Background: The Nonsense-Mediated mRNA Decay (NMD) pathway detects and degrades mRNAs containing premature termination codons, thereby preventing the accumulation of potentially detrimental truncated proteins. Intertissue variation in the efficiency of this mechanism has been suggested, which could have important implications for the understanding of genotypephenotype correlations in various genetic disorders. However, compelling evidence in favour of this hypothesis is lacking. Here, we have explored this question by measuring the ratio of mutant versus wild-type Men1 transcripts in thirteen tissues from mice carrying a heterozygous truncating mutation in the ubiquitously expressed Men1 gene.

The nonsense-mediated mRNA decay (NMD) mechanism is an evolutionarily conserved process ensuring the degradation of transcripts carrying premature termination codon(s). NMD is believed to prevent the synthesis of truncated proteins that could be detrimental to the cell. However, although numerous studies have assessed the efficiency of this mechanism at the mRNA level, data are lacking in regard to whether NMD fulfills its expected goal at the protein level. In this study, we have investigated whether endogenous alleles of breast cancer predisposing genes carrying nonsense codons were able to produce detectable amounts of truncated proteins in lymphoblastoid cell lines. A total of 20 truncating BRCA1 mutations were analyzed, along with the 1100delC CHEK2 and the 770delT TP53 mutations. All the studied alleles triggered NMD, the amount of mutant transcript ranging from 16 to 63% of that of the wild-type species. We found that BRCA1 and CHK2 truncated proteins could not be detected, even when NMD was inhibited. This suggests that BRCA1 and CHK2 truncated proteins are highly unstable. Conversely, the p53 protein encoded by the 770delT allele is as abundant as the wild-type protein, as removal of the C-terminal p53 domain leads to a stabilized mutant protein, whose abundance is markedly increased when NMD is inhibited. Therefore, our results show that it is not possible to infer the presence of truncated proteins in cells from carriers of a truncated mutation without experimental verification, as each case is expected to be different.

The 185delAG mutation (c.68_69delAG; ter39) in the BRCA1 gene is a founder Jewish Ashkenazi mutation that is carried by 1% of this population and has been identified in thousands of breast or ovarian cancer patients. We have previously described that transcripts bearing this mutation, as well as transcripts bearing the 188del11 mutation (c.71_81del; ter36), are not degraded by nonsense-mediated mRNA decay (NMD), contrary to our observations of other truncating mutations that introduce premature termination codons (PTCs) farther downstream in the coding sequence [Perrin-Vidoz et al., 2002]. To test the hypothesis that these two mutations fail to trigger NMD because of translation reinitiation, we have constructed BRCA1 minigenes and studied their protein expression after transient expression in HeLa cells. We show here that in the presence of a (PTC) at position 36 or 39, translation reinitiation occurs in the BRCA1 minigenes at position 128.

Introduction: Diabetes mellitus causes serious complications such as diabetic nephropathy. Diabetic nephropathy is now the most common reason of chronic kidney disease. Inflammation plays a crucial role in development and progression of diabetic nephropathy. The aim of this study was to evaluate the relationship of Inflammatory markers (neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio) with diabetic nephropathy in Syrian patients. Materials and methods: A total of 158 patients with type 2 diabetes mellitus were distributed into three groups according to urinary albumin-to-creatinine ratio: Group A, type 2 diabetic patients with normoalbuminuria (urinary albumin-to-creatinine ratio <30 mg/g); Group B, type 2 diabetic patients with microalbuminuria (urinary albumin-to-creatinine ratio ¼ 30-300 mg/g); Group C, type 2 diabetic patients with macroalbuminuria (urinary albumin-to-creatinine ratio !300 mg/g). Levels of inflammatory markers (neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio) were recorded and compared among the three groups. Results: Significant differences were detected between the groups in terms of neutrophil-to-lymphocyte ratio (p ¼ 0.000) and platelet-to-lymphocyte ratio (p ¼ 0.000). Receiver operating characteristic curve analysis of inflammatory markers and microalbuminuria prediction demonstrated an area under curve (AUC) of 0.869 for neutrophil-to-lymphocyte ratio (confidence interval: 0.813-0.926, p ¼ 0.000) and 0.739 for platelet-tolymphocyte ratio (confidence interval: 0.662-0.815, p ¼ 0.000). Conclusion:Increased neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio were significantly correlated with diabetic nephropathy, and high neutrophil-to-lymphocyte ratio & platelet-to-lymphocyte ratio may be served as a predictor and a prognostic risk marker of diabetic nephropathy.

Background Breast cancer is the most commonly occurring cancer in women worldwide. S100A14 is a novel important member of S100 proteins family. Its importance is due to its role in tumorigenesis and metastasis process. In this study, we aimed to determine serum levels of S100A14 protein in breast cancer patients and healthy individuals to know if it can be suggested as a new biomarker for breast cancer and to reveal whether it is correlated with cancer pathological features. Methods This cross-sectional study was performed in two groups: study group contains 46 breast cancer patients (29 metastatic and 17 non-metastatic) and control group contains 22 healthy women. Enzyme-linked immunoabsorbent assay was performed to determine S100A14 protein levels in samples. Pathological data were obtained for each patient. The data were statistically analyzed using Kruskal-Wallis H, Mann-Whitney U, and Spearman correlation tests. Results S100A14 serum levels were elevated in study group compared with control group (P < 0.05). S100A14 serum levels were significantly increased in distant breast cancer patients compared with regional breast cancer patients (P = 0.001). There was a strong positive correlation between serum S100A14 level and tumor grade (rs = 0.713, P < 0.001). Conclusion Our study indicated that S100A14 serum levels are elevated in breast cancer patients compared with control individuals. High S100A14 serum levels were correlated with poor tumor differentiation so it might have a prognostic significance for breast cancer tumors. The elevation of S100A14 levels in distant breast cancer patients suggests the ability of using serum S100A14 as a biomarker for detection of breast cancer metastasis.

Endometriosis is a very common debilitating disease that occurs in 6 to 10 percent of the general female population; in women with pain, infertility, or both, the frequency is 35–50%. Endometriosis is one of the most important causes of infertility. Our objective is to evaluate the effect of endometriosis and adenomyosis on IVF outcome (ongoing pregnancy). 65 women underwent In Vitro Fertilization (IVF) and embryos transfer who had endometriosis with or without adenomyosis were recruited in this retrospective study, resulting in 53.8% had a successful IVF attempt (get pregnant). The highest success rate of IVF was in women who were in mild of endometriosis and IVF failure rate was increased mainly in women who were in severe endometriosis. So, the presence of adenomyosis affects IVF outcome and decreases the rate of implantation.

Background Although there is relatively much information about the status of cystic fibrosis disease in different countries of the world, limited data are available on this disease among Syrian children. Therefore, we did a retrospective study that included 173 children diagnosed with cystic fibrosis according to the diagnostic criteria. This study was conducted to determine the diagnostic, clinical, and genetic characteristics of patients with cystic fibrosis in Syria and to assess the relationship between the genotype and the phenotype of disease in these patients. Results As a result of the early classical manifestations, CF diagnosis was established in the present study by the age of 1 year in 78.6%; the mortality rate was 23.1% (82.5% of them were in the first year of life). The prevalence of respiratory and gastrointestinal symptoms was 81.5% and 78.6%, respectively with an average age of 7.8 and 3.4 months. Consanguinity was reported in 75.7% of the families. The most common pathogenic variant in the sample was F508del (36%) followed by W1282X (17%). There was a statistical correlation between incidence of steatorrhea and the presence of class I pathogenic variants. A relationship between the mortality rate and the presence of class II pathogenic variants (pathogenic deletion variants) was also observed. There was no statistical relationship between other clinical manifestation and pathogenic variant classes. However, the incidence of most CF-related conditions was a little higher in the presence of classes I, II, and III pathogenic variants compared to their incidence in the presence of classes IV and V pathogenic variants. Conclusions The number of cases diagnosed with cystic fibrosis in Syria is less than the number of real cases, and there is a need to perform CFTR gene sequencing on large sample sizes, to determine all CFTR pathogenic variants that could exist in Syrian patients and to make a better evaluation of the relationship between genotype and phenotype of the disease.