Familial adenomatous polyposis (known also as classical or severe FAP) is a rare autosomal dominant colorectal cancer predisposition syndrome, characterized by the presence of hundreds to thousands of adenomatous polyps in the colon and rectum from an early age. In the absence of prophylactic surgery, colorectal cancer (CRC) is the inevitable consequence of FAP. The vast majority of FAP is caused by germline mutations in the adenomatous polyposis coli (APC) tumor suppressor gene (5q21). To date, most of the germline mutations in classical FAP result in truncation of the APC protein and 60% are mainly located within exon 15.
Material and methods
In this first nationwide study, we investigated the clinical and genetic features of 52 unrelated Algerian FAP families. We screened by PCR-direct sequencing the entire exon 15 of APC gene in 50 families and two families have been analyzed by NGS using a cancer panel of 30 hereditary cancer genes.
Results
Among 52 FAP index cases, 36 had 100 or more than 100 polyps, 37 had strong family history of FAP, 5 developed desmoids tumors, 15 had extra colonic manifestations and 21 had colorectal cancer. We detected 13 distinct germline mutations in 17 FAP families. Interestingly, 4 novel APC germline pathogenic variants never described before have been identified in our study.
Conclusions
The accumulating knowledge about the prevalence and nature of APC variants in Algerian population will contribute in the near future to the implementation of genetic testing and counseling for FAP patients.
Marine Biotechnology - Effects of CRISPR/Cas9 knockout of the melanocortin-4 receptor (mc4r) gene in channel catfish, Ictalurus punctatus, were investigated. Three sgRNAs targeting the channel... 相似文献
The Mrc1 and Tof1 proteins are conserved throughout evolution, and in budding yeast they are known to associate with the MCM helicase and regulate the progression of DNA replication forks. Previous work has shown that Mrc1 is important for the activation of checkpoint kinases in responses to defects in S phase, but both Mrc1 and Tof1 also regulate the normal process of chromosome replication. Here, we show that these two important factors control the normal progression of DNA replication forks in distinct ways. The rate of progression of DNA replication forks is greatly reduced in the absence of Mrc1 but much less affected by loss of Tof1. In contrast, Tof1 is critical for DNA replication forks to pause at diverse chromosomal sites where nonnucleosomal proteins bind very tightly to DNA, and this role is not shared with Mrc1. 相似文献
One factor that has the potential to regulate reactive oxygen species (ROS) generation is the mild uncoupling of oxidative phosphorylation, i.e. proton (H(+)) leak across the mitochondrial inner membrane. Proton leak has been shown to attenuate ROS generation, whereas ROS and their derivatives (such as superoxide and hydroxynonenal) have been shown to induce H(+) leak through uncoupling proteins (UCPs). This suggests the existence of a feedback loop between ROS and H(+) leak mediated through UCPs. Although the physiological functions of the new UCPs, such as UCP2 and UCP3, are still not established, extensive data support the idea that these mitochondrial carrier proteins are involved in the control of ROS generation. The molecular basis of both ROS generation and hydroxynonenal-induced uncoupling through UCPs is reviewed and the consequences of their interaction for protection against excessive ROS production at the expense of energy production is discussed. 相似文献
Essential oils obtained by hydrodistillation from different organs (flowers, leaves, stems and roots) of Tunisian coriander (Coriandrum sativum L.) was analyzed. GC and GC-MS analysis enabled us to identify 64 compounds and revealed great qualitative and quantitative differences between the analyzed parts. In all organs, the main compound was (E)-2-dodecenal, followed by (E)-2-tridecenal, gamma-cadinene, (Z)-myroxide, neryl acetate and eugenol. Multivariate analysis (PCA) revealed a high similarity in the essential oils composition between upper leaves and flowers in one hand and basal leaves, roots and stems on the other hand. Further, it has been reported an organ-dependant distribution of essential oil compounds. 相似文献
Recognition of lipopolysaccharide (LPS) by Toll-like receptor (TLR)4 initiates an intracellular signaling pathway leading to the activation of nuclear factor-kappaB (NF-kappaB). Although LPS-induced activation of NF-kappaB is critical to the induction of an efficient immune response, excessive or prolonged signaling from TLR4 can be harmful to the host. Therefore, the NF-kappaB signal transduction pathway demands tight regulation. In the present study, we describe the human protein Listeria INDuced (LIND) as a novel A20-binding inhibitor of NF-kappaB activation (ABIN) that is related to ABIN-1 and -2 and, therefore, is further referred to as ABIN-3. Similar to the other ABINs, ABIN-3 binds to A20 and inhibits NF-kappaB activation induced by tumor necrosis factor, interleukin-1, and 12-O-tetradecanoylphorbol-13-acetate. However, unlike the other ABINs, constitutive expression of ABIN-3 could not be detected in different human cells. Treatment of human monocytic cells with LPS strongly induced ABIN-3 mRNA and protein expression, suggesting a role for ABIN-3 in the LPS/TLR4 pathway. Indeed, ABIN-3 overexpression was found to inhibit NF-kappaB-dependent gene expression in response to LPS/TLR4 at a level downstream of TRAF6 and upstream of IKKbeta. NF-kappaB inhibition was mediated by the ABIN-homology domain 2 and was independent of A20 binding. Moreover, in vivo adenoviral gene transfer of ABIN-3 in mice reduced LPS-induced NF-kappaB activity in the liver, thereby partially protecting mice against LPS/D-(+)-galactosamine-induced mortality. Taken together, these results implicate ABIN-3 as a novel negative feedback regulator of LPS-induced NF-kappaB activation. 相似文献
While changes in intracellular calcium levels is a central step in platelet activation and thrombus formation, the contribution and mechanism of receptor-operated calcium entry (ROCE) via transient receptor potential channels (TRPCs) in platelets remains poorly defined. In previous studies, we have shown that TRPC6 regulates hemostasis and thrombosis, in mice. In the present studies, we employed a knockout mouse model system to characterize the role of TRPC6 in ROCE and platelet activation. It was observed that the TRPC6 deletion (Trpc6?/?) platelets displayed impaired elevation of intracellular calcium, i.e., defective ROCE. Moreover, these platelets also exhibited defects in a host of functional responses, namely aggregation, granule secretion, and integrin αIIbβ3. Interestingly, the aforementioned defects were specific to the thromboxane receptor (TPR), as no impaired responses were observed in response to ADP or the thrombin receptor-activating peptide 4 (TRAP4). The defect in ROCE in the Trpc6?/? was also observed with 1-oleoyl-2-acetyl-sn-glycerol (OAG). Finally, our studies also revealed that TRPC6 regulates clot retraction. Taken together, our findings demonstrate that TRPC6 directly regulates TPR-dependent ROCE and platelet function. Thus, TRPC6 may serve as a novel target for the therapeutic management of thrombotic diseases. 相似文献
ObjectivePhosphate (P) and zinc (Zn) are essential plant nutrients required for nodulation, nitrogen-fixation, plant growth and yield. Mostly applied P and Zn nutrients in the soil are converted into unavailable form. A small number of soil microbes have the ability to transform unsolvable forms of P and Zn to an available form. P-Zn-solubilizing rhizobacteria are potential alternates for P and Zn supplement. In the present study, the effect of two P-Zn-solubilizing bacterial strains (Bacillus sp. strain AZ17 and Pseudomonas sp. strain AZ5) was evaluated on the growth of chickpea plant.MethodologyBoth strains were purified from the rhizospheric soil of chickpea plant grown-up in sandy soil and rain-fed area (Thal desert). In vitro, both strains solubilize P and Zn as well both strain produce IAA and organic acids. In the field experiments, conducted in the rain-fed area, the positive influence of inoculation with both bacterial isolates AZ5 and AZ17 on chickpea growth was observed.ResultsThe application of inoculum (strains AZ5 and AZ17) resulted in up to 17.47% and 17.34% increase in grain yield of both types of chickpea grown in fertilized and non-fertilized soil, respectively over non-inoculated control. Strain AZ5 was the most effective inoculum, increasing up to 17.47%, 16.04%, 26.32%, 22.53%, 26.12% and 22.59% in grain yield, straw weight, nodules number, dry weight of nodules, Zn uptake and P uptake respectively, over control.ConclusionThese results indicated that Pseudomonas sp. strain AZ5 and Bacillus sp. strain AZ17 can serve as effective microbial inocula for chickpea, particularly in the rain-fed area. 相似文献
To study the putative effects of Advanced Oxidation Protein Products (AOPPs) and Advanced Glycation End Products (AGEs) in the development and progression of cardiovascular disease (CVD).
Methodology
AGEs, AOPPs, e-NOS, lipid profile, circulating stress and inflammatory biomarkers were evaluated among fifty cardiovascular patients and fifty controls. Independent student’s t-test was done for statistical analysis.
Results
The malondialdehyde mean level in CVD patients (5.45?nmol/ml) was significantly higher than control (1.36?nmol/ml) (p value?=?0.018). Nitric oxide in CVD patients (55.72?ng/ml) was remarkably increased as compared to normal subjects (19.19?ng/ml). A significant change in the mean serum level of AGEs in CVD patients (2.74?ng/ml) and normal individuals (0.85?ng/ml) was recorded (p value?=?0.000). The AOPPs also showed significant increased levels in CVD group (132.07?ng/ml) in comparison with normal subjects (83.05?ng/ml) (p value?=?0.011). The mean eNOS serum level in CVD group (15.50?U/L) was higher than control group (11.28?U/L) (p value?=?0.004). Cardiovascular disease patients, in comparison with healthy controls, showed increased level of total cholesterol (5.48?mmol/L vs 4.45?mmol/L), triglycerides (2.59?mmol/L vs 1.24?mmol/L), and low density lipoprotein (2.47?mmol/L vs 2.31?mmol/L) along with decrease in high density lipoprotein (1.39?mmol/L vs 1.74?mmol/L). The mean MMP-11 serum levels in CVD group (98.69?ng/ml) was almost double of control group (45.60?ng/ml) (p value?=?0.017). The mean serum level of TNF-α and IL1-α were 32.16?pg/ml and 6.64?pg/ml in CVD patient. The significant decreasing trend of SOD (p value?=?0.041), CAT (p value?=?0.018), GSH (p value?=?0.036) and GRx (p value?=?0.029) but increasing drift of GPx (0.023) level was observed in CVD patients.
Conclusion
This study provides strong evidence that CVD patients presented with elevated oxidative stress, enhanced inflammation and lipid profile in their serum. Therefore, the study strongly approves that AGEs, AOPPs, inflammatory and lipoxidative biomarkers hold predictive potential in causing and aggravating the disease, thus by controlling these factors CVD progression can be inhibited. 相似文献