Biochemical and mutational analyses of HEXA in a cohort of Egyptian patients with infantile Tay-Sachs disease. Expansion of the mutation spectrum.

BACKGROUND: Tay-Sachs disease (TSD), an autosomal recessively inherited neurodegenerative lysosomal storage disease, reported worldwide with a high incidence among population of Eastern European and Ashkenazi Jewish descent. Mutations in the alpha subunit of HEXA that encodes for the ß-hexosaminidase-A lead to deficient enzyme activity and TSD phenotype. This study is the first to highlight the HEXA sequence variations spectrum in a cohort of Egyptian patients with infantile TSD. RESULTS: This study involved 13 Egyptian infant/children patients presented with the infantile form of TSD, ten of the 13 patients were born to consanguineous marriages. ß-hexosaminidase-A enzyme activity was markedly reduced in the 13 patients with a mean activity of 3 µmol/L/h ± 1.56. Sanger sequencing of the HEXA' coding regions and splicing junctions enabled a detection rate of ~ 62% (8/13) in our patients revealing the molecular defects in eight patients; six homozygous-mutant children (five of them were the product of consanguineous marriages) and two patients showed their mutant alleles in heterozygous genotypes, while no disease-causing mutation was identified in the remaining patients. Regulatory intragenic mutations or del/dup may underlie the molecular defect in those patients showing no relevant pathogenic sequencing variants or in the two patients with a heterozygous genotype of the mutant allele. This research identified three novel, likely pathogenic variants in association with the TSD phenotype; two missense, c.920A > C (E307A) and c.952C > G (H318D) in exon 8, and a single base deletion c.484delG causing a frameshift E162Rfs*37 (p.Glu162ArgfsTer37) in exon 5. Three recurrent disease-causing missense mutations; c.1495C > T (R499C), c.1511G > A(R504H), and c.1510C > T(R504C) in exon 13 were identified in five of the eight patients. None of the variants was detected in 50 healthy Egyptians' DNA. Five variants, likely benign or of uncertain significance, S3T, I436V, E506E, and T2T, in exons 1, 11,13, & 1 were detected in our study. CONCLUSIONS: For the proper diagnostics, genetic counseling, and primary prevention, our study stresses the important role of Next Generation Sequencing approaches in delineating the molecular defect in TSD-candidate patients that showed negative Sanger sequencing or a heterozygous mutant allele in their genetic testing results. Interestingly, the three recurrent TSD associated mutations were clustered on chromosome 13 and accounted for 38% of the HEXA mutations detected in this study. This suggested exon 13 as the first candidate for sequencing screening in Egyptian patients with infantile TSD. Larger studies involving our regional population are recommended, hence unique disease associated pathogenic variations could be identified.

Three-dimensional hierarchically porous MoS2 foam as high-rate and stable lithium-ion battery anode.

Architected materials that actively respond to external stimuli hold tantalizing prospects for applications in energy storage, wearable electronics, and bioengineering. Molybdenum disulfide, an excellent two-dimensional building block, is a promising candidate for lithium-ion battery anode. However, the stacked and brittle two-dimensional layered structure limits its rate capability and electrochemical stability. Here we report the dewetting-induced manufacturing of two-dimensional molybdenum disulfide nanosheets into a three-dimensional foam with a structural hierarchy across seven orders of magnitude. Our molybdenum disulfide foam provides an interpenetrating network for efficient charge transport, rapid ion diffusion, and mechanically resilient and chemically stable support for electrochemical reactions. These features induce a pseudocapacitive energy storage mechanism involving molybdenum redox reactions, confirmed by in-situ X-ray absorption near edge structure. The extraordinary electrochemical performance of molybdenum disulfide foam outperforms most reported molybdenum disulfide-based Lithium-ion battery anodes and state-of-the-art materials. This work opens promising inroads for various applications where special properties arise from hierarchical architecture.

Radiosensitizing Effect of Bromelain Using Tumor Mice Model via Ki-67 and PARP-1 Inhibition.

Recent reports have shown that bromelain (BL), a pineapple extract, acts as an adjuvant therapy in cancer treatment and prevention of carcinogenesis. The present study was designed to investigate the possible mechanisms by which BL could radiosensitize tumor cells in vitro and in a mouse tumor model. BL has shown a significant reduction in the viability of the radioresistant human breast carcinoma (MCF-7) cell line using cell proliferation assay. The in vivo study was designed using the Ehrlich model in female albino mice, treated with BL (6 mg/kg b. wt., intraperitoneal, once daily for 10 days) 1 hour before exposure to a fractionated dose of gamma radiation (5 Gy, 1 Gy for 5 subsequent days). The radiosensitizing effect of BL was evident in terms of a significant reduction in tumor volume, poly ADP ribose polymerase-1 (PARP-1), the proliferation marker Ki-67 and nuclear factor kappa activated B cells (NF-κB) with a significant elevation in the reactive oxygen species (ROS) content and lipid peroxidation (LPO) in tumor cells. The present findings offer a novel insight into the radiosensitizing effect of BL and its potential application in the radiotherapy course.

Study of the Radiosensitizing and Radioprotective Efficacy of Bromelain (a Pineapple Extract): In Vitro and In Vivo.

This study hypothesizes that, bromelain (BL) acts as radiosensitizer of tumor cells and that it protects normal cells from radiation effects. In vitro and in vivo studies have been carried out to prove that assumption. In vitro MTT cell proliferation assay has shown that the irradiated Ehrlich ascites carcinoma (EAC) cell line could be sensitized by BL pretreatment. In vivo: animals were randomly divided into 5 groups, Group 1: control (PBS i.p for 10 days), Group 2: Ehrlich solid tumor (EST) bearing mice, Group 3: EST + γ-radiation (fractionated dose, 1 Gy × 5), Group 4: EST + BL (6 mg/kg, i.p), daily for 10 days, Group 5: EST + BL for 10 days followed by γ-irradiation (1 Gy × 5). The size and weight of tumors in gamma-irradiated EST bearing mice treated with BL decreased significantly with a significant amelioration in the histopathological examination. Besides, BL mitigated the effect of γ-irradiation on the liver relative gene expression of poly ADP ribose polymerase-1 (PARP1), nuclear factor kappa activated B cells (NF-κB), and peroxisome proliferator-activated receptor α (PPAR-α), and it restored liver function via amelioration of paraoxonase1 (PON1) activity, reactive oxygen species (ROS) content, lipid peroxidation (LPO) and serum aspartate transaminase (AST), alanine transaminase (ALT), and albumin (ALB). It is concluded that BL can be considered as a radio-sensitizer and radio-protector, suggesting a possible role in reducing radiation exposure dose during radiotherapy.

Mutational analysis of Aurora kinase C gene in Egyptian patients with macrozoospermia.

Macrozoospermia is a rare syndrome. The key marker of the disease is a high percentage of spermatozoa with abnormal phenotypes namely enlarged head and multiple tails. The presence of at least 70% of spermatozoa with a large head is usually associated with Aurora kinase C gene (AURKC) mutations. We sought to assess AURKC as a potential genetic actor of macrozoospermia in a sample of infertile Egyptian men. We recruited 30 patients and conducted a clinical examination, semen analysis, and DNA sequencing and RFLP for AURKC. We diagnosed 17 patients with characteristic macrozoospermia and classified them into eight severe and nine mild cases. We detected genetic variants of AURKC in five patients (29.4%): Three patients with severe macrozoospermia had c.144delC mutations in exon 3 (37.5% of the severe), and two mild cases had c.1157G>A polymorphism in the 3' UTR (22.2% of the mild). A successful intracytoplasmic sperm injection (ICSI) was achieved only with a severe macrozoospermia patient without apparent AURKC mutation. The present study is the first report to link macrozoospermia and AURKC mutations in Egypt. The study recommends macrozoospermia patients to perform AURKC gene analysis and attempt ICSI, even those with a high percentage of large head spermatozoa.

Shaping of ZSM-5-Based Catalysts via Spray Drying: Effect on Methanol-to-Olefins Performance.

Shaping and optimal compositional formulation are major challenges in the successful industrial application of heterogeneous catalysts. The choice of components during formulation plays a vital role in endowing the final catalyst's mechanical strength, durability, and lifetime and may even affect activity and selectivity. Herein, we evaluate the application of spray drying to manufacture spherical ZSM-5-based catalysts and their applicability in the methanol-to-olefins process. Several critical parameters of the spray drying process and various aspects related to catalyst formulation (binder, zeolite, and clay) are investigated. Chemical composition and structure of the clay matrix substantially influence the catalytic performance.

MicroRNAs 182 and 375 Sera Expression as Prognostic Biochemical Markers in Breast Cancer.

INTRODUCTION: Breast cancer (BC) is the most common malignancy among women; supporting the need for identification of novel prognostic biomarkers, circulating microRNAs (miRNAs) could serve as such in various cancers. The aim of this study was to explore the association between miRNAs 182 and 375 with BC stages and its receptors, based on their expression using real time PCR. MATERIALS AND METHODS: Detailed medical history was taken and blood samples were withdrawn from 80 female subjects divided over the studied groups. Patients ranged in age from 24 to 80 years and were classified as follows: group I included 10 noncancerous postmenopausal control subjects; group II included 32 postmenopausal patients with BC; group III included 10 noncancerous premenopausal control subjects; group IV included 24 premenopausal patients with BC; and group V included 6 patients with benign breast tumors. RESULTS: miRNA 182 expression was significantly higher in group II, group IV, and group V (3.36 ± 0.14, 2.52 ± 0.34, and 4.93 ± 0.3,9 respectively); miRNA 375 expression was significantly higher in group II, group IV, and group V (4.41 ± 0.40, 3.12 ± 0.35, and 11.28 ± 2.37, respectively) (P < .05). Both miRNAs were significantly associated with each other and with receptors used for the prognosis of BC even after multiple regression analysis. CONCLUSION: Accordingly, miRNAs 182 and 375 could be potential noninvasive markers used for the follow up of BC patients.

Association of Cholesterol Ester Transfer Protein Taq IB Polymorphism With Acute Coronary Syndrome in Egyptian National Patients.

BACKGROUND: The association between cholesterol ester transfer protein (CETP) Taq IB polymorphism and coronary artery disease (CAD) has been studied in different populations. Acute coronary syndrome (ACS) is a group of clinical symptoms within acute myocardial ischemia, including unstable angina (UA) and myocardial infarction (MI). Because there are no data reported in the literature concerning the cholesteryl ester transfer protein (CETP) Taq IB polymorphism in Egyptians, our study aimed to investigate the frequency of different CETP Taq IB genotypes in Egyptian patients with ACS and in healthy control individuals. METHODS: The current study was conducted with 70 hospitalized patients who had been diagnosed with ACS and 30 controls. We used real-time polymerase chain reaction (RT-PCR) to determine CETP Taq IB in individuals with different genotypes. RESULTS: The frequency of the GA genotype was significantly lower in UA patients, compared with the control group ( P <.05). CONCLUSIONS: The frequency of the CETP Taq IB genotypes and alleles in all groups was similar to that in other ethnic groups. Individuals with the Taq IB GA genotype may have a lower risk of UA.

Mutational Profile of 10 Afflicted Egyptian Families with 17-ß-HSD-3 Deficiency.

This study aimed at the detection of HSD17B3 gene mutations in Egyptian patients with suspected diagnosis of 46,XY DSD due to 17-ß-HSD-3 deficiency and at evaluation of phenotype/genotype relationship of these mutations. The study was conducted on 11 patients of 10 families which were provisionally diagnosed to have 17-ß-HSD-3 enzyme deficiency. Karyotyping, hormonal evaluation of testosterone, x0394;4-androstenedione, and dihydrotestosterone, and sequencing analysis of the 11 exons of the HSD17B3 gene were done. Mutations in HSD17B3 were detected in exons 2, 7, 8, 10, and 11, and 6 novel mutations were determined in exons 1, 2, 7, and 8. Two patients showed compound heterozygous mutations, while 8 families had probands with homozygous mutations. The current study shows that 17-ß-HSD-3 deficiency is not an uncommon disorder among Egyptian DSD cases. It was evidenced that the mutational profile of the disease is rather heterogeneous, relatively different from those reported in other populations, and has a high degree of novel genetic defects.

The biological significance of serum complements C3 and C4 in HCV-related chronic liver diseases and hepatocellular carcinoma.

This study aims to evaluate the diagnostic power of serum complements C3 and C4 in early detection of hepatocellular carcinoma (HCC) in HCV-infected patients with liver cirrhosis (LC). Twenty patients with HCC and twenty patients with chronic liver diseases (CLD) were recruited for the study. Twenty healthy non-HCV infected subjects were also included as negative controls. Serum complements C3 and C4 levels were estimated with nephelometry while HCV antibody was detected by third generation ELISA kits. Serum samples were also tested for alpha-fetoprotein by microparticle enzyme immunoassay kits. Serum levels of complements C3 (124.1 +/- 34.4 mg/dl) & C4 (55.9 +/- 28.8 mg/dl) in cases of liver cirrhosis without HCC, were lower than in HCC cirrhotic patients (136.9 +/- 39.1 mg/dl) and (62.3 +/- 20.7 mg/dl), respectively (P > 0.05). On the other hand, serum levels of C3 & C4 were significantly higher in HCC group than in controls (101.9 +/- 18.7 mg/dl) and (23.8 +/- 8.9 mg/dl), respectively (P < 0.01, P < 0.001). Regarding levels of C3 &C4 in CLD patients, they were significantly higher than controls (P < 0.05, P < 0.001). The optimal cut-off values selected by Receiver Operating Characteristic (ROC) curve were 112 mg/dl for C3 and 45 mg/dl for C4. Based on these data, the positive predictive values, negative predictive values, and the accuracies for C3 were 59.1%, 55.6%, and 58.1% and for C4 were 65.2%, 75%, and 67.7%, respectively. In conclusion, the combined use of both AFP and C4 at cut-off 8 ng/ml & 88.1 mg/dl, respectively will result in improving detection of HCC in HCV-related liver cirrhosis patients.