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Glioblastoma multiforme (GBM) is a complicated and heterogeneous brain tumor with short-term survival outcomes. Commercial therapies are not practical due to cell infiltration capacity, high proliferative rate, and blood–brain barrier. In this context, recognition of the molecular mechanism of tumor progression might help the development of new cancer therapeutics. Recently, more evidence has supported CD73 and downstream adenosine A2A/A2B receptor signaling playing a crucial role in glioblastoma pathogenesis; therefore, targeting CD73 in murine tumor models can reduce tumor development. CD73 is an ecto-enzyme inducing tumor metastasis, angiogenesis, and immune escape via the production of extracellular adenosine in the tumor microenvironment. In this review, we provided information about clinical characteristics as well as the therapeutic management of glioblastoma. Then, we focused on newly available experimental evidence distinguishing between the essential role of CD73 on this tumor growth and a new method for the treatment of GBM patients.

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Glioblastoma multiforme (GBM) is a complicated and heterogeneous brain tumor with short-term survival outcomes. Commercial therapies are not practical due to cell infiltration capacity, high proliferative rate, and blood-brain barrier. In this context, recognition of the molecular mechanism of tumor progression might help the development of new cancer therapeutics. Recently, more evidence has supported CD73 and downstream adenosine A2A/A2B receptor signaling playing a crucial role in glioblastoma pathogenesis; therefore, targeting CD73 in murine tumor models can reduce tumor development. CD73 is an ecto-enzyme inducing tumor metastasis, angiogenesis, and immune escape via the production of extracellular adenosine in the tumor microenvironment. In this review, we provided information about clinical characteristics as well as the therapeutic management of glioblastoma. Then, we focused on newly available experimental evidence distinguishing between the essential role of CD73 on this tumor growth and a new method for the treatment of GBM patients.

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Cold stress is an environmental cause of pulmonary hypertension syndrome (PHS) in broiler chickens. This factor could increase the rate of metabolic activity via thyroid hormones (T3 and T4). To evaluate the effect of these hormones on the heart, the plasma concentration of T3, T4, and the gene expression of their receptors (THRα and THRß) and many contractile proteins (ACTC1, MHCα, MHCß, RYR2, SERCA2, THRα, THRß, and troponin I) were measured in the right ventricle in 2 periods of age (21 and 35 d). Plasma T3 concentration was significantly higher in the PHS group of chickens than in the control one at 21 and 35 d while plasma T4 did not change. The relative expression of MHCα, RYR2, SERCA2, and THRα genes in the right ventricle tissues was only higher in PHS group of broilers than control group at 21 d (P < 0.05) whereas the expression of ACTC1, MHCß, and troponin I did not differ at 2 periods of age. The positive correlations between MHCα, RYR2, SERCA2, and T3, THRα were confirmed. The expression of THRß gene was only higher in PHS group of broilers than control at 35 d (P < 0.05). The data determined that cold stress could increase thyroid hormones and the gene expression of their receptor (THRα) in the pick of chicken growth (21 d) that they themselves elevates the expression of many genes related to contractile elements (MHCα, RYR2, and SERCA2), leading to adaptive right ventricle hypertrophy.

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BACKGROUND: TGF-ß isoforms play crucial roles in diverse cellular processes. Therefore, targeting and inhibiting TGF-ß signaling pathway provides a potential therapeutic opportunity. TGF-ß isoforms bind and bring the receptors (TßRII and TßRI) together to form a signaling complex in an ordered manner. OBJECTIVES: Herein, an antagonistic variant of TGF-ß (AnTß) has been designed and prepared to inhibit the formation of signaling complex and consequently its signaling pathway. This TGF-ß homodimeric variant contains intact TßRII binding sites and blocked TßRI binding sites by substituting three peptide segments. So, AnTß could only bind to TßRII, but prevent binding and recruitment of TßRI to form a signaling complex. MATERIALS AND METHODS: A reliable model of AnTß was built and refined using molecular dynamics (MD) simulation, followed by investigating the interactions of AnTß with the receptors using in silico docking studies. After expression of disulfide-linked AnTß in a SHuffle strain and purification of the protein using affinity chromatography, its biological activity was evaluated using Mink lung epithelial cells (Mvl Lu). RESULTS: No meaningful significant changes in AnTß structure were observed when compared with the native protein. Based on the docking analysis, AnTß binds to TßRII similar to TGF-ß and its binding to TßRI was diminished considerably which was consistent with our design purpose. Cell-based bioassay indicated that AnTß could modulate TGF-ß-induced cell growth inhibition. CONCLUSIONS: Our analysis suggests that the antagonistic potency of AnTß can be used as an anti-TGFß signaling factor in the future perspectives.

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OBJECTIVE: Organophosphorus Acid Anhydrolase (OPAA) is used as one of the most important enzymes in the decontamination process of organophosphate compounds. In this study, we aimed to evaluate the effects of amino acid substitution in OPAA's substrate-binding site on its catalytic activity using the rational engineering strategy. METHODS: The native and three mutant forms of OPAA enzyme including 4ZWP, 4ZWU and Mut6 were studied using the docking technique toward parathion, paraoxon and R-VX compounds. Furthermore, enzyme assay was performed on the native OPAA and Mut6 toward parathion. RESULTS: Docking results showed a decreased catalytic activity of the mutant forms toward parathion and paraoxon. Furthermore, enzyme assay showed in accordance with docking results a decreased activity of Mut6 compared to the native form. The results of docking prediction for R-VX showed an increased catalytic activity of 4ZWP and 4ZWU. 4ZWU had the highest activity, while the activity of Mut6 was lower than the native form. CONCLUSION: Amino acid positions of 212 and 342 seem to be important sites in the small pocket of OPAA affecting the enzyme catalytic activity. Therefore, substitution of these sites with appropriate amino acids depending on the substrate structure, can affect the enzyme catalytic efficiency (Tab. 2, Fig. 3, Ref. 30).

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Angiogenesis is a hallmark of various pathological conditions and is controlled by a variety of angiogenic factors. Blockade of vascular endothelial growth factor (VEGF) as the most pivotal stimulator of angiogenesis offers a promising therapeutic approach for some diseases, typically cancer. In the present study, a heterodimeric antagonistic VEGF was precisely designed based on structural information of recently-crystallized VEGF/VEGF receptor-2 (VEGFR-2/fetal liver kinase 1/kinase domain region) complex. Directed blocking of kinase domain region occurs via substitution of a VEGF receptor binding site by two peptide segments in one pole, whereas the binding domain of the other pole of VEGF was intact. Candidate peptides for substitution were selected considering to some sequence and structural criteria. A reliable model of modified VEGF was built, refined using molecular dynamics simulation and docked with VEGFR-2. Docking analysis revealed that binding affinity of mutant VEGF was notably diminished, corroborating our design. Heterodimeric VEGF was expressed, refolded and highly purified by two-step affinity chromatography. Dimerization of this antagonist was confirmed using some analytical techniques. Spectroscopic studies assured us to obtain the heterodimeric form of VEGF. Some angiogenic in vitro assays such endothelial cell proliferation and tube formation indicated that this antagonist is not only strongly capable of inhibiting angiogenesis (half maximal inhibitory concentration of 33 and 24 ng · mL(-1) , respectively), but also showed the highest inhibitory effect compared to all other heterodimeric VEGF variants. The high anti-angiogenic potency of this VEGF antagonist may allow its future use as an anti-tumor agent.

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CCL20/macrophage inflammatory protein-3α (MIP-3α) represents one of the potent chemoattractive proteins for dendritic cells (DCs). Herein, we investigated whether in vivo genetic modification of tumour cells aimed at intratumoural production of MIP-3α might lead to accumulation of DCs in tumour tissue. Mice injected with CT26, received recombinant adenovirus (Ad) vectors (AdMIP-3α) expressing MIP-3α protein. This was complemented by injections of CpG. Interestingly, MIP-3α gene therapy combined with CpG injections resulted in specific cytotoxicity. This was associated with significant suppression of tumour growth rate. These findings demonstrate the potential of strategies that utilize in vivo overexpression of chemokines.

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Cardiovascular disease (CVD) is responsible for the majority of deaths in chronic renal failure (CRF). Oxidative stress plays a key role in pathogenesis of atherosclerosis and CVD, which is promoted by the production of reactive oxygen species (ROS) and impaired antioxidant enzymes. These ROS react with nitric oxide (NO) to produce cytotoxic reactive nitrogen species that cause oxidative injury to the endothelium. This study evaluated biomarkers of oxidative stress, NOx (total NO(2) and NO(3)), and superoxide dismutase (SOD) enzyme in normal control and CRF patients as case group and correlated their association with CVD. This cross sectional study involved 173 CRF patients on different modes of treatment (hemodialysis, continuous ambulatory peritoneal dialysis (CAPD), and predialysis). Of these, 74 had CVD. The control group consisted of 33 healthy subjects who had no history of CRF and CVD. Both NOx and SOD levels were significantly lower (P<0.05, P<0.001, respectively) in the case group. Comparing between CRF patients with and without CVD, SOD level was found to be significantly lower in CRF patients with CVD (P<0.05). Logistic regression analysis showed significant association of CVD event with age, male gender, diabetes, SOD level, and lipid profile in CRF patients. Oxidative stress occurs in the CRF patients with or without CVD. This study found that NOx and SOD levels were reduced in all CRF patients with or without CVD. However, it was noted that the levels of these biomarkers of oxidative stress were significantly lower in CRF patients with CVD compared with CRF patients without CVD. Therefore, these oxidative stress markers maybe contributing factors in the pathogenesis of CVD in patients with CRF.

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AIMS OF THE STUDY: Idiopathic dilated cardiomyopathy (IDC) is a complex disease. The interest of this study were to investigate the epidemiology characteristics of the disease and to evaluate the prognostic echocardiographic markers by region in order to highlight the existence of genetic risk factors and/or environmental and to identify those patients who could benefit from early treatment and better care to avoid further complications of the disease. PATIENTS AND METHODS: This is a retrospective study based on the Fischer exact and bilateral Mann-Whitney test. RESULTS: We included 526 patients with dilated cardiomyopathies of them we detected 50 cases of IDC including 12 families: The average age was 39,3±15.2 years. The sex ratio was 2.6. Mean left ventricular end-diastolic diameter (DIVGd) was higher in patients from the North East region (44.3±6.2mm/m(2)). Using Receiver Operating Characteristics (ROC) curve, we found a threshold value of 40mm/m(2). The odds ratio associated with this cutoff was 9.2. CONCLUSION: Our results suggest that the prevalence and severity of IDC were higher in the North East region of Tunisia. Furthermore, large-scale prospective studies are needed to confirm these findings. In confirmation of a higher prevalence, a genetic study should be undertaken in this region.

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OBJECTIVE: Attempts to treat class II malocclusions without extraction in non-compliant patients have led to utilization of intraoral molar distalizing appliances. The purpose of this study was to investigate dental and skeletal effects of Bonded Molar Distalizer (BMD) which is a simple molar distalizing appliance. MATERIALS AND METHODS: Sixteen patients (12 girls, four boys) with bilateral half-cusp class II molar relationship, erupted permanent second molars and normal or vertical growth pattern were selected for bilateral distalization of maxillary molars via BMD. The screws were activated every other day, alternately. Lateral cephalograms and study models were obtained before treatment and after 11 weeks activation of the appliance. RESULTS: Significant amounts of molar distalization, molar distal tipping and anchorage loss were observed. The mean maxillary first molar distal movement was 1.22±0.936 mm with a distal tipping of 2.97±3.74 degrees in 11 weeks. The rate of distal movement was 0.48 mm per month. Reciprocal mesial movement of the first premolars was 2.26±1.12 mm with a mesial tipping of 4.25±3.12 degrees. Maxillary incisors moved 3.55±1.46 mm and tipped 9.87±5.03 degrees mesially. Lower anterior face height (LAFH) decreased 1.28±1.36 mm. CONCLUSION: BMD is appropriate for distalizing maxillary molars, especially in patients with critical LAFH, although significant amounts of anchorage loss occur using this appliance.

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Cardiomyopathies (CMs) are primary disorders of cardiac muscle. They are a major cause of morbidity and mortality for all ages and, like acquired forms of cardiovascular disease, often result in heart failure. Molecular genetic studies have made remarkable progress in defining the pathogenesis of CM. The present study was the first report to evaluate the relationship between class II major histocompatibility complex (MHC) genes (HLA-DRB1 and HLA-DQB1) and the genetic susceptibility to primary dilated cardiomyopathy (DCM) in Tunisian patients. The human leukocyte antigen (HLA)-DRB1 and -DQB1 alleles were analyzed in 76 patients with primary DCM and 111 ethnically matched healthy controls using polymerase chain reaction-sequence specific primers technique. An increased frequencies of HLA-DRB1*0401 (OR = 2.67, P < 0.001), HLA-DQB1*0302 (OR = 3.28, P = 0.001) and HLA-DQB1*0401 (OR = 6.26, P = 0.005) alleles were found in the patients with primary DCM compared with healthy controls. Individuals with HLA-DRB1*1301 (OR = 0.24, P < 0.001) and HLA-DQB1*0201 (OR = 0.49, P = 0.002) alleles have a protective effect against primary DCM. Two haplotypes were associated with increased risk of primary DCM: DRB1*0401/DQB1*0302 (OR = 4.53, P = 0.002) and DRB1*0401/DQB1*0401 (OR = 9.42, P = 0.004). In conclusion, our data suggest that the variation in class II HLA alleles could be a genetic factor involved in the susceptibility to primary DCM in the Tunisian population.

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This study was designed to assess the plausibility of an association between natural rotavirus infection and intussusception. It was conducted on 21 infants suffering from acute gastroenteritis (GE) complicated by intussusception who were compared to another 40 age- and sex-matched infants suffering from acute GE characterized by watery nonmucoid diarrhea without surgical complications. All enrolled patients were subjected to detailed history documentation, thorough clinical examination and laboratory investigations, complete stool analysis, and detection of rotavirus antigen in stools using the ELISA technique. Plain abdominal X-ray and ultrasound were also performed. The results of this study revealed 24 positive cases for rotavirus antigen in the stools of the acute uncomplicated GE patients (60.0%), while there were only ten positive cases in the intussusception group (47.6%). No significant difference in severity was detected between the two groups studied, especially in terms of signs of dehydration and need for IV fluids (p > 0.05). Most of the rotavirus positive cases among the intussusception group presented either in February or December (p < 0.05) with no significant seasonal pattern among the acute GE group (p > 0.05). In conclusion, rotavirus antigen retrieval from stools of GE patients complicated with intussusception was not statistically different from those detected among acute uncomplicated GE. Additionally, there was no association between seasonality or severity of rotavirus positive cases in acute GE patients and those with intussusception. It is thus prudent to say that wild rotavirus infection in GE patients does not carry an extra risk for the occurrence of intussusception.

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The mitogen-activated protein kinases (MAPKs) are signaling molecules that become enzymatically activated through phosphorylation by diverse stimuli. Hematopoietic cytokines, growth factors, and stimulated lymphocyte antigen receptors may activate specific MAPKs by altering the balance of MAPK-activating protein kinases and the protein phosphatases that target their activation sites. Hematopoietic protein tyrosine phosphatase (HePTP) is a hematopoiesis-specific cytoplasmic protein tyrosine phosphatase whose expression is induced by mitogenic stimuli. To investigate the role of HePTP in hematopoietic development, we constructed mice deficient in this phosphatase using the technique of homologous recombination. Primary lymphocytes from HePTP(-/-) mice show enhanced activation of extracellular stimulus-regulated kinase (ERK) after both phorbol myristate acetate (PMA) and anti-CD3-mediated T-cell receptor (TCR) stimulation, suggesting a true physiological relationship between these two molecules. Activation of MEK, the physiological activator of ERK, by anti-CD3 or PMA is not affected by HePTP deletion. The distribution of hematopoietic lineages in bone marrow and peripheral blood samples and the in vitro proliferative capacity of bone marrow progenitors from HePTP deletion mice do not deviate from those of matched littermate controls. Similarly, lymphocyte activation and development are indistinguishable in HePTP(-/-) mice and controls. We conclude that HePTP is a physiological regulator of ERK on the basis of these studies and hypothesize that its deletion is well compensated for in the developing mouse through reduction of ERK targets or enhancement of physiologically opposed signaling pathways.

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BACKGROUND: Glial tumors are the most common tumors of the central nervous system, affecting individuals of all ages. Conventional cytogenetics have been unable to identify a consistent chromosomal translocation or rearrangement in this group of tumors; thus, more advanced molecular cytogenetic approaches are required. METHODS AND RESULTS: In this study, 16 glial tumors, including two recurrences and six glioma cell lines, were analyzed by spectral karyotyping (SKY) and comparative genomic hybridization (CGH). From 169 rearrangements detected by SKY, chromosomes 1 and 10 were the most frequently affected by translocation (18 of 169 and 16 of 169 rearrangements, respectively). Other frequently altered chromosomes included chromosomes 3 (13 of 169 rearrangements), 5 (ten of 169 rearrangements), 7 (ten of 169 rearrangements ), and 11 (ten of 169 rearrangements). A clustering of centromeric breakpoints was detected in chromosomes 3, 5, 10, 11, 16, 17, and 20. CGH analysis identified consistent gain of part or all of chromosome 7 among the 10 astrocytic tumors (five of ten specimens) in the study group. Analysis of the three gangliogliomas and one ependymoma identified a much simpler pattern of primarily numerical change. CONCLUSION: Application of improved cytogenetic methods can increase our abilities to progress toward effective strategies of molecular diagnosis and classification of glial tumors.

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Otosclerosis is a hereditary disease frequently encountered in Caucasian populations (0.1 to 2% prevalence). In Tunisia, prevalence varies from 0.4% to 0.8%. The presence of a genetic factor associated with hormonal, biochemical or environmental factors, probably lead to variable expression of the otosclerosis according to age and sex. Mean age at onset of disease is 25 years (range 16-35 year) for 61.5% of affected women. In men this proportion is 50.2%. The incidence of otosclerosis is high in the 26-35 year age group. Our study showed that in northeastern areas of Tunisia, women in this age group were affected twice as often as men in this age group. This probably suggests that an endocrine mechanism is involved in disease etiology. However, in northwestern areas, there was no significant difference between the rates of otosclerosis between sexes. Geographical distribution of affected subjects according to the ethnic origin of their parents showed that the areas with the highest concentration of affected individuals were urban or seaside areas such as the gouvernorate of Nabeul. The frequency of otosclerosis was lower in rural areas and/or areas far from the seaside.

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A new, simple method based on information theory is introduced to predict the solvent accessibility of amino acid residues in various states defined by their different thresholds. Prediction is achieved by the application of information obtained from a single amino acid position or pair-information for a window of seventeen amino acids around the desired residue. Results obtained by pairwise information values are better than results from single amino acids. This reinforces the effect of the local environment on the accessibility of amino acid residues. The prediction accuracy of this method in a jackknife test system for two and three states is better than 70 and 60 %, respectively. A comparison of the results with those reported by others involving the same data set also testifies to a better prediction accuracy in our case.

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Geographically isolated populations have been successfully used to localize genes for recessive inherited diseases, including non-syndromic sensorineural recessive deafness (NSRD). To date, 25 loci for NSRD have been localized on human chromosomes (DFNB loci), and six of the corresponding genes have been identified. Here, we report on the contribution of the DFNB1 locus (GJB2 gene) to NRSD in seven affected families living in three northern Tunisian geographic isolates, and we provide evidence for genetic heterogeneity within isolates. This finding challenges the classical view of a single 'founder' mutation segregating in such isolates.

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