Multifocal gastrointestinal stromal tumor with osseous metaplasia: a case report.

BACKGROUND: Gastrointestinal stromal tumor is considered the most common mesenchymal neoplasm of the gastrointestinal tract. The majority of gastrointestinal stromal tumor cases are located in the stomach and usually affects older adults. Most of gastrointestinal stromal tumor cases are sporadic; however, few have a syndromic association, including Carney triad, Carney-Stratakis syndrome, familial gastrointestinal stromal tumor syndrome, and neurofibromatosis type 1. CASE PRESENTATION: Herein, we report a rare case of a 54-year-old Middle-Eastern female with multifocal gastrointestinal stromal tumor mixed type (epithelioid and spindle cell type) with osseous metaplasia. Fluoresce in situ hybridization analysis of platelet-derived growth factor receptor alpha revealed deletion in 42% of the tumor cells studied. Interestingly, next generation sequencing revealed platelet-derived growth factor receptor alpha exon 12 mutation (p.Y555C) and exon 14 mutation (p.N659Y). CONCLUSIONS: In conclusion, osseous metaplasia in GIST is a very rare event and only few cases are reported in the literature. The number of reported cases is inadequate to confirm the pathogenesis and the prognosis.

Saudi patient knowledge and awareness regarding smoking as a risk factor for urological diseases.

AIM: Our aim was to evaluate Saudi patient knowledge and awareness regarding smoking as a risk factor for bladder cancer, kidney cancer, and erectile dysfunction (ED). SETTINGS AND DESIGN: This quantitative cross-sectional study was conducted across three major tertiary hospitals in Riyadh, the capital city of Saudi Arabia. MATERIAL AND METHODS: A self-administered questionnaire was distributed to 539 patients in the urology outpatient clinic. STATISTICAL ANALYSIS: Data were analyzed using the Statistical Package for the Social Studies 21.0. For descriptive statistics, the frequency was calculated for all study variables. Chi-squared test was used for categorical variables. P < 0.05 was considered statistically significant. RESULTS: A total of 539 urological patients completed the questionnaire. There were 460 (85.4%) male and 79 (14.6%) female respondents. Only 60.9%, 41.2%, and 36.9% of participants were aware that smoking was a risk factor for ED, kidney cancer, and bladder cancer, respectively. CONCLUSIONS: The knowledge and awareness were low among urological patients regarding smoking as a risk factor for urological diseases.

Integrative assessment of CIP2A overexpression and mutational effects in human malignancies identifies possible deleterious variants.

KIAA1524 is the gene encoding the human cancerous inhibitor of PP2A (CIP2A) protein which is regarded as a novel target for cancer therapy. It is overexpressed in 65%-90% of tissues in almost all studied human cancers. CIP2A expression correlates with cancer progression, disease aggressivity in lung cancer besides poor survival and resistance to chemotherapy in breast cancer. Herein, a pan-cancer analysis of public gene expression datasets was conducted showing significant upregulation of CIP2A in cancerous and metastatic tissues. CIP2A overexpression also correlated with poor survival of cancer patients. To determine the non-coding variants associated with CIP2A overexpression, 5'UTR and 3'UTR variants were annotated and scored using RegulomeDB and Enformer deep learning model. The 5'UTR variants rs1239349555, rs1576326380, and rs1231839144 were predicted to be potential regulators of CIP2A overexpression scoring best on RegulomeDB annotations with a high "2a" rank of supporting experimental data. These variants also scored the highest on Enformer predictions. Analysis of the 3'UTR variants of CIP2A predicted rs56255137 and rs58758610 to alter binding sites of hsa-miR-500a-5 and (hsa-miR-3671, hsa-miR-5692a) respectively. Both variants were also found in linkage disequilibrium with rs11709183 and rs147863209 respectively at r2 ≥ 0.8. The aforementioned variants were found to be eQTL hits significantly associated with CIP2A overexpression. Further, analysis of rs11709183 and rs147863209 revealed a high "2b" rank on RegulomeDB annotations indicating a probable effect on DNAse transcription factors binding. The MuTarget analysis indicated that somatic mutations in TP53 are significantly associated with upregulated CIP2A in human cancers. Analysis of missense SNPs on CIP2A solved structure predicted seven deleterious effects. Four of these variants were also predicted as structurally and functionally destabilizing to CIP2A including; rs375108755, rs147942716, rs368722879, and rs367941403. Variant rs1193091427 was predicted as a potential intronic splicing mutation that might be responsible for the novel CIP2A variant (NOCIVA) in multiple myeloma. Finally, Enrichment of the Wnt/ß-catenin pathway within the CIP2A regulatory gene network suggested potential of therapeutic combinations between FTY720 with Wnt/ß-catenin, Plk1 and/or HDAC inhibitors to downregulate CIP2A which has been shown to be essential for the survival of different cancer cell lines.

In Silico and In Vivo Evaluation of SARS-CoV-2 Predicted Epitopes-Based Candidate Vaccine.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2, the causative agent of coronavirus disease (COVID-19)) has caused relatively high mortality rates in humans throughout the world since its first detection in late December 2019, leading to the most devastating pandemic of the current century. Consequently, SARS-CoV-2 therapeutic interventions have received high priority from public health authorities. Despite increased COVID-19 infections, a vaccine or therapy to cover all the population is not yet available. Herein, immunoinformatics and custommune tools were used to identify B and T-cells epitopes from the available SARS-CoV-2 sequences spike (S) protein. In the in silico predictions, six B cell epitopes QTGKIADYNYK, TEIYQASTPCNGVEG, LQSYGFQPT, IRGDEVRQIAPGQTGKIADYNYKLPD, FSQILPDPSKPSKRS and PFAMQMAYRFNG were cross-reacted with MHC-I and MHC-II T-cells binding epitopes and selected for vaccination in experimental animals for evaluation as candidate vaccine(s) due to their high antigenic matching and conserved score. The selected six peptides were used individually or in combinations to immunize female Balb/c mice. The immunized mice raised reactive antibodies against SARS-CoV-2 in two different short peptides located in receptor binding domain and S2 region. In combination groups, an additive effect was demonstrated in-comparison with single peptide immunized mice. This study provides novel epitope-based peptide vaccine candidates against SARS-CoV-2.

Bioinformatics Analysis of Allele Frequencies and Expression Patterns of ACE2, TMPRSS2 and FURIN in Different Populations and Susceptibility to SARS-CoV-2.

The virus responsible for the COVID-19 global health crisis, SARS-CoV-2, has been shown to utilize the ACE2 protein as an entry point to its target cells. The virus has been shown to rely on the actions of TMPRSS2 (a serine protease), as well as FURIN (a peptidase), for the critical priming of its spike protein. It has been postulated that variations in the sequence and expression of SARS-CoV-2's receptor (ACE2) and the two priming proteases (TMPRSS2 and FURIN) may be critical in contributing to SARS-CoV-2 infectivity. This study aims to examine the different expression levels of FURIN in various tissues and age ranges in light of ACE2 and TMPRSS2 expression levels using the LungMAP database. Furthermore, we retrieved expression quantitative trait loci (eQTLs) of the three genes and their annotation. We analyzed the frequency of the retrieved variants in data from various populations and compared it to the Egyptian population. We highlight FURIN's potential interplay with the immune response to SARS-CoV-2 and showcase a myriad of variants of the three genes that are differentially expressed across populations. Our findings provide insights into potential genetic factors that impact SARS-CoV-2 infectivity in different populations and shed light on the varying expression patterns of FURIN.

Glycolysis downregulation is a hallmark of HIV-1 latency and sensitizes infected cells to oxidative stress.

HIV-1 infects lymphoid and myeloid cells, which can harbor a latent proviral reservoir responsible for maintaining lifelong infection. Glycolytic metabolism has been identified as a determinant of susceptibility to HIV-1 infection, but its role in the development and maintenance of HIV-1 latency has not been elucidated. By combining transcriptomic, proteomic, and metabolomic analyses, we here show that transition to latent HIV-1 infection downregulates glycolysis, while viral reactivation by conventional stimuli reverts this effect. Decreased glycolytic output in latently infected cells is associated with downregulation of NAD+ /NADH. Consequently, infected cells rely on the parallel pentose phosphate pathway and its main product, NADPH, fueling antioxidant pathways maintaining HIV-1 latency. Of note, blocking NADPH downstream effectors, thioredoxin and glutathione, favors HIV-1 reactivation from latency in lymphoid and myeloid cellular models. This provides a "shock and kill effect" decreasing proviral DNA in cells from people living with HIV/AIDS. Overall, our data show that downmodulation of glycolysis is a metabolic signature of HIV-1 latency that can be exploited to target latently infected cells with eradication strategies.

Promising Antidiabetic and Antimicrobial Agents Based on Fused Pyrimidine Derivatives: Molecular Modeling and Biological Evaluation with Histopathological Effect.

Diabetes is the most common metabolic disorder in both developing and non-developing countries, and a well-recognized global health problem. The WHO anticipates an increase in cases from 171 million in 2000 to 366 million by 2030. In the present study, we focus on the preparation of pyrimidine derivatives as potential antidiabetic and antimicrobial agents. Thein vivoeffect on total serum glucose concentration, cholesterol and antioxidant activity was assessed in adult male albino Wister rats and compared to the reference drug glimperide. Promising results were observed for compound 5. The histopathological study confirms that compound 5 results in significant activity with liver maintenance. The antimicrobial activities were evaluated against several bacterial strains such as Salmonella typhimurium ATCC 25566, Bacillus cereus, Escherichia coli NRRN 3008, Pseudomonas aeruginosa ATCC 10145, Staphylococcus aureus ATCC 6538and fungi such as Rhizopus oligosporus, Mucor miehei and Asperillus niger. Compounds 4 and 5 showed a good inhibition of the bacterial zone compared to the reference drug cephradine. Finally, we suggest protein targets for these drugs based on computational analysis, and infer their activities from their predicted modes of binding using molecular modeling. The molecular modeling for compounds 4 and 5 resulted in improved docking scores and hydrogen bonding. The docking studies are in good agreement with the in vitro and in vivo studies.

A 37-Year-Old Saudi Man with a Calcified Intraventricular Astrocytoma.

BACKGROUND Pilocytic astrocytoma is a low-grade glioma that is common in children. Pilocytic astrocytoma is a slow-growing neoplasm that may calcify and occurs throughout the central nervous system, but it has a preference to be located infratentorial in children. CASE REPORT Herein, we report an unusual intraventricular location of pilocytic astrocytoma with extensive calcification in a 37-year-old Saudi man who mainly presented with a headache. Although pilocytic astrocytoma can arise throughout the central nervous system, it very rarely arises from the ventricles, especially the lateral ventricle. CONCLUSIONS The majority of intraventricular tumors arise within the third and fourth ventricles. The unusual intraventricular location and the unexpected age group are the main difficulties in diagnosing an adult with intraventricular pilocytic astrocytoma. Intraventricular pilocytic astrocytoma can be missed radiologically and misled pathologically; therefore, it should be considered within the differential diagnosis of intraventricular tumors. To the best of our knowledge, this is the first case to be reported in Saudi Arabia.

Pharmacokinetic Basis of the Hydroxychloroquine Response in COVID-19: Implications for Therapy and Prevention.

BACKGROUND AND OBJECTIVES: Chloroquine/hydroxychloroquine has recently been the subject of intense debate regarding its potential antiviral activity against SARS-Cov-2, the etiologic agent of COVID-19. Some report possible curative effects; others do not. Therefore, the objective of this study was to simulate possible scenarios of response to hydroxychloroquine in COVID-19 patients using mathematical modeling. METHODS: To shed some light on this controversial topic, we simulated hydroxychloroquine-based interventions on virus/host cell dynamics using a basic system of previously published differential equations. Mathematical modeling was implemented using Python programming language v 3.7. RESULTS: According to mathematical modeling, hydroxychloroquine may have an impact on the amplitude of the viral load peak and viral clearance if the drug is administered early enough (i.e., when the virus is still confined within the pharyngeal cavity). The effects of chloroquine/hydroxychloroquine may be fully explained only when also considering the capacity of this drug to increase the death rate of SARS-CoV-2-infected cells, in this case by enhancing the cell-mediated immune response. CONCLUSIONS: These considerations may not only be applied to chloroquine/hydroxychloroquine but may have more general implications for development of anti-COVID-19 combination therapies and prevention strategies through an increased death rate of the infected cells.

Computational prediction of vaccine potential epitopes and 3-dimensional structure of XAGE-1b for non-small cell lung cancer immunotherapy.

BACKGROUND: XAGE-1b is shown to be overexpressed in lung adenocarcinoma and to be a strong immunogenic antigen among non-small cell lung cancer (NSCLC) patients. However, 3D structure of XAGE-1b is not available and its confirmation has not been solved yet. METHODS: Multiple sequence alignment was run to select the most reliable templates. Homology modeling technique was performed using computer-based tool to generate 3-dimensional structure models, eight models were generated and assessed on basis of local and global quality. Immune Epitope Database (IEDB) tools were then used to determine potential B-Cell epitopes while NetMHCpan algorithms were used to enhance the determination for potential epitopes of both Cytotoxic T-lymphocytes and T-helper cells. RESULTS: Computational prediction was performed for B-Cell epitopes, prediction results generated; 3 linear epitopes where XAGE-1b (13-21) possessed the best score of 0.67, 5 discontinuous epitopes where XAGE-1b (40-52) possessed the best score of 0.67 based on the predicted model of the finest quality. For a potential vaccine design, computational prediction yielded potential Human Leukocyte Antigen (HLA) class I epitopes including HLA-B*08:01-restricted XAGE-1b (3-11) epitope which was the best with 0.2 percentile rank. Regarding HLA Class II epitopes, HLA-DRB1*12:01-restricted XAGE-1b (25-33) was the most antigenic epitope with 5.91 IC50 value. IC50 values were compared with experimental values and population coverage percentages of epitopes were computed. CONCLUSIONS: This study predicted a model of XAGE-1b tertiary structure which could explain its antigenic function and facilitate usage of predicted peptides for experimental validation towards designing immunotherapies against NSCLC.

Sildenafil Citrate Therapy for Oligohydramnios: A Randomized Controlled Trial.

OBJECTIVE: To compare sildenafil plus hydration with hydration alone in improving the amniotic fluid index and neonatal outcomes in pregnancies complicated by idiopathic oligohydramnios ( amniotic fluid index less than 5 cm without underlying maternal or fetal causes and with normal fetal growth). METHODS: This was an open-label randomized trial for women carrying singleton pregnancies at 30 weeks of gestation or more with idiopathic oligohydramnios detected during routine ultrasonogram. Women received either oral sildenafil citrate (25 mg every 8 hours) plus intravenous infusion of 2 L isotonic solution or fluids only until delivery. The primary study outcome was the amniotic fluid volume at 6 weeks of follow-up or the final volume before delivery, whichever occurred first. Secondary outcomes were duration of pregnancy prolongation, mode of delivery, and select neonatal outcomes. The study was powered to detect a 45% difference between groups, so, at an α level of 0.05 and 80% power, a sample size of 167 women was required. RESULTS: From February 24, 2015, through April 2016, 196 women were screened and 184 were randomized. Follow-up was completed in 166 (90%): 82 in the sildenafil group and 84 in the hydration group. Baseline characteristics were similar between groups. The amniotic fluid volume was higher in the sildenafil group at the final assessment (11.5 compared with 5.4 cm, P=.02). The sildenafil group delivered later (38.3 compared with 36.0 weeks of gestation, P=.001), had a lower rate of cesarean delivery (28% compared with 73%), and their neonates were less likely to be admitted to the neonatal intensive care unit (11% compared with 41%, P=.001). CONCLUSION: Sildenafil citrate increases amniotic fluid volume in pregnancies complicated by oligohydramnios. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT02372487.

Different routes and forms of uterotonics for treatment of retained placenta: a randomized clinical trial.

OBJECTIVES: To compare between three different uterotonics (oxytocin, carbetocin and misoprostol) given via three different routes (intraumbilical, intravenous and sublingual, respectively) in reducing the need for manual removal of placenta (MROP). METHODS: A randomized trial for cases with retained placenta 30 min following vaginal delivery. They received intraumbilical oxytocin, intravenous carbetocin or sublingual misoprostol. Main outcome measures were delivery of the placenta within 30 min following drug administration, and need for MROP. Secondary outcome measures were injection to placental delivery time, post-delivery hemoglobin, need for blood transfusion or additional uterotonics. RESULTS: The overall success rate was 66.7% (64/96), 71.3% (67/94) and 63.7% (58/91) for oxytocin, carbetocin and misoprostol groups, respectively (p > 0.05). When time needed to achieve placental delivery considered, a significant difference was observed with the shortest time for carbetocin (16.61 ± 3.76 min), then oxytocin (18.28 ± 3.34 min) and lastly misoprostol (23.00 ± 3.38 min) (p <0.001). Again, carbetocin group needed less additional uterotonics to achieve adequate uterine contractions (p <0.001). CONCLUSIONS: Although we aimed to exploit the advantage of certain drug over another, all seemed to have close efficacy but it would be important that further research should highlight availability, cost, ease of administration and storage requirements to determine which agent would best be used in this clinical scenario.

Survival and fertility rate of cooled dromedary camel spermatozoa supplemented with catalase enzyme.

The present study was planned to study the effects of addition of different concentrations of catalase enzyme (0, 250, 500 and 1,000 IU/ml) to cooled dromedary camel semen extended with tris-yolk-fructose extender on semen quality during storage at 5 C for up to 5 days. Conception rates of she-camels artificially inseminated with whole fresh or extended cooled dromedary camel semen with or without 500 IU/ml catalase enzyme were also estimated. The results showed that addition of catalase enzyme at concentrations of 250 or 500 IU/ml to extended cooled dromedary camel semen significantly increased (P<0.01) the percentage of sperm motility and significantly decreased (P<0.01) the percentages of dead spermatozoa, sperm abnormalities and acrosomal damage. The highest (P<0.01) percentage of sperm motility was recorded with extended cooled dromedary camel semen supplemented with catalase enzyme at a concentration of 500 IU/ml, and the lowest (P<0.01) value was recorded with catalase enzyme at a concentration of 1000 IU/ml. On the other hand, the lowest (P<0.01) percentages of dead spermatozoa, sperm abnormalities and acrosomal damage of spermatozoa were recorded with extended cooled dromedary camel semen supplemented with 500 IU/ml, and the highest (P<0.01) values were recorded with catalase enzyme at a concentration of 1,000 IU/ml. Advancement of the storage time at 5 C significantly decreased (P<0.01) the percentage of sperm motility and significantly increased (P<0.01) the percentages of dead spermatozoa, sperm abnormalities and acrosomal damage of spermatozoa. Moreover, the conception rates of she-camels artificially inseminated with whole fresh, extended cooled dromedary camel semen free-catalase enzyme and extended cooled dromedary camel semen supplemented with catalase enzyme at a concentration of 500 IU/ml were 46.15, 22.22 and 37.50%, respectively. In conclusion, the results show that addition of catalase enzyme at a concentration of 500 IU/ml to semen extender can be used as an agent for prolongation of dromedary camel sperm cell survival during storage at 5 C.