Potential drug candidates as P-glycoprotein inhibitors to reverse multidrug resistance in cancer: an in silico drug discovery study.

The failure of chemotherapy in the treatment of carcinoma is mainly due to the development of multidrug resistance (MDR), which is largely caused by the overexpression of P-glycoprotein (P-gp/ABCB1/MDR1). Until recently, the 3D structure of the P-gp transporter has not been experimentally resolved, which restricted the discovery of prospective P-gp inhibitors utilizing in silico techniques. In this study, the binding energies of 512 drug candidates in clinical or investigational stages were assessed as potential P-gp inhibitors employing in silico methods. On the basis of the available experimental data, the performance of the AutoDock4.2.6 software to predict the drug-P-gp binding mode was initially validated. Molecular docking and molecular dynamics (MD) simulations combined with molecular mechanics-generalized Born surface area (MM-GBSA) binding energy computations were subsequently conducted to screen the investigated drug candidates. Based on the current results, five promising drug candidates, namely valspodar, dactinomycin, elbasvir, temsirolimus, and sirolimus, showed promising binding energies against P-gp transporter with ΔGbinding values of -126.7, -112.1, -111.9, -102.9, and -101.4 kcal/mol, respectively. The post-MD analyses revealed the energetical and structural stabilities of the identified drug candidates in complex with the P-gp transporter. Furthermore, in order to mimic the physiological conditions, the potent drugs complexed with the P-gp were subjected to 100 ns MD simulations in an explicit membrane-water environment. The pharmacokinetic properties of the identified drugs were predicted and demonstrated good ADMET characteristics. Overall, these results indicated that valspodar, dactinomycin, elbasvir, temsirolimus, and sirolimus hold promise as prospective P-gp inhibitors and warrant further invitro/invivo investigations.

The association of genitourinary cancer among Saudi patients with gastrointestinal stromal tumors and a systematic literature review.

The gastrointestinal tract's most commonly occurring primary mesenchymal tumor is the gastrointestinal stromal tumor (GIST). However, few cases worldwide were reported associated with renal cell carcinoma (RCC). Therefore, we aimed to identify the association of genitourinary tumors in patients with GIST in our tertiary care hospital in Saudi Arabia and compare it to the literature. We identified all patients in the pathology department database with the diagnosis of GIST. We excluded duplicate and recurrent cases. We examined patients' files for the presence of RCC, adrenal tumors, or other genitourinary cancer. A systematic review of the association was conducted. From 2003 to 2020, 170 patients had a histopathologic diagnosis of primary GIST, 100 men and 70 women, median age of 57 (range 9-91) years at the time of diagnosis. The site of primary GIST was gastric 103, small bowel 43, mesenteric 5, omentum/peritoneum 7, abdomen 4, isolated adrenal 1, and other 7. Six patients had associated primary genitourinary cancer. Three patients had RCC (two clear cell RCC and one radiologic diagnosis only), and three had adrenal tumors (one adrenal carcinoma, one an isolated adrenal GIST, and one pheochromocytoma). In addition, two patients had a tumor invading the urinary bladder. Although the cohort included 63 men aged 60 or above (median 71 ± 8.7 years, range 60-94), none demonstrated clinical prostatic carcinoma. Data was compared to 69 systematic review articles. We report the rare association between GIST tumors and primary genitourinary cancer, mainly RCC and adrenal tumors. Also, we identified a secondary invasion of the urinary bladder. Unlike the reported series, none of the older male patients had clinical prostate cancer.

Antiapoptotic Gene Genotype and Allele Variations and the Risk of Lymphoma.

BACKGROUND: The findings of earlier investigations of antiapoptotic gene genotypes and allele variants on lymphoma risk are ambiguous. This study aimed to examine the relationship between the mutation in the antiapoptotic genes and lymphoma risk among Saudi patients. METHODS: This case-control study included 205 patients, 100 of whom had lymphoma (cases) and 105 who were healthy volunteers (controls). We used tetra amplification refractory mutation polymerase chain reaction (PCR) to identify antiapoptotic genes such as B-cell lymphoma-2 (BCL2-938 C > A), MCL1-rs9803935 T > G, and survivin (BIRC5-rs17882312 G > C and BIRC5-rs9904341 G > C). Allelic-specific PCR was used to identify alleles such as BIRC5-C, MCL1-G, and BIRC5-G. RESULTS: The dominant inheritance model among cases showed that mutations in all four antiapoptotic genes were more likely to be associated with the risk of lymphoma by the odds of 2.0-, 1.98-, 3.90-, and 3.29-fold, respectively, compared to controls. Apart from the BCL-2-A allele, all three specified alleles were more likely to be associated with lymphoma by the odds of 2.04-, 1.65-, and 2.11-fold, respectively. CONCLUSION: Unlike healthy individuals, lymphoma patients are more likely to have antiapoptotic gene genotypes and allele variants, apart from BCL-2-A alterations. In the future, these findings could be used to classify and identify patients at risk of lymphoma.

Potential Impact of PI3K-AKT Signaling Pathway Genes, KLF-14, MDM4, miRNAs 27a, miRNA-196a Genetic Alterations in the Predisposition and Progression of Breast Cancer Patients.

Genome-wide association studies have reported link between SNPs and risk of breast cancer. This study investigated the association of the selected gene variants by predicting them as possible target genes. Molecular technique advances with the availability of whole-exome sequencing (WES), now offer opportunities for simultaneous investigations of many genes. The experimental protocol for PI3K, AKT-1, KLF-14, MDM4, miRNAs 27a, and miR-196a genotyping was done by ARMS-PCR and sanger sequencing. The novel and known gene variants were studied by Whole-exome sequencing using Illumina NovaSeq 6000 platform. This case control study reports significant association between BC patients, healthy controls with the polymorphic variants of PI3K C > T, AKT-1 G > A KLF 14 C > T, MDM4 A > G, miR-27a A > G, miR-196a-2 C > T genes (p < 0.05). MDM4 A > G genotypes were strongly associated with BC predisposition with OR 2.08 & 2.15, p < 0.05) in codominant and dominant models respectively. MDM4 A allele show the same effective (OR1.76, p < 0.05) whereas it remains protective in recessive model for BC risk. AKT1G > A genotypes were strongly associated with the BC susceptibility in all genetic models whereas PI3K C > T genotypes were associated with breast cancer predisposition in recessive model OR 6.96. Polymorphic variants of KLF-14 A > G, MDM4G > A, MiR-27aA >G, miR-196a-C > T were strongly associated with stage, tamoxifen treatment. Risk variants have been reported by whole exome sequencing in our BC patients. It was concluded that a strong association between the PI3K-AKT signaling pathway gene variants with the breast cancer susceptibility and progression. Similarly, KLF 14-AA, MDM4-GA, miR27a-GG and miR-196a-CT gene variants were associated with the higher risk probability of BC and were strongly correlated with staging of the BC patients. This study also reported Low, novel, and intermediate-genetic-risk variants of PI3K, AKT-1, MDM4G & KLF-14 by utilizing whole-exome sequencing. These variants should be further investigated in larger cohorts' studies.

PheroxyPyrabenz and Carbopyrropyridin against major proteins of SARS CoV-2: a comprehensive in-silico molecular docking and dynamics simulation studies.

The pandemic that started in 2020 left us with so much information about viruses and respiratory diseases, and the cause behind it was severe acute respiratory syndrome coronavirus-2 (SARS CoV-2). The world is still recovering, which costs so many economic and other indirect disasters; despite that, no medications are available on the market. Although the WHO approved a few vaccines on an emergency basis, the remarks and the reinfection chances are still under investigation, and a few pharmaceutical companies are also claiming that a few medications can be effective. However, there is no situation in control. SARS CoV-2 mutates and comes in different forms, making the situation unpredictable. In this study, we have screened the complete Asinex's BioDesign library, which contains 170,269 compounds, and shorted the data against the docking score that helps in the identification of 4-[5-(3-Ethoxy-4-hydroxyphenyl)-1-(2-hydroxyethyl)-1H-pyrazol-3-yl]-1, 2-benzenediol (PheroxyPyrabenz) and 1-[(3R,4R)-1-(5-Aminopentanoyl)-4-hydroxy-3-pyrrolidinyl]-1H-pyrrolo[2,3-b]pyridine-4-carboxamide (Carbopyrropyridin) as a significant drug candidate that can work against the multiple proteins of the SARS CoV-2 resulting in seizing the complete biological process of the virus. Further, the study extended to Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) and molecular dynamics (MD) simulation of both the compounds with their complexity. The complete workflow of the study has shown satisfactory results, and both drug candidates can potentially stop the hunt for drugs against this virus after its experimental validation. Further, we checked both compounds' absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, showing case-proof validatory results.Communicated by Ramaswamy H. Sarma.

Enhancement of the Protective Activity of Vanillic Acid against Tetrachloro-Carbon (CCl4) Hepatotoxicity in Male Rats by the Synthesis of Silver Nanoparticles (AgNPs).

In the current study, the hepatoprotective activity of vanillic acid, silymarin, and vanillic acid-loaded silver nanoparticles (AgNPs) against CCl4-induced hepatotoxicity was tested in male rats for four weeks. Thirty male rats were divided into five groups (n = 6). The 1st group was a negative control, the 2nd group was a positive control, the 3rd group was treated with 100 mg/kg b.w. of vanillic acid, the 4th group was treated with 100 mg/kg b.w. of vanillic acid-AgNPs, and the 5th group was treated with 50 mg/kg b.w. of silymarin. The CCl4-induced hepatic toxicity in the 2nd group was revealed by the liver function and all other biochemical tests. Liver enzymes, bilirubin, lipid peroxidation, lactate dehydrogenase, and interleukin-6 were elevated, whereas, total protein, antioxidant enzymes, and irisin were decreased compared to the negative control. The hepatic tissues were also injured as a result of the CCl4-induced hepatotoxicity. Treating the hepatotoxic rats with vanillic acid moderately protected the rats of the 3rd group, whereas treatment with vanillic AgNPs and silymarin in G4 and G5, respectively, greatly protected the rats against the CCl4 hepatotoxicity, approaching the normal biochemical levels and liver tissue appearance. The biochemical tests were confirmed by the histological investigations of liver tissue.

Improvement of Zn (II) and Cd (II) Biosorption by Priestia megaterium PRJNA526404 Isolated from Agricultural Waste Water.

Heavy metals are considered as dangerous pollutants even in relatively low concentrations. Biosorption is an ecofriendly technology that uses microbial biomasses for adsorbing heavy metals from wastewater on their surfaces based on physicochemical pathways. Ten agricultural wastewater samples were collected from different sites in Sohag Governorate, Egypt. One hundred and nineteen zinc and cadmium-resistant bacterial isolates were recovered from the water samples. Interestingly, the isolate R1 was selected as the most resistant to Zn2+ and Cd2+. This isolate was morphologically and biochemically characterized and identified by sequencing of 16S rRNA gene as Priestia megaterium, and then deposited in the GenBank database under the accession number PRJNA526404. Studying the effects of pH and contact time on the biosorption process revealed that the maximum biosorption was achieved within 50 min at pH 7 and 8 for Zn2+ and Cd2+, respectively, by the living and lyophelized biomass of Priestia megaterium PRJNA526404. The preliminary characterization of the main chemical groups present on the cell wall, which are responsible for heavy metal biosorption, was performed by Infrared analysis (IR). Kinetics studies revealed that data were fitted towards the models hypothesized by Langmuir and Freundlich isotherm equations. The maximum capacity values (qmax) for biosorption of zinc and cadmium reached by using living and lyophelized biomass were 196.08; 227.27 and 178.57; 212.777 mg/g, respectively, and it was indicated that lyophilization improved efficiency of the biomass to heavy metals compared to living cells. The results indicated that Priestia megaterium PRJNA526404 had good application prospect in cadmium and zinc water remediation.

Resistance to Some New Drugs and Prevalence of ESBL- and MBL-Producing Enterobacteriaceae Uropathogens Isolated from Diabetic Patients.

Diabetes is a leading non-communicable disease and a risk factor for relapsing infections. The current study was aimed at investigating the prevalence and antibiotic susceptibility of carbapenem-resistant (CR) uropathogens of the family Enterobacteriaceae in diabetic patients. The data of 910 bacterial isolates was collected from diagnostic laboratories during January 2018 to December 2018. The bacterial isolates were identified using traditional methods including colonial characteristics, biochemical tests, and API (20E). Antimicrobial susceptibility and phenotypic characterization of ESBL, MBLs, and KPC was determined by utilizing CLSI recommended methods. The phenotypically positive isolates were further analyzed for resistance-encoding genes by manual PCR and Check-MDR CT103XL microarray. Susceptibility to colistin and cefiderocol was tested in accordance with CLSI guidelines. The data revealed that most of the patients were suffering from type 2 diabetes for a duration of more than a year and with uncontrolled blood sugar levels. Escherichia coli and Klebsiella pneumoniae were the most frequently encountered pathogens, followed by Enterobacter cloacae and Proteus mirabilis. More than 50% of the isolates showed resistance to 22 antibiotics, with the highest resistance (>80%) against tetracycline, ampicillin, and cefazolin. The uropathogens showed less resistance to non-ß-lactam antibiotics, including amikacin, fosfomycin, and nitrofurantoin. In the phenotypic assays, 495 (54.3%) isolates were found to be ESBL producers, while ESBL-TEM and -PER were the most prevalent ESBL types. The resistance to carbapenems was slightly less (250; 27.5%) than ESBL producers, yet more common amongst E. coli isolates. MBL production was a common feature in carbapenem-resistant isolates (71.2%); genotypic characterization also validated this trend. The isolates were found to be sensitive against the new drugs, cefiderocol and eravacycline. with 7−28% resistance, except for P. mirabilis which had 100% resistance against eravacycline. This study concludes that a few types of ESBL and carbapenemases are common in the uropathogens isolated from the diabetic patients, and antibiotic stewardship programs need to be revisited, particularly to cure UTIs in diabetic patients.

Identification and Characterization of Novel Mutations in Chronic Kidney Disease (CKD) and Autosomal Dominant Polycystic Kidney Disease (ADPKD) in Saudi Subjects by Whole-Exome Sequencing.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a condition usually caused by a single gene mutation and manifested by both renal and extrarenal features, eventually leading to end-stage renal disease (ESRD) by the median age of 60 years worldwide. Approximately 89% of ADPKD patients had either PKD1 or PKD2 gene mutations. The majority (85%) of the mutations are in the PKD1 gene, especially in the context of family history. Objectives: This study investigated the genetic basis and the undiscovered genes that are involved in ADPKD development among the Saudi population. Materials and Methods: In this study, 11 patients with chronic kidney disease were enrolled. The diagnosis of ADPKD was based on history and diagnostic images: CT images include enlargement of renal outlines, renal echogenicity, and presence of multiple renal cysts with dilated collecting ducts, loss of corticomedullary differentiation, and changes in GFR and serum creatinine levels. Next-generation whole-exome sequencing was conducted using the Ion Torrent PGM platform. Results: Of the 11 Saudi patients diagnosed with chronic kidney disease (CKD) and ADPKD, the most common heterozygote nonsynonymous variant in the PKD1 gene was exon15: (c.4264G > A). Two missense mutations were identified with a PKD1 (c.1758A > C and c.9774T > G), and one patient had a PKD2 mutation (c.1445T > G). Three detected variants were novel, identified at PKD1 (c.1758A > C), PKD2L2 (c.1364A > T), and TSC2 (deletion of a'a at the 3'UTR, R1680C) genes. Other variants in PKD1L1 (c.3813_381 4delinsTG) and PKD1L2 (c.404C > T) were also detected. The median age of end-stage renal disease for ADPK patients in Saudi Arabia was 30 years. Conclusion: This study reported a common variant in the PKD1 gene in Saudi patients with typical ADPKD. We also reported (to our knowledge) for the first time two novel missense variants in PKD1 and PKD2L2 genes and one indel mutation at the 3'UTR of the TSC2 gene. This study establishes that the reported mutations in the affected genes resulted in ADPKD development in the Saudi population by a median age of 30. Nevertheless, future protein−protein interaction studies to investigate the influence of these mutations on PKD1 and PKD2 functions are required. Furthermore, large-scale population-based studies to verify these findings are recommended.

Enzyme Profiling and Identification of Endophytic and Rhizospheric Bacteria Isolated from Arthrocnemum macrostachyum.

Endophytic and rhizospheric bacteria isolated from halophytic plants support their host to survive in hyper-saline soil. These bacteria are also known to produce various enzymes with potential industrial applications. In this study, the endophytic and rhizospheric bacteria were isolated from Arthrocnemum macrostachyum collected from Karachi, Pakistan, and their ability to produce various extracellular enzymes was assessed using commercial and natural substrates. In total, 11 bacterial strains were isolated (four endophytic; seven rhizospheric). Bacillus was found to be the most abundant genus (73%), followed by Glutamicibacter (27%). The isolates including Glutamicibacter endophyticus and Bacillus licheniformis are reported for the first time from A. macrostachyum. All of the isolates were capable of producing at least two of the five industrially important hydrolytic enzymes tested, i.e., xylanase, cellulase, amylase, pectinase, and lipase. Lipase production was found to be highest among the isolates, i.e., up to 18 IU mL-1. Although most of the isolates could grow at a wide range of temperatures (4-55 °C), pH (1-11), and salt concentrations (2-12%), under extreme conditions, very little growth was observed and the optimal growth was recorded between 2% and 6% NaCl, 25 and 45 °C, and 7 and 9 pH. Our results suggest that these isolates could be potential producers of enzymes with several biotechnological applications.

Microbial Degradation, Spectral analysis and Toxicological Assessment of Malachite Green Dye by Streptomyces exfoliatus.

Malachite green (MG) dye is a common environmental pollutant that threatens human health and the integrity of the Earth's ecosystem. The aim of this study was to investigate the potential biodegradation of MG dye by actinomycetes species isolated from planted soil near an industrial water effluent in Cairo, Egypt. The Streptomyces isolate St 45 was selected according to its high efficiency for laccase production. It was identified as S. exfoliatus based on phenotype and 16S rRNA molecular analysis and was deposited in the NCBI GenBank with the gene accession number OL720220. Its growth kinetics were studied during an incubation time of 144 h, during which the growth rate was 0.4232 (µ/h), the duplication time (td) was 1.64 d, and multiplication rate (MR) was 0.61 h, with an MG decolorization value of 96% after 120 h of incubation at 25 °C. Eleven physical and nutritional factors (mannitol, frying oil waste, MgSO4, NH4NO3, NH4Cl, dye concentration, pH, agitation, temperature, inoculum size, and incubation time) were screened for significance in the biodegradation of MG by S. exfoliatus using PBD. Out of the eleven factors screened in PBD, five (dye concentration, frying oil waste, MgSO4, inoculum size, and pH) were shown to be significant in the decolorization process. Central composite design (CCD) was applied to optimize the biodegradation of MG. Maximum decolorization was attained using the following optimal conditions: food oil waste, 7.5 mL/L; MgSO4, 0.35 g/L; dye concentration, 0.04 g/L; pH, 4.0; and inoculum size, 12.5%. The products from the degradation of MG by S. exfoliatus were characterized using high-performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS). The results revealed the presence of several compounds, including leuco-malachite green, di(tert-butyl)(2-phenylethoxy) silane, 1,3-benzenedicarboxylic acid, bis(2-ethylhexyl) ester, 1,4-benzenedicarboxylic acid, bis(2-ethylhexyl) ester, 1,2-benzenedicarboxylic acid, di-n-octyl phthalate, and 1,2-benzenedicarboxylic acid, dioctyl ester. Moreover, the phytotoxicity, microbial toxicity, and cytotoxicity tests confirmed that the byproducts of MG degradation were not toxic to plants, microbes, or human cells. The results of this work implicate S. exfoliatus as a novel strain for MG biodegradation in different environments.

In Vitro Evaluation of Leuconostoc mesenteroides Cell-Free-Supernatant GBUT-21 against SARS-CoV-2.

The unprecedented health catastrophe derived from the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2 infection) met with a phenomenal scientific response across the globe. Worldwide, the scientific community was focused on finding a cure for the deadly disease. A wide range of research studies has consistently revealed the link between SARS-CoV-2 infection severity and abnormal gut microbiomes, suggesting its potential in developing novel therapeutic approaches. Probiotics have been extensively studied to promote health in human hosts and reestablish a balance in the dysbiotic gut microbiome; however, there is strong skepticism about their safety and efficacy. Consequently, the metabolic signatures of probiotics, often referred to as "postbiotics", could prove of paramount importance for adjuvant cures in patients with SARS-CoV-2. Postbiotics exhibit safety, enhanced shelf-life, and stability and, therefore, could be implemented in SARS-CoV-2 prophylactic strategies with no undue adverse side effects. The current study is a preliminary investigation of the antiviral properties of postbiotic metabolites derived from Leuconostoc mesenteroides GBUT-21. The study focuses on the potential biological role in inactivating SARS-CoV-2 and reducing related inflammatory pathways.

Toxicity, Safety, and Efficacy Studies on Mesenchymal Stem Cells Derived from Decidua basalis in Wistar Albino Rats by Intravenous and Subcutaneous Routes.

Ex vivo expanded decidua-basalis(DB)-derived mesenchymal stem cells (MSCs) obtained from single donors have demonstrated therapeutic benefits in in vitro and in vivo studies. In this report, the intravenous and subcutaneous administration of DB-MSCs obtained from five healthy donors was assessed considering clinical grade proliferation, accessibility, and toxic effects in Wistar albino rats. The ability of the obtained DB-MSCs for differentiating, as well as their expression of several cell surface markers and immunomodulatory activities, were all assessed. Clinical standard proliferated cells were administered to animals intravenously and subcutaneously in a series of preclinical models in order to assess their in vivo toxicity, general safety, and tumorigenic possibilities. We established that DB cells exhibit structural and functional traits with MSCs. At various doses supplied intravenously or subcutaneously, the research showed no fatality, abnormal response to therapy, or substantial pathological modifications in the rats. Furthermore, there was no indication of prenatal damage in the same animal species when the rats were repeatedly treated with DBMSCs. Thus, DBMSCs were demonstrated to be non-toxic, non-teratogenic, and non-tumorigenic. To determine whether they can be administrated to human patients without risk, more investigation is recommended.

The State-of-the-Art of Gene Editing and its Application to Viral Infections and Diseases Including COVID-19.

Gene therapy delivers a promising hope to cure many diseases and defects. The discovery of gene-editing technology fueled the world with valuable tools that have been employed in various domains of science, medicine, and biotechnology. Multiple means of gene editing have been established, including CRISPR/Cas, ZFNs, and TALENs. These strategies are believed to help understand the biological mechanisms of disease progression. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been designated the causative virus for coronavirus disease 2019 (COVID-19) that emerged at the end of 2019. This viral infection is a highly pathogenic and transmissible disease that caused a public health pandemic. As gene editing tools have shown great success in multiple scientific and medical areas, they could eventually contribute to discovering novel therapeutic and diagnostic strategies to battle the COVID-19 pandemic disease. This review aims to briefly highlight the history and some of the recent advancements of gene editing technologies. After that, we will describe various biological features of the CRISPR-Cas9 system and its diverse implications in treating different infectious diseases, both viral and non-viral. Finally, we will present current and future advancements in combating COVID-19 with a potential contribution of the CRISPR system as an antiviral modality in this battle.

Clinical and Serological Findings of COVID-19 Participants in the Region of Makkah, Saudi Arabia.

Makkah in Saudi Arabia hosts the largest annual religious event in the world. Despite the many strict rules enacted, including Hajj cancellation, city lockdowns, and social distancing, the region has the second highest number of new COVID-19 cases in Saudi Arabia. Public health interventions that identify, isolate, and manage new cases could slow the infection rate. While RT-PCR is the current gold standard in SARS-CoV-2 identification, it yields false positive and negative results, which mandates the use of complementary serological tests. Here, we report the utility of serological assays during the acute phase of individuals with moderate and severe clinical manifestations of SARS-CoV-2 (COVID19). Fifty participants with positive RT-PCR results for SARS-CoV-2 were enrolled in this study. Following RT-PCR diagnosis, serum samples from the same participants were analyzed using in-house ELISA (IgM, IgA, and IgG) and microneutralization test (MNT) for the presence of antibodies. Of the 50 individuals analyzed, 43 (86%) showed a neutralizing antibody titer of ≥20. Univariate analysis with neutralizing antibodies as a dependent variable and the degree of disease severity and underlying medical conditions as fixed factors revealed that patients with no previous history of non-communicable diseases and moderate clinical manifestation had the strongest neutralizing antibody response "Mean: 561.11". Participants with severe symptoms and other underlying disorders, including deceased individuals, demonstrated the lowest neutralizing antibody response. Anti-spike protein antibody responses, as measured by ELISA, showed a statistically significant correlation with neutralizing antibodies. This reinforces the speculation that serological assays complement molecular testing for diagnostics; however, patients' previous medical history (anamnesis) should be considered in interpreting serological results.

BARD1 mystery: tumor suppressors are cancer susceptibility genes.

The full-length BRCA1-associated RING domain 1 (BARD1) gene encodes a 777-aa protein. BARD1 displays a dual role in cancer development and progression as it acts as a tumor suppressor and an oncogene. Structurally, BARD1 has homologous domains to BRCA1 that aid their heterodimer interaction to inhibit the progression of different cancers such as breast and ovarian cancers following the BRCA1-dependant pathway. In addition, BARD1 was shown to be involved in other pathways that are involved in tumor suppression (BRCA1-independent pathway) such as the TP53-dependent apoptotic signaling pathway. However, there are abundant BARD1 isoforms exist that are different from the full-length BARD1 due to nonsense and frameshift mutations, or deletions were found to be associated with susceptibility to various cancers including neuroblastoma, lung, breast, and cervical cancers. This article reviews the spectrum of BARD1 full-length genes and its different isoforms and their anticipated associated risk. Additionally, the study also highlights the role of BARD1 as an oncogene in breast cancer patients and its potential uses as a prognostic/diagnostic biomarker and as a therapeutic target for cancer susceptibility testing and treatment.

Developing a Multimodal Model for Detecting Higher-Grade Prostate Cancer Using Biomarkers and Risk Factors.

A technique to predict crucial clinical prostate cancer (PC) is desperately required to prevent diagnostic errors and overdiagnosis. To create a multimodal model that incorporates long-established messenger RNA (mRNA) indicators and conventional risk variables for identifying individuals with severe PC on prostatic biopsies. Urinary has gathered for mRNA analysis following a DRE and before a prostatic examination in two prospective multimodal investigations. A first group (n = 489) generated the multimodal risk score, which was then medically verified in a second group (n = 283). The reverse transcription qualitative polymerase chain reaction determined the mRNA phase. Logistic regression was applied to predict risk in patients and incorporate health risks. The area under the curve (AUC) was used to compare models, and clinical efficacy was assessed by using a DCA. The amounts of sixth homeobox clustering and first distal-less homeobox mRNA have been strongly predictive of high-grade PC detection. In the control subjects, the multimodal method achieved a total AUC of 0.90, with the most important aspects being the messenger riboneuclic acid features' PSA densities and previous cancer-negative tests as a nonsignificant design ability to contribute to PSA, aging, and background. An AUC of 0.86 was observed for one more model that added DRE as an extra risk component. Two methods were satisfactorily verified without any significant changes within the area under the curve in the validation group. DCA showed a massive net advantage and the highest decrease in inappropriate costs.

Translin facilitates RNA polymerase II dissociation and suppresses genome instability during RNase H2- and Dicer-deficiency.

The conserved nucleic acid binding protein Translin contributes to numerous facets of mammalian biology and genetic diseases. It was first identified as a binder of cancer-associated chromosomal translocation breakpoint junctions leading to the suggestion that it was involved in genetic recombination. With a paralogous partner protein, Trax, Translin has subsequently been found to form a hetero-octomeric RNase complex that drives some of its functions, including passenger strand removal in RNA interference (RNAi). The Translin-Trax complex also degrades the precursors to tumour suppressing microRNAs in cancers deficient for the RNase III Dicer. This oncogenic activity has resulted in the Translin-Trax complex being explored as a therapeutic target. Additionally, Translin and Trax have been implicated in a wider range of biological functions ranging from sleep regulation to telomere transcript control. Here we reveal a Trax- and RNAi-independent function for Translin in dissociating RNA polymerase II from its genomic template, with loss of Translin function resulting in increased transcription-associated recombination and elevated genome instability. This provides genetic insight into the longstanding question of how Translin might influence chromosomal rearrangements in human genetic diseases and provides important functional understanding of an oncological therapeutic target.

In Silico Identification of Hub Genes as Observing Biomarkers for Gastric Cancer Metastasis.

Perception of hub genes engaged in metastatic gastric cancer (mGC) promotes novel ways to diagnose and treat the illness. The goal of this investigation is to recognize the hub genes and reveal its molecular mechanism. In order to explore the potential facts for gastric cancer, the expression profiles of two different datasets were used (GSE161533 and GSE54129). The genes were confirmed to be part of the PPI network for gastric cancer pathogenesis and prognosis. In Cytoscape, the CytoHubba module was used to discover the hub genes. Responsible hub genes were identified. Data from Kaplan-Meier plotter confirmed the predictive value of these distinct genes in various stages of gastric malignancy. Upregulated and downregulated genes were identified to utilize for further analysis. Positive regulation by a host of viral process, positive regulation of granulocyte differentiation, negative regulation of histone H3-K9 methylation were found in DEGs analysis. In addition, five KEGG pathways were identified as an essential enhancer that include nucleotide excision repair; base excision repair; DNA replication; homologous recombination; and complement and coagulation cascades. POLE, BUB1B, POLD4, C3, BLM, CCT7, PRPF31, APEX1, PSMA7, and CDC45 were chosen as hub genes after combining the PPI results. Our study recommends that BUB1B, CCT7, APEX1, PSMA7, and CDC45 might be potential biomarkers for gastric cancer. These biomarkers are upregulated genes. Therefore, suppression of these genes will increase the survival rate in gastric cancer patients.

Genetic Diversity, Biofilm Formation, and Antibiotic Resistance of Pseudomonas aeruginosa Isolated from Cow, Camel, and Mare with Clinical Endometritis.

Pseudomonas aeruginosa is a ubiquitous opportunistic bacterium that causes diseases in animals and humans. This study aimed to investigate the genetic diversity, antimicrobial resistance, biofilm formation, and virulence and antibiotic resistance genes of P. aeruginosa isolated from the uterus of cow, camel, and mare with clinical endometritis and their drinking water. Among the 180 uterine swabs and 90 drinking water samples analysed, 54 (20%) P. aeruginosa isolates were recovered. Isolates were identified biochemically to the genus level by the automated Vitek 2 system and genetically by the amplification of the gyrB gene and the sequencing of the 16S rRNA gene. Multilocus sequence typing identified ten different sequence types for the P. aeruginosa isolates. The identification of ST2012 was significantly (p ≤ 0.05) higher than that of ST296, ST308, ST111, and ST241. The isolates exhibited significantly (p ≤ 0.05) increased resistance to piperacillin (77.8%), ciprofloxacin (59.3%), gentamicin (50%), and ceftazidime (38.9%). Eight (14.8%) isolates showed resistance to imipenem; however, none of the isolates showed resistance to colistin. Multidrug resistance (MDR) was observed in 24 isolates (44.4%) with a multiple antibiotic resistance index ranging from 0.44 to 0.77. MDR was identified in 30 (33.3%) isolates. Furthermore, 38.8% and 9.2% of the isolates exhibited a positive extended-spectrum-ß-lactamase (ESBL) and metallo-ß-lactamase (MBL) phenotype, respectively. The most prevalent ß-lactamase encoding genes were blaTEM and blaCTX-M, however, the blaIPM gene was not detected in any of the isolates. Biofilm formation was observed in 49 (90.7%) isolates classified as: 11.1% weak biofilm producers; 38.9% moderate biofilm producers; 40.7% strong biofilm producers. A positive correlation was observed between the MAR index and biofilm formation. In conclusion, the results highlighted that farm animals with clinical endometritis could act as a reservoir for MDR and virulent P. aeruginosa. The emergence of ESBLs and MBLs producing P. aeruginosa in different farm animals is a public health concern. Therefore, surveillance programs to monitor and control MDR P. aeruginosa in animals are required.