Severe acute respiratory syndrome coronavirus-2 natural animal reservoirs and experimental models: systematic review.

The current severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) outbreak has been rapidly spreading worldwide, causing serious global concern. The role that animal hosts play in disease transmission is still understudied and researchers wish to find suitable animal models for fundamental research and drug discovery. In this systematic review, we aimed to compile and discuss all articles that describe experimental or natural infections with SARS-CoV-2, from the initial discovery of the virus in December 2019 through to October 2020. We systematically searched four databases (Scopus, PubMed, Science Direct and Web of Science). The following data were extracted from the included studies: type of infection (natural or experimental), age, sample numbers, dose, route of inoculation, viral replication, detection method, clinical symptoms and transmission. Fifty-four studies were included, of which 34 were conducted on animal reservoirs (naturally or experimentally infected), and 20 involved models for testing vaccines and therapeutics. Our search revealed that Rousettus aegyptiacus (fruit bats), pangolins, felines, mink, ferrets and rabbits were all susceptible to SARS-CoV-2, while dogs were weakly susceptible and pigs, poultry, and tree shrews were not. In addition, virus replication in mice, mink, hamsters and ferrets resembled subclinical human infection, so these animals might serve as useful models for future studies to evaluate vaccines or antiviral agents and to study host-pathogen interactions. Our review comprehensively summarized current evidence on SARS-CoV-2 infection in animals and their usefulness as models for studying vaccines and antiviral drugs. Our findings may direct future studies for vaccine development, antiviral drugs and therapeutic agents to manage SARS-CoV-2-caused diseases.

Genetic polymorphisms associated with obesity in the Arab world: a systematic review.

BACKGROUND: Obesity, one of the most common chronic health conditions worldwide, is a multifactorial disease caused by complex genetic and environmental interactions. Several association studies have revealed a considerable number of candidate loci for obesity; however, the genotype-phenotype correlations remain unclear. To date, no comprehensive systematic review has been conducted to investigate the genetic risk factors for obesity among Arabs. OBJECTIVES: This study aimed to systematically review the genetic polymorphisms that are significantly associated with obesity in Arabs. METHODS: We searched four literature databases (PubMed, Science Direct, Scopus, and Google Scholar) from inception until May 2020 to obtain all reported genetic data related to obesity in Arab populations. Quality assessment and data extraction were performed individually by three investigators. RESULTS: In total, 59 studies comprising a total of 15,488 cases and 9,760 controls were included in the systematic review. A total of 76 variants located within or near 49 genes were reported to be significantly associated with obesity. Among the 76 variants, two were described as unique to Arabs, as they have not been previously reported in other populations, and 19 were reported to be distinctively associated with obesity in Arabs but not in non-Arab populations. CONCLUSIONS: There appears to be a unique genetic and clinical susceptibility profile of obesity in Arab patients.

Genetic Variants Associated With Alzheimer Disease in the 22 Arab Countries: A Systematic Review.

BACKGROUND AND AIMS: Alzheimer disease (AD) is a progressive and complex neurodegenerative disease. Approximately 70% of AD risk is attributed to genetic risk factors, including variants in amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes. Several studies have revealed a considerable number of candidate loci and genes for AD among different ethnic populations. However, the outcomes of these studies have been inconsistent. In this study, we aimed to investigate the spectrum of variants that are associated with the onset and development of AD among 22 Arab countries. METHODOLOGY: We systematically searched 4 literature databases (Science Direct, Scopus, PubMed, and Web of Science) from the date of inception until July 2020 using various search terms to obtain all the reported genetic data on Arab AD cases. RESULTS: In total, 18 studies were included, comprising a total of 2173 individuals, of whom 888 were clinically diagnosed AD patients and were genetically tested for genes and variants associated with AD. A total of 27 variants in 8 genes were found to be associated with AD. Of these variants, 17 were unique to the Arab population and 10 were shared with other ethnic groups. CONCLUSIONS: There is a dearth of studies on the genetics of AD in the Arab world. There seems to be distinctive genetic and clinical susceptibility profiles for Arab patients with AD.

Epidemiology of SARS-CoV2 in Qatar's primary care population aged 10 years and above.

BACKGROUND: There is an urgent need to elucidate the epidemiology of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and characterize its potential impact. Investing in characterising the SARS-CoV2 will help plan and improve the response to the pandemic. Furthermore, it will help identify the most efficient ways of managing the pandemic, avoiding public health policies and interventions that may be unduly restrictive of normal activity or unnecessarily costly. This paper describes the design and reports findings of a population based epidemiological study undertaken to characterise SARS-CoV2 in Qatar using limited resources in a timely manner. METHODS: Asymptomatic individuals ≥10 years registered with Qatar's publicly funded primary health provider were eligible. A stratified random sampling technique was utilized to identify the study sample. Participants were invited to an appointment where they completed a questionnaire and provided samples for polymerase chain reaction and Immunoglobulin M and G immunoassay tests. Data collected were analyzed to calculate point and period prevalence by sociodemographic, lifestyle and clinical characteristics. RESULTS: Of 18,918 individuals invited for the study, 2084 participated (response rate 10.8%). The overall point prevalence and period prevalence were estimated to be 1.6% (95% CI 1.1-2.2) and 14.6% (95% CI 13.1-16.2) respectively. Period prevalence of SARS-CoV2 infection was not considerably different across age groups (9.7-19.8%). It was higher in males compared to females (16.2 and 12.7% respectively). A significant variation was observed by nationality (7.1 to 22.2%) and municipalities (6.9-35.3%). CONCLUSIONS: The study provides an example of a methodologically robust approach that can be undertaken in a timely manner with limited resources. It reports much-needed epidemiological data about the spread of SARS-CoV2. Given the low prevalence rates, majority of the population in Qatar remains susceptible. Enhanced surveillance must continue to be in place, particularly due to the large number of asymptomatic cases observed. Robust contact tracing and social distancing measures are key to prevent future outbreaks.

Role of non-coding RNA networks in leukemia progression, metastasis and drug resistance.

Early-stage detection of leukemia is a critical determinant for successful treatment of the disease and can increase the survival rate of leukemia patients. The factors limiting the current screening approaches to leukemia include low sensitivity and specificity, high costs, and a low participation rate. An approach based on novel and innovative biomarkers with high accuracy from peripheral blood offers a comfortable and appealing alternative to patients, potentially leading to a higher participation rate.Recently, non-coding RNAs due to their involvement in vital oncogenic processes such as differentiation, proliferation, migration, angiogenesis and apoptosis have attracted much attention as potential diagnostic and prognostic biomarkers in leukemia. Emerging lines of evidence have shown that the mutational spectrum and dysregulated expression of non-coding RNA genes are closely associated with the development and progression of various cancers, including leukemia. In this review, we highlight the expression and functional roles of different types of non-coding RNAs in leukemia and discuss their potential clinical applications as diagnostic or prognostic biomarkers and therapeutic targets.

Deciphering the Role of Filamin B Calponin-Homology Domain in Causing the Larsen Syndrome, Boomerang Dysplasia, and Atelosteogenesis Type I Spectrum Disorders via a Computational Approach.

Filamins (FLN) are a family of actin-binding proteins involved in regulating the cytoskeleton and signaling phenomenon by developing a network with F-actin and FLN-binding partners. The FLN family comprises three conserved isoforms in mammals: FLNA, FLNB, and FLNC. FLNB is a multidomain monomer protein with domains containing an actin-binding N-terminal domain (ABD 1-242), encompassing two calponin-homology domains (assigned CH1 and CH2). Primary variants in FLNB mostly occur in the domain (CH2) and surrounding the hinge-1 region. The four autosomal dominant disorders that are associated with FLNB variants are Larsen syndrome, atelosteogenesis type I (AOI), atelosteogenesis type III (AOIII), and boomerang dysplasia (BD). Despite the intense clustering of FLNB variants contributing to the LS-AO-BD disorders, the genotype-phenotype correlation is still enigmatic. In silico prediction tools and molecular dynamics simulation (MDS) approaches have offered the potential for variant classification and pathogenicity predictions. We retrieved 285 FLNB missense variants from the UniProt, ClinVar, and HGMD databases in the current study. Of these, five and 39 variants were located in the CH1 and CH2 domains, respectively. These variants were subjected to various pathogenicity and stability prediction tools, evolutionary and conservation analyses, and biophysical and physicochemical properties analyses. Molecular dynamics simulation (MDS) was performed on the three candidate variants in the CH2 domain (W148R, F161C, and L171R) that were predicted to be the most pathogenic. The MDS analysis results showed that these three variants are highly compact compared to the native protein, suggesting that they could affect the protein on the structural and functional levels. The computational approach demonstrates the differences between the FLNB mutants and the wild type in a structural and functional context. Our findings expand our knowledge on the genotype-phenotype correlation in FLNB-related LS-AO-BD disorders on the molecular level, which may pave the way for optimizing drug therapy by integrating precision medicine.

Comparable antibody levels in heterologous and homologous mRNA COVID-19 vaccination, with superior neutralizing and IgA antibody responses in mRNA homologous boosting.

BACKGROUND: Priming with two doses of AZD1222 (Oxford-AstraZeneca; ChAd) followed by a third mRNA vaccine boosting is considered in several countries, yet comparisons between heterologous and homologous booster efficacy remain unexplored. AIM: To evaluate and contrast the immunogenicity of homologous and heterologous boosting regimens. METHOD: The study examined antibody responses in 1113 subjects, comprising 895 vaccine-naïve individuals across different vaccination strategies (partial, primary series, heterologous booster, homologous booster) and 218 unvaccinated, naturally infected individuals. Assessments included neutralizing total antibodies (NTAbs), total antibodies (TAbs), anti-S-RBD IgG, and anti-S1 IgA levels. RESULTS: The study found mRNA vaccines to exhibit superior immunogenicity in primary series vaccination compared to ChAd, with mRNA-1273 significantly enhancing NTAbs, TAbs, anti-S-RBD IgG, and anti-S1 IgA levels (p < 0.001). Both booster types improved antibody levels beyond primary outcomes, with no significant difference in TAbs and anti-S-RBD IgG levels between regimens. However, homologous mRNA boosters significantly outperformed heterologous boosters in enhancing NTAbs and anti-S1 IgA levels, with the BNT/BNT/BNT regimen yielding particularly higher enhancements (p < 0.05). CONCLUSION: The study concludes that although TAbs and anti-S-RBD IgG antibody levels are similar for both regimens, homologous mRNA boosting outperform heterologous regimen by enhancing anti-S1 IgA and neutralizing antibody levels.

Follow-Up and Comparative Assessment of SARS-CoV-2 IgA, IgG, Neutralizing, and Total Antibody Responses After BNT162b2 or mRNA-1273 Heterologous Booster Vaccination.

BACKGROUND: Priming with ChAdOx1 followed by heterologous boosting is considered in several countries. Nevertheless, analyses comparing the immunogenicity of heterologous booster to homologous primary vaccination regimens and natural infection are lacking. In this study, we aimed to conduct a comparative assessment of the immunogenicity between homologous primary vaccination regimens and heterologous prime-boost vaccination using BNT162b2 or mRNA-1273. METHODS: We matched vaccinated naïve (VN) individuals (n = 673) with partial vaccination (n = 64), primary vaccination (n = 590), and primary series plus mRNA vaccine heterologous booster (n = 19) with unvaccinated naturally infected (NI) individuals with a documented primary SARS-CoV-2 infection (n = 206). We measured the levels of neutralizing total antibodies (NTAbs), total antibodies (TAbs), anti-S-RBD IgG, and anti-S1 IgA titers. RESULTS: Homologous primary vaccination with ChAdOx1 not only showed less potent NTAb, TAb, anti-S-RBD IgG, and anti-S1 IgA immune responses compared to primary BNT162b2 or mRNA-1273 vaccination regimens (p < 0.05) but also showed ~3-fold less anti-S1 IgA response compared to infection-induced immunity (p < 0.001). Nevertheless, a heterologous booster led to an increase of ~12 times in the immune response when compared to two consecutive homologous ChAdOx1 immunizations. Furthermore, correlation analyses revealed that both anti-S-RBD IgG and anti-S1 IgA significantly contributed to virus neutralization among NI individuals, particularly in symptomatic and pauci-symptomatic individuals, whereas among VN individuals, anti-S-RBD IgG was the main contributor to virus neutralization. CONCLUSION: The results emphasize the potential benefit of using heterologous mRNA boosters to increase antibody levels and neutralizing capacity particularly in patients who received primary vaccination with ChAdOx1.

Enhancing the sensitivity of rapid antigen detection test (RADT) of different SARS-CoV-2 variants and lineages using fluorescence-labeled antibodies and a fluorescent meter.

RT-qPCR is considered the gold standard for diagnosis of COVID-19; however, it is laborious, time-consuming, and expensive. RADTs have evolved recently as relatively inexpensive methods to address these shortcomings, but their performance for detecting different SARS-COV-2 variants remains limited. RADT test performance could be enhanced using different antibody labeling and signal detection techniques. Here, we aimed to evaluate the performance of two antigen RADTs for detecting different SARS-CoV-2 variants: (i) the conventional colorimetric RADT (Ab-conjugated with gold beads); and (ii) the new Finecare™ RADT (Ab-coated fluorescent beads). Finecare™ is a meter used for the detection of a fluorescent signal. 187 frozen nasopharyngeal swabs collected in Universal transport (UTM) that are RT-qPCR positive for different SARS-CoV-2 variants were selected, including Alpha (n = 60), Delta (n = 59), and Omicron variants (n = 108). Sixty flu and 60 RSV-positive samples were included as negative controls (total sample number = 347). The conventional RADT showed sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 62.4% (95%CI: 54-70), 100% (95%CI: 97-100), 100% (95%CI: 100-100), and 58% (95%CI: 49-67), respectively. These measurements were enhanced using the Finecare™ RADT: sensitivity, specificity, PPV, and NPV were 92.6% (95%CI: 89.08-92.3), 96% (95%CI: 96-99.61), 98% (95%CI: 89-92.3), and 85% (95%CI: 96-99.6) respectively. The sensitivity of both RADTs could be greatly underestimated because nasopharyngeal swab samples collected UTM and stored at -80 °C were used. Despite that, our results indicate that the Finecare™ RADT is appropriate for clinical laboratory and community-based surveillance due to its high sensitivity and specificity.

Management of chronic myeloid leukaemia: current treatment options, challenges, and future strategies.

ABSTRACTSmall molecule therapy is a critical component of targeted anticancer treatment, with tyrosine kinase inhibitors (TKIs) being the first compounds to treat the clonal Chronic Myelogenous Leukaemia (CML) translocation t (9;22) (q34; q11) effectively since 2001. TKIs, such as imatinib, have improved the 10-year survival rate of CML patients to 80%. They bind the BCR::ABL1 kinase and inhibit downstream signaling pathways. However, therapy failure may be seen in 20-25% of CML patients due to intolerance or inadequacy related to BCR::ABL1 dependent or independent mechanisms. This review aimed to summarize current treatment options involving TKIs, resistance mechanisms and the prospective approaches to overcome TKI resistance. We highlight BCR::ABL1-dependent mechanisms of TKI resistance by reviewing clinically-documented BCR::ABL1 mutations and their consequences for TKI binding. In addition, we summarize BCR::ABL1 independent pathways, including the relevance of drug efflux, dysregulation of microRNA, and the involvement of alternative signaling pathways. We also discuss future approaches, such as gene-editing techniques in the context of CML, as potential therapeutic strategies.

High-sensitive detection and quantitation of thyroid-stimulating hormone (TSH) from capillary/fingerstick and venepuncture whole-blood using fluorescence-based rapid lateral flow immunoassay (LFIA).

Background: In the last decade, point of care testing (POCT) such as lateral flow immunoassays (LFIA) were developed for rapid TSH measurement. Most of these TSH-LFIAs are designed for qualitative measurements (i.e., if TSH values > 5, or >15 IU/L) and as screening tests for primary hypothyroidism in children and adults. Serum or plasma, but not venepuncture whole-blood or fingerstick/capillary, are usually used to quantify TSH accurately. Studies on performance evaluation of TSH-LFIAs POCT using venepuncture or fingerstick whole-blood are limited. Additionally, limited studies evaluated the performance and validity of TSH-LFIAs POCT compared to valid and reliable reference methods. To our knowledge, this is the first study to evaluate three different blood withdrawal techniques for evaluating POCT of TSH. Aim: We aim to evaluate the performance of a new fluorescence-based LFIA and its Finecare™ fluorescent reader for quantitative measurement of TSH from a fingerstick, venepuncture whole-blood, and serum. Methods: 102 fingerstick, venepuncture whole-blood, and serum samples (with normal and abnormal TSH values) were analyzed by Finecare™ Rapid Quantitative LFIA test and Roche CobasPro-c503 as a reference test. Results: Using serum, when compared to CobasPro-c503 reference method, Finecare™ showed high sensitivity [90.5 % (69.6-98.8)] and specificity [96.3 % (89.6-99.2)] for diagnosis of thyroid abnormalities (<0.35 or >4.5 mIU/L). The actual test values (mIU/L) of Finecare™ showed excellent agreement (Cohen's Kappa = 0.85) and strong correlation (r = 0.93, p < 0.0001) with CobasPro-c503. Using venepuncture whole-blood samples, Finecare™ showed similar results to serum with high sensitivity [95.2 % (76.2-99.9)], specificity [97.5 % (91.4-99.7)], excellent agreement (Cohen's Kappa = 0.91), and very strong correlation (r = 0.95, p < 0.0001) with CobasPro-c503. These results suggest that Finecare™ can be used for quantitative measurement of TSH using serum or venepuncture whole-blood. These key performance indicators were slightly decreased when fingerstick whole-blood samples were used: sensitivity [85.7 %(63.7-97)], specificity [90.0 %,(81.5-96)], good agreement (Cohen's Kappa = 0.7) and very strong correlation (r = 0.9, p < 0.0001) with CobasPro-c503. A subgroup analysis of abnormal TSH samples revealed a strong and significant correlation between the reference, Finecare™ whole-blood (r = 0.692; p = 0.0015), and fingerstick test Finecare™ (r = 0.66; p = 0.0025). A very strong correlation was also observed between Cobaspro-c508 serum and Finecare™ serum (r = 0.88; p < 0.0001). Conclusion: In comparison to the reference assay, our study demonstrates that Finecare™ exhibits high sensitivity, specificity, agreement, and a strong correlation. These findings provide evidence that Finecare™ is a reliable, valid, and accurate point-of-care test for TSH screening and quantitative measurement, especially in non- or small laboratory settings.

Prevalence, predictors, and outcomes of major congenital anomalies: A population-based register study.

Congenital anomalies (CAs) are a leading cause of morbidity and mortality in early life. We aimed to assess the incidence, risk factors, and outcomes of major CAs in the State of Qatar. A population-based retrospective data analysis of registry data retrieved from the Perinatal Neonatal Outcomes Research Study in the Arabian Gulf (PEARL-Peristat Study) between April 2017 and March 2018. The sample included 25,204 newborn records, which were audited between April 2017 and March 2018, of which 25,073 live births were identified and included in the study. Maternal risk factors and neonatal outcomes were assessed for association with specific CAs, including chromosomal/genetic, central nervous system (CNS), cardiovascular system (CVS), facial, renal, multiple congenital anomalies (MCAs) using univariate and multivariate analyses. The incidence of any CA among live births was 1.3% (n = 332). The most common CAs were CVS (n = 117; 35%), MCAs (n = 69, 21%), chromosomal/genetic (51; 15%), renal (n = 39; 12%), CNS (n = 20; 6%), facial (14, 4%), and other (GIT, Resp, Urogenital, Skeletal) (n = 22, 7%) anomalies. Multivariable regression analysis showed that multiple pregnancies, parity ≥ 1, maternal BMI, and demographic factors (mother's age and ethnicity, and infant's gender) were associated with various specific CAs. In-hospital mortality rate due to CAs was estimated to be 15.4%. CAs were significantly associated with high rates of caesarean deliveries (aOR 1.51; 95% CI 1.04-2.19), Apgar < 7 at 1 min (aOR 5.44; 95% CI 3.10-9.55), Apgar < 7 at 5 min (aOR 17.26; 95% CI 6.31-47.18), in-hospital mortality (aOR 76.16; 37.96-152.8), admission to neonatal intensive care unit (NICU) or perinatal death of neonate in labor room (LR)/operation theatre (OT) (aOR 34.03; 95% CI 20.51-56.46), prematurity (aOR 4.17; 95% CI 2.75-6.32), and low birth weight (aOR 5.88; 95% CI 3.92-8.82) before and after adjustment for the significant risk factors. This is the first study to assess the incidence, maternal risk factors, and neonatal outcomes associated with CAs in the state of Qatar. Therefore, a specialized congenital anomaly data registry is needed to identify risk factors and outcomes. In addition, counselling of mothers and their families may help to identify specific needs for pregnant women and their babies.

Follow up and comparative assessment of IgG, IgA, and neutralizing antibody responses to SARS-CoV-2 between mRNA-vaccinated naïve and unvaccinated naturally infected individuals over 10 months.

BACKGROUND: Evidence on the effectiveness of vaccination-induced immunity compared to SARS-CoV-2 natural immunity is warranted to inform vaccination recommendations. AIM: In this study, we aimed to conduct a comparative assessment of antibody responses between vaccinated naïve (VN) and unvaccinated naturally infected individuals (NI) over 10 Months. METHOD: The study comprised fully-vaccinated naïve individuals (VN; n = 596) who had no history of SARS-CoV-2 infection, and received two doses of either BNT162b2 or mRNA-1273, and naturally infected individuals who had a documented history of SARS-CoV-2 infection and no vaccination record (NI cohort; n = 218). We measured the levels of neutralizing total antibodies (NtAbs), anti-S-RBD IgG, and anti-S1 IgA titers among VN and NI up to ∼10 months from administration of the first dose, and up to ∼7 months from SARS-CoV-2 infection, respectively. To explore the relationship between the antibody responses and time, Spearman's correlation coefficient was computed. Furthermore, correlations between the levels of NtAbs/anti-S-RBD IgG and NtAbs/anti-S1 IgA were examined through pairwise correlation analysis. RESULTS: Up to six months, VN individuals had a significantly higher NtAb and anti-S-RBD IgG antibody responses compared to NI individuals. At the 7th month, there was a significant decline in antibody responses among VN individuals, but not NI individuals, with a minimum decrease of 3.7-fold (p < 0.001). Among VN individuals, anti-S1 IgA levels began to decrease significantly (1.4-fold; p = 0.007) after two months, and both NtAb and S-RBD IgG levels began to decline significantly (NtAb: 2.0-fold; p = 0.042, S-RBD IgG: 2.4-fold; p = 0.035) after three months. After 10 months, the most significant decline among VN individuals was observed for S-RBD-IgG (30.0-fold; P < 0.001), followed by NtAb (15.7-fold; P < 0.001) and S-IgA (3.7-fold; P < 0.001) (most stable). Moreover, after 5 months, there was no significant difference in the IgA response between the two groups. CONCLUSION: These findings have important implications for policymakers in the development of vaccination strategies, particularly in the consideration of booster doses to sustain long-lasting protection against COVID-19.

Association of single nucleotide polymorphisms with dyslipidemia and risk of metabolic disorders in the State of Qatar.

BACKGROUND: Dyslipidemia is recognized as one of the risk factors of cardiovascular diseases (CVDs), type 2 diabetes mellitus (T2DM), and non-alcoholic fatty liver disease (NAFLD). OBJECTIVE: The study aimed to investigate the association between selected single nucleotide polymorphisms (SNPs) with dyslipidemia and increased susceptibility risks of CVD, NAFLD, and/or T2DM in dyslipidemia patients in comparison with healthy control individuals from the Qatar genome project. METHODS: A community-based cross-sectional study was conducted among 2933 adults (859 dyslipidemia patients and 2074 healthy control individuals) from April to December 2021 to investigate the association between 331 selected SNPs with dyslipidemia and increased susceptibility risks of CVD, NAFLD and/or T2DM, and covariates. RESULTS: The genotypic frequencies of six SNPs were found to be significantly different in dyslipidemia patients subjects compared to the control group among males and females. In males, three SNPs were found to be significant, the rs11172113 in over-dominant model, the rs646776 in recessive and over-dominant models, and the rs1111875 in dominant model. On the other hand, two SNPs were found to be significant in females, including rs2954029 in recessive model, and rs1801251 in dominant and recessive models. The rs17514846 SNP was found for dominant and over-dominant models among males and only the dominant model for females. We found that the six SNPs linked to gender type had an influence in relation to disease susceptibility. When controlling for the four covariates (gender, obesity, hypertension, and diabetes), the difference between dyslipidemia and the control group remained significant for the six variants. Finally, males were three times more likely to have dyslipidemia in comparison with females, hypertension was two times more likely to be present in the dyslipidemia group, and diabetes was six times more likely to be in the dyslipidemia group. CONCLUSION: The current investigation provides evidence of association for a common SNP to coronary heart disease and suggests a sex-dependent effect and encourage potential therapeutic applications.

A review of bioinformatics tools and web servers in different microarray platforms used in cancer research.

Over the past decade, conventional lab work strategies have gradually shifted from being limited to a laboratory setting towards a bioinformatics era to help manage and process the vast amounts of data generated by omics technologies. The present work outlines the latest contributions of bioinformatics in analyzing microarray data and their application to cancer. We dissect different microarray platforms and their use in gene expression in cancer models. We highlight how computational advances empowered the microarray technology in gene expression analysis. The study on protein-protein interaction databases classified into primary, derived, meta-database, and prediction databases describes the strategies to curate and predict novel interaction networks in silico. In addition, we summarize the areas of bioinformatics where neural graph networks are currently being used, such as protein functions, protein interaction prediction, and in silico drug discovery and development. We also discuss the role of deep learning as a potential tool in the prognosis, diagnosis, and treatment of cancer. Integrating these resources efficiently, practically, and ethically is likely to be the most challenging task for the healthcare industry over the next decade; however, we believe that it is achievable in the long term.

Whole-exome sequencing analysis of NSCLC reveals the pathogenic missense variants from cancer-associated genes.

BACKGROUND: Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer. NSCLC accounts for 84% of all lung cancer cases. In recent years, advances in pathway understanding, methods for discovering novel genetic biomarkers, and new drugs designed to inhibit the signaling cascades have enabled clinicians to personalize therapy for NSCLC. OBJECTIVES: The primary aim of this study is to identify the genes associated with NSCLC that harbor pathogenic variants that could be causative for NSCLC. The second aim is to investigate their roles in different pathways that lead to NSCLC. METHODS: We examined exome-sequencing datasets from 54 NSCLC patients to characterize the variants associated with NSCLC. RESULTS: Our findings revealed that 17 variants in 14 genes were considered highly pathogenic, including CDKN2A, ERBB2, FOXP1, IDH1, JAK3, KMT2D, K-Ras, MSH3, MSH6, POLE, RNF43, TCF7L2, TP53, and TSC1. Gene set enrichment analysis revealed the involvement of transmembrane receptor protein tyrosine kinase activity, protein binding, ATP binding, phosphatidylinositol-4,5-bisphosphate 3-kinase, and Ras guanyl-nucleotide exchange factor activity. Pathway analysis of these genes yielded different cancer-related pathways, including colorectal, prostate, endometrial, pancreatic, PI3K-Akt signaling pathways, and signaling pathways regulating pluripotency of stem cells. Module 1 from protein-protein interactions (PPIs) identified genes that harbor pathogenic SNPs. Three of the most deleterious SNPs are ERBB2 (rs1196929947), K-Ras (rs121913529), and POLE (rs751425952). Interestingly, one patient has a pathogenic K-Ras variant (rs121913529) co-occurred with the missense variant (rs752054698) inTSC1 gene. CONCLUSION: This study maps highly pathogenic variants associated with NSCLC and investigates their contributions to the pathogenesis of NSCLC. This study sheds light on the potential applications of precision medicine in patients with NSCLC.

Investigation of differentially expressed genes and dysregulated pathways involved in multiple sclerosis.

Multiple Sclerosis (MS) is a neurodegenerative autoimmune and organ-specific demyelinating disorder, known to affect the central nervous system (CNS). While genetic studies have revealed several critical genes and diagnostic biomarkers associated with MS, the etiology of the disease remains poorly understood. This study is aimed at screening and identifying the key genes and canonical pathways associated with MS. Gene expression profiling of the microarray dataset GSE38010 was used to analyze two control brain samples (control 1; GSM931812, control 2; GSM931813), active inflammation stage samples (CAP1; GSM931815, CAP2; GSM931816) and late subsided stage samples (CP1; GSM931817, CP2; GSM931818) collected from patients ranging between 23 and 54years and both genders. This analysis yielded a list of 58,866 DEGs (29,433 for active-inflammation stage and 29,433 for late-subsided Stage). The interactions between the DEGs were then studied using STRING, Cytoscape software, and MCODE was employed to find the genes that form clusters. Functional enrichment and integrative analysis were performed using ClueGO/CluePedia and MetaCore™. Our data revealed dysregulated key canonical pathways in MS patients. In addition, we identified three hub genes (SCN2A, HTR2A, and HCN1) that may serve as potential biomarkers for the prognosis of MS. Furthermore, the expression patterns of HPCA and PLCB1 provide insights into the progressive stages of MS, indicating that these genes could be used in predicting MS progression. We were able to map potential biomarkers that could be used for the prognosis and diagnosis of MS.

Description of PTPRG genetic variants identified in a cohort of Chronic Myeloid Leukemia patients and their ability to influence response to Tyrosine kinase Inhibitors.

Tyrosine kinase inhibitors (TKIs) have remarkably transformed Ph+ chronic myeloid leukemia (CML) management; however, TKI resistance remains a major clinical challenge. Mutations in BCR-ABL1 are well studied but fail to explain 20-40% of resistant cases, suggesting the activation of alternative, BCR-ABL1-independent pathways. Protein Tyrosine Phosphatase Receptor Gamma (PTPRG), a tumor suppressor, was found to be well expressed in CML patients responsive to TKIs and remained at low level in resistant patients. In this study, we aimed to identify genetic variants in PTPRG that could potentially modulate TKIs response in CML patients. DNA was extracted from peripheral blood samples collected from two CML cohorts (Qatar and Italy) and targeted exome sequencing was performed. Among 31 CML patients, six were TKI-responders and 25 were TKI-non-responsive. Sequencing identified ten variants, seven were annotated and three were novel SNPs (c.1602_1603insC, c.85+14412delC, and c.2289-129delA). Among them, five variants were identified in 15 resistant cases. Of these, one novel exon variant (c.1602_1603insC), c.841-29C>T (rs199917960) and c.1378-224A>G (rs2063204) were found to be significantly different between the resistant cases compared to responders. Our findings suggest that PTPRG variants may act as an indirect resistance mechanism of BCR-ABL1 to affect TKI treatment.

Neutralizing antibodies against SARS-CoV-2 are higher but decline faster in mRNA vaccinees compared to individuals with natural infection.

BACKGROUND: Waning protection against emerging SARS-CoV-2 variants by pre-existing antibodies elicited because of current vaccination or natural infection is a global concern. Whether this is due to the waning of immunity to SARS-COV-2 remains unclear. AIM: We aimed to investigate the dynamics of antibody isotype responses amongst vaccinated naïve (VN) and naturally infected (NI) individuals. METHODS: We followed up antibody levels in COVID-19 messenger RNA (mRNA)-vaccinated subjects without prior infection (VN, n = 100) in two phases: phase-I (P-I) at ~ 1.4 and phase-II (P-II) at ~ 5.3 months. Antibody levels were compared with those of unvaccinated and naturally infected subjects (NI, n = 40) at ~ 1.7 (P-1) and 5.2 (P-II) months post-infection. Neutralizing antibodies (NTAb), anti-S-RBD-IgG, -IgM and anti-S-IgA isotypes were measured. RESULTS: The VN group elicited significantly greater antibody responses (P < 0.001) than the NI group at P-I, except for IgM. In the VN group, a significant waning in antibody response was observed in all isotypes. There was about an ~ 4-fold decline in NTAb levels (P < 0.001), anti-S-RBD-IgG (~5-fold, P < 0.001), anti-S-RBD-IgM (~6-fold, P < 0.001) and anti-S1-IgA (2-fold, P < 0.001). In the NI group, a significant but less steady decline was notable in S-RBD-IgM (~2-fold, P < 0.001), and a much smaller but significant difference in NTAb (<2-fold, P < 0.001) anti-S-RBD IgG (<2-fold, P = 0.005). Unlike the VN group, the NI group mounted a lasting anti-S1-IgA response with no significant decline. Anti-S1-IgA, which were ~ 3-fold higher in VN subjects compared with NI in P-1 (P < 0.001), dropped to almost the same levels, with no significant difference observed between the two groups in P-II. CONCLUSION: Whereas double-dose mRNA vaccination boosted antibody levels, vaccinated individuals' 'boost' was relatively short-lived.