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Chronic obstructive pulmonary disease (COPD) is a multifactorial progressive airflow obstruction in the lungs, accounting for high morbidity and mortality across the world. This study aims to identify potential COPD blood-based biomarkers by analyzing the dysregulated gene expression patterns in blood and lung tissues with the help of robust computational approaches. The microarray gene expression datasets from blood (136 COPD and 6 controls) and lung tissues (16 COPD and 19 controls) were analyzed to detect shared differentially expressed genes (DEGs). Then these DEGs were used to construct COPD protein network-clusters and functionally enrich them against gene ontology annotation terms. The hub genes in the COPD network clusters were then queried in GWAS catalog and in several cancer expression databases to explore their pathogenic roles in lung cancers. The comparison of blood and lung tissue datasets revealed 63 shared DEGs. Of these DEGs, 12 COPD hub gene-network clusters ( SREK1 , TMEM67 , IRAK2 , MECOM , ASB4 , C1QTNF2 , CDC42BPA , DPF3 , DET1 , CCDC74B , KHK , and DDX3Y ) connected to dysregulations of protein degradation, inflammatory cytokine production, airway remodeling, and immune cell activity were prioritized with the help of protein interactome and functional enrichment analysis. Interestingly, IRAK2 and MECOM hub genes from these COPD network clusters are known for their involvement in different pulmonary diseases. Additional COPD hub genes like SREK1 , TMEM67 , CDC42BPA , DPF3 , and ASB4 were identified as prognostic markers in lung cancer, which is reported in 1% of COPD patients. This study identified 12 gene network- clusters as potential blood based genetic biomarkers for COPD diagnosis and prognosis.

Vedolizumab is a humanized monoclonal antibody used to treat moderate-to-severe inflammatory bowel disease (IBD). The aim of the study was to assess the effectiveness of the induction of vedolizumab trough level in predicting short-term (week 14) clinical outcomes, and covariates that affect the response in Saudi Arabian patients. This prospective, real-life study included a total of 16 patients (4 Crohn's disease (CD) and 12 ulcerative colitis (UC)) with a confirmed diagnosis of IBD and generally naïve to receiving vedolizumab therapy. Using ELISA assay, vedolizumab induction trough and peak levels were measured at weeks 0, 2, and 6. The follow-up assessment was at week 14, where clinical outcomes were measured using the partial Mayo score for UC, and the CD activity score (CDAI), and Harvey Bradshaw index (HBI) for CD. At week 14, 9 patients (52.9%) out of 16 patients demonstrated response to therapy; clinical remission was reported in 5 patients (29.4%), and in 4 cases a clinical response was noted (23.5%). Clinical remission at week 14 was linked significantly with week 6 median vedolizumab levels in responders (25.1 µg/ml 95% CI: 16.5–42.9) compared to non-responders (7.7 µg/ml, 95% CI: 4.6–10.6) ( P  = 0.002 ) . Receiver operator curve analysis at week 6 identified a cut-off > 8.00 µg/mL for short-term clinical remission. Also, at week 14, BMI significantly correlated with week 6 vedolizumab trough levels ( P  = 0.02). No other covariates correlated with drug levels at any time point examined. Week 6 early vedolizumab trough level measurements in IBD patients predicted short-term week 14 clinical remission.

Chronic obstructive pulmonary disease (COPD) is a multifactorial progressive airflow obstruction in the lungs, accounting for high morbidity and mortality across the world. This study aims to identify potential COPD blood-based biomarkers by analyzing the dysregulated gene expression patterns in blood and lung tissues with the help of robust computational approaches. The microarray gene expression datasets from blood (136 COPD and 6 controls) and lung tissues (16 COPD and 19 controls) were analyzed to detect shared differentially expressed genes (DEGs). Then these DEGs were used to construct COPD protein network-clusters and functionally enrich them against gene ontology annotation terms. The hub genes in the COPD network clusters were then queried in GWAS catalog and in several cancer expression databases to explore their pathogenic roles in lung cancers. The comparison of blood and lung tissue datasets revealed 63 shared DEGs. Of these DEGs, 12 COPD hub gene-network clusters (SREK1, TMEM67, IRAK2, MECOM, ASB4, C1QTNF2, CDC42BPA, DPF3, DET1, CCDC74B, KHK, and DDX3Y) connected to dysregulations of protein degradation, inflammatory cytokine production, airway remodeling, and immune cell activity were prioritized with the help of protein interactome and functional enrichment analysis. Interestingly, IRAK2 and MECOM hub genes from these COPD network clusters are known for their involvement in different pulmonary diseases. Additional COPD hub genes like SREK1, TMEM67, CDC42BPA, DPF3, and ASB4 were identified as prognostic markers in lung cancer, which is reported in 1% of COPD patients. This study identified 12 gene network- clusters as potential blood based genetic biomarkers for COPD diagnosis and prognosis.

Asthma is a life-threatening and chronic inflammatory lung disease that is posing a true global health challenge. The genetic basis of the disease is fairly well examined. However, the molecular crosstalk between microRNAs (miRNAs), target genes, and transcription factors (TFs) networks and their contribution to disease pathogenesis and progression is not well explored. Therefore, this study was aimed at dissecting the molecular network between mRNAs, miRNAs, and TFs using robust computational biology approaches. The transcriptomic data of bronchial epithelial cells of severe asthma patients and healthy controls was studied by different systems biology approaches like differentially expressed gene detection, functional enrichment, miRNA-target gene pairing, and mRNA-miRNA-TF molecular networking. We detected the differential expression of 1703 (673 up-and 1030 down-regulated) genes and 71 (41 up-and 30 down-regulated) miRNAs in the bronchial epithelial cells of asthma patients. The DEGs were found to be enriched in key pathways like IL-17 signaling (KEGG: 04657), Th1 and Th2 cell differentiation (KEGG: 04658), and the Th17 cell differentiation (KEGG: 04659) (p-values = 0.001). The results from miRNAs-target gene pairs-transcription factors (TFs) have detected the key roles of 3 miRs (miR-181a-2-3p; miR-203a-3p; miR-335-5p), 6 TFs (TFAM, FOXO1, GFI1, IRF2, SOX9, and HLF) and 32 miRNA target genes in eliciting autoimmune reactions in bronchial epithelial cells of the respiratory tract. Through systemic implementation of comprehensive system biology tools, this study has identified key miRNAs, TFs, and miRNA target gene pairs as potential tissue-based asthma biomarkers.

Celiac disease (CeD) is a gastrointestinal autoimmune disorder, whose specific molecular basis is not yet fully interpreted. Therefore, in this study, we compared the global gene expression profile of duodenum tissues from CeD patients, both at the time of disease diagnosis and after two years of the gluten-free diet. A series of advanced systems biology approaches like differential gene expression, protein–protein interactions, gene network-cluster analysis were deployed to annotate the candidate pathways relevant to CeD pathogenesis. The duodenum tissues from CeD patients revealed the differential expression of 106 up- and 193 down-regulated genes. The pathway enrichment of differentially expressed genes (DEGs) highlights the involvement of biological pathways related to loss of cell division regulation (cell cycle, p53 signalling pathway), immune system processes (NOD-like receptor signalling pathway, Th1, and Th2 cell differentiation, IL-17 signalling pathway) and impaired metabolism and absorption (mineral and vitamin absorptions and drug metabolism) in celiac disease. The molecular dysfunctions of these 3 biological events tend to increase the number of intraepithelial lymphocytes (IELs) and villous atrophy of the duodenal mucosa promoting the development of CeD. For the first time, this study highlights the involvement of aberrant cell division, immune system, absorption, and metabolism pathways in CeD pathophysiology and presents potential novel therapeutic opportunities.

Background/Objectives: Vedolizumab (VDZ) is the new monoclonal drug targeting α4β7 integrin for patients with moderate/severe IBD. Between 30 and 45% of patients fail to respond to VDZ after 14–16 weeks of treatment. The aim of the study was to explore the genetic profile of vedolizumab-treated Arab IBD patients in Saudi Arabia to identify the potential biomarkers to differentiate the responders from non-responders. Methods: A cohort of 16 patients with IBD, including 4 with Crohn’s disease and 12 with ulcerative colitis, were recruited. Following 16 weeks of VDZ treatment, nine were found to be responders and seven non-responders. Blood samples were collected for the whole exome sequencing of DNA from all patients. The variants in the whole-exome sequencing data were analyzed with a variety of bioinformatics tools and databases, such as Polyphen2, Mutation Taster, CADD, FATHMM, Open Target Platform, TOPPFun, STRING, and GTEx. Results: More than 1.6 million variants from 16 samples were analyzed. The rare variant analysis prioritized NOD2, IL23, IL10, IL27, and TRAF1 genes in non-responders. NOD2, IL23, IL10, IL27, and TRAF1 were found to be the significant IBD risk factors in multiple genome-wide association studies, and their pro-inflammatory activity might contribute to the inherent resistance to VDZ. Rare variants of CARD9, TYK2, IL4, and NLRP1 genes present in VDZ responders enhance the anti-inflammatory/immune modulation effects. Conclusions: This investigation is the first to apply whole-exome sequencing to identify the potential drug response biomarkers for the IBD drug VDZ in Saudi Arabia.

Obesity is connected to the activation of chronic inflammatory pathways in both adipocytes and macrophages located in adipose tissues. The nuclear factor (NF)-κB is a central molecule involved in inflammatory pathways linked to the pathology of different complex metabolic disorders. Investigating the gene expression data in the adipose tissue would potentially unravel disease relevant gene interactions. The present study is aimed at creating a signature molecular network and at prioritizing the potential biomarkers interacting with NF-κB family of proteins in obesity using system biology approaches. The dataset GSE88837 associated with obesity was downloaded from Gene Expression Omnibus (GEO) database. Statistical analysis represented the differential expression of a total of 2650 genes in adipose tissues (p = <0.05). Using concepts like correlation, semantic similarity, and theoretical graph parameters we narrowed down genes to a network of 23 genes strongly connected with NF-κB family with higher significance. Functional enrichment analysis revealed 21 of 23 target genes of NF-κB were found to have a critical role in the pathophysiology of obesity. Interestingly, GEM and PPP1R13L were predicted as novel genes which may act as potential target or biomarkers of obesity as they occur with other 21 target genes with known obesity relationship. Our study concludes that NF-κB and prioritized target genes regulate the inflammation in adipose tissues through several molecular signaling pathways like NF-κB, PI3K-Akt, glucocorticoid receptor regulatory network, angiogenesis and cytokine pathways. This integrated system biology approaches can be applied for elucidating functional protein interaction networks of NF-κB protein family in different complex diseases. Our integrative and network-based approach for finding therapeutic targets in genomic data could accelerate the identification of novel drug targets for obesity.

Background Consanguineous marriage is a major contributing factor for many genetic diseases and a burden to the healthcare system and national economy due to costly long-term care. Earlier studies highlighted the significantly limited awareness of the higher prevalence of genetic disease due to consanguinity even among the educated Arabs. In Saudi Arabia, more than 50% of marriages are between first cousins. This national study aims to gauge the level of the public awareness regarding the consanguinity and its impact on prevalence of genetic diseases across the Saudi Arabia. Methods A cross-sectional bilingual online survey was conducted across Saudi Arabia, distributed through a variety of social media platforms for all residents. Pooled summary data was used from the participants. Results Majority of the 9191 participants are < 30 years of age (72.85%), single (61.35%), women (74.12%) and college educated (77.16%). Consanguineous marriages are common in the extended family of 61.24% of participants. Though majority of them (85.45%) recognise the higher genetic disease risk associated with consanguinity, low awareness among men was observed (76.61 vs 88.53%). Sickle cell anaemia and thalassemia were not considered as genetic diseases by 60.68% of males and 48.39% of females, though they are the most common genetic diseases in Saudi Arabia. More women are aware of the carrier screening tests than men (42.62 vs 34.56%). Only 6.87% know the rationale behind the national mandatory premarital screening tests and the diseases screened. Although almost all (99.18%) are active users of the social media, 47.77% of men and 57.17% of women use them to search for health-related information. Conclusion The present study, one of the largest national surveys in highly consanguineous society, highlights that even the young and college-educated participants have low awareness of the genetic disease burden, which is strikingly high in all corners of the country. Social media platforms can be used by genetic professionals and national organizations to disseminate the reliable educational material to the public to reduce the national healthcare and economic burden in the future.

Colorectal cancer (CRC) is the leading cancer among Saudis, and mutations in , , and genes are therapeutically significant due to their association with pathways critical for cell cycle regulation. This study evaluates the prevalence and frequency of somatic mutations in these actionable genes in Saudi CRC patients and assesses their pathogenicity with bioinformatics methods. The study employed the TruSight Tumor 15 next-generation sequencing (NGS) panel on 86 colorectal cancer (CRC) samples to detect somatic mutations in , , and genes. Bioinformatic analyses of NGS sequences included variant annotation with ANNOVAR, pathogenicity prediction, variant reclassification with CancerVar, and extensive structural analysis. Additionally, molecular docking assessed the binding of Encorafenib to wild-type and mutant proteins, providing insights into the therapeutic relevance of pathogenic variants. Out of 86 tumor samples, 40 (46.5%) harbored somatic mutations within actionable genes ( : 2.3%, : 43%, : 2.3%). Fourteen missense variants were identified ( : n = 1, : n = 11, : n = 2). Variants with strong clinical significance included V600E (2.32%) and G12D (18.60%). Variants with potential clinical significance included several and an mutation, while variants of unknown significance included E49K and R102Q. One variant was novel: R102Q, and two were rare: E49K and G138E. We further extended the CancerVar prediction capability by adding new pathogenicity prediction tools. Molecular docking demonstrated that Encorafenib inhibits the V600E variant BRAF protein less effectively compared to its wild-type counterpart. Overall, this study highlights the importance of comprehensive molecular screening and bioinformatics in understanding the mutational landscape of CRC in the Saudi population, ultimately improving targeted drug treatments.

Uterine leiomyomas (UL) are highly prevalent benign smooth muscle tumors, seen in approximately 70% of women. These hormone responsive tumors are also known to secrete prolactin (PRL), a hormone of the anterior pituitary gland. Elevated levels of serum prolactin are a common clinical finding in different gynecological pathologies including UL. However, the underlying causes for this elevation are not yet clear. Therefore, the main objective of this study is to measure the serum PRL in UL patients and also to investigate its molecular connection with coding region somatic mutations of the PRL gene. The serum PRL levels of UL patients were measured through the ELISA method. The coding region PRL gene mutations in UL and corresponding myometrium tissues were screened through the Sanger sequencing method. Uterine leiomyoma patients demonstrated significant elevation of the PRL hormone level in serum samples ( ≤ 0.01). No somatic coding region mutations in the PRL gene were identified. However, four germline variants (c.570G>A, c.205-102T>A, c.312+177T>C and c.269C>T) were detected. This study is the first one to confirm that serum PRL level elevation among UL patients is not connected to somatic mutations in the PRL gene. However, PRL genetic polymorphisms may indirectly contribute to the disease etiology.