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Article ; Online: Correlation of NTRK1 Downregulation with Low Levels of Tumor-Infiltrating Immune Cells and Poor Prognosis of Prostate Cancer Revealed by Gene Network Analysis

Arash Bagherabadi / Amirreza Hooshmand / Nooshin Shekari / Prithvi Singh / Samaneh Zolghadri / Agata Stanek / Ravins Dohare

Genes, Vol 13, Iss 840, p

2022 Volume 840

Abstract: Prostate cancer (PCa) is a life-threatening heterogeneous malignancy of the urinary tract. Due to the incidence of prostate cancer and the crucial need to elucidate its molecular mechanisms, we searched for possible prognosis impactful genes in PCa using ...

Abstract	Prostate cancer (PCa) is a life-threatening heterogeneous malignancy of the urinary tract. Due to the incidence of prostate cancer and the crucial need to elucidate its molecular mechanisms, we searched for possible prognosis impactful genes in PCa using bioinformatics analysis. A script in R language was used for the identification of Differentially Expressed Genes (DEGs) from the GSE69223 dataset. The gene ontology (GO) of the DEGs and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed. A protein–protein interaction (PPI) network was constructed using the STRING online database to identify hub genes. GEPIA and UALCAN databases were utilized for survival analysis and expression validation, and 990 DEGs (316 upregulated and 674 downregulated) were identified. The GO analysis was enriched mainly in the “collagen-containing extracellular matrix”, and the KEGG pathway analysis was enriched mainly in “focal adhesion”. The downregulation of neurotrophic receptor tyrosine kinase 1 (NTRK1) was associated with a poor prognosis of PCa and had a significant positive correlation with infiltrating levels of immune cells. We acquired a collection of pathways related to primary PCa, and our findings invite the further exploration of NTRK1 as a biomarker for early diagnosis and prognosis, and as a future potential molecular therapeutic target for PCa.
Keywords	prostate cancer ; systems biology ; bioinformatics ; gene network analysis ; biomarker ; Genetics ; QH426-470
Subject code	570
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Exploring the role of miR-200 family in regulating CX3CR1 and CXCR1 in lung adenocarcinoma tumor microenvironment

Archana Sharma / Prithvi Singh / Rishabh Jha / Saleh A. Almatroodi / Faris Alrumaihi / Arshad Husain Rahmani / Hajed Obaid Alharbi / Ravins Dohare / Mansoor Ali Syed

Scientific Reports, Vol 13, Iss 1, Pp 1-

implications for therapeutic intervention

2023 Volume 15

Abstract: Abstract Lung adenocarcinoma (LUAD) is the most common malignant subtype of lung cancer (LC). miR-200 family is one of the prime miR regulators of epithelial-mesenchymal transition (EMT) and worst overall survival (OS) in LC patients. The study aimed to ... ...

Abstract	Abstract Lung adenocarcinoma (LUAD) is the most common malignant subtype of lung cancer (LC). miR-200 family is one of the prime miR regulators of epithelial-mesenchymal transition (EMT) and worst overall survival (OS) in LC patients. The study aimed to identify and validate the key differentially expressed immune-related genes (DEIRGs) regulated by miR-200 family which may serve for therapeutic aspects in LUAD tumor microenvironment (TME) by affecting cancer progression, invasion, and metastasis. The study identified differentially expressed miRNAs (DEMs) in LUAD, consisting of hsa-miR-200a-3p and hsa-miR-141-5p, respectively. Two highest-degree subnetwork motifs identified from 3-node miRNA FFL were: (i) miR-200a-3p-CX3CR1-SPIB and (ii) miR-141-5p-CXCR1-TBX21. TIMER analysis showed that the expression levels of CX3CR1 and CXCR1 were significantly positively correlated with infiltrating levels of M0-M2 macrophages and natural killer T (NKT) cells. The OS of LUAD patients was significantly affected by lower expression levels of hsa-miR-200a-3p, CX3CR1 and SPIB. These DEIRGs were validated using the human protein atlas (HPA) web server. Further, we validated the regulatory role of hsa-miR-200a-3p in an in-vitro indirect co-culture model using conditioned media from M0, M1 and M2 polarized macrophages (THP-1) and LUAD cell lines (A549 and H1299 cells). The results pointed out the essential role of hsa-miR-200a-3p regulated CX3CL1 and CX3CR1 expression in progression of LC TME. Thus, the study augments a comprehensive understanding and new strategies for LUAD treatment where miR-200 family regulated immune-related genes, especially chemokine receptors, which regulate the metastasis and invasion of LUAD, leading to the worst associated OS.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2023-09-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Identification of differentially expressed genes in small and non-small cell lung cancer based on meta-analysis of mRNA

Nitesh Shriwash / Prithvi Singh / Shweta Arora / Syed Mansoor Ali / Sher Ali / Ravins Dohare

Heliyon, Vol 5, Iss 6, Pp e01707- (2019)

2019

Abstract: Lung cancer has the lowest survival rate spread globally resulting in a large number of deaths. This is attributed to insufficient measures such as lack of early detection and chemoresistance in the patients. It can be subdivided into two histological ... ...

Abstract	Lung cancer has the lowest survival rate spread globally resulting in a large number of deaths. This is attributed to insufficient measures such as lack of early detection and chemoresistance in the patients. It can be subdivided into two histological groups: Non-Small-Cell Lung Cancer (NSCLC), which is most prevalent (85% of all lung cancers) but less destructive; and Small-Cell Lung Cancer (SCLC), which is intermittently metastatic and less prevalent (15% of all lung cancers). The present study deals with the analysis of gene expression of two subtypes to identify the Differentially Expressed Genes (DEGs). For this study, we selected two datasets from the Omnibus database, which included 50 non-small cell lung cancer samples, 31 small cell lung cancer samples, and 48 samples from normal lung tissue. After DEGs identification using the meta-analysis approach, they were then subjected to further analysis following p-value adjustment via the Benjamini-Hochberg method. We identified 440 overexpressed and 489 underexpressed genes in NSCLC, and 489 overexpressed and 525 underexpressed genes in SCLC, compared with normal lung tissues. Furthermore, we identified 3 overlapping genes between upregulated DEGs in NSCLC and downregulated DEGs in SCLC; and 8 overlapping genes between upregulated DEGs in SCLC and downregulated DEGs in NSCLC. Accordingly, a Protein-Protein Interaction (PPI) network of the overlapping genes was generated, which contained a total of 261 genes, of which the top five were TRIM29, ANK3, CSTA, FGG, and AGR2. These five candidate genes reported herein may prove to be potential therapeutic targets.
Keywords	Systems biology ; Bioinformatics ; Biological science ; Gene expression ; Science (General) ; Q1-390 ; Social sciences (General) ; H1-99
Subject code	610
Language	English
Publishing date	2019-06-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Unravelling the Role of miR-20b-5p, CCNB1, HMGA2 and E2F7 in Development and Progression of Non-Small Cell Lung Cancer (NSCLC)

Shweta Arora / Prithvi Singh / Arshad Husain Rahmani / Saleh A. Almatroodi / Ravins Dohare / Mansoor Ali Syed

Biology, Vol 9, Iss 201, p

2020 Volume 201

Abstract: Lung cancer is a prime cause of worldwide cancer deaths, with non-small cell lung cancer (NSCLC) as a frequent subtype. Surgical resection, chemotherapy are the currently used treatment methods. Delayed detection, poor prognosis, tumor heterogeneity, and ...

Abstract	Lung cancer is a prime cause of worldwide cancer deaths, with non-small cell lung cancer (NSCLC) as a frequent subtype. Surgical resection, chemotherapy are the currently used treatment methods. Delayed detection, poor prognosis, tumor heterogeneity, and chemoresistance make them relatively ineffective. Genomic medicine is a budding aspect of cancer therapeutics, where miRNAs are impressively involved. miRNAs are short ncRNAs that bind to 3’UTR of target mRNA, causing its degradation or translational repression to regulate gene expression. This study aims to identify important miRNA-mRNA-TF interactions in NSCLC using bioinformatics analysis. GEO datasets containing mRNA expression data of NSCLC were used to determine differentially expressed genes (DEGs), and identification of hub genes-BIRC5, CCNB1, KIF11, KIF20A, and KIF4A (all functionally enriched in cell cycle). The FFL network involved, comprised of miR-20b-5p, CCNB1, HMGA2, and E2F7. KM survival analysis determines that these components may be effective prognostic biomarkers and would be a new contemplation in NSCLC therapeutics as they target cell cycle and immunosurveillance mechanisms via HMGA2 and E2F7. They provide survival advantage and evasion of host immune response (via downregulation of cytokines-IL6, IL1R1 and upregulation of chemokines-CXCL13, CXCL14) to NSCLC. The study has provided innovative targets, but further validation is needed to confirm the proposed mechanism.
Keywords	NSCLC ; eigengene ; feed-forward loop ; prognosis ; module ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2020-08-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Structural Features of Nucleoprotein CST/Shelterin Complex Involved in the Telomere Maintenance and Its Association with Disease Mutations

Mohd. Amir / Parvez Khan / Aarfa Queen / Ravins Dohare / Mohamed F. Alajmi / Afzal Hussain / Asimul Islam / Faizan Ahmad / Md. Imtaiyaz Hassan

Cells, Vol 9, Iss 2, p

2020 Volume 359

Abstract: Telomere comprises the ends of eukaryotic linear chromosomes and is composed of G-rich (TTAGGG) tandem repeats which play an important role in maintaining genome stability, premature aging and onsets of many diseases. Majority of the telomere are ... ...

Abstract	Telomere comprises the ends of eukaryotic linear chromosomes and is composed of G-rich (TTAGGG) tandem repeats which play an important role in maintaining genome stability, premature aging and onsets of many diseases. Majority of the telomere are replicated by conventional DNA replication, and only the last bit of the lagging strand is synthesized by telomerase (a reverse transcriptase). In addition to replication, telomere maintenance is principally carried out by two key complexes known as shelterin (TRF1, TRF2, TIN2, RAP1, POT1, and TPP1) and CST (CDC13/CTC1, STN1, and TEN1). Shelterin protects the telomere from DNA damage response (DDR) and regulates telomere length by telomerase; while, CST govern the extension of telomere by telomerase and C strand fill-in synthesis. We have investigated both structural and biochemical features of shelterin and CST complexes to get a clear understanding of their importance in the telomere maintenance. Further, we have analyzed ~115 clinically important mutations in both of the complexes. Association of such mutations with specific cellular fault unveils the importance of shelterin and CST complexes in the maintenance of genome stability. A possibility of targeting shelterin and CST by small molecule inhibitors is further investigated towards the therapeutic management of associated diseases. Overall, this review provides a possible direction to understand the mechanisms of telomere borne diseases, and their therapeutic intervention.
Keywords	telomere shortening ; mutations ; cst complex ; shelterin complex ; ob-fold proteins ; structural genomics ; cancer ; telomere replication ; small molecule inhibitors ; Biology (General) ; QH301-705.5
Subject code	612
Language	English
Publishing date	2020-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Sequence, structure and evolutionary analysis of cold shock domain proteins, a member of OB fold family

Amir, Mohd / Asimul Islam / Faizan Ahmad / Md. Imtaiyaz Hassan / Ravins Dohare / Vijay Kumar

Journal of evolutionary biology. 2018 Dec., v. 31, no. 12

2018

Abstract: The cold shock domain (CSD) belongs to the oligosaccharide/oligonucleotide‐binding fold superfamily which is highly conserved from prokaryotes to higher eukaryotes, and appears to function as RNA chaperones. CSD is involved in diverse cellular processes, ...

Abstract	The cold shock domain (CSD) belongs to the oligosaccharide/oligonucleotide‐binding fold superfamily which is highly conserved from prokaryotes to higher eukaryotes, and appears to function as RNA chaperones. CSD is involved in diverse cellular processes, including adaptation to low temperatures, nutrient stress, cellular growth and developmental processes. Structural Classification of Proteins (SCOP) database broadly classifies OB fold proteins into 18 different superfamilies, including nucleic acid‐binding superfamily (NAB). The NAB is further divided into 17 families together with cold shock DNA‐binding protein family (CSDB). The CSDB have more than 240 000 sequences in UniProt database consisting of 32 domains including CSD. Among these domains, CSD is the second largest sequence contributor (> 40 398 sequences). Herein, we have systematically analysed the relative abundance and distribution of CSD proteins based on sequences, structures, repeats and gene ontology (GO) molecular functions in all domains of life. Analysis of sequence distribution suggesting that CSDs are largely found in bacteria (83–94%) with single CSD repeat. However, repeat distribution in eukaryota varies from 1 to 5 in combination with other auxiliary domain that makes CSD proteins functionally more diverse compared to the bacterial counterparts. Further, analysis of repeats distributions on evolutionary scale suggest that existence of CSD in multiple repeats is mainly driven through speciation, gene shuffling and gene duplication events.
Keywords	bacteria ; cell growth ; cold ; cold stress ; DNA shuffling ; DNA-binding proteins ; eukaryotic cells ; gene duplication ; gene ontology ; prokaryotic cells ; RNA ; temperature
Language	English
Dates of publication	2018-12
Size	p. 1903-1917.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	JOURNAL ARTICLE
ZDB-ID	1465318-7
ISSN	1420-9101 ; 1010-061X
ISSN (online)	1420-9101
ISSN	1010-061X
DOI	10.1111/jeb.13382
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Survival-Based Biomarker Module Identification Associated with Oral Squamous Cell Carcinoma (OSCC)

Prithvi Singh / Arpita Rai / Amit Kumar Verma / Mohammed A. Alsahli / Arshad Husain Rahmani / Saleh A. Almatroodi / Faris Alrumaihi / Kapil Dev / Anuradha Sinha / Shweta Sankhwar / Ravins Dohare

Biology, Vol 10, Iss 760, p

2021 Volume 760

Abstract: Head and neck squamous cell carcinoma (HNSC) is one of the most common malignant tumors worldwide with a high rate of morbidity and mortality, with 90% of predilections occurring for oral squamous cell carcinoma (OSCC). Cancers of the mouth account for ... ...

Abstract	Head and neck squamous cell carcinoma (HNSC) is one of the most common malignant tumors worldwide with a high rate of morbidity and mortality, with 90% of predilections occurring for oral squamous cell carcinoma (OSCC). Cancers of the mouth account for 40% of head and neck cancers, including squamous cell carcinomas of the tongue, floor of the mouth, buccal mucosa, lips, hard and soft palate, and gingival. OSCC is the most devastating and commonly occurring oral malignancy, with a mortality rate of 500,000 deaths per year. This has imposed a strong necessity to discover driver genes responsible for its progression and malignancy. In the present study we filtered oral squamous cell carcinoma tissue samples from TCGA-HNSC cohort, which we followed by constructing a weighted PPI network based on the survival of patients and the expression profiles of samples collected from them. We found a total of 46 modules, with 18 modules having more than five edges. The KM and ME analyses revealed a single module (with 12 genes) as significant in the training and test datasets. The genes from this significant module were subjected to pathway enrichment analysis for identification of significant pathways and involved genes. Finally, the overlapping genes between gene sets ranked on the basis of weighted PPI module centralities (i.e., degree and eigenvector), significant pathway genes, and DEGs from a microarray OSCC dataset were considered as OSCC-specific hub genes. These hub genes were clinically validated using the IHC images available from the Human Protein Atlas (HPA) database.
Keywords	module ; survival rate ; weighted network ; key genes ; protein–protein interaction ; Biology (General) ; QH301-705.5
Subject code	616
Language	English
Publishing date	2021-08-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Comprehensive Integrative Analysis Reveals the Association of KLF4 with Macrophage Infiltration and Polarization in Lung Cancer Microenvironment

Shweta Arora / Prithvi Singh / Shaniya Ahmad / Tanveer Ahmad / Ravins Dohare / Saleh A. Almatroodi / Faris Alrumaihi / Arshad Husain Rahmani / Mansoor Ali Syed

Cells, Vol 10, Iss 2091, p

2021 Volume 2091

Abstract: Macrophage polarization and infiltration to the tumor microenvironment (TME) is a critical determining factor for tumor progression. Macrophages are polarized into two states—M1 (pro-inflammatory, anti-tumorigenic and stimulated by LPS or IFN-γ ) and M2 ( ...

Abstract	Macrophage polarization and infiltration to the tumor microenvironment (TME) is a critical determining factor for tumor progression. Macrophages are polarized into two states—M1 (pro-inflammatory, anti-tumorigenic and stimulated by LPS or IFN-γ ) and M2 (anti-inflammatory pro-tumorigenic and stimulated by IL-4 ) phenotypes. Specifically, M2 macrophages enhance tumor cell growth and survival. Recent evidences suggest the pivotal role of microRNAs in macrophage polarization during the development of Non-small cell lung cancer (NSCLC), thus proposing a new therapeutic option to target lung cancer. In silico analysis determined cogent upregulation of KLF4 , downregulation of IL-1β and miR-34a-5p in NSCLC tissues, consequently worsening the overall survival of NSCLC patients. We observed a significant association of KLF4 with macrophage infiltration and polarization in NSCLC. We found that KLF4 is critically implicated in M2 polarization of macrophages, which, in turn, promotes tumorigenesis. KLF4 expression correlated with miR-34a-5p and IL-1β in a feed-forward loop (FFL), both of which are implicated in immune regulation. Mechanistic overexpression of miR-34a-5p in macrophages ( IL-4 stimulated) inhibits KLF4 , along with downregulation of ARG1 , REL-1MB (M2 macrophage specific markers), and upregulation of IL-1β , IL-6 , (M1 macrophage specific markers), demonstrating macrophage polarization switch from M2 to M1 phenotype. Moreover, co-culture of these macrophages with NSCLC cells reduces their proliferation, wound healing, clonogenic capacity and enhanced NO-mediated apoptosis. Further, transfection of miR-34a-5p in NSCLC cells, also degrades KLF4 , but enhances the expression of KLF4 regulated genes— IL-1β , IL-6 (pro-inflammatory mediators), which is further enhanced upon co-culture with IL-4 stimulated macrophages. Additionally, we observed a significant increase in i-NOS /NO content upon co-culture, suggesting polarization reversion of macrophages from M2 to M1, and eventually leading to anti-tumor effects. ...
Keywords	KLF4 ; tumor-associated macrophages (TAMs) ; tumor microenvironment (TME) ; non-small cell lung cancer (NSCLC) ; macrophage polarization ; IL-1β ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2021-08-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Transcriptomic analysis delineates potential signature genes and miRNAs associated with the pathogenesis of asthma

Prithvi Singh / Archana Sharma / Rishabh Jha / Shweta Arora / Rafiq Ahmad / Arshad Husain Rahmani / Saleh A. Almatroodi / Ravins Dohare / Mansoor Ali Syed

Scientific Reports, Vol 10, Iss 1, Pp 1-

2020 Volume 13

Abstract: Abstract Asthma is a multifarious disease affecting several million people around the world. It has a heterogeneous risk architecture inclusive of both genetic and environmental factors. This heterogeneity can be utilised to identify differentially ... ...

Abstract	Abstract Asthma is a multifarious disease affecting several million people around the world. It has a heterogeneous risk architecture inclusive of both genetic and environmental factors. This heterogeneity can be utilised to identify differentially expressed biomarkers of the disease, which may ultimately aid in the development of more localized and molecularly targeted therapies. In this respect, our study complies with meta-analysis of microarray datasets containing mRNA expression profiles of both asthmatic and control patients, to identify the critical Differentially Expressed Genes (DEGs) involved in the pathogenesis of asthma. We found a total of 30 DEGs out of which 13 were involved in the pathway and functional enrichment analysis. Moreover, 5 DEGs were identified as the hub genes by network centrality-based analysis. Most hub genes were involved in protease/antiprotease pathways. Also, 26 miRNAs and 20 TFs having an association with these hub genes were found to be intricated in a 3-node miRNA Feed-Forward Loop. Out of these, miR-34b and miR-449c were identified as the key miRNAs regulating the expression of SERPINB2 gene and SMAD4 transcription factor. Thus, our study is suggestive of certain miRNAs and unexplored pathways which may pave a way to unravel critical therapeutic targets in asthma.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2020-08-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Structural Analysis and Conformational Dynamics of STN1 Gene Mutations Involved in Coat Plus Syndrome

Mohd. Amir / Taj Mohammad / Vijay Kumar / Mohammed F. Alajmi / Md. Tabish Rehman / Afzal Hussain / Perwez Alam / Ravins Dohare / Asimul Islam / Faizan Ahmad / Md. Imtaiyaz Hassan

Frontiers in Molecular Biosciences, Vol

2019 Volume 6

Abstract: The human CST complex (CTC1–STN1–TEN1) is associated with telomere functions including genome stability. We have systemically analyzed the sequence of STN and performed structure analysis to establish its association with the Coat Plus (CP) syndrome. ... ...

Abstract	The human CST complex (CTC1–STN1–TEN1) is associated with telomere functions including genome stability. We have systemically analyzed the sequence of STN and performed structure analysis to establish its association with the Coat Plus (CP) syndrome. Many deleterious non-synonymous SNPs have been identified and subjected for structure analysis to find their pathogenic association and aggregation propensity. A 100-ns all-atom molecular dynamics simulation of WT, R135T, and D157Y structures revealed significant conformational changes in the case of mutants. Changes in hydrogen bonds, secondary structure, and principal component analysis further support the structural basis of STN1 dysfunction in such mutations. Free energy landscape analysis revealed the presence of multiple energy minima, suggesting that R135T and D157Y mutations destabilize and alter the conformational dynamics of STN1 and thus may be associated with the CP syndrome. Our study provides a valuable direction to understand the molecular basis of CP syndrome and offer a newer therapeutics approach to address CP syndrome.
Keywords	CST complex protein ; STN1 ; molecular dynamics simulation ; OB folds protein ; mutational landscape analysis ; sequence and structure analysis ; Biology (General) ; QH301-705.5
Subject code	612
Language	English
Publishing date	2019-06-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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