Human Genetics And Molecular Medicine - Research Publications
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Item Studies on Genomic Alterations in HER2-Positive Breast Cancer–Focus on Design, Synthesis & Evaluation of Anilinoquinazoline Analogues as Potential HER2 inhibitors(Central University of Punjab, 2019) Singla, Heena; Munshi, Anjana; Kumar, VinodHuman epidermal growth factor receptor 2-positive (HER2-positive) breast cancer is an aggressive breast cancer subtype characterized by HER2 overexpression/amplification. Genomic alterations of HER2 and others have been reported to be associated with, HER2 overexpression and prediction of trastuzumab-response. The current study was carried out to identify genomic alterations associated with HER2-positive breast cancer and evaluate their association with clinical outcome in response to trastuzumab therapy given to HER2- positive breast cancer patients. Global Sequencing Array (GSA) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) techniques were used to determine alterations in HER2 and other HER2-interacting as well as signaling-related genes implicated in the disease. In addition, 20 formalin fixed paraffin-embedded (FFPE) tissue samples were also evaluated by GSA for identifying significant variations associated with the disease as well as response to trastuzumab therapy. A germline variant in HER2 gene (I655V) was found to be significantly associated with the risk of the disease (p < 0.01). A nonsense mutation in PTPN11 (K99X), a pathogenic CCND1 splice site variant (P241P), a hotspot missense mutation in PIK3CA (E542K) and a hotspot missense mutation in TP53 (R249S); were observed in 25%, 75%, 30% and 40% of the HER2-positive breast cancer tissue samples, respectively. Mutant CCND1 (P241P) and PIK3CA (E542K) were found to be significantly associated with reduced disease-free survival (DFS) in patients treated with trastuzumab (p: 0.018 and 0.005, respectively). These results indicate that HER2, PTPN11, CCND1 and PIK3CA genes are important biomarkers in HER2-positive breast cancer. Moreover, the patients harboring mutant CCND1 and PIK3CA exhibit a poorer clinical outcome as compared to those carrying wild-type CCND1 and PIK3CA. Development of resistance and disease-relapse are the major problems associated with trastuzumab. Tyrosine-kinase inhibitors (TKIs) present better option to address the issues associated with trastuzumab. However, problems of resistance and ineffectiveness as monotherapy; persist with the currently available TKIs as well. We synthesized anilinoquinazoline-based compounds and evaluated them for anti-proliferative activity against HER2-positive breast cancer. Of the synthesized compounds (HS-2, HS-3, HS-5, HS-8 and HS-9), three (HS-3, HS-5 and HS-8) were evaluated for biological activity. HS-8 proved to be most-effective against SKBR3 (HER2-positive breast cancer cells) (IC50=2.8µM) iv with a lesser cytotoxicity towards the MDA-MB-231 (Triple-negative breast cancer cells) (IC50=3.2µM) and no toxicity towards FR-2 (normal breast epithelial cells).Item Human-lymphocyte cell friendly starch-hydroxyapatite biodegradable composites: Hydrophilic mechanism, mechanical, and structural impact(John Wiley and Sons Inc., 2019) Pramanik S.; Agarwala P.; Vasudevan K.; Sarkar K.Biodegradable starch (Str) polymer was derived from potato, a plant-based natural carbohydrate polymers source, by one-pot synthesis. Hydroxyapatite (HA) was produced from goat bone by step sintering. The inexpensive starch/HA thin film composites were fabricated by customized spin coating. This study revealed that the hydrogen bond energy and distance have significant effect on glass transition temperature of the polymer. The 40 wt % HA contained starch (StrHA40) composite thin film showed excellent tensile strength (3.03 + ?0.03 MPa), elongation (21.5 + ?5.5%) and modulus (15.5 + ?0.2 MPa) closed to human skin. The in vitro swelling and biodegradation kinetics of pristine starch and pure HA has been controlled and improved by using suitable composition. This study postulated the probable water molecule-adsorption mechanisms of pristine starch and starch/HA composite films. The StrHA40 composite showed excellent biocompatibility to the human-blood derived lymphocyte cells. Therefore, the starch/HA thin film composite-based biodegradable scaffolds developed in the present study can be an excellent potential candidate for soft tissue regeneration and/or replacement applications. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019, 137, 48913.Item ACE-Triggered Hypertension Incites Stroke: Genetic, Molecular, and Therapeutic Aspects(Springer, 2019) Vasudeva K.; Balyan R.; Munshi A.Stroke is the second largest cause of death worldwide. Angiotensin converting enzyme (ACE) gene has emerged as an important player in the pathogenesis of hypertension and consequently stroke. It encodes ACE enzyme that converts the inactive decapeptide angiotensin I to active octapeptide, angiotensin II (Ang II). Dysregulation in the expression of ACE gene, on account of genetic variants or regulation by miRNAs, alters the levels of ACE in the circulation. Variable expression of ACE affects the levels of Ang II. Ang II acts through different signal transduction pathways via various tyrosine kinases (receptor/non-receptor) and protein serine/threonine kinases, initiating a downstream cascade of molecular events. In turn these activated molecular pathways might lead to hypertension and inflammation thereby resulting in cardiovascular and cerebrovascular diseases including stroke. In order to regulate the overexpression of ACE, many ACE inhibitors and blockers have been developed, some of which are still under clinical trials.Item Association study identified biologically relevant receptor genes with synergistic functions in celiac disease(NLM (Medline), 2019) Banerjee, P; Bhagavatula, S; Sood, A; Midha, V; Thelma, B.K; Senapati, S.Receptors are essential mediators of cellular physiology, which facilitate molecular and cellular cross-talk with the environment. Nearly 20% of the all known celiac disease (CD) genes are receptors by function. We hypothesized that novel biologically relevant susceptibility receptor genes act in synergy in CD pathogenesis. We attempted to identify novel receptor genes in CD by re-analyzing published Illumina Immunochip dense genotype data for a north Indian and a European (Dutch) cohort. North Indian dataset was screened for 269 known receptor genes. Association statistics for SNPs were considered with minor allele frequency >15% and association P ≤ 0.005 to attend desired study power. Identified markers were tested for cross-ethnic replication in a European CD dataset. Markers were analyzed in-silico to explain their functional significance in CD. Six novel SNPs from MOG (rs29231, p = 1.21e-11), GABBR1 (rs3025643, p = 1.60e-7), OR2H2 (rs1233388, p = 0.0002), ABCF1 (rs9262119, p = 0.0005), ADRA1A (rs10102024, p = 0.003), and ACVR2A (rs7560426, p = 0.004) were identified in north Indians, of which three genes namely, GABBR1 (rs3025643, p = 5.38e-8), OR2H2 (rs1233388, p = 3.29e-5) and ABCF1 (rs9262119, p = 0.0002) were replicated in Dutch. Tissue specific functional annotation, potential epigenetic regulation, co-expression, protein-protein interaction and pathway enrichment analyses indicated differential expression and synergistic function of key genes that could alter cellular homeostasis, ubiquitination mediated phagosome pathway and cellular protein processing to contribute for CD. At present multiple therapeutic compounds/drugs are available targeting GABBR1 and ADRA1A, which could be tested for their effectiveness against CD in controlled drug trials.Item KIBRA Team Up with Partners to Promote Breast Cancer Metastasis(Springer, 2019) Singh G; Mishra, S; Chander, HarishAmong women, breast cancer is the most frequently diagnosed cancer. Most of the breast cancers represent metastasis to distant organs at the time of diagnosis and accounts for the majority of deaths. Metastasis is characterized by many genetic aberrations including mutations, overexpression of oncogenes etc. KIBRA (KIdney/BRAin protein), a scaffolding protein is recently described as an important player in the process of invasion and metastasis. The Kidney/BRAin protein through its different domains interacts with various proteins to couple cytoskeleton arrangement, cell polarity and migration. N terminal and C terminal of the protein contains the WW, Internal C 2 & putative class III PDZ domain that interacts with DDR1, DLC1 & PKCζ. These protein-protein interactions equip the breast cancer cells to invade and metastasize. Here, we discuss a comprehensive knowledge about the KIBRA protein, its domains and the interacting partners involved in metastasis of breast cancer. © 2019, Arányi Lajos Foundation.Item Serum homocysteine could be used as a predictive marker for chronic obstructive pulmonary disease: A meta-analysis(Frontiers Media S.A., 2019) Chaudhary, D; Sharma, N; Senapati, SabyasachiBackground: Serum homocysteine (Hcy) level is inversely related with concentration of folic acid, which is an essential micronutrient for metabolism and energy homeostasis. Serum concentrations of Hcy have been reported to have strong correlation with smoking, which is a major risk factor for pathogenesis of chronic obstructive pulmonary disease (COPD) irrespective of ethnicity and gender. Therefore, we performed a systematic review based meta-analysis to evaluate the overall contribution of Hcy in COPD. Method: Published literature on association of serum Hcy with COPD were obtained through conventional web search and eligible literature were selected based on stringent inclusion/exclusion criteria. Continuous variable data was presented as mean and standard deviation. The variable data was analyzed using RevMan 5 statistical tool to meta-analyze mean differences (MD) with 95 % CI for case-control studies. Result: Four case-control studies met the inclusion criteria for this study. A total of 145 COPD subjects and 107 healthy controls were analyzed. Elevated serum homocysteine concentration was found to induce risk for COPD (MD = 3.05). Conclusion: Molecular role of Hcy in COPD pathogenesis or prognosis is not clear but existing literature suggests that smoking disturbs folic acid metabolism and promotes Hcy accumulation. This study suggested the contribution of Hcy in COPD pathogenesis. However, large scale prospective cohort study and replication studies with more power are warranted to confirm the results. © 2019 Chaudhary, Sharma and Senapati.Item Systematic review and meta-analysis confirms significant contribution of surfactant protein D in chronic obstructive pulmonary disease(Frontiers Media S.A., 2019) Nandy, D; Sharma, N; Senapati, SabyasachiBackground: Surfactant protein D (SFTPD) is a lung specific protein which performs several key regulatory processes to maintain overall lung function. Several infectious and immune mediated diseases have been shown to be associated with SFTPD. Recent findings have suggested the serum concentration of SFTPD can be used as a diagnostic or prognostic marker for chronic obstructive pulmonary disease (COPD) and acute exacerbation COPD (AECOPD). But these findings lack replication studies from different ethnic populations and meta-analysis, to establish SFTPD as reliable diagnostic or prognostic biomarker for COPD and associated conditions. Methods: We performed systematic literature search based on stringent inclusion and exclusion criteria to identify eligible studies to perform a meta-analysis. Our objective was to assess the predictability of serum SFTPD concentration and SFTPD allelic conformation at rs721917 (C > T) with COPD and AECOPD outcome. These variables were compared between COPD and healthy controls, where mean difference (MD), and odds ratio (OR) were calculated to predict the overall effect size. Review manager (RevMan-v5.3) software was used to analyse the data. Results: A total of eight published reports were included in this study. Comparative serum SFTPD concentration data were extracted from six studies and three studies were evaluated for assessment of genetic marker from SFTPD. Our study identified strong association of elevated serum SFTPD with COPD and AECOPD. Significant association of risk was also observed for "T" allele or "TT" genotype of rs721917 from SFTPD with COPD and AECOPD. Conclusion: Serum concentration and alleleic conformation of SFTPD has a significantly high predictive value for COPD and AECOPD. Thus, these can be tested further and could be applied as a predictive or prognostic marker. © 2019 Frontiers Media S.A. All Rights Reserved.Item Systematic review and meta-analysis to establish the association of common genetic variations in Vitamin D binding protein with chronic obstructive pulmonary disease(Frontiers Media S.A., 2019) Khanna, R; Nandy, D; Senapati, SabyasachiBackground: Vitamin-D binding protein (DBP) also known as GC protein, is a major determinant for vitamin- D metabolism and transport. GC1F, GC1S, and GC2 are the three allelic variants (denoted as rs4588 and rs7041) of GC, and known to be associated with chronic obstructive pulmonary disease (COPD). However, contradictory reports and population specific risk attributed by these alleles warranted detailed genetic epidemiology study to establish the association between GC variants and COPD. In this study we performed a meta-analysis and investigated the genetic architecture of GC locus to establish the association and uncover the plausible reason for allelic heterogeneity. Methods: Published cross-sectional case control studies were screened and meta-analysis was performed between GC variants and COPD outcome. RevMan-v5.3 software was used to perform random and/or fixed models to calculate pooled odds ratio (Meta-OR). Linkage disequilibrium (LD) and haplotypes at GC locus were evaluated using 1000 Genomes genotype data. In silico functional implications of rs4588 and rs7041 was tested using publicly available tools. Results: GC1F allele and GC1F/1F genotype were found to confer COPD risk in overall meta-analysis. GC1S/1S was found to confer risk only among Europeans. In silico investigation of rs4588 and rs7041 identified strong eQTL effects and potential role in regulation of GC expression. Large differences in allele frequencies, linkage disequilibrium (LD) and haplotypes were identified at GC locus across different populations (Japanese, African, Europeans, and Indians), which may explain the variable association of different GC alleles in different populations. Conclusion: GC1F and GC1F/1F impose significant genetic risk for COPD, among Asians. Considerable differences in allele frequencies and LD structure in GC locus may impose population specific risk. Copyright © 2019 Khanna, Nandy and Senapati. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Item Computational investigation of binding mechanism of substituted pyrazinones targeting corticotropin releasing factor-1 receptor deliberated for anti-depressant drug design(Taylor and Francis, 2019) Shekhar, M.S; Venkatachalam, T; Sharma, C.S; Pratap, Singh, H; Kalra, Sourav; Kumar, N.In spite of various research investigations towards anti-depressant drug discovery program, no one drug has not yet launched last 20 years. Corticotropin-releasing factor-1 (CRF-1) is one of the most validated targets for the development of antagonists against depression, anxiety and post-traumatic stress disorders. Various research studies suggest that pyrazinone based CRF-1 receptor antagonists were found to be highly potent and efficacious. In this research investigation, we identified the pharmacophore and binding pattern through 2D and 3D-QSAR and molecular docking respectively. Molecular dynamics studies were also performed to explore the binding pattern recognition. We establish the relationship between activity and pharmacophoric features to design new potent compounds. The best 2D-QSAR model was generated through multiple linear regression method with r2 value of 0.97 and q2 value of 0.89. Also 3D-QSAR model was obtained through k-nearest neighbor molecular field analysis method with q2 value of 0.52 and q2_se value of 0.36. Molecular docking and binding energy were also evaluated to define binding patterns and pharmacophoric groups, including (i) hydrogen bond with residue Asp284, Glu305 and (ii) π–π stacking with residue Trp9. Compound 11i has the highest binding affinity compared to reference compounds, so this compound could be a potent drug for stress related disorders. Most of the compounds, including reference compounds were found within acceptable range of physicochemical parameters. These observations could be provided the leads for the design and optimization of novel CRF-1 receptor antagonists. Communicated by Ramaswamy H. Sarma. © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.Item Genetics of idiopathic generalized epilepsy: An overview(Neurology Society of India, 2014) Prasad, D.K.V.; Satyanarayana, U.; Munshi, AnjanaIdiopathic generalized epilepsy (IGE) is a common type of epilepsy. Strong support for a genetic role in IGE comes from twin and family studies. Several subtypes of IGE have been reported but families often have members affected with different subtypes. Major advances have been made in the understanding of genetic basis of monogenic inherited epilepsies. However, most IGEs are complex genetic diseases and some susceptible IGE genes are shared across subtypes that determine subtypes in specific combinations. The high throughput technologies like deoxyribonucleic acid microarrays and sequencing technologies have the potential to identify causative genes or loci in non-familial cases.