{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T21:50:10Z","timestamp":1771969810461,"version":"3.50.1"},"reference-count":131,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2022,3,29]],"date-time":"2022-03-29T00:00:00Z","timestamp":1648512000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100010803","name":"Department of Biotechnology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100010803","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Department of Health Research, Ministry of Health and Family Welfare"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,5,13]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Network medicine provides network theoretical tools, methods and properties to study underlying laws governing human interactome to identify disease states and disease complexity leading to drug discovery. Within this framework, we investigated the topological properties of ovarian cancer network (OCN) and the roles of hubs to understand OCN organization to address disease states and complexity. The OCN constructed from the experimentally verified genes exhibits fractal nature in the topological properties with deeply rooted functional communities indicating self-organizing behavior. The network properties at all levels of organization obey one parameter scaling law which lacks centrality lethality rule. We showed that $\\langle k\\rangle $ can be taken as a scaling parameter, where, power law exponent can be estimated from the ratio of network diameters. The betweenness centrality $C_B$ shows two distinct behaviors one shown by high degree hubs and the other by segregated low degree nodes. The $C_B$ power law exponent is found to connect the exponents of distributions of high and low degree nodes. OCN showed the absence of rich-club formation which leads to the missing of a number of attractors in the network causing formation of weakly tied diverse functional modules to keep optimal network efficiency. In OCN, provincial and connector hubs, which includes identified key regulators, take major responsibility to keep the OCN integrity and organization. Further, most of the key regulators are found to be over expressed and positively correlated with immune infiltrates. Finally, few potential drugs are identified related to the key regulators.<\/jats:p>","DOI":"10.1093\/bib\/bbac085","type":"journal-article","created":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T20:16:25Z","timestamp":1645474585000},"source":"Crossref","is-referenced-by-count":16,"title":["Network medicine in ovarian cancer: topological properties to drug discovery"],"prefix":"10.1093","volume":"23","author":[{"given":"Keilash","family":"Chirom","sequence":"first","affiliation":[{"name":"School of Computational & Integrative Sciences, Jawaharlal Nehru University, New Delhi-110067, India"},{"name":"Department of Zoology, Deshbandhu College, University of Delhi, New Delhi, 110019, India"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6693-0401","authenticated-orcid":false,"given":"Md Zubbair","family":"Malik","sequence":"additional","affiliation":[{"name":"School of Computational & Integrative Sciences, Jawaharlal Nehru University, New Delhi-110067, India"}]},{"given":"Irengbam Rocky","family":"Mangangcha","sequence":"additional","affiliation":[{"name":"Department of Zoology, Deshbandhu College, University of Delhi, New Delhi, 110019, India"}]},{"given":"Pallavi","family":"Somvanshi","sequence":"additional","affiliation":[{"name":"School of Computational & Integrative Sciences, Jawaharlal Nehru University, New Delhi-110067, India"}]},{"given":"R K Brojen","family":"Singh","sequence":"additional","affiliation":[{"name":"School of Computational & Integrative Sciences, Jawaharlal Nehru University, New Delhi-110067, India"}]}],"member":"286","published-online":{"date-parts":[[2022,3,29]]},"reference":[{"key":"2022051813444475300_ref1","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1038\/nrc3983","article-title":"The dynamic control of signal transduction networks in cancer cells","volume":"15","author":"Kolch","year":"2015","journal-title":"Nat Rev Cancer"},{"key":"2022051813444475300_ref2","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/nrg2499","article-title":"The evolution of hierarchical gene regulatory networks","volume":"10","author":"Erwin","year":"2009","journal-title":"Nat Rev Genet"},{"key":"2022051813444475300_ref3","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1126\/science.298.5594.824","article-title":"Network motifs: simple building blocks of complex networks","volume":"298","author":"Milo","year":"2002","journal-title":"Science"},{"key":"2022051813444475300_ref4","doi-asserted-by":"crossref","DOI":"10.1016\/j.cell.2010.09.050","article-title":"SnapShot: network motifs","volume":"143","author":"Shoval","year":"2010","journal-title":"Cell"},{"key":"2022051813444475300_ref5","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nrg1272","article-title":"Network biology: understanding the cells\u2019s functional organization","volume":"5","author":"Barabasi","year":"2004","journal-title":"Nat Rev Genet"},{"key":"2022051813444475300_ref6","first-page":"12","article-title":"The multifractal model of asset returns. 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paper","author":"Mandelbrot","year":"1997"},{"issue":"3","key":"2022051813444475300_ref55","doi-asserted-by":"crossref","DOI":"10.1103\/PhysRevE.80.036115","article-title":"Community detection in networks with positive and negative links","volume":"80","author":"Traag","year":"2009","journal-title":"Phys Rev E"},{"issue":"3\u20135","key":"2022051813444475300_ref56","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.physrep.2009.11.002","article-title":"Community detection in graphs","volume":"486","author":"Fortunato","year":"2010","journal-title":"Phys Rep"},{"key":"2022051813444475300_ref57","doi-asserted-by":"crossref","DOI":"10.1093\/acprof:oso\/9780199206650.001.0001","volume-title":"Networks: An Introduction","author":"Newman","year":"2010"},{"key":"2022051813444475300_ref58","doi-asserted-by":"crossref","first-page":"2825","DOI":"10.1073\/pnas.1106612109","article-title":"A small world of weak ties provides optimal global integration of self-similar modules in functional brain networks","volume":"109","author":"Gallos","year":"2012","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022051813444475300_ref59","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1177\/1073858406293182","article-title":"Small-world brain networks","volume":"12","author":"Bassett","year":"2006","journal-title":"Neuroscientist"},{"key":"2022051813444475300_ref60","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1111\/j.1749-6632.2010.05888.x","article-title":"The human connectome: a complex network","volume":"1224","author":"Sporns","year":"2011","journal-title":"Ann N Y Acad Sci"},{"key":"2022051813444475300_ref61","volume-title":"Handbook of Stochastic Methods","author":"Gardiner","year":"2003","edition":"3rd"},{"key":"2022051813444475300_ref62","first-page":"1215","volume-title":"Encyclopedia of Library and Information 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networks","volume":"89","author":"Newman","year":"2002","journal-title":"Phys Rev Lett"},{"key":"2022051813444475300_ref73","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1038\/nphys209","article-title":"Detecting rich-club ordering in complex networks","volume":"2","author":"Colizza","year":"2006","journal-title":"Nat Phys"},{"key":"2022051813444475300_ref74","doi-asserted-by":"crossref","first-page":"15775","DOI":"10.1523\/JNEUROSCI.3539-11.2011","article-title":"Rich-club organization of the human connectome","volume":"31","author":"Van den Heuvel","year":"2011","journal-title":"J Neurosci"},{"key":"2022051813444475300_ref75","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.neuroimage.2014.03.066","article-title":"Rich club organization supports a diverse set of functional network 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growth","volume":"23","author":"Altomare","year":"2004","journal-title":"Oncogene"},{"key":"2022051813444475300_ref82","doi-asserted-by":"crossref","first-page":"11718","DOI":"10.1158\/0008-5472.CAN-06-1968","article-title":"A specific role for AKT3 in the genesis of ovarian cancer through modulation of G(2)-M phase transition","volume":"66","author":"Cristiano","year":"2006","journal-title":"Cancer Res"},{"key":"2022051813444475300_ref83","doi-asserted-by":"crossref","first-page":"2097","DOI":"10.1016\/S0002-9440(10)64681-0","article-title":"Frequent loss of PTEN expression is linked to elevated phosphorylated Akt levels, but not associated with p27 and cyclin D1 expression, in primary epithelial ovarian carcinomas","volume":"158","author":"Kurose","year":"2001","journal-title":"Am J Pathol"},{"issue":"1","key":"2022051813444475300_ref84","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1158\/0008-5472.CAN-13-2961","article-title":"Akt1 and akt3 exert opposing roles in the regulation of vascular tumor growth","volume":"75","author":"Phung","year":"2015","journal-title":"Cancer Res"},{"key":"2022051813444475300_ref85","doi-asserted-by":"crossref","first-page":"3792","DOI":"10.1021\/pr400455j","article-title":"Characterization of a chemical affinity probe targeting Akt kinases","volume":"12","author":"Pachl","year":"2013","journal-title":"J Proteome Res"},{"key":"2022051813444475300_ref86","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0100880","article-title":"Discovery of novel AKT inhibitors with enhanced anti-tumor effects in combination with the MEK inhibitor","volume":"9","author":"Dumble","year":"2014","journal-title":"PLoS One"},{"key":"2022051813444475300_ref87","first-page":"1","article-title":"Phase I dose-escalation trial of the oral AKT inhibitor uprosertib in combination with the oral MEK1\/MEK2 inhibitor trametinib in patients with solid tumors","author":"Tolcher","year":"2020","journal-title":"Cancer Chemother Pharmacol"},{"issue":"11","key":"2022051813444475300_ref88","doi-asserted-by":"crossref","first-page":"1874","DOI":"10.2174\/13816128113199990532","article-title":"Epigenetic modification restores functional PR expression in endometrial cancer cells","volume":"20","author":"Yang","year":"2014","journal-title":"Curr Pharm Des"},{"key":"2022051813444475300_ref89","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1016\/j.molimm.2005.07.034","article-title":"MT110: a novel bispecific single-chain antibody construct with high efficacy in eradicating established tumors","volume":"43","author":"Brischwein","year":"2006","journal-title":"Mol Immunol"},{"issue":"3","key":"2022051813444475300_ref90","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1002\/cncr.29062","article-title":"Solitomab, an epithelial cell adhesion molecule\/CD3 bispecific antibody (BiTE), is highly active against primary chemotherapy-resistant ovarian cancer cell lines in vitro and fresh tumor cells ex vivo","volume":"121","author":"English","year":"2015","journal-title":"Cancer"},{"key":"2022051813444475300_ref91","doi-asserted-by":"crossref","DOI":"10.1200\/JCO.2020.38.15_suppl.3593","volume-title":"Phase I study of regorafenib and sildenafil in advanced solid tumors","author":"Poklepovic","year":"2020"},{"key":"2022051813444475300_ref92","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/35075138","article-title":"Lethality and centrality in protein networks","volume":"411","author":"Jeong","year":"2001","journal-title":"Nature"},{"key":"2022051813444475300_ref93","article-title":"Fast unfolding of communities in large networks","volume":"10","author":"Blondel","year":"2008","journal-title":"J Stat Mech"},{"key":"2022051813444475300_ref94","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1038\/s41591-019-0424-4","article-title":"Genomic and transcriptomic profiling expands precision cancer medicine: the WINTHER 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factors","volume":"13","author":"Cannistra","year":"1995","journal-title":"J Clin Oncol"},{"issue":"14","key":"2022051813444475300_ref98","first-page":"5318","article-title":"CD44 expression indicates favorable prognosis in epithelial ovarian cancer","volume":"9","author":"Sillanpaa","year":"2000","journal-title":"Clin Cancer Res"},{"issue":"14","key":"2022051813444475300_ref99","doi-asserted-by":"crossref","first-page":"3791","DOI":"10.1158\/0008-5472.CAN-16-2545","article-title":"Akt signaling is sustained by a CD44 splice isoform-mediated positive feedback loop","volume":"77","author":"Liu","year":"2017","journal-title":"Cancer Res"},{"key":"2022051813444475300_ref100","article-title":"Et al","volume-title":"A KRAS-variant in ovarian cancer acts as a genetic marker of cancer risk","author":"Ratner"},{"issue":"4","key":"2022051813444475300_ref101","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1002\/1878-0261.12453","article-title":"Functional KRAS mutations and a potential role for PI3K\/AKT activation in Wilms tumors (vol 11, pg 405, 2017)","volume":"13","author":"Polosukhina","year":"2019","journal-title":"Mol Oncol"},{"issue":"4","key":"2022051813444475300_ref102","doi-asserted-by":"crossref","first-page":"e530","DOI":"10.1002\/onco.13702","article-title":"KRAS-mutated, estrogen receptor-positive low-grade serous ovarian cancer: unraveling an exceptional response mystery","volume":"26","author":"Kato","year":"2021","journal-title":"Oncologist"},{"key":"2022051813444475300_ref103","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1038\/s41591-019-0407-5","article-title":"Molecular profiling of cancer patients enables personalized combination therapy: the I-PREDICT study","volume":"25","author":"Sicklick","year":"2019","journal-title":"Nat Med"},{"key":"2022051813444475300_ref104","article-title":"Prognostic implications of RAS alterations in diverse malignancies and impact of targeted therapies","author":"Kato","year":"2019","journal-title":"Int J Cancer"},{"issue":"1","key":"2022051813444475300_ref105","first-page":"S4","article-title":"GeneMANIA: a real-time multiple association network integration algorithm for predicting gene function","volume":"9","author":"Sara","year":"2008","journal-title":"Genome Biol"},{"key":"2022051813444475300_ref106","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.biosystems.2014.11.005","article-title":"CytoNCA: a cytoscape plugin for centrality analysis and evaluation of protein interaction networks","volume":"127","author":"Tang","year":"2015","journal-title":"Biosystems"},{"issue":"4","key":"2022051813444475300_ref107","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1038\/nprot.2012.004","article-title":"Topological analysis and interactive visualization of biological networks and protein structures","volume":"7","author":"Doncheva","year":"2012","journal-title":"Nat Protoc"},{"issue":"2","key":"2022051813444475300_ref108","doi-asserted-by":"crossref","DOI":"10.1103\/PhysRevE.67.026112","article-title":"Hierarchical organization in complex networks","volume":"l67","author":"Ravasz","year":"2003","journal-title":"Physical Review E"},{"issue":"5569","key":"2022051813444475300_ref109","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1126\/science.1065103","article-title":"Specificity and stability in topology of protein networks","volume":"296","author":"Maslov","year":"2002","journal-title":"Science"},{"issue":"25","key":"2022051813444475300_ref110","doi-asserted-by":"crossref","DOI":"10.1103\/PhysRevLett.87.258701","article-title":"Dynamical and correlation properties of the internet","volume":"87","author":"Pastor-Satorras","year":"2001","journal-title":"Phys Rev Lett"},{"key":"2022051813444475300_ref111","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1142\/9789812771681_0005","volume-title":"In Large Scale Structure And Dynamics Of Complex Networks: From Information Technology to Finance and Natural Science","author":"Barrat","year":"2007"},{"issue":"4","key":"2022051813444475300_ref112","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/j.socnet.2005.11.005","article-title":"A graph-theoretic perspective on centrality","volume":"28","author":"Borgatti","year":"2006","journal-title":"Social Networks"},{"issue":"2","key":"2022051813444475300_ref113","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1080\/0022250X.2001.9990249","article-title":"A faster algorithm for betweenness centrality","volume":"25","author":"Brandes","year":"2001","journal-title":"Journal of mathematical sociology"},{"issue":"2","key":"2022051813444475300_ref114","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1049\/iet-syb:20060038","article-title":"Graph theory and networks in biology","volume":"1","author":"Mason","year":"2007","journal-title":"IET Syst Biol"},{"issue":"2","key":"2022051813444475300_ref115","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.scico.2003.12.008","article-title":"Roles in networks","volume":"53","author":"Canright","year":"2004","journal-title":"Science of Computer Programming"},{"issue":"1\u20133","key":"2022051813444475300_ref116","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1159\/000094195","article-title":"Spreading on networks: a topographic view","volume":"3","author":"Canright","year":"2006","journal-title":"Complexus"},{"issue":"e623","key":"2022051813444475300_ref117","article-title":"The coefficient of determination R-squared is more informative than SMAPE, MAE, MAPE, MSE and RMSE in regression analysis evaluation","volume":"7","author":"Chicco","year":"2021","journal-title":"PeerJ Comput Sci"},{"issue":"7","key":"2022051813444475300_ref118","first-page":"557","article-title":"Correlation and causation","volume":"XX","author":"Wright","year":"1921","journal-title":"J Agric Res"},{"issue":"10","key":"2022051813444475300_ref119","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1038\/ng.2764","article-title":"The cancer genome atlas pan-cancer analysis project","volume":"45","author":"Weinstein","year":"2013","journal-title":"Nat Genet"},{"issue":"6509","key":"2022051813444475300_ref120","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1126\/science.aaz1776","article-title":"The GTEx consortium atlas of genetic regulatory effects across human tissues","volume":"369","year":"2020","journal-title":"Science"},{"key":"2022051813444475300_ref121","doi-asserted-by":"crossref","DOI":"10.1038\/s41587-020-0546-8","article-title":"Visualizing and interpreting cancer genomics data via the Xena platform","author":"Goldman","year":"2020","journal-title":"Nat Biotechnol"},{"key":"2022051813444475300_ref122","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1186\/1471-2105-12-77","article-title":"pROC: an open-source package for R and S+ to analyze and compare ROC curves","volume":"12","author":"Robin","year":"2011","journal-title":"BMC Bioinformatics"},{"key":"2022051813444475300_ref123","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.2147\/DMSO.S209118","article-title":"Gene expression profiling reveals candidate biomarkers and probable molecular mechanism in diabetic peripheral neuropathy","volume":"12","author":"Zhou","year":"2019","journal-title":"Diabetes Metab Syndr Obes"},{"issue":"W1","key":"2022051813444475300_ref124","doi-asserted-by":"crossref","first-page":"W98","DOI":"10.1093\/nar\/gkx247","article-title":"GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses","volume":"45","author":"Tang","year":"2017","journal-title":"Nucleic Acids Res"},{"issue":"21","key":"2022051813444475300_ref125","doi-asserted-by":"crossref","first-page":"e108","DOI":"10.1158\/0008-5472.CAN-17-0307","article-title":"TIMER: a web server for comprehensive analysis of tumor-infiltrating immune cells","volume":"77","author":"Li","year":"2017","journal-title":"Cancer Res"},{"issue":"D1","key":"2022051813444475300_ref126","doi-asserted-by":"crossref","first-page":"D1068","DOI":"10.1093\/nar\/gkx1143","article-title":"DGIdb 3.0: a redesign and expansion of the drug-gene interaction database","volume":"46","author":"Cotto","year":"2018","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"2022051813444475300_ref127","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The protein data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res"},{"issue":"3","key":"2022051813444475300_ref128","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s10822-013-9644-8","article-title":"Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments","volume":"27","author":"Madhavi Sastry","year":"2013","journal-title":"J Comput Aided Mol 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