Although a defective vitamin D endocrine system has been widely suspected to be associated in SARS-CoV-2 pathobiology, the status of the vitamin D endocrine system and vitamin D-modulated genes in lung cells of patients infected with SARS-CoV-2 remains unknown. To understand the significance of the vitamin D endocrine system in SARS-CoV-2 pathobiology, computational approaches were applied to transcriptomic datasets from bronchoalveolar lavage fluid (BALF) cells of such patients or healthy individuals. Levels of vitamin D receptor, retinoid X receptor, and CYP27A1 in BALF cells of patients infected with SARS-CoV-2 were found to be reduced. Additionally, 107 differentially expressed, predominantly downregulated genes, as potentially modulated by vitamin D endocrine system, were identified in transcriptomic datasets from patient’s cells. Further analysis of differentially expressed genes provided eight novel genes with a conserved motif with vitamin D-responsive elements, implying the role of both direct and indirect mechanisms of gene expression by the dysregulated vitamin D endocrine system in SARS-CoV-2-infected cells. Protein–protein interaction network of differentially expressed vitamin D-modulated genes were enriched in the immune system, NF-κB/cytokine signaling, and cell cycle regulation as top predicted pathways that might be affected in the cells of such patients. In brief, the results presented here povide computational evidence to implicate a dysregulated vitamin D endocrine system in the pathobiology of SARS-CoV-2 infection.

No abstract

PfTopoVIB PfHsp90 ATP 143.657 (96) 129.333 (81) Radicicol 76.4008 (2) 91.7911 (9) Analog 1 105.184 (8) 92.585 (4) Analog 2 133.823 (9) No docked poses Analog 3 74.1867 (2) 89.926 (12) Analog 4 87.0343 (5) 92.2888 (7) Analog 5 88.8705 (2) 101.406 (14) Analog 6 108.647 (2) No docked poses Analog 7 77.5334 (2) No docked poses Analog 8 84.9003 (2) 98.4773 (7) Analog 9 87.3219 (2) 98.7025 (11) Analog 10 92.3465 (1) 104.188 (8) Analog 11 77.623 (4) 84.8962 (20) Analog 12 68.6989 (1) 93.066 (5) Analog 13 73.1041 (3) 89.7777 (2) Analog 14 82.7546 (3) 90.8558 (5) Analog 15 88.8888 (15) 96.9247 (52) Analog 16 76.4399 (2) 90.5099 (5) Analog 17 76.4532 (1) 95.5775 (20) Analog 18 76.0733 (1) 106.118 (5) Analog 19 No docked poses 96.8303 (13) Analog 20 No docked poses 66.8629 (2) Analog 21 77.4023 (5) 96.0849 (7) Analog 22 83.9107 (5) 105.157 (13) Analog 23 76.1084 (4) 86.745 (9) Analog 24 77.7701 (6) 84.7549 (6) Analog 25 88.8888 (15) 96.9247 (52) Analog 26 92.0622 (37) 106.204 (15) Analog 27 113.034 (92) 107.629 (90) Analog 28 126.111 (81) 111.54 (89) Analog 29 146.569 (91) 107.773 (30) Analog 30 116.084 (92) 121.593 (74) Analog 31 121.53 (95) 119.932 (38) Analog 32 No docked poses No docked poses Analog 33 124.066 (87) 99.2816 (89) Analog 34 111.149 (94) 113.188 (86) Analog 35 104.421(96) 113.064 (81) Analog 36 89.2511 (26) 80.1705 (2) Analog 37 87.3713 (14) 93.9307 (22) Analog 38 100.184 (58) 86.4046 (6) Analog 39 109.044 (21) 85.967 (21) Analog 40 91.7332 (27) 92.2866 (33) Analog 41 106.414 (52) 101.088 (37) Analog 42 95.2177 (19) 96.2555 (22) Analog 43 109.439 (11) 93.4571 (13) Analog 44 108.03 (67) 79.2665 (8) Analog 45 90.5919 (40) 92.064 (63) Analog 46 103.04 (56) 97.2199 (71) Analog 47 86.6312 (10) 96.4127 (15) Analog 48 103.04 (56) 97.2199 (71) Analog 49 98.6211 (17) 92.5781 (48) Analog 50 77.7701 (6) 84.7549 (6) Analog 51 76.1084 (4) 86.745 (9) Analog 52 120.296 (60) 115.213 (16) Analog 53 115.77 (62) 104.267 (23) Analog 54 86.4992 (2) 90.9012 (23) Analog 55 No docked poses 83.4545 (11) Analog 56 81.7324 (3) 87.2365 (17) Analog 57 No docked poses 94.1162 (15) Analog 58 69.6464 (2) 89.5652 (12) Analog 59 91.3509 (3) 98.6856 (6) Analog 60 103.441 (38) 105.537 (44) Analog 61 124.531 (85) 112.673 (81) Analog 62 105.573 (95) 108.981 (67) Analog 63 No docked poses No docked poses Analog 64 105.808 (96) 111.198 (79) Analog 65 127.171 (86) 107.959 (14) Analog 66 127.312 (77) 112.49 (11) Analog 67 134.451 (91) 118.745 (88) Analog 68 80.1883 (1) 80.9545 (6) Analog 69 94.0426 (26) 97.3786 (18) Analog 70 96.43 (16) 106.191 (27) Analog 71 106.638 (11) 114.339 (36) Analog 72 71.6177 (3) 89.3496 (9) Analog 73 78.2695 (5) 89.3019 (11) Analog 74 No docked poses 97.7812 (7) Analog 75 98.4877 (42) 124.62 (70) Analog 76 128.528 (91) 113.804 (85) Analog 77 103.528 (36) 89.1453 (3) Analog 78 126.025 (40) 91.7578 (8) Analog 79 130.084 (92) 58.4248 (1) Analog 80 119.39 (93) 126.137 (9) Analog 81 71.7722 (2) 90.548 (22) Analog 82 No docked poses 89.7058 (6) Analog 83 93.4051 (5) 106.048 (15) Analog 84 117.584 (6) 82.8479 (2) Analog 85 85.9...

No abstract

To define the growing significance of cellular targets and/or effectors of cancer drugs, we examined the fitness dependency of cellular targets and effectors of cancer drug targets across human cancer cells from 19 cancer types. We observed that the deletion of 35 out of 47 cellular effectors and/or targets of oncology drugs did not result in the expected loss of cell fitness in appropriate cancer types for which drugs targeting or utilizing these molecules for their actions were approved. Additionally, our analysis recognized 43 cellular molecules as fitness genes in several cancer types in which these drugs were not approved, and thus, providing clues for repurposing certain approved oncology drugs in such cancer types. For example, we found a widespread upregulation and fitness dependency of several components of the mevalonate and purine biosynthesis pathways (currently targeted by bisphosphonates, statins, and pemetrexed in certain cancers) and an association between the overexpression of these molecules and reduction in the overall survival duration of patients with breast and other hard-to-treat cancers, for which such drugs are not approved. In brief, the present analysis raised cautions about off-target and undesirable effects of certain oncology drugs in a subset of cancers where the intended cellular effectors of drug might not be good fitness genes and that this study offers a potential rationale for repurposing certain approved oncology drugs for targeted therapeutics in additional cancer types.

Although a defective vitamin D pathway has been widely suspected to be associated in SARS-CoV-2 pathobiology, the status of the vitamin D pathway and vitamin D-modulated genes in lung cells of patients infected with SARS-CoV-2 remains unknown. To understand the significance of the vitamin D pathway in SARS-CoV-2 pathobiology, computational approaches were applied to transcriptomic datasets from bronchoalveolar lavage fluid (BALF) cells of such patients or healthy individuals. Levels of vitamin D receptor, retinoid X receptor, and CYP27A1 in BALF cells of patients infected with SARS-CoV-2 were found to be reduced. Additionally, 107 differentially expressed, predominantly downregulated genes modulated by vitamin D were identified in transcriptomic datasets from patient’s cells. Further analysis of differentially expressed genes provided eight novel genes with a conserved motif with vitamin D-responsive elements, implying the role of both direct and indirect mechanisms of gene expression by the dysregulated vitamin D pathway in SARS-CoV-2-infected cells. Network analysis of differentially expressed vitamin D-modulated genes identified pathways in the immune system, NF-KB/cytokine signaling, and cell cycle regulation as top predicted pathways that might be affected in the cells of such patients. In brief, the results provided computational evidence to implicate a dysregulated vitamin D pathway in the pathobiology of SARS-CoV-2 infection.

No abstract

Most epithelial cancer types are polygenic in nature and are driven by coordinated dysregulation of multiple regulatory pathways, genes, and protein modifications. The process of coordinated regulation of cancer promoting pathways in response to extrinsic and intrinsic signals facilitates the dysregulation of several pathways with complementary functions, contributing to the hallmarks of cancer. Dysregulation and hyperactivation of cell surface human epidermal growth factor receptors (HERs) and cytoskeleton remodeling by p21-activated kinases (PAKs) are two prominent interconnected aspects of oncogenesis. We briefly discuss the discoveries and significant advances in the area of coordinated regulation of HERs and PAKs in the development and progression of breast and other epithelial cancers. We also discuss how initial studies involving heregulin signaling via HER3-HER2 axis and HER2-overexpressing breast cancer cells not only discovered a mechanistic role of PAK1 in breast cancer pathobiology but also acted as a bridge in generating a broader cancer research interest in other PAK family members and cancer types and catalyzed establishing the role of PAKs in human cancer, at-large. In addition, growth factor stimulation of the PAK pathway also helped to recognize new facets of PAKs, connecting the PAK pathway to oncogenesis, nuclear signaling, gene expression, mitotic progression, DNA damage response, among other phenotypic responses, and shaped the field of PAK cancer research. Finally, we recount some of the current limitations of HER-and PAK-directed therapeutics in counteracting acquired therapeutic resistance and discuss how cancer's as a polygenic disease may be best targeted with a polygenic approach.