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Pharmacogenomics and chemical library screens reveal a novel SCF(SKP2) inhibitor that overcomes bortezomib resistance in multiple myeloma.

Fri, 2016-09-30 07:02

Pharmacogenomics and chemical library screens reveal a novel SCF(SKP2) inhibitor that overcomes bortezomib resistance in multiple myeloma.

Leukemia. 2016 Sep 28;

Authors: Malek E, Abdel-Malek MA, Jagannathan S, Vad N, Karns R, Jegga AG, Broyl A, van Duin M, Sonneveld P, Cottini F, Anderson KC, Driscoll JJ

Abstract
While clinical benefit of the proteasome inhibitor (PI) bortezomib for multiple myeloma (MM) patients remains unchallenged, dose-limiting toxicities and drug resistance limit the long-term utility. The E3 ubiquitin (Ub) ligase Skp1-Cullin-1-Skp2 (SCF(Skp2)) promotes proteasomal degradation of the cell cycle inhibitor p27 to enhance tumor growth. Increased SKP2 expression and reduced p27 levels are frequent in human cancers and are associated with therapeutic resistance. SCF(Skp2) activity is increased by the Cullin-1-binding protein Commd1 and the Skp2-binding protein Cks1B. Here, we observed higher CUL1, COMMD1 and SKP2 mRNA levels in CD138(+) cells isolated from bortezomib-resistant MM patients. Higher CUL1, COMMD1, SKP2 and CKS1B mRNA levels in patient CD138(+) cells correlated with decreased progression-free and overall survival. Genetic knockdown of CUL1, COMMD1 or SKP2 disrupted the SCF(Skp2) complex, stabilized p27 and increased the number of annexin-V positive cells after bortezomib treatment. Chemical library screens identified a novel compound, designated DT204, that reduced Skp2 binding to Cullin-1 and Commd1, and synergistically enhanced bortezomib-induced apoptosis. DT204 co-treatment with bortezomib overcame drug resistance and reduced the in vivo growth of myeloma tumors in murine models with survival benefit. Taken together, the results provide proof-of-concept for rationally-designed drug combinations that incorporate SCF(Skp2) inhibitors to treat bortezomib resistant disease.Leukemia accepted article preview online, 28 September 2016. doi:10.1038/leu.2016.258.

PMID: 27677741 [PubMed - as supplied by publisher]

IL-31-Driven Skin Remodeling Involves Epidermal Cell Proliferation and Thickening That Lead to Impaired Skin-Barrier Function.

Thu, 2016-08-25 07:02

IL-31-Driven Skin Remodeling Involves Epidermal Cell Proliferation and Thickening That Lead to Impaired Skin-Barrier Function.

PLoS One. 2016;11(8):e0161877

Authors: Singh B, Jegga AG, Shanmukhappa KS, Edukulla R, Khurana GH, Medvedovic M, Dillon SR, Madala SK

Abstract
Interleukin-31 (IL-31) is a type 2 helper T-cell-derived cytokine that has recently been shown to cause severe inflammation and tissue remodeling in multiple chronic diseases of the skin and lungs. IL-31 is upregulated in allergic and inflammatory diseases, including atopic dermatitis, asthma, cutaneous T-cell lymphomas, and allergic rhinitis, as well as autoimmune diseases such as systemic erythematosus. Overexpression of IL-31 in T cells causes severe inflammation, with histological features similar to skin lesions of patients with atopic dermatitis. However, the molecular mechanisms involved in IL31-driven pathological remodeling in skin diseases remain largely unknown. Here, we studied the role of IL-31 in skin damage as a result of intradermal administration of recombinant IL-31 into mice. Notably, IL-31 was sufficient to increase epidermal basal-cell proliferation and thickening of the epidermal skin layer. Our findings demonstrate a progressive increase in transepidermal water loss with chronic administration of IL-31 into the skin. Further, analysis of the skin transcriptome indicates a significant increase in the transcripts involved in epidermal-cell proliferation, epidermal thickening, and mechanical integrity. In summary, our findings demonstrate an important role for IL-31 signaling in epidermal cell proliferation and thickening that together may lead to impaired skin-barrier function in pathological remodeling of the skin.

PMID: 27556734 [PubMed - as supplied by publisher]

Data mining differential clinical outcomes associated with drug regimens using adverse event reporting data.

Wed, 2016-07-13 06:47

Data mining differential clinical outcomes associated with drug regimens using adverse event reporting data.

Nat Biotechnol. 2016 Jul 12;34(7):697-700

Authors: Sarangdhar M, Tabar S, Schmidt C, Kushwaha A, Shah K, Dahlquist JE, Jegga AG, Aronow BJ

PMID: 27404875 [PubMed - as supplied by publisher]

Canonical genetic signatures of the adult human brain.

Wed, 2016-06-01 21:27
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Canonical genetic signatures of the adult human brain.

Nat Neurosci. 2015 Dec;18(12):1832-44

Authors: Hawrylycz M, Miller JA, Menon V, Feng D, Dolbeare T, Guillozet-Bongaarts AL, Jegga AG, Aronow BJ, Lee CK, Bernard A, Glasser MF, Dierker DL, Menche J, Szafer A, Collman F, Grange P, Berman KA, Mihalas S, Yao Z, Stewart L, Barabási AL, Schulkin J, Phillips J, Ng L, Dang C, Haynor DR, Jones A, Van Essen DC, Koch C, Lein E

Abstract
The structure and function of the human brain are highly stereotyped, implying a conserved molecular program responsible for its development, cellular structure and function. We applied a correlation-based metric called differential stability to assess reproducibility of gene expression patterning across 132 structures in six individual brains, revealing mesoscale genetic organization. The genes with the highest differential stability are highly biologically relevant, with enrichment for brain-related annotations, disease associations, drug targets and literature citations. Using genes with high differential stability, we identified 32 anatomically diverse and reproducible gene expression signatures, which represent distinct cell types, intracellular components and/or associations with neurodevelopmental and neurodegenerative disorders. Genes in neuron-associated compared to non-neuronal networks showed higher preservation between human and mouse; however, many diversely patterned genes displayed marked shifts in regulation between species. Finally, highly consistent transcriptional architecture in neocortex is correlated with resting state functional connectivity, suggesting a link between conserved gene expression and functionally relevant circuitry.

PMID: 26571460 [PubMed - indexed for MEDLINE]

IRAK1 is a novel DEK transcriptional target and is essential for head and neck cancer cell survival.

Wed, 2016-06-01 21:27
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IRAK1 is a novel DEK transcriptional target and is essential for head and neck cancer cell survival.

Oncotarget. 2015 Dec 22;6(41):43395-407

Authors: Adams AK, Bolanos LC, Dexheimer PJ, Karns RA, Aronow BJ, Komurov K, Jegga AG, Casper KA, Patil YJ, Wilson KM, Starczynowski DT, Wells SI

Abstract
The chromatin-binding DEK protein was recently reported to promote the growth of HPV+ and HPV- head and neck squamous cell carcinomas (HNSCCs). Relevant cellular and molecular mechanism(s) controlled by DEK in HNSCC remain poorly understood. While DEK is known to regulate specific transcriptional targets, global DEK-dependent gene networks in HNSCC are unknown. To identify DEK transcriptional signatures we performed RNA-Sequencing (RNA-Seq) in HNSCC cell lines that were either proficient or deficient for DEK. Bioinformatic analyses and subsequent validation revealed that IRAK1, a regulator of inflammatory signaling, and IRAK1-dependent regulatory networks were significantly repressed upon DEK knockdown in HNSCC. According to TCGA data, 14% of HNSCC specimens overexpressed IRAK1, thus supporting possible oncogenic functions. Furthermore, genetic or pharmacologic inhibition of IRAK1 in HNSCC cell lines was sufficient to attenuate downstream signaling such as ERK1/2 and to induce HNSCC cell death by apoptosis. Finally, targeting DEK and IRAK1 simultaneously enhanced cell death as compared to targeting either alone. Our findings reveal that IRAK1 promotes cell survival and is an attractive therapeutic target in HNSCC cells. Thus, we propose a model wherein IRAK1 stimulates tumor signaling and phenotypes both independently and in conjunction with DEK.

PMID: 26527316 [PubMed - in process]

Concept Modeling-based Drug Repositioning.

Wed, 2016-06-01 21:27
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Concept Modeling-based Drug Repositioning.

AMIA Jt Summits Transl Sci Proc. 2015;2015:222-6

Authors: Patchala J, Jegga AG

Abstract
Our hypothesis is that drugs and diseases sharing similar biomedical and genomic concepts are likely to be related, and thus repositioning opportunities can be identified by ranking drugs based on the incidence of shared similar concepts with diseases and vice versa. To test this, we constructed a probabilistic topic model based on the Unified Medical Language System (UMLS) concepts that appear in the disease and drug related abstracts in MEDLINE. The resulting probabilistic topic associations were used to measure the similarity between disease and drugs. The success of the proposed model is evaluated using a set of repositioned drugs, and comparing a drug's ranking based on its similarity to the original and new indication. We then applied the model to rare disorders and compared them to all approved drugs to facilitate "systematically serendipitous" discovery of relationships between rare diseases and existing drugs, some of which could be potential repositioning candidates.

PMID: 26306277 [PubMed]

Pharmacological inhibition of apical sodium-dependent bile acid transporter changes bile composition and blocks progression of sclerosing cholangitis in multidrug resistance 2 knockout mice.

Wed, 2016-06-01 21:27
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Pharmacological inhibition of apical sodium-dependent bile acid transporter changes bile composition and blocks progression of sclerosing cholangitis in multidrug resistance 2 knockout mice.

Hepatology. 2016 Feb;63(2):512-23

Authors: Miethke AG, Zhang W, Simmons J, Taylor AE, Shi T, Shanmukhappa SK, Karns R, White S, Jegga AG, Lages CS, Nkinin S, Keller BT, Setchell KD

Abstract
UNLABELLED: Deficiency of multidrug resistance 2 (mdr2), a canalicular phospholipid floppase, leads to excretion of low-phospholipid "toxic" bile causing progressive cholestasis. We hypothesize that pharmacological inhibition of the ileal, apical sodium-dependent bile acid transporter (ASBT), blocks progression of sclerosing cholangitis in mdr2(-/-) mice. Thirty-day-old, female mdr2(-/-) mice were fed high-fat chow containing 0.006% SC-435, a minimally absorbed, potent inhibitor of ASBT, providing, on average, 11 mg/kg/day of compound. Bile acids (BAs) and phospholipids were measured by mass spectrometry. Compared with untreated mdr2(-/-) mice, SC-435 treatment for 14 days increased fecal BA excretion by 8-fold, lowered total BA concentration in liver by 65%, reduced total BA and individual hydrophobic BA concentrations in serum by >98%, and decreased plasma alanine aminotransferase, total bilirubin, and serum alkaline phosphatase levels by 86%, 93%, and 55%, respectively. Liver histology of sclerosing cholangitis improved, and extent of fibrosis decreased concomitant with reduction of hepatic profibrogenic gene expression. Biliary BA concentrations significantly decreased and phospholipids remained low and unchanged with treatment. The phosphatidylcholine (PC)/BA ratio in treated mice corrected toward a ratio of 0.28 found in wild-type mice, indicating decreased bile toxicity. Hepatic RNA sequencing studies revealed up-regulation of putative anti-inflammatory and antifibrogenic genes, including Ppara and Igf1, and down-regulation of several proinflammatory genes, including Ccl2 and Lcn2, implicated in leukocyte recruitment. Flow cytometric analysis revealed significant reduction of frequencies of hepatic CD11b(+) F4/80(+) Kupffer cells and CD11b(+) Gr1(+) neutrophils, accompanied by expansion of anti-inflammatory Ly6C(-) monocytes in treated mdr2(-/-) mice.
CONCLUSION: Inhibition of ASBT reduces BA pool size and retention of hydrophobic BA, favorably alters the biliary PC/BA ratio, profoundly changes the hepatic transcriptome, attenuates recruitment of leukocytes, and abrogates progression of murine sclerosing cholangitis.

PMID: 26172874 [PubMed - in process]

Polycomb repressive complex 1 controls uterine decidualization.

Wed, 2016-05-18 16:52
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Polycomb repressive complex 1 controls uterine decidualization.

Sci Rep. 2016;6:26061

Authors: Bian F, Gao F, Kartashov AV, Jegga AG, Barski A, Das SK

Abstract
Uterine stromal cell decidualization is an essential part of the reproductive process. Decidual tissue development requires a highly regulated control of the extracellular tissue remodeling; however the mechanism of this regulation remains unknown. Through systematic expression studies, we detected that Cbx4/2, Rybp, and Ring1B [components of polycomb repressive complex 1 (PRC1)] are predominantly utilized in antimesometrial decidualization with polyploidy. Immunofluorescence analyses revealed that PRC1 members are co-localized with its functional histone modifier H2AK119ub1 (mono ubiquitination of histone-H2A at lysine-119) in polyploid cell. A potent small-molecule inhibitor of Ring1A/B E3-ubiquitin ligase or siRNA-mediated suppression of Cbx4 caused inhibition of H2AK119ub1, in conjunction with perturbation of decidualization and polyploidy development, suggesting a role for Cbx4/Ring1B-containing PRC1 in these processes. Analyses of genetic signatures by RNA-seq studies showed that the inhibition of PRC1 function affects 238 genes (154 up and 84 down) during decidualization. Functional enrichment analyses identified that about 38% genes primarily involved in extracellular processes are specifically targeted by PRC1. Furthermore, ~15% of upregulated genes exhibited a significant overlap with the upregulated Bmp2 null-induced genes in mice. Overall, Cbx4/Ring1B-containing PRC1 controls decidualization via regulation of extracellular gene remodeling functions and sheds new insights into underlying molecular mechanism(s) through transcriptional repression regulation.

PMID: 27181215 [PubMed - in process]

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