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  • 1
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 9, No. 2 ( 2011-02-01), p. 195-202
    Abstract: Ethyl 2-((2,3-bis(nitrooxy)propyl)disulfanyl)benzoate (GT-094) is a novel nitric oxide (NO) chimera containing an nonsteroidal anti-inflammatory drug (NSAID) and NO moieties and also a disulfide pharmacophore that in itself exhibits cancer chemopreventive activity. In this study, the effects and mechanism of action of GT-094 were investigated in RKO and SW480 colon cancer cells. GT-094 inhibited cell proliferation and induced apoptosis in both cell lines and this was accompanied by decreased mitochondrial membrane potential (MMP) and induction of reactive oxygen species (ROS), and these responses were reversed after cotreatment with the antioxidant glutathione. GT-094 also downregulated genes associated with cell growth [cyclin D1, hepatocyte growth factor receptor (c-Met), epidermal growth factor receptor (EGFR)], survival (bcl-2, survivin), and angiogenesis [VEGF and its receptors (VEGFR1 and VEGFR2)] . Results of previous RNA interference studies in this laboratory has shown that these genes are regulated, in part, by specificity protein (Sp) transcription factors Sp1, Sp3, and Sp4 that are overexpressed in colon and other cancer cell lines and not surprisingly, GT-094 also decreased Sp1, Sp3, and Sp4 in colon cancer cells. GT-094–mediated repression of Sp and Sp-regulated gene products was due to downregulation of microRNA-27a (miR-27a) and induction of ZBTB10, an Sp repressor that is regulated by miR-27a in colon cancer cells. Moreover, the effects of GT-094 on Sp1, Sp3, Sp4, miR-27a, and ZBTB10 were also inhibited by glutathione suggesting that the anticancer activity of GT-094 in colon cancer cells is due, in part, to activation of an ROS-miR-27a:ZBTB10-Sp transcription factor pathway. Mol Cancer Res; 9(2); 195–205. ©2010 AACR.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 2
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 16, No. 7 ( 2018-07-01), p. 1125-1137
    Abstract: In aggressive prostate cancers, the oncoprotein STMN1 (also known as stathmin 1 and oncoprotein 18) is often overexpressed. STMN1 is involved in various cellular processes, including cell proliferation, motility, and tumor metastasis. Here, it was found that the expression of STMN1 RNA and protein is elevated in metastatic prostate cancers. Knockdown of STMN1 resulted in reduced proliferation and invasion of cells and tumor growth and metastasis in vivo. Furthermore, miR-34a downregulated STMN1 by directly binding to its 3′-UTR. Overexpression of miR-34a in prostate cancer cells reduced proliferation and colony formation, suggesting that it is a tumor suppressor. The transcriptional corepressor C-terminal binding protein 1 (CtBP1) negatively regulated expression of miR-34a. Furthermore, gene expression profiling of STMN1-modulated prostate cancer cells revealed molecular alterations, including elevated expression of growth differentiation factor 15 (GDF15), which is involved in cancer progression and potentially in STMN1-mediated oncogenesis. Thus, in prostate cancer, CtBP1-regulated miR-34a modulates STMN1 expression and is involved in cancer progression through the CtBP1\miR-34a\STMN1\GDF15 axis. Implications: The CtBP1\miR-34a\STMN1\GDF15 axis is a potential therapeutic target for treatment of aggressive prostate cancer. Mol Cancer Res; 16(7); 1125–37. ©2017 AACR.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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    SSG: 12
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  • 3
    Online Resource
    Online Resource
    Comprehensive Publications ; 2019
    In:  International Journal of Financial Management and Economics Vol. 2, No. 1 ( 2019-01-01), p. 76-79
    In: International Journal of Financial Management and Economics, Comprehensive Publications, Vol. 2, No. 1 ( 2019-01-01), p. 76-79
    Type of Medium: Online Resource
    ISSN: 2617-9210 , 2617-9229
    URL: Issue
    Language: Unknown
    Publisher: Comprehensive Publications
    Publication Date: 2019
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  • 4
    In: JMIR Research Protocols, JMIR Publications Inc., Vol. 9, No. 10 ( 2020-10-30), p. e23241-
    Abstract: India has the largest burden of drug‑resistant organisms compared with other countries around the world, including multiresistant and extremely drug‑resistant tuberculosis and resistant Gram‑negative and Gram‑positive bacteria. Antibiotic resistant bacteria are found in all living hosts and in the environment and move between hosts and ecosystems. An intricate interplay of infections, exposure to antibiotics, and disinfectants at individual and community levels among humans, animals, birds, and fishes triggers evolution and spread of resistance. The One Health framework proposes addressing antibiotic resistance as a complex multidisciplinary problem. However, the evidence base in the Indian context is limited. Objective This multisectoral, trans-species surveillance project aims to document the infection and resistance patterns of 7 resistant-priority bacteria and the risk factors for resistance following the One Health framework and geospatial epidemiology. Methods This hospital- and community-based surveillance adopts a cross-sectional design with mixed methodology (quantitative, qualitative, and spatial) data collection. This study is being conducted at 6 microbiology laboratories and communities in Khurda district, Odisha, India. The laboratory surveillance collects data on bacteria isolates from different hosts and their resistance patterns. The hosts for infection surveillance include humans, animals (livestock, food chain, and pet animals), birds (poultry), and freshwater fishes (not crustaceans). For eligible patients, animals, birds and fishes, detailed data from their households or farms on health care seeking (for animals, birds and fishes, the illness, and care seeking of the caretakers), antibiotic use, disinfection practices, and neighborhood exposure to infection risks will be collected. Antibiotic prescription and use patterns at hospitals and clinics, and therapeutic and nontherapeutic antibiotic and disinfectant use in farms will also be collected. Interviews with key informants from animal breeding, agriculture, and food processing will explore the perceptions, attitudes, and practices related to antibiotic use. The data analysis will follow quantitative (descriptive and analytical), qualitative, and geospatial epidemiology principles. Results The study was funded in May 2019 and approved by Institute Ethics Committees in March 2019. The data collection started in September 2019 and shall continue till March 2021. As of June 2020, data for 56 humans, 30 animals and birds, and fishes from 10 ponds have been collected. Data analysis is yet to be done. Conclusions This study will inform about the bacterial infection and resistance epidemiology among different hosts, the risk factors for infection, and resistance transmission. In addition, it will identify the potential triggers and levers for further exploration and action. International Registered Report Identifier (IRRID) DERR1-10.2196/23241
    Type of Medium: Online Resource
    ISSN: 1929-0748
    Language: English
    Publisher: JMIR Publications Inc.
    Publication Date: 2020
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  • 5
    In: International Journal of Cancer, Wiley, Vol. 132, No. 4 ( 2013-02-15), p. 795-806
    Type of Medium: Online Resource
    ISSN: 0020-7136
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    Language: English
    Publisher: Wiley
    Publication Date: 2013
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  • 6
    In: Oncotarget, Impact Journals, LLC, Vol. 5, No. 16 ( 2014-08-30), p. 6654-6669
    Type of Medium: Online Resource
    ISSN: 1949-2553
    URL: Issue
    Language: English
    Publisher: Impact Journals, LLC
    Publication Date: 2014
    detail.hit.zdb_id: 2560162-3
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  • 7
    In: Oncotarget, Impact Journals, LLC, Vol. 6, No. 27 ( 2015-09-15), p. 23445-23461
    Type of Medium: Online Resource
    ISSN: 1949-2553
    URL: Issue
    Language: English
    Publisher: Impact Journals, LLC
    Publication Date: 2015
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  • 8
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 5206-5206
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 5206-5206
    Abstract: Background: C-terminal Binding Protein 1 (CtBP1), a transcriptional co-repressor that regulates the expression of tumor suppressors and genes involved in cell death, is known to play a critical role in multiple cancers. Earlier, we showed that CtBP1 is overexpressed in metastatic prostate cancer. Furthermore, our studies indicated a role for CtBP1 in conferring radiation resistance to prostate cancer cell lines. We also demonstrated the functional role of CtBP1 in regulating prostate cancer cell growth in vitro and tumor growth and metastasis in vivo. Methods and Results: Our gene expression profiling and bioinformatics analysis found that multiple potential tumor suppressors are reactivated upon CtBP1 knockdown in multiple prostate cancer cell lines. We next validated these targets of CtBP1-mediated repression by qRTPCR and western blotting using CtBP1 stable knockdown prostate cancer cell lines, and in normal prostate epithelial PrEC cells overexpressing CtBP1. Our studies confirmed that CtBP1 targets multiple genes including SP8 transcription factor and kallikrein-related peptidase 10 (KLK10) among others. Knockdown of the reactivated gene led to a reversion of these cells to a more aggressive phenotype. Furthermore, our studies confirmed that the CtBP1 target genes are down-regulated in metastatic prostate cancer. Conclusion: Taken together, our studies demonstrated that dysregulated expression of CtBP1 plays an important role in prostate cancer progression by down-regulating the expression of multiple potential tumor suppressor genes. Thus, targeting CtBP1 in aggressive prostate cancer may have clinical significance. Citation Format: Balabhadrapatruni V. S. K. Chakravarthi, Satya Pathi, Heng Zheng, Javed Siddiqui, Lakshmi P. Kunju, Nallasivam Palanisamy, Sooryanarayana Varambally. Role of CtBP1 as a transcriptional corepressor in prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5206. doi:10.1158/1538-7445.AM2013-5206
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 9
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1959-1959
    Abstract: Myelodysplastic syndrome (MDS) is a heterogeneous group of hematopoietic stem cell disorders. Approximately 70% of patients diagnosed with higher-risk (HR) MDS progress to acute myeloid leukemia (AML). Cyclin-dependent kinase 9 (CDK9) influences transcription through phosphorylation and activation of RNA polymerase II (RPB1), which increases the levels of key oncogenic survival genes like myeloid cell leukemia-1 (MCL-1). MCL-1 dependent malignancies can be identified through a functional assay by adding a NOXA mimetic MCL-1 antagonist peptide to patient samples and measuring the subsequent induction of apoptosis. The assay has been tested in bone marrow mononuclear cells (BMMCs) from AML and MDS patients to examine MCL-1 dependency prior to therapy with alvocidib. Approximately 25% of AML patient BMMCs and 60% of MDS patient BMMCs are MCL-1 dependent (data not shown). We hypothesized that the hypomethylating agents (HMAs) azacitidine and decitabine, which are currently approved for treatment of MDS, can increase MCL-1 dependency through re-expression of pro-apoptotic proteins like NOXA, normally repressed through DNA methylation in malignancies. In the MV-4-11 AML cell line and primary CD34+ MDS BMMCs, alvocidib treatment resulted in a dose dependent reduction in p-RPB1 and MCL-1. In cell viability assays using CellTiter-Glo, treatment with alvocidib and azacitidine resulted in IC50 values of ~100 nM and ~3000 nM, respectively in both cell types. Treatment with HMAs increased NOXA expression and alvocidib suppressed MCL-1 expression, whereas sequential treatment of azacitidine and alvocidib showed both NOXA induction and MCL-1 suppression. Sequential treatment of azacitidine and alvocidib showed synergistic apoptosis induction compared with either treatment alone. Azacitidine treatment sensitized MV-4-11 and MDS BMMCs to MCL-1 inhibition in an MCL-1 dependency assay. In an in vivo efficacy study using the MOLM13 AML xenograft model, the combination of alvocidib and azacitidine or decitabine inhibited tumor growth 71% and 84%, respectively. Alvocidib, azacitidine and decitabine alone showed 51%, 5.7% and 19% tumor growth inhibition (TGI), respectively. Pharmacodynamic analysis in a Phase 1 trial with alvocidib (clinicaltrials.gov, NCT03593915) showed DNA methylation of NOXA gene locus was reduced and NOXA gene expression was upregulated, while MCL-1 gene expression was suppressed in peripheral blood mononuclear cells (PBMCs) after azacitidine and alvocidib treatment. These pre-clinical and clinical data suggest that an alvocidib/HMA combination may constitute a viable therapeutic regimen whose rationale focuses on hypertargeting of NOXA/MCL-1. Taken together, these studies indicate that the combination of alvocidib and HMAs drives AML/MDS cells toward MCL-1 dependent apoptosis. Citation Format: Yuta Matsumura, Ethika Tyagi, Satya Pathi, Dan D. Vo, Tianxiang Zhu, Suman Verma, Clifford J. Whatcott, Stephen P. Anthony, Adam Siddiqui, Jason M. Foulks, David J. Bearss, Steven L. Warner. CDK9 inhibition combined with hypomethylating agents target MCL-1 dependency in MDS and AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1959.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 10
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 4188-4188
    Abstract: Background: MicroRNAs are endogenous non-coding RNAs that can interfere with protein expression either by inducing the cleavage of specific target mRNAs or, in most cases, by inhibiting their translation. MicroRNA profiling studies using normal and cancer tissues suggested that a number of them are either overexpressed or down-regulated in tumors. Previously, we showed that miR-101 binds to a complementary sequence in the 3’UTR of EZH2, an oncogenic histone methyltransferase, and represses its expression. Our studies also demonstrated that ectopic miR-101 overexpression inhibits invasion of the aggressive prostate cell line DU145, and stable overexpression of miR-101 results in a reduction in tumor volume in vivo. Furthermore, we found that the genomic deletion of miR-101 during cancer progression leads to a concomitant increase in EZH2. COX2 is also a known target of miR-101 in colorectal cancers. Methods and Results: In the present study, bioinformatic analysis and functional studies revealed that miR-101 regulates multiple genes in prostate and breast cancer. Targets of miR-101 include oncoprotein STMN1 as well as Positive cofactor 4 (SUB1), a gene that is overexpressed in metastatic breast cancer. Investigation using 3’UTR luciferase reporter assays confirmed the regulation of these genes by miR-101. Furthermore, we validated the overexpression of STMN1 and SUB1 in aggressive prostate cancer by RTPCR and immunoblot analysis. We also demonstrated that ectopic overexpression of miR-101 in cancer cells down-regulated the expression of these genes. Immunohistochemical staining on prostate cancer tissue microarray representing aggressive and metastatic prostate cancer showed that STMN1 is highly expressed in metastatic prostate cancer. Tumor xenograft studies indicated that miR-101 target genes are involved in tumor growth. Together, these data identifies a critical tumor suppressive role for miR-101 and suggest that a loss of miR-101 in cancer leads to overexpression of multiple oncogenes. Conclusion: Overall, our studies indicate that miR-101 that is often down-regulated in multiple cancers due to genomic loss, acts as a master regulator of multiple oncogenes in cancer and reintroduction of miR-101 may have therapeutic benefit. Citation Format: Balabhadrapatruni V. S. K. Chakravarthi, Rohit Mehra, Rui Wang, Irfan A. Asangani, Qi Cao, Satya Pathi, Robert J. Lonigro, Christopher Maher, Daniel F. Camacho, Natalie McGregor, Nallasivam Palanisamy, Kenneth J. Pienta, Arul M. Chinnaiyan, Sooryanarayana Varambally. The role of microRNA-101 as a master tumor suppressor in cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4188. doi:10.1158/1538-7445.AM2013-4188
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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