The Experts below are selected from a list of 123285 Experts worldwide ranked by ideXlab platform
Setsuo Hirohashi - One of the best experts on this subject based on the ideXlab platform.
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expression profiling in ovarian clear cell carcinoma identification of hepatocyte nuclear factor 1β as a Molecular marker and a possible Molecular Target for therapy of ovarian clear cell carcinoma
American Journal of Pathology, 2003Co-Authors: Akira Tsuchiya, Michiie Sakamoto, Jun Yasuda, Makoto Chuma, Tsutomu Ohta, Misao Ohki, Toshiharu Yasugi, Yuji Taketani, Setsuo HirohashiAbstract:Of all of the epithelial ovarian cancers, clear cell carcinoma (CCC) of the ovary has the worst prognosis. We applied the oligonucleotide array technique to identify genes generally involved in CCC. Of the ∼12,600 genes that were analyzed, 28 were expressed significantly differently between four CCC and seven non-CCC cell lines. Among 16 up-regulated genes in CCC, we further investigated a transcription factor, hepatocyte nuclear factor-1β (HNF-1β). We validated up-regulation of HNF-1β in CCC in terms of both mRNA and protein level using real-time quantitative reverse transcriptase-polymerase chain reaction and immunoblotting. Immunohistochemical analysis of 83 surgically resected ovarian cancers showed that almost all CCC specimens (21 of 22 cases) had nuclear staining for HNF-1β, whereas most non-CCC specimens (60 of 61 cases) showed no immunostaining or only focal and faint staining in the nucleus. Furthermore, we investigated the significance of HNF-1β expression in CCC using RNA interference. The reduction of HNF-1β expression by RNA interference induced apoptotic cell death in ovarian CCC cells, which was confirmed by terminal dUTP nick-end labeling and fluorescence-activated cell-sorting analyses. Our results suggest that HNF-1β is not only an excellent CCC-specific Molecular marker but also a Molecular Target for therapy of ovarian CCC.
Silvio J Gutkind - One of the best experts on this subject based on the ideXlab platform.
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mtor as a Molecular Target in hpv associated oral and cervical squamous carcinomas
Clinical Cancer Research, 2012Co-Authors: Alfredo A Molinolo, Christina A Marsh, Mohamed El Dinali, Nitin Gangane, Kaitlin Jennison, Stephen M Hewitt, Vyomesh Patel, Tanguy Y Seiwert, Silvio J GutkindAbstract:Purpose: The incidence of head and neck squamous cell carcinomas (HNSCC) associated with human papillomavirus (HPV) infection has increased over the past decades in the United States. We aimed at examining the global impact of HPV-associated HNSCC and whether the established key role of mTOR activation in HNSCC is also observed in HPV + HNSCC lesions, thereby providing novel treatment options for HPV-associated HNSCC patients. Experimental Design: An international HNSCC tissue microarray (TMA) was used to analyze the expression of p16 INK4A , a surrogate for HPV infection, and Akt-mTOR pathway activation. Results were confirmed in a large collection of HPV − and HPV + HNSCC cases and in a cervical cancer (CCSCC) TMA. Observations were validated in HNSCC and CCSCC-derived cell lines, which were xenografted into immunodeficient mice for tumorigenesis assays. Results: Approximately 20% of all HNSCC lesions could be classified as HPV + , irrespective of their country of origin. mTOR pathway activation was observed in most HPV + HNSCC and CCSCC lesions and cell lines. The preclinical efficacy of mTOR inhibition by rapamycin and RAD001 was explored in HPV + HNSCC and CCSCC tumor xenografts. Both mTOR inhibitors effectively decreased mTOR activity in vivo and caused a remarkable decrease in tumor burden. These results emphasize the emerging global impact of HPV-related HNSCCs and indicate that the activation of the mTOR pathway is a widespread event in both HPV − and HPV-associated HNSCC and CCSCC lesions. Conclusions: The emerging results may provide a rationale for the clinical evaluation of mTOR inhibitors as a Molecular Targeted approach for the treatment of HPV-associated malignancies. Clin Cancer Res; 18(9); 2558–68. ©2012 AACR.
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mammalian Target of rapamycin a Molecular Target in squamous cell carcinomas of the head and neck
Cancer Research, 2005Co-Authors: Panomwat Amornphimoltham, Alfredo A Molinolo, Vyomesh Patel, Akrit Sodhi, Nikolaos G Nikitakis, John J Sauk, Edward A Sausville, Silvio J GutkindAbstract:Emerging knowledge on how the dysregulated function of signaling networks contributes to the malignant growth of squamous cell carcinoma of the head and neck (HNSCC) can now be exploited to identify novel mechanism-based anticancer treatments. In this regard, we have observed that persistent activation of the serine/threonine kinase Akt is a frequent event in HNSCC, and that blockade of its upstream kinase, 3′-phosphoinositide-dependent kinase 1, potently inhibits tumor cell growth. Akt promotes cell proliferation by its ability to coordinate mitogenic signaling with energy- and nutrient-sensing pathways that control protein synthesis through the atypical serine/threonine kinase, mammalian Target of rapamycin (mTOR). This kinase, in turn, phosphorylates key eukaryotic translation regulators, including p70-S6 kinase and the eukaryotic translation initiation factor, 4E binding protein 1. Indeed, we show here that aberrant accumulation of the phosphorylated active form of S6, the most downstream Target of the Akt-mTOR-p70-S6 kinase pathway, is a frequent event in clinical specimens from patients with HNSCC and their derived cell lines. Of interest, this enhanced level of the phosphorylated active form of S6 was rapidly reduced in HNSCC cell lines and HNSCC xenograft models at clinically relevant doses of rapamycin, which specifically inhibits mTOR. Furthermore, we observed that rapamycin displays a potent antitumor effect in vivo , as it inhibits DNA synthesis and induces the apoptotic death of HNSCC cells, ultimately resulting in tumor regression. These findings identify the Akt-mTOR pathway as a potential therapeutic Target for HNSCC, and may provide the rationale for the early clinical evaluation of rapamycin and its analogues in patients with HNSCC.
Oliver Werz - One of the best experts on this subject based on the ideXlab platform.
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Identification and functional analysis of cyclooxygenase-1 as a Molecular Target of boswellic acids
Biochemical Pharmacology, 2008Co-Authors: Ulf Siemoneit, Bettina Hofmann, Nicole Kather, Tobias Lamkemeyer, Johannes Madlung, Johann Jauch, Lutz Franke, Daniel Poeckel, Gisbert Schneider, Oliver WerzAbstract:Boswellic acids (BAs) are assumed as the anti-inflammatory principles of Boswellia species. Initially, it was found that BAs inhibit leukotriene biosynthesis and 5-lipoxygenase (EC number 1.13.11.34), whereas suppression of prostaglandin formation and inhibition of cyclooxygenases (COX, EC number 1.14.99.1) has been excluded. Recently, we demonstrated that BAs also interfere with platelet-type 12-lipoxygenase. Here, we show that BAs, preferably 3-O-acetyl-11-keto-β-BA (AKBA), concentration-dependently inhibit COX-1 product formation in intact human platelets (IC50= 6 μM) as well as the activity of isolated COX-1 enzyme in cell-free assays (IC50= 32 μM). The inhibitory effect of AKBA is reversible, and increased levels of arachidonic acid (AA) as substrate for COX-1 impair the efficacy. COX-1 in platelet lysates or isolated COX-1 selectively bound to an affinity matrix composed of immobilized BAs linked via glutaric acid to sepharose and this binding was reversed by ibuprofen or AA. Automated Molecular docking of BAs into X-ray structures of COX-1 yielded positive Chemscore values for BAs, indicating favorable binding to the active site of the enzyme. In contrast, COX-2 was less efficiently inhibited by BAs as compared to COX-1, and pull-down experiments as well as docking studies exclude strong affinities of BAs towards COX-2. In conclusion, BAs, in particular AKBA, directly interfere with COX-1 and may mediate their anti-inflammatory actions not only by suppression of lipoxygenases, but also by inhibiting cyclooxygenases, preferentially COX-1. © 2007 Elsevier Inc. All rights reserved.
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Rev boswellic acids Molecular Target
Curr Med Chem, 2006Co-Authors: Daniel Poeckel, Oliver WerzAbstract:Gum resin extracts of Boswellia species have been traditionally applied in folk medicine for centuries to treat various chronic inflammatory diseases, and experimental data from animal models and studies with human subjects confirmed the potential of B. spec extracts for the treatment of not only inflammation but also of cancer. Analysis of the ingredients of these extracts revealed that the pentacyclic triterpenes boswellic acids (BAs) possess biological activities and appear to be responsible for the respective pharmacological actions. Approaches in order to elucidate the Molecular mechanisms underlying the biological effects of BAs identified 5-lipoxygenase, human leukocyte elastase, toposiomerase I and II, as well as IkappaB kinases as Molecular Targets of BAs. Moreover, it was shown that depending on the cell type and the structure of the BAs, the compounds differentially interfere with signal transduction pathways including Ca(2+/-) and MAPK signaling in various blood cells, related to functional cellular processes important for inflammatory reactions and tumor growth. This review summarizes the biological actions of BAs on the cellular and Molecular level and attempts to put the data into perspective of the beneficial effects manifested in animal studies and trials with human subjects related to inflammation and cancer.
Flavio Kapczinski - One of the best experts on this subject based on the ideXlab platform.
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tnf α as a Molecular Target in bipolar disorder
Progress in Neuro-psychopharmacology & Biological Psychiatry, 2008Co-Authors: Elisa Brietzke, Flavio KapczinskiAbstract:Abstract The pathophysiology of bipolar disorder (BD) is poorly understood. An emerging body of evidence points to impairments in neuroplasticity, cell resilience and neuronal survival as the main neuropathological correlates of BD. It has been suggested that inflammatory cytokines, particularly TNF-α may play a critical role in this process. In the present review we examine the evidence suggesting that TNF-α regulates apoptotic cascades which may be related to neuronal and glial loss in BD. Current evidence suggests that an increase in serum levels of TNF-α takes place during manic and depressive episodes. The present article reviews the therapeutic implications of TNF-α signaling pathways involvement in the pathophysiology of BD.
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TNF-alpha as a Molecular Target in bipolar disorder.
Progress in neuro-psychopharmacology & biological psychiatry, 2008Co-Authors: Elisa Brietzke, Flavio KapczinskiAbstract:The pathophysiology of bipolar disorder (BD) is poorly understood. An emerging body of evidence points to impairments in neuroplasticity, cell resilience and neuronal survival as the main neuropathological correlates of BD. It has been suggested that inflammatory cytokines, particularly TNF-alpha may play a critical role in this process. In the present review we examine the evidence suggesting that TNF-alpha regulates apoptotic cascades which may be related to neuronal and glial loss in BD. Current evidence suggests that an increase in serum levels of TNF-alpha takes place during manic and depressive episodes. The present article reviews the therapeutic implications of TNF-alpha signaling pathways involvement in the pathophysiology of BD.
Akira Tsuchiya - One of the best experts on this subject based on the ideXlab platform.
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expression profiling in ovarian clear cell carcinoma identification of hepatocyte nuclear factor 1β as a Molecular marker and a possible Molecular Target for therapy of ovarian clear cell carcinoma
American Journal of Pathology, 2003Co-Authors: Akira Tsuchiya, Michiie Sakamoto, Jun Yasuda, Makoto Chuma, Tsutomu Ohta, Misao Ohki, Toshiharu Yasugi, Yuji Taketani, Setsuo HirohashiAbstract:Of all of the epithelial ovarian cancers, clear cell carcinoma (CCC) of the ovary has the worst prognosis. We applied the oligonucleotide array technique to identify genes generally involved in CCC. Of the ∼12,600 genes that were analyzed, 28 were expressed significantly differently between four CCC and seven non-CCC cell lines. Among 16 up-regulated genes in CCC, we further investigated a transcription factor, hepatocyte nuclear factor-1β (HNF-1β). We validated up-regulation of HNF-1β in CCC in terms of both mRNA and protein level using real-time quantitative reverse transcriptase-polymerase chain reaction and immunoblotting. Immunohistochemical analysis of 83 surgically resected ovarian cancers showed that almost all CCC specimens (21 of 22 cases) had nuclear staining for HNF-1β, whereas most non-CCC specimens (60 of 61 cases) showed no immunostaining or only focal and faint staining in the nucleus. Furthermore, we investigated the significance of HNF-1β expression in CCC using RNA interference. The reduction of HNF-1β expression by RNA interference induced apoptotic cell death in ovarian CCC cells, which was confirmed by terminal dUTP nick-end labeling and fluorescence-activated cell-sorting analyses. Our results suggest that HNF-1β is not only an excellent CCC-specific Molecular marker but also a Molecular Target for therapy of ovarian CCC.
