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Herbert Chen - One of the best experts on this subject based on the ideXlab platform.
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chrysin suppresses achaete scute complex like 1 and alters the neuroendocrine phenotype of Carcinoids
Cancer Gene Therapy, 2015Co-Authors: Yash R Somnay, Renata Jaskulasztul, Herbert Chen, Barbara Zarebczan Dull, Jacob EideAbstract:Carcinoids are neuroendocrine neoplasms that cause significant morbidity and mortality and for which few effective therapies are available. Given the recent identification of the anticancer flavonoid chrysin, we sought to investigate its therapeutic potential in Carcinoids. Here we report chrysin’s ability to modulate the achaete-scute complex-like 1 (ASCL1), a neuroendocrine-specific transcription factor highly implicated in the malignant phenotype of Carcinoids and other neuroendocrine cancers. Moreover, we elucidate the role of ASCL1 in Carcinoid growth and bioactivity. Treatment of two Carcinoid cell lines (BON and H727) with varying chrysin concentrations suppressed cell proliferation, while reducing expression of ASCL1 and the neuroendocrine biomarker chromogranin A (CgA), demonstrated by western blotting. Propidium iodide and phycoerythrin AnnexinV/7-aminoactinomycin D staining and sorting following chrysin treatment revealed S/G2 phase arrest and apoptosis, respectively. This was corroborated by chrysin-induced cleavage of caspase-3 and poly ADP-ribose polymerase and activation of p21Waf1/Cip1. Furthermore, direct ASCL1 knockdown with an ASCL1-specific small interfering RNA inhibited CgA and synaptophysin expression as well as Carcinoid proliferation, while also reducing cyclin B1 and D1 and increasing p21Waf1/Cip1 and p27Kip1 expression, suggesting an arrest of the cell cycle. Collectively, these findings warrant the deliberation of targeted ASCL1 suppression by chrysin or other agents as a therapeutic approach for Carcinoid management.
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identification of a novel raf 1 pathway activator that inhibits gastrointestinal Carcinoid cell growth
Molecular Cancer Therapeutics, 2010Co-Authors: Mackenzie R Cook, Muthusamy Kunnimalaiyaan, Scott N Pinchot, Renata Jaskulasztul, Herbert ChenAbstract:Carcinoids are neuroendocrine tumors (NET) that secrete hormones, including serotonin, resulting in the malignant Carcinoid syndrome. In addition to the significant morbidity associated with the syndrome, Carcinoids are frequently metastatic at diagnosis, and untreated mortality at 5 years exceeds 70%. Surgery is the only curative option, and the need for other therapies is clear. We have previously shown that activation of Raf-1 inhibits Carcinoid cell proliferation. We investigated the ability of leflunomide (LFN), a Food and Drug Administration–approved medication for the treatment of rheumatoid arthritis, and its active metabolite teriflunomide (TFN) as a potential anti-NET treatment. LFN and TFN inhibit the in vitro proliferation of gastrointestinal Carcinoid cells and induce G2-M phase arrest. Daily oral gavage of nude mice with subcutaneous xenografted Carcinoid tumors confirms that LFN can inhibit NET growth in vivo . Treatment with TFN suppresses the cellular levels of serotonin and chromogranin A, a glycopeptide co-secreted with bioactive hormones. Additionally, TFN reduces the level of achaete-scute complex-like 1 (ASCL1), a NET marker correlated with survival. These effects are associated with the activation of the Raf-1/mitiogen-activated protein kinase kinase/extracellular signal–regulated kinase-1/2 pathway, and blockade of mitiogen-activated protein kinase kinase signaling reversed the effects of TFN on markers of the cell cycle and ASCL1 expression. In summary, LFN and TFN inhibit Carcinoid cell proliferation in vitro and in vivo and alter the expression of NET markers. This compound thus represents an attractive target for further clinical investigation. Mol Cancer Ther; 9(2); 429–37
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regulation of neuroendocrine differentiation in gastrointestinal Carcinoid tumor cells by notch signaling
The Journal of Clinical Endocrinology and Metabolism, 2005Co-Authors: Eric K Nakakura, Muthusamy Kunnimalaiyaan, Virote Sriuranpong, Kornel E Schuebel, Michael Borges, Brendan J Collins, Herbert Chen, Barry D. Nelkin, Edward C. Hsiao, Douglas W BallAbstract:Context: Gastrointestinal (GI) Carcinoid tumors elaborate serotonin and other vasoactive substances, causing the Carcinoid syndrome. Based on developmental biology data, we hypothesized that basic helix-loop-helix transcription factors, including achaete-scute complex homolog-like 1 (Ascl1)/hASH1, and the Notch signaling pathway might regulate the neuroendocrine phenotype in GI Carcinoids. Objective: The aim of this study was to evaluate expression of developmental transcription factors and Notch signaling components in GI Carcinoids and model their interaction in a relevant GI Carcinoid cell line. Design: Fourteen GI Carcinoid tumor specimens, five paired adjacent normal tissues, fetal tissues, and tumor cell lines were analyzed by RT-PCR and immunoblot. BON Carcinoid cells were further analyzed after Notch overexpression for neuroendocrine marker expression, serotonin production, and growth. Setting: The study was conducted in an academic referral center. Patients or Other Participants: Deidentified arc...
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zm336372 a raf 1 activator suppresses growth and neuroendocrine hormone levels in Carcinoid tumor cells
Molecular Cancer Therapeutics, 2005Co-Authors: Jamie J Van Gompel, Muthusamy Kunnimalaiyaan, Kyle D Holen, Herbert ChenAbstract:Neuroendocrine tumors, such as Carcinoids, are highly metastatic neoplasms that secrete bioactive hormones resulting in Carcinoid syndrome. Few curative treatments exist outside of surgical resection. We have previously shown that activation of the Raf-1 signaling pathway can suppress hormone production in Carcinoid tumor cells. In this study, we investigated a novel treatment for Carcinoid tumor cell growth based on pharmacologic Raf-1 activation using the compound ZM336372. Treatment of Carcinoid tumor cells with ZM336372 resulted in progressive phosphorylation of Raf-1, mitogen-activated protein kinase 1/2, and extracellular signal–regulated kinase 1/2. Importantly, exposure to ZM336372 resulted in a significant reduction of bioactive hormone levels as well as the transcription factor, human achaete-scute homologue-1 in Carcinoid tumor cells. Furthermore, treatment with ZM336372 led to a marked suppression of cellular proliferation and induction of the cell cycle inhibitors p21 and p18. In summary, ZM336372 targets both proliferation and palliative issues associated with Carcinoid tumor cells, and therefore, warrants further investigation as a possible therapeutic strategy for patients with Carcinoid tumors.
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gastrointestinal Carcinoid tumors factors that predict outcome
World Journal of Surgery, 2004Co-Authors: Jamie J Van Gompel, Rebecca S Sippel, Thomas F. Warner, Herbert ChenAbstract:Gastrointestinal (GI) Carcinoids are neuroendocrine tumors originating in multiple locations throughout the GI tract. The prognosis for patients with GI Carcinoid tumors is diverse. To determine the factors that significantly affect prognosis, we reviewed our experience. Between 1992 and 2000 a total of 70 patients with GI Carcinoid tumors underwent surgical resection at our institution. The patients were grouped into three categories based on the origin of the Carcinoid tumor: foregut, midgut, hindgut. The mean age of the patients was 56 ± 2 years. All patients with foregut Carcinoids had symptoms upon presentation, whereas 61% of those with midgut Carcinoids and only 37% of those with hindgut Carcinoids had symptoms (p < 0.001). The factors that most strongly affected survival on univariate analysis were a symptomatic presentation and the site of origin. Patients with foregut or midgut lesions had lower 5-year disease-free survivals than those with hindgut tumors. Moreover, the size of the primary tumor and the presence of liver metastases were not independent predictors of survival. Despite the larger tumor size and the higher incidence of liver metastases, patients with foregut Carcinoids appear to have the same prognosis as those with midgut Carcinoids. These data therefore suggest that the outcomes of patients with Carcinoid tumors are highly dependent on the presence of symptoms and the site of origin.
Asif Rashid - One of the best experts on this subject based on the ideXlab platform.
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genetic alterations in goblet cell Carcinoids of the vermiform appendix and comparison with gastrointestinal Carcinoid tumors
Modern Pathology, 2003Co-Authors: Mirela Stancu, Charita Wallace, Patrick S Houlihan, Tsung Teh Wu, Stanley R Hamilton, Asif RashidAbstract:Genetic Alterations in Goblet Cell Carcinoids of the Vermiform Appendix and Comparison with Gastrointestinal Carcinoid Tumors
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Genetic Alterations in Goblet Cell Carcinoids of the Vermiform Appendix and Comparison with Gastrointestinal Carcinoid Tumors
Modern Pathology, 2003Co-Authors: Mirela Stancu, Charita Wallace, Patrick S Houlihan, Tsung Teh Wu, Stanley R Hamilton, Asif RashidAbstract:Goblet cell Carcinoid is a relatively rare neuroendocrine tumor of the vermiform appendix with poorly understood molecular pathogenesis. We studied the clinicopathologic features and genetic alterations, including allelic loss of chromosomes 11q, 16q, and 18q; sequencing of the K-ras , β-catenin, and DPC4 ( SMAD4 ) genes; and p53 overexpression and loss of DPC4 by immunohistochemistry; in 16 goblet cell Carcinoids. We compared the allelic loss in goblet cell Carcinoids to those in 18 gastrointestinal Carcinoid tumors. For goblet cell Carcinoids, appendiceal perforation was the most common (70%, 7/10) clinical presentation. The mean tumor size was 2.0 ± 1.5 cm (range, 0.4 to 4.5 cm). The tumor invaded to appendiceal serosa in 50% (8/16) of patients, and two patients had metastasis in lymph nodes or adjoining viscera. With mean follow-up of 24 ± 14 months (median, 23 mo), 1 of 10 patients had died of disease, and 2 others had tumor recurrence. All four patients with metastases, recurrences, and/or death from disease had serosal involvement at presentation ( P = .02). Loss of heterozygosity of chromosome 11q was present in 25% of goblet cell Carcinoids, 14% of ileal Carcinoid tumors, and 9% of nonileal Carcinoid tumors; of chromosome 16q in 38%, 29%, and 0 ( P = .02); and of chromosome 18q in 56%, 86%, and 9% ( P = .002), respectively. No mutations of K-ras , β-catenin, or DPC4 genes; p53 overexpression; or loss of staining for DPC4 was present in any tumors. These findings suggest that allelic loss of chromosomes 11q, 16q, and 18q in goblet cell Carcinoids and ileal Carcinoids may have an important role in the pathogenesis of these tumors.
Emanuele Crocetti - One of the best experts on this subject based on the ideXlab platform.
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gastrointestinal Carcinoid tumours a population based study
Italian Journal of Gastroenterology and Hepatology, 1997Co-Authors: Emanuele CrocettiAbstract:AIM: The aim of this study was to provide further information on the descriptive epidemiology of gastrointestinal Carcinoids. METHODS: Data was drawn from the Tuscany Tumour Registry, a population-based registry active in the province of Florence. All the Carcinoid tumours reported for the period 1985-1991 in gastrointestinal organs were analysed. Incidence, mortality and survival data are presented. RESULTS: There were 53 gastrointestinal Carcinoid tumours in 29 males and 24 females. The site distribution was: 19 small intestine, 8 colon, 7 appendix, 6 stomach, 6 rectum, 1 large bowel (not specified), and 6 from known metastases. The overall age-adjusted incidence rate was 0.42/100,000. At diagnosis, 33 Carcinoids showed evidence of invasion and/or spreading. Seven patients had two independent tumours. As of 31.12.94, nineteen patients had died. The overall observed and relative 5-year survival rates were 66.1% and 75.1%, respectively. CONCLUSIONS: In the province of Florence, the incidence of gastrointestinal Carcinoid tumours is low. Probably, this result, is in part due to the low autopsy rate. The overall survival rate is quite good, with the best prognosis seen for appendiceal Carcinoids and the worst for colon and stomach Carcinoids. 1.9% of the patients had a further tumour diagnosis.
Mirela Stancu - One of the best experts on this subject based on the ideXlab platform.
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genetic alterations in goblet cell Carcinoids of the vermiform appendix and comparison with gastrointestinal Carcinoid tumors
Modern Pathology, 2003Co-Authors: Mirela Stancu, Charita Wallace, Patrick S Houlihan, Tsung Teh Wu, Stanley R Hamilton, Asif RashidAbstract:Genetic Alterations in Goblet Cell Carcinoids of the Vermiform Appendix and Comparison with Gastrointestinal Carcinoid Tumors
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Genetic Alterations in Goblet Cell Carcinoids of the Vermiform Appendix and Comparison with Gastrointestinal Carcinoid Tumors
Modern Pathology, 2003Co-Authors: Mirela Stancu, Charita Wallace, Patrick S Houlihan, Tsung Teh Wu, Stanley R Hamilton, Asif RashidAbstract:Goblet cell Carcinoid is a relatively rare neuroendocrine tumor of the vermiform appendix with poorly understood molecular pathogenesis. We studied the clinicopathologic features and genetic alterations, including allelic loss of chromosomes 11q, 16q, and 18q; sequencing of the K-ras , β-catenin, and DPC4 ( SMAD4 ) genes; and p53 overexpression and loss of DPC4 by immunohistochemistry; in 16 goblet cell Carcinoids. We compared the allelic loss in goblet cell Carcinoids to those in 18 gastrointestinal Carcinoid tumors. For goblet cell Carcinoids, appendiceal perforation was the most common (70%, 7/10) clinical presentation. The mean tumor size was 2.0 ± 1.5 cm (range, 0.4 to 4.5 cm). The tumor invaded to appendiceal serosa in 50% (8/16) of patients, and two patients had metastasis in lymph nodes or adjoining viscera. With mean follow-up of 24 ± 14 months (median, 23 mo), 1 of 10 patients had died of disease, and 2 others had tumor recurrence. All four patients with metastases, recurrences, and/or death from disease had serosal involvement at presentation ( P = .02). Loss of heterozygosity of chromosome 11q was present in 25% of goblet cell Carcinoids, 14% of ileal Carcinoid tumors, and 9% of nonileal Carcinoid tumors; of chromosome 16q in 38%, 29%, and 0 ( P = .02); and of chromosome 18q in 56%, 86%, and 9% ( P = .002), respectively. No mutations of K-ras , β-catenin, or DPC4 genes; p53 overexpression; or loss of staining for DPC4 was present in any tumors. These findings suggest that allelic loss of chromosomes 11q, 16q, and 18q in goblet cell Carcinoids and ileal Carcinoids may have an important role in the pathogenesis of these tumors.
Chengquan Zhao - One of the best experts on this subject based on the ideXlab platform.
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cdx2 may be a useful marker to distinguish primary ovarian Carcinoid from gastrointestinal metastatic Carcinoids to the ovary
Human Pathology, 2013Co-Authors: Mohamed Mokhtar Desouki, Joshua Lioyd, Haodong Xu, Ross Barner, Chengquan ZhaoAbstract:Primary ovarian Carcinoids and metastatic tumors share similar morphologic features. Metastatic Carcinoids must be excluded from primary ones for prognostic and therapeutic reasons. Gastrointestinal neuroendocrine (Carcinoid) tumors are much more common with the majority arising from small intestine and appendix. The aim of this study is to evaluate the role of immunohistochemistry for CDX2 in differentiating primary ovarian from metastatic Carcinoids of primary gastrointestinal origin. Thirty primary pure ovarian Carcinoids, 16 primary ovarian Carcinoids arising in association with benign teratomas, 10 ovarian Carcinoids metastatic from primary gastrointestinal tract and 70 gastrointestinal neuroendocrine tumors were studied for the expression of CDX2 by immunohistochemistry. CDX2 expression revealed that 40 (57.1%) of 70 cases of gastrointestinal Carcinoids and 9 (90%) of 10 ovarian metastatic Carcinoids showed positive nuclear staining (diffuse or focal). On the other hand, 3 (18.8%) of 16 primary Carcinoids with teratomatous elements showed weak positivity. Among the 70 gastrointestinal Carcinoids, CDX2 was positive in 38 (90.5%) of 42 cases in the duodenum, small intestine, appendix, and only in 2 (11.8%) of 17 cases of colorectal Carcinoids and none of the 11 cases in the stomach. It is concluded that CDX2 may be a useful marker to distinguish primary ovarian Carcinoid from metastasis from small intestinal and appendiceal neuroendocrine tumors.
