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Herbert Chen - One of the best experts on this subject based on the ideXlab platform.
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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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akt and pten expression in human Gastrointestinal Carcinoid tumors
American Journal of Translational Research, 2009Co-Authors: Susan C Pitt, Muthusamy Kunnimalaiyaan, Ruth Davis, Herbert ChenAbstract:Activation of Akt (protein kinase B) and loss of phosphatase and tensin homolog (PTEN) expression have been associated with disease recurrence and reduced survival in several cancers. We evaluated the expression patterns and prognostic value of active, phosphorylated Akt (pAkt) and PTEN in Gastrointestinal (GI) Carcinoid tumors. Total Akt, pAkt, and PTEN expression was assessed by Western blot analysis in 14 tumor samples from patients with GI Carcinoid tumors. Expression levels were quantified with volume analysis software and correlated with clinical parameters. Total Akt, pAkt, and PTEN proteins were detectable in all tumor samples. The expression of activated pAkt and pAkt:PTEN ratios were significantly associated with elevated serum chromogranin A measurements (r=0.77 and 0.78, respectively, P≤0.02 for both). In addition, pAkt:PTEN expression ratios positively correlated with older age (r=0.65, P=0.017). Increased pAkt and pAkt:PTEN expression both were associated with reduced survival (r= -0.51, P=0.06 and r= -0.50, P=0.09, respectively). Patients with pAkt:PTEN ratios greater than one also had dramatically reduced overall survival, but this finding did not achieve statistical significance (36 vs. 153 months, P=0.19). These data suggest that pAkt and PTEN expression levels may be useful tools in understanding tumor biology and perhaps predicting survival in patients with Carcinoid tumors. Furthermore, cumulative mutations may lead to upregulation of pAkt and loss of PTEN expression as patients age explaining why older age is associated with a worse prognosis in patients with Carcinoid tumors.
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raf 1 activation in Gastrointestinal Carcinoid cells decreases tumor cell adhesion
American Journal of Surgery, 2007Co-Authors: David Yu Greenblatt, Muthusamy Kunnimalaiyaan, Herbert ChenAbstract:Abstract Background Gastrointestinal Carcinoid tumors are highly metastatic. Activation of the Raf-1 signaling pathway in Carcinoid cells results in morphologic changes. These Raf-1–induced structural changes may affect cellular adhesion, thereby altering metastatic potential. Methods An estrogen-inducible Raf-1 cell line (BON-raf) was used to study the effects of Raf-1 on cellular adhesion. Cell adhesion was measured before and after Raf-1 induction. Western blot analysis was used to confirm Raf-1 activation and measure levels of an essential adhesion regulator, β-catenin. Results Estrogen treatment of BON-raf cells resulted in Raf-1 activation and a marked decrease (68%) in cell adhesion. In the absence of Raf-1 induction, Carcinoid cells expressed high levels of β-catenin. Raf-1 activation led to decreased expression of β-catenin. Conclusions Raf-1 induction in Carcinoid cells results in a significant decrease in adhesion. Furthermore, the important adhesion regulator, β-catenin, is decreased in activated BON-raf cells. These Raf-1-related changes in adhesion may alter the metastatic phenotype of Carcinoid cells.
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conservation of the notch1 signaling pathway in Gastrointestinal Carcinoid cells
American Journal of Physiology-gastrointestinal and Liver Physiology, 2005Co-Authors: Muthusamy Kunnimalaiyaan, Kelly Traeger, Herbert ChenAbstract:Gastrointestinal (GI) Carcinoid cells secrete multiple neuroendocrine (NE) markers and hormones including 5-hydroxytryptamine and chromogranin A. We were interested in determining whether activatio...
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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, Herbert Chen, Virote Sriuranpong, Edward C Hsiao, Kornel E Schuebel, Michael Borges, Brendan J Collins, Barry D Nelkin, 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...
Muthusamy Kunnimalaiyaan - One of the best experts on this subject based on the ideXlab platform.
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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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akt and pten expression in human Gastrointestinal Carcinoid tumors
American Journal of Translational Research, 2009Co-Authors: Susan C Pitt, Muthusamy Kunnimalaiyaan, Ruth Davis, Herbert ChenAbstract:Activation of Akt (protein kinase B) and loss of phosphatase and tensin homolog (PTEN) expression have been associated with disease recurrence and reduced survival in several cancers. We evaluated the expression patterns and prognostic value of active, phosphorylated Akt (pAkt) and PTEN in Gastrointestinal (GI) Carcinoid tumors. Total Akt, pAkt, and PTEN expression was assessed by Western blot analysis in 14 tumor samples from patients with GI Carcinoid tumors. Expression levels were quantified with volume analysis software and correlated with clinical parameters. Total Akt, pAkt, and PTEN proteins were detectable in all tumor samples. The expression of activated pAkt and pAkt:PTEN ratios were significantly associated with elevated serum chromogranin A measurements (r=0.77 and 0.78, respectively, P≤0.02 for both). In addition, pAkt:PTEN expression ratios positively correlated with older age (r=0.65, P=0.017). Increased pAkt and pAkt:PTEN expression both were associated with reduced survival (r= -0.51, P=0.06 and r= -0.50, P=0.09, respectively). Patients with pAkt:PTEN ratios greater than one also had dramatically reduced overall survival, but this finding did not achieve statistical significance (36 vs. 153 months, P=0.19). These data suggest that pAkt and PTEN expression levels may be useful tools in understanding tumor biology and perhaps predicting survival in patients with Carcinoid tumors. Furthermore, cumulative mutations may lead to upregulation of pAkt and loss of PTEN expression as patients age explaining why older age is associated with a worse prognosis in patients with Carcinoid tumors.
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raf 1 activation in Gastrointestinal Carcinoid cells decreases tumor cell adhesion
American Journal of Surgery, 2007Co-Authors: David Yu Greenblatt, Muthusamy Kunnimalaiyaan, Herbert ChenAbstract:Abstract Background Gastrointestinal Carcinoid tumors are highly metastatic. Activation of the Raf-1 signaling pathway in Carcinoid cells results in morphologic changes. These Raf-1–induced structural changes may affect cellular adhesion, thereby altering metastatic potential. Methods An estrogen-inducible Raf-1 cell line (BON-raf) was used to study the effects of Raf-1 on cellular adhesion. Cell adhesion was measured before and after Raf-1 induction. Western blot analysis was used to confirm Raf-1 activation and measure levels of an essential adhesion regulator, β-catenin. Results Estrogen treatment of BON-raf cells resulted in Raf-1 activation and a marked decrease (68%) in cell adhesion. In the absence of Raf-1 induction, Carcinoid cells expressed high levels of β-catenin. Raf-1 activation led to decreased expression of β-catenin. Conclusions Raf-1 induction in Carcinoid cells results in a significant decrease in adhesion. Furthermore, the important adhesion regulator, β-catenin, is decreased in activated BON-raf cells. These Raf-1-related changes in adhesion may alter the metastatic phenotype of Carcinoid cells.
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conservation of the notch1 signaling pathway in Gastrointestinal Carcinoid cells
American Journal of Physiology-gastrointestinal and Liver Physiology, 2005Co-Authors: Muthusamy Kunnimalaiyaan, Kelly Traeger, Herbert ChenAbstract:Gastrointestinal (GI) Carcinoid cells secrete multiple neuroendocrine (NE) markers and hormones including 5-hydroxytryptamine and chromogranin A. We were interested in determining whether activatio...
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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, Herbert Chen, Virote Sriuranpong, Edward C Hsiao, Kornel E Schuebel, Michael Borges, Brendan J Collins, Barry D Nelkin, 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...
Asif Rashid - One of the best experts on this subject based on the ideXlab platform.
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identification of cancer stem cells in human Gastrointestinal Carcinoid and neuroendocrine tumors
Gastroenterology, 2011Co-Authors: Puja Gaur, Asif Rashid, Eric Sceusi, Shaija Samuel, Yunfei Zhou, Jia Lu, Federico Tozzi, Gabriel Lopezberestein, Pablo E Vivasmejia, Jason B FlemingAbstract:Background & Aims Metastatic Gastrointestinal neuroendocrine tumors (NETs) frequently are refractory to chemotherapy. Chemoresistance in various malignancies has been attributed to cancer stem cells (CSCs). We sought to identify Gastrointestinal neuroendocrine CSCs (N-CSCs) in surgical specimens and a NET cell line and to characterize novel N-CSC therapeutic targets. Methods Human Gastrointestinal NETs were evaluated for CSCs using the Aldefluor (Stemcell Technologies, Vancouver, Canada) assay. An in vitro, sphere-forming assay was performed on primary NET cells. CNDT2.5, a human midgut Carcinoid cell line, was used for in vitro (sphere-formation) and in vivo (tumorigenicity assays) CSC studies. N-CSC protein expression was characterized using Western blotting. In vivo, systemic short interfering RNA administration targeted Src. Results By using the Aldefluor assay, aldehyde dehydrogenase–positive (ALDH+) cells comprised 5.8% ± 1.4% (mean ± standard error of the mean) of cells from 19 patient samples. Although many primary cell lines failed to grow, CNDT96 ALDH+ cells formed spheres in anchorage-independent conditions, whereas ALDH- cells did not. CNDT2.5 ALDH+ cells formed spheres, whereas ALDH- cells did not. In vivo, ALDH+ CNDT2.5 cells generated more tumors, with shorter latency than ALDH- or sham-sorted cells. Compared with non-CSCs, ALDH+ cells demonstrated increased expression of activated Src, Erk, Akt, and mammalian target of rapamycin (mTOR). In vivo, anti-Src short interfering RNA treatment of ALDH+ tumors reduced tumor mass by 91%. Conclusions CSCs are present in NETs, as shown by in vitro sphere formation and in vivo tumorigenicity assays. Src was activated in N-CSCs and represents a potential therapeutic target in Gastrointestinal NETs.
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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, Tsung Teh Wu, Charita Wallace, Patrick S Houlihan, 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, Tsung Teh Wu, Charita Wallace, Patrick S Houlihan, 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.
Chisin Changchien - One of the best experts on this subject based on the ideXlab platform.
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upper Gastrointestinal Carcinoid tumors incidentally found by endoscopic examinations
World Journal of Gastroenterology, 2005Co-Authors: Sengkee Chuah, Tsunghui Hu, Kingwah Chiu, Kengliang Wu, Yehpin Chou, Shengnan Lu, Shueshian Chiou, Chisin ChangchienAbstract:AIM: This study shares Asian clinical experiences of Carcinoid tumors that originated in the upper Gastrointestinal tract. METHODS: From May 1987 to June 2002, we had found only 13 cases of histologically confi rmed Carcinoid tumors in the upper Gastrointestinal tract by endoscopic examinations. There were eight males and fi ve females. The mean age was 53.16±20.51 years that ranged from 26 to 82 years. Each of their clinical presentations, locations, tumor morphology, and size and the treatment outcome were analyzed and discussed.
Franco Uggeri - One of the best experts on this subject based on the ideXlab platform.
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Palliative management strategies of advanced Gastrointestinal Carcinoid neoplasms
Langenbeck's Archives of Surgery, 2005Co-Authors: Paola Sartori, Chiara Mussi, Carlo Angelini, Stefano Crippa, R Caprotti, Franco UggeriAbstract:Background/aims Optimal management of Gastrointestinal Carcinoid neoplasms that metastasize to the liver is controversial. Although operative resection seems to be the most effective approach to metastatic disease, hepatic metastases are usually multicentric and often non-resectable. We investigated the effectiveness of several forms of palliative tumor cytoreduction followed by administration of somatostatin analogues in advanced Carcinoid neoplasms. Methods We reviewed our experience with 34 patients with Gastrointestinal Carcinoid neoplasms. Eighteen patients had metastases and 14 had hormonal symptoms. Twenty-two patients underwent radical surgery, ten with multiple liver metastases were treated with a combination of debulking (resection, radiofrequency ablation, chemoembolization), followed by medical treatment with long-acting octreotide and eventually by radiolabelled somatostatin analogues, and two patients with intractable disease received only biotherapies. Results The six patients with metastatic disease who underwent radical curative liver resection had a median survival of 52 months, compared with a median survival of 48 months in the ten patients who underwent palliative debulking. Symptomatic improvement was observed in all the patients after debulking procedures. The two patients who underwent only medical treatment died after 9 and 18 months. Conclusions Aggressive tumor debulking should be performed in patients with liver metastases already at diagnosis even when complete resection is not feasible because the combination of cytoreductive procedures followed by biotherapies may provide good long-term survival and achieves symptom control in most patients with advanced disease.
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palliative management strategies of advanced Gastrointestinal Carcinoid neoplasms
Langenbeck's Archives of Surgery, 2005Co-Authors: Paola Sartori, Chiara Mussi, Carlo Angelini, Stefano Crippa, R Caprotti, Franco UggeriAbstract:Background/aims Optimal management of Gastrointestinal Carcinoid neoplasms that metastasize to the liver is controversial. Although operative resection seems to be the most effective approach to metastatic disease, hepatic metastases are usually multicentric and often non-resectable. We investigated the effectiveness of several forms of palliative tumor cytoreduction followed by administration of somatostatin analogues in advanced Carcinoid neoplasms.
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Gastrointestinal Carcinoids. Prognosis and survival.
Minerva Chirurgica, 2003Co-Authors: R Caprotti, Paola Sartori, Chiara Mussi, Corrado Angelini, Fabrizio Romano, A Scaini, Muselli P, Franco UggeriAbstract:BACKGROUND: Gastrointestinal Carcinoid tumors are rare and little is known about factors related to prognosis in patients with Carcinoid disease. Aim of this study is to determine the impact of clinical presentation variables on the management and survival. METHODS: We have evaluated 31 consecutive patients with Gastrointestinal Carcinoid tu-mours who underwent surgical intervention at the I Department of Surgery of Milano-Bicocca University over 15 years (1985-1999). Tumor distribution, hormone production, prognostic factors and survival were analysed. RESULTS: Carcinoid syndrome was the only clinical pattern diagnostic of Carcinoid tumour. Most common symptoms were abdominal pain (64%), nausea and vomiting (48%). High levels of urinary 5-hydroxyindolacetic acid were significantly associated with Carcinoid syndrome and metastatic disease. Tumor size, depth and gender were significant predictors of metastases. Age, gender, tumor size, metastatic spread and location were statistically significant predictors of death. CONCLUSIONS: Clinical presentation was non specific except for those patients affected by Carcinoid syndrome. Ten years overall survival was 43%, with 52% metastatic spread incidence. The extent of surgical resection should be modulated on patient related risk factors. Poor prognostic factors affecting survival were: age, gender, metastatic disease, depth of invasion and tumour size.
