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Ronny Drapkin - One of the best experts on this subject based on the ideXlab platform.
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cyclin e1 deregulation occurs early in secretory cell transformation to promote formation of Fallopian Tube derived high grade serous ovarian cancers
Cancer Research, 2014Co-Authors: Alison M Karst, Paul M Jones, Natalie Vena, Azra H Ligon, Joyce F Liu, Michelle S Hirsch, Dariush Etemadmoghadam, David D L Bowtell, Ronny DrapkinAbstract:Fallopian Tube is now generally considered the dominant site of origin for high-grade serous ovarian carcinoma. However, the molecular pathogenesis of Fallopian Tube-derived serous carcinomas are poorly understood and there are few experimental studies examining the transformation of human Fallopian Tube cells. Prompted by recent genomic analyses that identified Cyclin E1 (CCNE1) gene amplification as a candidate oncogenic driver in serous ovarian carcinoma, we evaluated the functional role of CCNE1 in serous carcinogenesis. CCNE1 was expressed in early and late stage human tumor samples. In primary human Fallopian Tube secretory epithelial cells, CCNE1 expression imparted malignant characteristics to untransformed cells if p53 was compromised, promoting an accumulation of DNA damage and altered transcription of DNA damage response genes related to DNA replication stress. Together our findings corroborate the hypothesis that Cyclin E1 dysregulation acts to drive malignant transformation in Fallopian Tube secretory cells that are the site of origin of serous ovarian carcinomas.
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abstract pr02 cyclin e1 deregulation occurs early during Fallopian Tube tumorigenesis and promotes secretory cell transformation
Clinical Cancer Research, 2013Co-Authors: Alison M Karst, Paul M Jones, Natalie Vena, Azra H Ligon, Joyce F Liu, Michelle S Hirsch, Dariush Etemadmoghadam, David D L Bowtell, Ronny DrapkinAbstract:The Fallopian Tube has been implicated as the dominant site of origin for high-grade serous ovarian carcinoma. However, the molecular pathogenesis of Fallopian Tube-derived serous cancer is poorly understood and there are few experimental studies examining the transformation of human Fallopian Tube cells. Recent genomic analyses have identified CCNE1 (Cyclin E1) gene amplification as a potential oncogenic driver of high-grade serous ovarian carcinoma development. Here, we examine the oncogenic role of Cyclin E1 in serous carcinogenesis, first by characterizing its expression in both late-stage and early-stage human tumor samples, and secondly, by generating an experimental model of Cyclin E1-mediated transformation using primary human Fallopian Tube secretory epithelial cells. Using fluorescent in situ hybridization and immunohistochemical analyses, we show that Cyclin E1 is strongly expressed in a subset of late-stage high-grade serous carcinomas harboring CCNE1 amplification and that aberrant Cyclin E1 expression can occur very early during serous tumorigenesis, evident in non-invasive tubal carcinoma and putative precursor lesions. To examine the effects of constitutive Cyclin E1 expression in untransformed cells, we immortalized human Fallopian Tube secretory epithelial cells with TERT (telomerase reverse transcriptase) and mutant TP53 R175H (representing early genetic alterations in serous tumorigenesis), followed by overexpression of CCNE1 or a vector control. Using a series of in vitro assays, we show that inappropriate Cyclin E1 expression imparts malignant characteristics to immortal Fallopian Tube secretory epithelial cells, including accelerated proliferation, loss of contact inhibition, and clonal growth ability. In addition, we use a combination of DNA damage assays and PCR array profiling to demonstrate that Cyclin E1 induces DNA double-strand and single-strand breaks, accompanied by up-regulation of DNA damage response genes involved in managing DNA replication stress. In sum, our results suggest that constitutive Cyclin E1 expression drives over-proliferation of untransformed but p53-compromised Fallopian Tube secretory epithelial cells, accompanied by an accumulation of DNA damage and altered expression of DNA damage response genes. Our data supports the hypothesis that Cyclin E1 promotes Fallopian Tube transformation by inducing replication stress-associated DNA damage, thus leading to chromosomal instability, and that CCNE1 amplification is a major driver of Cyclin E1 overexpression in high-grade serous carcinoma. This abstract is also presented as Poster A1. Citation Format: Alison M. Karst, Paul M. Jones, Natalie Vena, Azra H. Ligon, Joyce F. Liu, Michelle S. Hirsch, Dariush Etemadmoghadam, David D. Bowtell, Ronny Drapkin. Cyclin E1 deregulation occurs early during Fallopian Tube tumorigenesis and promotes secretory cell transformation. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr PR02.
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Primary culture and immortalization of human Fallopian Tube secretory epithelial cells
Nature Protocols, 2012Co-Authors: Alison M Karst, Ronny DrapkinAbstract:Primary human Fallopian Tube secretory epithelial cell (FTSEC) cultures are useful for studying normal Fallopian Tube epithelial biology, as well as for developing models of Fallopian Tube disease, such as cancer. Because of the limited ability of primary human FTSECs to proliferate in vitro , it is necessary to immortalize them in order to establish a cell line that is suitable for long-term culture and large-scale in vitro experimentation. This protocol describes the isolation of FTSECs from human Fallopian Tube tissue, conditions for primary FTSEC culture and techniques for establishing immortal FTSEC lines. The entire process, from primary cell isolation to establishment of an immortal cell line, may take up to 2 months. Once established, immortal FTSECs can typically be maintained for at least 30 passages.
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does the fimbria have an embryologic origin distinct from that of the rest of the Fallopian Tube
Fertility and Sterility, 2008Co-Authors: Leslie A Garrett, Ronny Drapkin, Sara O Vargas, Marc R. LauferAbstract:OBJECTIVE: To propose a new theory describing the development of the Fallopian Tube fimbria. DESIGN: Case series report. SETTING: Metropolitan tertiary care children's hospital. PATIENT(S): Two girls, aged 12 and 20 years, who presented with pelvic pain. INTERVENTION(S): Magnetic resonance imaging, laparoscopy with salpingectomy, and pathologic analysis. MAIN OUTCOME MEASURE(S): Description of a novel theory regarding the embryologic development of the Fallopian Tube and its fimbria. RESULT(S): In two non-sexually active girls the cause of their pelvic pain was found to be a hydrosalpinx associated with a discontinuous Fallopian Tube in which the fimbriated end did not directly communicate with the remainder of the Fallopian Tube. CONCLUSION(S): The two cases of pure congenital Fallopian Tube atresia, the presence of fimbriae in patients with mullerian (uterine, cervical, and vaginal) agenesis, and the role of the fimbria in ovarian-like and peritoneal cancers, support a novel hypothesis that the fimbria of the Fallopian Tube may arise separately from the rest of the Tube.
Alison M Karst - One of the best experts on this subject based on the ideXlab platform.
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yap induces high grade serous carcinoma in Fallopian Tube secretory epithelial cells
Oncogene, 2016Co-Authors: Guohua Hua, Steven W Remmenga, Kerry J Rodabough, Jixin Dong, Liguo Yang, Subodh M Lele, Peixin Yang, Jin Zhou, Alison M KarstAbstract:Accumulating evidence indicates that ovarian high-grade serous carcinoma (HGSC) originates from Fallopian Tube secretory epithelial cells (FTSECs). However, the molecular mechanisms underlying the initiation and progression of HGSC derived from FTSECs remains unclear. In this study, we found that the Hippo/Yes-associated protein (YAP) signaling pathway has a critical role in the initiation and progression of Fallopian Tube and ovarian HGSC. Importantly, YAP was overexpressed in inflammatory and cancerous Fallopian Tube tissues. Further, overexpression of wild-type YAP, or constitutively active YAP in immortalized FTSECs, induced cell proliferation, migration, colony formation and tumorigenesis. Moreover, the Hippo/YAP and the fibroblast growth factor (FGF) signaling pathways formed an autocrine/paracrine-positive feedback loop to drive the progression of the FTSEC-derived HGSC. Evidence in this study strongly suggests that combined therapy with inhibitors of YAP (such as verteporfin) and FGF receptors (such as BGJ398) can provide a novel therapeutic strategy to treat Fallopian Tube and ovarian HGSC.
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cyclin e1 deregulation occurs early in secretory cell transformation to promote formation of Fallopian Tube derived high grade serous ovarian cancers
Cancer Research, 2014Co-Authors: Alison M Karst, Paul M Jones, Natalie Vena, Azra H Ligon, Joyce F Liu, Michelle S Hirsch, Dariush Etemadmoghadam, David D L Bowtell, Ronny DrapkinAbstract:Fallopian Tube is now generally considered the dominant site of origin for high-grade serous ovarian carcinoma. However, the molecular pathogenesis of Fallopian Tube-derived serous carcinomas are poorly understood and there are few experimental studies examining the transformation of human Fallopian Tube cells. Prompted by recent genomic analyses that identified Cyclin E1 (CCNE1) gene amplification as a candidate oncogenic driver in serous ovarian carcinoma, we evaluated the functional role of CCNE1 in serous carcinogenesis. CCNE1 was expressed in early and late stage human tumor samples. In primary human Fallopian Tube secretory epithelial cells, CCNE1 expression imparted malignant characteristics to untransformed cells if p53 was compromised, promoting an accumulation of DNA damage and altered transcription of DNA damage response genes related to DNA replication stress. Together our findings corroborate the hypothesis that Cyclin E1 dysregulation acts to drive malignant transformation in Fallopian Tube secretory cells that are the site of origin of serous ovarian carcinomas.
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abstract pr02 cyclin e1 deregulation occurs early during Fallopian Tube tumorigenesis and promotes secretory cell transformation
Clinical Cancer Research, 2013Co-Authors: Alison M Karst, Paul M Jones, Natalie Vena, Azra H Ligon, Joyce F Liu, Michelle S Hirsch, Dariush Etemadmoghadam, David D L Bowtell, Ronny DrapkinAbstract:The Fallopian Tube has been implicated as the dominant site of origin for high-grade serous ovarian carcinoma. However, the molecular pathogenesis of Fallopian Tube-derived serous cancer is poorly understood and there are few experimental studies examining the transformation of human Fallopian Tube cells. Recent genomic analyses have identified CCNE1 (Cyclin E1) gene amplification as a potential oncogenic driver of high-grade serous ovarian carcinoma development. Here, we examine the oncogenic role of Cyclin E1 in serous carcinogenesis, first by characterizing its expression in both late-stage and early-stage human tumor samples, and secondly, by generating an experimental model of Cyclin E1-mediated transformation using primary human Fallopian Tube secretory epithelial cells. Using fluorescent in situ hybridization and immunohistochemical analyses, we show that Cyclin E1 is strongly expressed in a subset of late-stage high-grade serous carcinomas harboring CCNE1 amplification and that aberrant Cyclin E1 expression can occur very early during serous tumorigenesis, evident in non-invasive tubal carcinoma and putative precursor lesions. To examine the effects of constitutive Cyclin E1 expression in untransformed cells, we immortalized human Fallopian Tube secretory epithelial cells with TERT (telomerase reverse transcriptase) and mutant TP53 R175H (representing early genetic alterations in serous tumorigenesis), followed by overexpression of CCNE1 or a vector control. Using a series of in vitro assays, we show that inappropriate Cyclin E1 expression imparts malignant characteristics to immortal Fallopian Tube secretory epithelial cells, including accelerated proliferation, loss of contact inhibition, and clonal growth ability. In addition, we use a combination of DNA damage assays and PCR array profiling to demonstrate that Cyclin E1 induces DNA double-strand and single-strand breaks, accompanied by up-regulation of DNA damage response genes involved in managing DNA replication stress. In sum, our results suggest that constitutive Cyclin E1 expression drives over-proliferation of untransformed but p53-compromised Fallopian Tube secretory epithelial cells, accompanied by an accumulation of DNA damage and altered expression of DNA damage response genes. Our data supports the hypothesis that Cyclin E1 promotes Fallopian Tube transformation by inducing replication stress-associated DNA damage, thus leading to chromosomal instability, and that CCNE1 amplification is a major driver of Cyclin E1 overexpression in high-grade serous carcinoma. This abstract is also presented as Poster A1. Citation Format: Alison M. Karst, Paul M. Jones, Natalie Vena, Azra H. Ligon, Joyce F. Liu, Michelle S. Hirsch, Dariush Etemadmoghadam, David D. Bowtell, Ronny Drapkin. Cyclin E1 deregulation occurs early during Fallopian Tube tumorigenesis and promotes secretory cell transformation. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr PR02.
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Primary culture and immortalization of human Fallopian Tube secretory epithelial cells
Nature Protocols, 2012Co-Authors: Alison M Karst, Ronny DrapkinAbstract:Primary human Fallopian Tube secretory epithelial cell (FTSEC) cultures are useful for studying normal Fallopian Tube epithelial biology, as well as for developing models of Fallopian Tube disease, such as cancer. Because of the limited ability of primary human FTSECs to proliferate in vitro , it is necessary to immortalize them in order to establish a cell line that is suitable for long-term culture and large-scale in vitro experimentation. This protocol describes the isolation of FTSECs from human Fallopian Tube tissue, conditions for primary FTSEC culture and techniques for establishing immortal FTSEC lines. The entire process, from primary cell isolation to establishment of an immortal cell line, may take up to 2 months. Once established, immortal FTSECs can typically be maintained for at least 30 passages.
S J Sondheimer - One of the best experts on this subject based on the ideXlab platform.
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transcervical Fallopian Tube recanalization a safe and effective therapy for patients with proximal tubal obstruction
International Journal of Fertility, 1992Co-Authors: Keith B Isaacson, M Amendola, M Banner, M Glassner, S J SondheimerAbstract:Over a 13-month period, 14 patients with proximal tubal obstruction underwent transcervical Fallopian Tube recanalization under fluoroscopic guidance in an outpatient setting at the hospital of the University of Pennsylvania. Twenty-one of 24 attempted tubal dilations (87.5%) were successful, as demonstrated by tubal opacification and contrast spillage into the peritoneal cavity at the conclusion of the procedure. Four intrauterine pregnancies, and no ectopic pregnancies, have followed the recanalization. One pregnancy ended in an early miscarriage, one patient delivered a healthy term female, and two pregnancies are ongoing at greater than twenty weeks' gestation. Two procedure-related complications occurred: in one patient, the isthmic segment of a Fallopian Tube was perforated, but healed without incident, and another patient experienced a low-grade fever, which resolved with p.o. antibiotics. We therefore conclude that Fallopian Tube recanalization is a well-tolerated, safe, and effective procedure for the treatment of proximal tubal occlusion.
N Gadoth - One of the best experts on this subject based on the ideXlab platform.
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paraneoplastic cerebellar degeneration heralding Fallopian Tube adenocarcinoma
International Journal of Gynecological Cancer, 2001Co-Authors: R Levite, A Fishman, A Kesler, M Altaras, N GadothAbstract:The objective of this paper is to describe an 81-year-old woman with subacute cerebellar degeneration due to Fallopian Tube adenocarcinoma. Serum anti-Yo antibodies were used to screen for pelvic malignancy. Their presence led to a meticulous search, which included bilateral salpingoophorectomy. Subsequently an occult Fallopian Tube adenocarcinoma was discovered. This case report highlights the diagnostic value of antineuroneal antibodies in females with subacute neurologic impairment in the form of paraneoplastic syndrome.
Daisuke Aoki - One of the best experts on this subject based on the ideXlab platform.
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Paraneoplastic cerebellar degeneration with Fallopian Tube adenocarcinoma
Gynecologic oncology, 2005Co-Authors: Yudai Tanaka, Nao Suzuki, Masaki Takao, Akiko Ichikawa, Nobuyuki Susumu, Daisuke AokiAbstract:Background. Paraneoplastic cerebellar degeneration (PCD) is rarely caused by Fallopian Tube adenocarcinoma. Case. We present a patient with PCD and Fallopian Tube cancer. Anti-Yo antibody, one of an anti-neuronal antibody, was positive in serum and cerebrospinal fluid. She was also positive for HLA A24, which is common in patients with PCD. Radical surgery did not significantly ameliorate her neurological impairment, although the dysarthria improved slightly. Conclusion. This case highlights the importance of detecting the underlying malignancy in patients with subacute neurological impairment and shows that Fallopian Tube cancer can potentially cause PCD.