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https://www.readbyqxmd.com/read/29444438/commonly-occurring-cell-subsets-in-high-grade-serous-ovarian-tumors-identified-by-single-cell-mass-cytometry
#1
Veronica D Gonzalez, Nikolay Samusik, Tiffany J Chen, Erica S Savig, Nima Aghaeepour, David A Quigley, Ying-Wen Huang, Valeria Giangarrà, Alexander D Borowsky, Neil E Hubbard, Shih-Yu Chen, Guojun Han, Alan Ashworth, Thomas J Kipps, Jonathan S Berek, Garry P Nolan, Wendy J Fantl
We have performed an in-depth single-cell phenotypic characterization of high-grade serous ovarian cancer (HGSOC) by multiparametric mass cytometry (CyTOF). Using a CyTOF antibody panel to interrogate features of HGSOC biology, combined with unsupervised computational analysis, we identified noteworthy cell types co-occurring across the tumors. In addition to a dominant cell subset, each tumor harbored rarer cell phenotypes. One such group co-expressed E-cadherin and vimentin (EV), suggesting their potential role in epithelial mesenchymal transition, which was substantiated by pairwise correlation analyses...
February 13, 2018: Cell Reports
https://www.readbyqxmd.com/read/29434467/genomic-analysis-using-regularized-regression-in-high-grade-serous-ovarian-cancer
#2
Yanina Natanzon, Madalene Earp, Julie M Cunningham, Kimberly R Kalli, Chen Wang, Sebastian M Armasu, Melissa C Larson, David Dl Bowtell, Dale W Garsed, Brooke L Fridley, Stacey J Winham, Ellen L Goode
High-grade serous ovarian cancer (HGSOC) is a complex disease in which initiation and progression have been associated with copy number alterations, epigenetic processes, and, to a lesser extent, germline variation. We hypothesized that, when summarized at the gene level, tumor methylation and germline genetic variation, alone or in combination, influence tumor gene expression in HGSOC. We used Elastic Net (ENET) penalized regression method to evaluate these associations and adjust for somatic copy number in 3 independent data sets comprising tumors from more than 470 patients...
2018: Cancer Informatics
https://www.readbyqxmd.com/read/29416699/lgr5-and-lgr6-in-stem-cell-biology-and-ovarian-cancer
#3
REVIEW
Adam J Schindler, Arisa Watanabe, Stephen B Howell
Wnt signaling plays a fundamental role in patterning of the embryo and maintenance of stem cells in numerous epithelia. Epithelial stem cells are closeted in niches created by surrounding differentiated cells that express secreted Wnt and R-spondin proteins that influence proliferation rate and fate determination of stem cell daughters. R-spondins act through the LGR receptors to enhance Wnt signaling. This close association of stem cells with more differentiated regulatory cells expressing Wnt-pathway ligands is a feature replicated in all of the epithelial stem cell systems thus far examined...
January 2, 2018: Oncotarget
https://www.readbyqxmd.com/read/29402501/hoxa4-hoxb3-gene-expression-signature-as-a-biomarker-of-recurrence-in-patients-with-high-grade-serous-ovarian-cancer-following-primary-cytoreductive-surgery-and-first-line-adjuvant-chemotherapy
#4
Katherine R Miller, Jai N Patel, Qing Zhang, Eric J Norris, James Symanowski, Chad Michener, Jalid Sehouli, Ioana Braicu, Darla D Destephanis, Ashley P Sutker, Wendell Jones, Chad A Livasy, Charles Biscotti, Ram N Ganapathi, David L Tait, Mahrukh K Ganapathi
OBJECTIVES: Aberrant homeobox (HOX) gene expression is reported in high-grade serous ovarian carcinoma (HGSOC), however, its prognostic significance remains unclear. METHODS: HOX genes associated with progression-free survival (PFS) in a discovery cohort of primary HGSOC samples with RNA sequencing data, and those previously reported to be associated with clinical outcomes, were selected for qPCR testing in an independent training cohort of primary HGSOC samples (n=71)...
February 2, 2018: Gynecologic Oncology
https://www.readbyqxmd.com/read/29340034/prexasertib-a-cell-cycle-checkpoint-kinases-1-and-2-inhibitor-increases-in-vitro-toxicity-of-parp-inhibition-by-preventing-rad51-foci-formation-in-brca-wild-type-high-grade-serous-ovarian-cancer
#5
Ethan Brill, Takuhei Yokoyama, Jayakumar Nair, Minshu Yu, Yeong-Ran Ahn, Jung-Min Lee
PARP inhibitors (PARPi) have been effective in high-grade serous ovarian cancer (HGSOC), although clinical activity is limited against BRCA wild type HGSOC. The nearly universal loss of normal p53 regulation in HGSOCs causes dysfunction in the G1/S checkpoint, making tumor cells reliant on Chk1-mediated G2/M cell cycle arrest for DNA repair. Therefore, Chk1 is a reasonable target for a combination strategy with PARPi in treating BRCA wild type HGSOC. Here we investigated the combination of prexasertib mesylate monohydrate (LY2606368), a Chk1 and Chk2 inhibitor, and a PARP inhibitor, olaparib, in HGSOC cell lines (OVCAR3, OV90, PEO1 and PEO4) using clinically attainable concentrations...
December 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29335712/white-blood-cell-brca1-promoter-methylation-status-and-ovarian-cancer-risk
#6
Per E Lønning, Elisabet O Berge, Merete Bjørnslett, Laura Minsaas, Ranjan Chrisanthar, Hildegunn Høberg-Vetti, Cécile Dulary, Florence Busato, Silje Bjørneklett, Christine Eriksen, Reidun Kopperud, Ulrika Axcrona, Ben Davidson, Line Bjørge, D Gareth Evans, Anthony Howell, Helga B Salvesen, Imre Janszky, Kristian Hveem, Pål R Romundstad, Lars J Vatten, Jörg Tost, Anne Dørum, Stian Knappskog
Background: The role of normal tissue gene promoter methylation in cancer risk is poorly understood. Objective: To assess associations between normal tissue BRCA1 methylation and ovarian cancer risk. Design: 2 case-control (initial and validation) studies. Setting: 2 hospitals in Norway (patients) and a population-based study (control participants). Participants: 934 patients and 1698 control participants in the initial study; 607 patients and 1984 control participants in the validation study...
January 16, 2018: Annals of Internal Medicine
https://www.readbyqxmd.com/read/29321820/dysregulation-of-akt3-along-with-a-small-panel-of-mrnas-stratifies-high-grade-serous-ovarian-cancer-from-both-normal-epithelia-and-benign-tumor-tissues
#7
Pourya Naderi Yeganeh, Christine Richardson, Zahra Bahrani-Mostafavi, David L Tait, M Taghi Mostafavi
Screening methods of High-Grade Serous Ovarian Cancer (HGSOC) lack specificity and sensitivity, partly due to benign tumors producing false-positive findings. We utilized a differential expression analysis pipeline on malignant tumor (MT) and normal epithelial (NE) samples, and also filtered the results to discriminate between MT and benign tumor (BT). We report that a panel of 26 dysregulated genes stratifies MT from both BT and NE. We further validated our findings by utilizing unsupervised clustering methods on two independent datasets...
November 2017: Genes & Cancer
https://www.readbyqxmd.com/read/29305171/susd2-promotes-cancer-metastasis-and-confers-cisplatin-resistance-in-high-grade-serous-ovarian-cancer
#8
Ying Xu, Chunying Miao, Chengjuan Jin, Chunping Qiu, Yinuo Li, Xiaomei Sun, Min Gao, Nan Lu, Beihua Kong
The activation of Notch3 is associated with potential progression of ovarian cancer, tumor invasion, metastasis and chemoresistance, which account for poor prognosis of high grade serous ovarian cancer (HGSOC). However, the underlying mechanisms of Notch3 are not yet very clear. Here we show that SUSD2 is one of Notch3-regulating genes and the elevated protein expression of SUSD2 in HGSOC. We also found that its high expression level was significantly correlated with worse overall survival, early recurrence and lymph nodes metastasis...
January 2, 2018: Experimental Cell Research
https://www.readbyqxmd.com/read/29285388/metronomic-cyclophosphamide-induced-long-term-remission-after-recurrent-high-grade-serous-ovarian-cancer-a-case-study
#9
Leonora Wijnandina de Boo, Annelie Johanna Elisabeth Vulink, Monique Elisabeth Martina Maria Bos
Metronomic oral cyclophosphamide has gained increasing interest in recent years as a promising maintenance therapy in advanced, platinum-sensitive, high-grade serous ovarian cancer (HGSOC). Metronomic treatment with cyclophosphamide refers to the frequent, usually daily, administration of a low (oral) dose of cyclophosphamide with no prolonged drug-free breaks. Main advantages of this treatment are the effective reduction of tumour activity, oral administration in an outpatient setting, low cost and the low toxicity profile...
December 2017: Molecular and Clinical Oncology
https://www.readbyqxmd.com/read/29283581/ratio-dependent-synergism-of-a-doxorubicin-and-olaparib-combination-in-2d-and-spheroid-models-of-ovarian-cancer
#10
Sina Eetezadi, James C Evans, Yen Ting Shen, Raquel De Souza, Micheline Piquette-Miller, Christine Allen
Ovarian cancer is the fourth leading cause of death in women in developed countries. Even though patients with the most lethal form of the disease (HGSOC; high grade serous ovarian cancer) respond well to initial treatment, they often relapse with progressively resistant disease. Inhibitors of the poly(ADP-ribose) polymerase (PARP) enzymes are a relatively new class of molecularly targeted small molecule drugs that show promise in overcoming resistance. The present study explores the combination of a DNA damaging agent, doxorubicin (DOX), with the PARP inhibitor, olaparib (OLP) in order to achieve optimal synergy of both drugs in serous ovarian cancer...
December 28, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29221157/high-ptpn13-expression-in-high-grade-serous-ovarian-carcinoma-is-associated-with-a-better-patient-outcome
#11
Véronique D'Hondt, Magalie Lacroix-Triki, Marta Jarlier, Florence Boissiere-Michot, Carole Puech, Peter Coopman, Dionyssios Katsaros, Gilles Freiss
Background: Chromosome 4q loss of heterozygosity (LOH) is frequently observed in high-grade serous ovarian carcinoma (HGSOC). However, this LOH has not been clearly associated with the inactivation of any tumor suppressor gene(s). As the tumor suppressor gene PTPN13 is located on chromosome 4q21, we investigated its expression in HGSOC. Methods: PTPN13 protein expression was investigated by immunohistochemistry (IHC) in normal ovary epithelium and in 30 HGSOC samples, whereas PTPN13 mRNA expression was quantified by RT-PCR in another independent cohort of 28 HGSOC samples...
November 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29196464/deconstruction-of-a-metastatic-tumor-microenvironment-reveals-a-common-matrix-response-in-human-cancers
#12
Oliver M T Pearce, Robin Delaine-Smith, Eleni Maniati, Sam Nichols, Jun Wang, Steffen Böhm, Vinothini Rajeeve, Dayem Ullah, Probir Chakravarty, Roanne R Jones, Anne Montfort, Tom Dowe, John Gribben, J Louise Jones, Hemant M Kocher, Jonathan S Serody, Benjamin G Vincent, John Connelly, James D Brenton, Claude Chelala, Pedro R Cutillas, Michelle Lockley, Conrad Bessant, Martin Knight, Frances R Balkwill
We have profiled, for the first time, an evolving human metastatic microenvironment, measuring gene expression, matrisome proteomics, cytokine and chemokine levels, cellularity, ECM organization and biomechanical properties, all on the same sample. Using biopsies of high-grade serous ovarian cancer (HGSOC) metastases that ranged from minimal to extensive disease, we show how non-malignant cell densities and cytokine networks evolve with disease progression. Multivariate integration of the different components allowed us to define for the first time, gene and protein profiles that predict extent of disease and tissue stiffness, whilst also revealing the complexity and dynamic nature of matrisome remodeling during development of metastases...
December 1, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29163813/the-novel-zip4-regulation-and-its-role-in-ovarian-cancer
#13
Qipeng Fan, Qingchun Cai, Pengfei Li, Wenyan Wang, Jing Wang, Emily Gerry, Tian-Li Wang, Ie-Ming Shih, Kenneth P Nephew, Yan Xu
Our RNAseq analyses revealed that ZIP4 is a top gene up-regulated in more aggressive ovarian cancer cells. ZIP4's role in cancer stem cells has not been reported in any type of cancer. In addition, the role and regulation of ZIP4, a zinc transporter, have been studied in the context of extracellular zinc transporting. Factors other than zinc with ZIP4 regulatory effects are essentially unknown. ZIP4 expression and its regulation in epithelial ovarian cancer cells was assessed by immunoblotting, quantitative PCR, or immunohistochemistry staining in human ovarian tissues...
October 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/29157627/letrozole-may-be-a-valuable-maintenance-treatment-in-high-grade-serous-ovarian-cancer-patients
#14
V Heinzelmann-Schwarz, A Knipprath Mészaros, S Stadlmann, F Jacob, A Schoetzau, K Russell, M Friedlander, G Singer, M Vetter
OBJECTIVES: Endocrine therapy is used as maintenance in estrogen receptor (ER) positive breast cancers and has been proposed in low-grade serous ovarian cancers (LGSOC). Here we examine a rationale for its use as maintenance in high-grade serous ovarian cancers (HGSOC). METHODS: We accessed the TCGA PANCAN dataset to evaluate the expression of ESR1. ESR1 expression data on all cancers (n=8901) and HGSOC (n=527) were followed by investigation of ER expression via immunohistochemistry (IHC) (n=4071)...
January 2018: Gynecologic Oncology
https://www.readbyqxmd.com/read/29141850/autoantibodies-against-hsf1-and-ccdc155-as-biomarkers-of-early-stage-high-grade-serous-ovarian-cancer
#15
Amy L Wilson, Laura R Moffitt, Nadine Duffield, Adam Rainczuk, Tom W Jobling, Magdalena Plebanski, Andrew N Stephens
BACKGROUND: Tumor-directed circulating autoantibodies (AAbs) are a well-established feature of many solid tumor types, and are often observed prior to clinical disease manifestation. As such, they may provide a good indicator of early disease development. We have conducted a pilot study to identify novel AAbs as markers of early stage HGSOCs. METHODS: A rare cohort of patients with early (FIGO stage Ia-c) HGSOCs for IgG, IgA and IgM-mediated AAb reactivity using high content protein arrays (containing 9184 individual proteins)...
November 15, 2017: Cancer Epidemiology, Biomarkers & Prevention
https://www.readbyqxmd.com/read/29132874/combining-serum-microrna-and-ca-125-as-prognostic-indicators-of-preoperative-surgical-outcome-in-women-with-high-grade-serous-ovarian-cancer
#16
Jaynish S Shah, Gregory B Gard, Jean Yang, Jayne Maidens, Susan Valmadre, Patsy S Soon, Deborah J Marsh
OBJECTIVES: The most widely used approach for the clinical management of women with high-grade serous ovarian cancer (HGSOC) is surgery, followed by platinum and taxane based chemotherapy. The degree of macroscopic disease remaining at the conclusion of surgery is a key prognostic factor determining progression free and overall survival. We sought to develop a non-invasive test to assist surgeons to determine the likelihood of achieving complete surgical resection. This knowledge could be used to plan surgical approaches for optimal clinical management...
November 10, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/29130934/recurrent-ubiquitin-b-silencing-in-gynecological-cancers-establishes-dependence-on-ubiquitin-c
#17
Alexia T Kedves, Scott Gleim, Xiaoyou Liang, Dennis M Bonal, Frederic Sigoillot, Fred Harbinski, Sneha Sanghavi, Christina Benander, Elizabeth George, Prafulla C Gokhale, Quang-De Nguyen, Paul T Kirschmeier, Robert J Distel, Jeremy Jenkins, Michael S Goldberg, William C Forrester
Transcriptional repression of ubiquitin B (UBB) is a cancer-subtype-specific alteration that occurs in a substantial population of patients with cancers of the female reproductive tract. UBB is 1 of 2 genes encoding for ubiquitin as a polyprotein consisting of multiple copies of ubiquitin monomers. Silencing of UBB reduces cellular UBB levels and results in an exquisite dependence on ubiquitin C (UBC), the second polyubiquitin gene. UBB is repressed in approximately 30% of high-grade serous ovarian cancer (HGSOC) patients and is a recurrent lesion in uterine carcinosarcoma and endometrial carcinoma...
November 13, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29061967/high-grade-serous-ovarian-carcinomas-originate-in-the-fallopian-tube
#18
S Intidhar Labidi-Galy, Eniko Papp, Dorothy Hallberg, Noushin Niknafs, Vilmos Adleff, Michael Noe, Rohit Bhattacharya, Marian Novak, Siân Jones, Jillian Phallen, Carolyn A Hruban, Michelle S Hirsch, Douglas I Lin, Lauren Schwartz, Cecile L Maire, Jean-Christophe Tille, Michaela Bowden, Ayse Ayhan, Laura D Wood, Robert B Scharpf, Robert Kurman, Tian-Li Wang, Ie-Ming Shih, Rachel Karchin, Ronny Drapkin, Victor E Velculescu
High-grade serous ovarian carcinoma (HGSOC) is the most frequent type of ovarian cancer and has a poor outcome. It has been proposed that fallopian tube cancers may be precursors of HGSOC but evolutionary evidence for this hypothesis has been limited. Here, we perform whole-exome sequence and copy number analyses of laser capture microdissected fallopian tube lesions (p53 signatures, serous tubal intraepithelial carcinomas (STICs), and fallopian tube carcinomas), ovarian cancers, and metastases from nine patients...
October 23, 2017: Nature Communications
https://www.readbyqxmd.com/read/29057791/emerging-therapeutics-to-overcome-chemoresistance-in-epithelial-ovarian-cancer-a-mini-review
#19
REVIEW
Robert Cornelison, Danielle C Llaneza, Charles N Landen
Ovarian cancer is the fifth leading cause of cancer death among women and the most lethal gynecologic malignancy. One of the leading causes of death in high-grade serous ovarian cancer (HGSOC) is chemoresistant disease, which may present as intrinsic or acquired resistance to therapies. Here we discuss some of the known molecular mechanisms of chemoresistance that have been exhaustively investigated in chemoresistant ovarian cancer, including drug efflux pump multidrug resistance protein 1 (MDR1), the epithelial-mesenchymal transition, DNA damage and repair capacity...
October 18, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29049607/dose-response-association-of-cd8-tumor-infiltrating-lymphocytes-and-survival-time-in-high-grade-serous-ovarian-cancer
#20
Ellen L Goode, Matthew S Block, Kimberly R Kalli, Robert A Vierkant, Wenqian Chen, Zachary C Fogarty, Aleksandra Gentry-Maharaj, Aleksandra Toloczko, Alexander Hein, Aliecia L Bouligny, Allan Jensen, Ana Osorio, Andreas D Hartkopf, Andy Ryan, Anita Chudecka-Glaz, Anthony M Magliocco, Arndt Hartmann, Audrey Y Jung, Bo Gao, Brenda Y Hernandez, Brooke L Fridley, Bryan M McCauley, Catherine J Kennedy, Chen Wang, Chloe Karpinskyj, Christiani B de Sousa, Daniel G Tiezzi, David L Wachter, Esther Herpel, Florin Andrei Taran, Francesmary Modugno, Gregg Nelson, Jan Lubinski, Janusz Menkiszak, Jennifer Alsop, Jenny Lester, Jesús García-Donas, Jill Nation, Jillian Hung, José Palacios, Joseph H Rothstein, Joseph L Kelley, Jurandyr M de Andrade, Luis Robles-Díaz, Maria P Intermaggio, Martin Widschwendter, Matthias W Beckmann, Matthias Ruebner, Mercedes Jimenez-Linan, Naveena Singh, Oleg Oszurek, Paul R Harnett, Peter F Rambau, Peter Sinn, Philipp Wagner, Prafull Ghatage, Raghwa Sharma, Robert P Edwards, Roberta B Ness, Sandra Orsulic, Sara Y Brucker, Sharon E Johnatty, Teri A Longacre, Ursula Eilber, Valerie McGuire, Weiva Sieh, Yanina Natanzon, Zheng Li, Alice S Whittemore, Anna deFazio, Annette Staebler, Beth Y Karlan, Blake Gilks, David D Bowtell, Estrid Høgdall, Francisco J Candido Dos Reis, Helen Steed, Ian G Campbell, Jacek Gronwald, Javier Benítez, Jennifer M Koziak, Jenny Chang-Claude, Kirsten B Moysich, Linda E Kelemen, Linda S Cook, Marc T Goodman, María José García, Peter A Fasching, Stefan Kommoss, Suha Deen, Susanne K Kjaer, Usha Menon, James D Brenton, Paul D P Pharoah, Georgia Chenevix-Trench, David G Huntsman, Stacey J Winham, Martin Köbel, Susan J Ramus
Importance: Cytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors. Objective: To define the prognostic role of CD8+ TILs in epithelial ovarian cancer. Design, Setting, and Participants: This was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consortium...
October 12, 2017: JAMA Oncology
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