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https://www.readbyqxmd.com/read/28097235/a-patient-derived-xenograft-platform-to-study-brca-deficient-ovarian-cancers
#1
Erin George, Hyoung Kim, Clemens Krepler, Brandon Wenz, Mehran Makvandi, Janos L Tanyi, Eric Brown, Rugang Zhang, Patricia Brafford, Stephanie Jean, Robert H Mach, Yiling Lu, Gordon B Mills, Meenhard Herlyn, Mark Morgan, Xiaochen Zhang, Robert Soslow, Ronny Drapkin, Neil Johnson, Ying Zheng, George Cotsarelis, Katherine L Nathanson, Fiona Simpkins
Approximately 50% of high-grade serous ovarian cancers (HGSOCs) have defects in genes involved in homologous recombination (HR) (i.e., BRCA1/2). Preclinical models to optimize therapeutic strategies for HR-deficient (HRD) HGSOC are lacking. We developed a preclinical platform for HRD HGSOCs that includes primary tumor cultures, patient-derived xenografts (PDXs), and molecular imaging. Models were characterized by immunohistochemistry, targeted sequencing, and reverse-phase protein array analysis. We also tested PDX tumor response to PARP, CHK1, and ATR inhibitors...
January 12, 2017: JCI Insight
https://www.readbyqxmd.com/read/28073843/active-estrogen-receptor-alpha-signaling-in-ovarian-cancer-models-and-clinical-specimens
#2
Courtney L Andersen, Matthew J Sikora, Michelle M Boisen, Tianzhou Ma, Alec Christie, George Tseng, Yong Seok Park, Soumya Luthra, Uma Chandran, Paul Haluska, Gina Mantia-Smaldone, Kunle Odunsi, Karen McLean, Adrian V Lee, Esther Elishaev, Robert P Edwards, Steffi Oesterreich
PURPOSE: High-grade serous ovarian cancer (HGSOC) is an aggressive disease with few available targeted therapies. Despite high expression of estrogen receptor-alpha in ~80% of HGSOC and some small but promising clinical trials of endocrine therapy, estrogen receptor-alpha has been understudied as a target in this disease. We sought to identify hormone-responsive, estrogen receptor-alpha-dependent HGSOC. EXPERIMENTAL DESIGN: We characterized endocrine response in HGSOC cells across culture conditions (2-D, 3-D, forced suspension) and in patient-derived xenograft (PDX) explants, assessing proliferation and gene expression...
January 10, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28065619/tumor-associated-macrophage-expression-of-pd-l1-in-implants-of-high-grade-serous-ovarian-carcinoma-a-comparison-of-matched-primary-and-metastatic-tumors
#3
Chelsea E Gottlieb, Anne M Mills, Janet V Cross, Kari L Ring
OBJECTIVE: Data on PD-L1 expression in high grade serous ovarian carcinoma (HGSOC) is mixed. Some studies report robust tumor staining and others identify expression limited to tumor-associated macrophages (TAM). TAM PD-L1 expression is induced in HGSOC metastatic implants from patients who have undergone chemotherapy. However, it is unclear whether TAM acquisition of PD-L1 plays a role in treatment naïve tumors. We investigated PD-L1 expression in primary ovarian tumors and matched metastatic implants from predominantly treatment-naïve HGSOC...
January 5, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28017893/circulating-mirna-landscape-identifies-mir-1246-as-promising-diagnostic-biomarker-in-high-grade-serous-ovarian-carcinoma-a-validation-across-two-independent-cohorts
#4
Paola Todeschini, Elisa Salviato, Lara Paracchini, Manuela Ferracin, Marco Petrillo, Laura Zanotti, Germana Tognon, Angela Gambino, Enrica Calura, Giulia Caratti, Paolo Martini, Luca Beltrame, Lorenzo Maragoni, Daniela Gallo, Franco E Odicino, Enrico Sartori, Giovanni Scambia, Massimo Negrini, Antonella Ravaggi, Maurizio D'Incalci, Sergio Marchini, Eliana Bignotti, Chiara Romualdi
High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic neoplasm, with five-year survival rate below 30%. Early disease detection is of utmost importance to improve HGSOC cure rate. Sera from 168 HGSOC patients and 65 healthy controls were gathered together from two independent collections and stratified into a training set, for miRNA marker identification, and a validation set, for data validation. An innovative statistical approach for microarray data normalization was developed to identify differentially expressed miRNAs...
December 22, 2016: Cancer Letters
https://www.readbyqxmd.com/read/27997533/exploratory-analysis-of-tp53-mutations-in-circulating-tumour-dna-as-biomarkers-of-treatment-response-for-patients-with-relapsed-high-grade-serous-ovarian-carcinoma-a-retrospective-study
#5
Christine A Parkinson, Davina Gale, Anna M Piskorz, Heather Biggs, Charlotte Hodgkin, Helen Addley, Sue Freeman, Penelope Moyle, Evis Sala, Karen Sayal, Karen Hosking, Ioannis Gounaris, Mercedes Jimenez-Linan, Helena M Earl, Wendi Qian, Nitzan Rosenfeld, James D Brenton
BACKGROUND: Circulating tumour DNA (ctDNA) carrying tumour-specific sequence alterations may provide a minimally invasive means to dynamically assess tumour burden and response to treatment in cancer patients. Somatic TP53 mutations are a defining feature of high-grade serous ovarian carcinoma (HGSOC). We tested whether these mutations could be used as personalised markers to monitor tumour burden and early changes as a predictor of response and time to progression (TTP). METHODS AND FINDINGS: We performed a retrospective analysis of serial plasma samples collected during routine clinical visits from 40 patients with HGSOC undergoing heterogeneous standard of care treatment...
December 2016: PLoS Medicine
https://www.readbyqxmd.com/read/27993965/targeting-the-atr-chk1-axis-with-parp-inhibition-results-in-tumor-regression-in-brca-mutant-ovarian-cancer-models
#6
Hyoung Kim, Erin George, Ryan L Ragland, Stavros Rafail, Rugang Zhang, Clemens Krepler, Mark Morgan, Meenhard Herlyn, Eric J Brown, Fiona Simpkins
PURPOSE: PARP inhibition (PARPi) has modest clinical activity in recurrent BRCA mutant (BRCAMUT) high-grade serous ovarian cancers (HGSOC). We hypothesized that PARPi increases dependence on ATR/CHK1 such that combination PARPi with ATR/CHK1 blockade results in increased cell death and tumor regression. EXPERIMENTAL DESIGN: Effects of PARPi (olaparib), CHK1 inhibition (CHK1i;MK8776) or ATR inhibition (ATRi;AZD6738) alone or in combination on survival, colony formation, cell-cycle, genome instability and apoptosis were evaluated in BRCA1/2MUT HGSOC cells...
December 19, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27984374/cd56-neural-cell-adhesion-molecule-expression-in-ovarian-carcinomas-association-with-high-grade-and-advanced-stage-but-not-with-neuroendocrine-differentiation
#7
Hans-Christian Bösmüller, Philipp Wagner, Deborah Lam Pham, Anna K Fischer, Karen Greif, Christine Beschorner, Bence Sipos, Falko Fend, Annette Staebler
OBJECTIVE: Neural cell adhesion molecule (CD56) has been proposed as a potential marker for neuroendocrine differentiation in carcinomas, together with synaptophysin and chromogranin A. However, CD56 immunoreactivity by itself can be found in a broad variety of tumors, including ovarian neoplasms. CD56 has recently been suggested as a potential target for antibody-based therapy. However, for ovarian carcinoma, there is only limited data available regarding the pattern of CD56 immunoreactivity, coexpression of neuroendocrine markers, and correlation with histological types and clinical parameters...
December 15, 2016: International Journal of Gynecological Cancer
https://www.readbyqxmd.com/read/27940126/comparative-transcriptome-analysis-links-distinct-peritoneal-tumor-spread-types-miliary-and-non-miliary-with-putative-origin-tubes-and-ovaries-in-high-grade-serous-ovarian-cancer
#8
Katharina Auer, Anna Bachmayr-Heyda, Stefanie Aust, Thomas W Grunt, Dietmar Pils
High grade serous ovarian cancer (HGSOC) is characterized by extensive local, i.e. peritoneal, tumor spread, manifested in two different clinical presentations, miliary (many millet sized peritoneal implants) and non-miliary (few large exophytically growing peritoneal nodes), and an overall unfavorable outcome. HGSOC is thought to arise from fallopian tube secretory epithelial cells, via so called serous tubal intraepithelial carcinomas (STICs) but an ovarian origin was never ruled out for at least some cases...
December 7, 2016: Cancer Letters
https://www.readbyqxmd.com/read/27899992/beside-p53-and-pten-identification-of-molecular-alterations-of-the-ras-mapk-and-pi3k-akt-signaling-pathways-in-high-grade-serous-ovarian-carcinomas-to-determine-potential-novel-therapeutic-targets
#9
Shuhui Chen, Elisa Cavazza, Catherine Barlier, Julia Salleron, Pierre Filhine-Tresarrieu, Céline Gavoilles, Jean-Louis Merlin, Alexandre Harlé
Despite great histological and molecular heterogeneity, the clinical management of high-grade ovarian carcinomas remains unspecialized. As a major subgroup, high-grade serous ovarian carcinomas (HGSOCs) require novel therapies. In addition to utilizing conventional histological prognostic markers and performing oncogenetic investigations, the molecular diagnostic method of next generation sequencing (NGS) was performed to identify 'druggable' targets that could provide access to innovative therapy. The present study was performed in 45 HGSOC patients (mean age, 59...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27899818/bnc2-is-a-putative-tumor-suppressor-gene-in-high-grade-serous-ovarian-carcinoma-and-impacts-cell-survival-after-oxidative-stress
#10
Laura Cesaratto, Eleonora Grisard, Michela Coan, Luigi Zandonà, Elena De Mattia, Elena Poletto, Erika Cecchin, Fabio Puglisi, Vincenzo Canzonieri, Maria Teresa Mucignat, Antonella Zucchetto, Gabriele Stocco, Alfonso Colombatti, Milena S Nicoloso, Riccardo Spizzo
Rs3814113 is the single-nucleotide polymorphism (SNP) showing the strongest association with high-grade serous ovarian carcinoma (HGSOC) incidence and is located in an intergenic region about 44 kb downstream of basonuclin 2 (BNC2) gene. Lifetime number of ovulations is associated with increased risk to develop HGSOC, probably because of cell damage of extrauterine Müllerian epithelium by ovulation-induced oxidative stress. However, the impact of low-penetrance HGSOC risk alleles (e.g. rs3814113) on the damage induced by oxidative stress remains unclear...
September 22, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27899771/-perspectives-of-individualized-treatment-by-genome-wide-analyses-in-ovarian-cancer
#11
Noriomi Matsumura, Ken Yamaguchi, Ryusuke Murakami, Masaki Mandai, Ikuo Konishi
Genome-wide analyses have recently been reported for ovarian cancer. High-grade serous ovarian carcinoma(HGSOC) almost exclusively harbor TP53 mutations and prominent copy number aberrations. Approximately 20% of HGSOCs harbor BRCA mutations, in which case PARP inhibitors may be effective. HGSOCs are classified into 4 molecular subtypes with distinct histopathological features by transcriptional profiling. These subtypes differ in prognosis and drug sensitivity. Additionally, a whole-genome analysis for HGSOC has revealed various factors that can induce resistance to chemotherapy...
November 2016: Gan to Kagaku Ryoho. Cancer & Chemotherapy
https://www.readbyqxmd.com/read/27898521/pathogenesis-and-heterogeneity-of-ovarian-cancer
#12
Paul T Kroeger, Ronny Drapkin
PURPOSE OF REVIEW: The most common type of ovarian cancer, high-grade serous ovarian carcinoma (HGSOC), was originally thought to develop from the ovarian surface epithelium. However, recent data suggest that the cells that undergo neoplastic transformation and give rise to the majority of HGSOC are from the fallopian tube. This development has impacted both translational research and clinical practice, revealing new opportunities for early detection, prevention, and treatment of ovarian cancer...
February 2017: Current Opinion in Obstetrics & Gynecology
https://www.readbyqxmd.com/read/27856443/genomics-of-ovarian-cancer-progression-reveals-diverse-metastatic-trajectories-including-intraepithelial-metastasis-to-the-fallopian-tube
#13
Mark A Eckert, Shawn Pan, Kyle M Hernandez, Rachel M Loth, Jorge Andrade, Samuel L Volchenboum, Pieter Faber, Anthony Montag, Ricardo Lastra, Marcus E Peter, S Diane Yamada, Ernst Lengyel
: Accumulating evidence has supported the fallopian tube rather than the ovary as the origin for high-grade serous ovarian cancer (HGSOC). To understand the relationship between putative precursor lesions and metastatic tumors, we performed whole-exome sequencing on specimens from eight HGSOC patient progression series consisting of serous tubal intraepithelial carcinomas (STIC), invasive fallopian tube lesions, invasive ovarian lesions, and omental metastases. Integration of copy number and somatic mutations revealed patient-specific patterns with similar mutational signatures and copy-number variation profiles across all anatomic sites, suggesting that genomic instability is an early event in HGSOC...
December 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27852697/chromosomal-instability-in-cell-free-dna-as-a-highly-specific-biomarker-for-detection-of-ovarian-cancer-in-women-with-adnexal-masses
#14
Adriaan Vanderstichele, Pieter Busschaert, Dominiek Smeets, Chiara Landolfo, Els Van Nieuwenhuysen, Karin Leunen, Patrick Neven, Frederic Amant, Sven Mahner, Elena Ioana Braicu, Robert Zeilinger, An Coosemans, Dirk Timmerman, Diether Lambrechts, Ignace Vergote
PURPOSE: Chromosomal instability is a hallmark of ovarian cancer. Here, we explore copy number alteration (CNA) profiling in cell-free DNA as a potential biomarker to detect malignancy in patients presenting with an adnexal mass. EXPERIMENTAL DESIGN: We prospectively enrolled 68 patients with an adnexal mass, of which 57 were diagnosed with invasive or borderline carcinoma and 11 with benign disease. Cell-free DNA was extracted from plasma and analyzed by low-coverage whole-genome sequencing...
November 14, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27833898/nuak1-ark5-is-associated-with-poor-prognosis-in-ovarian-cancer
#15
Neil T Phippen, Nicholas W Bateman, Guisong Wang, Kelly A Conrads, Wei Ao, Pang-Ning Teng, Tracy A Litzi, Julie Oliver, G Larry Maxwell, Chad A Hamilton, Kathleen M Darcy, Thomas P Conrads
BACKGROUND AND OBJECTIVE: Nua kinase 1 (NUAK1) was identified in multigene signatures of survival and suboptimal debulking in high-grade serous ovarian cancer (HGSOC). This study investigates the individual clinical and biologic contributions of NUAK1 in HGSOC patients and cell lines. METHODS: Public transcript expression, clinical, and outcome data were used to interrogate the relationship between NUAK1 and clinicopathologic factors and patient outcomes including progression-free survival (PFS) and molecular subtypes using logistic and Cox modeling...
2016: Frontiers in Oncology
https://www.readbyqxmd.com/read/27798111/the-ring-finger-domain-e3-ubiquitin-ligases-brca1-and-the-rnf20-rnf40-complex-in-global-loss-of-the-chromatin-mark-histone-h2b-monoubiquitination-h2bub1-in-cell-line-models-and-primary-high-grade-serous-ovarian-cancer
#16
Kristie-Ann Dickson, Alexander J Cole, Anthony J Gill, Adele Clarkson, Gregory B Gard, Angela Chou, Catherine J Kennedy, Beric R Henderson, Sian Fereday, Nadia Traficante, Kathryn Alsop, David D Bowtell, Anna deFazio, Roderick Clifton-Bligh, Deborah J Marsh
Enzymatic factors driving cancer-associated chromatin remodelling are of increasing interest as the role of the cancer epigenome in gene expression and DNA repair processes becomes elucidated. Monoubiquitination of histone H2B at lysine 120 (H2Bub1) is a central histone modification that functions in histone cross-talk, transcriptional elongation, DNA repair, maintaining centromeric chromatin and replication-dependent histone mRNA 3'-end processing, as well as being required for the differentiation of stem cells...
October 25, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27788210/nuclear-commd1-is-associated-with-cisplatin-sensitivity-in-ovarian-cancer
#17
Alina Fedoseienko, Hylke W Wieringa, G Bea A Wisman, Evelien Duiker, Anna K L Reyners, Marten H Hofker, Ate G J van der Zee, Bart van de Sluis, Marcel A T M van Vugt
Copper metabolism MURR1 domain 1 (COMMD1) protein is a multifunctional protein, and its expression has been correlated with patients' survival in different types of cancer. In vitro studies revealed that COMMD1 plays a role in sensitizing cancer cell lines to cisplatin, however, the mechanism and its role in platinum sensitivity in cancer has yet to be established. We evaluated the role of COMMD1 in cisplatin sensitivity in A2780 ovarian cancer cells and the relation between COMMD1 expression and response to platinum-based therapy in advanced stage high-grade serous ovarian cancer (HGSOC) patients...
2016: PloS One
https://www.readbyqxmd.com/read/27788148/a-systems-biology-comparison-of-ovarian-cancers-implicates-putative-somatic-driver-mutations-through-protein-protein-interaction-models
#18
Mary Qu Yang, Laura Elnitski
Ovarian carcinomas can be aggressive with a high mortality rate (e.g., high-grade serous ovarian carcinomas, or HGSOCs), or indolent with much better long-term outcomes (e.g., low-malignant-potential, or LMP, serous ovarian carcinomas). By comparing LMP and HGSOC tumors, we can gain insight into the mechanisms underlying malignant progression in ovarian cancer. However, previous studies of the two subtypes have been focused on gene expression analysis. Here, we applied a systems biology approach, integrating gene expression profiles derived from two independent data sets containing both LMP and HGSOC tumors with protein-protein interaction data...
2016: PloS One
https://www.readbyqxmd.com/read/27775699/susd2-expression-in-high-grade-serous-ovarian-cancer-correlates-with-increased-patient-survival-and-defective-mesothelial-clearance
#19
J N Sheets, M Iwanicki, J F Liu, B E Howitt, M S Hirsch, J A A Gubbels, R Drapkin, K A Egland
The cause of death among the majority of epithelial ovarian cancer (EOC) patients involves passive dissemination of cancer cells within the peritoneal cavity and subsequent implantation of cancer spheroids into adjacent organs. Thus, it is important to identify the factors that mediate EOC metastasis and implantation, including clearance of the mesothelium. Sushi domain containing 2 (SUSD2) encodes a type I transmembrane protein containing several functional domains inherent to adhesion molecules. Immunohistochemical analysis determined the presence of SUSD2 in several subtypes of EOC, with the strongest staining observed in high-grade serous ovarian carcinomas (HGSOCs)...
October 24, 2016: Oncogenesis
https://www.readbyqxmd.com/read/27765068/genome-wide-methylation-profiling-of-ovarian-cancer-patient-derived-xenografts-treated-with-the-demethylating-agent-decitabine-identifies-novel-epigenetically-regulated-genes-and-pathways
#20
Tushar Tomar, Steven de Jong, Nicolette G Alkema, Rieks L Hoekman, Gert Jan Meersma, Harry G Klip, Ate Gj van der Zee, G Bea A Wisman
BACKGROUND: In high-grade serous ovarian cancer (HGSOC), intrinsic and/or acquired resistance against platinum-containing chemotherapy is a major obstacle for successful treatment. A low frequency of somatic mutations but frequent epigenetic alterations, including DNA methylation in HGSOC tumors, presents the cancer epigenome as a relevant target for innovative therapy. Patient-derived xenografts (PDXs) supposedly are good preclinical models for identifying novel drug targets. However, the representativeness of global methylation status of HGSOC PDXs compared to their original tumors has not been evaluated so far...
October 20, 2016: Genome Medicine
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