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https://www.readbyqxmd.com/read/29352572/phase-i-combination-study-of-the-parp-inhibitor-veliparib-plus-carboplatin-and-gemcitabine-in-patients-with-advanced-ovarian-cancer-and-other-solid-malignancies
#1
Heidi J Gray, Katherine Bell-McGuinn, Gini F Fleming, Mihaela Cristea, Hao Xiong, Danielle Sullivan, Yan Luo, Mark D McKee, Wijith Munasinghe, Lainie P Martin
OBJECTIVE: Determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of veliparib combined with carboplatin and gemcitabine in patients with advanced ovarian cancer and other nonhematologic malignancies. METHODS: In this phase I study, patients with metastatic or unresectable solid tumors and ≤2 prior chemotherapy regimens received veliparib combined with carboplatin area under the curve (AUC) 4 on day 1 and gemcitabine 800mg/m2 on days 1 and 8 of a 21-day cycle for maximum 10cycles, followed by optional veliparib maintenance therapy...
January 15, 2018: Gynecologic Oncology
https://www.readbyqxmd.com/read/29344385/improving-attendance-to-genetic-counselling-services-for-gynaecological-oncology-patients
#2
Hanoon P Pokharel, Neville F Hacker, Lesley Andrews
Background: Gynaecological cancers may be the sentinel malignancy in women who carry a mutation in BRCA1 or 2, a mis-match repair gene causing Lynch Syndrome or other genes. Despite published guidelines for referral to a genetics service, a substantial number of women do not attend for the recommended genetic assessment. The study aims to determine the outcomes of systematic follow-up of patients diagnosed with ovarian or endometrial cancer from Gynaecologic-oncology multidisciplinary meetings who were deemed appropriate for genetics assessment...
2018: Gynecologic Oncology Research and Practice
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
#3
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/29330845/the-association-between-smoking-and-cancer-incidence-in-brca1-and-brca2-mutation-carriers
#4
Kwang-Pil Ko, Shana J Kim, Tomasz Huzarski, Jacek Gronwald, Jan Lubinski, Henry T Lynch, Susan Armel, Sue K Park, Beth Karlan, Christian F Singer, Susan L Neuhausen, Steven A Narod, Joanne Kotsopoulos
Tobacco smoke is an established carcinogen, but the association between tobacco smoking and cancer risk in BRCA mutation carriers is not clear. The aim of this study was to evaluate prospectively the association between tobacco smoking and cancer incidence in a cohort of BRCA1 and BRCA2 mutation carriers. The study population consisted of unaffected BRCA mutation carriers. Information on lifestyle including smoking histories, reproductive factors, and past medical histories was obtained through questionnaires...
January 13, 2018: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29327596/fertility-preservation-in-brca-mutated-women-when-and-how
#5
Michaël Grynberg, Jade Raad, Marjorie Comtet, Claire Vinolas, Isabelle Cédrin-Durnerin, Charlotte Sonigo
BRCA 1 and 2 genes play a critical role in the safeguarding of DNA integrity. It is now well established that BRCA1 and BRCA2-mutated women are at increased risk of breast and ovarian cancers. However, several lines of evidence indicate that this genetic status may also be associated with ovarian dysfunction, in particular a reduced ovarian reserve. Considering the gonadal toxicity of cancer treatments and the recommendation of prophylactic bilateral salpingo-oophorectomy around 40 years, young BRCA mutation carriers are confronted with difficult family planning decisions...
January 12, 2018: Future Oncology
https://www.readbyqxmd.com/read/29313444/poly-adp-ribose-polymerase-inhibitors-in-the-management-of-ovarian-cancer
#6
Maurie Markman
There is considerable interest and enthusiasm within the clinical gynecologic oncology community regarding the potential for poly (ADP-ribose) polymerase inhibitors to play a critically relevant role in the management of epithelial ovarian cancer and particularly (although not exclusively) in the setting of known mutations in the BRCA gene. This review will briefly highlight the biological rational for the use of poly (ADP-ribose) polymerase inhibitors in this malignancy, followed by summary of currently available clinical data supporting the delivery of agents approved by the US Food and Drug Administration for non-investigative use...
January 2018: Women's Health
https://www.readbyqxmd.com/read/29310832/comprehensive-brca-mutation-analysis-in-the-greek-population-experience-from-a-single-clinical-diagnostic-center
#7
Angela Apessos, Konstantinos Agiannitopoulos, Georgia Pepe, Georgios N Tsaousis, Eirini Papadopoulou, Vasiliki Metaxa-Mariatou, Angeliki Tsirigoti, Chrysoula Efstathiadou, Christos Markopoulos, Grigorios Xepapadakis, Vasileios Venizelos, Aris Tsiftsoglou, Ioannis Natsiopoulos, George Nasioulas
Germline mutations in the BRCA1 and BRCA2 genes are associated with hereditary predisposition to breast and ovarian cancer. Sensitive and accurate detection of BRCA1 and BRCA2 mutations is crucial for personalized clinical management of individuals affected by breast or ovarian cancer, and for the identification of at-risk healthy relatives. We performed molecular analysis of the BRCA1 and BRCA2 genes in 898 Greek families, using Sanger sequencing or Next Generation Sequencing for the detection of small insertion/deletion frameshift, nonsynonymous, truncating and splice-site alterations and MLPA for the detection of large genomic rearrangements...
January 2018: Cancer Genetics
https://www.readbyqxmd.com/read/29300376/cost-effectiveness-analysis-of-germ-line-brca-testing-in-women-with-breast-cancer-and-cascade-testing-in-family-members-of-mutation-carriers
#8
Haitham W Tuffaha, Andrew Mitchell, Robyn L Ward, Luke Connelly, James R G Butler, Sarah Norris, Paul A Scuffham
PurposeTo evaluate the cost-effectiveness of BRCA testing in women with breast cancer, and cascade testing in family members of BRCA mutation carriers.MethodsA cost-effectiveness analysis was conducted using a cohort Markov model from a health-payer perspective. The model estimated the long-term benefits and costs of testing women with breast cancer who had at least a 10% pretest BRCA mutation probability, and the cascade testing of first- and second-degree relatives of women who test positive.ResultsCompared with no testing, BRCA testing of affected women resulted in an incremental cost per quality-adjusted life-year (QALY) gained of AU$18,900 (incremental cost AU$1,880; incremental QALY gain 0...
January 4, 2018: Genetics in Medicine: Official Journal of the American College of Medical Genetics
https://www.readbyqxmd.com/read/29298171/expression-of-%C3%AE-v-tubulin-in-secretory-cells-of-the-fallopian-tube-epithelium-marks-cellular-atypia
#9
Deepti Mathew, Yanhua Wang, Anne Van Arsdale, Susan Band Horwitz, Hayley McDaid
OBJECTIVES: Class V Beta tubulin isotype (βV-tubulin) was recently found to have tissue-specific expression patterns in epithelial tissues with secretory function and aberrant expression in tumors. The aims of this pilot study were (a) to examine expression of βV-tubulin in the fallopian tube epithelium (FTE) of patients who underwent salpingectomy, (b) to characterize FTE atypia in high-risk patients with BRCA mutations, and (c) to determine expression of βV-tubulin in serous ovarian neoplasms...
January 3, 2018: International Journal of Gynecological Cancer
https://www.readbyqxmd.com/read/29297111/high-prevalence-of-deleterious-brca1-and-brca2-germline-mutations-in-arab-breast-and-ovarian-cancer-patients
#10
Al-Joharah Alhuqail, Areej Alzahrani, Hannah Almubarak, Sarah Al-Qadheeb, Lamyaa Alghofaili, Nisreen Almoghrabi, Hamed Alhussaini, Ben Ho Park, Dilek Colak, Bedri Karakas
PURPOSE: The BRCA1 and BRCA2 (BRCA) genes are heavily involved in mammalian cell DNA repair processes. Germline pathogenic mutations in BRCA increase the lifetime risk of developing breast and/or ovarian cancer in women. In the Arabian Peninsula, most breast and ovarian cancers are diagnosed as early-onset cases, some of which may be due to germline variants in BRCA genes. To identify the BRCA germline mutation frequency and spectrum in the Arab breast and ovarian cancers, we have sequenced the protein-coding exons of these genes...
January 2, 2018: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29288066/cost-effectiveness-of-population-based-brca1-founder-mutation-testing-in-sephardi-jewish-women
#11
Shreeya Patel, Rosa Legood, D Gareth Evans, Clare Turnbull, Antonis C Antoniou, Usha Menon, Ian Jacobs, Ranjit Manchanda
BACKGROUND: Population-based BRCA1/BRCA2 founder-mutation testing has been demonstrated as cost-effective compared to family-history(FH) based testing in Ashkenazi Jewish(AJ) women. However, only one of the three AJ BRCA1/BRCA2 founder-mutations (185delAG(c.68_69delAG), 5382insC(c.5266dupC) and 6174delT(c.5946delT)) is found in the Sephardi Jewish(SJ) population (185delAG(c.68_69delAG)) and the overall prevalence of BRCA mutations in the SJ population is accordingly lower (0.7% compared to 2...
December 26, 2017: American Journal of Obstetrics and Gynecology
https://www.readbyqxmd.com/read/29287922/gynaecological-neoplasms-in-common-familial-syndromes-lynch-and-hboc
#12
REVIEW
Carla Bartosch, Blaise Clarke, Tjalling Bosse
Recognising hereditary predisposition in a cancer patient has implications both for the patient and the patient's kindred. For the latter, cascade germline testing can reassure those not-at-risk family members while carriers can be enrolled in cancer screening and prevention programs that are medically effective and economically sustainable for health care systems. Furthermore, in many of these syndromes, ramifications of molecular phenotypes are increasing, and it is now emerging that, in addition, they convey prognostic and predictive information...
December 26, 2017: Pathology
https://www.readbyqxmd.com/read/29286205/uptake-of-risk-reducing-surgery-in-brca-gene-carriers-in-wales-uk
#13
Jennifer Long, Thomas G Evans, Damian Bailey, Michael H Lewis, Kate Gower-Thomas, Alexandra Murray
Women who inherit a mutated copy of the BRCA gene have a higher lifetime risk of developing breast cancer. No large epidemiological studies exist looking at BRCA mutation carriers in UK populations. All patients with BRCA1/BRCA2 mutation identified between 1995 and 2015 were included. Individuals were identified from a prospectively gathered data base. Genetics case-notes were obtained and retrospective analysis performed. 581 female BRCA mutation carriers were identified with a median age of 34 (18-81) at the time of testing...
December 29, 2017: Breast Journal
https://www.readbyqxmd.com/read/29282679/the-preventive-intervention-of-hereditary-breast-cancer
#14
Ayong Cao, Liang Huang, Zhimin Shao
Approximately 5-10% of breast cancer is considered to be hereditary. Familial breast cancers exhibit a dominant hereditary pattern, which typically have an early age of onset and are accompanied by symptoms of ovarian cancer, bilateral breast cancer, or male breast cancer. BRCA gene mutation carriers should be regarded as high-risk groups for breast cancer, which necessitates early examination of breast cancer. Studies have built up kinds of predictive models and recommended that female BRCA mutation carriers should receive breast self-test training and take monthly breast self-examination...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29278600/ovarian-cancer-prevention-screening-and-early-detection-report-from-the-11th-biennial-ovarian-cancer-research-symposium
#15
Jeremy Chien, Elizabeth M Poole
OBJECTIVE: The aim of this study is to provide a summary report on recent research advances in ovarian cancer prevention, screening, and early detection that were presented at the 11th Biennial Ovarian Cancer Research Symposium in Seattle, Wash. METHODS: At the symposium, researchers from around the world participated in the poster, invited oral presentation and keynote presentation, and discussed the latest advances in the areas of cancer prevention, screening, and early detection...
November 2017: International Journal of Gynecological Cancer
https://www.readbyqxmd.com/read/29278246/twitter-and-non-elites-interpreting-power-dynamics-in-the-life-story-of-the-brca-twitter-stream
#16
Stefania Vicari
In May 2013 and March 2015, actress Angelina Jolie wrote in the New York Times about her choice to undergo preventive surgery. In her two op-eds, she explained that - as a carrier of the BRCA1 gene mutation - preventive surgery was the best way to lower her heightened risk of developing breast and ovarian cancer. By applying a digital methods approach to BRCA-related tweets from 2013 and 2015, before, during, and after the exposure of Jolie's story, this study maps and interprets Twitter discursive dynamics at two time points of the BRCA Twitter stream...
September 2017: Soc Media Soc
https://www.readbyqxmd.com/read/29277326/identification-of-the-functional-alteration-signatures-across-different-cancer-types-with-support-vector-machine-and-feature-analysis
#17
ShaoPeng Wang, YuDong Cai
Cancers are regarded as malignant proliferations of tumor cells present in many tissues and organs, which can severely curtail the quality of human life. The potential of using plasma DNA for cancer detection has been widely recognized, leading to the need of mapping the tissue-of-origin through the identification of somatic mutations. With cutting-edge technologies, such as next-generation sequencing, numerous somatic mutations have been identified, and the mutation signatures have been uncovered across different cancer types...
December 19, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29262321/bet-bromodomain-inhibition-synergizes-with-parp-inhibitor-in-epithelial-ovarian-cancer
#18
Sergey Karakashev, Hengrui Zhu, Yuhki Yokoyama, Bo Zhao, Nail Fatkhutdinov, Andrew V Kossenkov, Andrew J Wilson, Fiona Simpkins, David Speicher, Dineo Khabele, Benjamin G Bitler, Rugang Zhang
PARP inhibition is known to be an effective clinical strategy in BRCA mutant cancers, but PARP inhibition has not been applied to BRCA-proficient tumors. Here, we show the synergy of BET bromodomain inhibition with PARP inhibition in BRCA-proficient ovarian cancers due to mitotic catastrophe. Treatment of BRCA-proficient ovarian cancer cells with the BET inhibitor JQ1 downregulated the G2-M cell-cycle checkpoint regulator WEE1 and the DNA-damage response factor TOPBP1. Combining PARP inhibitor Olaparib with the BET inhibitor, we observed a synergistic increase in DNA damage and checkpoint defects, which allowed cells to enter mitosis despite the accumulation of DNA damage, ultimately causing mitotic catastrophe...
December 19, 2017: Cell Reports
https://www.readbyqxmd.com/read/29260919/the-development-of-parp-as-a-successful-target-for-cancer-therapy
#19
Roberto Ferrara, Francesca Simionato, Chiara Ciccarese, Elisabetta Grego, Sara Cingarlini, Roberto Iacovelli, Emilio Bria, Giampaolo Tortora, Davide Melisi
PARP1 and BRCA genes are essential genome caretakers and their interaction has been the first example of synthetic lethality, a genetic concept proposed in the early 20th century, but deeply explored in cancer patients only in the last decade. Areas covered: This review describes PARP1 and BRCA main functions and different roles in genome protection. Furthermore, an overview of the principle mechanisms of action and resistance to PARP inhibitors (PARPi) is presented. This review illustrates the concept of BRCAness, and how this discovery has broadened the routes of PARPi to several different malignancies such as ovarian, breast and prostate cancer...
December 20, 2017: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/29259228/metabolomics-reveals-novel-blood-plasma-biomarkers-associated-to-the-brca1-mutated-phenotype-of-human-breast-cancer
#20
Bàrbara Roig, Marta Rodríguez-Balada, Sara Samino, Eric W-F Lam, Sandra Guaita-Esteruelas, Ana R Gomes, Xavier Correig, Joan Borràs, Oscar Yanes, Josep Gumà
Hereditary breast and ovarian cancer syndrome (HBOC) is partly due to the presence of mutations in the BRCA genes. Triple-negative (TN) breast cancer (BC) shares histological characteristics with germline BRCA1 mutation-associated tumours. We have investigated the metabolic profiles of human breast cancer (BC) cell lines carrying BRCA1 pathogenic mutations by non-targeted liquid chromatography coupled to mass spectrometry technology. Based on our in vitro results, we performed a targeted metabolomic analysis of plasma samples from TN HBOC patients taking into account their BRCA1 genotype...
December 19, 2017: Scientific Reports
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