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https://www.readbyqxmd.com/read/28088330/genomic-insights-in-gynecologic-cancer
#1
Erika Roddy, Jocelyn Chapman
Recent technological advances in DNA sequencing have enabled a remarkably detailed understanding of the molecular changes that define gynecologic and other cancers. Several groups have carried out large-scale genomic analyses of ovarian, uterine, and most recently, cervical cancer. These analyses have led to new insights into the molecular changes characterizing these cancers, which provide insight into clinical outcomes. These molecular characterizations have similarly led to new genomic-based classification schemas, which may better stratify clinical outcomes, help prognosticate and guide treatments...
November 11, 2016: Current Problems in Cancer
https://www.readbyqxmd.com/read/28087320/poly-adp-ribose-polymerase-activity-and-inhibition-in-cancer
#2
REVIEW
Caleb Dulaney, Samuel Marcrom, Jennifer Stanley, Eddy S Yang
Genomic instability resultant from defective DNA repair mechanisms is a fundamental hallmark of cancer. The poly(ADP-ribose) polymerase (PARP) proteins 1, 2 and 3 catalyze the polymerization of poly(ADP-ribose) and covalent attachment to proteins in a phylogenetically ancient form of protein modification. PARPs play a role in base excision repair, homologous recombination, and non-homologous end joining. The discovery that loss of PARP activity had cytotoxic effects in cells deficient in homologous recombination has sparked a decade of translational research efforts that culminated in the FDA approval of an oral PARP inhibitor for clinical use in patients with ovarian cancer and defective homologous recombination...
January 10, 2017: Seminars in Cell & Developmental Biology
https://www.readbyqxmd.com/read/28073364/lack-of-mre11-rad50-nbs1-mrn-complex-detection-occurs-frequently-in-low-grade-epithelial-ovarian-cancer
#3
Simone Brandt, Eleftherios P Samartzis, Anne-Katrin Zimmermann, Daniel Fink, Holger Moch, Aurelia Noske, Konstantin J Dedes
BACKGROUND: BRCA1/2-deficient ovarian carcinomas are recognized as target for Poly (ADP-ribose) polymerase (PARP) inhibitors. BRCA1 and BRCA2 proteins are involved in homologous recombination repair of double-strand DNA breaks. The relevance of other homologous recombination repair proteins, e.g. MRE11, RAD50, NBS1 (MRN complex) in ovarian carcinomas is unclear. The objective of this study was to investigate the prevalence of lack of MRE11, RAD50, NBS1 protein detection in epithelial ovarian cancer (EOC)...
January 10, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28049488/intracellular-trafficking-and-cellular-uptake-mechanism-of-phbv-nanoparticles-for-targeted-delivery-in-epithelial-cell-lines
#4
Juan P Peñaloza, Valeria Márquez-Miranda, Mauricio Cabaña-Brunod, Rodrigo Reyes-Ramírez, Felipe M Llancalahuen, Cristian Vilos, Fernanda Maldonado-Biermann, Luis A Velásquez, Juan A Fuentes, Fernando D González-Nilo, Maité Rodríguez-Díaz, Carolina Otero
BACKGROUND: Nanotechnology is a science that involves imaging, measurement, modeling and a manipulation of matter at the nanometric scale. One application of this technology is drug delivery systems based on nanoparticles obtained from natural or synthetic sources. An example of these systems is synthetized from poly(3-hydroxybutyrate-co-3-hydroxyvalerate), which is a biodegradable, biocompatible and a low production cost polymer. The aim of this work was to investigate the uptake mechanism of PHBV nanoparticles in two different epithelial cell lines (HeLa and SKOV-3)...
January 3, 2017: Journal of Nanobiotechnology
https://www.readbyqxmd.com/read/28044342/in-vitro-cytotoxicity-and-combination-effects-of-the-docetaxel-conjugated-and-doxorubicin-conjugated-poly-lactic-acid-poly-ethylene-glycol-folate-based-polymeric-micelles-in-human-ovarian-cancer-cells
#5
Zahra Hami, Seyed Mahdi Rezayat, Kambiz Gilani, Mohsen Amini, Mahmoud Ghazi-Khansari
OBJECTIVES: The pH-sensitive doxorubicin (DOX)-conjugated and docetaxel (DTX)-conjugated poly(lactic acid)-poly(ethylene glycol)-folate (PLA-PEG-FOL)-based polymeric micelles were developed and characterized in this study. KEY FINDINGS: The drugs were released from the micelles (particle size, ~185 nm) in a pH-dependent manner. The drug-conjugated PLA-PEG-FOL micelles showed higher cellular uptake than nontargeting ones. Single agent and combination in-vitro cytotoxicity studies were also performed using the two drugs in both free and their micellar forms in SKOV3 human ovarian cancer cells using three different cytotoxicity assays...
January 3, 2017: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/28028375/response-of-brca1-mutated-gallbladder-cancer-to-olaparib-a-case-report
#6
Yuan Xie, Yan Jiang, Xiao-Bo Yang, An-Qiang Wang, Yong-Chang Zheng, Xue-Shuai Wan, Xin-Ting Sang, Kai Wang, Da-Dong Zhang, Jia-Jia Xu, Fu-Gen Li, Hai-Tao Zhao
Gallbladder cancer (GBC), although considered as a relatively rare malignancy, is the most common neoplasm of the biliary tract system. The late diagnosis and abysmal prognosis present challenges to treatment. The overall 5-year survival rate for metastatic GBC patients is extremely low. BRCA1 and BRCA2 are the breast cancer susceptibility genes and their mutation carriers are at a high risk for cancer development, both in men and women. Olaparib, an oral poly ADP-ribose polymerase inhibitor, has been approved by the Food and Drug Administration and the European Commission for the treatment of ovarian cancer with any BRCA1/2 mutations...
December 14, 2016: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/28003870/new-perspective-on-maintenance-therapies-for-platinum-sensitive-recurrent-ovarian-cancer-in-women-with-germline-and-somatic-mutations-in-brca1-and-brca2-genes
#7
I Vergote, V Bours, B Blaumeiser, J-F Baurain
Ovarian cancer (OC) is the seventh most common cancer in women. Although women diagnosed with OC are usually treated frontline with platinum-based chemotherapy, most of them relapse once treatment is halted. Therefore, maintenance therapies have been developed to secure the response and delay further chemotherapy. There are two established maintenance therapies for women affected by platinum-sensitive recurrent OC: bevacizumab, a humanized monoclonal antibody targeting vascular endothelial growth factor, and olaparib, an inhibitor of poly (adenosine diphosphate [ADP]-ribose) polymerase (PARPi)...
September 2016: Facts, Views & Vision in ObGyn
https://www.readbyqxmd.com/read/28003236/targeting-dna-repair-in-cancer-beyond-parp-inhibitors
#8
REVIEW
Jessica S Brown, Brent O'Carrigan, Stephen P Jackson, Timothy A Yap
: Germline aberrations in critical DNA-repair and DNA damage-response (DDR) genes cause cancer predisposition, whereas various tumors harbor somatic mutations causing defective DDR/DNA repair. The concept of synthetic lethality can be exploited in such malignancies, as exemplified by approval of poly(ADP-ribose) polymerase inhibitors for treating BRCA1/2-mutated ovarian cancers. Herein, we detail how cellular DDR processes engage various proteins that sense DNA damage, initiate signaling pathways to promote cell-cycle checkpoint activation, trigger apoptosis, and coordinate DNA repair...
January 2017: Cancer Discovery
https://www.readbyqxmd.com/read/27995810/a-comprehensive-look-of-poly-adp-ribose-polymerase-inhibition-strategies-and-future-directions-for-cancer-therapy
#9
Chandan Kumar, Nidhi Rani, Palanisamy Thanga Velan Lakshmi, Annamalai Arunachalam
The finding of promising drugs represents a huge challenge in cancer therapeutics, therefore it is important to seek out novel approaches and elucidate essential cellular processes in order to identify potential drug targets. Studies on DNA repair pathway suggested that an enzyme, PARP, which plays a significant role in DNA repair responses, could be targeted in cancer therapy. Hence, the efficacy of PARP inhibitors in cancer therapy has been investigated and has progressed from the laboratory to clinics, with olaparib having already been approved by the US FDA for ovarian cancer treatment...
January 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/27993805/5th-ovarian-cancer-consensus-conference-of-the-gynecologic-cancer-intergroup-recurrent-disease
#10
M K Wilson, E Pujade-Lauraine, D Aoki, M R Mirza, D Lorusso, A M Oza, A du Bois, I Vergote, A Reuss, M Bacon, M Friedlander, D Rincon, F Joly, S-J Chang, A M Ferrero, R J Edmondson, P Wimberger, J Maenpaa, D Gaffney, R Zhang, A Okamoto, G Stuart, K Ochiai
This manuscript reports the consensus statements regarding recurrent ovarian cancer (ROC), reached at the 5th Ovarian Cancer Consensus Conference (OCCC), which was held in Tokyo, Japan, in November 2015. Three important questions were identified: (1) What are the subgroups for clinical trials in ROC? The historical definition of using platinum-free interval (PFI) to categorize patients as having platinum-sensitive/resistant disease was replaced by therapy-free interval (TFI). TFI can be broken down into TFIp (platinum-free interval), TFInp (non-platinum-free interval) and TFIb (biological agent-free interval)...
December 19, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27993796/phase-i-dose-escalation-study-of-the-pi3kinase-pathway-inhibitor-bkm120-and-the-oral-poly-adp-ribose-polymerase-parp-inhibitor-olaparib-for-the-treatment-of-high-grade-serous-ovarian-and-breast-cancer
#11
U A Matulonis, G M Wulf, W T Barry, M Birrer, S N Westin, S Farooq, K M Bell-McGuinn, E Obermayer, C Whalen, T Spagnoletti, W Luo, H Liu, R C Hok, C Aghajanian, D B Solit, G B Mills, B S Taylor, H Won, M F Berger, S Palakurthi, J Liu, L C Cantley, E Winer
BACKGROUND: Based upon preclinical synergy in murine models, we performed a phase 1 trial to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetics, and biomarkers of response for the combination of BKM120, a PI3K inhibitor, and olaparib, a PARP inhibitor. PATIENTS AND METHODS: Olaparib was administered twice daily (tablet formulation) and BKM120 daily on a 28-day cycle, both orally. A 3 + 3 dose-escalation design was employed with the primary objective of defining the combination MTD, and secondary objectives were to define toxicities, activity, and pharmacokinetic profiles...
December 19, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27978798/combination-platinum-based-and-dna-damage-response-targeting-cancer-therapy-evolution-and-future-directions
#12
Spyridon P Basourakos, Likun Li, Ana M Aparicio, Paul G Corn, Jeri Kim, Timothy C Thompson
Maintenance of genomic stability is a critical determinant of cell survival and is necessary for growth and progression of malignant cells. Alkylating factors, i.e., interstrand crosslinking (ICL) agents, including platinum-based agents, are first-line chemotherapy treatment for many solid human cancers. In malignant cells, ICL triggers the DNA damage response (DDR) including DNA repair, and mainly involves the nucleotide excision repair (NER) pathway. When the damage burden is high and lesions cannot be repaired, malignant cells are unable to divide and ultimately undergo cell death either through mitotic catastrophe or apoptosis...
December 14, 2016: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/27959575/effect-of-ginsenoside-rh-2-via-activation-of-caspase-3-and-bcl-2-insensitive-pathway-in-ovarian-cancer-cells
#13
Jin Hee Kim, Jae-Sun Choi
Ginsenoside has been reported to have therapeutic effects for some types of cancer, but its effect on ovarian cancer cells has not been evaluated. In this study, we monitored the effects of ginsenoside-Rh2 (Rh2) on the inhibition of cell proliferation and the apoptotic process in the ovarian cancer cell line SKOV3 using an MTT assay and TUNEL assay. We found that Rh2 inhibited cell proliferation and significantly induced apoptosis. We confirmed the apoptotic effects of Rh2 using western blot analysis of apoptosis-related proteins...
December 13, 2016: Physiological Research
https://www.readbyqxmd.com/read/27958297/delivering-widespread-brca-testing-and-parp-inhibition-to-patients-with-ovarian-cancer
#14
REVIEW
Angela George, Stan Kaye, Susana Banerjee
The treatment of patients with ovarian cancer is rapidly changing following the success of poly [ADP-ribose] polymerase (PARP) inhibitors in clinical trials. Olaparib is the first PARP inhibitor to be approved by the EMA and FDA for BRCA-mutated ovarian cancer. Germ line BRCA mutation status is now established as a predictive biomarker of potential benefit from treatment with a PARP inhibitor; therefore, knowledge of the BRCA status of an individual patient with ovarian cancer is essential, in order to guide treatment decisions...
December 13, 2016: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/27956521/dual-targeting-nanoparticles-for-in-vivo-delivery-of-suicide-genes-to-chemotherapy-resistant-ovarian-cancer-cells
#15
Emiliano Cocco, Yang Deng, Erik M Shapiro, Ileana Bortolomai, Salvatore Lopez, Ken Lin, Stefania Bellone, Jiajia Cui, Gulden Menderes, Jonathan D Black, Carlton L Schwab, Elena Bonazzoli, Fan Yang, Federica Predolini, Luca Zammataro, Gary Altwerger, Christopher de Haydu, Mitchell Clark, Julio Alvarenga, Elena Ratner, Masoud Azodi, Dan-Arin Silasi, Peter E Schwartz, Babak Litkouhi, W Mark Saltzman, Alessandro D Santin
Ovarian cancer is the most lethal gynecologic cancer. Claudin-3 and-4, the receptors for Clostridium Perfringens Enterotoxin (CPE), are overexpressed in over 70% of these tumors. Here we synthesized and characterized poly(lactic-co-glycolic-acid) (PLGA) nanoparticles (NP) modified with the carboxi-terminal binding domain of CPE (c-CPE-NP) for the delivery of suicide gene therapy to chemotherapy-resistant ovarian cancer cells. As a therapeutic payload we generated a plasmid encoding for the Diphteria Toxin subunit-A (DT-A) under the transcriptional control of the p16 promoter, a gene highly differentially expressed in ovarian cancer cells...
December 12, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27917619/practical-guidance-on-the-use-of-olaparib-capsules-as-maintenance-therapy-for-women-with-brca-mutations-and-platinum-sensitive-recurrent-ovarian-cancer
#16
REVIEW
Michael Friedlander, Susana Banerjee, Linda Mileshkin, Clare Scott, Catherine Shannon, Jeffrey Goh
Olaparib is the first oral poly(ADP-ribose) polymerase inhibitor to be approved as maintenance monotherapy for treatment of patients with platinum-sensitive relapsed BRCA-mutated (BRCAm) serous ovarian cancer. This review provides practical guidance on the use of olaparib (capsule formulation) in the maintenance setting. The article focuses on the key toxicities that can arise with olaparib therapy and recommendations for their management. Nausea, vomiting, fatigue and anemia are the most commonly reported adverse events in olaparib clinical trials and are generally mild to moderate and transient in nature in most patients...
December 2016: Asia-Pacific Journal of Clinical Oncology
https://www.readbyqxmd.com/read/27911475/carboplatin-complexed-and-crgd-conjugated-unimolecular-nanoparticles-for-targeted-ovarian-cancer-therapy
#17
Yuyuan Wang, Liwei Wang, Guojun Chen, Shaoqin Gong
Platinum-based chemotherapy has been widely used to treat cancers including ovarian cancer; however, it suffers from dose-limiting toxicity. Judiciously designed drug nanocarriers can enhance the anticancer efficacy of platinum-based chemotherapy while reducing its systemic toxicity. Herein the authors report a stable and water-soluble unimolecular nanoparticle constructed from a hydrophilic multi-arm star block copolymer poly(amidoamine)-b-poly(aspartic acid)-b-poly(ethylene glycol) (PAMAM-PAsp-PEG) conjugated with both cRGD (cyclo(Arg-Gly-Asp-D-Phe-Cys) peptide and cyanine5 (Cy5) fluorescent dye as a platinum-based drug nanocarrier for targeted ovarian cancer therapy...
December 1, 2016: Macromolecular Bioscience
https://www.readbyqxmd.com/read/27910741/topotecan-liposomes-a-visit-from-a-molecular-to-a-therapeutic-platform
#18
Shivani Saraf, Ankit Jain, Pooja Hurkat, Sanjay Kumar Jain
Topotecan (TPT), a potent anticancer camptothecin analog, is well described for the treatment of ovarian cancer, but has also anticancer activity against small-cell and non-small-cell lung cancer, breast cancer, and acute leukemia. Various nanocarriers, including liposomes, have been exploited for targeted delivery of TPT. However, there are a number of challenges with TPT delivery using TPT liposomes (TLs), such as low encapsulation efficiency, physiological pH labile E ring (hydrolysis), accelerated blood clearance, multidrug resistance, and cancer metastases...
2016: Critical Reviews in Therapeutic Drug Carrier Systems
https://www.readbyqxmd.com/read/27908594/rucaparib-in-relapsed-platinum-sensitive-high-grade-ovarian-carcinoma-ariel2-part-1-an-international-multicentre-open-label-phase-2-trial
#19
Elizabeth M Swisher, Kevin K Lin, Amit M Oza, Clare L Scott, Heidi Giordano, James Sun, Gottfried E Konecny, Robert L Coleman, Anna V Tinker, David M O'Malley, Rebecca S Kristeleit, Ling Ma, Katherine M Bell-McGuinn, James D Brenton, Janiel M Cragun, Ana Oaknin, Isabelle Ray-Coquard, Maria I Harrell, Elaina Mann, Scott H Kaufmann, Anne Floquet, Alexandra Leary, Thomas C Harding, Sandra Goble, Lara Maloney, Jeff Isaacson, Andrew R Allen, Lindsey Rolfe, Roman Yelensky, Mitch Raponi, Iain A McNeish
BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitors have activity in ovarian carcinomas with homologous recombination deficiency. Along with BRCA1 and BRCA2 (BRCA) mutations genomic loss of heterozygosity (LOH) might also represent homologous recombination deficiency. In ARIEL2, we assessed the ability of tumour genomic LOH, quantified with a next-generation sequencing assay, to predict response to rucaparib, an oral PARP inhibitor. METHODS: ARIEL2 is an international, multicentre, two-part, phase 2, open-label study done at 49 hospitals and cancer centres in Australia, Canada, France, Spain, the UK, and the USA...
November 28, 2016: Lancet Oncology
https://www.readbyqxmd.com/read/27907908/prevalence-and-clinical-significance-of-brca1-2-germline-and-somatic-mutations-in-taiwanese-patients-with-ovarian-cancer
#20
Angel Chao, Ting-Chang Chang, Nina Lapke, Shih-Ming Jung, Peter Chi, Chien-Hung Chen, Lan-Yan Yang, Cheng-Tao Lin, Huei-Jean Huang, Hung-Hsueh Chou, Jui-Der Liou, Shu-Jen Chen, Tzu-Hao Wang, Chyong-Huey Lai
Germline and somatic BRCA1/2 mutations define a subset of patients with ovarian cancer who may benefit from treatment with poly (ADP-ribose) polymerase inhibitors. Unfortunately, data on the frequency of BRCA1/2 germline mutations in Taiwanese patients with ovarian cancer are scarce, with the prevalence of somatic mutations being unknown. We aim to investigate the occurrence of BRCA1/2 mutations in 99 Taiwanese patients with ovarian cancer which included serous (n = 46), endometrioid (n = 24), and clear cell (n = 29) carcinomas...
November 19, 2016: Oncotarget
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