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https://www.readbyqxmd.com/read/29146938/computational-investigation-of-homologous-recombination-dna-repair-deficiency-in-sporadic-breast-cancer
#1
Yue Wang, Matthew H Ung, Sharon Cantor, Chao Cheng
BRCAness has important implications in the management and treatment of patients with breast and ovarian cancer. In this study, we propose a computational framework to measure the BRCAness of breast and ovarian tumor samples based on their gene expression profiles. We define a characteristic profile for BRCAness by comparing gene expression differences between BRCA1/2 mutant familial tumors and sporadic breast cancer tumors while adjusting for relevant clinical factors. With this BRCAness profile, our framework calculates sample-specific BRCA scores, which indicates homologous recombination (HR)-mediated DNA repair pathway activity of samples...
November 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29146772/cre-dependent-cas9-expressing-pigs-enable-efficient-in-vivo-genome-editing
#2
Kepin Wang, Qin Jin, Degong Ruan, Yi Yang, Qishuai Liu, Han Wu, Zhiwei Zhou, Zhen Ouyang, Zhaoming Liu, Yu Zhao, Bentian Zhao, Quanjun Zhang, Jiangyun Peng, Chengdan Lai, Nana Fan, Yanhui Liang, Ting Lan, Nan Li, Xiaoshan Wang, Xinlu Wang, Yong Fan, Pieter A Doevendans, Joost P G Sluijter, Pentao Liu, Xiaoping Li, Liangxue Lai
Despite being time-consuming and costly, generating genome-edited pigs holds great promise for agricultural, biomedical, and pharmaceutical applications. To further facilitate genome editing in pigs, we report here establishment of a pig line with Cre-inducible Cas9 expression that allows a variety of ex vivo genome editing in fibroblast cells including single- and multigene modifications, chromosome rearrangements, and efficient in vivo genetic modifications. As a proof of principle, we were able to simultaneously inactivate five tumor suppressor genes (TP53, PTEN, APC, BRCA1, and BRCA2) and activate one oncogene (KRAS), achieved by delivering Cre recombinase and sgRNAs, which caused rapid lung tumor development...
November 16, 2017: Genome Research
https://www.readbyqxmd.com/read/29146522/germline-genetic-features-of-young-individuals-with-colorectal-cancer
#3
Elena M Stoffel, Erika Koeppe, Jessica Everett, Peter Ulintz, Mark Kiel, Jenae Osborne, Linford Williams, Kristen Hanson, Stephen B Gruber, Laura S Rozek
BACKGROUND & AIMS: The incidence of colorectal cancer (CRC) in individuals younger than 50 years old is increasing. We sought to ascertain the proportion of young CRC cases associated with genetic predisposition. METHODS: We performed a retrospective study of individuals diagnosed with CRC at an age younger than 50 years, evaluated by the clinical genetics service at a single tertiary care cancer center from 1998 through 2015. We collected data on patient histories, tumor phenotypes, and results of germline DNA sequencing...
November 12, 2017: Gastroenterology
https://www.readbyqxmd.com/read/29145865/the-endonuclease-eepd1-mediates-synthetic-lethality-in-rad52-depleted-brca1-mutant-breast-cancer-cells
#4
Robert Hromas, Hyun-Suk Kim, Gurjit Sidhu, Elizabeth Williamson, Aruna Jaiswal, Taylor A Totterdale, Jocelyn Nole, Suk-Hee Lee, Jac A Nickoloff, Kimi Y Kong
BACKGROUND: Proper repair and restart of stressed replication forks requires intact homologous recombination (HR). HR at stressed replication forks can be initiated by the 5' endonuclease EEPD1, which cleaves the stalled replication fork. Inherited or acquired defects in HR, such as mutations in breast cancer susceptibility protein-1 (BRCA1) or BRCA2, predispose to cancer, including breast and ovarian cancers. In order for these HR-deficient tumor cells to proliferate, they become addicted to a bypass replication fork repair pathway mediated by radiation repair protein 52 (RAD52)...
November 16, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/29143969/the-molecular-basis-of-cytotoxicity-of-%C3%AE-spinasterol-from-ganoderma-resinaceum-induction-of-apoptosis-and-overexpression-of-p53-in-breast-and-ovarian-cancer-cell-lines
#5
Nada K Sedky, Zaynab El Gammal, Amir E Wahba, Eman Mosad, Zahraa Y Waly, Amira Ali El-Fallal, Reem K Arafa, Nagwa El-Badri
OBJECTIVES: Despite advances in therapy of breast and ovarian cancers, they still remain among the most imperative causes of cancer death in women. The first can be considered one of the most widespread diseases among females, while the latter is more lethal and needs prompt treatment. Thus, the research field can still benefit from discovery of new compounds that can be of potential use in management of these grave illnesses. We hereby aimed to assess the antitumor activity of the phytosterol α-spinasterol isolated from Ganoderma resinaceum mushroom on human breast cancer cell lines (MCF-7, MDA-MB-231), as well as, on human ovarian cancer cell line (SKOV-3)...
November 16, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29140388/titanium-activates-the-dna-damage-response-pathway-in-oral-epithelial-cells-a-pilot-study
#6
Fernando Suárez-López Del Amo, Ivan Rudek, Vivian Petersen Wagner, Manoela D Martins, Francisco O'Valle, Pablo Galindo-Moreno, William V Giannobile, Hom-Lay Wang, Rogerio M Castilho
PURPOSE: To evaluate the effect of titanium (Ti) particles on oral epithelial cell homeostasis and the potential of dental implants to release Ti debris upon insertion. MATERIALS AND METHODS: Dental implants with varying surface treatments were employed to determine the feasibility of particle release during implant placement as well as the impact of free Ti debris on oral epithelial cells. Ti particles derived from implant surfaces were isolated and cultured in direct contact with normal oral epithelial cells for 48 hours...
November 2017: International Journal of Oral & Maxillofacial Implants
https://www.readbyqxmd.com/read/29138572/current-status-of-poly-adp-ribose-polymerase-inhibitors-and-future-directions
#7
REVIEW
Akihiro Ohmoto, Shinichi Yachida
Inhibitors of poly(ADP-ribose) polymerases (PARPs), which play a key role in DNA damage/repair pathways, have been developed as antitumor agents based on the concept of synthetic lethality. Synthetic lethality is the idea that cell death would be efficiently induced by simultaneous loss of function of plural key molecules, for example, by exposing tumor cells with inactivating gene mutation of BRCA-mediated DNA repair to chemically induced inhibition of PARPs. Indeed, three PARP inhibitors, olaparib, rucaparib and niraparib have already been approved in the US or Europe, mainly for the treatment of BRCA-mutant ovarian cancer...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29138344/targeting-the-mycn-parp-dna-damage-response-pathway-inneuroendocrine-prostate-cancer
#8
Wei Zhang, Bo Liu, Wenhui Wu, Likun Li, Bradley M Broom, Spyridon M Basourakos, Dimitrios Korentzelos, Yang Luan, Jianxiang Wang, Guang Yang, Sanghee Park, Abul K Azad, Xuhong Cao, Jeri Kim, Paul Corn, Christopher Logothetis, Ana M Aparicio, Arul M Chinnayan, Nora M Navone, Patricia Troncoso, Timothy C Thompson
PURPOSE: We investigated MYCN-regulated molecular pathways in castration-resistant prostate cancer (CRPC) classified by morphological criteria as adenocarcinoma or neuroendocrine to extend the molecular phenotype, establish driver pathways, and identify novel approaches to combination therapy for NEPC. RESULTS: Using comparative bioinformatics analyses of CRPC-Adeno and CRPC-Neuro RNA sequence data from public datasets and a panel of 28 PDX models we identified a MYCN-PARP-DNA damage response (DDR) pathway that is enriched in CRPC with neuroendocrine differentiation (NED) and CRPC-Neuro...
November 14, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29138343/a-phase-i-clinical-trial-of-the-poly-adp-ribose-polymerase-inhibitor-veliparib-and-weekly-topotecan-in-patients-with-solid-tumors
#9
Andrea E Wahner Hendrickson, Michael E Menefee, Lynn C Hartmann, Harry J Long, Donald W Northfelt, Joel M Reid, Felix Boakye-Agyeman, Olumide Kayode, Karen S Flatten, Maria I Harrell, Elizabeth M Swisher, Guy G Poirer, Daniel Satele, Jacob B Allred, Janet L Lensing, Alice Chen, Jiuping Jay Ji, Yiping Zhang, Charles Erlichman, Paul Haluska, Scott H Kaufmann
PURPOSE: To determine the dose limiting toxicities (DLTs), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of veliparib in combination with weekly topotecan in patients with solid tumors. Correlative studies were included to assess the impact of topotecan and veliparib on poly(ADP-ribose) levels in peripheral blood mononuclear cells, serum pharmacokinetics of both agents, and potential association of germline repair gene mutations with outcome. EXPERIMENTAL DESIGN: Eligible patients had metastatic nonhematological malignancies with measurable disease...
November 14, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29137324/loss-of-brca1-promotor-hypermethylation-in-recurrent-high-grade-ovarian-cancer
#10
Katharina Prieske, Stefan Prieske, Simon A Joosse, Fabian Trillsch, Donata Grimm, Eike Burandt, Sven Mahner, Barbara Schmalfeldt, Karin Milde-Langosch, Leticia Oliveira-Ferrer, Linn Woelber
Background: Approximately 20-25% of ovarian cancers are attributable to germline or somatic BRCA1/2 mutations, resulting in defects in the homologous recombination pathway. Inactivation of these genes can also be mediated by epigenetic changes, e.g., hypermethylation of CpG islands in the promoter regions. In such homologous recombination deficient tumors, platinum based chemotherapy is in general effective, however, loss of hypermethylation might lead to refractory disease. The aim of this study was to evaluate the stability of BRCA1 promoter hypermethylation in recurrent disease after platinum based chemotherapy...
October 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29137223/hormone-induced-dna-damage-response-and-repair-mediated-by-cyclin-d1-in-breast-and-prostate-cancer
#11
REVIEW
Gabriele Di Sante, Agnese Di Rocco, Claudia Pupo, Mathew C Casimiro, Richard G Pestell
Cell cycle control proteins govern events that leads to the production of two identical daughter cells. Distinct sequential temporal phases, Gap 1 (G1), Gap 0 (G0), Synthesis (S), Gap 2 (G2) and Mitosis (M) are negotiated through a series of check points during which the favorability of the local cellular environment is assessed, prior to replicating DNA [1]. Cyclin D1 has been characterized as a key regulatory subunit of the holoenzyme that promotes the G1/S-phase transition through phosphorylating the pRB protein...
October 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29136592/human-sirtuin-3-sirt3-deacetylates-histone-h3-lysine-56-to-promote-nonhomologous-end-joining-repair
#12
Amrita Sengupta, Devyani Haldar
Human sirtuin 3 (SIRT3) is a conserved NAD(+) dependent deacetylase, which functions in important cellular processes including transcription, metabolism, oxidative stress response. It is a robust mitochondrial deacetylase; however, few studies have indicated its nuclear functions. Here we report interaction of SIRT3 with core histones and identified acetylated histone H3 lysine 56 (H3K56ac) as its novel substrate, in addition to known substrates acetylated H4K16 and H3K9. Further, we showed in response to DNA damage SIRT3 localizes to the repair foci colocalizing with γH2AX and nonhomologous end joining (NHEJ) marker p53-binding protein 1 (53BP1)...
November 8, 2017: DNA Repair
https://www.readbyqxmd.com/read/29133960/divergent-roles-for-clusterin-in-lung-injury-and-repair
#13
David M Habiel, Ana Camelo, Milena Espindola, Timothy Burwell, Richard Hanna, Elena Miranda, Alan Carruthers, Matthew Bell, Ana Lucia Coelho, Hao Liu, Fernanda Pilataxi, Lori Clarke, Ethan Grant, Arthur Lewis, Bethany Moore, Darryl A Knight, Cory M Hogaboam, Lynne A Murray
Lung fibrosis is an unabated wound healing response characterized by the loss and aberrant function of lung epithelial cells. Herein, we report that extracellular Clusterin promoted epithelial cell apoptosis whereas intracellular Clusterin maintained epithelium viability during lung repair. Unlike normal and COPD lungs, IPF lungs were characterized by significantly increased extracellular Clusterin whereas the inverse was evident for intracellular Clusterin. In vitro and in vivo studies demonstrated that extracellular Clusterin promoted epithelial cell apoptosis while intercellular Clusterin modulated the expression of the DNA repair proteins, MSH2, MSH6, OGG1 and BRCA1...
November 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29133618/therapeutic-impact-of-nanoparticle-therapy-targeting-tumor-associate-macrophages
#14
Courtney Penn, Kun Yang, Hong Zong, Jae-Young Lim, Alex Cole, Dongli Yang, James Baker, Sascha N Goonewardena, Ronald J Buckanovich
Antiangiogenic therapies, despite initial encouragement, have demonstrated a limited benefit in ovarian cancer. Laboratory studies suggest anti-angiogenic therapy induced hypoxia can induce tumor "stemness' as resistance to antiangiogenic therapy develops and limits the therapeutic benefit. Resistance to antiangiogenic therapy and an induction of tumor stemness may be mediated by proangiogenic tumor associated macrophages (TAMs). As such TAMs have been proposed as a therapeutic target. We demonstrate here that ovarian TAMs express high levels of the folate receptor-2 (FOLR2) and can be selectively targeted using G5-dendrimer nanoparticles using methotrexate as both a ligand and a toxin...
November 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29133208/homozygous-loss-of-function-brca1-variant-causing-a-fanconi-anemia-like-phenotype-a-clinical-report-and-review-of-previous-patients
#15
Bruna L Freire, Thais K Homma, Mariana F A Funari, Antônio M Lerario, Aline de Medeiros Leal, Elvira D Rodrigues Pereira Velloso, Alexsandra C Malaquias, Alexander A L Jorge
BACKGROUND: Fanconi Anemia (FA) is a rare and heterogeneous genetic syndrome. It is associated with short stature, bone marrow failure, high predisposition to cancer, microcephaly and congenital malformation. Many genes have been associated with FA. Previously, two adult patients with biallelic pathogenic variant in Breast Cancer 1 gene (BRCA1) had been identified in Fanconi Anemia-like condition. CLINICAL REPORT: The proband was a 2.5 year-old girl with severe short stature, microcephaly, neurodevelopmental delay, congenital heart disease and dysmorphic features...
November 10, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/29133135/characterization-detection-and-treatment-approaches-for-homologous-recombination-deficiency-in-cancer
#16
REVIEW
Grainne M O'Kane, Ashton A Connor, Steven Gallinger
Investigations of carcinogenesis have evolved from the identification of clonal driver mutations in candidate genes to the integration of large volumes of genomic and transcriptomic data revealing recurrently altered pathways and signatures of mutational processes. Inactivation of BRCA1, BRCA2, or PALB2 impairs efficient double-strand break repair (DSBR), giving rise to a spectrum of homologous recombination deficiency (HRD) cancer phenotypes. Harnessing HRD therapeutically has been promising in a number of tumors; these approaches include leveraging synthetic lethality by targeting alternative repair pathways via PARP inhibition, inducing HRD to modulate potential tumor vulnerabilities, and preventing mechanisms of drug resistance...
November 10, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/29132681/-dna-repair-as-a-therapeutic-target
#17
REVIEW
Lauriane Eberst, Medhi Brahmi, Philippe A Cassier
The transmission of an intact and stable genetic code at each cell division relies on different DNA repair systems. Germline mutations of some of these genes cause cancer predisposition, whereas somatic mutations are frequently found in various cancer types, generating genomic instability. As a consequence, cancer cell becomes more susceptible to additional DNA damage. Pharmacological inhibition of DNA repair pathways exploits this frailty: it triggers more damages than cancer cell can tolerate, finally leading to apoptosis...
November 10, 2017: Bulletin du Cancer
https://www.readbyqxmd.com/read/29128690/transcriptome-based-biological-dosimetry-of-gamma-radiation-in-arabidopsis-using-dna-damage-response-genes
#18
Tae Ho Ryu, Jin Kyu Kim, Jeong-Il Kim, Jin-Hong Kim
Plants are used as representative reference biota for the biological assessment of environmental risks such as ionizing radiation due to their immobility. This study proposed a faster, more economical, and more effective method than conventional cytogenetic methods for the biological dosimetry of ionizing radiation in plants (phytodosimetry). We compared various dose-response curves for the radiation-induced DNA damage response (DDR) in Arabidopsis thaliana after relatively "low-dose" gamma irradiation (3, 6, 12, 24, and 48 Gy) below tens of Gy using comet (or single-cell gel electrophoresis), gamma-H2AX, and transcriptomic assays of seven DDR genes (AGO2, BRCA1, GRG, PARP1, RAD17, RAD51, and RPA1E) using quantitative real time PCR...
November 9, 2017: Journal of Environmental Radioactivity
https://www.readbyqxmd.com/read/29127590/body-mass-index-diet-and-exercise-testing-possible-linkages-to-breast-cancer-risk-via-dna-methylation
#19
Arielle S Gillman, Casey K Gardiner, Claire E Koljack, Angela D Bryan
PURPOSE: To examine DNA methylation as a mechanism linking diet, physical activity, weight status, and breast cancer risk. METHODS: Insufficiently active women of varying weight status, without a history of cancer, completed a maximal exercise test, clinical measurement of height and weight, and a dietary intake measure. They also provided blood samples, which were analyzed to ascertain average methylation of candidate genes related to breast cancer (BRCA1, RUNX3, GALNT9, and PAX6) and inflammation (TLR4 and TLR6)...
November 10, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29126833/brca1-and-brca2-expression-patterns-and-prognostic-significance-in-digestive-system-cancers
#20
Gui-Hua Wang, Chun-Mei Zhao, Ying Huang, Wei Wang, Shu Zhang, Xudong Wang
The role of BRCA1 and BRCA2 genes is mainly to maintain genome integrity in response to DNA damage through different mechanisms. Deregulation of BRCA1 and BRCA2 is associated with the development of tumor and altered sensitivity to chemotherapeutic agents. In this study, we determined protein expression of BRCA1 and BRCA2 in four digestive system cancers (gastric cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic cancer) by immunohistochemistry (IHC) on tissue microarrays. A total of 1546 samples of four types of cancer tissues, their matched adjacent non-tumor tissues, and corresponding benign tissues were studied respectively...
November 7, 2017: Human Pathology
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