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https://www.readbyqxmd.com/read/28448241/prediction-of-breast-and-prostate-cancer-risks-in-male-brca1-and-brca2-mutation-carriers-using-polygenic-risk-scores
#1
Julie Lecarpentier, Valentina Silvestri, Karoline B Kuchenbaecker, Daniel Barrowdale, Joe Dennis, Lesley McGuffog, Penny Soucy, Goska Leslie, Piera Rizzolo, Anna Sara Navazio, Virginia Valentini, Veronica Zelli, Andrew Lee, Ali Amin Al Olama, Jonathan P Tyrer, Melissa Southey, Esther M John, Thomas A Conner, David E Goldgar, Saundra S Buys, Ramunas Janavicius, Linda Steele, Yuan Chun Ding, Susan L Neuhausen, Thomas V O Hansen, Ana Osorio, Jeffrey N Weitzel, Angela Toss, Veronica Medici, Laura Cortesi, Ines Zanna, Domenico Palli, Paolo Radice, Siranoush Manoukian, Bernard Peissel, Jacopo Azzollini, Alessandra Viel, Giulia Cini, Giuseppe Damante, Stefania Tommasi, Paolo Peterlongo, Florentia Fostira, Ute Hamann, D Gareth Evans, Alex Henderson, Carole Brewer, Diana Eccles, Jackie Cook, Kai-Ren Ong, Lisa Walker, Lucy E Side, Mary E Porteous, Rosemarie Davidson, Shirley Hodgson, Debra Frost, Julian Adlard, Louise Izatt, Ros Eeles, Steve Ellis, Marc Tischkowitz, Andrew K Godwin, Alfons Meindl, Andrea Gehrig, Bernd Dworniczak, Christian Sutter, Christoph Engel, Dieter Niederacher, Doris Steinemann, Eric Hahnen, Jan Hauke, Kerstin Rhiem, Karin Kast, Norbert Arnold, Nina Ditsch, Shan Wang-Gohrke, Barbara Wappenschmidt, Dorothea Wand, Christine Lasset, Dominique Stoppa-Lyonnet, Muriel Belotti, Francesca Damiola, Laure Barjhoux, Sylvie Mazoyer, Mattias Van Heetvelde, Bruce Poppe, Kim De Leeneer, Kathleen B M Claes, Miguel de la Hoya, Vanesa Garcia-Barberan, Trinidad Caldes, Pedro Perez Segura, Johanna I Kiiski, Kristiina Aittomäki, Sofia Khan, Heli Nevanlinna, Christi J van Asperen, Tibor Vaszko, Miklos Kasler, Edith Olah, Judith Balmaña, Sara Gutiérrez-Enríquez, Orland Diez, Alex Teulé, Angel Izquierdo, Esther Darder, Joan Brunet, Jesús Del Valle, Lidia Feliubadalo, Miquel Angel Pujana, Conxi Lazaro, Adalgeir Arason, Bjarni A Agnarsson, Oskar Th Johannsson, Rosa B Barkardottir, Elisa Alducci, Silvia Tognazzo, Marco Montagna, Manuel R Teixeira, Pedro Pinto, Amanda B Spurdle, Helene Holland, Jong Won Lee, Min Hyuk Lee, Jihyoun Lee, Sung-Won Kim, Eunyoung Kang, Zisun Kim, Priyanka Sharma, Timothy R Rebbeck, Joseph Vijai, Mark Robson, Anne Lincoln, Jacob Musinsky, Pragna Gaddam, Yen Y Tan, Andreas Berger, Christian F Singer, Jennifer T Loud, Mark H Greene, Anna Marie Mulligan, Gord Glendon, Irene L Andrulis, Amanda Ewart Toland, Leigha Senter, Anders Bojesen, Henriette Roed Nielsen, Anne-Bine Skytte, Lone Sunde, Uffe Birk Jensen, Inge Sokilde Pedersen, Lotte Krogh, Torben A Kruse, Maria A Caligo, Sook-Yee Yoon, Soo-Hwang Teo, Anna von Wachenfeldt, Dezheng Huo, Sarah M Nielsen, Olufunmilayo I Olopade, Katherine L Nathanson, Susan M Domchek, Christa Lorenchick, Rachel C Jankowitz, Ian Campbell, Paul James, Gillian Mitchell, Nick Orr, Sue Kyung Park, Mads Thomassen, Kenneth Offit, Fergus J Couch, Jacques Simard, Douglas F Easton, Georgia Chenevix-Trench, Rita K Schmutzler, Antonis C Antoniou, Laura Ottini
Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray...
April 27, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28446639/concordance-of-genomic-alterations-by-next-generation-sequencing-ngs-in-tumor-tissue-versus-circulating-tumor-dna-in-breast-cancer
#2
Young Kwang Chae, Andrew A Davis, Sarika Jain, Cesar Santa-Maria, Lisa Flaum, Nike Beaubier, Leonidas C Platanias, William Gradishar, Francis J Giles, Massimo Cristofanilli
While identifying genomic alterations in tumor tissue is the current gold-standard technique for molecular profiling, circulating tumor DNA (ctDNA) represents a non-invasive method of assessing genomic alterations using peripheral blood. The concordance of genomic alterations between two commercially-available ctDNA and tissue biopsies was compared in 45 patients with breast cancer using paired next-generation sequencing tissue and ctDNA biopsies. Across all genes, concordance between the two platforms was 91...
April 26, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28445046/lead-discovery-of-dual-g-quadruplex-stabilizers-and-poly-adp-ribose-polymerases-parps-inhibitors-a-new-avenue-in-anticancer-treatment
#3
Erica Salvati, Lorenzo Botta, Jussara Amato, Francesco Saverio Di Leva, Pasquale Zizza, Antimo Gioiello, Bruno Pagano, Grazia Graziani, Madalena Tarsounas, Antonio Randazzo, Ettore Novellino, Annamaria Biroccio, Sandro Cosconati
G-quadruplex stabilizers are an established opportunity in anticancer chemotherapy. To circumvent the antiproliferative effects of G4 ligands, cancer cells recruit PARP enzymes at telomeres. Herein, starting from the structural similarity of a potent G4 ligand previously discovered by our group and a congeneric PARP inhibitor, a library of derivatives was synthesized to discover the first dual G4/PARP ligand. We demonstrate that a properly decorated thieno[3,2-c]quinolin-4(5H)-one stabilizes the G4 fold in vitro and in cells, induces a DNA damage response localized to telomeres, inhibits PARylation in cells and has an antiproliferative effect in BRCA2 deficient tumor cells...
April 26, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28444533/breast-cancer-risk-models-a-comprehensive-overview-of-existing-models-validation-and-clinical-applications
#4
REVIEW
Jessica A Cintolo-Gonzalez, Danielle Braun, Amanda L Blackford, Emanuele Mazzola, Ahmet Acar, Jennifer K Plichta, Molly Griffin, Kevin S Hughes
Numerous models have been developed to quantify the combined effect of various risk factors to predict either risk of developing breast cancer, risk of carrying a high-risk germline genetic mutation, specifically in the BRCA1 and BRCA2 genes, or the risk of both. These breast cancer risk models can be separated into those that utilize mainly hormonal and environmental factors and those that focus more on hereditary risk. Given the wide range of models from which to choose, understanding what each model predicts, the populations for which each is best suited to provide risk estimations, the current validation and comparative studies that have been performed for each model, and how to apply them practically is important for clinicians and researchers seeking to utilize risk models in their practice...
April 25, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/28442502/ribonucleotide-reductase-large-subunit-rrm1-as-a-novel-therapeutic-target-in-multiple-myeloma
#5
Morihiko Sagawa, Hiroto Ohguchi, Takeshi Harada, Mehmet K Samur, Yu-Tzu Tai, Nikhil C Munshi, Masahiro Kizaki, Teru Hideshima, Kenneth C Anderson
Purpose: To investigate the biologic and clinical significance of ribonucleotide reductase (RR) in multiple myeloma (MM). <p>Experimental Design: We assessed the impact of RR expression on patient outcome in MM. We then characterized the effect of genetic and pharmacological inhibition of RRM1 on MM growth and survival using siRNA and clofarabine (CLO), respectively, both in vitro and in vivo mouse xenograft model.</p> <p>Results: Newly diagnosed MM patients with higher RRM1 expression have shortened survival...
April 25, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28439188/next-generation-sequencing-reveals-high-prevalence-of-brca1-and-brca2-variants-of-unknown-significance-in-early-onset-breast-cancer-in-african-american-women
#6
Luisel Ricks-Santi, J Tyson McDonald, Bert Gold, Michael Dean, Nicole Thompson, Muneer Abbas, Bradford Wilson, Yasmine Kanaan, Tammey J Naab, Georgia Dunston
BACKGROUND: Variants of unknown significance (VUSs) have been identified in BRCA1 and BRCA2 and account for the majority of all identified sequence alterations. Notably, VUSs occur disproportionately in people of African descent hampering breast cancer (BCa) management and prevention efforts in the population. Our study sought to identify and characterize mutations associated with increased risk of BCa at young age. METHODS: In our study, the spectrum of mutations in BRCA1 and BRCA2 was enumerated in a cohort of 31 African American women of early age at onset breast cancer, with a family history of breast or cancer in general and/or with triple negative breast cancer...
2017: Ethnicity & Disease
https://www.readbyqxmd.com/read/28436987/genomic-consequences-of-aberrant-dna-repair-mechanisms-stratify-ovarian-cancer-histotypes
#7
Yi Kan Wang, Ali Bashashati, Michael S Anglesio, Dawn R Cochrane, Diljot S Grewal, Gavin Ha, Andrew McPherson, Hugo M Horlings, Janine Senz, Leah M Prentice, Anthony N Karnezis, Daniel Lai, Mohamed R Aniba, Allen W Zhang, Karey Shumansky, Celia Siu, Adrian Wan, Melissa K McConechy, Hector Li-Chang, Alicia Tone, Diane Provencher, Manon de Ladurantaye, Hubert Fleury, Aikou Okamoto, Satoshi Yanagida, Nozomu Yanaihara, Misato Saito, Andrew J Mungall, Richard Moore, Marco A Marra, C Blake Gilks, Anne-Marie Mes-Masson, Jessica N McAlpine, Samuel Aparicio, David G Huntsman, Sohrab P Shah
We studied the whole-genome point mutation and structural variation patterns of 133 tumors (59 high-grade serous (HGSC), 35 clear cell (CCOC), 29 endometrioid (ENOC), and 10 adult granulosa cell (GCT)) as a substrate for class discovery in ovarian cancer. Ab initio clustering of integrated point mutation and structural variation signatures identified seven subgroups both between and within histotypes. Prevalence of foldback inversions identified a prognostically significant HGSC group associated with inferior survival...
April 24, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28431939/modulation-of-hat-activity-by-the-brca2n372hvariation-is-a-novel-mechanism-of-paclitaxel-resistance-in-breast-cancer-cell-lines
#8
Woo Sun Kwon, Sun Young Rha, Hei-Cheul Jeung, Tae Soo Kim, Hyun Cheol Chung
Paclitaxel stabilizes microtubule polymerization, enhances microtubule assembly, andG2/M arrests, leading to cell death. Paclitaxel resistance has been attributed to a variety of mechanisms. In the present study, we define a new resistance mechanism to paclitaxel based onBRCA2variation. Chemo-sensitivity to paclitaxel based on the variations was compared. Restoration of paclitaxel sensitivity was induced indirectly with combined treatment of paclitaxel and HDAC inhibitor. Variant and wild type of BRCA2 clones were obtained from wild and variant cells, respectively...
April 18, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28431926/multiple-repair-pathways-mediate-cellular-tolerance-to-resveratrol-induced-dna-damage
#9
Ying Liu, Xiaohua Wu, Xiaoqing Hu, Ziyuan Chen, Hao Liu, Shunichi Takeda, Yong Qing
Resveratrol (RSV) has been reported to exert health benefits for the prevention and treatment of many diseases, including cancer. The anticancer mechanisms of RSV seem to be complex and may be associated with genotoxic potential. To better understand the genotoxic mechanisms, we used wild-type (WT) and a panel of isogenic DNA-repair deficient DT40 cell lines to identify the DNA damage effects and molecular mechanisms of cellular tolerance to RSV. Our results showed that RSV induced significant formation of γ-H2AX foci and chromosome aberrations (CAs) in WT cells, suggesting direct DNA damage effects...
April 18, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/28429680/the-inhibitory-effects-of-hydamtiq-a-novel-parp-inhibitor-on-growth-in-human-tumor-cell-lines-with-defective-dna-damage-response-pathways
#10
Enrico Mini, Ida Landini, Laura Lucarini, Andrea Lapucci, Cristina Napoli, Gabriele Perrone, Renato Tassi, Emanuela Masini, Flavio Moroni, Stefania Nobili
The poly(ADP-ribose) polymerase (PARP) enzymes play key roles in the regulation of cellular processes (e.g. DNA damagerepair, genomic stability). It has been shown that PARP inhibitors (PARPIs) are selectively cytotoxic against cells with dysfunctions in genes involved in DNA repair mechanisms (synthetic lethality). Drug induced PARP inhibition potentiates the activity of anticancer drugs such as 5-fluorouracil in enhancing DNA damage, whose repair involves PARP1 activity.The aim of this study was to evaluate the growth inhibitory effects of a novel PARPI, HYDAMTIQ, on human tumor cell lines characterized by different features with regard to DNA damage response pathways (BRCA mutational status, microsatellite status and ATM expression level) and degree of sensitivity/resistance to 5-fluorouracil...
April 20, 2017: Oncology Research
https://www.readbyqxmd.com/read/28423802/a-lens-for-evaluating-genetic-information-governance-models-balancing-equity-efficiency-and-sustainability
#11
Espen Skorve, Polyxeni Vassilakopoulou, Margunn Aanestad, Thomas Grünfeld
This paper draws from the literature on collective action and the governance of the commons to address the governance of genetic data on variants of specific genes. Specifically, the data arrangements under study relate to the BRCA genes (BRCA1 and BRCA2) which are linked to breast and ovarian cancer. These data are stored in global genetic data repositories and accessed by researchers and clinicians, from both public and private institutions. The current BRCA data arrangements are fragmented and politicized as there are multiple tensions around data ownership and sharing...
2017: Studies in Health Technology and Informatics
https://www.readbyqxmd.com/read/28423763/learning-healthcare-system-for-the-prescription-of-genetic-testing-in-the-gynecological-cancer-risk
#12
Cristina Suárez-Mejías, Alicia Martínez-García, María Ángeles Martínez-Maestre, José Manuel Silvan-Alfaro, Jesús Moreno Conde, Carlos Luis Parra-Calderón
Clinical evidence demonstrates that BRCA 1 and BRCA2 mutations can develop a gynecological cancer but genetic testing has a high cost to the healthcare system. Besides, several studies in the literature indicate that performing these genetic tests to the population is not cost-efficient. Currently, our physicians do not have a system to provide them the support for prescribing genetic tests. A Decision Support System for prescribing these genetic tests in BRCA1 and BRCA2 and preventing gynecological cancer risks has been designed, developed and deployed in the Virgen del Rocío University Hospital (VRUH)...
2017: Studies in Health Technology and Informatics
https://www.readbyqxmd.com/read/28423363/multiple-gene-panel-analysis-in-a-case-series-of-255-women-with-hereditary-breast-and-ovarian-cancer
#13
Gianluca Tedaldi, Michela Tebaldi, Valentina Zampiga, Rita Danesi, Valentina Arcangeli, Mila Ravegnani, Ilaria Cangini, Francesca Pirini, Elisabetta Petracci, Andrea Rocca, Fabio Falcini, Dino Amadori, Daniele Calistri
As new genes predisposing to breast (BC) and ovarian cancer (OC) are constantly emerging, the use of panels of genes analyzed by Next-Generation Sequencing (NGS) is increasing in clinical diagnostics. The identification of a large number of new germline mutations allows for deeper knowledge of cancer predisposition, although raising many questions about patient management.BC and OC patients recruited by our counseling service between 2012-2015 were included in this study. DNA was extracted from peripheral blood and a panel of 94 genes involved in hereditary tumors was analyzed by NGS...
April 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423155/the-role-of-genetic-testing-in-patients-with-breast-cancer-a-review
#14
Olivia M Valencia, Selyne E Samuel, Rebecca K Viscusi, Taylor S Riall, Leigh A Neumayer, Hassan Aziz
Importance: In the United States from 2009 to 2013, the incidence of breast cancer was the highest of any cancer and the death rate was second to that of lung cancer. Approximately 5% to 10% of breast cancers are inheritable. Observations: BRCA1 and BRCA2 germline mutations account for up to 30% of inheritable breast cancers and are the most commonly assessed mutations in patients presenting with early-onset breast cancer, triple-negative breast cancer, bilateral breast cancer, and a family history of breast cancer...
April 19, 2017: JAMA Surgery
https://www.readbyqxmd.com/read/28422718/validation-and-optimization-of-the-ion-torrent-s5-xl-sequencer-and-oncomine-workflow-for-brca1-and-brca2-genetic-testing
#15
Saeam Shin, Yoonjung Kim, Seoung Chul Oh, Nae Yu, Seung-Tae Lee, Jong Rak Choi, Kyung-A Lee
In this study, we validated the analytical performance of BRCA1/2 sequencing using Ion Torrent's new bench-top sequencer with amplicon panel with optimized bioinformatics pipelines. Using 43 samples that were previously validated by Illumina's MiSeq platform and/or by Sanger sequencing/multiplex ligation-dependent probe amplification, we amplified the target with the Oncomine™ BRCA Research Assay and sequenced on Ion Torrent S5 XL (Thermo Fisher Scientific, Waltham, MA, USA). We compared two bioinformatics pipelines for optimal processing of S5 XL sequence data: the Torrent Suite with a plug-in Torrent Variant Caller (Thermo Fisher Scientific), and commercial NextGENe software (Softgenetics, State College, PA, USA)...
April 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28419251/evaluating-genetic-variants-associated-with-breast-cancer-risk-in-high-and-moderate-penetrance-genes-in-asians
#16
Mi-Ryung Han, Wei Zheng, Qiuyin Cai, Yu-Tang Gao, Ying Zheng, Manjeet K Bolla, Kyriaki Michailidou, Joe Dennis, Qin Wang, Alison M Dunning, Paul Brennan, Shou-Tung Chen, Ji-Yeob Choi, Mikael Hartman, Hidemi Ito, Artitaya Lophatananon, Keitaro Matsuo, Hui Miao, Kenneth Muir, Suleeporn Sangrajrang, Chen-Yang Shen, Soo Hwang Teo, Chiu-Chen Tseng, Anna H Wu, Cheng Har Yip, Daehee Kang, Yong-Bing Xiang, Douglas F Easton, Xiao-Ou Shu, Jirong Long
Over the past 20 years, high-penetrance pathogenic mutations in genes BRCA1, BRCA2, TP53, PTEN, STK11, and CDH1 and moderate-penetrance mutations in genes CHEK2, ATM, BRIP1, PALB2, RAD51C, RAD50, and NBN have been identified for breast cancer. In the present study, we investigated whether there are additional variants in these 13 genes associated with breast cancer among women of Asian ancestry. We analyzed up to 654 single nucleotide polymorphisms (SNPs) from 6269 cases and 6624 controls of Asian descent included in the Breast Cancer Association Consortium (BCAC), and up to 236 SNPs from 5794 cases and 5529 controls included in the Shanghai Breast Cancer Genetics Study (SBCGS)...
April 17, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/28419182/molecular-classification-of-pulmonary-sarcomatoid-carcinomas-suggests-new-therapeutic-opportunities
#17
N Pécuchet, T Vieira, N Rabbe, M Antoine, H Blons, J Cadranel, P Laurent-Puig, M Wislez
Background: Pulmonary sarcomatoid carcinoma (SC) is a rare disease with poor prognosis and with strong inter- and intratumor heterogeneity. However, molecular classification is currently focused on activating MET mutations. We sought to better characterize the molecular diversity of SC using mutational signatures that reflect different mutational processes, such as tobacco-associated adducts (signature 4), BRCA1/BRCA2 deficiency (signature 3) or APOBEC enzyme deamination (signatures 2&13)...
April 13, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28418854/association-between-the-brca2-rs144848-polymorphism-and-cancer-susceptibility-a-meta-analysis
#18
REVIEW
Qiuyan Li, Rongwei Guan, Yuandong Qiao, Chang Liu, Ning He, Xuelong Zhang, Xueyuan Jia, Haiming Sun, Jingcui Yu, Lidan Xu
The BRCA2 gene plays an important role in cancer carcinogenesis, and polymorphisms in this gene have been associated with cancer risk. The BRCA2 rs144848 polymorphism has been associated with several cancers, but results have been inconsistent. In the present study, a meta-analysis was performed to assess the association between the rs144848 polymorphism and cancer risk. Literature was searched from the databases of PubMed, Embase and Google Scholar before April 2016. The fixed or random effects model was used to calculate pooled odd ratios on the basis of heterogeneity...
March 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28418444/associations-between-cancer-predisposition-testing-panel-genes-and-breast-cancer
#19
Fergus J Couch, Hermela Shimelis, Chunling Hu, Steven N Hart, Eric C Polley, Jie Na, Emily Hallberg, Raymond Moore, Abigail Thomas, Jenna Lilyquist, Bingjian Feng, Rachel McFarland, Tina Pesaran, Robert Huether, Holly LaDuca, Elizabeth C Chao, David E Goldgar, Jill S Dolinsky
Importance: Germline pathogenic variants in BRCA1 and BRCA2 predispose to an increased lifetime risk of breast cancer. However, the relevance of germline variants in other genes from multigene hereditary cancer testing panels is not well defined. Objective: To determine the risks of breast cancer associated with germline variants in cancer predisposition genes. Design, Setting, and Participants: A study population of 65 057 patients with breast cancer receiving germline genetic testing of cancer predisposition genes with hereditary cancer multigene panels...
April 13, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/28415599/brca1-missense-polymorphisms-are-associated-with-poor-prognosis-of-pancreatic-cancer-patients-in-a-chinese-population
#20
Ying Zhu, Kan Zhai, Juntao Ke, Jiaoyuan Li, Yajie Gong, Yang Yang, Jianbo Tian, Yi Zhang, Danyi Zou, Xiating Peng, Jing Gong, Rong Zhong, Kun Huang, Jiang Chang, Xiaoping Miao
Pancreatic cancer is a highly lethal disease with limited prognostic marker. BRAC1 and BRCA2 are two classic tumor suppressor genes which play an important role in DNA repair. Somatic mutations and germline genetic variants on BRCA1/2 have been found associated with the tumorigenesis of pancreatic cancer. However, the correlations between BRCA1/2 polymorphism and pancreatic cancer prognosis remained unknown. In this study, we genotyped three tag missense variants on BRCA1/2 in 603 sporadic pancreatic cancer patients in a Chinese population...
March 21, 2017: Oncotarget
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