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Alkes Price

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https://www.readbyqxmd.com/read/29545095/durvalumab-as-third-line-or-later-treatment-for-advanced-non-small-cell-lung-cancer-atlantic-an-open-label-single-arm-phase-2-study
#1
Marina Chiara Garassino, Byoung-Chul Cho, Joo-Hang Kim, Julien Mazières, Johan Vansteenkiste, Hervé Lena, Jesus Corral Jaime, Jhanelle E Gray, John Powderly, Christos Chouaid, Paolo Bidoli, Paul Wheatley-Price, Keunchil Park, Ross A Soo, Yifan Huang, Catherine Wadsworth, Phillip A Dennis, Naiyer A Rizvi
BACKGROUND: Immune checkpoint inhibitors are a new standard of care for patients with advanced non-small-cell lung cancer (NSCLC) without EGFR tyrosine kinase or anaplastic lymphoma kinase (ALK) genetic aberrations (EGFR-/ALK-), but clinical benefit in patients with EGFR mutations or ALK rearrangements (EGFR+/ALK+) has not been shown. We assessed the effect of durvalumab (anti-PD-L1) treatment in three cohorts of patients with NSCLC defined by EGFR/ALK status and tumour expression of PD-L1...
March 12, 2018: Lancet Oncology
https://www.readbyqxmd.com/read/29507487/standardizing-biomarker-testing-for-canadian-patients-with-advanced-lung-cancer
#2
B Melosky, N Blais, P Cheema, C Couture, R Juergens, S Kamel-Reid, M-S Tsao, P Wheatley-Price, Z Xu, D N Ionescu
Background: The development and approval of both targeted and immune therapies for patients with advanced non-small cell lung cancer (nsclc) has significantly improved patient survival rates and quality of life. Biomarker testing for patients newly diagnosed with nsclc, as well as for patients progressing after treatment with epidermal growth factor receptor ( EGFR ) inhibitors, is the standard of care in Canada and many parts of the world. Methods: A group of thoracic oncology experts in the field of thoracic oncology met to describe the standard for biomarker testing for lung cancer in the Canadian context, focusing on evidence-based recommendations for standard-of-care testing for EGFR , anaplastic lymphoma kinase ( ALK ), ROS1 , BRAF V600 and programmed death-ligand (PD-L1) at the time of diagnosis of advanced disease and EGFR T790M upon progression...
February 2018: Current Oncology
https://www.readbyqxmd.com/read/29496957/quantitative-analysis-of-population-scale-family-trees-with-millions-of-relatives
#3
Joanna Kaplanis, Assaf Gordon, Tal Shor, Omer Weissbrod, Dan Geiger, Mary Wahl, Michael Gershovits, Barak Markus, Mona Sheikh, Melissa Gymrek, Gaurav Bhatia, Daniel G MacArthur, Alkes L Price, Yaniv Erlich
Family trees have vast applications in multiple fields from genetics to anthropology and economics. However, the collection of extended family trees is tedious and usually relies on resources with limited geographical scope and complex data usage restrictions. Here, we collected 86 million profiles from publicly-available online data shared by genealogy enthusiasts. After extensive cleaning and validation, we obtained population-scale family trees, including a single pedigree of 13 million individuals. We leveraged the data to partition the genetic architecture of longevity by inspecting millions of relative pairs and to provide insights into the geographical dispersion of families...
March 1, 2018: Science
https://www.readbyqxmd.com/read/29110330/multiethnic-polygenic-risk-scores-improve-risk-prediction-in-diverse-populations
#4
Carla Márquez-Luna, Po-Ru Loh, Alkes L Price
Methods for genetic risk prediction have been widely investigated in recent years. However, most available training data involves European samples, and it is currently unclear how to accurately predict disease risk in other populations. Previous studies have used either training data from European samples in large sample size or training data from the target population in small sample size, but not both. Here, we introduce a multiethnic polygenic risk score that combines training data from European samples and training data from the target population...
December 2017: Genetic Epidemiology
https://www.readbyqxmd.com/read/28951389/genetically-determined-plasma-lipid-levels-and-risk-of-diabetic-retinopathy-a-mendelian-randomization-study
#5
Lucia Sobrin, Yong He Chong, Qiao Fan, Alfred Gan, Lynn K Stanwyck, Georgia Kaidonis, Jamie E Craig, Jihye Kim, Wen-Ling Liao, Yu-Chuen Huang, Wen-Jane Lee, Yi-Jen Hung, Xiuqing Guo, Yang Hai, Eli Ipp, Samuela Pollack, Heather Hancock, Alkes Price, Alan Penman, Paul Mitchell, Gerald Liew, Albert V Smith, Vilmundur Gudnason, Gavin Tan, Barbara E K Klein, Jane Kuo, Xiaohui Li, Mark W Christiansen, Bruce M Psaty, Kevin Sandow, Richard A Jensen, Ronald Klein, Mary Frances Cotch, Jie Jin Wang, Yucheng Jia, Ching J Chen, Yii-Der Ida Chen, Jerome I Rotter, Fuu-Jen Tsai, Craig L Hanis, Kathryn P Burdon, Tien Yin Wong, Ching-Yu Cheng
Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR ( N = 2,969 case and 4,096 control subjects) and severe DR ( N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables...
December 2017: Diabetes
https://www.readbyqxmd.com/read/28892061/linkage-disequilibrium-dependent-architecture-of-human-complex-traits-shows-action-of-negative-selection
#6
COMPARATIVE STUDY
Steven Gazal, Hilary K Finucane, Nicholas A Furlotte, Po-Ru Loh, Pier Francesco Palamara, Xuanyao Liu, Armin Schoech, Brendan Bulik-Sullivan, Benjamin M Neale, Alexander Gusev, Alkes L Price
Recent work has hinted at the linkage disequilibrium (LD)-dependent architecture of human complex traits, where SNPs with low levels of LD (LLD) have larger per-SNP heritability. Here we analyzed summary statistics from 56 complex traits (average N = 101,401) by extending stratified LD score regression to continuous annotations. We determined that SNPs with low LLD have significantly larger per-SNP heritability and that roughly half of this effect can be explained by functional annotations negatively correlated with LLD, such as DNase I hypersensitivity sites (DHSs)...
October 2017: Nature Genetics
https://www.readbyqxmd.com/read/28749898/recurrence-of-granular-corneal-dystrophy-type-1-after-phototherapeutic-keratectomy-lamellar-keratoplasty-and-penetrating-keratoplasty-in-a-single-population
#7
Darrell R Lewis, Marianne O Price, Matthew T Feng, Francis W Price
PURPOSE: To describe the recurrence of granular corneal dystrophy type 1 (GCD1) after penetrating keratoplasty (PKP), anterior lamellar keratoplasty (ALK), deep anterior lamellar keratoplasty (DALK), and phototherapeutic keratectomy (PTK) in a single population. The time required to achieve best-corrected visual acuity (BCVA) after each intervention was also analyzed. METHODS: Retrospective review of all patients with GCD1 from a single center between 1989 and 2016...
October 2017: Cornea
https://www.readbyqxmd.com/read/28637796/quantifying-the-genetic-correlation-between-multiple-cancer-types
#8
Sara Lindström, Hilary Finucane, Brendan Bulik-Sullivan, Fredrick R Schumacher, Christopher I Amos, Rayjean J Hung, Kristin Rand, Stephen B Gruber, David Conti, Jennifer B Permuth, Hui-Yi Lin, Ellen L Goode, Thomas A Sellers, Laufey T Amundadottir, Rachael Stolzenberg-Solomon, Alison Klein, Gloria Petersen, Harvey Risch, Brian Wolpin, Li Hsu, Jeroen R Huyghe, Jenny Chang-Claude, Andrew Chan, Sonja Berndt, Rosalind Eeles, Douglas Easton, Christopher A Haiman, David J Hunter, Benjamin Neale, Alkes L Price, Peter Kraft
Background: Many cancers share specific genetic risk factors, including both rare high-penetrance mutations and common SNPs identified through genome-wide association studies (GWAS). However, little is known about the overall shared heritability across cancers. Quantifying the extent to which two distinct cancers share genetic origin will give insights to shared biological mechanisms underlying cancer and inform design for future genetic association studies. Methods: In this study, we estimated the pair-wise genetic correlation between six cancer types (breast, colorectal, lung, ovarian, pancreatic, and prostate) using cancer-specific GWAS summary statistics data based on 66,958 case and 70,665 control subjects of European ancestry...
September 2017: Cancer Epidemiology, Biomarkers & Prevention
https://www.readbyqxmd.com/read/28436984/genomic-analyses-identify-hundreds-of-variants-associated-with-age-at-menarche-and-support-a-role-for-puberty-timing-in-cancer-risk
#9
Felix R Day, Deborah J Thompson, Hannes Helgason, Daniel I Chasman, Hilary Finucane, Patrick Sulem, Katherine S Ruth, Sean Whalen, Abhishek K Sarkar, Eva Albrecht, Elisabeth Altmaier, Marzyeh Amini, Caterina M Barbieri, Thibaud Boutin, Archie Campbell, Ellen Demerath, Ayush Giri, Chunyan He, Jouke J Hottenga, Robert Karlsson, Ivana Kolcic, Po-Ru Loh, Kathryn L Lunetta, Massimo Mangino, Brumat Marco, George McMahon, Sarah E Medland, Ilja M Nolte, Raymond Noordam, Teresa Nutile, Lavinia Paternoster, Natalia Perjakova, Eleonora Porcu, Lynda M Rose, Katharina E Schraut, Ayellet V Segrè, Albert V Smith, Lisette Stolk, Alexander Teumer, Irene L Andrulis, Stefania Bandinelli, Matthias W Beckmann, Javier Benitez, Sven Bergmann, Murielle Bochud, Eric Boerwinkle, Stig E Bojesen, Manjeet K Bolla, Judith S Brand, Hiltrud Brauch, Hermann Brenner, Linda Broer, Thomas Brüning, Julie E Buring, Harry Campbell, Eulalia Catamo, Stephen Chanock, Georgia Chenevix-Trench, Tanguy Corre, Fergus J Couch, Diana L Cousminer, Angela Cox, Laura Crisponi, Kamila Czene, George Davey Smith, Eco J C N de Geus, Renée de Mutsert, Immaculata De Vivo, Joe Dennis, Peter Devilee, Isabel Dos-Santos-Silva, Alison M Dunning, Johan G Eriksson, Peter A Fasching, Lindsay Fernández-Rhodes, Luigi Ferrucci, Dieter Flesch-Janys, Lude Franke, Marike Gabrielson, Ilaria Gandin, Graham G Giles, Harald Grallert, Daniel F Gudbjartsson, Pascal Guénel, Per Hall, Emily Hallberg, Ute Hamann, Tamara B Harris, Catharina A Hartman, Gerardo Heiss, Maartje J Hooning, John L Hopper, Frank Hu, David J Hunter, M Arfan Ikram, Hae Kyung Im, Marjo-Riitta Järvelin, Peter K Joshi, David Karasik, Manolis Kellis, Zoltan Kutalik, Genevieve LaChance, Diether Lambrechts, Claudia Langenberg, Lenore J Launer, Joop S E Laven, Stefania Lenarduzzi, Jingmei Li, Penelope A Lind, Sara Lindstrom, YongMei Liu, Jian'an Luan, Reedik Mägi, Arto Mannermaa, Hamdi Mbarek, Mark I McCarthy, Christa Meisinger, Thomas Meitinger, Cristina Menni, Andres Metspalu, Kyriaki Michailidou, Lili Milani, Roger L Milne, Grant W Montgomery, Anna M Mulligan, Mike A Nalls, Pau Navarro, Heli Nevanlinna, Dale R Nyholt, Albertine J Oldehinkel, Tracy A O'Mara, Sandosh Padmanabhan, Aarno Palotie, Nancy Pedersen, Annette Peters, Julian Peto, Paul D P Pharoah, Anneli Pouta, Paolo Radice, Iffat Rahman, Susan M Ring, Antonietta Robino, Frits R Rosendaal, Igor Rudan, Rico Rueedi, Daniela Ruggiero, Cinzia F Sala, Marjanka K Schmidt, Robert A Scott, Mitul Shah, Rossella Sorice, Melissa C Southey, Ulla Sovio, Meir Stampfer, Maristella Steri, Konstantin Strauch, Toshiko Tanaka, Emmi Tikkanen, Nicholas J Timpson, Michela Traglia, Thérèse Truong, Jonathan P Tyrer, André G Uitterlinden, Digna R Velez Edwards, Veronique Vitart, Uwe Völker, Peter Vollenweider, Qin Wang, Elisabeth Widen, Ko Willems van Dijk, Gonneke Willemsen, Robert Winqvist, Bruce H R Wolffenbuttel, Jing Hua Zhao, Magdalena Zoledziewska, Marek Zygmunt, Behrooz Z Alizadeh, Dorret I Boomsma, Marina Ciullo, Francesco Cucca, Tõnu Esko, Nora Franceschini, Christian Gieger, Vilmundur Gudnason, Caroline Hayward, Peter Kraft, Debbie A Lawlor, Patrik K E Magnusson, Nicholas G Martin, Dennis O Mook-Kanamori, Ellen A Nohr, Ozren Polasek, David Porteous, Alkes L Price, Paul M Ridker, Harold Snieder, Tim D Spector, Doris Stöckl, Daniela Toniolo, Sheila Ulivi, Jenny A Visser, Henry Völzke, Nicholas J Wareham, James F Wilson, Amanda B Spurdle, Unnur Thorsteindottir, Katherine S Pollard, Douglas F Easton, Joyce Y Tung, Jenny Chang-Claude, David Hinds, Anna Murray, Joanne M Murabito, Kari Stefansson, Ken K Ong, John R B Perry
The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10-8 ) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues...
June 2017: Nature Genetics
https://www.readbyqxmd.com/read/28343628/functional-architectures-of-local-and-distal-regulation-of-gene-expression-in-multiple-human-tissues
#10
Xuanyao Liu, Hilary K Finucane, Alexander Gusev, Gaurav Bhatia, Steven Gazal, Luke O'Connor, Brendan Bulik-Sullivan, Fred A Wright, Patrick F Sullivan, Benjamin M Neale, Alkes L Price
Genetic variants that modulate gene expression levels play an important role in the etiology of human diseases and complex traits. Although large-scale eQTL mapping studies routinely identify many local eQTLs, the molecular mechanisms by which genetic variants regulate expression remain unclear, particularly for distal eQTLs, which these studies are not well powered to detect. Here, we leveraged all variants (not just those that pass stringent significance thresholds) to analyze the functional architecture of local and distal regulation of gene expression in 15 human tissues by employing an extension of stratified LD-score regression that produces robust results in simulations...
April 6, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28342113/crizotinib-for-untreated-anaplastic-lymphoma-kinase-positive-non-small-cell-lung-cancer-an-evidence-review-group-perspective-of-a-nice-single-technology-appraisal
#11
REVIEW
Philip Morgan, Nerys Woolacott, Mousumi Biswas, Teumzghi Mebrahtu, Melissa Harden, Robert Hodgson
As part of the National Institute for Health and Care Excellence (NICE) single technology appraisal process, the manufacturer of crizotinib submitted evidence on the clinical and cost effectiveness of crizotinib in untreated anaplastic lymphoma kinase-positive (ALK-positive) non-small-cell lung cancer (NSCLC). Crizotinib has previously been assessed by NICE for patients with previously treated ALK-positive NSCLC (TA 296). It was not approved in this previous appraisal, but had been made available through the cancer drugs fund...
September 2017: PharmacoEconomics
https://www.readbyqxmd.com/read/28050149/treatment-patterns-and-survival-in-patients-with-alk-positive-non-small-cell-lung-cancer-a-canadian-retrospective-study
#12
S Kayaniyil, M Hurry, J Wilson, P Wheatley-Price, B Melosky, J Rothenstein, V Cohen, C Koch, J Zhang, K Osenenko, G Liu
BACKGROUND: Crizotinib was the first agent approved for the treatment of anaplastic lymphoma kinase (ALK)-positive (+) non-small-cell lung cancer (nsclc), followed by ceritinib. However, patients eventually progress or develop resistance to crizotinib. With limited real-world data available, the objective of the present work was to evaluate treatment patterns and survival after crizotinib in patients with locally advanced or metastatic ALK+ nsclc in Canada. METHODS: In this retrospective study at 6 oncology centres across Canada, medical records of patients with locally advanced or metastatic ALK+ nsclc were reviewed...
December 2016: Current Oncology
https://www.readbyqxmd.com/read/28017371/mixed-model-association-with-family-biased-case-control-ascertainment
#13
Tristan J Hayeck, Po-Ru Loh, Samuela Pollack, Alexander Gusev, Nick Patterson, Noah A Zaitlen, Alkes L Price
Mixed models have become the tool of choice for genetic association studies; however, standard mixed model methods may be poorly calibrated or underpowered under family sampling bias and/or case-control ascertainment. Previously, we introduced a liability threshold-based mixed model association statistic (LTMLM) to address case-control ascertainment in unrelated samples. Here, we consider family-biased case-control ascertainment, where case and control subjects are ascertained non-randomly with respect to family relatedness...
January 5, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/27814745/deep-targeted-sequencing-of-12-breast-cancer-susceptibility-regions-in-4611-women-across-four-different-ethnicities
#14
Sara Lindström, Akweley Ablorh, Brad Chapman, Alexander Gusev, Gary Chen, Constance Turman, A Heather Eliassen, Alkes L Price, Brian E Henderson, Loic Le Marchand, Oliver Hofmann, Christopher A Haiman, Peter Kraft
BACKGROUND: Although genome-wide association studies (GWASs) have identified thousands of disease susceptibility regions, the underlying causal mechanism in these regions is not fully known. It is likely that the GWAS signal originates from one or many as yet unidentified causal variants. METHODS: Using next-generation sequencing, we characterized 12 breast cancer susceptibility regions identified by GWASs in 2288 breast cancer cases and 2323 controls across four populations of African American, European, Japanese, and Hispanic ancestry...
November 5, 2016: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/27773431/population-structure-of-uk-biobank-and-ancient-eurasians-reveals-adaptation-at-genes-influencing-blood-pressure
#15
Kevin J Galinsky, Po-Ru Loh, Swapan Mallick, Nick J Patterson, Alkes L Price
Analyzing genetic differences between closely related populations can be a powerful way to detect recent adaptation. The very large sample size of the UK Biobank is ideal for using population differentiation to detect selection and enables an analysis of the UK population structure at fine resolution. In this study, analyses of 113,851 UK Biobank samples showed that population structure in the UK is dominated by five principal components (PCs) spanning six clusters: Northern Ireland, Scotland, northern England, southern England, and two Welsh clusters...
November 3, 2016: American Journal of Human Genetics
https://www.readbyqxmd.com/read/27694958/reference-based-phasing-using-the-haplotype-reference-consortium-panel
#16
Po-Ru Loh, Petr Danecek, Pier Francesco Palamara, Christian Fuchsberger, Yakir A Reshef, Hilary K Finucane, Sebastian Schoenherr, Lukas Forer, Shane McCarthy, Goncalo R Abecasis, Richard Durbin, Alkes L Price
Haplotype phasing is a fundamental problem in medical and population genetics. Phasing is generally performed via statistical phasing in a genotyped cohort, an approach that can yield high accuracy in very large cohorts but attains lower accuracy in smaller cohorts. Here we instead explore the paradigm of reference-based phasing. We introduce a new phasing algorithm, Eagle2, that attains high accuracy across a broad range of cohort sizes by efficiently leveraging information from large external reference panels (such as the Haplotype Reference Consortium; HRC) using a new data structure based on the positional Burrows-Wheeler transform...
November 2016: Nature Genetics
https://www.readbyqxmd.com/read/27663502/ld-hub-a-centralized-database-and-web-interface-to-perform-ld-score-regression-that-maximizes-the-potential-of-summary-level-gwas-data-for-snp-heritability-and-genetic-correlation-analysis
#17
MULTICENTER STUDY
Jie Zheng, A Mesut Erzurumluoglu, Benjamin L Elsworth, John P Kemp, Laurence Howe, Philip C Haycock, Gibran Hemani, Katherine Tansey, Charles Laurin, Beate St Pourcain, Nicole M Warrington, Hilary K Finucane, Alkes L Price, Brendan K Bulik-Sullivan, Verneri Anttila, Lavinia Paternoster, Tom R Gaunt, David M Evans, Benjamin M Neale
MOTIVATION: LD score regression is a reliable and efficient method of using genome-wide association study (GWAS) summary-level results data to estimate the SNP heritability of complex traits and diseases, partition this heritability into functional categories, and estimate the genetic correlation between different phenotypes. Because the method relies on summary level results data, LD score regression is computationally tractable even for very large sample sizes. However, publicly available GWAS summary-level data are typically stored in different databases and have different formats, making it difficult to apply LD score regression to estimate genetic correlations across many different traits simultaneously...
January 15, 2017: Bioinformatics
https://www.readbyqxmd.com/read/27449804/a-phase-ii-study-of-pf-03446962-in-patients-with-advanced-malignant-pleural-mesothelioma-cctg-trial-ind-207
#18
Paul Wheatley-Price, Quincy Chu, Maria Bonomi, Jean Seely, Ashish Gupta, Glenwood Goss, John Hilton, Ronald Feld, Christopher W Lee, John R Goffin, Andrew Maksymiuk, Nevin Murray, Linda Hagerman, Penelope A Bradbury
There is no approved second-line systemic therapy option for malignant pleural mesothelioma (MPM), but targeting angiogenesis is an area of investigation. PF-03446962 is a fully human antibody against activin receptor-like kinase 1, which is commonly expressed in tumor vasculature. We performed a multicenter, open label, single-arm, two-stage phase II study of PF-03446962 in patients with MPM and progressive disease after platinum-based chemotherapy. In total, 17 patients were enrolled, but no partial or complete responses were observed...
November 2016: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/27321947/transethnic-genetic-correlation-estimates-from-summary-statistics
#19
Brielin C Brown, Chun Jimmie Ye, Alkes L Price, Noah Zaitlen
The increasing number of genetic association studies conducted in multiple populations provides an unprecedented opportunity to study how the genetic architecture of complex phenotypes varies between populations, a problem important for both medical and population genetics. Here, we have developed a method for estimating the transethnic genetic correlation: the correlation of causal-variant effect sizes at SNPs common in populations. This methods takes advantage of the entire spectrum of SNP associations and uses only summary-level data from genome-wide association studies...
July 7, 2016: American Journal of Human Genetics
https://www.readbyqxmd.com/read/27270109/fast-and-accurate-long-range-phasing-in-a-uk-biobank-cohort
#20
Po-Ru Loh, Pier Francesco Palamara, Alkes L Price
Recent work has leveraged the extensive genotyping of the Icelandic population to perform long-range phasing (LRP), enabling accurate imputation and association analysis of rare variants in target samples typed on genotyping arrays. Here we develop a fast and accurate LRP method, Eagle, that extends this paradigm to populations with much smaller proportions of genotyped samples by harnessing long (>4-cM) identical-by-descent (IBD) tracts shared among distantly related individuals. We applied Eagle to N ≈ 150,000 samples (0...
July 2016: Nature Genetics
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