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https://www.readbyqxmd.com/read/27885265/the-disparate-origins-of-ovarian-cancers-pathogenesis-and-prevention-strategies
#1
Anthony N Karnezis, Kathleen R Cho, C Blake Gilks, Celeste Leigh Pearce, David G Huntsman
Ovarian cancer is the fifth cause of cancer-related death in women and comprises a histologically and genetically broad range of tumours, including those of epithelial, sex cord-stromal and germ cell origin. Recent evidence indicates that high-grade serous ovarian carcinoma, clear cell carcinoma and endometrioid carcinoma primarily arise from tissues that are not normally present in the ovary. These histogenetic pathways are informing risk-reduction strategies for the prevention of ovarian and ovary-associated cancers and have highlighted the importance of the seemingly unique ovarian microenvironment...
November 25, 2016: Nature Reviews. Cancer
https://www.readbyqxmd.com/read/27822414/differences-in-mek-inhibitor-efficacy-in-molecularly-characterized-low-grade-serous-ovarian-cancer-cell-lines
#2
Marta Llauradó Fernández, Gabriel E DiMattia, Amy Dawson, Sylvia Bamford, Shawn Anderson, Bryan T Hennessy, Michael S Anglesio, Trevor G Shepherd, Clara Salamanca, Josh Hoenisch, Anna Tinker, David G Huntsman, Mark S Carey
Advanced or recurrent low-grade serous ovarian cancers (LGSC) are resistant to conventional systemic treatments. LGSC carry mutations in RAS or RAF, leading to several clinical trials evaluating MEK inhibitors (MEKi). As LGSC cell lines and xenografts have been difficult to establish, little is known about the efficacy and on-target activity of MEKi treatment in this disease. We compared four different MEKi (trametinib, selumetinib, binimetinib and refametinib) in novel LGSC patient-derived cell lines. Molecular characterization of these cells included copy-number variation and hotspot mutational analysis...
2016: American Journal of Cancer Research
https://www.readbyqxmd.com/read/27810330/foxl2-402c-g-mutation-can-be-identified-in-the-circulating-tumor-dna-of-patients-with-adult-granulosa-cell-tumors
#3
Anniina Färkkilä, Melissa K McConechy, Winnie Yang, Aline Talhouk, Ying Ng, Amy Lum, Ryan D Morin, Kevin Bushell, Annika Riska, Jessica N McAlpine, C Blake Gilks, Leila Unkila-Kallio, Mikko Anttonen, David G Huntsman
Adult granulosa cell tumors (AGCTs) of the ovary are molecularly characterized by the pathognomonic FOXL2 402C>G (C134W) mutation. To improve diagnostics and follow-up, we developed a specific digital droplet PCR (ddPCR) assay to detect the FOXL2 mutation in the circulating tumor DNA (ctDNA) of AGCT patients. Optimization of the ddPCR assay was performed using a TaqMan primer/probe with the RainDance RainDrop digital PCR system. The ddPCR assay was performed on circulating cell-free DNA extracted from 120 serial plasma samples collected prospectively from 35 AGCT patients...
October 31, 2016: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/27729941/conditional-survival-of-metastatic-renal-cell-carcinoma-patients-treated-with-high-dose-interleukin-2
#4
David M Gill, David D Stenehjem, Kinjal Parikh, Joseph Merriman, Arun Sendilnathan, Archana M Agarwal, Andrew W Hahn, Sumati Gupta, Srinivas Kiran Tantravahi, Wolfram E Samlowski, Neeraj Agarwal
Conditional survival (CS) is a clinically useful prediction measure which adjusts a patient's prognosis based on their duration of survival since initiation of therapy. CS has been described in numerous malignancies, and recently described in patients with metastatic renal cell carcinoma (mRCC) who received vascular endothelial growth factor tyrosine kinase inhibitor (VEGFTKI) therapy. However, CS has been not reported in the context of mRCC treated with high-dose interleukin-2 therapy (HDIL-2). A total of 176 patients with histologically confirmed metastatic clear cell RCC (mccRCC) treated with HDIL-2 at the University of Utah Huntsman Cancer Institute from 1988-2012 were evaluated...
2016: Ecancermedicalscience
https://www.readbyqxmd.com/read/27721458/dies1-vista-expression-loss-is-a-recurrent-event-in-gastric-cancer-due-to-epigenetic-regulation
#5
Patrícia Oliveira, Joana Carvalho, Sara Rocha, Mafalda Azevedo, Inês Reis, Vânia Camilo, Bárbara Sousa, Sofia Valente, Joana Paredes, Raquel Almeida, David Huntsman, Carla Oliveira
Dies1/VISTA induces embryonic stem-cell differentiation, via BMP-pathway, but also acts as inflammation regulator and immune-response modulator. Dies1 inhibition in a melanoma-mouse model led to increased tumour-infiltrating T-cells and decreased tumour growth, emphasizing Dies1 relevance in tumour-microenvironment. Dies1 is involved in cell de/differentiation, inflammation and cancer processes, which mimic those associated with Epithelial-to-Mesenchymal-Transition (EMT). Despite this axis linking Dies1 with EMT and cancer, its expression, modulation and relevance in these contexts is unknown...
October 10, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27713570/quantitative-profiling-of-single-formalin-fixed-tumour-sections-proteomics-for-translational-research
#6
Christopher S Hughes, Melissa K McConechy, Dawn R Cochrane, Tayyebeh Nazeran, Anthony N Karnezis, David G Huntsman, Gregg B Morin
Although re-sequencing of gene panels and mRNA expression profiling are now firmly established in clinical laboratories, in-depth proteome analysis has remained a niche technology, better suited for studying model systems rather than challenging materials such as clinical trial samples. To address this limitation, we have developed a novel and optimized platform called SP3-Clinical Tissue Proteomics (SP3-CTP) for in-depth proteome profiling of practical quantities of tumour tissues, including formalin fixed and paraffin embedded (FFPE)...
October 7, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27662035/frequent-nfib-associated-gene-rearrangement-in-adenoid-cystic-carcinoma-of-the-vulva
#7
Deyin Xing, Salwa Bakhsh, Nataliya Melnyk, Christina Isacson, Julie Ho, David G Huntsman, C Blake Gilks, Brigitte M Ronnett, Hugo M Horlings
Adenoid cystic carcinoma is a rare malignant tumor that usually arises in the major and minor salivary glands and other locations containing secretory glands, including the lower female genital tract. Lower female genital tract carcinomas with adenoid cystic differentiation can be subclassified into 2 distinct groups based on the presence or absence of high-risk HPV. Cervical mixed carcinomas with some adenoid cystic differentiation are high-risk HPV-related but pure adenoid cystic carcinomas of vulvar and cervical origin appear to be unrelated to high-risk HPV...
September 22, 2016: International Journal of Gynecological Pathology
https://www.readbyqxmd.com/read/27587788/a-meta-analysis-of-multiple-myeloma-risk-regions-in-african-and-european-ancestry-populations-identifies-putatively-functional-loci
#8
Kristin A Rand, Chi Song, Eric Dean, Daniel J Serie, Karen Curtin, Xin Sheng, Donglei Hu, Carol Ann Huff, Leon Bernal-Mizrachi, Michael H Tomasson, Sikander Ailawadhi, Seema Singhal, Karen Pawlish, Edward S Peters, Cathryn H Bock, Alex Stram, David J Van Den Berg, Christopher K Edlund, David V Conti, Todd Zimmerman, Amie E Hwang, Scott Huntsman, John Graff, Ajay Nooka, Yinfei Kong, Silvana L Pregja, Sonja I Berndt, William J Blot, John Carpten, Graham Casey, Lisa Chu, W Ryan Diver, Victoria L Stevens, Michael R Lieber, Phyllis J Goodman, Anselm J M Hennis, Ann W Hsing, Jayesh Mehta, Rick A Kittles, Suzanne Kolb, Eric A Klein, Cristina Leske, Adam B Murphy, Barbara Nemesure, Christine Neslund-Dudas, Sara S Strom, Ravi Vij, Benjamin A Rybicki, Janet L Stanford, Lisa B Signorello, John S Witte, Christine B Ambrosone, Parveen Bhatti, Esther M John, Leslie Bernstein, Wei Zheng, Andrew F Olshan, Jennifer J Hu, Regina G Ziegler, Sarah J Nyante, Elisa V Bandera, Brenda M Birmann, Sue A Ingles, Michael F Press, Djordje Atanackovic, Martha J Glenn, Lisa A Cannon-Albright, Brandt Jones, Guido Tricot, Thomas G Martin, Shaji K Kumar, Jeffrey L Wolf, Sandra L Deming Halverson, Nathaniel Rothman, Angela R Brooks-Wilson, S Vincent Rajkumar, Laurence N Kolonel, Stephen J Chanock, Susan L Slager, Richard K Severson, Nalini Janakiraman, Howard R Terebelo, Elizabeth E Brown, Anneclaire J De Roos, Ann F Mohrbacher, Graham A Colditz, Graham G Giles, John J Spinelli, Brian C Chiu, Nikhil C Munshi, Kenneth C Anderson, Joan Levy, Jeffrey A Zonder, Robert Z Orlowski, Sagar Lonial, Nicola J Camp, Celine M Vachon, Elad Ziv, Daniel O Stram, Dennis J Hazelett, Christopher A Haiman, Wendy Cozen
BACKGROUND: Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma. METHODS: We performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality...
December 2016: Cancer Epidemiology, Biomarkers & Prevention
https://www.readbyqxmd.com/read/27563487/clinically-inspired-automatic-classification-of-ovarian-carcinoma-subtypes
#9
Aïcha BenTaieb, Masoud S Nosrati, Hector Li-Chang, David Huntsman, Ghassan Hamarneh
CONTEXT: It has been shown that ovarian carcinoma subtypes are distinct pathologic entities with differing prognostic and therapeutic implications. Histotyping by pathologists has good reproducibility, but occasional cases are challenging and require immunohistochemistry and subspecialty consultation. Motivated by the need for more accurate and reproducible diagnoses and to facilitate pathologists' workflow, we propose an automatic framework for ovarian carcinoma classification. MATERIALS AND METHODS: Our method is inspired by pathologists' workflow...
2016: Journal of Pathology Informatics
https://www.readbyqxmd.com/read/27562491/concurrent-arid1a-and-arid1b-inactivation-in-endometrial-and-ovarian-dedifferentiated-carcinomas
#10
Mackenzie Coatham, Xiaodong Li, Anthony N Karnezis, Lien N Hoang, Basile Tessier-Cloutier, Bo Meng, Robert A Soslow, C Blake Gilks, David G Huntsman, Colin J R Stewart, Lynne M Postovit, Martin Köbel, Cheng-Han Lee
Dedifferentiated carcinoma of the endometrium or the ovary is an aggressive epithelial malignancy that comprises an endometrioid carcinoma together with an undifferentiated carcinoma. We recently reported that inactivation of BRG1 or INI1, core subunits of the switch/sucrose non-fermenting (SWI/SNF) complex, was the likely molecular event underlying dedifferentiation in about half of dedifferentiated carcinomas. In this study, we performed a genomic screen that included other members of the SWI/SNF complex to better delineate the molecular basis in the remainder of these tumours...
August 26, 2016: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/27499902/in-depth-molecular-profiling-of-the-biphasic-components-of-uterine-carcinosarcomas
#11
Melissa K McConechy, Lien N Hoang, Michael Herman Chui, Janine Senz, Winnie Yang, Nirit Rozenberg, Robertson Mackenzie, Jessica N McAlpine, David G Huntsman, Blaise A Clarke, Cyril Blake Gilks, Cheng-Han Lee
Uterine carcinosarcoma is a clinically aggressive malignancy composed of a mix of carcinomatous and sarcomatous elements. We performed targeted next-generation sequencing of 27 uterine cancer and sarcoma genes together with immunohistochemical analyses of selected proteins in 30 uterine carcinosarcomas. This included 13 cases in which the distinct carcinoma and sarcoma components were sequenced separately and 10 cases where the metastatic tumours were analysed in addition to the primary tumours. We identified non-synonymous somatic mutations in 90% of the cases, with 27 of 30 cases (90%) harbouring TP53 alterations...
July 2015: Journal of Pathology. Clinical Research
https://www.readbyqxmd.com/read/27421752/molecular-classification-of-endometrial-carcinoma-on-diagnostic-specimens-is-highly-concordant-with-final-hysterectomy-earlier-prognostic-information-to-guide-treatment
#12
Aline Talhouk, Lien N Hoang, Melissa K McConechy, Quentin Nakonechny, Joyce Leo, Angela Cheng, Samuel Leung, Winnie Yang, Amy Lum, Martin Köbel, Cheng-Han Lee, Robert A Soslow, David G Huntsman, C Blake Gilks, Jessica N McAlpine
OBJECTIVE: Categorization and risk stratification of endometrial carcinomas is inadequate; histomorphologic assessment shows considerable interobserver variability, and risk of metastases and recurrence can only be derived after surgical staging. We have developed a Proactive Molecular Risk classification tool for Endometrial cancers (ProMisE) that identifies four distinct prognostic subgroups. Our objective was to assess whether molecular classification could be performed on diagnostic endometrial specimens obtained prior to surgical staging and its concordance with molecular classification performed on the subsequent hysterectomy specimen...
October 2016: Gynecologic Oncology
https://www.readbyqxmd.com/read/27355533/efficacy-and-safety-of-midostaurin-in-advanced-systemic-mastocytosis
#13
MULTICENTER STUDY
Jason Gotlib, Hanneke C Kluin-Nelemans, Tracy I George, Cem Akin, Karl Sotlar, Olivier Hermine, Farrukh T Awan, Elizabeth Hexner, Michael J Mauro, David W Sternberg, Matthieu Villeneuve, Alice Huntsman Labed, Eric J Stanek, Karin Hartmann, Hans-Peter Horny, Peter Valent, Andreas Reiter
BACKGROUND: Advanced systemic mastocytosis comprises rare hematologic neoplasms that are associated with a poor prognosis and lack effective treatment options. The multikinase inhibitor midostaurin inhibits KIT D816V, a primary driver of disease pathogenesis. METHODS: We conducted an open-label study of oral midostaurin at a dose of 100 mg twice daily in 116 patients, of whom 89 with mastocytosis-related organ damage were eligible for inclusion in the primary efficacy population; 16 had aggressive systemic mastocytosis, 57 had systemic mastocytosis with an associated hematologic neoplasm, and 16 had mast-cell leukemia...
June 30, 2016: New England Journal of Medicine
https://www.readbyqxmd.com/read/27297428/molecularly-defined-adult-granulosa-cell-tumor-of-the-ovary-the-clinical-phenotype
#14
Melissa K McConechy, Anniina Färkkilä, Hugo M Horlings, Aline Talhouk, Leila Unkila-Kallio, Hannah S van Meurs, Winnie Yang, Nirit Rozenberg, Noora Andersson, Katharina Zaby, Saara Bryk, Ralf Bützow, Johannes B G Halfwerk, Gerrit K J Hooijer, Marc J van de Vijver, Marrije R Buist, Gemma G Kenter, Sara Y Brucker, Bernhard Krämer, Annette Staebler, Maaike C G Bleeker, Markku Heikinheimo, Stefan Kommoss, C Blake Gilks, Mikko Anttonen, David G Huntsman
The histopathologic features of adult granulosa cell tumors (AGCTs) are relatively nonspecific, resulting in misdiagnosis of other cancers as AGCT, a problem that has not been well characterized. FOXL2 mutation testing was used to stratify 336 AGCTs from three European centers into three categories: 1) FOXL2 mutant molecularly defined AGCT (MD-AGCT) (n = 256 of 336), 2) FOXL2 wild-type AGCT (n = 17 of 336), 3) misdiagnosed other tumor types (n = 63 of 336). All statistical tests were two-sided. The overall and disease-specific survival of the misdiagnosed cases was lower than in the MD-AGCTs (P < ...
November 2016: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/27182968/divergent-modes-of-clonal-spread-and-intraperitoneal-mixing-in-high-grade-serous-ovarian-cancer
#15
Andrew McPherson, Andrew Roth, Emma Laks, Tehmina Masud, Ali Bashashati, Allen W Zhang, Gavin Ha, Justina Biele, Damian Yap, Adrian Wan, Leah M Prentice, Jaswinder Khattra, Maia A Smith, Cydney B Nielsen, Sarah C Mullaly, Steve Kalloger, Anthony Karnezis, Karey Shumansky, Celia Siu, Jamie Rosner, Hector Li Chan, Julie Ho, Nataliya Melnyk, Janine Senz, Winnie Yang, Richard Moore, Andrew J Mungall, Marco A Marra, Alexandre Bouchard-Côté, C Blake Gilks, David G Huntsman, Jessica N McAlpine, Samuel Aparicio, Sohrab P Shah
We performed phylogenetic analysis of high-grade serous ovarian cancers (68 samples from seven patients), identifying constituent clones and quantifying their relative abundances at multiple intraperitoneal sites. Through whole-genome and single-nucleus sequencing, we identified evolutionary features including mutation loss, convergence of the structural genome and temporal activation of mutational processes that patterned clonal progression. We then determined the precise clonal mixtures comprising each tumor sample...
July 2016: Nature Genetics
https://www.readbyqxmd.com/read/27148575/lessons-learned-from-the-application-of-whole-genome-analysis-to-the-treatment-of-patients-with-advanced-cancers
#16
Janessa Laskin, Steven Jones, Samuel Aparicio, Stephen Chia, Carolyn Ch'ng, Rebecca Deyell, Peter Eirew, Alexandra Fok, Karen Gelmon, Cheryl Ho, David Huntsman, Martin Jones, Katayoon Kasaian, Aly Karsan, Sreeja Leelakumari, Yvonne Li, Howard Lim, Yussanne Ma, Colin Mar, Monty Martin, Richard Moore, Andrew Mungall, Karen Mungall, Erin Pleasance, S Rod Rassekh, Daniel Renouf, Yaoqing Shen, Jacqueline Schein, Kasmintan Schrader, Sophie Sun, Anna Tinker, Eric Zhao, Stephen Yip, Marco A Marra
Given the success of targeted agents in specific populations it is expected that some degree of molecular biomarker testing will become standard of care for many, if not all, cancers. To facilitate this, cancer centers worldwide are experimenting with targeted "panel" sequencing of selected mutations. Recent advances in genomic technology enable the generation of genome-scale data sets for individual patients. Recognizing the risk, inherent in panel sequencing, of failing to detect meaningful somatic alterations, we sought to establish processes to integrate data from whole-genome analysis (WGA) into routine cancer care...
October 2015: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27100627/loss-of-smarca4-brg1-protein-expression-by-immunohistochemistry-in-small-cell-carcinoma-of-the-ovary-hypercalcemic-type-distinguishes-these-tumors-from-their-mimics
#17
Blaise A Clarke, Leora Witkowski, Tuyet Nhung Ton Nu, Patricia A Shaw, C Blake Gilks, David Huntsman, Tony Karnezis, Neil Sebire, Janez Lamovec, Lawrence M Roth, Colin Jr Stewart, Martin Hasselblatt, William D Foulkes, W Glenn McCluggage
AIMS: Molecular interrogation of small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) has revealed that it is a monogenetic tumor characterized by alteration of SMARCA4 (BRG1), a member of the Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex. A large majority of cases show loss of expression of the corresponding SMARCA4/BRG1 protein. Furthermore, three cases of SCCOHT with retained SMARCA4 protein expression demonstrated loss of expression of SMARCB1/ INI1...
April 21, 2016: Histopathology
https://www.readbyqxmd.com/read/27096160/single-patient-molecular-testing-with-nanostring-ncounter-data-using-a-reference-based-strategy-for-batch-effect-correction
#18
Aline Talhouk, Stefan Kommoss, Robertson Mackenzie, Martin Cheung, Samuel Leung, Derek S Chiu, Steve E Kalloger, David G Huntsman, Stephanie Chen, Maria Intermaggio, Jacek Gronwald, Fong C Chan, Susan J Ramus, Christian Steidl, David W Scott, Michael S Anglesio
A major weakness in many high-throughput genomic studies is the lack of consideration of a clinical environment where one patient at a time must be evaluated. We examined generalizable and platform-specific sources of variation from NanoString gene expression data on both ovarian cancer and Hodgkin lymphoma patients. A reference-based strategy, applicable to single-patient molecular testing is proposed for batch effect correction. The proposed protocol improved performance in an established Hodgkin lymphoma classifier, reducing batch-to-batch misclassification while retaining accuracy and precision...
2016: PloS One
https://www.readbyqxmd.com/read/27087319/point-mutations-in-exon-1b-of-apc-reveal-gastric-adenocarcinoma-and-proximal-polyposis-of-the-stomach-as-a-familial-adenomatous-polyposis-variant
#19
Jun Li, Susan L Woods, Sue Healey, Jonathan Beesley, Xiaoqing Chen, Jason S Lee, Haran Sivakumaran, Nicci Wayte, Katia Nones, Joshua J Waterfall, John Pearson, Anne-Marie Patch, Janine Senz, Manuel A Ferreira, Pardeep Kaurah, Robertson Mackenzie, Alireza Heravi-Moussavi, Samantha Hansford, Tamsin R M Lannagan, Amanda B Spurdle, Peter T Simpson, Leonard da Silva, Sunil R Lakhani, Andrew D Clouston, Mark Bettington, Florian Grimpen, Rita A Busuttil, Natasha Di Costanzo, Alex Boussioutas, Marie Jeanjean, George Chong, Aurélie Fabre, Sylviane Olschwang, Geoffrey J Faulkner, Evangelos Bellos, Lachlan Coin, Kevin Rioux, Oliver F Bathe, Xiaogang Wen, Hilary C Martin, Deborah W Neklason, Sean R Davis, Robert L Walker, Kathleen A Calzone, Itzhak Avital, Theo Heller, Christopher Koh, Marbin Pineda, Udo Rudloff, Martha Quezado, Pavel N Pichurin, Peter J Hulick, Scott M Weissman, Anna Newlin, Wendy S Rubinstein, Jone E Sampson, Kelly Hamman, David Goldgar, Nicola Poplawski, Kerry Phillips, Lyn Schofield, Jacqueline Armstrong, Cathy Kiraly-Borri, Graeme K Suthers, David G Huntsman, William D Foulkes, Fatima Carneiro, Noralane M Lindor, Stacey L Edwards, Juliet D French, Nicola Waddell, Paul S Meltzer, Daniel L Worthley, Kasmintan A Schrader, Georgia Chenevix-Trench
Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is an autosomal-dominant cancer-predisposition syndrome with a significant risk of gastric, but not colorectal, adenocarcinoma. We mapped the gene to 5q22 and found loss of the wild-type allele on 5q in fundic gland polyps from affected individuals. Whole-exome and -genome sequencing failed to find causal mutations but, through Sanger sequencing, we identified point mutations in APC promoter 1B that co-segregated with disease in all six families...
May 5, 2016: American Journal of Human Genetics
https://www.readbyqxmd.com/read/27057137/endosialin-and-associated-protein-expression-in-soft-tissue-sarcomas-a-potential-target-for-anti-endosialin-therapeutic-strategies
#20
Daniel J O'Shannessy, Hongyue Dai, Melissa Mitchell, Shane Huntsman, Stephen Brantley, David Fenstermacher, Damon R Reed
Endosialin (CD248, TEM-1) is expressed in pericytes, tumor vasculature, tumor fibroblasts, and some tumor cells, including sarcomas, with limited normal tissue expression, and appears to play a key role in tumor-stromal interactions, including angiogenesis. Monoclonal antibodies targeting endosialin have entered clinical trials, including soft tissue sarcomas. We evaluated a cohort of 94 soft tissue sarcoma samples to assess the correlation between gene expression and protein expression by immunohistochemistry for endosialin and PDGFR-β, a reported interacting protein, across available diagnoses...
2016: Sarcoma
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