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Levi A. Garraway

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https://www.readbyqxmd.com/read/28515055/exome-sequencing-of-african-american-prostate-cancer-reveals-loss-of-function-erf-mutations
#1
Franklin W Huang, Juan Miguel Mosquera, Andrea Garofalo, Coyin Oh, Maria Baco, Ali Amin-Mansour, Bokang Rabasha, Samira Bahl, Stephanie A Mullane, Brian D Robinson, Saud Aldubayan, Francesca Khani, Beerinder Karir, Eejung Kim, Jeremy Chimene-Weiss, Matan Hofree, Alessandro Romanel, Joseph R Osborne, Jong Wook Kim, Gissou Azabdaftari, Anna Woloszynska-Read, Karen Sfanos, Angelo M De Marzo, Francesca Demichelis, Stacey Gabriel, Eliezer M Van Allen, Jill Mesirov, Pablo Tamayo, Mark A Rubin, Isaac J Powell, Levi A Garraway
African-American men have the highest incidence and mortality from prostate cancer. Whether a biological basis exists for this disparity remains unclear. Exome sequencing (n=102) and targeted validation (n = 90) of localized primary hormone-naïve prostate cancer in African-American men identified several gene mutations not previously observed in this context, including recurrent loss-of-function mutations in ERF, an ETS transcriptional repressor, in 5% of cases. Analysis of existing prostate cancer cohorts revealed ERF deletions in 3% of primary prostate cancers and mutations or deletions in ERF in 3-5% of lethal castration-resistant prostate cancers...
May 17, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28464947/erratum-to-unraveling-the-clonal-hierarchy-of-somatic-genomic-aberrations
#2
Davide Prandi, Sylvan C Baca, Alessandro Romanel, Christopher E Barbieri, Juan-Miguel Mosquera, Jacqueline Fontugne, Himisha Beltran, Andrea Sboner, Levi A Garraway, Mark A Rubin, Francesca Demichelis
No abstract text is available yet for this article.
May 2, 2017: Genome Biology
https://www.readbyqxmd.com/read/28420421/analysis-of-100-000-human-cancer-genomes-reveals-the-landscape-of-tumor-mutational-burden
#3
Zachary R Chalmers, Caitlin F Connelly, David Fabrizio, Laurie Gay, Siraj M Ali, Riley Ennis, Alexa Schrock, Brittany Campbell, Adam Shlien, Juliann Chmielecki, Franklin Huang, Yuting He, James Sun, Uri Tabori, Mark Kennedy, Daniel S Lieber, Steven Roels, Jared White, Geoffrey A Otto, Jeffrey S Ross, Levi Garraway, Vincent A Miller, Phillip J Stephens, Garrett M Frampton
BACKGROUND: High tumor mutational burden (TMB) is an emerging biomarker of sensitivity to immune checkpoint inhibitors and has been shown to be more significantly associated with response to PD-1 and PD-L1 blockade immunotherapy than PD-1 or PD-L1 expression, as measured by immunohistochemistry (IHC). The distribution of TMB and the subset of patients with high TMB has not been well characterized in the majority of cancer types. METHODS: In this study, we compare TMB measured by a targeted comprehensive genomic profiling (CGP) assay to TMB measured by exome sequencing and simulate the expected variance in TMB when sequencing less than the whole exome...
April 19, 2017: Genome Medicine
https://www.readbyqxmd.com/read/28125075/assigning-clinical-meaning-to-somatic-and-germ-line-whole-exome-sequencing-data-in-a-prospective-cancer-precision-medicine-study
#4
Arezou A Ghazani, Nelly M Oliver, Joseph P St Pierre, Andrea Garofalo, Irene R Rainville, Elaine Hiller, Daniel J Treacy, Vanesa Rojas-Rudilla, Sam Wood, Elizabeth Bair, Michael Parello, Franklin Huang, Marios Giannakis, Frederick H Wilson, Elizabeth H Stover, Steven M Corsello, Tom Nguyen, Huma Q Rana, Alanna J Church, Carol Lowenstein, Carrie Cibulskis, Ali Amin-Mansour, Jennifer Heng, Lauren Brais, Abigail Santos, Patrick Bauer, Amanda Waldron, Peter Lo, Megan Gorman, Christine A Lydon, Marisa Welch, Philip McNamara, Stacey Gabriel, Lynette M Sholl, Neal I Lindeman, Judy E Garber, Steven Joffe, Eliezer M Van Allen, Stacy W Gray, Pasi A Ja Nne, Levi A Garraway, Nikhil Wagle
PURPOSE: Implementing cancer precision medicine in the clinic requires assessing the therapeutic relevance of genomic alterations. A main challenge is the systematic interpretation of whole-exome sequencing (WES) data for clinical care. METHODS: One hundred sixty-five adults with metastatic colorectal and lung adenocarcinomas were prospectively enrolled in the CanSeq study. WES was performed on DNA extracted from formalin-fixed paraffin-embedded tumor biopsy samples and matched blood samples...
January 26, 2017: Genetics in Medicine: Official Journal of the American College of Medical Genetics
https://www.readbyqxmd.com/read/28069687/adaptive-resistance-of-melanoma-cells-to-raf-inhibition-via-reversible-induction-of-a-slowly-dividing-de-differentiated-state
#5
Mohammad Fallahi-Sichani, Verena Becker, Benjamin Izar, Gregory J Baker, Jia-Ren Lin, Sarah A Boswell, Parin Shah, Asaf Rotem, Levi A Garraway, Peter K Sorger
Treatment of BRAF-mutant melanomas with MAP kinase pathway inhibitors is paradigmatic of the promise of precision cancer therapy but also highlights problems with drug resistance that limit patient benefit. We use live-cell imaging, single-cell analysis, and molecular profiling to show that exposure of tumor cells to RAF/MEK inhibitors elicits a heterogeneous response in which some cells die, some arrest, and the remainder adapt to drug. Drug-adapted cells up-regulate markers of the neural crest (e.g., NGFR), a melanocyte precursor, and grow slowly...
January 9, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28062669/people
#6
(no author information available yet)
Charles S. Fuchs, MD, MPH; Levi A. Garraway, MD, PhD; and Laurie H. Glimcher, MD, are featured.
January 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28028240/suppression-of-19s-proteasome-subunits-marks-emergence-of-an-altered-cell-state-in-diverse-cancers
#7
Peter Tsvetkov, Ethan Sokol, Dexter Jin, Zarina Brune, Prathapan Thiru, Mahmoud Ghandi, Levi A Garraway, Piyush B Gupta, Sandro Santagata, Luke Whitesell, Susan Lindquist
The use of proteasome inhibitors to target cancer's dependence on altered protein homeostasis has been greatly limited by intrinsic and acquired resistance. Analyzing data from thousands of cancer lines and tumors, we find that those with suppressed expression of one or more 19S proteasome subunits show intrinsic proteasome inhibitor resistance. Moreover, such proteasome subunit suppression is associated with poor outcome in myeloma patients, where proteasome inhibitors are a mainstay of treatment. Beyond conferring resistance to proteasome inhibitors, proteasome subunit suppression also serves as a sentinel of a more global remodeling of the transcriptome...
January 10, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27906693/believe-the-miracles-of-biomedical-science-and-human-suffering
#8
Levi A Garraway
No abstract text is available yet for this article.
December 1, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27882345/institutional-implementation-of-clinical-tumor-profiling-on-an-unselected-cancer-population
#9
Lynette M Sholl, Khanh Do, Priyanka Shivdasani, Ethan Cerami, Adrian M Dubuc, Frank C Kuo, Elizabeth P Garcia, Yonghui Jia, Phani Davineni, Ryan P Abo, Trevor J Pugh, Paul van Hummelen, Aaron R Thorner, Matthew Ducar, Alice H Berger, Mizuki Nishino, Katherine A Janeway, Alanna Church, Marian Harris, Lauren L Ritterhouse, Joshua D Campbell, Vanesa Rojas-Rudilla, Azra H Ligon, Shakti Ramkissoon, James M Cleary, Ursula Matulonis, Geoffrey R Oxnard, Richard Chao, Vanessa Tassell, James Christensen, William C Hahn, Philip W Kantoff, David J Kwiatkowski, Bruce E Johnson, Matthew Meyerson, Levi A Garraway, Geoffrey I Shapiro, Barrett J Rollins, Neal I Lindeman, Laura E MacConaill
BACKGROUND. Comprehensive genomic profiling of a patient's cancer can be used to diagnose, monitor, and recommend treatment. Clinical implementation of tumor profiling in an enterprise-wide, unselected cancer patient population has yet to be reported. METHODS. We deployed a hybrid-capture and massively parallel sequencing assay (OncoPanel) for all adult and pediatric patients at our combined cancer centers. Results were categorized by pathologists based on actionability. We report the results for the first 3,727 patients tested...
November 17, 2016: JCI Insight
https://www.readbyqxmd.com/read/27811909/fusobacterium-nucleatum-in-colorectal-carcinoma-tissue-according-to-tumor-location
#10
Kosuke Mima, Yin Cao, Andrew T Chan, Zhi Rong Qian, Jonathan A Nowak, Yohei Masugi, Yan Shi, Mingyang Song, Annacarolina da Silva, Mancang Gu, Wanwan Li, Tsuyoshi Hamada, Keisuke Kosumi, Akiko Hanyuda, Li Liu, Aleksandar D Kostic, Marios Giannakis, Susan Bullman, Caitlin A Brennan, Danny A Milner, Hideo Baba, Levi A Garraway, Jeffrey A Meyerhardt, Wendy S Garrett, Curtis Huttenhower, Matthew Meyerson, Edward L Giovannucci, Charles S Fuchs, Reiko Nishihara, Shuji Ogino
OBJECTIVES: Evidence suggests a possible role of Fusobacterium nucleatum in colorectal carcinogenesis, especially in right-sided proximal colorectum. Considering a change in bowel contents and microbiome from proximal to distal colorectal segments, we hypothesized that the proportion of colorectal carcinoma enriched with F. nucleatum might gradually increase along the bowel subsites from rectum to cecum. METHODS: A retrospective, cross-sectional analysis was conducted on 1,102 colon and rectal carcinomas in molecular pathological epidemiology databases of the Nurses' Health Study and the Health Professionals Follow-up Study...
November 3, 2016: Clinical and Translational Gastroenterology
https://www.readbyqxmd.com/read/27797976/genomic-heterogeneity-and-exceptional-response-to-dual-pathway-inhibition-in-anaplastic-thyroid-cancer
#11
William J Gibson, Daniel T Ruan, Vera A Paulson, Justine A Barletta, Glenn J Hanna, Stefan Kraft, Antonio Calles, Matthew A Nehs, Francis D Moore, Amaro Taylor-Weiner, Jeremiah A Wala, Travis I Zack, Thomas C Lee, Fiona M Fennessy, Erik K Alexander, Tom Thomas, Pasi A Janne, Levi A Garraway, Scott L Carter, Rameen Beroukhim, Jochen H Lorch, Eliezer M Van Allen
Purpose: Cancers may resist single-agent targeted therapies when the flux of cellular growth signals is shifted from one pathway to another. Blockade of multiple pathways may be necessary for effective inhibition of tumor growth. We document a case in which a patient with anaplastic thyroid carcinoma (ATC) failed to respond to either mTOR/PI3K or combined RAF/MEK inhibition but experienced a dramatic response when both drug regimens were combined.Experimental Design: Multi-region whole-exome sequencing of five diagnostic and four autopsy tumor biopsies was performed...
May 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27760322/genomic-correlates-of-immune-cell-infiltrates-in-colorectal-carcinoma
#12
Marios Giannakis, Xinmeng Jasmine Mu, Sachet A Shukla, Zhi Rong Qian, Ofir Cohen, Reiko Nishihara, Samira Bahl, Yin Cao, Ali Amin-Mansour, Mai Yamauchi, Yasutaka Sukawa, Chip Stewart, Mara Rosenberg, Kosuke Mima, Kentaro Inamura, Katsuhiko Nosho, Jonathan A Nowak, Michael S Lawrence, Edward L Giovannucci, Andrew T Chan, Kimmie Ng, Jeffrey A Meyerhardt, Eliezer M Van Allen, Gad Getz, Stacey B Gabriel, Eric S Lander, Catherine J Wu, Charles S Fuchs, Shuji Ogino, Levi A Garraway
No abstract text is available yet for this article.
October 18, 2016: Cell Reports
https://www.readbyqxmd.com/read/27760319/phenotypic-characterization-of-a-comprehensive-set-of-mapk1-erk2-missense-mutants
#13
Lisa Brenan, Aleksandr Andreev, Ofir Cohen, Sasha Pantel, Atanas Kamburov, Davide Cacchiarelli, Nicole S Persky, Cong Zhu, Mukta Bagul, Eva M Goetz, Alex B Burgin, Levi A Garraway, Gad Getz, Tarjei S Mikkelsen, Federica Piccioni, David E Root, Cory M Johannessen
Tumor-specific genomic information has the potential to guide therapeutic strategies and revolutionize patient treatment. Currently, this approach is limited by an abundance of disease-associated mutants whose biological functions and impacts on therapeutic response are uncharacterized. To begin to address this limitation, we functionally characterized nearly all (99.84%) missense mutants of MAPK1/ERK2, an essential effector of oncogenic RAS and RAF. Using this approach, we discovered rare gain- and loss-of-function ERK2 mutants found in human tumors, revealing that, in the context of this assay, mutational frequency alone cannot identify all functionally impactful mutants...
October 18, 2016: Cell Reports
https://www.readbyqxmd.com/read/27659046/high-order-drug-combinations-are-required-to-effectively-kill-colorectal-cancer-cells
#14
Thomas Horn, Stéphane Ferretti, Nicolas Ebel, Angela Tam, Samuel Ho, Fred Harbinski, Ali Farsidjani, Matthew Zubrowski, William R Sellers, Robert Schlegel, Dale Porter, Erick Morris, Jens Wuerthner, Sébastien Jeay, Joel Greshock, Ensar Halilovic, Levi A Garraway, Giordano Caponigro, Joseph Lehár
Like classical chemotherapy regimens used to treat cancer, targeted therapies will also rely upon polypharmacology, but tools are still lacking to predict which combinations of molecularly targeted drugs may be most efficacious. In this study, we used image-based proliferation and apoptosis assays in colorectal cancer cell lines to systematically investigate the efficacy of combinations of two to six drugs that target critical oncogenic pathways. Drug pairs targeting key signaling pathways resulted in synergies across a broad spectrum of genetic backgrounds but often yielded only cytostatic responses...
December 1, 2016: Cancer Research
https://www.readbyqxmd.com/read/27604488/systematic-functional-characterization-of-resistance-to-pi3k-inhibition-in-breast-cancer
#15
Xiuning Le, Rajee Antony, Pedram Razavi, Daniel J Treacy, Flora Luo, Mahmoud Ghandi, Pau Castel, Maurizio Scaltriti, José Baselga, Levi A Garraway
PIK3CA (which encodes the PI3K alpha isoform) is the most frequently mutated oncogene in breast cancer. Small-molecule PI3K inhibitors have shown promise in clinical trials; however, intrinsic and acquired resistance limits their utility. We used a systematic gain-of-function approach to identify genes whose upregulation confers resistance to the PI3K inhibitor BYL719 in breast cancer cells. Among the validated resistance genes, Proviral Insertion site in Murine leukemia virus (PIM) kinases conferred resistance by maintaining downstream PI3K effector activation in an AKT-independent manner...
October 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27482935/bidirectional-cross-talk-between-patient-derived-melanoma-and-cancer-associated-fibroblasts-promotes-invasion-and-proliferation
#16
Benjamin Izar, Cailin E Joyce, Stephanie Goff, Nancy L Cho, Parin M Shah, Gaurav Sharma, Jingjing Li, Nageatte Ibrahim, Jason Gold, F Stephen Hodi, Levi A Garraway, Carl D Novina, Monica M Bertagnolli, Charles H Yoon
Tumor-stroma interactions are critical for epithelial-derived tumors, and among the stromal cell types, cancer-associated fibroblasts (CAFs) exhibit multiple functions that fuel growth, dissemination, and drug resistance. However, these interactions remain insufficiently characterized in non-epithelial tumors such as malignant melanoma. We generated monocultures of melanoma cells and matching CAFs from patients' metastatic lesions, distinguished by oncogenic drivers and immunoblotting of characteristic markers...
August 2, 2016: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/27482819/long-term-drug-administration-in-the-adult-zebrafish-using-oral-gavage-for-cancer-preclinical-studies
#17
Michelle Dang, Rachel E Henderson, Levi A Garraway, Leonard I Zon
Zebrafish are a major model for chemical genetics, and most studies use embryos when investigating small molecules that cause interesting phenotypes or that can rescue disease models. Limited studies have dosed adults with small molecules by means of water-borne exposure or injection techniques. Challenges in the form of drug delivery-related trauma and anesthesia-related toxicity have excluded the adult zebrafish from long-term drug efficacy studies. Here, we introduce a novel anesthetic combination of MS-222 and isoflurane to an oral gavage technique for a non-toxic, non-invasive and long-term drug administration platform...
July 1, 2016: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/27460824/the-impact-of-tumor-profiling-approaches-and-genomic-data-strategies-for-cancer-precision-medicine
#18
Andrea Garofalo, Lynette Sholl, Brendan Reardon, Amaro Taylor-Weiner, Ali Amin-Mansour, Diana Miao, David Liu, Nelly Oliver, Laura MacConaill, Matthew Ducar, Vanesa Rojas-Rudilla, Marios Giannakis, Arezou Ghazani, Stacy Gray, Pasi Janne, Judy Garber, Steve Joffe, Neal Lindeman, Nikhil Wagle, Levi A Garraway, Eliezer M Van Allen
BACKGROUND: The diversity of clinical tumor profiling approaches (small panels to whole exomes with matched or unmatched germline analysis) may engender uncertainty about their benefits and liabilities, particularly in light of reported germline false positives in tumor-only profiling and use of global mutational and/or neoantigen data. The goal of this study was to determine the impact of genomic analysis strategies on error rates and data interpretation across contexts and ancestries...
July 26, 2016: Genome Medicine
https://www.readbyqxmd.com/read/27433846/inherited-dna-repair-gene-mutations-in-men-with-metastatic-prostate-cancer
#19
MULTICENTER STUDY
Colin C Pritchard, Joaquin Mateo, Michael F Walsh, Navonil De Sarkar, Wassim Abida, Himisha Beltran, Andrea Garofalo, Roman Gulati, Suzanne Carreira, Rosalind Eeles, Olivier Elemento, Mark A Rubin, Dan Robinson, Robert Lonigro, Maha Hussain, Arul Chinnaiyan, Jake Vinson, Julie Filipenko, Levi Garraway, Mary-Ellen Taplin, Saud AlDubayan, G Celine Han, Mallory Beightol, Colm Morrissey, Belinda Nghiem, Heather H Cheng, Bruce Montgomery, Tom Walsh, Silvia Casadei, Michael Berger, Liying Zhang, Ahmet Zehir, Joseph Vijai, Howard I Scher, Charles Sawyers, Nikolaus Schultz, Philip W Kantoff, David Solit, Mark Robson, Eliezer M Van Allen, Kenneth Offit, Johann de Bono, Peter S Nelson
BACKGROUND: Inherited mutations in DNA-repair genes such as BRCA2 are associated with increased risks of lethal prostate cancer. Although the prevalence of germline mutations in DNA-repair genes among men with localized prostate cancer who are unselected for family predisposition is insufficient to warrant routine testing, the frequency of such mutations in patients with metastatic prostate cancer has not been established. METHODS: We recruited 692 men with documented metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis...
August 4, 2016: New England Journal of Medicine
https://www.readbyqxmd.com/read/27407122/whole-exome-sequencing-in-two-extreme-phenotypes-of-response-to-vegf-targeted-therapies-in-patients-with-metastatic-clear-cell-renal-cell-carcinoma
#20
Andre P Fay, Guillermo de Velasco, Thai H Ho, Eliezer M Van Allen, Bradley Murray, Laurence Albiges, Sabina Signoretti, A Ari Hakimi, Melissa L Stanton, Joaquim Bellmunt, David F McDermott, Michael B Atkins, Levi A Garraway, David J Kwiatkowski, Toni K Choueiri
Advances in next-generation sequencing have provided a unique opportunity to understand the biology of disease and mechanisms of sensitivity or resistance to specific agents. Renal cell carcinoma (RCC) is a heterogeneous disease and highly variable clinical responses have been observed with vascular endothelial growth factor (VEGF)-targeted therapy (VEGF-TT). We hypothesized that whole-exome sequencing analysis might identify genotypes associated with extreme response or resistance to VEGF-TT in metastatic (mRCC)...
July 2016: Journal of the National Comprehensive Cancer Network: JNCCN
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