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Levi A. Garraway

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https://www.readbyqxmd.com/read/27906693/believe-the-miracles-of-biomedical-science-and-human-suffering
#1
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
#2
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
#3
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
#4
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 Tomas, Pasi A Janne, Levi A Garraway, Scott L Carter, Rameen Beroukhim, Jochen H Lorch, Eliezer 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 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...
October 17, 2016: 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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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...
2016: Genome Medicine
https://www.readbyqxmd.com/read/27433846/inherited-dna-repair-gene-mutations-in-men-with-metastatic-prostate-cancer
#12
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
#13
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
https://www.readbyqxmd.com/read/27392080/clinical-sequencing-exploratory-research-consortium-accelerating-evidence-based-practice-of-genomic-medicine
#14
Robert C Green, Katrina A B Goddard, Gail P Jarvik, Laura M Amendola, Paul S Appelbaum, Jonathan S Berg, Barbara A Bernhardt, Leslie G Biesecker, Sawona Biswas, Carrie L Blout, Kevin M Bowling, Kyle B Brothers, Wylie Burke, Charlisse F Caga-Anan, Arul M Chinnaiyan, Wendy K Chung, Ellen W Clayton, Gregory M Cooper, Kelly East, James P Evans, Stephanie M Fullerton, Levi A Garraway, Jeremy R Garrett, Stacy W Gray, Gail E Henderson, Lucia A Hindorff, Ingrid A Holm, Michelle Huckaby Lewis, Carolyn M Hutter, Pasi A Janne, Steven Joffe, David Kaufman, Bartha M Knoppers, Barbara A Koenig, Ian D Krantz, Teri A Manolio, Laurence McCullough, Jean McEwen, Amy McGuire, Donna Muzny, Richard M Myers, Deborah A Nickerson, Jeffrey Ou, Donald W Parsons, Gloria M Petersen, Sharon E Plon, Heidi L Rehm, J Scott Roberts, Dan Robinson, Joseph S Salama, Sarah Scollon, Richard R Sharp, Brian Shirts, Nancy B Spinner, Holly K Tabor, Peter Tarczy-Hornoch, David L Veenstra, Nikhil Wagle, Karen Weck, Benjamin S Wilfond, Kirk Wilhelmsen, Susan M Wolf, Julia Wynn, Joon-Ho Yu
No abstract text is available yet for this article.
July 7, 2016: American Journal of Human Genetics
https://www.readbyqxmd.com/read/27329820/integrated-genetic-and-pharmacologic-interrogation-of-rare-cancers
#15
Andrew L Hong, Yuen-Yi Tseng, Glenn S Cowley, Oliver Jonas, Jaime H Cheah, Bryan D Kynnap, Mihir B Doshi, Coyin Oh, Stephanie C Meyer, Alanna J Church, Shubhroz Gill, Craig M Bielski, Paula Keskula, Alma Imamovic, Sara Howell, Gregory V Kryukov, Paul A Clemons, Aviad Tsherniak, Francisca Vazquez, Brian D Crompton, Alykhan F Shamji, Carlos Rodriguez-Galindo, Katherine A Janeway, Charles W M Roberts, Kimberly Stegmaier, Paul van Hummelen, Michael J Cima, Robert S Langer, Levi A Garraway, Stuart L Schreiber, David E Root, William C Hahn, Jesse S Boehm
Identifying therapeutic targets in rare cancers remains challenging due to the paucity of established models to perform preclinical studies. As a proof-of-concept, we developed a patient-derived cancer cell line, CLF-PED-015-T, from a paediatric patient with a rare undifferentiated sarcoma. Here, we confirm that this cell line recapitulates the histology and harbours the majority of the somatic genetic alterations found in a metastatic lesion isolated at first relapse. We then perform pooled CRISPR-Cas9 and RNAi loss-of-function screens and a small-molecule screen focused on druggable cancer targets...
2016: Nature Communications
https://www.readbyqxmd.com/read/27325104/pediatric-type-nodal-follicular-lymphoma-a-biologically-distinct-lymphoma-with-frequent-mapk-pathway-mutations
#16
Abner Louissaint, Kristian T Schafernak, Julia T Geyer, Alexandra E Kovach, Mahmoud Ghandi, Dita Gratzinger, Christine G Roth, Christian N Paxton, Sunhee Kim, Chungdak Namgyal, Ryan Morin, Elizabeth A Morgan, Donna S Neuberg, Sarah T South, Marian H Harris, Robert P Hasserjian, Ephraim P Hochberg, Levi A Garraway, Nancy Lee Harris, David M Weinstock
Pediatric-type nodal follicular lymphoma (PTNFL) is a variant of follicular lymphoma (FL) characterized by limited-stage presentation and invariably benign behavior despite often high-grade histological appearance. It is important to distinguish PTNFL from typical FL in order to avoid unnecessary treatment; however, this distinction relies solely on clinical and pathological criteria, which may be variably applied. To define the genetic landscape of PTNFL, we performed copy number analysis and exome and/or targeted sequencing of 26 PTNFLs (16 pediatric and 10 adult)...
August 25, 2016: Blood
https://www.readbyqxmd.com/read/27310333/clinical-validation-of-chemotherapy-response-biomarker-ercc2-in-muscle-invasive-urothelial-bladder-carcinoma
#17
David Liu, Elizabeth R Plimack, Jean Hoffman-Censits, Levi A Garraway, Joaquim Bellmunt, Eliezer Van Allen, Jonathan E Rosenberg
No abstract text is available yet for this article.
August 1, 2016: JAMA Oncology
https://www.readbyqxmd.com/read/27260156/genomic-copy-number-dictates-a-gene-independent-cell-response-to-crispr-cas9-targeting
#18
Andrew J Aguirre, Robin M Meyers, Barbara A Weir, Francisca Vazquez, Cheng-Zhong Zhang, Uri Ben-David, April Cook, Gavin Ha, William F Harrington, Mihir B Doshi, Maria Kost-Alimova, Stanley Gill, Han Xu, Levi D Ali, Guozhi Jiang, Sasha Pantel, Yenarae Lee, Amy Goodale, Andrew D Cherniack, Coyin Oh, Gregory Kryukov, Glenn S Cowley, Levi A Garraway, Kimberly Stegmaier, Charles W Roberts, Todd R Golub, Matthew Meyerson, David E Root, Aviad Tsherniak, William C Hahn
UNLABELLED: The CRISPR/Cas9 system enables genome editing and somatic cell genetic screens in mammalian cells. We performed genome-scale loss-of-function screens in 33 cancer cell lines to identify genes essential for proliferation/survival and found a strong correlation between increased gene copy number and decreased cell viability after genome editing. Within regions of copy-number gain, CRISPR/Cas9 targeting of both expressed and unexpressed genes, as well as intergenic loci, led to significantly decreased cell proliferation through induction of a G2 cell-cycle arrest...
August 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27251777/distinct-genetic-profiles-of-extracranial-and-intracranial-acral-melanoma-metastases
#19
Gaurav Sharma, Christine G Lian, William M Lin, Ali Amin-Mansour, Judit Jané-Valbuena, Levi Garraway, Wendi Bao, Charles H Yoon, Nageatte Ibrahim
BACKGROUND: There is limited knowledge of the genetic alterations in acral melanoma metastases at different anatomic sites. Here, we characterized the genetic abnormalities of metastases in a 51-year-old man with stage IIIC heel melanoma who developed concomitant brain and cutaneous metastases in spite of multiple treatment modalities. METHODS: Melanoma cells were isolated following palliative resection of the patient's cortical tumor and biopsy of cutaneous thigh metastasis...
October 2016: Journal of Cutaneous Pathology
https://www.readbyqxmd.com/read/27238081/trim24-is-an-oncogenic-transcriptional-activator-in-prostate-cancer
#20
Anna C Groner, Laura Cato, Jonas de Tribolet-Hardy, Tiziano Bernasocchi, Hana Janouskova, Diana Melchers, René Houtman, Andrew C B Cato, Patrick Tschopp, Lei Gu, Andrea Corsinotti, Qing Zhong, Christian Fankhauser, Christine Fritz, Cédric Poyet, Ulrich Wagner, Tiannan Guo, Ruedi Aebersold, Levi A Garraway, Peter J Wild, Jean-Philippe Theurillat, Myles Brown
Androgen receptor (AR) signaling is a key driver of prostate cancer (PC). While androgen-deprivation therapy is transiently effective in advanced disease, tumors often progress to a lethal castration-resistant state (CRPC). We show that recurrent PC-driver mutations in speckle-type POZ protein (SPOP) stabilize the TRIM24 protein, which promotes proliferation under low androgen conditions. TRIM24 augments AR signaling, and AR and TRIM24 co-activated genes are significantly upregulated in CRPC. Expression of TRIM24 protein increases from primary PC to CRPC, and both TRIM24 protein levels and the AR/TRIM24 gene signature predict disease recurrence...
June 13, 2016: Cancer Cell
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