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charles sawyers

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https://www.readbyqxmd.com/read/29610475/the-long-tail-of-oncogenic-drivers-in-prostate-cancer
#1
Joshua Armenia, Stephanie A M Wankowicz, David Liu, Jianjiong Gao, Ritika Kundra, Ed Reznik, Walid K Chatila, Debyani Chakravarty, G Celine Han, Ilsa Coleman, Bruce Montgomery, Colin Pritchard, Colm Morrissey, Christopher E Barbieri, Himisha Beltran, Andrea Sboner, Zafeiris Zafeiriou, Susana Miranda, Craig M Bielski, Alexander V Penson, Charlotte Tolonen, Franklin W Huang, Dan Robinson, Yi Mi Wu, Robert Lonigro, Levi A Garraway, Francesca Demichelis, Philip W Kantoff, Mary-Ellen Taplin, Wassim Abida, Barry S Taylor, Howard I Scher, Peter S Nelson, Johann S de Bono, Mark A Rubin, Charles L Sawyers, Arul M Chinnaiyan, Nikolaus Schultz, Eliezer M Van Allen
Comprehensive genomic characterization of prostate cancer has identified recurrent alterations in genes involved in androgen signaling, DNA repair, and PI3K signaling, among others. However, larger and uniform genomic analysis may identify additional recurrently mutated genes at lower frequencies. Here we aggregate and uniformly analyze exome sequencing data from 1,013 prostate cancers. We identify and validate a new class of E26 transformation-specific (ETS)-fusion-negative tumors defined by mutations in epigenetic regulators, as well as alterations in pathways not previously implicated in prostate cancer, such as the spliceosome pathway...
April 2, 2018: Nature Genetics
https://www.readbyqxmd.com/read/29608138/a-conversation-with-charles-sawyers
#2
Ushma S Neill
No abstract text is available yet for this article.
April 2, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29598901/macrocyclic-%C3%AE-helical-peptide-therapeutic-modality-a-perspective-of-learnings-and-challenges
#3
Tomi K Sawyer, Anthony W Partridge, Hung Yi Kristal Kaan, Yu-Chi Juang, Shuhui Lim, Charles Johannes, Tsz Ying Yuen, Chandra Verma, Srinivasaraghavan Kannan, Pietro Aronica, Yaw Sing Tan, Brad Sherborne, Sookhee Ha, Jerome Hochman, Shiying Chen, Laura Surdi, Andrea Peier, Berengere Sauvagnat, Peter J Dandliker, Christopher J Brown, Simon Ng, Fernando Ferrer, David P Lane
Macrocyclic α-helical peptides have emerged as a compelling new therapeutic modality to tackle targets confined to the intracellular compartment. Within the scope of hydrocarbon-stapling there has been significant progress to date, including the first stapled α-helical peptide to enter into clinical trials. The principal design concept of stapled α-helical peptides is to mimic a cognate (protein) ligand relative to binding its target via an α-helical interface. However, it was the proclivity of such stapled α-helical peptides to exhibit cell permeability and proteolytic stability that underscored their promise as unique macrocyclic peptide drugs for intracellular targets...
March 16, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29565726/short-course-anti-microbial-therapy-does-not-increase-treatment-failure-rate-in-patients-with-intra-abdominal-infection-involving-fungal-organisms
#4
Nathan R Elwood, Christopher A Guidry, Therese M Duane, Joseph Cuschieri, Charles H Cook, Patrick J O'Neill, Reza Askari, Lena M Napolitano, Nicholas Namias, E Patchen Dellinger, Christopher M Watson, Kaysie L Banton, David P Blake, Taryn E Hassinger, Robert G Sawyer
BACKGROUND: Fungi frequently are isolated in intra-abdominal infections (IAI). The Study to Optimize Peritoneal Infection Therapy (STOP-IT) recently suggested short-course treatment for patients with IAI. It remains unclear whether the presence of fungi in IAI affects the optimal duration of anti-microbial therapy. We hypothesized that a shorter treatment course in IAI with fungal organisms would be associated with a higher rate of treatment failure. METHODS: Patients enrolled in the STOP-IT trial were stratified according to the presence or absence of a fungal isolate...
March 22, 2018: Surgical Infections
https://www.readbyqxmd.com/read/29417929/challenges-in-validating-candidate-therapeutic-targets-in-cancer
#5
Jeffrey Settleman, Charles L Sawyers, Tony Hunter
More than 30 published articles have suggested that a protein kinase called MELK is an attractive therapeutic target in human cancer, but three recent reports describe compelling evidence that it is not. These reports highlight the caveats associated with some of the research tools that are commonly used to validate candidate therapeutic targets in cancer research.
February 8, 2018: ELife
https://www.readbyqxmd.com/read/29369701/targeting-dna-repair-in-prostate-cancer
#6
Wassim Abida, Charles L Sawyers
No abstract text is available yet for this article.
April 1, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29258679/role-of-androgen-receptor-variants-in-prostate-cancer-report-from-the-2017-mission-androgen-receptor-variants-meeting
#7
Jun Luo, Gerhardt Attard, Steven P Balk, Charlotte Bevan, Kerry Burnstein, Laura Cato, Artem Cherkasov, Johann S De Bono, Yan Dong, Allen C Gao, Martin Gleave, Hannelore Heemers, Mayuko Kanayama, Ralf Kittler, Joshua M Lang, Richard J Lee, Christopher J Logothetis, Robert Matusik, Stephen Plymate, Charles L Sawyers, Luke A Selth, Howard Soule, Wayne Tilley, Nancy L Weigel, Amina Zoubeidi, Scott M Dehm, Ganesh V Raj
CONTEXT: Although a number of studies have demonstrated the importance of constitutively active androgen receptor variants (AR-Vs) in prostate cancer, questions still remain about the precise role of AR-Vs in the progression of castration-resistant prostate cancer (CRPC). OBJECTIVE: Key stakeholders and opinion leaders in prostate cancer convened on May 11, 2017 in Boston to establish the current state of the field of AR-Vs. EVIDENCE ACQUISITION: The meeting "Mission Androgen Receptor Variants" was the second of its kind sponsored by the Prostate Cancer Foundation (PCF)...
December 16, 2017: European Urology
https://www.readbyqxmd.com/read/29121144/positron-emission-tomography-computed-tomography-based-assessments-of-androgen-receptor-expression-and-glycolytic-activity-as-a-prognostic-biomarker-for-metastatic-castration-resistant-prostate-cancer
#8
Josef J Fox, Somali C Gavane, Estelle Blanc-Autran, Sadek Nehmeh, Mithat Gönen, Brad Beattie, Hebert A Vargas, Heiko Schöder, John L Humm, Samson W Fine, Jason S Lewis, Stephen B Solomon, Joseph R Osborne, Darren Veach, Charles L Sawyers, Wolfgang A Weber, Howard I Scher, Michael J Morris, Steven M Larson
Importance: Androgen receptor-signaling inhibitor (ARSi) drugs prolong life in metastatic castration-resistant prostate cancer (mCRPC), but such tumors eventually become resistant and progress. Comprehensive positron emission tomography/computed tomography (PET/CT) imaging using fluoro-2-D-deoxyglucose F 18 ([18F]-FDG) for glycolysis (Glyc) and fluorodihydrotestosterone F 18 ([18F]-FDHT) for androgen receptor (AR) expression determine heterogeneity of imaging phenotypes, which may be useful in distinguishing patients who will benefit from ARSi drugs from those who need alternative treatments...
February 1, 2018: JAMA Oncology
https://www.readbyqxmd.com/read/29067575/inguinal-hernia-repair-is-there-a-benefit-to-using-the-robot
#9
Eric J Charles, J Hunter Mehaffey, Carlos A Tache-Leon, Peter T Hallowell, Robert G Sawyer, Zequan Yang
BACKGROUND: The number of robotic surgical procedures performed yearly is constantly rising, due to improved dexterity and visualization capabilities compared with conventional methods. We hypothesized that outcomes after robotic-assisted inguinal hernia repair would not be significantly different from outcomes after laparoscopic or open repair. METHODS: All patients undergoing inguinal hernia repair between 2012 and 2016 were identified using institutional American College of Surgeons National Surgical Quality Improvement Program data...
April 2018: Surgical Endoscopy
https://www.readbyqxmd.com/read/29057879/deletion-of-3p13-14-locus-spanning-foxp1-to-shq1-cooperates-with-pten-loss-in-prostate-oncogenesis
#10
Haley Hieronymus, Phillip J Iaquinta, John Wongvipat, Anuradha Gopalan, Rajmohan Murali, Ninghui Mao, Brett S Carver, Charles L Sawyers
A multigenic locus at 3p13-14, spanning FOXP1 to SHQ1, is commonly deleted in prostate cancer and lost broadly in a range of cancers but has unknown significance to oncogenesis or prognosis. Here, we report that FOXP1-SHQ1 deletion cooperates with PTEN loss to accelerate prostate oncogenesis and that loss of component genes correlates with prostate, breast, and head and neck cancer recurrence. We demonstrate that Foxp1-Shq1 deletion accelerates prostate tumorigenesis in mice in combination with Pten loss, consistent with the association of FOXP1-SHQ1 and PTEN loss observed in human cancers...
October 20, 2017: Nature Communications
https://www.readbyqxmd.com/read/29020201/novel-method-suggests-global-superiority-of-short-duration-antibiotics-for-intra-abdominal-infections
#11
Arthur R Celestin, Stephen R Odom, Konstantia Angelidou, Scott R Evans, Raul Coimbra, Christopher A Guidry, Joseph Cuschieri, Kaysie L Banton, Patrick J O'Neill, Reza Askari, Nicholas Namias, Therèse M Duane, Jeffrey A Claridge, E Patchen Dellinger, Robert A Sawyer, Charles H Cook
Desirability of outcome ranking and response adjusted for duration of antibiotic risk (DOOR/RADAR) are novel and innovative methods of evaluating data in antibiotic trials. We analyzed data from a noninferiority trial of short-course antimicrobial therapy for intra-abdominal infection (STOP-IT), and results suggest global superiority of short-duration therapy for intra-abdominal infections.
October 16, 2017: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
https://www.readbyqxmd.com/read/28994635/does-isolation-of-enterococcus-affect-outcomes-in-intra-abdominal-infections
#12
James M Sanders, Jeffrey M Tessier, Robert Sawyer, E P Dellinger, Preston R Miller, Nicholas Namias, Michaela West, Charles H Cook, P J O'Neill, Lena Napolitano, Rishi Rattan, Joseph Cuschieri, Jeffrey A Claridge, Chris A Guidry, Reza Askari, Kaysie Banton, Ori Rotstein, Billy J Moore, Therese M Duane
BACKGROUND: Enterococci are isolated frequently as pathogens in patients with intra-abdominal infections (IAIs) and may predict poor clinical outcomes. It remains controversial whether enterococci warrant an altered treatment approach with regard to antimicrobial treatment. PATIENTS AND METHODS: The study population was derived from the Study to Optimize Peritoneal Infection Therapy (STOP-IT) trial database. Through post hoc analysis subjects were stratified into two groups based on isolation of Enterococcus...
October 10, 2017: Surgical Infections
https://www.readbyqxmd.com/read/28891793/regulation-of-the-glucocorticoid-receptor-via-a-bet-dependent-enhancer-drives-antiandrogen-resistance-in-prostate-cancer
#13
Neel Shah, Ping Wang, John Wongvipat, Wouter R Karthaus, Wassim Abida, Joshua Armenia, Shira Rockowitz, Yotam Drier, Bradley E Bernstein, Henry W Long, Matthew L Freedman, Vivek K Arora, Deyou Zheng, Charles L Sawyers
In prostate cancer, resistance to the antiandrogen enzalutamide (Enz) can occur through bypass of androgen receptor (AR) blockade by the glucocorticoid receptor (GR). In contrast to fixed genomic alterations, here we show that GR-mediated antiandrogen resistance is adaptive and reversible due to regulation of GR expression by a tissue-specific enhancer. GR expression is silenced in prostate cancer by a combination of AR binding and EZH2-mediated repression at the GR locus, but is restored in advanced prostate cancers upon reversion of both repressive signals...
September 11, 2017: ELife
https://www.readbyqxmd.com/read/28873162/mutation-detection-in-patients-with-advanced-cancer-by-universal-sequencing-of-cancer-related-genes-in-tumor-and-normal-dna-vs-guideline-based-germline-testing
#14
Diana Mandelker, Liying Zhang, Yelena Kemel, Zsofia K Stadler, Vijai Joseph, Ahmet Zehir, Nisha Pradhan, Angela Arnold, Michael F Walsh, Yirong Li, Anoop R Balakrishnan, Aijazuddin Syed, Meera Prasad, Khedoudja Nafa, Maria I Carlo, Karen A Cadoo, Meg Sheehan, Megan H Fleischut, Erin Salo-Mullen, Magan Trottier, Steven M Lipkin, Anne Lincoln, Semanti Mukherjee, Vignesh Ravichandran, Roy Cambria, Jesse Galle, Wassim Abida, Marcia E Arcila, Ryma Benayed, Ronak Shah, Kenneth Yu, Dean F Bajorin, Jonathan A Coleman, Steven D Leach, Maeve A Lowery, Julio Garcia-Aguilar, Philip W Kantoff, Charles L Sawyers, Maura N Dickler, Leonard Saltz, Robert J Motzer, Eileen M O'Reilly, Howard I Scher, Jose Baselga, David S Klimstra, David B Solit, David M Hyman, Michael F Berger, Marc Ladanyi, Mark E Robson, Kenneth Offit
Importance: Guidelines for cancer genetic testing based on family history may miss clinically actionable genetic changes with established implications for cancer screening or prevention. Objective: To determine the proportion and potential clinical implications of inherited variants detected using simultaneous sequencing of the tumor and normal tissue ("tumor-normal sequencing") compared with genetic test results based on current guidelines. Design, Setting, and Participants: From January 2014 until May 2016 at Memorial Sloan Kettering Cancer Center, 10 336 patients consented to tumor DNA sequencing...
September 5, 2017: JAMA: the Journal of the American Medical Association
https://www.readbyqxmd.com/read/28815210/lpxk-is-essential-for-growth-of-acinetobacter-baumannii-atcc-19606-relationship-to-toxic-accumulation-of-lipid-a-pathway-intermediates
#15
Jun-Rong Wei, Daryl L Richie, Mina Mostafavi, Louis E Metzger, Christopher M Rath, William S Sawyer, Kenneth T Takeoka, Charles R Dean
Acinetobacter baumannii ATCC 19606 can grow without lipid A, the major component of lipooligosaccharide. However, we previously reported that depletion of LpxH (the fourth enzyme in the lipid A biosynthetic pathway) prevented growth of this strain due to toxic accumulation of lipid A pathway intermediates. Here, we explored whether a similar phenomenon occurred with depletion of LpxK, a kinase that phosphorylates disaccharide 1-monophosphate (DSMP) at the 4' position to yield lipid IVA. An A. baumannii ATCC 19606 derivative with LpxK expression under the control of an isopropyl β-d-1-thiogalactopyranoside (IPTG)-regulated expression system failed to grow without induction, indicating that LpxK is essential for growth...
July 2017: MSphere
https://www.readbyqxmd.com/read/28688647/effect-of-hypothermia-on-splenic-leukocyte-modulation-and-survival-duration-in-severely-septic-rats
#16
Rhett N Willis, Eric J Charles, Christopher A Guidry, Mahendra D Chordia, Stephen W Davies, Zequan Yang, Robert G Sawyer
BACKGROUND: Therapeutic hypothermia (HT) in severe septic shock is associated with prolonged survival. We hypothesized that moderate HT would prolong survival and modulate the inflammatory response in rats with septic shock by exerting its therapeutic effect on splenic leukocytes. MATERIALS AND METHODS: Severe septic shock was created in rats by cecal ligation and incision (CLI). One hour after CLI or laparotomy, rats were randomized to sham, normothermia (NT), or 4 h of HT followed by 2 h of rewarming...
July 2017: Journal of Surgical Research
https://www.readbyqxmd.com/read/28650745/longer-duration-antimicrobial-therapy-does-not-prevent-treatment-failure-in-high-risk-patients-with-complicated-intra-abdominal-infections
#17
Taryn E Hassinger, Christopher A Guidry, Ori D Rotstein, Therese M Duane, Heather L Evans, Charles H Cook, Patrick J O'Neill, John E Mazuski, Reza Askari, Lena M Napolitano, Nicholas Namias, Preston R Miller, E Patchen Dellinger, Raul Coimbra, Christine S Cocanour, Kaysie L Banton, Joseph Cuschieri, Kimberley Popovsky, Robert G Sawyer
BACKGROUND: Recent studies have suggested the length of treatment of intra-abdominal infections (IAIs) can be shortened without detrimental effects on patient outcomes. However, data from high-risk patient populations are lacking. We hypothesized that patients at high risk for treatment failure will benefit from a longer course of antimicrobial therapy. METHODS: Patients enrolled in the Study to Optimize Peritoneal Infection Therapy (STOP-IT) trial were evaluated retrospectively to identify risk factors associated with treatment failure, which was defined as the composite outcome of recurrent IAI, surgical site infection, or death...
August 2017: Surgical Infections
https://www.readbyqxmd.com/read/28614298/erf-mutations-reveal-a-balance-of-ets-factors-controlling-prostate-oncogenesis
#18
Rohit Bose, Wouter R Karthaus, Joshua Armenia, Wassim Abida, Phillip J Iaquinta, Zeda Zhang, John Wongvipat, Elizabeth V Wasmuth, Neel Shah, Patrick S Sullivan, Michael G Doran, Ping Wang, Anna Patruno, Yilin Zhao, Deyou Zheng, Nikolaus Schultz, Charles L Sawyers
Half of all prostate cancers are caused by the TMPRSS2-ERG gene-fusion, which enables androgens to drive expression of the normally silent E26 transformation-specific (ETS) transcription factor ERG in prostate cells. Recent genomic landscape studies of such cancers have reported recurrent point mutations and focal deletions of another ETS member, the ETS2 repressor factor ERF. Here we show these ERF mutations cause decreased protein stability and mostly occur in tumours without ERG upregulation. ERF loss recapitulates the morphological and phenotypic features of ERG gain in normal mouse prostate cells, including expansion of the androgen receptor transcriptional repertoire, and ERF has tumour suppressor activity in the same genetic background of Pten loss that yields oncogenic activity by ERG...
June 29, 2017: Nature
https://www.readbyqxmd.com/read/28486022/wound-concerns-and-healthcare-consumption-of-resources-after-colorectal-surgery-an-opportunity-for-innovation
#19
Puja M Shah, Heather L Evans, Amy Harrigan, Robert G Sawyer, Charles M Friel, Traci L Hedrick
BACKGROUND: Significant portions of patients undergoing colorectal surgical procedures have minor incision disturbances, yet very few meet definitions for surgical site infection (SSI). We sought to investigate the natural history of incision disturbances with a focus on the patient experience and resource utilization. We hypothesize that patients who have an incision disturbance consume frequent healthcare resources in the post-operative period despite the fact that most never receive a diagnosis of SSI...
July 2017: Surgical Infections
https://www.readbyqxmd.com/read/28130854/isotope-labelling-by-reduction-of-nitriles-application-to-the-synthesis-of-isotopologues-of-tolmetin-and-celecoxib
#20
Kate Ellis-Sawyer, Ryan A Bragg, Nick Bushby, Charles S Elmore, Michael J Hickey
The aryl methyl group is found in many drug-like compounds, but there are limited ways of preparing compounds with an isotope label in this methyl position. The process of cyanation of an aryl halide followed by complete reduction of the nitrile to a methyl group was investigated as a route for preparing stable and radiolabelled isotopologues of drug-like compounds. Using this methodology, carbon-13, deuterium, carbon-14, and tritium labelled isotopologues of the nonsteroidal anti-inflammatory drug tolmetin were produced, as well as carbon-13, deuterium, and carbon-14 labelled isotopologues of another nonsteroidal anti-inflammatory drug, celecoxib...
April 2017: Journal of Labelled Compounds & Radiopharmaceuticals
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