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https://www.readbyqxmd.com/read/29764952/samhd1-phosphorylation-coordinates-the-anti-hiv-1-response-by-diverse-interferons-and-tyrosine-kinase-inhibition
#1
Matthew A Szaniawski, Adam M Spivak, James E Cox, Jonathan L Catrow, Timothy Hanley, Elizabeth S C P Williams, Michel J Tremblay, Alberto Bosque, Vicente Planelles
Macrophages are susceptible to human immunodeficiency virus type 1 (HIV-1) infection despite abundant expression of antiviral proteins. Perhaps the most important antiviral protein is the restriction factor sterile alpha motif domain and histidine/aspartic acid domain-containing protein 1 (SAMHD1). We investigated the role of SAMHD1 and its phospho-dependent regulation in the context of HIV-1 infection in primary human monocyte-derived macrophages and the ability of various interferons (IFNs) and pharmacologic agents to modulate SAMHD1...
May 15, 2018: MBio
https://www.readbyqxmd.com/read/29763816/design-of-a-phase-3-trial-of-intracoronary-administration-of-human-adenovirus-5-encoding-human-adenylyl-cyclase-type-6-rt-100-gene-transfer-in-patients-with-heart-failure-with-reduced-left-ventricular-ejection-fraction-the-flourish-clinical-trial
#2
William F Penny, Timothy D Henry, Matthew W Watkins, Amit N Patel, H Kirk Hammond
The prognosis of patients with HFrEF remains poor despite the use of current medical and device therapies. Preclinical studies of HFrEF using IC delivery of RT-100, a replication deficient, E1/E3-deleted human adenovirus 5 encoding human AC6 was associated with favorable effects on LV function and remodeling. A recent multicenter, double-blind, placebo-controlled, phase 2 study demonstrated the safety of IC delivery of RT-100 in HFrEF patients and potential efficacy at the higher doses. This phase 2 dose finding study, which included doses not expected to be effective, identified a potential reduction in congestive heart failure admissions in the AC6-treated group one year after randomization...
April 6, 2018: American Heart Journal
https://www.readbyqxmd.com/read/29762717/durable-complete-responses-in-some-recurrent-high-grade-glioma-patients-treated-with-toca-511-toca-fc
#3
Timothy F Cloughesy, Joseph Landolfi, Michael A Vogelbaum, Derek Ostertag, James B Elder, Stephen Bloomfield, Bob Carter, Clark C Chen, Steven N Kalkanis, Santosh Kesari, Albert Lai, Ian Y Lee, Linda M Liau, Tom Mikkelsen, Phioanh Nghiemphu, David Piccioni, William Accomando, Oscar R Diago, Daniel J Hogan, Dawn Gammon, Noriyuki Kasahara, Thian Kheoh, Douglas J Jolly, Harry E Gruber, Asha Das, Tobias Walbert
Background: Vocimagene amiretrorepvec (Toca 511) is an investigational gamma-retroviral replicating vector encoding cytosine deaminase that, when used in combination with extended-release 5-fluorocytosine (Toca FC), results preclinically in local production of 5-fluorouracil, depletion of immune-suppressive myeloid cells, and subsequent induction of anti-tumor immunity. Recurrent high grade glioma (rHGG) patients have a high unmet need for effective therapies that produce durable responses lasting more than 6 months...
May 12, 2018: Neuro-oncology
https://www.readbyqxmd.com/read/29760953/hyperglycemia-potentiates-a-shift-from-apoptosis-to-rip1-dependent-necroptosis
#4
William D McCaig, Payal S Patel, Sergey A Sosunov, Nicole L Shakerley, Tori A Smiraglia, Miranda M Craft, Katharine M Walker, Matthew A Deragon, Vadim S Ten, Timothy J LaRocca
Apoptosis and necroptosis are the primary modes of eukaryotic cell death, with apoptosis being non-inflammatory while necroptosis is highly inflammatory. We previously demonstrated that, once activated, necroptosis is enhanced by hyperglycemia in several cell types. Here, we determine if hyperglycemia affects apoptosis similarly. We show that hyperglycemia does not enhance extrinsic apoptosis but potentiates a shift to RIP1-dependent necroptosis. This is due to increased levels and activity of RIP1, RIP3, and MLKL, as well as decreased levels and activity of executioner caspases under hyperglycemic conditions following stimulation of apoptosis...
2018: Cell Death Discovery
https://www.readbyqxmd.com/read/29752776/influence-of-prehospital-airway-management-on-neurological-outcome-in-patients-transferred-to-a-heart-attack-centre-following-out-of-hospital-cardiac-arrest
#5
Timothy Edwards, Julia Williams, Michaela Cottee
OBJECTIVE: To describe the association between prehospital airway management and neurological outcomes in patients transferred by the ambulance service directly to a heart attack centre (HAC) post-return of spontaneous circulation (ROSC). METHODS: A retrospective observational cohort study in which ambulance records were reviewed to determine prehospital airway management strategy and collect physiological and demographic data. HAC notes were obtained to determine in-hospital management and quantify neurological outcome via the cerebral performance category (CPC) scale...
May 11, 2018: Emergency Medicine Australasia: EMA
https://www.readbyqxmd.com/read/29751612/advice-and-frequently-asked-questions-faqs-for-citizen-science-environmental-health-assessments
#6
Timothy M Barzyk, Hongtai Huang, Ronald Williams, Amanda Kaufman, Jonathan Essoka
Citizen science provides quantitative results to support environmental health assessments (EHAs), but standardized approaches do not currently exist to translate findings into actionable solutions. The emergence of low-cost portable sensor technologies and proliferation of publicly available datasets provides unparalleled access to supporting evidence; yet data collection, analysis, interpretation, visualization, and communication are subjective approaches that must be tailored to a decision-making audience capable of improving environmental health...
May 11, 2018: International Journal of Environmental Research and Public Health
https://www.readbyqxmd.com/read/29748316/common-and-rare-coding-genetic-variation-underlying-the-electrocardiographic-pr-interval
#7
Honghuang Lin, Jessica van Setten, Albert V Smith, Nathan A Bihlmeyer, Helen R Warren, Jennifer A Brody, Farid Radmanesh, Leanne Hall, Niels Grarup, Martina Müller-Nurasyid, Thibaud Boutin, Niek Verweij, Henry J Lin, Ruifang Li-Gao, Marten E van den Berg, Jonathan Marten, Stefan Weiss, Bram P Prins, Jeffrey Haessler, Leo-Pekka Lyytikäinen, Hao Mei, Tamara B Harris, Lenore J Launer, Man Li, Alvaro Alonso, Elsayed Z Soliman, John M Connell, Paul L Huang, Lu-Chen Weng, Heather S Jameson, William Hucker, Alan Hanley, Nathan R Tucker, Yii-Der Ida Chen, Joshua C Bis, Kenneth M Rice, Colleen M Sitlani, Jan A Kors, Zhijun Xie, Chengping Wen, Jared W Magnani, Christopher P Nelson, Jørgen K Kanters, Moritz F Sinner, Konstantin Strauch, Annette Peters, Melanie Waldenberger, Thomas Meitinger, Jette Bork-Jensen, Oluf Pedersen, Allan Linneberg, Igor Rudan, Rudolf A de Boer, Peter van der Meer, Jie Yao, Xiuqing Guo, Kent D Taylor, Nona Sotoodehnia, Jerome I Rotter, Dennis O Mook-Kanamori, Stella Trompet, Fernando Rivadeneira, André Uitterlinden, Mark Eijgelsheim, Sandosh Padmanabhan, Blair H Smith, Henry Völzke, Stephan B Felix, Georg Homuth, Uwe Völker, Massimo Mangino, Timothy D Spector, Michiel L Bots, Marco Perez, Mika Kähönen, Olli T Raitakari, Vilmundur Gudnason, Dan E Arking, Patricia B Munroe, Bruce M Psaty, Cornelia M van Duijn, Emelia J Benjamin, Jonathan Rosand, Nilesh J Samani, Torben Hansen, Stefan Kääb, Ozren Polasek, Pim van der Harst, Susan R Heckbert, J Wouter Jukema, Bruno H Stricker, Caroline Hayward, Marcus Dörr, Yalda Jamshidi, Folkert W Asselbergs, Charles Kooperberg, Terho Lehtimäki, James G Wilson, Patrick T Ellinor, Steven A Lubitz, Aaron Isaacs
BACKGROUND: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability. METHODS: We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry...
May 2018: Circulation. Genomic and precision medicine
https://www.readbyqxmd.com/read/29748278/recent-asian-origin-of-chytrid-fungi-causing-global-amphibian-declines
#8
Simon J O'Hanlon, Adrien Rieux, Rhys A Farrer, Gonçalo M Rosa, Bruce Waldman, Arnaud Bataille, Tiffany A Kosch, Kris A Murray, Balázs Brankovics, Matteo Fumagalli, Michael D Martin, Nathan Wales, Mario Alvarado-Rybak, Kieran A Bates, Lee Berger, Susanne Böll, Lola Brookes, Frances Clare, Elodie A Courtois, Andrew A Cunningham, Thomas M Doherty-Bone, Pria Ghosh, David J Gower, William E Hintz, Jacob Höglund, Thomas S Jenkinson, Chun-Fu Lin, Anssi Laurila, Adeline Loyau, An Martel, Sara Meurling, Claude Miaud, Pete Minting, Frank Pasmans, Dirk S Schmeller, Benedikt R Schmidt, Jennifer M G Shelton, Lee F Skerratt, Freya Smith, Claudio Soto-Azat, Matteo Spagnoletti, Giulia Tessa, Luís Felipe Toledo, Andrés Valenzuela-Sánchez, Ruhan Verster, Judit Vörös, Rebecca J Webb, Claudia Wierzbicki, Emma Wombwell, Kelly R Zamudio, David M Aanensen, Timothy Y James, M Thomas P Gilbert, Ché Weldon, Jaime Bosch, François Balloux, Trenton W J Garner, Matthew C Fisher
Globalized infectious diseases are causing species declines worldwide, but their source often remains elusive. We used whole-genome sequencing to solve the spatiotemporal origins of the most devastating panzootic to date, caused by the fungus Batrachochytrium dendrobatidis , a proximate driver of global amphibian declines. We traced the source of B. dendrobatidis to the Korean peninsula, where one lineage, Bd ASIA-1, exhibits the genetic hallmarks of an ancestral population that seeded the panzootic. We date the emergence of this pathogen to the early 20th century, coinciding with the global expansion of commercial trade in amphibians, and we show that intercontinental transmission is ongoing...
May 11, 2018: Science
https://www.readbyqxmd.com/read/29748060/haemodynamically-derived-pulmonary-artery-pulsatility-index-predicts-mortality-in-pulmonary-arterial-hypertension
#9
Sula Mazimba, Timothy S Welch, Hunter Mwansa, Khadijah K Breathett, Jamie L W Kennedy, Andrew D Mihalek, William C Harding, Manu M Mysore, David X Zhuo, Kenneth C Bilchick
BACKGROUND: Pulmonary artery (PA) pulsitility index (PAPi) is a novel haemodynamic index shown to predict right ventricular failure in acute inferior myocardial infarction and post left ventricular assist device surgery. We hypothesised that PAPi calculated as [PA systolic pressure - PA diastolic pressure]/right atrial pressure (RAP) would be associated with mortality in the National Institutes of Health Registry for Primary Pulmonary Hypertension (NIH-RPPH). METHODS: The impact of PAPi, the Pulmonary Hypertension Connection (PHC) risk score, right ventricular stroke work, pulmonary artery capacitance (PAC), other haemodynamic indices, and demographic characteristics was evaluated in 272 NIH-RPPH patients using multivariable Cox proportional hazards (CPH) regression and receiver operating characteristic (ROC) analysis...
April 17, 2018: Heart, Lung & Circulation
https://www.readbyqxmd.com/read/29746225/clinical-radiologic-pathologic-and-molecular-characteristics-of-long-term-survivors-of-diffuse-intrinsic-pontine-glioma-dipg-a-collaborative-report-from-the-international-and-european-society-for-pediatric-oncology-dipg-registries
#10
Lindsey M Hoffman, Sophie E M Veldhuijzen van Zanten, Niclas Colditz, Joshua Baugh, Brooklyn Chaney, Marion Hoffmann, Adam Lane, Christine Fuller, Lili Miles, Cynthia Hawkins, Ute Bartels, Eric Bouffet, Stewart Goldman, Sarah Leary, Nicholas K Foreman, Roger Packer, Katherine E Warren, Alberto Broniscer, Mark W Kieran, Jane Minturn, Melanie Comito, Emmett Broxson, Chie-Schin Shih, Soumen Khatua, Murali Chintagumpala, Anne Sophie Carret, Nancy Yanez Escorza, Timothy Hassall, David S Ziegler, Nicholas Gottardo, Hetal Dholaria, Renee Doughman, Martin Benesch, Rachid Drissi, Javad Nazarian, Nada Jabado, Nathalie Boddaert, Pascale Varlet, Géraldine Giraud, David Castel, Stephanie Puget, Chris Jones, Esther Hulleman, Piergiorgio Modena, Marzia Giagnacovo, Manila Antonelli, Torsten Pietsch, Gerrit H Gielen, David T W Jones, Dominik Sturm, Stefan M Pfister, Nicolas U Gerber, Michael A Grotzer, Elke Pfaff, André O von Bueren, Darren Hargrave, Guirish A Solanki, Filip Jadrijevic Cvrlje, Gertjan J L Kaspers, William P Vandertop, Jacques Grill, Simon Bailey, Veronica Biassoni, Maura Massimino, Raphaël Calmon, Esther Sanchez, Brigitte Bison, Monika Warmuth-Metz, James Leach, Blaise Jones, Dannis G van Vuurden, Christof M Kramm, Maryam Fouladi
Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of < 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs). Materials and Methods Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia...
May 10, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29743592/a-novel-three-dimensional-high-throughput-screening-approach-identifies-inducers-of-a-mutant-kras-selective-lethal-phenotype
#11
Smitha Kota, Shurong Hou, William Guerrant, Franck Madoux, Scott Troutman, Virneliz Fernandez-Vega, Nina Alekseeva, Neeharika Madala, Louis Scampavia, Joseph Kissil, Timothy P Spicer
The RAS proteins are the most frequently mutated oncogenes in cancer, with highest frequency found in pancreatic, lung, and colon tumors. Moreover, the activity of RAS is required for the proliferation and/or survival of these tumor cells and thus represents a high-value target for therapeutic development. Direct targeting of RAS has proven challenging for multiple reasons stemming from the biology of the protein, the complexity of downstream effector pathways and upstream regulatory networks. Thus, significant efforts have been directed at identifying downstream targets on which RAS is dependent...
May 10, 2018: Oncogene
https://www.readbyqxmd.com/read/29742358/application-of-integrated-drug-screening-kinome-analysis-to-identify-inhibitors-of-gemcitabine-resistant-pancreatic-cancer-cell-growth
#12
Linas J Krulikas, Ian M McDonald, Benjamin Lee, Denis O Okumu, Michael P East, Thomas S K Gilbert, Laura E Herring, Brian T Golitz, Carrow I Wells, Allison D Axtman, William J Zuercher, Timothy M Willson, Dmitri Kireev, Jen Jen Yeh, Gary L Johnson, Antonio T Baines, Lee M Graves
Continuous exposure of a pancreatic cancer cell line MIA PaCa-2 (MiaS ) to gemcitabine resulted in the formation of a gemcitabine-resistant subline (MiaR ). In an effort to discover kinase inhibitors that inhibited MiaR growth, MiaR cells were exposed to kinase inhibitors (PKIS-1 library) in a 384-well screening format. Three compounds (UNC10112721A, UNC10112652A, and UNC10112793A) were identified that inhibited the growth of MiaR cells by more than 50% (at 50 nM). Two compounds (UNC10112721A and UNC10112652A) were classified as cyclin-dependent kinase (CDK) inhibitors, whereas UNC10112793A was reported to be a PLK inhibitor...
May 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29736411/a-functional-genomic-screen-in-vivo-identifies-ceacam5-as-a-clinically-relevant-driver-of-breast-cancer-metastasis
#13
Emily Powell, Jiansu Shao, Hector M Picon, Christopher Bristow, Zhongqi Ge, Michael Peoples, Frederick Robinson, Sabrina L Jeter-Jones, Christopher Schlosberg, Caitlin L Grzeskowiak, Fei Yang, Yun Wu, Ignacio Wistuba, Stacy L Moulder, William F Symmans, Kenneth L Scott, John R Edwards, Han Liang, Timothy P Heffernan, Helen Piwnica-Worms
Tumor cells disseminate early in tumor development making metastasis-prevention strategies difficult. Identifying proteins that promote the outgrowth of disseminated tumor cells may provide opportunities for novel therapeutic strategies. Despite multiple studies demonstrating that the mesenchymal-to-epithelial transition (MET) is critical for metastatic colonization, key regulators that initiate this transition remain unknown. We serially passaged lung metastases from a primary triple negative breast cancer xenograft to the mammary fat pads of recipient mice to enrich for gene expression changes that drive metastasis...
2018: NPJ Breast Cancer
https://www.readbyqxmd.com/read/29729257/association-between-bacteremia-from-specific-microbes-and-subsequent-diagnosis-of-colorectal-cancer
#14
Thomas N Y Kwong, Xiansong Wang, Geicho Nakatsu, Tai Cheong Chow, Timothy Tipoe, Rudin Z W Dai, Kelvin K K Tsoi, Martin C S Wong, Gary Tse, Matthew T V Chan, Francis K L Chan, Siew C Ng, Justin C Y Wu, William K K Wu, Jun Yu, Joseph J Y Sung, Sunny H Wong
BACKGROUND & AIMS: Colorectal cancer (CRC) development has been associated with increased proportions of Bacteroides fragilis and certain Streptococcus, Fusobacterium, and Peptostreptococcus species in the intestinal microbiota. We investigated associations between bacteremia from specific intestinal microbes and occurrence of CRC. METHODS: We performed a retrospective study, collecting data from13,096 adult patients (exposed group) in Hong Kong hospitalized with bacteremia (identified by blood culture test), without a previous diagnosis of cancer, from January 1, 2006 through December 31, 2015...
May 2, 2018: Gastroenterology
https://www.readbyqxmd.com/read/29727311/identifying-clinical-factors-which-predict-for-early-failure-patterns-following-resection-for-pancreatic-adenocarcinoma-in-patients-who-received-adjuvant-chemotherapy-without-chemoradiation
#15
Steve Walston, Joseph Salloum, Carmine Grieco, Evan Wuthrick, Dayssy A Diaz, Christian Barney, Andrei Manilchuk, Carl Schmidt, Mary Dillhoff, Timothy M Pawlik, Terence M Williams
OBJECTIVES: The role of radiation therapy (RT) in resected pancreatic cancer (PC) remains incompletely defined. We sought to determine clinical variables which predict for local-regional recurrence (LRR) to help select patients for adjuvant RT. MATERIALS AND METHODS: We identified 73 patients with PC who underwent resection and adjuvant gemcitabine-based chemotherapy alone. We performed detailed radiologic analysis of first patterns of failure. LRR was defined as recurrence of PC within standard postoperative radiation volumes...
April 30, 2018: American Journal of Clinical Oncology
https://www.readbyqxmd.com/read/29722661/phase-2-study-of-bortezomib-combined-with-temozolomide-and-regional-radiation-therapy-for-upfront-treatment-of-patients-with-newly-diagnosed-glioblastoma-multiforme-safety-and-efficacy-assessment
#16
Xiao-Tang Kong, Nhung T Nguyen, Yoon J Choi, Guicheng Zhang, HuyTram N Nguyen, Emese Filka, Stacey Green, William H Yong, Linda M Liau, Richard M Green, Tania Kaprealian, Whitney B Pope, P Leia Nghiemphu, Timothy Cloughesy, Andrew Lassman, Albert Lai
PURPOSE: To assess the safety and efficacy of upfront treatment using bortezomib combined with standard radiation therapy (RT) and temozolomide (TMZ), followed by adjuvant bortezomib and TMZ for ≤24 cycles, in patients with newly diagnosed glioblastoma multiforme (GBM). METHODS AND MATERIALS: Twenty-four patients with newly diagnosed GBM were enrolled. The patients received standard external beam regional RT with concurrent TMZ beginning 3 to 6 weeks after surgery, followed by adjuvant TMZ and bortezomib for ≤24 cycles or until tumor progression...
April 1, 2018: International Journal of Radiation Oncology, Biology, Physics
https://www.readbyqxmd.com/read/29719700/direct-observation-of-vibrational-energy-dispersal-via-methyl-torsions
#17
Adrian M Gardner, William D Tuttle, Laura E Whalley, Timothy G Wright
Explicit evidence for the role of methyl rotor levels in promoting energy dispersal is reported. A set of coupled zero-order vibration/vibration-torsion (vibtor) levels in the S1 state of para -fluorotoluene ( p FT) are investigated. Two-dimensional laser-induced fluorescence (2D-LIF) and two-dimensional zero-kinetic-energy (2D-ZEKE) spectra are reported, and the assignment of the main features in both sets of spectra reveals that the methyl torsion is instrumental in providing a route for coupling between vibrational levels of different symmetry classes...
February 28, 2018: Chemical Science
https://www.readbyqxmd.com/read/29708428/interpathologist-diagnostic-agreement-for-non-small-cell-lung-carcinomas-using-current-and-recent-classifications
#18
William K Funkhouser, D Neil Hayes, Dominic T Moore, W Keith Funkhouser, Jason P Fine, HeeJoon Jo, Nana Nikolaishvilli-Feinberg, Mervi Eeva, Juneko E Grilley-Olson, Peter M Banks, Paolo Graziano, Elizabeth L Boswell, Goran Elmberger, Kirtee Raparia, Craig F Hart, Lynette M Sholl, Norris J Nolan, Karen J Fritchie, Ersie Pouagare, Timothy C Allen, Keith E Volmar, Paul W Biddinger, Daniel T Kleven, Michael J Papez, Deborah V Spencer, Natasha Rekhtman, Mari Mino-Kenudson, Lida Hariri, Brandon Driver, Philip T Cagle
CONTEXT: - Measurement of interpathologist diagnostic agreement (IPDA) should allow pathologists to improve current diagnostic criteria and disease classifications. OBJECTIVES: - To determine how IPDA for pathologists' diagnoses of non-small cell lung carcinoma (NSCLC) is affected by the addition of a set of mucin and immunohistochemical (IHC) stains to hematoxylin-eosin (H&E) alone, by recent NSCLC reclassifications, by simplification of these classifications, and by pathologists' practice location, pulmonary pathology expertise, practice duration, and lung carcinoma case exposure...
April 30, 2018: Archives of Pathology & Laboratory Medicine
https://www.readbyqxmd.com/read/29707717/vibrations-of-the-p-chlorofluorobenzene-cation
#19
David J Kemp, Laura E Whalley, William D Tuttle, Adrian M Gardner, Benjamin T Speake, Timothy G Wright
The vibrations of the ground state cation (X[combining tilde]2B1) of para-chlorofluorobenzene (pClFB) have been investigated using zero-electron-kinetic-energy (ZEKE) spectroscopy. ZEKE spectra were recorded using different vibrational levels of the S1 state as intermediate levels, for which assignments were put forward in an earlier paper [W. D. Tuttle, A. M. Gardner, and T. G. Wright, Chem. Phys. Lett., 2017, 684, 339]. These different intermediate levels dramatically modify the Franck-Condon factors for the ionization step...
April 30, 2018: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/29703731/dysregulation-of-sphingolipid-metabolism-contributes-to-bortezomib-induced-neuropathic-pain
#20
Katherine Stockstill, Timothy M Doyle, Xisheng Yan, Zhoumou Chen, Kali Janes, Joshua W Little, Kathryn Braden, Filomena Lauro, Luigino Antonio Giancotti, Caron Mitsue Harada, Ruchi Yadav, Wen Hua Xiao, Jack M Lionberger, William L Neumann, Gary J Bennett, Han-Rong Weng, Sarah Spiegel, Daniela Salvemini
The development of chemotherapy-induced painful peripheral neuropathy is a major dose-limiting side effect of many chemotherapeutics, including bortezomib, but the mechanisms remain poorly understood. We now report that bortezomib causes the dysregulation of de novo sphingolipid metabolism in the spinal cord dorsal horn to increase the levels of sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) ligands, S1P and dihydro-S1P. Accordingly, genetic and pharmacological disruption of S1PR1 with multiple S1PR1 antagonists, including FTY720, blocked and reversed neuropathic pain...
April 27, 2018: Journal of Experimental Medicine
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