tbuckley/cabot-search huggingface dataset:
PAM50 Risk of Recurrence Score Predicts 10-Year Distant Recurrence in a Comprehensive Danish Cohort of Postmenopausal Women Allocated to 5 Years of Endocrine Therapy for Hormone Receptor–Positive Early Breast Cancer
Authors: Anne-Vibeke Lænkholm, Maj-Britt Jensen, Jens Ole Eriksen, Birgitte Bruun Rasmussen, Ann S. Knoop, Wesley Buckingham, Sean Ferree, Carl Schaper, Torsten O. Nielsen, Taryn Haffner, Torben Kibøl, Maj-Lis Møller Talman, Anne Marie Bak Jylling, Tomasz Piotr Tabor, Bent Ejlertsen
Journal: Journal of Clinical Oncology (2018)

Purpose The PAM50-based Prosigna risk of recurrence (ROR) score has been validated in randomized clinical trials to predict 10-year distant recurrence (DR). The value of Prosigna for predicting DR was examined in a comprehensive nationwide Danish cohort consisting of postmenopausal women with hormone receptor-positive early breast cancer treated with 5 years of endocrine therapy alone. Patients and Methods Using the population-based Danish Breast Cancer Cooperative Group database, follow-up data were collected on all patients diagnosed from 2000 through 2003 who, by nationwide guidelines, were treated with endocrine therapy for 5 years. Primary tumor blocks from 2,740 patients were tested with Prosigna and, after determination of human epidermal growth factor receptor 2 (HER2) status, data from 2,558 hormone receptor-positive/HER2-negative samples were analyzed, including 1,395 node-positive patients. Fine and Gray models were applied to determine the prognostic value of ROR for DR. Results Median follow-up for recurrence was 9.2 years. Twenty-six percent of the node-positive patients were classified as low ROR (n = 359) with a DR risk of 3.5% (95% confidence interval [CI], 1.9% to 6.1%) versus a DR risk of 22.1% (95% CI, 18.6% to 25.8%) at 10 years for patients classified as high ROR (n = 648). Node-negative patients classified as low and high ROR had a risk of DR of 5.0% (95% CI, 2.9% to 8.0%) and 17.8% (95% CI, 14.0% to 22.0%), respectively. Luminal B tumors (n = 947; DR risk, 18.4% [95% CI: 15.7% to 21.3%]) had a significantly worse outcome than luminal A tumors (n = 1,474,;DR risk, 7.6% [95% CI: 6.1% to 9.2%]; P < .001). Conclusion Prosigna ROR score improved the prediction of outcome in this nationwide Danish population. In a real-world setting, Prosigna can reliably identify node-negative patients and a significant proportion of patients with one to three positive nodes who can be spared treatment with adjuvant chemotherapy.
Abstract 16396: Atrial Fibrillation Upregulation of Nucleoside Diphosphate Kinase, Induces Proarrhythmic Sarcoplasmic Reticulum Ca 2+ Leak in Canine Atria
Authors: Marina Schaefer, Issam Abu-Taha, Xiao Yan Qi, Vanessa Gundlach, Patrice Naud, Jordi Heijman, Markus Kamler, Thomas Wieland, Stanley Nattel, Dobromir Dobrev
Journal: Circulation (2017)

Background: Nucleoside diphosphate kinases (NDPK-B and NDPK-C) form complexes with Gs proteins, modulating cAMP signaling via receptor-independent G protein activation. Atrial fibrillation (AF) is ...
BGB-3111 in Combination with Obinutuzumab in Patients with Chronic Lymphocytic Leukemia and Follicular Lymphoma
Authors: Constantine S. Tam, Hang Quach, Andrew Nicol, Xavier Badoux, Hannah Rose, H. Miles Prince, Michael F. Leahy, Richard Eek, Nicholas Wickham, Sushrut S. Patil, Jane Huang, Xiaoping Zhang, Lai Wang, Eric Hedrick, William Novotny, Ian W. Flinn
Journal: Blood (2017)
Phase I Trial of Pomalidomide, Bortezomib, and Dexamethasone As Frontline Treatment of AL Amyloidosis
Authors: Jeffrey A Zonder, Vaishali Sanchorawala, Vishal Kukreti, Sascha A Tuchman, Yubin Kang, Divaya Bhutani, Steven Burt, Christiane Houde, Kathy A. Reichel, Silva Pregja, Jeffrey V Matous
Journal: Blood (2017)
Clinical Efficacy of Benralizumab in Patients With Severe, Uncontrolled Eosinophilic Asthma and Nasal Polyposis: Pooled Analysis of the SIROCCO and CALIMA Trials
Authors: Jorge Maspero, Tim Harrison, Viktoria Werkström, Yanping Wu, Gokul Gopalan, James Zangrilli
Journal: Journal of Allergy and Clinical Immunology (2018)
CG '806, a First-in-Class Non-Covalent Pan-FLT3/BTK Inhibitor, Exerts Superior Potency Against B-Cell Malignant Cells
Authors: Hongying Zhang, Andrea Local, Khalid Benbatoul, Peter Folger, Susan Sheng, Cheng-Yu Tsai, Stephen Howell, William Rice
Journal: Blood (2017)
Endothelial Activation and Blood-Brain Barrier Disruption in Neurotoxicity after CD19 CAR-T Cell Immunotherapy
Authors: Cameron J. Turtle, Kevin A. Hay, Laila-Aicha Hanafi, Juliane Gust, W. Conrad Liles, José A. López, Junmei Chen, Dominic W. Chung, Mark M Wurfel, Susanna Harju-Baker, Hasan Ozpolat, Daniel Li, David Myerson, Luis F. Gonzalez-Cuyar, Cecilia Yeung, Kathleen R. Fink, Stanley R. Riddell, David G. Maloney
Journal: Blood (2017)
Economic Evaluation for the US of Venetoclax Versus Allogeneic Hematopoietic Stem-Cell Transplantation for Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia with 17p Deletion
Authors: Nimer Alsaid, Ali McBride, Mok Oh, Daniel Persky, Faiz Anwer, Leslie Andritsos, Abhijeet Kumar, Seongseok Yun, Ivo Abraham
Journal: Blood (2017)
Bone edema on magnetic resonance imaging predicts erosive progression on computed tomography at 12 months in RA patients in Adalimumab and Methotrexate combination therapy
Authors: Uffe Døhn, Bo Jannik Ejbjerg, Michael Sejer Hansen, Merete Lund Hetland, Annette Hansen, Ole Rintek Madsen, Maria Hasselquist, Jakob Møllenbach Møller, Mikkel Østergaard
Journal: Annals of the Rheumatic Diseases (2010)
RESPIRE 1: a phase III placebo-controlled randomised trial of ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis
Authors: Anthony De Soyza, Timothy Aksamit, Tiemo-Joerg Bandel, Margarita Criollo, J. Stuart Elborn, Elisabeth Operschall, Eva Polverino, Katrin Roth, Kevin L. Winthrop, Robert Wilson
Journal: European Respiratory Journal (2018)

We evaluated the efficacy and safety of ciprofloxacin dry powder for inhalation (DPI) in patients with non-cystic fibrosis bronchiectasis, two or more exacerbations in the previous year and pre-defined bacteria in sputum.In this phase III, double-blind, placebo-controlled trial, patients were randomised 2:1 to twice-daily ciprofloxacin DPI 32.5 mg or placebo in two treatment regimens consisting of on/off treatment cycles of 14 or 28 days for 48 weeks. The primary end-points were time to first exacerbation and frequency of exacerbations.A total of 416 patients were randomised to the 14-day on/off regimen (ciprofloxacin DPI (n=137) and placebo (n=68)) or the 28-day on/off regimen (ciprofloxacin DPI (n=141) and placebo (n=70)). Ciprofloxacin DPI 14 days on/off significantly prolonged time to first exacerbation versus pooled placebo (median time >336 versus 186 days; hazard ratio 0.53, 97.5% CI 0.36-0.80; p=0.0005) and reduced the frequency of exacerbations compared with matching placebo by 39% (mean number of exacerbations 0.6 versus 1.0; incidence rate ratio 0.61, 97.5% CI 0.40-0.91; p=0.0061). Outcomes for ciprofloxacin DPI 28 days on/off were not statistically significantly different from placebo. The safety profile of ciprofloxacin DPI was favourable.Ciprofloxacin DPI was well tolerated and has the potential to be an effective treatment option in non-cystic fibrosis bronchiectasis.
A pilot study of lower doses of ibrutinib in patients with chronic lymphocytic leukemia
Authors: Lisa S. Chen, Prithviraj Bose, Nichole D. Cruz, Yongying Jiang, Qi Wu, Philip A. Thompson, Shuju Feng, Michael H. Kroll, Wei Qiao, Xuelin Huang, Nitin Jain, William G. Wierda, Michael J. Keating, Varsha Gandhi
Journal: Blood (2018)
Glycogen synthase kinase 3β induces apoptosis in lung cancer cells through modulating survivin expression
Authors: Jiansha Li, Mingyou Xing, Min Zhu, Xi Wang, Manxiang Wang, Sheng Zhou, Naping Li, Muxiang Zhou, Renliang Wu
Journal: Cancer Research (2008)

3375   GSK3β, a regulator of numerous signaling pathways, is involved in a wide range of cellular processes, including cell proliferation, differentiation, apoptosis and metabolism. Here, we report a novel function of GSK3β to interact with survivin, a member of inhibitor-of-apoptosis protein (IAP) family, and to modulate its expression in regulating apoptosis in human lung cancer cells. Co-immunoprecipitation assay revealed that GSK3β was able to bind survivin, and activation of GSK3β induced translocation of survivin from the cytoplasm to the nucleus. The GSK3β-mediated nuclear localization of survivin resulted in G1 cell-cycle arrest and apoptosis in a human lung adenocarcinoma cell line A549. In contrast, inactivation of GSK3β, either by transfection of a dominant-negative mutant inhibitor DN-GSK3β or by selective inhibitor LiCl, increased cytoplasmic survivin expression leading to cell cycle progression and proliferation. These results identify a pro-apoptotic role of GSK3β through modulating survivin expression in lung cancer cells and suggest a potential of pharmacologic activation of GSK3β in therapeutics of lung cancer patients.
Letter by Koutsampasopoulos et al Regarding Article, “Evidence Supporting the Existence of a Distinct Obese Phenotype of Heart Failure With Preserved Ejection Fraction”
Authors: Konstantinos Koutsampasopoulos, Christina Ouzouni, Ioannis Vogiatzis
Journal: Circulation (2018)

We read with great interest an original research article on a possible obese phenotype of heart failure with preserved ejection fraction (HFpEF) by Obokata et al 1 published recently in your journal, which provided extremely important data regarding the cardiovascular structure, function, exercise capacity, and reserve in subjects with obesity-related HFpEF compared with individuals with nonobese HFpEF and controls without HF (heart failure).In this retrospective study, diabetes mellitus (DM) was more prevalent in patients with obesity-related HFpEF compared with controls and nonobese patients with HFpEF.Although the authors suggest that obesity may be considered a specific HFpEF phenotype, it is difficult to separately assess the contribution of DM in obesity-related HFpEF.DM is suggested to be a common contributor to the development of HF. 2 In patients with HFpEF, DM is associated with an increased risk of developing adverse HF outcomes, such as hospitalization for worsening HF and death related to HF. 3,4 Because DM induces oxidative stress, vascular inflammation, and endothelial dysfunction, it plays a key role in the pathophysiology of HFpEF, and therefore obesity-related HFpEF may be confounded by DM. 5 For these reasons, to support the existence of a distinct obese phenotype of HF-pEF, it would be interesting and clinically meaningful to know whether any differences exist between patients with obesity with and without DM within the HFpEF spectrum.This finding could provide a better understanding of the relationship among obesity, DM, and HFpEF; alternative explanations of the underlying mechanisms; and possible differentiations in treatment approach.
Complement activation predicts adverse pregnancy outcome in patients with systemic lupus erythematosus and/or antiphospholipid antibodies
Authors: Mimi Y Kim, Marta M Guerra, Elianna Kaplowitz, Carl A Laskin, Michelle Petri, D Ware Branch, Michael D Lockshin, Lisa R Sammaritano, Joan T Merrill, T Flint Porter, Allen Sawitzke, Anne M Lynch, Jill P Buyon, Jane E Salmon
Journal: Annals of the Rheumatic Diseases (2018)

Objective Studies in mouse models implicate complement activation as a causative factor in adverse pregnancy outcomes (APOs). We investigated whether activation of complement early in pregnancy predicts APOs in women with systemic lupus erythematosus (SLE) and/or antiphospholipid (aPL) antibodies. Methods The PROMISSE Study enrolled pregnant women with SLE and/or aPL antibodies (n=487) and pregnant healthy controls (n=204) at &lt;12 weeks gestation and evaluated them monthly. APOs were: fetal/neonatal death, preterm delivery &lt;36 weeks because of placental insufficiency or preeclampsia and/or growth restriction &lt;5th percentile. Complement activation products were measured on serial blood samples obtained at each monthly visit. Results APO occurred in 20.5% of SLE and/or aPL pregnancies. As early as 12–15 weeks, levels of Bb and sC5b-9 were significantly higher in patients with APOs and remained elevated through 31 weeks compared with those with normal outcomes. Moreover, Bb and sC5b-9 were significantly higher in patients with SLE and/or aPL without APOs compared with healthy controls. In logistic regression analyses, Bb and sC5b-9 at 12–15 weeks remained significantly associated with APO (OR adj =1.41 per SD increase; 95% CI 1.06 to 1.89; P=0.019 and OR adj =1.37 per SD increase; 95% CI 1.05 to 1.80; P=0.022, respectively) after controlling for demographic and clinical risk factors for APOs in PROMISSE. When analyses were restricted to patients with aPL (n=161), associations between Bb at 12–15 weeks and APOs became stronger (OR adj =2.01 per SD increase; 95% CI 1.16 to 3.49; P=0.013). Conclusion In pregnant patients with SLE and/or aPL, increased Bb and sC5b-9 detectable early in pregnancy are strongly predictive of APOs and support activation of complement, particularly the alternative pathway, as a contributor to APOs.
Extracellular vesicle–mediated transfer of constitutively active MyD88L265P engages MyD88wt and activates signaling
Authors: Mateja Manček-Keber, Duško Lainšček, Mojca Benčina, Jiaji G. Chen, Rok Romih, Zachary R. Hunter, Steven P. Treon, Roman Jerala
Journal: Blood (2018)
Limitations in Current Peanut Oral Immunotherapy (POIT) Practices in the U.S
Authors: Michael S. Blaiss, Stephen A. Tilles, Jay A. Lieberman, Marie Cassese, Nicholas Georgitseas, Aditya Venugopal, Ellen Zigmont, Kristin Bennett, Daniel Petroni
Journal: Journal of Allergy and Clinical Immunology (2018)
Physicians Join Frontline Efforts to Curb Gun Injuries, Deaths
Authors: Bridget M. Kuehn
Journal: JAMA (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Doing without metarepresentation: Scenario construction explains the epistemic generativity and privileged status of episodic memory
Authors: Markus Werning, Sen Cheng
Journal: Behavioral and Brain Sciences (2018)

Abstract Episodic memories are distinct from semantic memories in that they are epistemically generative and privileged. Whereas Mahr &amp; Csibra (M&amp;C) develop a metarepresentational account of epistemic vigilance, we propose an explanation that builds on our notion of scenario construction: The way an event of the past is presented in episodic memory recall explains the epistemic generativity and privilegedness of episodic memory.
Efficacy and Safety of Long-Term Ixazomib Maintenance Therapy in Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) Not Undergoing Transplant: An Integrated Analysis of Four Phase 1/2 Studies
Authors: Meletios A. Dimopoulos, Jacob Laubach, Maria Asuncion Echeveste Gutierrez, Norbert Grząśko, Craig C Hofmeister, Jesus F. San Miguel, Shaji K Kumar, Vickie Lu, Zhaoyang Teng, Guohui Liu, Catriona Byrne, Deborah Berg, Richard Labotka, Helgi van de Velde, Paul G Richardson
Journal: Blood (2017)
Endoscopic ultrasonography-guided obliteration of a left inferior phrenic artery pseudoaneurysm in a patient with alcoholic chronic pancreatitis
Authors: Deepak Gunjan, Shivanand Gamanagatti, Pramod Garg
Journal: Endoscopy (2018)

A 43-year-old man who was known to have alcoholic chronic pancreatitis presented with upper gastrointestinal bleeding (UGIB) with shock in September 2016. He was resuscitated with crystalloids and a blood transfusion. He underwent gastroduodenoscopy, colonoscopy, and computed tomographic angiography (CTA), but no source of bleeding was revealed. He had a second episode of UGIB in December 2017. CTA on this occasion revealed contrast extravasation, probably from the left inferior phrenic artery (LIPA) ([Fig. 1]). Digital subtraction angiography (DSA) confirmed the contrast leak from the LIPA ([Fig. 2]) but embolization could not be performed owing to dissection of the artery during wire manipulation. Percutaneous thrombin (500 units) was therefore injected using a trans-splenic approach under Doppler ultrasonography guidance ([Fig. 3]) with subsequent thrombosis of the pseudoaneurysm.
Response to: ‘Simultaneous inhibition of α4/β7 integrin and tumor necrosis factor-α in concomitant spondyloarthritis and inflammatory bowel disease’ by Richard <i>et al</i>
Authors: Gaëlle Varkas, Dirk Elewaut
Journal: Annals of the Rheumatic Diseases (2018)

We thank Dr Richard et al for their interest in our work and the communication of their experiences in daily practice.1 In patients affected with both spondyloarthritis (SpA) and refractory inflammatory bowel disease (IBD) despite anti-tumour necrosis factor (TNF) therapy, treatment options are limited. While anti-TNF therapy has shown remarkable efficacy in the treatment of both axial and peripheral SpA, even long term, the results in IBD were less satisfying.2 3 With the introduction of vedolizumab, a new mode of action and hope for refractory patients was installed.4 5 Nevertheless, as we reported earlier, vedolizumab did not show any efficacy in a series of patients with SpA  and might even induce SpA-like disease in certain individuals.6 …
Comparison of the Effects of the Thrombopoietin (TPO) Receptor Agonist Romiplostim in Patients with Immune Thrombocytopenia (ITP) for ≤1 Year Vs. >1 Year
Authors: David J Kuter, Adrian Newland, Beng H Chong, Francesco Rodeghiero, Monica Tejeda Romero, Ingrid Pabinger, Yuqi Chen, Kejia Wang, Bhakti Mehta, Melissa Eisen
Journal: Blood (2017)
A Brief Exposure-Based Treatment vs Cognitive Processing Therapy for Posttraumatic Stress Disorder: A Randomized Noninferiority Clinical Trial
Authors: Denise M. Sloan, Brian P. Marx, Daniel J. Lee, Patricia A. Resick
Journal: JAMA Psychiatry (2018)

Written exposure therapy (WET), a 5-session intervention, has been shown to efficaciously treat posttraumatic stress disorder (PTSD). However, this treatment has not yet been directly compared with a first-line PTSD treatment such as cognitive processing therapy (CPT).
Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors
Authors: Angeliki Giannelou, Hongying Wang, Qing Zhou, Yong Hwan Park, Mones S Abu-Asab, Kris Ylaya, Deborah L Stone, Anna Sediva, Rola Sleiman, Lucie Sramkova, Deepika Bhatla, Elisavet Serti, Wanxia Li Tsai, Dan Yang, Kevin Bishop, Blake Carrington, Wuhong Pei, Natalie Deuitch, Stephen Brooks, Jehad H Edwan, Sarita Joshi, Seraina Prader, Daniela Kaiser, William C Owen, Abdullah Al Sonbul, Yu Zhang, Julie E Niemela, Shawn M Burgess, Manfred Boehm, Barbara Rehermann, JaeJin Chae, Martha M Quezado, Amanda K Ombrello, Rebecca H Buckley, Alexi A Grom, Elaine F Remmers, Jana M Pachlopnik, Helen C Su, Gustavo Gutierrez-Cruz, Stephen M Hewitt, Raman Sood, Kimberly Risma, Katherine R Calvo, Sergio D Rosenzweig, Massimo Gadina, Markus Hafner, Hong-Wei Sun, Daniel L Kastner, Ivona Aksentijevich
Journal: Annals of the Rheumatic Diseases (2018)

To characterise the clinical features, immune manifestations and molecular mechanisms in a recently described autoinflammatory disease caused by mutations in TRNT1, a tRNA processing enzyme, and to explore the use of cytokine inhibitors in suppressing the inflammatory phenotype.We studied nine patients with biallelic mutations in TRNT1 and the syndrome of congenital sideroblastic anaemia with immunodeficiency, fevers and developmental delay (SIFD). Genetic studies included whole exome sequencing (WES) and candidate gene screening. Patients' primary cells were used for deep RNA and tRNA sequencing, cytokine profiling, immunophenotyping, immunoblotting and electron microscopy (EM).We identified eight mutations in these nine patients, three of which have not been previously associated with SIFD. Three patients died in early childhood. Inflammatory cytokines, mainly interleukin (IL)-6, interferon gamma (IFN-γ) and IFN-induced cytokines were elevated in the serum, whereas tumour necrosis factor (TNF) and IL-1β were present in tissue biopsies of patients with active inflammatory disease. Deep tRNA sequencing of patients' fibroblasts showed significant deficiency of mature cytosolic tRNAs. EM of bone marrow and skin biopsy samples revealed striking abnormalities across all cell types and a mix of necrotic and normal-appearing cells. By immunoprecipitation, we found evidence for dysregulation in protein clearance pathways. In 4/4 patients, treatment with a TNF inhibitor suppressed inflammation, reduced the need for blood transfusions and improved growth.Mutations of TRNT1 lead to a severe and often fatal syndrome, linking protein homeostasis and autoinflammation. Molecular diagnosis in early life will be crucial for initiating anti-TNF therapy, which might prevent some of the severe disease consequences.
JNJ-38877605: a selective Met kinase inhibitor inducing regression of Met-driven tumor models.
Authors: Timothy Perera, Tom Lavrijssen, Boud Janssens, Tamara Geerts, Peter King, Laurence Mevellec, Maxwell Cummings, Tianbao Lu, Dana Johnson, Martin Page
Journal: Cancer Research (2008)

4837  The Met receptor tyrosine kinase and its ligand, hepatocytegrowth factor (HGF), have been implicated in the developmentand progression of several human cancers and have become compelling targets for developing anti-neoplastic agents. JNJ-38877605 was selected following extensive structure-based drug design and is a smallmolecule, ATP-competitive, inhibitor of the catalyticactivity of Met kinase (IC50 4 nM). JNJ-38877605 exhibited~600-fold selectivity (vs cFMS IC50 2.6μM ; the next most potently inhibited kinase) for Met compared with a panel of ~250 diversetyrosine and serine-threonine kinases. In cellular studies,JNJ-38877605 was found to potently inhibit HGF-stimulated and constitutively activatedMet phosphorylation, and HGF and Met-driven phenotypessuch as cell motility,invasion, cell proliferation (exclusively in Met amplified cells), and/or morphology of a variety of tumor cells. JNJ-38877605 inhibits all known HGF-stimulated or constitutivelyactivated downstream mediators of the Met kinase pathway. JNJ-38877605 showed excellent oral bioavailability approaching 100% in all species examined. In addition, a single dose of JNJ-38877605 was observed toinhibit Met phosphorylation in tumor xenografts for up to16 h following a single oral dose. Inhibition of Met phosphorylation was associated withdose-dependent tumor growth inhibition using a range of oral dosing regimens. JNJ-38877605 was observed to induce significant tumor regression in large, well established MET gene amplified gastric cancer models and in Met pathway- activated (autocrine or paracrine) models.The highly favourable preclinical properties of JNJ-38877605 together with the extremely clean GLP toxicity profile of this compound has resulted in the selection of this potent and uniquely selective Met inhibitor for clinical evaluation.