tbuckley/cabot-search huggingface dataset:
Pivotal role of glutamine synthetase in ammonia detoxification
Authors: Theodorus B.M. Hakvoort, Youji He, Wim Kulik, Jacqueline L.M. Vermeulen, Suzanne Duijst, Jan M. Ruijter, Jurgen H. Runge, Nicolaas E.P. Deutz, S. Eleonore Koehler, Wouter H. Lamers
Journal: Hepatology (2016)

Glutamine synthetase (GS) catalyzes condensation of ammonia with glutamate to glutamine. Glutamine serves, with alanine, as a major nontoxic interorgan ammonia carrier. Elimination of hepatic GS expression in mice causes only mild hyperammonemia and hypoglutaminemia but a pronounced decrease in the whole-body muscle-to-fat ratio with increased myostatin expression in muscle. Using GS-knockout/liver and control mice and stepwise increments of enterally infused ammonia, we show that ∼35% of this ammonia is detoxified by hepatic GS and ∼35% by urea-cycle enzymes, while ∼30% is not cleared by the liver, independent of portal ammonia concentrations ≤2 mmol/L. Using both genetic (GS-knockout/liver and GS-knockout/muscle) and pharmacological (methionine sulfoximine and dexamethasone) approaches to modulate GS activity, we further show that detoxification of stepwise increments of intravenously (jugular vein) infused ammonia is almost totally dependent on GS activity. Maximal ammonia-detoxifying capacity through either the enteral or the intravenous route is ∼160 μmol/hour in control mice. Using stable isotopes, we show that disposal of glutamine-bound ammonia to urea (through mitochondrial glutaminase and carbamoylphosphate synthetase) depends on the rate of glutamine synthesis and increases from ∼7% in methionine sulfoximine-treated mice to ∼500% in dexamethasone-treated mice (control mice, 100%), without difference in total urea synthesis. Conclusions: Hepatic GS contributes to both enteral and systemic ammonia detoxification. Glutamine synthesis in the periphery (including that in pericentral hepatocytes) and glutamine catabolism in (periportal) hepatocytes represents the high-affinity ammonia-detoxifying system of the body. The dependence of glutamine-bound ammonia disposal to urea on the rate of glutamine synthesis suggests that enhancing peripheral glutamine synthesis is a promising strategy to treat hyperammonemia. Because total urea synthesis does not depend on glutamine synthesis, we hypothesize that glutamate dehydrogenase complements mitochondrial ammonia production. (Hepatology 2017;65:281-293).
Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature
Authors: David Kavanagh, Sarah McGlasson, Alexa Jury, Jac Williams, Neil Scolding, Chris Bellamy, Claudia Gunther, Diane Ritchie, Daniel P. Gale, Yashpal S. Kanwar, Rachel Challis, Holly Buist, James Overell, Belinda Weller, Oliver Flossmann, Mark Blunden, Eric P. Meyer, Thomas Krucker, Stephen J. W. Evans, Iain L. Campbell, Andrew P. Jackson, Siddharthan Chandran, David P. J. Hunt
Journal: Blood (2016)
Dramatic Alterations of Anti-Bacterial Mait-Cell Network in Alcoholic Liver Disease
Authors: A. Riva, V. Patel, K. Mehta, C. Lopez, G. Wright, S. Tarff, D. Shawcross, J. Ryan, A. Evans, M. Simonova, T. Hadzhiolova, S. Pavlova, K. Kazarov, J. Wendon, V. Patel, J. Bajaj, A. Unser, R. Williams, S. Chokshi
Journal: Journal of Hepatology (2016)
Nicotine Mediates CD161a <sup>+</sup> Renal Macrophage Infiltration and Premature Hypertension in the Spontaneously Hypertensive Rat
Authors: Sailesh C. Harwani, Jason Ratcliff, Fayyaz S. Sutterwala, Zuhair K. Ballas, David K. Meyerholz, Mark W. Chapleau, Francois M. Abboud
Journal: Circulation Research (2016)

Rationale: Renal inflammation contributes to the pathophysiology of hypertension. CD161a + immune cells are dominant in the (SHR) spontaneously hypertensive rat and expand in response to nicotinic cholinergic activation. Objective: We aimed to phenotype CD161a + immune cells in prehypertensive SHR after cholinergic activation with nicotine and determine if these cells are involved in renal inflammation and the development of hypertension. Methods and Results: Studies used young SHR and WKY (Wistar–Kyoto) rats. Splenocytes and bone marrow cells were exposed to nicotine ex vivo, and nicotine was infused in vivo. Blood pressures, kidney, serum, and urine were obtained. Flow cytometry, Luminex/ELISA, immunohistochemistry, confocal microscopy, and Western blot were used. Nicotinic cholinergic activation induced proliferation of CD161a + /CD68 + macrophages in SHR-derived splenocytes, their renal infiltration, and premature hypertension in SHR. These changes were associated with increased renal expression of MCP-1 (monocyte chemoattractant protein-1) and VLA-4 (very-late antigen-4). LLT1 (lectin-like transcript 1), the ligand for CD161a, was overexpressed in SHR kidney, whereas vascular cellular and intracellular adhesion molecules were similar to those in WKY. Inflammatory cytokines were elevated in SHR kidney and urine after nicotine infusion. Nicotine-mediated renal macrophage infiltration/inflammation was enhanced in denervated kidneys, not explained by angiotensin II levels or expression of angiotensin type-1/2 receptors. Moreover, expression of the anti-inflammatory α7-nAChR (α7-nicotinic acetylcholine receptor) was similar in young SHR and WKY rats. Conclusions: A novel, inherited nicotinic cholinergic inflammatory effect exists in young SHR, measured by expansion of CD161a + /CD68 + macrophages. This leads to renal inflammation and premature hypertension, which may be partially explained by increased renal expression of LLT-1, MCP-1, and VLA-4.
Pharmacokinetic Analyses of Ledipasvir/Sofosbuvir in HCV-Infected Subjects with Advanced Liver Disease And/ or following Liver Transplantation
Authors: K.L. Garrison, P. German, S. Arterburn, S. De-Oertel, D. Brainard, J. Ling, F. Jin, A. Mathias
Journal: Journal of Hepatology (2016)
Genomic analysis of the molecular neuropathology of tuberous sclerosis using a human stem cell model
Authors: Nils Grabole, Jitao David Zhang, Stefan Aigner, Nadine Ruderisch, Veronica Costa, Felix C. Weber, Michel Theron, Nikolaos Berntenis, Olivia Spleiss, Martin Ebeling, Gene W. Yeo, Ravi Jagasia, Anna Kiialainen
Journal: Genome Medicine (2016)

Tuberous sclerosis complex (TSC) is a genetic disease characterized by benign tumor growths in multiple organs and neurological symptoms induced by mTOR hyperfunction. Because the molecular pathology is highly complex and the etiology poorly understood, we employed a defined human neuronal model with a single mTOR activating mutation to dissect the disease-relevant molecular responses driving the neuropathology and suggest new targets for treatment.We investigate the disease phenotype of TSC by neural differentiation of a human stem cell model that had been deleted for TSC2 by genome editing. Comprehensive genomic analysis was performed by RNA sequencing and ribosome profiling to obtain a detailed genome-wide description of alterations on both the transcriptional and translational level. The molecular effect of mTOR inhibitors used in the clinic was monitored and comparison to published data from patient biopsies and mouse models highlights key pathogenic processes.TSC2-deficient neural stem cells showed severely reduced neuronal maturation and characteristics of astrogliosis instead. Transcriptome analysis indicated an active inflammatory response and increased metabolic activity, whereas at the level of translation ribosomal transcripts showed a 5'UTR motif-mediated increase in ribosome occupancy. Further, we observed enhanced protein synthesis rates of angiogenic growth factors. Treatment with mTOR inhibitors corrected translational alterations but transcriptional dysfunction persisted.Our results extend the understanding of the molecular pathophysiology of TSC brain lesions, and suggest phenotype-tailored pharmacological treatment strategies.
Vaccine-Induced HCV-Specific CD8+ T Cell Response Restricted by the Protective HLA Allele B*27: Broad Cross-Recognition of Evolving Viral Variants
Authors: K. Frohnmüller, L. Swadling, K. Nitschke, P. Klenerman, R. Thimme, E. Barnes, C. Neumann-Haefelin
Journal: Journal of Hepatology (2016)
Efficacy and safety in genetic and clinical subgroups: Phase III RESONATETM trial of ibrutinib vs ofatumumab in CLL/SLL
Authors: Stephen P. Mulligan, Jennifer R . Brown, Peter Hillmen, Susan O'Brien, Jacqueline C. Barrientos, Nishitha M. Reddy, Steven Coutre, Ulrich Jaeger, Danelle F. James, John C. Byrd
Journal: Annals of Oncology (2015)
Sustained Virologic Response Predicts Fibrosis Regression Measured by Fibrotest in HCV-Infected Patients
Authors: X. Forns, T.M. Welzel, E. Cohen, I.M. Jacobson, M. Davis, R. Reindollar, Y.B. Hu, D.E. Dylla, J.V. Enejosa, R. Trinh, M.S. Sulkowski
Journal: Journal of Hepatology (2016)
Protective T-Cell Responses to Several Recombinant Aspergillus Antigens May Be Detected Since the Onset of the Infection in Patients with Invasive Aspergillosis, and May Be Exploited for Therapeutic Purposes,
Authors: Leonardo Potenza, Daniela Vallerini, Patrizia Barozzi, Giovanni Riva, Forghieri Fabio, Johan Maertens, Anna Candoni, Anne Beauvais, Remi Beau, Roberto Marasca, Chiara Quadrelli, Javier Arroyo, Michel Monod, Monica Morselli, Monica Maccaferri, Ambra Paolini, Patrizia Comoli, Luigina Romani, Franco Narni, Jean Paul Latge, Mario Luppi
Journal: Blood (2011)
Une épidémie nosocomiale de gale dans un hôpital en Espagne
Authors: A. Larrosa, M Cortés-Blanco, S. Martinez, C Clerencia, L J Urdaniz, J Urban, J Garcia
Journal: Eurosurveillance (2003)

Une epidemie de gale s'est declaree dans un service d'un hopital regional de Barbastro (Huesca, Espagne), entre novembre 2002 et janvier 2003. L'epidemie etait liee a un patient contamine par des sarcoptes de la gale lors de son admission au service le 1er novembre 2002. Le premier cas est survenu le 5 novembre 2002 et le dernier le 5 janvier 2003. Au total, 17 cas ont ete identifies dont 11 membres du personnel et six patients. L'epidemie a ete attribuee a un diagnostic tardif, et au manque de protections individuelles de la part de certains personnels soignants. Le port de blouses a manches courtes est une pratique a risque habituelle dans ce service. Le contact avec des objets contamines, des animaux, des vetements infestes ou le contact intime avec d'autres personnes que le partenaire habituel n'ont pas ete retenus comme facteurs de risque. Les differents groupes de soignants dans ce service presentaient le meme risque de contamination et la transmission est probablement liee a un contact de personne a personne. La mise en place de recommandations specifiques pour la prevention et le traitement de la gale, de meme qu'un systeme de surveillance actif, ont eu un role fondamental dans la lutte contre cette epidemie.
Novel regional age-associated DNA methylation changes within human common disease-associated loci
Authors: Christopher G. Bell, Yudong Xia, Wei Yuan, Fei Gao, Kirsten Ward, Leonie Roos, Massimo Mangino, Pirro G. Hysi, Jordana Bell, Jun Wang, Timothy D. Spector
Journal: Genome biology (2016)

Advancing age progressively impacts on risk and severity of chronic disease. It also modifies the epigenome, with changes in DNA methylation, due to both random drift and variation within specific functional loci.In a discovery set of 2238 peripheral-blood genome-wide DNA methylomes aged 19-82 years, we identify 71 age-associated differentially methylated regions within the linkage disequilibrium blocks of the single nucleotide polymorphisms from the NIH genome-wide association study catalogue. This included 52 novel regions, 29 within loci not covered by 450 k or 27 k Illumina array, and with enrichment for DNase-I Hypersensitivity sites across the full range of tissues. These age-associated differentially methylated regions also show marked enrichment for enhancers and poised promoters across multiple cell types. In a replication set of 2084 DNA methylomes, 95.7 % of the age-associated differentially methylated regions showed the same direction of ageing effect, with 80.3 % and 53.5 % replicated to p < 0.05 and p < 1.85 × 10-8, respectively.By analysing the functionally enriched disease and trait-associated regions of the human genome, we identify novel epigenetic ageing changes, which could be useful biomarkers or provide mechanistic insights into age-related common diseases.
Evaluation of sorafenib in combination with local microtherapy guided by gadolinium-EOB-DTPA enhanced MRI in patients with inoperable hepatocellular carcinoma.
Authors: J. Ricke, K. Schuette, I. W. Graziadei, A. Jakob, C. Verslype, B. Sangro, J. Walecki, H. J. Klümpen, B. Peynircioglu, S. Yalcin, C. Bartolozzi, H. Amthauer, P. Malfertheiner
Journal: Journal of Clinical Oncology (2011)

TPS175 Background: Treatment strategy in early HCC is directed to the local removal of the tumor (resection, liver transplantation, RFA, PEI) with the attempt to cure the disease. In intermediate and advanced stages of HCC patients receive treatment with palliative intent (TACE, sorafenib, SIRT). Studies with the combined use of locoregional and systemic therapy with their potential of a beneficial synergism are few and conducted in a small number of patients. Methods: This phase II study is composed of three sub-studies with the following primary objectives: (1) In patients in whom local ablation is appropriate to determine if sorafenib in combination with radiofrequency ablation (RFA) prolongs the time-to-recurrence in comparison with RFA + placebo. Primary endpoint (PEP): time to recurrence, survival analysis by stratified log-rank test, one-sided α = 0.05, n = 290 pts. (2) In patients in whom RFA is not appropriate (palliative treatment group) to determine if the combination of yttrium-90-microspheres (SIRT) + sorafenib improves the overall survival in comparison to sorafenib alone. PEP: overall survival, log-rank test for final analysis after 240 reported deaths with a nominal critical point of 1.993 with one-sided α = 0.0231, n = 375 pts. (3) To test the diagnostic and staging accuracy of Gd-EOB-DTPA enhanced MRI with contrast-enhanced multisclice CT. PEP: correct stratification of patients to a palliative versus local ablation treatment strategy; tested using generalized estimation equations (GEEs) with independent working correlation matrix taking into account the correlations between readers and between modalities through robust variance estimates; one-sided α = 2.5%, n = 830 pts. This trial has already started with 7 out of 830 patients enrolled until January 31st 2011 and will recruit in 41 European centers in 14 countries: Germany, Austria, Switzerland, The Netherlands, Poland, Belgium, France, Italy, Spain, Turkey, Serbia, Slovenia, Croatia and Great Britain.
Effectiveness and Safety of Ombitasvir, Paritaprevir, Ritonavir and Dasabuvir Patients with Genotype 1 Chronic Hepatitis C Virus Infection: Results from the Spanish Real World Cohort
Authors: J.L. Calleja, D. Rincon, B. Ruiz-Antoran, B. Sacristan, C. Perello, S. Lens, I. Fernanadez, F. Gea, R.M. Morillas, J. Cabezas, J.M. Pascasio, M. Prieto, J. Turnes, M.A. Serra, J. Arenas, X. Torras, L. Bonet, C. Fernandez, J. Samaniego, A. Hernandez-Albujar, J. Ampuero, J.M. Moreno, F. Saez-Royuela, C. Alvarez-Navascues, M. Diago, G. Sanchez-Antolin, J. de la Vega, J.J. Sanchez-Ruano, R. Andrade, M. Butti, J.A. Carrion, E. Molina, M.A. Simon, J.R. Salcines, F. Jorquera, S. Montoliu, A. Ahumada, T. Hernaez, J. Crespo
Journal: Journal of Hepatology (2016)
Frequency and Prognostic Significance of Hypercalcemia in Patients with Multiple Myeloma: An Analysis of the Database of the Greek Myeloma Study Group
Authors: Efstathios Kastritis, Eirini Katodritou, Anastasia Pouli, Eleftheria Hatzimichael, Sosana Delimpasi, Eurydiki Michalis, Athanasios Zomas, Zafiris Kartasis, Agapi Parcharidou, Dimitra Gika, Panagiotis Repousis, Ekaterini Stefanoudaki, Argiris Symeonidis, Panayiotis Panayiotidis, Konstantinos Konstantopoulos, Evangelos Terpos, Meletios Athanasios Dimopoulos
Journal: Blood (2011)
HIV/HCV Coinfection in Spain: Prevalence and Patient Characteristics
Authors: J. Berenguer, A. Rivero, I. Jarrín, M.J. Núñez, C. Quereda, M. Crespo, M.J. Téllez, P. Domingo, J.A. Iribarren, J. González-García
Journal: Journal of Hepatology (2016)
Only One-Third of Patients with Hepatocellular Carcinoma Were Diagnosed by Screening, Surveillance, or without Symptoms: A Meta-Analysis of 40 Studies and 20,349 Patients with Diverse Underlying Liver Disease and World Regions
Authors: M.Q. Jin, R.H. Le, M. Jin, C. Zhao, M.H. Le, A. Nguyen, B. Kwan, V.L. Chen, V. Wong, Y.-S. Lim, W.-L. Chuang, M.-L. Yu, G. Wong, M. Nguyen
Journal: Journal of Hepatology (2016)
TTP889, a Novel Orally Active Partial Inhibitor of FIXa Inhibits Clotting in Two A/V Shunt Models without Prolonging Bleeding Times.
Authors: Robert Rothlein, Jane M. Shen, Najih Naser, Devi R. Gohimukkula, Thomas B. Caligan, Robert C. Andrews, Ann Marie Schmidt, Eric A. Rose, Adnan M. M. Mjalli
Journal: Blood (2005)
Investment Case for a Comprehensive Package of Interventions against Hepatitis B in China
Authors: S. Nayagam, P. Chan, K. Zhao, E. Sicuri, X. Wang, J. Jia, L. Wei, N. Walsh, L.E. Rodewald, G. Zhang, W. Ailing, D. Lixia, J. Chang, W. Hou, Y. Qiu, B. Sui, Y. Xiao, H. Zhuang, M. Thursz, F. Scano, D. Low-Beer, B. Schwartländer, Y. Wang, T. Hallett
Journal: Journal of Hepatology (2016)
Whole Blood Coagulation Tests are not Equally able to Detect Haemostatic Prothrombotic Alterations in Patients with Liver Cirrhosis and Hepatocellular Carcinoma: Rotational Thromboelastometry versus Thrombingeneration Test
Authors: A. Zanetto, A. Ferrarese, E. Nadal, I. Bortoluzzi, E. Campello, L. Spiezia, U. Cillo, A. Vitale, F. Farinati, G. Germani, F.P. Russo, S. Gavasso, P. Simioni, P. Burra, M. Senzolo
Journal: Journal of Hepatology (2016)
Sofosbuvir/Velpatasvir Fixed Dose Combination for 12 Weeks in HCV Infected Patients Previously Treated with Placebo: Results of the Deferred Treatment Study (GS-US-342-1446 Study)
Authors: T. Asselah, S. Shafran, S. Bourgeois, C.-L. Lai, M. Cramp, P. Mathurin, B. Willems, M.H. Nguyen, M.N. Davis, K.C. Huang, E. Svarovskaia, A. Osinusi, J. Mcnally, D. Brainard, J. McHutchison, O.S. Shaikh, T.T. Tran
Journal: Journal of Hepatology (2016)
Comparing Individual and Population Prevention Benefits of Early Direct-Acting Antiviral Treatment for HCV
Authors: N.K. Martin, P. Vickerman, G.J. Dore, J. Grebely, A. Miners, J. Cairns, G.R. Foster, S.J. Hutchinson, D.J. Goldberg, T.C.S. Martin, M. Ramsay, M. Hickman
Journal: Journal of Hepatology (2016)
Role of <i>KEAP1</i>/<i>NRF2</i> and <i>TP53</i> Mutations in Lung Squamous Cell Carcinoma Development and Radiation Resistance
Authors: Youngtae Jeong, Ngoc T. Hoang, Alexander Lovejoy, Henning Stehr, Aaron M. Newman, Andrew J. Gentles, William Kong, Diana Truong, Shanique Martin, Aadel Chaudhuri, Diane Heiser, Li Zhou, Carmen Say, Justin N. Carter, Susan M. Hiniker, Billy W. Loo, Robert B. West, Philip Beachy, Ash A. Alizadeh, Maximilian Diehn
Journal: Cancer Discovery (2016)

Abstract Lung squamous cell carcinoma (LSCC) pathogenesis remains incompletely understood, and biomarkers predicting treatment response remain lacking. Here, we describe novel murine LSCC models driven by loss of Trp53 and Keap1, both of which are frequently mutated in human LSCCs. Homozygous inactivation of Keap1 or Trp53 promoted airway basal stem cell (ABSC) self-renewal, suggesting that mutations in these genes lead to expansion of mutant stem cell clones. Deletion of Trp53 and Keap1 in ABSCs, but not more differentiated tracheal cells, produced tumors recapitulating histologic and molecular features of human LSCCs, indicating that they represent the likely cell of origin in this model. Deletion of Keap1 promoted tumor aggressiveness, metastasis, and resistance to oxidative stress and radiotherapy (RT). KEAP1/NRF2 mutation status predicted risk of local recurrence after RT in patients with non–small lung cancer (NSCLC) and could be noninvasively identified in circulating tumor DNA. Thus, KEAP1/NRF2 mutations could serve as predictive biomarkers for personalization of therapeutic strategies for NSCLCs. Significance: We developed an LSCC mouse model involving Trp53 and Keap1, which are frequently mutated in human LSCCs. In this model, ABSCs are the cell of origin of these tumors. KEAP1/NRF2 mutations increase radioresistance and predict local tumor recurrence in radiotherapy patients. Our findings are of potential clinical relevance and could lead to personalized treatment strategies for tumors with KEAP1/NRF2 mutations. Cancer Discov; 7(1); 86–101. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 1
O.01: Acquired Resistance to EGFR-TKIs in EGFR-Mutant Lung Adenocarcinoma Among Hispanics (RBIOP-CLICaP)
Authors: Andrés F. Cardona, Oscar Arrieta, Martín I. Zapata, Leonardo Rojas, Beatriz Wills, Hernán Carranza, Noemi Reguart, Carlos Vargas, Jorge Otero, Luis Corrales-Rodriguez, Claudio Martin, Pilar Archila, Mauricio Cuello, Carlos Ortiz, Rafael Rosell
Journal: Journal of Thoracic Oncology (2016)
Chimeric Anti CD-20 Monoclonal Antibody-Rituximab in Refractory Childhood Idiopathic Thrombocytopenic Purpura: An Indian Experience.
Authors: Ajay Sharma, Velu Nair, Deepak K. Mishra, Jyoti Kotwal, Gurvinder S. Chopra, N. K. Bhandari, Mohan B. Agarwal, Ramji Rai
Journal: Blood (2005)
Apoptosis Repressor with Caspase Recruitment Domain (ARC) Increases AML Cell Migration and Adhesion in Vitro and in Vivo by Regulating Leukemia-Stroma Interactions.
Authors: Bing Z Carter, Po Yee Mak, Ye Chen, Rodrigo Jacamo, Vivian Ruvolo, Duncan H Mak, Teresa McQueen, Marina Konopleva, Steven M. Kornblau, Michael Andreeff
Journal: Blood (2012)
Sequence-Specific Pharmacokinetic and Pharmacodynamic Phase I/Ib Study of Olaparib Tablets and Carboplatin in Women's Cancer
Authors: Jung-Min Lee, Cody J. Peer, Minshu Yu, Lauren Amable, Nicolas Gordon, Christina M. Annunziata, Nicole Houston, Andrew K.L. Goey, Tristan M. Sissung, Bernard Parker, Lori Minasian, Victoria L. Chiou, Robert F. Murphy, Brigitte C. Widemann, William D. Figg, Elise C. Kohn
Journal: Clinical Cancer Research (2016)

Abstract Purpose: Our preclinical studies showed that the PARP inhibitor, olaparib, prior to carboplatin attenuated carboplatin cytotoxicity. We evaluated sequence-specific pharmacokinetic and pharmacodynamic effects, safety, and activity of the combination. Experimental Design: Eligible patients had metastatic or recurrent women's cancer. Olaparib tablets were introduced (100 or 200 mg twice daily, days 1–7) in a 3 + 3 dose escalation with carboplatin AUC4 or 5 every 21 days, up to eight cycles, followed by olaparib 300 mg twice daily maintenance. Patients were randomly assigned to starting schedule: cohort A (olaparib days 1–7, carboplatin on day 8) or B (carboplatin on day 1, olaparib days 2–8) during cycle 1. Patients received the reversed scheme in cycle 2. Blood was collected for olaparib pharmacokinetics, platinum–DNA adducts, comet assay, and PAR concentrations. The primary objectives were to examine schedule-dependent effects on olaparib pharmacokinetics and platinum–DNA adducts. Results: A total of 77 (60 ovarian, 14 breast, and 3 uterine cancer) patients were treated. Dose-limiting toxicity was thrombocytopenia and neutropenia, defining olaparib 200 mg twice daily + carboplatin AUC4 as the MTD. Olaparib clearance was increased approximately 50% when carboplatin was given 24 hours before olaparib. In vitro experiments demonstrated carboplatin preexposure increased olaparib clearance due to intracellular olaparib uptake. Quantities of platinum–DNA adducts were not different as a function of the order of drug administration. Responses included 2 CRs and 31 PRs (46%) with a higher RR in BRCA mutation carriers compared with nonmutation carriers (68% vs. 19%). Conclusions: Tablet olaparib with carboplatin is a safe and active combination. Carboplatin preexposure causes intracellular olaparib accumulation reducing bioavailable olaparib, suggesting carboplatin should be administered prior to olaparib. Clin Cancer Res; 23(6); 1397–406. ©2016 AACR.