tbuckley/cabot-search huggingface dataset:
Apnoeic oxygenation via high-flow nasal cannula oxygen combined with non-invasive ventilation preoxygenation for intubation in hypoxaemic patients in the intensive care unit: the single-centre, blinded, randomised controlled OPTINIV trial
Authors: Samir Jaber, Marion Monnin, Mehdi Girard, Matthieu Conseil, Moussa Cisse, Julie Carr, Martin Mahul, Jean Marc Delay, Fouad Belafia, Gérald Chanques, Nicolas Molinari, Audrey De Jong
Journal: Intensive Care Medicine (2016)
TCT-758 The WISE trial - A multi center trial of the WIRION Embolic Protection System in carotid stenting
Authors: Dierk Scheinert, Horst Sievert, Stefan Rohde, Joachim Schofer, Harald G. Mudra, Marc Bosiers, Alberto Cremonesi, Uri Rosenschein, Zeller Thomas, Henrik Schroeder, Bernhard Reimers
Journal: Journal of the American College of Cardiology (2015)
Fetal Hemoglobin in Sickle Cell Anemia: A Novel Method for High-Resolution Discovery of Associated Genomic Copy Number Variations
Authors: Daniel Dworkis, Paola Sebastiani, Efthymia Melista, Jason Parente, Griffin Lester, Jeffrey F Quinn, David H.K. Chui, Martin H. Steinberg, Clinton T. Baldwin
Journal: Blood (2008)
CONVERT: An international randomised trial of concurrent chemo-radiotherapy (cCTRT) comparing twice-daily (BD) and once-daily (OD) radiotherapy schedules in patients with limited stage small cell lung cancer (LS-SCLC) and good performance status (PS).
Authors: Corinne Faivre-Finn, Michael Snee, Linda Ashcroft, Wiebke Appel, Fabrice Barlesi, Adityanarayan Bhatnagar, Andrea Bezjak, Felipe Cardenal, Pierre Fournel, Susan Harden, Cécile Le Pechoux, Rhona Margaret McMenemin, Nazia Mohammed, Mary E.R. O'Brien, Jason R Pantarotto, Veerle Surmont, Jan Van Meerbeeck, Penella J. Woll, Paul Lorigan, Fiona Helen Blackhall
Journal: Journal of Clinical Oncology (2016)

8504 Background: cCTRT is the standard of care for good PS LS-SCLC but there is no international consensus on a standard regimen. BD RT has not been adopted widely due to concerns regarding logistics and toxicity. Our aim was to compare overall survival and toxicity of BD with OD RT using modern conformal RT techniques given concurrently with chemotherapy. Methods: Patients were randomised 1:1 to receive 45Gy in 30 BD fractions over 3 weeks or 66Gy in 33 OD fractions over 6.5 weeks starting on day 22 of cycle 1 chemotherapy (4 to 6 cycles of Cisplatin 25mg/m2 days 1-3 or 75mg/m2 day 1 with Etoposide 100mg/m2 days 1-3), followed by PCI if indicated. RT was planned using 3D conformal or IMRT. Patients were stratified by centre, 4/6 cycles CT and PS 0,1/2. The primary endpoint was 2-year survival and all analyses were by intention to treat. Results: 547 patients (274 BD and 273 OD) were recruited between April 2008 and November 2013 from 88 centres. Patients' characteristics were well balanced in both arms. 88% and 86% of patients in BD and OD arms received PCI. At a median follow up of 45 months for those alive; two-year survival was 56% (95% CI 50-61) vs 51% (95% CI 45-57) and median overall survival was 30 months (95% CI 24-34) versus 25 months (95% CI 21-31) (HR 1.17, 95% CI 0.95-1.45; p = 0.15) for BD and OD treatment, respectively. Toxicities were comparable except for significantly more grade 3/4 neutropenia (74% BD vs 65% OD, p = 0.03). There was no statistical difference, between BD and OD respectively, in rates of febrile neutropenia (23.4%, 18%), grade 2 oesophagitis (63%, 55%), grade 3/4 oesophagitis (19%, 19%), and grade 3/4 radiation pneumonitis was rare (2.5%, 2.2%). 3 patients died from RT toxicity within 3 months of completing RT (1 BD vs 2 OD). Conclusions: OD RT did not result in a superior survival or worse toxicity than BD RT, supporting the use of either regimen for standard of care treatment of LS-SCLC with good PS. The survival for both regimens was higher than previously reported and using modern RT techniques radiation toxicities were lower than expected. Clinical trial information: NCT00433563. Clinical trial information: ISRCTN91927162.
A study to explore the correlation of trough level concentration and <i>ABCB1, OCT1, ABCG2</i> genetic polymorphisms with imatinib mesylate induced thrombocytopenia in chronic myeloid leukemia patients.
Authors: Dubashi Biswajit, Jose Francis, Rajan Sundaram, Suresh Chandra Pradhan, Adithan Chandrasekaran
Journal: Journal of Clinical Oncology (2015)

e13564 Background: Imatinib mesylate is presently the first line treatment for chronic myeloid leukemia (CML). Therapeutic drug monitoring (TDM) and pharmacogenetic screening is warranted for better management of imatinib therapy. The trough level concentration measurement is of significance in identifying poor responders at initial stage; but its relation with occurrence of adverse events is not well studied. The present study was undertaken to explore the impact of TDM and drug transport gene polymorphisms on thrombocytopenia which was the most commonly occurred adverse event in the study cohort. Methods: A total of 119 (Philadelphia chromosome positive and on T. Imatinib treatment) patients were included in the study. The blood samples for trough level concentration assessment of imatinib at steady state (after minimum period of seven days) in CML patients were collected between 21-27 hours after last drug administration and was estimated using LC-MS/MS technique. The genotyping for ABCB1, OCT1 and ABCG2 was carried out on Real Time Thermocycler using validated Real time Taqman SNP genotyping probes. Results: The trough level concentration at steady state was analyzed and the results were available for 73 patients. The mean±SD trough level concentration was found to be 1430.7±438.7 ng/ml. The trough level concentration at steady state was significantly higher in patients with grade 2-4 thrombocytopenia compared to patients without the adverse event (p-value-0.0331). The study could not find any relation between the drug transporter gene polymorphism with the incidence of thrombocytopenia. The trough level concentration was significantly different between the normal and variant genotypes of ABCB1 2677 G > T/A (p-value-0.0210). Conclusions: The study results emphasizes the role of routine therapeutic drug monitoring for better management of CML patients.
Pathological complete response (pCR) in stage II and III breast cancer patients treated with neoadjuvant chemotherapy (CT): Dose dense ACx4 followed by AT/Tx4 (weekly paclitaxel)
Authors: A. E. Alarcon-Rozas, R. Melendez, J. Ramirez, F. Salas, J. Ramirez, J. Guevara, A. Galarreta, E. Hernandez, F. Viayrada, J. Torres
Journal: Journal of Clinical Oncology (2006)

10746 Background: This is a prospective study of a single Institution to determine the pCR in stage II and II breast cancer patients after dose dense and sequential CT using the most active drugs. Patients and Methods: Between June/2004 and July/2005 we collected 28 patients, they have echocardiogram and needle biopsy for IHC before starting the treatment. All of them received Adriamicin 60mg/m 2 in 3hrs infusion and Cyclophosphamide 600mg/m 2 x4 in dose dense schedule (every 2 weeks) with G-CSF support and then Adriamicin 60mg/m 2 and Taxol 80mg/m 2 days 1,8 every 3 weeks. Once the treatment was finished they went to surgery. Results: Six (21%) patients were stage II and 22 (79%) were stage III; 8 (35%) patients achieve pCR, 50% of them had Her2/neu positive and 7/8 (90%) were ER/PR negative; 60% (5) had T more than 5cm and 75% were post menopausal. 12 patients had clinical complete remission. Eight patients had progressive disease with 50% ER/PR negative, 37% Her2/neu positive and all of them with T more than 5cm. 50% were premenopausal. Conclusion: This is one of the highest pCR of the literature (35%) achieved and it is interesting to note that 90% of them were ER/PR negative, so this is a potential target group for CT intensification. There is a group of patients (with progressive disease) that will never respond to CT, and it would be worst in the adjuvant setting (blindly treatment) because the great toxicity. We need more studies to confirm this hypothesis. No significant financial relationships to disclose.
The genetic landscape of clinical resistance to RAF inhibition in melanoma.
Authors: Eliezer Mendel Van Allen, Nikhil Wagle, Scott L. Carter, Antje Sucker, Deborah Norman Farlow, Eran Hodis, Amaro Taylor-Weiner, Carola Berking, Friederike Egberts, Jessica Cecile Hassel, Helen Gogas, Ralf Gutzmer, Simone M. Goldinger, Carmen Loquai, Selma Ugurel, Lisa Zimmer, Stacey B. Gabriel, Gad Getz, Levi A. Garraway, Dirk Schadendorf
Journal: Journal of Clinical Oncology (2013)

11009 Background: Although single-agent RAF inhibition has proved effective in metastatic BRAF V600 -mutant melanoma, most patients relapse and some are intrinsically resistant. While several genetic resistance effectors have been identified, a comprehensive assessment of the genetic resistance spectrum in a large patient cohort may further inform resistance patterns and treatment strategies. Methods: Pre-treatment and post-relapse biopsies were obtained from BRAF V600 melanoma patients treated with vemurafenib or dabrafenib. Whole exome sequencing of tumor and normal samples was performed to identify exome-wide mutations, insertion/deletions, and chromosomal copy number alterations. Since somatic allelic fraction comparisons across treatment time points must account for variable stromal admixture between biopsies, novel algorithms were applied to impute purity and tumor cell ploidy, thus determining the “cancer cell fraction” (CCF) of each alteration. Those with enriched CCF in post-relapse samples were nominated as potential resistance effectors. Results: 30 patients (towards a goal of 77) were sequenced to a mean depth of 145-fold coverage. In acquired resistance patients (on drug ≥ 12 weeks, n=18), NRAS Q61R (28%) and BRAF amplifications (6%) were observed. The remaining patients had multiple clonally enriched alterations in the post-relapse tumors that may drive resistance, including MEK1 mutations at residues previously noted in an in vitro mutagenesis screen for vemurafenib resistance. In the intrinsic resistance cohort (on drug &lt; 12 weeks, n=12), multiple putative resistance mutations not previously observed in the setting of acquired resistance were identified. Conclusions: In addition to reported genetic resistance mechanisms, we identified new MEK1 mutations in resistant samples. For the majority of patients (67%) without events in these genes, computational algorithms identified new candidate drivers of RAF inhibitor resistance. Alterations that predict intrinsic or acquired resistance may also inform new approaches to melanoma therapy. Future studies incorporating longitudinal biopsies and genetic profiling will underpin a robust assessment of clinical resistance in melanoma and other cancers.
GW27-e0533 A higher baseline plasma uric acid level is an independent predictor of arterial stiffness: a community-based prospective study
Authors: Xiao-Han Ding, Xiaona Wang, Ruihua Cao, Xu Yang, Wenkai Xiao, Yun Zhang, Yongyi Bai, Hongmei Wu, Ping Ye
Journal: Journal of the American College of Cardiology (2016)
Small molecule Bcl-2 inhibitor enhances apoptosis induction by gemcitabine or sulindac sulfide in BxPC-3 pancreatic cancer cells
Authors: E. N. Freeburg, F. Sinicrope
Journal: Journal of Clinical Oncology (2004)

4256 Background. Bcl-2 regulates the cytochrome-c dependent, mitochondrial apoptotic pathway. HA14–1 is a small molecular compound that interacts with Bcl-2 to inhibit its anti-apoptotic effect in vitro. We determined whether HA14–1 can increase the apoptotic susceptibility of BxPC-3 human pancreatic cancer cells to gemcitabine (2',2'-difluorodeoxycytidine) or sulindac sulfide, known inducers of cytochrome c release and apoptosis (Clin Cancer Res., 7:2527–36, 2001; Cancer Res., 62:6323–28, 2002). Methods. BxPC-3, CFPAC-1 and PANC-1 cells were grown in media supplemented with and 10% fetal bovine serum. Bcl-2 expression was analyzed in cell lysates by immunoblotting (anti-bcl-2 MoAb; Upstate) . BxPC-3 cells were cultured for 24 hr and then incubated with HA14–1 (0, 15, 30 μM; Calbiochem) alone and in combination with gemcitabine (0, 5, 10 nM; Eli Lilly) or sulindac sulfide (120, 140 μM; Sigma Chemical) for 48 hr. Both floating and attached cells were harvested and analyzed for apoptosis by Annexin V-FITC labeling (BD PharMingen). Results. BxPC-3 cells were found to express Bcl-2 proteins at a higher level than in CFPAC-1 or PANC-1 cell lines, and were utilized for subsequent experiments. HA14–1 alone induced apoptosis and a 2-fold increase was seen at the 30 μM. As single agents, gemcitabine (5, 10 nM) induced a 4-fold increase in apoptosis whereas sulindac sulfide (120 μM) induced a 2-fold induction. The combination of HA14–1 with gemcitabine or sulindac sulfide produced a dose-dependent increase in apoptosis. HA14–1 (15 μM) and gemcitabine (5 nM) or HA14–1 (15 μM) plus sulindac sulfide (120 μM) induced apoptosis to a greater extent than did either gemcitabine (2.8-fold increase) or sulindac sulfide (2.7-fold increase) alone. Conclusion. Bcl-2 regulates apoptotic susceptibility to gemcitabine and sulindac sulfide in BxPC-3 cells, as shown by the ability of HA14–1 to enhance apoptosis induction by these drugs. Therefore, Bcl-2 antagonism may increase the effectiveness of these agents against human pancreatic cancers. No significant financial relationships to disclose.
A Prospective Study in Ph+ Chronic Myeloid Leukemia (CML) Patients Showing That Interphase Fluorescence in Situ Hybridization (FISH) Is Effective as Conventional Cytogenetics for Definition of Cytogenetic Response. Correlation with Molecular Response (by the GIMEMA CML WP).
Authors: Nicoletta Testoni, S. Luatti, G. Marzocchi, M. Amabile, C. Gamberini, F. Buontempo, C. Baldazzi, I. Iacobucci, M. Mancini, A. Cuneo, G. Specchia, S. Kerim, G. Rege-Cambrin, E. Giugliano, U. Giussani, E. Abruzzese, M.G. Grimoldi, B. Modaferri, F. Castagnetti, F. Palandri, C. Mecucci, P. Bernasconi, A. Gozzetti, G. Palka, L. Zanatta, A. Zaccaria, G. Martinelli, G. Rosti, Michele Baccarani
Journal: Blood (2006)
A phase I trial and pharmacokinetic study of trebananib (AMG386) in children with recurrent or refractory solid tumors: A Children’s Oncology Group Phase 1 Consortium report.
Authors: Sarah Leary, Julie R. Park, Joel M. Reid, Andrew T. Ralya, Sylvain Baruchel, Bing Wu, Ashish M Ingle, Charlotte H Ahern, Brenda Weigel, Susan Blaney
Journal: Journal of Clinical Oncology (2013)

2538 Background: Trebananib is a first-in-class peptibody (peptide-Fc fusion protein) that selectively inhibits Angiopoietin 1 and Angiopoietin 2 to inhibit interaction with the Tie2 receptor tyrosine kinase and prevent angiogenesis by a VEGF independent mechanism. A pediatric phase 1 trial was performed to define the dose limiting toxicities (DLT), maximum tolerated dose (MTD) and pharmacokinetics (PK) of trebananib. Methods: Trebananib was administered as a weekly 30 - 60 minute IV infusion. Three dose levels (10, 15 or 30 mg/kg/dose) were evaluated using a rolling-six design. PK sampling and analysis of peripheral blood biomarkers was performed during the first 4 weeks of therapy. Results: Fifteen eligible patients (14 evaluable for toxicity) with a median age of 14 yrs (range, 3 to 20) and diagnoses of neuroblastoma (n=4), rhabdomyosarcoma (n=3), Ewing sarcoma (n=3), osteosarcoma (n=2), other soft tissue sarcoma (n=2), or nasopharyngeal carcinoma (n=1) have been enrolled. There were no DLTs observed at either the 10 mg/kg (n=6 pts) or 15 mg/kg (n=3 pts) dose. 1/6 pts receiving 30 mg/kg/dose developed DLT (venous thrombosis at a central line site). Non-dose limiting grade 3 or 4 toxicities included lymphopenia (n=2) hypertension (n=1), and neutropenia (n=1). Response in evaluable patients after eight weeks of therapy included stable disease (n=6 pts) and progressive disease (n=7 pts). PK were linear over the 3 dose levels, with t 1/2 and Cl p values of 69±18 h and 1.6±0.5 ml/h/kg, respectively. Conclusions: Trebananib is well tolerated in pediatric patients with recurrent or refractory solid tumors with recommended Phase 2 dose of 30 mg/kg. Correlative biology studies will be presented. Further study is planned to evaluate tolerability and changes in vascular permeability in patients with primary CNS tumors. Clinical trial information: NCT01538095.
Consequences of the Now-or-Never bottleneck for signed versus spoken languages
Authors: Karen Emmorey
Journal: Behavioral and Brain Sciences (2016)

Abstract Signed and spoken languages emerge, change, are acquired, and are processed under distinct perceptual, motor, and memory constraints. Therefore, the Now-or-Never bottleneck has different ramifications for these languages, which are highlighted in this commentary. The extent to which typological differences in linguistic structure can be traced to processing differences provides unique evidence for the claim that structure is processing.
Structural Racism and Supporting Black Lives — The Role of Health Professionals
Authors: Rachel R. Hardeman, Eduardo M. Medina, Katy B. Kozhimannil
Journal: New England Journal of Medicine (2016)

Structural racism leads to increased rates of premature death and reduced levels of overall health and well-being — an epidemic affecting our whole society. As clinicians and researchers, we wield power, privilege, and responsibility for dismantling structural racism.
Experimentally Increasing the Compliance of Titin Through RNA Binding Motif-20 (RBM20) Inhibition Improves Diastolic Function In a Mouse Model of Heart Failure With Preserved Ejection Fraction
Authors: Mei Methawasin, Joshua G. Strom, Rebecca E. Slater, Vanessa Fernandez, Chandra Saripalli, Henk Granzier
Journal: Circulation (2016)

Background: Left ventricular (LV) stiffening contributes to heart failure with preserved ejection fraction (HFpEF), a syndrome with no effective treatment options. Increasing the compliance of titin in the heart has become possible recently through inhibition of the splicing factor RNA binding motif-20. Here, we investigated the effects of increasing the compliance of titin in mice with diastolic dysfunction. Methods: Mice in which the RNA recognition motif (RRM) of one of the RNA binding motif-20 alleles was floxed and that expressed the MerCreMer transgene under control of the αMHC promoter (referred to as cRbm20 ΔRRM mice) were used. Mice underwent transverse aortic constriction (TAC) surgery and deoxycorticosterone acetate (DOCA) pellet implantation. RRM deletion in adult mice was triggered by injecting raloxifene ( cRbm20 ΔRRM -raloxifene), with dimethyl sulfoxide (DMSO)–injected mice ( cRbm20 ΔRRM -DMSO) as the control. Diastolic function was investigated with echocardiography and pressure-volume analysis; passive stiffness was studied in LV muscle strips and isolated cardiac myocytes before and after elimination of titin-based stiffness. Treadmill exercise performance was also studied. Titin isoform expression was evaluated with agarose gels. Results: cRbm20 ΔRRM -raloxifene mice expressed large titins in the hearts, called supercompliant titin (N2BAsc), which, within 3 weeks after raloxifene injection, made up ≈45% of total titin. TAC/DOCA cRbm20 ΔRRM -DMSO mice developed LV hypertrophy and a marked increase in LV chamber stiffness as shown by both pressure-volume analysis and echocardiography. LV chamber stiffness was normalized in TAC/DOCA cRbm20 ΔRRM -raloxifene mice that expressed N2BAsc. Passive stiffness measurements on muscle strips isolated from the LV free wall revealed that extracellular matrix stiffness was equally increased in both groups of TAC/DOCA mice ( cRbm20 ΔRRM -DMSO and cRbm20 ΔRRM -raloxifene). However, titin-based muscle stiffness was reduced in the mice that expressed N2BAsc (TAC/DOCA cRbm20 ΔRRM -raloxifene). Exercise testing demonstrated significant improvement in exercise tolerance in TAC/DOCA mice that expressed N2BAsc. Conclusions: Inhibition of the RNA binding motif-20–based titin splicing system upregulates compliant titins, which improves diastolic function and exercise tolerance in the TAC/DOCA model. Titin holds promise as a therapeutic target for heart failure with preserved ejection fraction.
Soluble Monomeric Von Willebrand Factor A1A2A3 (R1450E) Mutant Fragment Enhances Shear-Induced Platelet Aggregation and Platelet Adhesion to Fibrin(ogen) Via αIIbβ3 Under High Shear Stress.
Authors: Miguel A. Cruz, Katie E. Sowa, Scott M. Smith
Journal: Blood (2009)
TCT-205 High and low platelet reactivity on clopidogrel, prasugrel and ticagrelor in acute coronary syndrome patients: insight from a real-life large cohort
Authors: Myriam Amsallem, Jean-Guillaume Dillinger, Stephane Manzo-Silberman, Claire Bal dit Sollier, Giorgos Sideris, Mathilde Baudet, Ludovic Drouet, Patrick Henry
Journal: Journal of the American College of Cardiology (2015)
TCT-254 Utility of A Simplified Risk Tool To Predicts Long-Term Mortality in ST-elevation Myocardial Infarction
Authors: Matias Yudi, Omar Farouque, William Chan, Jay Ramchand, Nicholas Jones, Cheng Yee Goh, Dharsh Fernando, Angela Brennan, Christopher Reid, Stephen J. Duffy, Andrew Ajani, David Clark
Journal: Journal of the American College of Cardiology (2015)
Novel Three– and Four–Drug Combinations of Bortezomib, Dexamethasone, Cyclophosphamide, and Lenalidomide, for Newly Diagnosed Multiple Myeloma: Encouraging Results From the Multi-Center, Randomized, Phase 2 EVOLUTION Study.
Authors: Shaji Kumar, Ian W. Flinn, Parameswaran N. Hari, Natalie Callander, Stephen J. Noga, A. Keith Stewart, Jonathan Glass, Noopur Raje, Robert M. Rifkin, Hongliang Shi, Iain J. Webb, Paul G. Richardson, S. Vincent Rajkumar
Journal: Blood (2009)
Concomitant implantation of Impella<sup>®</sup> on top of veno‐arterial extracorporeal membrane oxygenation may improve survival of patients with cardiogenic shock
Authors: Federico Pappalardo, Christian Schulte, Marina Pieri, Benedikt Schrage, Rachele Contri, Gerold Soeffker, Teresa Greco, Rosalba Lembo, Kai Müllerleile, Antonio Colombo, Karsten Sydow, Michele De Bonis, Florian Wagner, Hermann Reichenspurner, Stefan Blankenberg, Alberto Zangrillo, Dirk Westermann
Journal: European Journal of Heart Failure (2016)