tbuckley/cabot-search huggingface dataset:
Ultrasound in management of rheumatoid arthritis: ARCTIC randomised controlled strategy trial
Authors: Espen A Haavardsholm, Anna-Birgitte Aga, Inge Christoffer Olsen, Siri Lillegraven, Hilde B Hammer, Till Uhlig, Hallvard Fremstad, Tor Magne Madland, Åse Stavland Lexberg, Hilde Haukeland, Erik Rødevand, Christian Høili, Hilde Stray, Anne Noraas, Inger Johanne Widding Hansen, Gunnstein Bakland, Lena Bugge Nordberg, Désirée van der Heijde, Tore K Kvien
Journal: BMJ (2016)

To determine whether a treatment strategy based on structured ultrasound assessment would lead to improved outcomes in rheumatoid arthritis, compared with a conventional strategy. Multicentre, open label, two arm, parallel group, randomised controlled strategy trial. Ten rheumatology departments and one specialist centre in Norway, from September 2010 to September 2015. 238 patients were recruited between September 2010 and April 2013, of which 230 (141 (61%) female) received the allocated intervention and were analysed for the primary outcome. The main inclusion criteria were age 18-75 years, fulfilment of the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis, disease modifying anti-rheumatic drug naivety with indication for disease modifying drug therapy, and time from first patient reported swollen joint less than two years. Patients with abnormal kidney or liver function or major comorbidities were excluded. 122 patients were randomised to an ultrasound tight control strategy targeting clinical and imaging remission, and 116 patients were randomised to a conventional tight control strategy targeting clinical remission. Patients in both arms were treated according to the same disease modifying anti-rheumatic drug escalation strategy, with 13 visits over two years. The primary endpoint was the proportion of patients with a combination between 16 and 24 months of clinical remission, no swollen joints, and non-progression of radiographic joint damage. Secondary outcomes included measures of disease activity, radiographic progression, functioning, quality of life, and adverse events. All participants who attended at least one follow-up visit were included in the full analysis set. 26 (22%) of the 118 analysed patients in the ultrasound tight control arm and 21 (19%) of the 112 analysed patients in the clinical tight control arm reached the primary endpoint (mean difference 3.3%, 95% confidence interval -7.1% to 13.7%). Secondary endpoints (disease activity, physical function, and joint damage) were similar between the two groups. Six (5%) patients in the ultrasound tight control arm and seven (6%) patients in the conventional arm had serious adverse events. The systematic use of ultrasound in the follow-up of patients with early rheumatoid arthritis treated according to current recommendations is not justified on the basis of the ARCTIC results. The findings highlight the need for randomised trials assessing the clinical application of medical technology.Trial registration Clinical trials NCT01205854.
Cotreatment with Pioglitazone, a Synthetic Ligand for Peroxisome Proliferator-Activated Receptor γ (PPARγ), Enhances Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-Induced Apoptosis of Human Leukemia Cells.
Authors: Joo-In Park, Hoon Han, Ji-Seon Han, Hyuk-Chan Kwon, Jin-Yeong Han, Jin-Sook Jeong, Yoe-Sik Bae, Jong-Young Kwak
Journal: Blood (2004)
Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders (AD) or major toxicity with ipilimumab (IPI).
Authors: Alexander M. Menzies, Douglas Buckner Johnson, Sangeetha Ramanujam, Victoria Atkinson, Annie N.M. Wong, John J Park, Jennifer Leigh McQuade, Alexander Noor Shoushtari, Katy K. Tsai, Zeynep Eroglu, Oliver Klein, Jessica Cecile Hassel, Jeffrey Alan Sosman, Alex Guminski, Ryan J. Sullivan, Antoni Ribas, Matteo S. Carlino, Michael A. Davies, Shahneen Kaur Sandhu, Georgina V. Long
Journal: Journal of Clinical Oncology (2016)

9515 Background: Anti-PD1-antibodies (PD1) have activity in many cancers, and are standard care for melanoma, lung and renal cancer. All trials excluded patients (pts) with significant preexisting AD or major immune-related adverse events (irAEs) with IPI. We sought to explore the safety and efficacy of PD1 in such pts. Methods: Pts with advanced melanoma and preexisting AD and/or major irAEs with prior IPI (requiring systemic immunosuppression, [IS]) treated with PD1 were retrospectively identified. Data regarding AD, IPI and PD1 treatments, toxicity and outcome were examined. Results: 119 pts were included, 95 with prior IPI. 109 received pembrolizumab, 10 nivolumab. 86 (72%) had ≥ 3 months (mo) follow-up, median (med) 4.6 mo, with med PFS 6.8 mo. 31 (26%) had died. Of 52 pts with preexisting AD, 15 (29%) had active symptoms at PD1 start and 16 (31%) were on IS. The ORR was 33%. 20 (38%) flared with PD1 after a med 1.3 mo, including 7/13 with rheumatoid arthritis, 3/3 with polymyalgia rheumatica, 2/2 with Sjogren’s syndrome, 1/2 with scleroderma, 2/2 with immune thrombocytopaenic purpura, 3/8 with psoriasis, 1/4 with Graves’ disease, 0/6 with gastrointestinal (GI) (including 3 Crohn’s disease) and 0/5 with neurological disorders. 3 (6%) had grade (G) 3 flare, and 2 (4%) discontinued PD1 for flare. 15 (29%) developed other irAEs (5 G3), 3 (6%) discontinued PD1. 67 pts had irAEs requiring IS with prior IPI (9 G2, 51 G3, 7 G4), including 47 with ≥ G3 colitis (15 had infliximab), 2 with G4 hepatitis (1 had antithymocyte globulin), and 9 with hypophysitis. All irAEs except hypophysitis had resolved at PD1 start except in 1 pt (arthritis), 5 were on IS at PD1 start. The ORR was 40%. 2 (3%) had recurrence of IPI irAEs with PD1 (arthritis, colitis), but 23 (34%) developed new irAEs (13, 19% ≥ G3), and 11 (16%) discontinued PD1. There were no treatment related deaths. Conclusions: PD1 have efficacy in pts with preexisting AD and/or major irAEs with IPI. PD1 may flare preexisting AD, particularly rheumatologic, but GI and neurological disorders may flare less. In pts with prior major irAEs with IPI recurrence of the same irAE is rare, but new irAEs occur. The rate of irAEs in these pts appears higher than in clinical trial pts.
Defibrillator Implantation in Patients with Nonischemic Systolic Heart Failure
Authors: Lars Køber, Jens J. Thune, Jens C. Nielsen, Jens Haarbo, Lars Videbæk, Eva Korup, Gunnar Jensen, Per Hildebrandt, Flemming H. Steffensen, Niels E. Bruun, Hans Eiskjær, Axel Brandes, Anna M. Thøgersen, Finn Gustafsson, Kenneth Egstrup, Regitze Videbæk, Christian Hassager, Jesper H. Svendsen, Dan E. Høfsten, Christian Torp-Pedersen, Steen Pehrson
Journal: New England Journal of Medicine (2016)

The benefit of an implantable cardioverter-defibrillator (ICD) in patients with symptomatic systolic heart failure caused by coronary artery disease has been well documented. However, the evidence for a benefit of prophylactic ICDs in patients with systolic heart failure that is not due to coronary artery disease has been based primarily on subgroup analyses. The management of heart failure has improved since the landmark ICD trials, and many patients now receive cardiac resynchronization therapy (CRT).In a randomized, controlled trial, 556 patients with symptomatic systolic heart failure (left ventricular ejection fraction, ≤35%) not caused by coronary artery disease were assigned to receive an ICD, and 560 patients were assigned to receive usual clinical care (control group). In both groups, 58% of the patients received CRT. The primary outcome of the trial was death from any cause. The secondary outcomes were sudden cardiac death and cardiovascular death.After a median follow-up period of 67.6 months, the primary outcome had occurred in 120 patients (21.6%) in the ICD group and in 131 patients (23.4%) in the control group (hazard ratio, 0.87; 95% confidence interval [CI], 0.68 to 1.12; P=0.28). Sudden cardiac death occurred in 24 patients (4.3%) in the ICD group and in 46 patients (8.2%) in the control group (hazard ratio, 0.50; 95% CI, 0.31 to 0.82; P=0.005). Device infection occurred in 27 patients (4.9%) in the ICD group and in 20 patients (3.6%) in the control group (P=0.29).In this trial, prophylactic ICD implantation in patients with symptomatic systolic heart failure not caused by coronary artery disease was not associated with a significantly lower long-term rate of death from any cause than was usual clinical care. (Funded by Medtronic and others; DANISH ClinicalTrials.gov number, NCT00542945 .).
Functional Subclone Profiling for Prediction of Treatment-Induced Intratumor Population Shifts and Discovery of Rational Drug Combinations in Human Glioblastoma
Authors: Roman Reinartz, Shanshan Wang, Sied Kebir, Daniel J. Silver, Anja Wieland, Tong Zheng, Marius Küpper, Laurèl Rauschenbach, Rolf Fimmers, Timothy M. Shepherd, Daniel Trageser, Andreas Till, Niklas Schäfer, Martin Glas, Axel M. Hillmer, Sven Cichon, Amy A. Smith, Torsten Pietsch, Ying Liu, Brent A. Reynolds, Anthony Yachnis, David W. Pincus, Matthias Simon, Oliver Brüstle, Dennis A. Steindler, Björn Scheffler
Journal: Clinical Cancer Research (2016)

Investigation of clonal heterogeneity may be key to understanding mechanisms of therapeutic failure in human cancer. However, little is known on the consequences of therapeutic intervention on the clonal composition of solid tumors.Here, we used 33 single cell-derived subclones generated from five clinical glioblastoma specimens for exploring intra- and interindividual spectra of drug resistance profiles in vitro In a personalized setting, we explored whether differences in pharmacologic sensitivity among subclones could be employed to predict drug-dependent changes to the clonal composition of tumors.Subclones from individual tumors exhibited a remarkable heterogeneity of drug resistance to a library of potential antiglioblastoma compounds. A more comprehensive intratumoral analysis revealed that stable genetic and phenotypic characteristics of coexisting subclones could be correlated with distinct drug sensitivity profiles. The data obtained from differential drug response analysis could be employed to predict clonal population shifts within the naïve parental tumor in vitro and in orthotopic xenografts. Furthermore, the value of pharmacologic profiles could be shown for establishing rational strategies for individualized secondary lines of treatment.Our data provide a previously unrecognized strategy for revealing functional consequences of intratumor heterogeneity by enabling predictive modeling of treatment-related subclone dynamics in human glioblastoma. Clin Cancer Res; 23(2); 562-74. ©2016 AACR.
Breast cancer and high-risk diagnosis in core biopsies stratified by ethnicity.
Authors: E. Kim, J. Sharko, B. Drohan, C. Roche, M. Specht, M. Gadd, B. L. Smith, K. S. Hughes
Journal: Journal of Clinical Oncology (2010)

1584 Background: There is limited data on the incidence of high-risk breast lesions and breast cancer identified in core biopsies stratified by ethnicity. This study evaluated the differential profile of high-risk lesions categorized as severe ADH, LCIS, ALH, ADH, and breast cancer among Asian (A), African American (AA), and Caucasian (C) patients. Methods: With IRB approval, 27,931 breast pathology reports, from 1/1990 to 6/2007, were retrospectively evaluated using Natural Language Processing. Of these, 3,179 core biopsy reports were identified. Diagnosis was assigned and categorized by most severe diagnosis identified in this biopsy or subsequent follow-on biopsies. Categories and rankings were 1: Cancer (severity ranked as invasive cancer > DCIS) and 2: High Risk Lesions (severity ranked as severe ADH > LCIS >ALH > ADH). Inclusion criteria were female gender, patient care within Partner's Health system, and documentation of ethnicity limited to (A), (AA), and (C). Statistical analysis was performed by the chi square test. Results: Of the 3,179 core reports, 106 (3.3%) were (A), 145 (4.6%) were (AA), and 2,928 (92.1%) were (C). There was no difference between ethnic groups for high-risk lesions. For invasive breast cancer, there was a statistical difference between (A) and (C), OR = 1.28 (1.12-1.41) and between (AA) and (C) OR=1.26 (1.15-1.40). For DCIS, there was a statistical difference between (AA) and (C) OR=1.06 (1.02-1.11). Conclusions: Caucasians had a significantly higher incidence of invasive cancer in core biopsy when compared to Asians and African Americans, and a significantly higher incidence of DCIS in core biopsy when compared to African Americans. Our study illustrates the differential profile of breast disease found by core biopsy between ethnicity, which might be explained by the density of breast and cancer biology. Our sample size is relatively small, hindering statistical significance; however, trends are identified in the rates of high-risk lesions that should be investigated further. High-risk lesion DCIS Invasive Benign (A) 10.4% (11/106) 5.7% (6/106) 24.5% (26/106) 59.4% (63/106) (AA) 4.8% (7/145) 4.8% (7/145) 22.1% (32/145) 68.3% (99/145) (C) 6.6% (194/2,928) 11.4% (335/2,928) 35.3% (1,033/2,928) 46.7% (1,366/2,928) No significant financial relationships to disclose.
Breast-feeding: Time to Teach What We Preach
Authors: Susan Dixon
Journal: JAMA (1993)

<h3>To the Editor.</h3> —We strongly agree with Freed's<sup>1</sup>assessment of the lack of training in breast-feeding but would take it back a step further. Physicians are not trained in this area because faculty have little or no knowledge in the field of lactation management. In our Lactation Management Education Curriculum project, we have had the opportunity to assess the knowledge and skills of members of multidisciplinary teams of faculty who identify themselves as being interested, and often experienced, in this area. Although beginning competencies vary widely, substantial increases in knowledge and skills are seen in all, when the scientific material is presented and supervised clinical experiences are provided. These faculty teams return home ready to teach lactation management as we do other areas of medicine: with scientifically based didactic material, for small and large group presentations, and with bedside and clinic teaching. In our own institution, pediatrics, obstetrics, and
Caloric Restriction Leads to Browning of White Adipose Tissue through Type 2 Immune Signaling
Authors: Salvatore Fabbiano, Nicolas Suárez-Zamorano, Dorothée Rigo, Christelle Veyrat-Durebex, Ana Stevanovic Dokic, Didier J. Colin, Mirko Trajkovski
Journal: Cell Metabolism (2016)
Mir∼17-92 Identifies BCL2 As a Therapeutic Target In BCR-ABL Positive B-Lineage Acute Lymphoblastic Leukemia
Authors: Matthias Eder, Alex Elder, David Barzan, Karin Battmer, Simon Bomken, Melanie Ricke-Hoch, Anke Schröder, Letizia Venturini, Heike Pfeiffer, Helen J Blair, Josef Vormoor, Oliver G. Ottmann, Arnold Ganser, Andreas Pich, Denise Hilfiker-Kleiner, Olaf Heidenreich, Michaela Scherr
Journal: Blood (2013)
INT6/EIF3E Controls the RNF8-Dependent Ubiquitylation Pathway and Facilitates DNA Double-Strand Break Repair in Human Cells
Authors: Christelle Morris, Nozomi Tomimatsu, Sandeep Burma, Pierre Jalinot
Journal: Cancer Research (2016)

Abstract Unrepaired DNA double-strand breaks (DSB) are the most destructive chromosomal lesions driving genomic instability, a core hallmark of cancer. Here, we identify the antioncogenic breast cancer factor INT6/EIF3E as an essential regulator of DSB repair that promotes homologous recombination (HR)–mediated repair and, to a lesser extent, nonhomologous end-joining repair. INT6 silencing impaired the accrual of the ubiquitin ligase RNF8 at DSBs and the formation of ubiquitin conjugates at DSB sites, especially Lys63-linked polyubiquitin chains, resulting in impaired recruitment of BRCA1, BRCA2, and RAD51, which are all involved in HR repair. In contrast, INT6 deficiency did not affect the accumulation of RNF168, 53BP1, or RPA at DSBs. In INT6-silenced cells, there was also an alteration in DNA damage-induced localization of MDC1, a key target for ATM phosphorylation, which is a prerequisite for RNF8 recruitment. The attenuated DNA damage localization of RNF8 resulting from INT6 depletion could be attributed to the defective retention of ATM previously reported by us. Our findings deepen insights into how INT6 protects against breast cancer by showing how it functions in DSB repair, with potential clinical implications for cancer therapy. Cancer Res; 76(20); 6054–65. ©2016 AACR.
Hypokalemic Respiratory Arrest in Diabetic Ketoacidosis
Authors: M. Frenkel
Journal: JAMA (1987)

<h3>To the Editor.—</h3> I read with interest and some nostalgia the CASE REPORT by Dorin and Crapo<sup>1</sup>on hypokalemic respiratory arrest during treatment of diabetic ketoacidosis. It shows why clinicians in the 1940s<sup>2,3</sup>advised giving potassium in diabetic ketoacidosis—a routine intervention ever since. Historically, it may be interesting for your readers to know that it was inTHE JOURNALthat Holler<sup>2</sup>40 years ago published a nearly identical case. He was the first, to my knowledge, to draw attention to this cause of respiratory paralysis and its treatment.
<i>Staphylococcus aureus</i> vaccines: Deviating from the carol
Authors: Dominique Missiakas, Olaf Schneewind
Journal: The Journal of Experimental Medicine (2016)

Staphylococcus aureus, a commensal of the human nasopharynx and skin, also causes invasive disease, most frequently skin and soft tissue infections. Invasive disease caused by drug-resistant strains, designated MRSA (methicillin-resistant S. aureus), is associated with failure of antibiotic therapy and elevated mortality. Here we review polysaccharide-conjugate and subunit vaccines that were designed to prevent S. aureus infection in patients at risk of bacteremia or surgical wound infection but failed to reach their clinical endpoints. We also discuss vaccines with ongoing trials for combinations of polysaccharide-conjugates and subunits. S. aureus colonization and invasive disease are not associated with the development of protective immune responses, which is attributable to a large spectrum of immune evasion factors. Two evasive strategies, assembly of protective fibrin shields via coagulases and protein A–mediated B cell superantigen activity, are discussed as possible vaccine targets. Although correlates for protective immunity are not yet known, opsonophagocytic killing of staphylococci by phagocytic cells offers opportunities to establish such criteria.
Determination of the Maximum Tolerated Dose of Panobinostat in Combination with Cytarabine and Mitoxantrone As Salvage Therapy for Relapsed/Refractory Acute Myeloid Leukemia
Authors: Richard F. Schlenk, Jürgen Krauter, Markus Schaich, Didier Bouscary, Hervé Dombret, Ivo J. Winiger, Margaret Squier, Anita Zahlten, Lu Wang, Oliver G. Ottmann
Journal: Blood (2011)
Identification of Site-specific Recurrence Following Primary Radiation Therapy for Prostate Cancer Using C-11 Choline Positron Emission Tomography/Computed Tomography: A Nomogram for Predicting Extrapelvic Disease
Authors: William P. Parker, Brian J. Davis, Sean S. Park, Kenneth R. Olivier, Richard Choo, Mark A. Nathan, Val J. Lowe, Timothy J. Welch, Jaden D. Evans, William S. Harmsen, Harras B. Zaid, Ilya Sobol, Daniel M. Moreira, Rimki Haloi, Matthew K. Tollefson, Matthew T. Gettman, Stephen A. Boorjian, Lance A. Mynderse, R. Jeffrey Karnes, Eugene D. Kwon
Journal: European Urology (2016)
Increasing Precision in Adjuvant Therapy for Breast Cancer
Authors: Clifford A. Hudis, Maura Dickler
Journal: New England Journal of Medicine (2016)

Genomic testing of tumors can enable improved matching of individual patients or groups with treatments, but it can also identify situations where a specific intervention is not effective. In the recently reported results of the Trial Assigning Individualized Options for Treatment (TAILORx), investigators showed how one assay — the 21-gene recurrence score — could select a cohort of patients who had a 99% chance of 5-year survival without distant metastasis in whom currently available cytotoxic adjuvant chemotherapy could not be justified.1 A similar result was also seen in the West German Study Group PlanB trial.2 As we consider the practical . . .
Targeted High-Throughput Sequencing For The Detection Of Mutations Associated With Myeloproliferative Neoplasms
Authors: Ferrari Robin, Sakuntala Ale, Aysha Patel, Mikel Valgañón, Hui En Foong, Mary Alikian, Kikkeri Naresh, Dragana Milojkovic, Jane F Apperley, Letizia Foroni, Gareth Gerrard
Journal: Blood (2013)
<i>RBM5-AS1</i> Is Critical for Self-Renewal of Colon Cancer Stem-like Cells
Authors: Serena Di Cecilia, Fan Zhang, Ana Sancho, SiDe Li, Francesca Aguiló, Yifei Sun, Madhumitha Rengasamy, Weijia Zhang, Luigi Del Vecchio, Francesco Salvatore, Martin J. Walsh
Journal: Cancer Research (2016)

Abstract Cancer-initiating cells (CIC) undergo asymmetric growth patterns that increase phenotypic diversity and drive selection for chemotherapeutic resistance and tumor relapse. WNT signaling is a hallmark of colon CIC, often caused by APC mutations, which enable activation of β-catenin and MYC. Accumulating evidence indicates that long noncoding RNAs (lncRNA) contribute to the stem-like character of colon cancer cells. In this study, we report enrichment of the lncRNA RBM5-AS1/LUST during sphere formation of colon CIC. Its silencing impaired WNT signaling, whereas its overexpression enforced WNT signaling, cell growth, and survival in serum-free media. RBM5-AS1 has been little characterized previously, and we determined it to be a nuclear-retained transcript that selectively interacted with β-catenin. Mechanistic investigations showed that silencing or overexpression of RBM5-AS1 caused a respective loss or retention of β-catenin from TCF4 complexes bound to the WNT target genes SGK1, YAP1, and MYC. Our work suggests that RBM5-AS1 activity is critical for the functional enablement of colon cancer stem-like cells. Furthermore, it defines the mechanism of action of RBM5-AS1 in the WNT pathway via physical interactions with β-catenin, helping organize transcriptional complexes that sustain colon CIC function. Cancer Res; 76(19); 5615–27. ©2016 AACR.