tbuckley/cabot-search huggingface dataset:
Benralizumab Reduces Exacerbations and Improves Lung Function in Patients From Republic of Korea With Severe, Uncontrolled Asthma: Subgroup Analysis of the SIROCCO Trial
Authors: Hae-Sim Park, Sang Haak Lee, Viktoria Werkström, Yanping Wu, James Zangrilli, Gokul Gopalan
Journal: Journal of Allergy and Clinical Immunology (2018)

In the Phase III SIROCCO RCT (Lancet. 2016;388:2115–270), benralizumab significantly improved asthma exacerbations, lung function, and symptoms for patients with severe, uncontrolled eosinophilic asthma. This subanalysis evaluated benralizumab for patients from the Republic of Korea in SIROCCO. SIROCCO (N=1,204) included patients aged 12–75 years with severe asthma uncontrolled by high-dosage ICS/LABA. Patients received 48 weeks' benralizumab 30 mg SC Q4W or Q8W (first three doses Q4W), or placebo. This analysis covered the patient subset from the Republic of Korea with baseline blood eosinophils ≥300 cells/μL. Of 122 patients randomized, 86 had baseline blood eosinophils ≥300 cells/μL. Benralizumab reduced the annual asthma exacerbation rate by 70% (Q4W; marginal rate 0.90, rate ratio 0.30 [95% CI, 0.13–0.65], p=0.003; n=28) and 85% (Q8W; marginal rate 0.45, rate ratio 0.15 [95% CI, 0.06–0.36], p<0.001; n=30) vs. placebo (marginal rate 3.03; n=28); and increased prebronchodilator FEV1 by 0.270 L (Q4W; 95% CI, 0.039–0.500, p=0.023; n=28) and 0.362 L (Q8W; 95% CI, 0.143–0.582, p=0.002; n=30) vs. placebo (n=27). There was no difference from placebo in total asthma symptom score for either regimen (Q4W: −0.28 [95% CI, −0.84 to 0.28, p=0.319; n=27]; Q8W: +0.07 [95% CI, −0.46 to 0.61, p=0.790; n=30] vs. placebo [n=28]). Adverse event rates approximated those of the overall SIROCCO population. Benralizumab meaningfully reduced asthma exacerbations, improved lung function, and was generally well tolerated in patients with severe, eosinophilic asthma from the Republic of Korea. Symptom scores were more variable, which is likely related to small sample size.
Matching degree between PI3K/AKT/mTOR (PAM) pathway mutations (mut) and therapy (ttx) as predictor of clinical benefit (ClinBen) in early trials.
Authors: Juan Martin Liberal, Ana Maria Martinez de Castro, Rodrigo Dienstmann, Cinta Hierro, Maria Ochoa de Olza, Irene Brana, Analia Azaro, Guillem Argiles, Cristina Cruz Zambrano, Mafalda Oliveira, Cristina Saura, Ana Oaknin, Helena Aguilar, Elena Sanchez, Paolo Nuciforo, Ana Vivancos, Josep Tabernero, Jordi Rodon Ahnert
Journal: Journal of Clinical Oncology (2016)

2572 Background: Drugs targeting aberrations in the PAM pathway are in clinical development but it is not completely clear if mut and ttx matching increases chances of ClinBen. Methods: Retrospective analysis of patients (pts) with molecular tumor profile treated with single agent PAM inhibitors (inh) in early trials at VHIO. Matching degrees were: supermatched (mut in PAM treated with a specific selective inh, such as PIK3CA mut - PI3Kα inh), matched (mut in PAM treated with a non-selective inh, such as PIK3CA mut - AKT inh) and unmatched(PAM inh without PAM mut). ClinBen was defined as partial response or stable disease for > 4 months (m). Time to treatment failure (TTF) was defined as time between start of ttx and end for any cause. Results: From Jul 09 to Dec 15, 97 pts with known molecular tumor profile by Sequenom (82 pts) or Amplicon (15 pts) received 99 PAM inh. Median age 58 years (23-77); 60 F, 37 M. Tumor types were colorectal (CRC) 42%, breast (BC) 20%, gynecological (GYN) 19%, other 10%. Median prior ttx lines was 2 (0-8). Median time from diagnosis of metastatic disease until PAM inh was 28 m (CI95% 23-34). Most pts (77%) had ≥ 75% dose recommended. Ttx was matched to PAM mut in 70 pts. Of those, 59 were supermatched. PIK3CA mut were the most common (65%). ClinBen was seen in 24% pts (supermatched 30%, matched 18% and unmatched 13%). Supermatched had a better trend for ClinBen compared to matched (OR 2.0, p = 0.49) or unmatched (OR 2.7, p = 0.11). ClinBen was significantly lower (12%) if coexisting RAS mut (OR 0.3, p = 0.05) and higher in BC (45%, OR 5.8, p = 0.007) and GYN tumors (35%, OR 3.9, p = 0.04) compared to CRC (11%). In a multivariate regression, factors influencing ClinBen were supermatched ttx (OR 4.3, p = 0.10 vs matched; OR 4.87, p = 0.02 vs unmatched) and CRC primary (lower benefit, OR 0.16, p = 0.02). Median TTF was 2 m (CI95% 1.9-2.4). TTF was associated with matching degree (supermatched vs matched HR 0.3, p = 0.002; supermatched vs unmatchedHR 0.7, p = 0.2) and tumor type (BC vs CRC HR 0.42, p = 0.02; GYN vs CRC HR 0.49, p = 0.06) in a multivariate Cox model. Conclusions: Our results suggest that single agent PAM inh have the highest chance of ClinBen and longer TTF when given as supermatchedttx in non-CRC pts.
Abstract 12122: Persistence With Antiarrhythmic Agents in Atrial Fibrillation: Insights From the Veterans Health Administration
Authors: Cynthia Jackevicius, Mintu Turakhia, Vidal Essebag, Louise Pilote, Thomas Glorioso, Jack V Tu, Meytal Tsadok, Mark J Eisenberg, Clare Atzema, Lingyun Lu, Elham Rahme, Karin H Humphries, P. Michael Ho
Journal: Circulation (2015)

Background: There is limited information on patterns of persistence with antiarrhythmic drugs (AADs) in atrial fibrillation (AF). Nonpersistence may represent failure of AADs or patient/physician choice, therefore, we characterized AAD persistence patterns following discharge in patients admitted to the hospital with AF. Methods: This retrospective cohort study of patients with AF, diagnosed on index AF admission in the Veterans Health Administration from 2001-2010 used national inpatient, outpatient, pharmacy claims, and vital status data to identify patients and characterize persistence. We identified prescriptions for all initial AAs dispensed after AF diagnosis. Patients were considered nonpersistent if they had &gt;30-day gap in filling a repeat AAD prescription. Results: Of 206,331 patients with AF, 43,262 (21%) received an AAD, age was 68.1±10.4 years, 98% were male, and CHA2DS2-VASc score was 2 (IQR: 1-3). Patients were followed for 2 years after their index AAD prescription. Among AAD-treated patients, most received amiodarone (68%). In the 2 years after their first AAD was dispensed, 43% discontinued their AAD. The lowest rates of nonpersistence were with dofetilide (29%) and sotalol (33%). Median time to nonpersistence was 143 days (IQR 90, 289). Of patients who were nonpersistent (&gt;30-day gap), 46% restarted the same AAD, 7% switched to a different AAD, 33% switched to a rate control strategy, and 14% stopped the AAD strategy completely. Conclusion: Among patients with AF, 4 in 10 patients are nonpersistent with their initial AAD. Nearly 50% of patients restart their same AAD after nonpersistence, suggesting intermittent medication use likely due to patient nonadherence. One-third of patients who had initiated a rhythm control strategy with an AAD switched to a rate control strategy, indicating possible AAD failure. Given the magnitude of nonpersistence, future studies on predictors and outcomes of nonpersistence with AAD in AF are needed.
Abstract #2921: Pharmacokinetics and pharmacodynamics of a selective proteasome inhibitor MLN9708 in nonclinical species following either intravenous or oral administration
Authors: Li Yu, Alex Bulychev, Lisa O'Brien, William Riorden, Shaoxia Yu, Martin Paton, Kym Cardoza, Bret Bannerman, Erik Kupperman
Journal: Cancer Research (2009)

MLN9708 is Millennium\#8217;s second generation proteasome inhibitor, following bortezomib for Injection, a first-in-class proteasome inhibitor that is currently used for the treatment of multiple myeloma and relapsed mantle cell lymphoma. MLN9708 will be in clinical development for evaluation of safety and effectiveness in both hematologic and non-hematologic malignancies. MLN9708 immediately hydrolyzes to MLN2238, the biologically active form, upon exposure to aqueous solutions or plasma. MLN9708 was developed as a clinical formulation. In the present studies, the pharmacokinetics (PK) and pharmacodynamics (PD) of MLN2238 were investigated in SCID mice bearing human CWR22 tumor xenografts, Spague-Dawley rats, Beagle dogs and Cynomolgus monkeys following either intravenous or oral administration of a solution of MLN2238. These results demonstrate that 1) MLN2238 had a very low blood clearance (CLb, 0.0087 - 0.050 L/hr/kg) and a moderate blood volume of distribution at steady-state (Vss,b,1.26 - 2.78L/kg) with a long terminal half-life (t1/2) >24 hr in all species tested; 2) MLN2238 demonstrated moderate to excellent oral bioavailability in two species studied (rats and dogs, 40-80%); and 3) MLN2238 showed lower in vivo blood EC50s in rats (114 ng/mL), dogs (134 ng/mL), and monkeys (97.6 ng/mL) than in the mouse (257 ng/mL). In addition, at a well-tolerated dose of MLN2238, rats, dogs, and monkeys showed blood 20S inhibition at levels similar to those observed in the tumor-bearing mouse model at efficacious doses, and 4) MLN2238 showed higher proteasome inhibition in the tumor tissues than in the blood, consistent with improved antitumor activities compared to bortezomib in mouse tumor models. In conclusion, the nonclinical studies demonstrated good PK/PD properties of MLN2238 across several species and support clinical development of MLN9708.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2921.
Hepatitis B virus reactivation during direct-acting antiviral therapy for hepatitis C: a systematic review and meta-analysis
Authors: Marcus M Mücke, Lisa I Backus, Victoria T Mücke, Nicola Coppola, Carmen M Preda, Ming-Lun Yeh, Lydia S Y Tang, Pamela S Belperio, Eleanor M Wilson, Ming-Lung Yu, Stefan Zeuzem, Eva Herrmann, Johannes Vermehren
Journal: The Lancet. Gastroenterology & hepatology (2018)
Acalabrutinib Monotherapy in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: Updated Results from the Phase 1/2 ACE-CL-001 Study
Authors: John C. Byrd, William G Wierda, Anna Schuh, Stephen Devereux, Jorge M. Chaves, Jennifer R. Brown, Peter Hillmen, Peter Martin, Farrukh T. Awan, Deborah M. Stephens, Paolo Ghia, Jacqueline C. Barrientos, John M. Pagel, Jennifer A. Woyach, Prista Charuworn, Ahmed Hamdy, Raquel Izumi, Priti Patel, Wayne M. Rothbaum, Min Hui Wang, Richard R. Furman
Journal: Blood (2017)
Therapeutic Challenge with a CDK 4/6 Inhibitor Induces an RB-Dependent SMAC-Mediated Apoptotic Response in Non–Small Cell Lung Cancer
Authors: Chellappagounder Thangavel, Ettickan Boopathi, Yi Liu, Christopher McNair, Alex Haber, Maryna Perepelyuk, Anshul Bhardwaj, Sankar Addya, Adam Ertel, Sunday Shoyele, Ruth Birbe, Joseph M. Salvino, Adam P. Dicker, Karen E. Knudsen, Robert B. Den
Journal: Clinical Cancer Research (2018)

Purpose: The retinoblastoma tumor suppressor (RB), a key regulator of cell-cycle progression and proliferation, is functionally suppressed in up to 50% of non-small cell lung cancer (NSCLC). RB function is exquisitely controlled by a series of proteins, including the CyclinD-CDK4/6 complex. In this study, we interrogated the capacity of a CDK4/6 inhibitor, palbociclib, to activate RB function.Experimental Design and Results: We employed multiple isogenic RB-proficient and -deficient NSCLC lines to interrogate the cytostatic and cytotoxic capacity of CDK 4/6 inhibition in vitro and in vivo We demonstrate that while short-term exposure to palbociclib induces cellular senescence, prolonged exposure results in inhibition of tumor growth. Mechanistically, CDK 4/6 inhibition induces a proapoptotic transcriptional program through suppression of IAPs FOXM1 and Survivin, while simultaneously augmenting expression of SMAC and caspase-3 in an RB-dependent manner.Conclusions: This study uncovers a novel function of RB activation to induce cellular apoptosis through therapeutic administration of a palbociclib and provides a rationale for the clinical evaluation of CDK 4/6 inhibitors in the treatment of patients with NSCLC. Clin Cancer Res; 24(6); 1402-14. ©2018 AACR.
Infections à coxsackie en 2002 en Grèce : véritable épidémie ou effet médiatique ?
Authors: M Exindari, G Gioula, D Raptis, V Mavroidi, E Bouzia, V Kyriazopoulou
Journal: Eurosurveillance (2005)

Le but de l’etude etait de fournir des donnees probantes quant a la realite de l’epidemie de coxsackie B survenue en Grece en 2002. Les donnees sur les infections a coxsackie B recentes confirmees microbiologiquement du Nord de la Grece entre 1998 et 2001 ont ete comparees aux donnees de 2002. 
Les infections etaient confirmees serologiquement par detection des anticorps IgM aux virus du coxsackie B1-B6 par immunofluorescence indirecte. Les serums de 2701 patients residant dans le nord de la Grece, correspondant a des cas suspectes d’infections a coxsackie B ont ete analyses (2056 pour la periode de 1998 a 2001 et 645 en 2002). 
La comparaison entre les resultats des cas microbiologiquement confirmes et les donnees disponibles au laboratoire entre les deux periodes indiquaient que :
- Le nombre total de patients analyses par annee etait plus eleve en 2002 (645 compares a une moyenne annuelle de 514 en 1998-2001). 
- La proportion d’infections recentes confirmees microbiologiquement etait moins elevee en 2002 (27,8% contre 32,7%) et l’incidence etait estimee a 0,66/10 000 pour 2002 et 0,32-0,84/10 000 pour 1998-2001.
- La distribution par classes d’âge etait differente : les proportions de cas chez les enfants par rapport au cas chez les adultes etaient inversees en 2002 compare a 1998-2001, la proportion d’enfants en 2002 etant plus forte. La difference entre les deux periodes etait statistiquement significative. En 2002, la classe d’âge la plus affectee etait celle des 3-5 ans.
- La distribution saisonniere etait similaire pour les deux periodes, avec un pic au printemps et un autre a l’automne. Trois deces sont survenus en avril 2002, et aucun entre 1998 et 2001. 
- Les syndromes cliniques associes variaient egalement : les cas d’infections respiratoires, principalement de pneumonie, ont augmente de 5,75% a 24,3% chez les enfants en 2002 et les cas de myopericardite etaient en hausse chez les adultes, passant de 13% en 1998-2001 a 29,5% en 2002. 
Ce dernier resultat, associe au role des medias (en raison des trois cas decedes) et a la panique qui s’est ensuivie dans le public, suggerait l’existence d’une epidemie, mais notre etude n’a pas permis de confirmer l’existence d’une telle epidemie.
Safety and tolerability of a novel, polyclonal human anti-MERS coronavirus antibody produced from transchromosomic cattle: a phase 1 randomised, double-blind, single-dose-escalation study
Authors: John H Beigel, Jocelyn Voell, Parag Kumar, Kanakatte Raviprakash, Hua Wu, Jin-An Jiao, Eddie Sullivan, Thomas Luke, Richard T Davey
Journal: The Lancet Infectious Diseases (2018)
Predicting response to oxygen therapy in obstructive sleep apnoea patients using a 10-minute daytime test
Authors: David Wang, Keith K. Wong, Luke Rowsell, Garrick W. Don, Brendon J. Yee, Ronald R. Grunstein
Journal: European Respiratory Journal (2018)

There is no satisfactory treatment for obstructive sleep apnoea (OSA). Supplemental low-flow oxygen therapy (LFO2) has been shown to reduce hypoxaemia and is well tolerated by patients with OSA. However, oxygen therapy may be beneficial only to certain subsets of patients with OSA. In this study, we evaluated a 10-min awake ventilatory chemoreflex test in predicting individual OSA response to 2 months of LFO2 therapy.At baseline, patients with OSA underwent ventilatory chemoreflex testing in the afternoon, prior to the overnight polysomnography. Subjects were reassessed with polysomnography after 2 months of nocturnal oxygen treatment.20 patients with OSA completed the study. After 2 months of O2 treatment, changes in the apnoea-hypopnoea index (AHI) were significantly correlated with baseline CO2 ventilatory response threshold (VRT) and chemosensitivity (p<0.05). In predicting a fall in AHI, the area under the receiver operating characteristic curve (AUC) was 0.79 for VRT and 0.89 for chemosensitivity. When these two variables were combined in a logistic regression model, the prediction effect became stronger with an AUC of 0.97, sensitivity of 0.92 and specificity of 0.83.Our awake ventilatory chemoreflex test could be considered a simple potential clinical tool to predict individual OSA response to oxygen therapy. It could provide a novel personalised medicine approach to OSA treatment.
An ulcer on the nipple
Authors: Jianjun Qiao, Sha Zhou, Hong Fang
Journal: BMJ (2018)

A 39 year old woman presented with an asymptomatic ulcer on her left nipple. The ulcer had been present for five weeks. She also reported malaise. She denied any travel history in the past three months, but recalled a history of breast bites and breast-genital contact during sexual intercourse, which had occurred two weeks before the skin lesion appeared. Physical examination revealed demarcated ulceration with a border that was slightly elevated, crusted, and indurated (fig 1). Left axillary lymphadenopathy was noted. Fig 1 Demarcated ulceration with slightly elevated, crusted, and indurated border on the left nipple
Could conjunctivitis in patients with atopic dermatitis treated with dupilumab be caused by colonization with <i>Demodex</i> and increased interleukin-17 levels?: reply from the authors
Authors: M. de Bruin-Weller, N.M.H. Graham, G. Pirozzi, B. Shumel
Journal: British Journal of Dermatology (2018)

Linked Article:de Bruin‐Weller et al. Br J Dermatol 2018; 178:1083–1101.
Abstract 20343: Usefulness of Echocardiography in Children and Adolescents With New Onset Supraventricular Tachycardia
Authors: Kaitlin L’Italien, Steven Conlon, Tami Ackley, Naomi Kertesz, Anna Kamp
Journal: Circulation (2016)

Introduction: Supraventricular tachycardia (SVT) is the most common sustained arrhythmia in children. Patients with SVT and Wolff-Parkinson-White (WPW) are known to have 10-30% incidence of congeni...
Impact of Ruxolitinib in Myelofibrosis Allogeneic Stem Cell Transplant Outcome---a Pilot Study
Authors: Joyson Poulose, Jozef Malysz, David F Claxton, W. Christopher Ehmann, Shin Mineishi, Witold B. Rybka, Raymond J. Hohl, Jeffrey J Pu
Journal: Blood (2017)
Immunological changes induced by Pru p 3-glycodendrimers
Authors: Maria Francisca Palomares, Francisca Gomez, Ainhoa Mascaraque, Gador Bogas, Javier Ramos-Soriano, Maria José Rodríguez, Maria Jose Torres Jaén, Javier Rojo, Cristobalina Mayorga
Journal: Journal of Allergy and Clinical Immunology (2018)
MBD2 Ablation Impairs Lymphopoiesis and Impedes Progression and Maintenance of T-ALL
Authors: Mi Zhou, Kuangguo Zhou, Ling Cheng, Xing Chen, Jue Wang, Xiao-Min Wang, Yingchi Zhang, Qilin Yu, Shu Zhang, Di Wang, Liang Huang, Mei Huang, Ding Ma, Tao Cheng, Cong-Yi Wang, Weiping Yuan, Jianfeng Zhou
Journal: Cancer Research (2018)

Aberrant DNA methylation patterns in leukemia might be exploited for therapeutic targeting. In this study, we employed a genetically deficient mouse model to explore the role of the methylated DNA binding protein MBD2 in normal and malignant hematopoiesis. MBD2 ablation led to diminished lymphocytes. Functional defects of the lymphoid compartment were also observed after in vivo reconstitution of MBD2-deficient hematopoietic stem cells (HSC). In an established model of Notch1-driven T-cell acute lymphoblastic leukemia (T-ALL), MBD2 ablation impeded malignant progression and maintenance by attenuating the Wnt signaling pathway. In clinical specimens of human T-ALL, Wnt signaling pathway signatures were significantly enhanced and positively correlated with the expression and function of MBD2. Furthermore, a number of typical Wnt signaling inhibitory genes were abnormally hypermethylated in primary human T-ALL. Abnormal activation of Wnt signaling in T-ALL was switched off by MBD2 deletion, partially by reactivating epigenetically silenced Wnt signaling inhibitors. Taken together, our results define essential roles for MBD2 in lymphopoiesis and T-ALL and suggest MBD2 as a candidate therapeutic target in T-ALL.Significance: This study highlights a methylated DNA binding protein as a candidate therapeutic target to improve the treatment of T-cell acute lymphoblastic leukemias, as a new starting point for developing epigenetic therapy in this and other lymphoid malignancies. Cancer Res; 78(7); 1632-42. ©2018 AACR.
Winter pressure is putting junior doctors’ training at risk, leaders warn
Authors: Abi Rimmer
Journal: BMJ (2018)

Junior doctors are being forced to miss opportunities for training because of winter pressure on the NHS, doctors’ leaders have warned.

On 2 January NHS England advised hospitals to postpone elective procedures until the end of January and to defer outpatient appointments and day case surgery in a bid to ease mounting pressure on services.1

Sarah Hallett, deputy chair of the BMA’s Junior Doctors Committee, said that the deferrals in elective surgery and clinics were having a detrimental effect on trainees in surgery in particular, though all trainees were being affected. She …
What counts as ‘the evidence’? A need for an urgent review of injury risk in school rugby
Authors: Joe Piggin, Alan Bairner
Journal: British Journal of Sports Medicine (2018)

In March 2016, an open letter called for the removal of tackling in school rugby union.1 In response, the Chief Medical Officers (CMOs) of the UK consulted, gathered evidence and continued with the status quo—they endorsed tackling in school rugby.2 The CMOs stated that ‘the evidence does not support the conclusions and recommendations laid out in [the] open letter’. The CMOs relied on a report from the UK Physical Activity Expert Group (PAEG) and a review article by Dr Ross Tucker and colleagues in the  British Journal of Sports Medicine .3 4 

We highlight five problems with the evidence that the CMOs used to make their decision stemming from a report to the CMOs by the PAEG.

In responding to an assertion that ‘concussion is a common injury’ in rugby, the PAEG stated: ‘It seems that before the sustained programme of education and awareness in rugby concussions were under reported, and it may be now that true concussion is over-reported, making it currently difficult to ascertain where the true incidence lies’. We draw the PAEG’s attention to research published in 2016 about attitudes towards concussion in community rugby.5 Based on qualitative research with 20 young male …
An Ethical Bone to PICC: Considering a Harm Reduction Approach for a Second Valve Replacement for a Person Who Uses Drugs
Authors: Daniel Z. Buchman, Marie-Josee Lynch
Journal: The American Journal of Bioethics (2018)

This situation is one that often triggers a request for a health care ethics consultation: A person who uses drugs (PWUD) has developed infective endocarditis (IE) and needs a valve replacement, or...