tbuckley/cabot-search huggingface dataset:
Improving 1-Year Outcomes of Infrainguinal Limb Revascularization
Authors: Katriina Heikkila, David C. Mitchell, Ian M. Loftus, Amundeep S. Johal, Sam Waton, David A. Cromwell
Journal: Circulation (2018)

Background: The availability and diversity of lower limb revascularization procedures have increased in England in the past decade. We investigated whether these developments in care have translated to improvements in patient pathways and outcomes. Methods: Individual-patient records from Hospital Episode Statistics were used to identify 103 934 patients who underwent endovascular (angioplasty) or surgical (endarterectomy, profundaplasty, or bypass) lower limb revascularization for infrainguinal peripheral artery disease in England between January 2006 and December 2015. Major lower limb amputations and deaths within 1 year after revascularization were ascertained from Hospital Episode Statistics and Office for National Statistics mortality records. Competing risks regression was used to estimate the cumulative incidence of major amputation and death, adjusted for patient age, sex, comorbidity score, indication for the intervention (intermittent claudication, severe limb ischemia without record of tissue loss, severe limb ischemia with a record of ulceration, severe limb ischemia with a record of gangrene/osteomyelitis), and comorbid diabetes mellitus. Results: The estimated 1-year risk of major amputation decreased from 5.7% (in 2006–2007) to 3.9% (in 2014–2015) following endovascular revascularization, and from 11.2% (2006–2007) to 6.6% (2014–2015) following surgical procedures. The risk of death after both types of revascularization also decreased. These trends were observed for all indication categories, with the largest reductions found in patients with severe limb ischemia with ulceration or gangrene. Overall, morbidity increased over the study period, and a larger proportion of patients was treated for the severe end of the peripheral artery disease spectrum using less invasive procedures. Conclusions: Our findings show that from 2006 to 2015, the overall survival increased and the risk of major lower limb amputation decreased following revascularization. These observations suggest that patient outcomes after lower limb revascularization have improved during a period of centralization and specialization of vascular services in the United Kingdom.
Hsp72 protects against liver injury via attenuation of hepatocellular death, oxidative stress, and JNK signaling
Authors: Kateryna Levada, Nurdan Guldiken, Xiaoji Zhang, Giovanna Vella, Fa-Rong Mo, Laura P. James, Johannes Haybaeck, Sonja M. Kessler, Alexandra K. Kiemer, Thomas Ott, Daniel Hartmann, Norbert Hüser, Marianne Ziol, Christian Trautwein, Pavel Strnad
Journal: Journal of Hepatology (2018)
Antitumor Effects of Blocking Protein Neddylation in T315I-BCR-ABL Leukemia Cells and Leukemia Stem Cells
Authors: Chang Liu, Danian Nie, Juan Li, Xin Du, Yuhong Lu, Yangqiu Li, Jingfeng Zhou, Yanli Jin, Jingxuan Pan
Journal: Cancer Research (2018)

Imatinib revolutionized the treatment of chronic myeloid leukemia (CML), but drug resistance and disease recurrence remain a challenge. In this study, we suggest a novel strategy based on blocking protein neddylation to address BCR-ABL point mutations and leukemia stem cells (LSC) that lie at the root of imatinib-resistant recurrences. On the basis of the finding that the NEDD8-activating enzyme subunit NAE1 is overexpressed in CML cells, we hypothesized that the function of certain neddylation-dependent protein substrates might be targeted to therapeutic ends in imatinib-resistant CML cells and LSCs. In support of this hypothesis, we demonstrated that the NAE1 inhibitor MLN4924 induced G2-M-phase arrest and apoptosis in bulk CML cells with wild-type p53, regardless of their T315I mutation status in BCR-ABL. Moreover, MLN4924 inhibited the survival and self-renewal of primary human CML CD34+ cells and LSCs in CML-bearing mice via accumulation of p27kip1 in the nucleus. Notably, p27kip1 silencing attenuated the suppressive effect of MLN4924 on the maintenance of LSCs in CML-bearing mice. Taken together, our findings offer a preclinical proof of concept for targeting protein neddylation as a novel therapeutic strategy to override mutational and LSC-derived imatinib resistance in CML.Significance: These findings highlight a mediator of protein neddylation, a type of protein turnover mechanism, as a viable therapeutic target against imatinib-resistant forms of chronic myelogenous leukemia. Cancer Res; 78(6); 1522-36. ©2018 AACR.
The Multicentre, Double-Blinded, Placebo-Controlled Clinical-Trial (Pre-GvHD) for Prediction and Pre-Emptive Treatment of Acute GvHD
Authors: Eva M Weissinger, Metzger Jochen, Michael Schleuning, Christoph Schmid, Diethelm Messinger, Gernot Beutel, Eva-Maria Wagner, Johannes Schetelig, Herrad Baurmann, Andreas Rank, Friedrich Stolzl, Kerstin Schäfer-Eckhard, Karin Westphal, Wolfgang Bethge, Donald w. Bunjes, Daniela Heidenreich, Stefan Klein, Daniel Wolff, Ernst Holler, Hans H Kreipe, Danny Jonigk, Irina Türüchanow, Clara Rothmann, Julia Raad, Annika Durban, Iyas Hamwi, Steve Ehrlich, Patrick Schweier, Jurgen Krauter, Michael Stadler, Arnold Ganser
Journal: Blood (2017)
<i>Lolium perenne</i> peptide immunotherapy is well tolerated and elicits a protective B‐cell response in seasonal allergic rhinitis patients
Authors: R. Mösges, A. F. Koch, E. Raskopf, J. Singh, K. Shah‐Hosseini, A. Astvatsatourov, B. Hauswald, Y. Yarin, F. Corazza, L. Haazen, S. Pirotton, S. Allekotte, G. Zadoyan, T. Legon, S. R. Durham, M. H. Shamji
Journal: Allergy (2018)

Systemic allergic reactions are a risk for allergen immunotherapy that utilizes intact allergen preparations. We evaluated the safety, efficacy and immune mechanisms of short-course treatment with adjuvant-free Lolium perenne peptides (LPP) following a 6-week dose-escalation protocol.In a prospective, dose-escalation study, 61 grass pollen-allergic patients received 2 subcutaneous injections of LPP once weekly for 6 weeks. Safety was assessed evaluating local reactions, systemic reactions and adverse events. The clinical effect of LPP was determined by reactivity to the conjunctival provocation test (CPT). Specific IgE, IgG4 and blocking antibodies were measured at baseline (V1), during (V6) and after treatment (V8).No fatality, serious adverse event or epinephrine use was reported. Mean wheal diameters after injections were <0.6 cm and mean redness diameters <2.5 cm, independent of dose. Transient and mostly mild adverse events were reported in 33 patients. Two patients experienced a grade I and 4 patients a grade II reaction (AWMF classification). At V8, 69.8% of patients became nonreactive to CPT. sIgG4 levels were higher at V6 (8.1-fold, P < .001) and V8 (12.2-fold, P < .001) than at V1. The sIgE:sIgG4 ratio decreased at V6 (-54.6%, P < .001) and V8 (-71.6%, P < .001) compared to V1. The absolute decrease in IgE-facilitated allergen binding was 18% (P < .001) at V6 and 25% (P < .001) at V8.Increasing doses of subcutaneous LPP appeared safe, substantially diminished reactivity to CPT and induced blocking antibodies as early as 4 weeks after treatment initiation. The benefit/risk balance of LPP immunotherapy remains to be further evaluated in large studies.
Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study
Authors: Hagop Kantarjian, Farhad Ravandi, Nicholas J Short, Xuelin Huang, Nitin Jain, Koji Sasaki, Naval Daver, Naveen Pemmaraju, Joseph D Khoury, Jeffrey Jorgensen, Yesid Alvarado, Marina Konopleva, Guillermo Garcia-Manero, Tapan Kadia, Musa Yilmaz, Gautam Bortakhur, Jan Burger, Steven Kornblau, William Wierda, Courtney DiNardo, Alessandra Ferrajoli, Jovitta Jacob, Rebecca Garris, Susan O'Brien, Elias Jabbour
Journal: The Lancet Oncology (2018)
CQC suspends inspections in response to winter pressures
Authors: Gareth Iacobucci
Journal: BMJ (2018)

The Care Quality Commission (CQC) has announced that it will suspend inspections for nearly all general practices and other parts of the NHS that have a “good” or “outstanding” rating, to help services manage intense pressures this winter.

The regulator said that it had made the decision in response to increased pressure on the NHS and social care, as services try to manage increased demand partly due to a rise in respiratory illness and flu. …
Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a critical appraisal
Authors: J. Thomson, A.G.H. Wernham, H.C. Williams
Journal: British Journal of Dermatology (2018)

Blauvelt et al. aimed to compare the long-term efficacy and safety of dupilumab with medium-potency topical corticosteroids (TCS) vs. placebo with TCS in adults with moderate-to-severe atopic dermatitis (AD).This multicentre randomized, double-blinded, placebo-controlled trial was conducted in hospitals, clinics and academic institutions across 161 sites in 14 countries.Adults with moderate-to-severe AD were randomly assigned (3: 1: 3) to receive subcutaneous dupilumab 300 mg once weekly plus TCS, dupilumab 300 mg every 2 weeks plus TCS or placebo plus TCS until week 52.Co-primary efficacy end points were percentage of patients achieving Investigator's Global Assessment (IGA) 0/1 and 2 points or higher improvement from baseline, and Eczema Area and Severity Index 75% improvement from baseline (EASI-75) at week 16.In total, 740 patients were included in the trial: 319 were randomly assigned to dupilumab once weekly, 106 to dupilumab every 2 weeks and 315 to the placebo arm. At week 16, more patients in the dupilumab groups achieved the co-primary end points: IGA 0/1 [39% (n = 125) once-weekly dosing, 39% (n = 41) every 2 weeks dosing vs. 12% (n = 39) receiving placebo; P < 0·0001] and EASI-75 [64% (n = 204) and 69% (n = 73) vs. 23% (n = 73); P < 0·0001]. While no new safety signals were identified, adverse effects were noted in 261 (83%) of those receiving dupilumab once weekly plus TCS, 97 (88%) receiving dupilumab every 2 weeks plus TCS and 266 (84%) for those receiving placebo plus TCS. Rates of conjunctivitis, injection site reactions and local herpes simplex infections were higher in the dupilumab groups than in the placebo group.Blauvelt et al. concluded that dupilumab treatment added to TCS improved AD up to week 52 vs. TCS alone, and also demonstrated acceptable safety.
Are smoker asthmatics different than non-smokers in terms of symptoms, risk factors and comorbidities?
Authors: Bilun Gemicioglu, Benan Musellim, Berk Degirmenci, Esra Sari, Ipek Calik, Firuze Ozgokce, Onur Merzifonlu
Journal: Journal of Allergy and Clinical Immunology (2018)
Complement Receptor C5aR1 Plays an Evolutionarily Conserved Role in Successful Cardiac Regeneration
Authors: Niranjana Natarajan, Yamen Abbas, Donald M. Bryant, Juan Manuel Gonzalez-Rosa, Michka Sharpe, Aysu Uygur, Lucas H. Cocco-Delgado, Nhi Ngoc Ho, Norma P. Gerard, Craig J. Gerard, Calum A. MacRae, Caroline E. Burns, C. Geoffrey Burns, Jessica L. Whited, Richard T. Lee
Journal: Circulation (2018)

Defining conserved molecular pathways in animal models of successful cardiac regeneration could yield insight into why adult mammals have inadequate cardiac regeneration after injury. Insight into the transcriptomic landscape of early cardiac regeneration from model organisms will shed light on evolutionarily conserved pathways in successful cardiac regeneration.Here we describe a cross-species transcriptomic screen in 3 model organisms for cardiac regeneration: axolotl, neonatal mice, and zebrafish. Apical resection to remove ≈10% to 20% of ventricular mass was carried out in these model organisms. RNA-sequencing analysis was performed on the hearts harvested at 3 time points: 12, 24, and 48 hours after resection. Sham surgery was used as internal control.Genes associated with inflammatory processes were found to be upregulated in a conserved manner. Complement receptors (activated by complement components, part of the innate immune system) were found to be highly upregulated in all 3 species. This approach revealed induction of gene expression for complement 5a receptor 1 in the regenerating hearts of zebrafish, axolotls, and mice. Inhibition of complement 5a receptor 1 significantly attenuated the cardiomyocyte proliferative response to heart injury in all 3 species. Furthermore, after left ventricular apical resection, the cardiomyocyte proliferative response was diminished in mice with genetic deletion of complement 5a receptor 1.These data reveal that activation of complement 5a receptor 1 mediates an evolutionarily conserved response that promotes cardiomyocyte proliferation after cardiac injury and identify complement pathway activation as a common pathway of successful heart regeneration.
Collapsing the Tumor Ecosystem: Preventing Adaptive Response to Treatment by Inhibiting Transcription
Authors: Alessandro Carugo, Giulio F. Draetta
Journal: Cancer Discovery (2018)

Abstract Summary: Adaptation and resistance to treatment are the results of a multitude of (epi)genetic events unmasked or directly triggered by therapies targeting the genetic driver(s) of a dominant cell population within a tumor mass. Rusan and colleagues report that drug-tolerant cells are sensitive to THZ1, a dual CDK7/12 inhibitor, which, by impairing the transcriptional machinery, can prevent cellular rewiring to survive therapeutic attack. Cancer Discov; 8(1); 17–9. ©2018 AACR. See related article by Rusan et al., p. 59.
Computerized planimetry to assess clinical responsiveness in a phase II randomized trial of topical R333 for discoid lupus erythematosus
Authors: J.K. Presto, L.G. Okon, R. Feng, D.J. Wallace, R. Furie, D. Fiorentino, V.P. Werth
Journal: British Journal of Dermatology (2018)

R333 is a topical janus kinase and spleen tyrosine kinase inhibitor being evaluated for discoid lupus erythematosus (DLE) treatment. There is no validated measure to assess the area of active DLE lesions. To evaluate R333 efficacy and assess a technique to measure responsiveness. Fifty‐four patients with DLE were randomized in a double‐blind design to R333 or placebo. Primary end point was the proportion of patients achieving ≥ 50% decrease in erythema and scale based on lesional Cutaneous Lupus Erythematosus Disease Area and Severity IndexTM for all treated lesions at week 4. Two‐dimensional (2D) area measurements for each lesion were recorded at baseline and weeks 1–6. Eighty‐eight photographs (44 pre‐ and 44 post‐treatment) were obtained from the trial and change in size of active areas was analysed by computerized planimetry and physician‐assessed area change (PAAC). Thirty‐six patients were randomized to R333 and 18 patients were randomized to placebo. Primary end point was not achieved. There was a strong association between lesion activity and physician global assessment (P < 0·001). Photos of 42 patients assessed by computerized planimetry demonstrated excellent inter‐ and intra‐rater reliability. Area change by computerized planimetry showed a strong correlation with PAAC (Spearman r = 0·72). Area change by 2D measurements showed a weak correlation with PAAC (Spearman r = 0·29). Four weeks of R333 treatment did not result in significant improvement in lesion activity. Lesion activity and area change using computerized planimetry are better determinants of responsiveness than area change using 2D measurements.
Abstract 19955: Rapid Deployment Aortic Valve Shows Satisfactory Immediate Outcomes in High-risk Patients, as a Valid Alternative in the Era of Transcatheter Aortic Valve Implantation
Authors: Vincenzo Caruso, Darren Titmarsh, Kimberly Hassan, Sudhir Bhusari, Inderpaul Birdi
Journal: Circulation (2016)

Introduction:  In the last few years, alongside the development of Transcatheter Aortic Valve Implantation, new surgical aortic valve have entered the clinical arena as alternative treatment in high-risk patient.   Hypothesis:  To assess the immediate outcomes in high-risk patients undergone Rapid Deployment Aortic Valve Replacement (RD-AVR).   Methods:  From April 2014 to June 2016, 83 patients (mean age 79.15 ± 5.99 years, mean logistic Euroscore 10.58 ± 5.62) underwent RD-AVR. Octogenarians constituted 53.01% of the cohort (n=44). Conventional median sternotomy (n=71, 85.54%) or minimally invasive technique (n=12, 14.45%) were choose according the different cases.   Results:  An Intuity Elite Valve System was successfully implanted in all patients, except one (success rate, 96.32%). In-hospital mortality was 1.2%. The mean aortic cross clamping time was 53.36 ± 22.07 minutes, significantly lower for isolated RD-AVR, 38.96 ± 8.63 minutes, than for RD-AVR plus other concomitant procedures, 64.91 ± 11.96 minutes, p vs  11.45 ± 6.45). Freedom from permanent pacemaker implantation and stroke was 96.38%, and 98.79%, respectively. No para-valvular leakage, more than mild, was observed. Mean post-operative effective orifice area index (EOAi) was 0.77 cm 2 /m 2 ; a severe patient-prosthesis mismatch was observed in 1 patient (1.2%), who was asymptomatic.   Conclusions:  Aortic valve replacement with Intuity Elite Valve System appears to be an easily reproducible technique with satisfactory immediate outcomes in high-risk patients. Minimally invasive approach provides a faster recovery. More investigations are needed to assess the long-term outcomes of these new aortic valves.
Vitreoretinal Complications and Outcomes in 92 Eyes Undergoing Surgery for Modified Osteo-Odonto-Keratoprosthesis
Authors: Pukhraj Rishi, Ekta Rishi, Vishvesh Agarwal, Sridevi Nair, Geetha Iyer, Bhaskar Srinivasan, Shweta Agarwal
Journal: Ophthalmology (2018)
Perspective: APOBEC mutagenesis in drug resistance and immune escape in HIV and cancer evolution
Authors: S. Venkatesan, R. Rosenthal, N. Kanu, N. McGranahan, J. Bartek, S.A. Quezada, J. Hare, R.S. Harris, C. Swanton
Journal: Annals of Oncology (2018)

The apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) mutational signature has only recently been detected in a multitude of cancers through next-generation sequencing. In contrast, APOBEC has been a focus of virology research for over a decade. Many lessons learnt regarding APOBEC within virology are likely to be applicable to cancer. In this review, we explore the parallels between the role of APOBEC enzymes in HIV and cancer evolution. We discuss data supporting the role of APOBEC mutagenesis in creating HIV genome heterogeneity, drug resistance, and immune escape variants. We hypothesize similar functions of APOBEC will also hold true in cancer.
The Rate of Systemic Reactions In Pediatric Patients Receiving Standardized Allergen Subcutaneous Immunotherapy Is Elevated and Not Affected by Seasonal Dose Adjustment
Authors: Sultan Albuhairi, Tatyana Sare, Paul Lakin, Kristel El Khoury, Elena Crestani, Lynda C. Schneider, Rocco Anzaldi, Al Paterson, Rima A. Rachid
Journal: Journal of Allergy and Clinical Immunology (2018)
Selective EGF-Receptor Inhibition in CD4+ T Cells Induces Anergy and Limits Atherosclerosis
Authors: Lynda Zeboudj, Mikael Maître, Lea Guyonnet, Ludivine Laurans, Jeremie Joffre, Jeremie Lemarie, Simon Bourcier, Wared Nour-Eldine, Coralie Guérin, Jonas Friard, Abdelilah Wakkach, Elizabeth Fabre, Alain Tedgui, Ziad Mallat, Pierre-Louis Tharaux, Hafid Ait-Oufella
Journal: Journal of the American College of Cardiology (2018)
Bile acids in glucose metabolism in health and disease
Authors: Hagit Shapiro, Aleksandra A. Kolodziejczyk, Daniel Halstuch, Eran Elinav
Journal: The Journal of Experimental Medicine (2018)

Bile acids (BAs) are cholesterol-derived metabolites that facilitate the intestinal absorption and transport of dietary lipids. Recently, BAs also emerged as pivotal signaling molecules controlling glucose, lipid, and energy metabolism by binding to the nuclear hormone farnesoid X receptor (FXR) and Takeda G protein receptor 5 (TGR5) in multiple organs, leading to regulation of intestinal incretin secretion, hepatic gluconeogenesis, glycogen synthesis, energy expenditure, inflammation, and gut microbiome configuration. Alterations in BA metabolism and signaling are associated with obesity and type 2 diabetes mellitus (T2DM), whereas treatment of T2DM patients with BA sequestrants, or bariatric surgery in morbidly obese patients, results in a significant improvement in glycemic response that is associated with changes in the BA profile and signaling. Herein, we review the roles of BAs in glucose metabolism in health and disease; highlight the limitations, unknowns, and challenges in understanding the impact of BAs on the glycemic response; and discuss how this knowledge may be harnessed to develop innovative therapeutic approaches for the treatment of hyperglycemia and diabetes.
microRNA-219 Reduces Viral Load and Pathologic Changes in Theiler's Virus-Induced Demyelinating Disease
Authors: Ana Lis Moyano, Jeffrey Steplowski, Haibo Wang, Kyung-No Son, Diana I. Rapolti, Jeffrey Marshall, Vince Elackattu, Michael S. Marshall, Amy K. Hebert, Cory R. Reiter, Viviana Ulloa, Katarzyna C. Pituch, Maria I. Givogri, Q. Richard Lu, Howard L. Lipton, Ernesto R. Bongarzone
Journal: Molecular Therapy (2018)

Analysis of microRNA (miR) expression in the central nervous system white matter of SJL mice infected with the BeAn strain of Theiler's murine encephalomyelitis virus (TMEV) revealed a significant reduction of miR-219, a critical regulator of myelin assembly and repair. Restoration of miR-219 expression by intranasal administration of a synthetic miR-219 mimic before disease onset ameliorates clinical disease, reduces neurogliosis, and partially recovers motor and sensorimotor function by negatively regulating proinflammatory cytokines and virus RNA replication. Moreover, RNA sequencing of host lesions showed that miR-219 significantly downregulated two genes essential for the biosynthetic cholesterol pathway, Cyp51 (lanosterol 14-α-demethylase) and Srebf1 (sterol regulatory element-binding protein-1), and reduced cholesterol biosynthesis in infected mice and rat CG-4 glial precursor cells in culture. The change in cholesterol biosynthesis had both anti-inflammatory and anti-viral effects. Because RNA viruses hijack endoplasmic reticulum double-layered membranes to provide a platform for RNA virus replication and are dependent on endogenous pools of cholesterol, miR-219 interference with cholesterol biosynthesis interfered virus RNA replication. These findings demonstrate that miR-219 inhibits TMEV-induced demyelinating disease through its anti-inflammatory and anti-viral properties.
Early‐life gut microbiome and egg allergy
Authors: M. Fazlollahi, Y. Chun, A. Grishin, R. A. Wood, A. W. Burks, P. Dawson, S. M. Jones, D. Y. M. Leung, H. A. Sampson, S. H. Sicherer, S. Bunyavanich
Journal: Allergy (2018)

Gut microbiota may play a role in egg allergy. We sought to examine the association between early-life gut microbiota and egg allergy.