tbuckley/cabot-search huggingface dataset:
Pre-existing antibody profiles related to immune-related adverse events in advanced non-small cell lung cancer patients treated with anti PD-1 antibody
Authors: Y. Toi, S. Sugawara, J. Sugisaka, H. Ono, M. Asou, K. Tsurumi, K. Suzuki, H. Shimizu, Y. Domeki, T. Aiba, S. Kawana, R. Saito, K. Terayama, Y. Kawashima, A. Nakamura, S. Yamanda, Y. Kimura, Y. Honda
Journal: Annals of Oncology (2018)
Genomic-DNA Exposed By Somatic Gene Mutations Engages the cGAS/STING Axis to License the NLRP3 Inflammasome in Myelodysplastic Syndromes
Authors: Amy F McLemore, Kathy L McGraw, Hsin-An Hou, Grace A Ward, Alexis H Onimus, Nicole D. Vincelette, Matthew A. Rodrigues, Neelkamal Chaudhary, Ling Zhang, Benjamin S. Meyer, Erika A Eksioglu, Sheng Wei, Alan F. List
Journal: Blood (2018)
Platelet Protein Disulfide Isomerase Promotes Glycoprotein Ibα–Mediated Platelet-Neutrophil Interactions Under Thromboinflammatory Conditions
Authors: Jing Li, Kyungho Kim, Si-Yeon Jeong, Joyce Chiu, Bei Xiong, Pavel A. Petukhov, Xiangrong Dai, Xiaoyi Li, Robert K. Andrews, Xiaoping Du, Philip J. Hogg, Jaehyung Cho
Journal: Circulation (2019)

Platelet-neutrophil interactions contribute to vascular occlusion and tissue damage in thromboinflammatory disease. Platelet glycoprotein Ibα (GPIbα), a key receptor for the cell-cell interaction, is believed to be constitutively active for ligand binding. Here, we established the role of platelet-derived protein disulfide isomerase (PDI) in reducing the allosteric disulfide bonds in GPIbα and enhancing the ligand-binding activity under thromboinflammatory conditions.Bioinformatic analysis identified 2 potential allosteric disulfide bonds in GPIbα. Agglutination assays, flow cytometry, surface plasmon resonance analysis, a protein-protein docking model, proximity ligation assays, and mass spectrometry were used to demonstrate a direct interaction between PDI and GPIbα and to determine a role for PDI in regulating GPIbα function and platelet-neutrophil interactions. Also, real-time microscopy and animal disease models were used to study the pathophysiological role of PDI-GPIbα signaling under thromboinflammatory conditions.Deletion or inhibition of platelet PDI significantly reduced GPIbα-mediated platelet agglutination. Studies using PDI-null platelets and recombinant PDI or Anfibatide, a clinical-stage GPIbα inhibitor, revealed that the oxidoreductase activity of platelet surface-bound PDI was required for the ligand-binding function of GPIbα. PDI directly bound to the extracellular domain of GPIbα on the platelet surface and reduced the Cys4-Cys17 and Cys209-Cys248 disulfide bonds. Real-time microscopy with platelet-specific PDI conditional knockout and sickle cell disease mice demonstrated that PDI-regulated GPIbα function was essential for platelet-neutrophil interactions and vascular occlusion under thromboinflammatory conditions. Studies using a mouse model of ischemia/reperfusion-induced stroke indicated that PDI-GPIbα signaling played a crucial role in tissue damage.Our results demonstrate that PDI-facilitated cleavage of the allosteric disulfide bonds tightly regulates GPIbα function, promoting platelet-neutrophil interactions, vascular occlusion, and tissue damage under thromboinflammatory conditions.
Excellent Outcome of Young Patients (18-60 years) with Favourable-Prognosis Diffuse Large B-Cell Lymphoma (DLBCL) Treated with 4 Cycles CHOP Plus 6 Applications of Rituximab: Results of the 592 Patients of the Flyer Trial of the Dshnhl/GLA
Authors: Viola Poeschel, Gerhard Held, Marita Ziepert, Bettina Altmann, Mathias Witzens-Harig, Harald Holte, Lorenz Thurner, Andreas Viardot, Peter Borchmann, Lothar Kanz, Ulrich Keller, Christian Schmidt, Rolf Mahlberg, Bernd Metzner, Reinhard Marks, Heinz-Gert Hoeffkes, Konstantinos Christofyllakis, Josif Amam, Christian Berdel, Stephan Stilgenbauer, Norbert Schmitz, Lorenz Truemper, Niels Murawski, Markus Loeffler, Michael Pfreundschuh
Journal: Blood (2018)
Impact of London's low emission zone on air quality and children's respiratory health: a sequential annual cross-sectional study
Authors: Ian S Mudway, Isobel Dundas, Helen E Wood, Nadine Marlin, Jeenath B Jamaludin, Stephen A Bremner, Louise Cross, Andrew Grieve, Alex Nanzer, Ben M Barratt, Sean Beevers, David Dajnak, Gary W Fuller, Anna Font, Grainne Colligan, Aziz Sheikh, Robert Walton, Jonathan Grigg, Frank J Kelly, Tak H Lee, Chris J Griffiths
Journal: The Lancet Public Health (2018)

Low emission zones (LEZ) are an increasingly common, but unevaluated, intervention aimed at improving urban air quality and public health. We investigated the impact of London's LEZ on air quality and children's respiratory health.We did a sequential annual cross-sectional study of 2164 children aged 8-9 years attending primary schools between 2009-10 and 2013-14 in central London, UK, following the introduction of London's LEZ in February, 2008. We examined the association between modelled pollutant exposures of nitrogen oxides (including nitrogen dioxide [NO2]) and particulate matter with a diameter of less than 2·5 μm (PM2·5) and less than 10 μm (PM10) and lung function: postbronchodilator forced expiratory volume in 1 s (FEV1, primary outcome), forced vital capacity (FVC), and respiratory or allergic symptoms. We assigned annual exposures by each child's home and school address, as well as spatially resolved estimates for the 3 h (0600-0900 h), 24 h, and 7 days before each child's assessment, to isolate long-term from short-term effects.The percentage of children living at addresses exceeding the EU limit value for annual NO2 (40 μg/m3) fell from 99% (444/450) in 2009 to 34% (150/441) in 2013. Over this period, we identified a reduction in NO2 at both roadside (median -1·35 μg/m3 per year; 95% CI -2·09 to -0·61; p=0·0004) and background locations (-0·97; -1·56 to -0·38; p=0·0013), but not for PM10. The effect on PM2·5 was equivocal. We found no association between postbronchodilator FEV1 and annual residential pollutant attributions. By contrast, FVC was inversely correlated with annual NO2 (-0·0023 L/μg per m3; -0·0044 to -0·0002; p=0·033) and PM10 (-0·0090 L/μg per m3; -0·0175 to -0·0005; p=0·038).Within London's LEZ, a smaller lung volume in children was associated with higher annual air pollutant exposures. We found no evidence of a reduction in the proportion of children with small lungs over this period, despite small improvements in air quality in highly polluted urban areas during the implementation of London's LEZ. Interventions that deliver larger reductions in emissions might yield improvements in children's health.National Institute for Health Research Biomedical Research Centre at Guy's and St Thomas' National Health Service (NHS) Foundation Trust and King's College London, NHS Hackney, Lee Him donation, and Felicity Wilde Charitable Trust.
Axicabtagene Ciloleucel in the Real World: Outcomes and Predictors of Response, Resistance and Toxicity
Authors: Caron A. Jacobson, Bradley Hunter, Philippe Armand, Yusuke Kamihara, Jerome Ritz, Scott J Rodig, Kyle Wright, Mikel Lipschitz, Robert A. Redd, Marcela V. Maus, Yi-Bin Chen, Jeremy S. Abramson, Justin Kline, Jonathon B. Cohen, Joseph Maakaron, Samantha Jaglowski, Stephen D. Smith, David G. Maloney, Ajay K. Gopal, Matthew J. Frigault, Utkarsh H. Acharya
Journal: Blood (2018)
Peripheral blood neutrophil-to-lymphocyte ratio in NK/T-cell lymphoma - prognostic significance and correlation with tumor transcriptomic profiles
Authors: T. Khee Ming, B. Chia, J.Q. Lim, L.P. Khoo, C.L. Cheng, L. Tan, J.Y. Chan, E.Y.L. Poon, N. Somasundaram, M. Farid, T.P.L. Tang, M. Tao, D.M.Z. Cheah, Y. Laurensia, J.W.L. Pang, S.J. Kim, W.S. Kim, C.K. Ong, S.T. Lim, T. Song
Journal: Annals of Oncology (2018)
WD40 repeat and FYVE domain containing 3 is essential for cardiac development
Authors: Shasha Zhang, Zongpei Song, Lin An, Xiaoyun Liu, Xiao-Wen Hu, Amber Naz, Rujiang Zhou, Xizhi Guo, Lin He, Hongxin Zhu
Journal: Cardiovascular Research (2018)

WD40 repeat and FYVE domain containing 3 (WDFY3) is an adaptor protein involved in selective degradation of protein aggregates by autophagy. Recent studies have revealed that Wdfy3 is critical in the regulation of brain development and osteoclastogenesis in vivo. However, the function of Wdfy3 in cardiac development remains completely unknown. In this study, we explore the role of Wdfy3 in cardiac morphogenesis using Wdfy3-deficient mice. Wdfy3 was expressed in the developing heart in mice and peaked at embryonic day 12.5 (E12.5). Loss of Wdfy3 in mice led to embryonic and neonatal lethality. Wdfy3-deficient mice displayed various congenital heart defects including membranous ventricular septal defect (VSD), aortic overriding (AO), double outlet right ventricle (DORV), thinning of ventricular wall, ventricular dilation, and disorganized ventricular trabeculation at E14.5. Cell proliferation was reduced in the hearts from Wdfy3-deficient mice at E12.5 and E14.5, which was associated with enhanced p21 expression. Cardiomyocyte differentiation was diminished as demonstrated by reduced Myh6 and MLC2v in Wdfy3-deficient mice at E14.5. In addition, Nkx2-5 and Mef2c, two cardiac transcription factors regulating cardiomyocyte differentiation, were decreased in Wdfy3-deficient mice at E14.5. Apoptotic cell death remained unaltered. These data suggest that reduced cell proliferation and cardiomyocyte differentiation contribute to cardiac defects in Wdfy3-deficient mice. Mechanistically, loss of Wdfy3 led to a reduction in protein levels of Notch 1 intracellular domain and its downstream targets Hes1 and Hey1, which was accompanied with enhanced full-length Notch1 protein levels. In vitro luciferase assay showed that Wdfy3 deficiency induced activity of p21 promoter, while diminished activity of Hes1 promoter through modulation of Notch1 signalling. Moreover, Wdfy3 was co-localized with Notch1 in primary embryonic cardiomyocytes. Endogenous Wdfy3 physically interacted with full-length Notch1 in the developing heart. These results suggest that Notch1 signalling is perturbed in the hearts from Wdfy3-deficient mice. No alteration of autophagy was detected in the hearts from Wdfy3-deficient mice. Taken together, our data suggest that Wdfy3 plays an essential role in cardiac development, which may be mediated by modulation of Notch1 signalling.
Development and Validation of a Simple Hip Fracture Risk Prediction Tool for Type 2 Diabetes: The Fremantle Diabetes Study Phase I
Authors: Wendy A. Davis, Emma J. Hamilton, David G. Bruce, Timothy M.E. Davis
Journal: Diabetes Care (2018)

To develop a type 2 diabetes hip fracture risk tool in community-based patients, to validate it in an independent cohort, and to compare its performance against the only published prediction equation to include type 2 diabetes as a risk factor (QFracture).Hip fracture hospitalizations in 1,251 participants with type 2 diabetes aged 40-89 years from the longitudinal Fremantle Diabetes Study Phase I (FDS1) were ascertained between entry (1993-1996) and end-2012. Competing risk regression modeling determined independent predictors of time to first fracture over 10 years and the coefficients incorporated in a risk model. The model was validated in 286 participants with type 2 diabetes from the Busselton Health Study (BHS).Fifty FDS1 participants (4.0%) experienced a first hip fracture during 10,306 person-years of follow-up. Independent predictors of fracture were older age, female sex, lower BMI, peripheral sensory neuropathy, and estimated glomerular filtration rate <45 mL/min/1.73 m2. The model-predicted mean 10-year incident fracture risk was 3.3% with good discrimination, calibration, and accuracy. For a 3% cutoff, sensitivity was 76.0%, specificity 71.9%, positive predictive value (PPV) 10.1%, and negative predictive value (NPV) 98.6%. Model performance in the small BHS sample was also good (sensitivity 66.7%, specificity 79.8%, PPV 6.2%, and NPV 99.2%). QFracture performed well in FDS1 but required availability of 25 variables.The FDS1 hip fracture risk equation is a simple validated adjunct to type 2 diabetes management that uses variables that are readily available in routine care.
Thrombectomy can be considered up to 24 hours after onset of stroke, says NICE
Authors: Susan Mayor
Journal: BMJ (2018)

Patients with acute ischaemic stroke should be considered for thrombectomy up to 24 hours after the onset of symptoms, the National Institute for Health and Care Excellence (NICE) has recommended in a draft guideline update,1 as new evidence shows that extending the eligibility period beyond the current 12 hour limit reduces disability and is cost effective.

The guideline committee recommended that thrombectomy should be offered to patients with acute ischaemic stroke whose symptoms started in the previous 24 hours. Confirmed occlusion of the proximal …
Impact of Cytokine Release Syndrome on Outcomes after T-Cell Replete Peripheral Blood Haploidentical Donor Transplantation
Authors: Caner Saygin, John L Vaughn, Joseph Coleman, Marcin Puto, Julianna Roddy, Sam Penza, Jonathan E. Brammer, Yvonne Efebera, Don M. Benson, Sumithira Vasu, Alison R. Walker, Alice S. Mims, Bhavana Bhatnagar, Bradley Wayne Blaser, Maria Chaudhry, Hannah K. Choe, Karilyn Larkin, Meixiao Long, Ashley E. Rosko, Nicole Grieselhuber, Sarah A Wall, Steven Devine, Samantha Jaglowski, Basem M. William
Journal: Blood (2018)
Impact of Myelofibrosis at Presentation on Outcomes in Chronic Myeloid Leukemia in Chronic Phase
Authors: Ravichandran Ambalathandi, Rajani Priya Yedla, Nageswara Reddy Palukuri, Stalin Chowdary Bala, Meher Lakshmi Konatam, Sadashivudu Gundeti, Venkateswar Rao Pydi
Journal: Blood (2018)
FRI0576 Pulmonary ultrasound in the assessment of interstitial lung disease in rheumatoid arthritis
Authors: M. Moreno, K. Almaguer, J. Gutierrez, A. Bernal-Gonzalez, C. Bertolazzi, E. Cruz-Arenas, C. Pineda, S. Ruta, M. Gutierrez
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Interstitial lung disease (ILD) is an extra-articular complication in rheumatoid arthritis (RA) that may lead to severe impairment of respiratory function. High-resolution computer tomography (HRCT) is the most common imaging technique used in the assessment of ILD. However, the costs and the ionising radiation may limit its use in routine practice. Recently, US is generating interesting data that may support its use and validity in the assessment of ILD in rheumatic diseases<sup>1,2</sup>. <h3>Objectives</h3> To investigate the correlation between lung US and HRCT findings in the assessment of ILD in patients with RA. <h3>Methods</h3> Patients with diagnosis of RA according to <sup>ACR 2010</sup> classification criteria with respiratory symptoms and previous diagnosis of ILD by HRCT were included. Clinical examination, pulmonary function test (PFT) and lung US were performed in all patients. Lung US was performed by a rheumatologist expert in US who was blinded to clinical and HRCT data. Serologic tests (anti-CCP, ESR, RF, ANA) were taken. Lung US was performed in 14 intercostal spaces (IS) and quantified according the following semiquantitative scoring: grade 0=normal (≤5 B-lines); grade 1=mild (≥6 to≤15 B-lines); grade 2=moderate (≥16 to≤30 B-lines); and grade 3=marked (≥30 B-lines). The Warrick score (extension) was used to interpret the HRCT findings. <h3>Results</h3> A total of 32 patients with RA (25 women and 7 men) were included. Mean age was 59.37 (±SD 13.66) years, and the mean disease duration was 58.75 (±SD 52.52) months. Sixteen patients were smokers and 75% were positive to anti-CCP. Moreover, the mean of DAS-28 was 3.71 (±SD 1.01). A total 448 IS were assessed by US. Lung US was positive for ILD in 28 patients (87.5%). From those, 7 patients (21.8%) with severe ILD,12 patients (37.5%) with moderate, 9 patients (28.1%) with mild. Four patients (12.5%) showed normal lung US assessment. A significant linear correlation was found between the US score and the HRCT score (p&lt;0.000; correlation coefficient=0.75). A negative correlation was found between US B-line assessments and DLCO (p≤0.000). No association was founded with DAS28, anti-CCP, PFT. Sensitivity and specificity of ultrasound for ILD was 87.5% and 98% respectively. <h3>Conclusions</h3> Our study demonstrates that lung US may be a potential tool for the assessment of ILD also in patients with RA. It can be adopted in future as a screening tool to use at moment of the first diagnosis of RA. <h3>References</h3> [1] Tardella M. Ultrasound in the Assessment of Pulmonary Fibrosis in Connective Tissue Disorders: Correlation with High-Resolution Computed Tomography. J Rheumatol2012;39:1641–7. [2] Margaritopoulos G. Comorbidities in interstitial lung diseases. Eur Respir Rev2017;26:1–15. <h3>Disclosure of Interest</h3> None declared
Abstract 2949: Human Atrial Natriuretic Peptide Improves Myocardial Efficiency in Patients with Heart Failure Due to Idiopathic Dilated Cardiomyopathy
Authors: Toshiro Shinke, Junya Shite, Yusuke Tanino, Hiromasa Otake, Oscar Luis, Daisuke Ogasawara, Takahiro Sawada, Mitsuhiro Yokoyama
Journal: Circulation (2006)

Background: Human atrial natriuretic peptide (hANP) has a great benefit with its vasodilating and natriuretic capacities for the treatment of heart failure (HF). Previous in-vitro studies have show...
PTU-057 Iron deficiency anaemia referral under the two week rule: is primary care getting it right?
Authors: SM Thackray, MC Hillier, KS Matwala, W Chew, AV Gunasekera
Journal: Gut (2017)

Introduction  One of the criteria under the Two Week Referral (TWR) rule for suspected GI malignancy is iron deficiency anaemia (IDA). It is hypothesised that there is a high degree of imprecision in the sensitivity between IDA and other causes of anaemia in primary care. The aim of the present study is to determine the percentage of patients referred under the TWR that were diagnosed correctly with IDA by primary care.  Method  A retrospective observational study was completed on patients referred to St Peter’s Hospital between April and October 2016 under the TWR for suspected gastrointestinal malignancy. CT, OGD, colonoscopy and haematological results were analysed for each patient, alongside referral documentation from the GP.  Results  641 patients were referred, of which 571 were analysed. Of the 571, 14% (80) had been referred by with reported IDA, of which: 32.5% (26/80) were identified as true IDA on haematological analysis; 35.0% (28/80) were anaemias of another underlying cause, and the remaining 32.5% (26/80) showed no signs of anaemia. Of the 80 referrals for IDA, 67.5% (54) were false positives, and there were a further 2.3% (13/571) patients whose IDA was not picked up in the primary care setting.  Conclusion  The present study highlights that despite clear NICE guidelines, there is significant imprecision in the detection and referral of IDA under the TWR. We have identified that of the 571 patients involved, 14% (80) were referred with IDA of which 67.5% (54) were inaccurate referrals. Enforcing objectives to target these faults could go a long way to meeting the Sustainability and Transformation plans to reduce wasteful activity.  Disclosure of Interest  None Declared
Interim analysis of prospective observational study on the efficacy of nivolumab for Japanese advanced melanoma patients (CREATIVE study)
Authors: Y. Nakamura, A. Takahashi, K. Namikawa, T. Takenouchi, S. Kitano, T. Fujita, K. Kubota, T. Yamanaka, Y. Kawakami, N. Yamazaki
Journal: Annals of Oncology (2018)
Hepatitis C: NHS seeks to identify 55 000 patients for treatment
Authors: Nigel Hawkes
Journal: BMJ (2018)

NHS records will be used to identify 55 000 people who tested positive for hepatitis C from 1996 to 2017 to encourage them to come forward for treatment.

The patients identified by Public Health England (PHE) will be sent letters explaining that the infection is now curable, in the hope that many will respond positively. Their GPs will be told in advance that the letters are about to be sent so that they can raise any concerns they have, such as a patient having a terminal diagnosis or having already been treated and cured.

The proactive policy announced by PHE and NHS England marks a complete change of tack. When the direct acting antivirals for hepatitis C were launched and found to be cost effective NHS England’s first instinct was to control costs by rationing the numbers of people treated.

A junior health minister, Lord O’Shaughnessy, admitted earlier …
Efficacy of individual and group hypnotherapy in irritable bowel syndrome (IMAGINE): a multicentre randomised controlled trial
Authors: Carla E Flik, Wijnand Laan, Nicolaas P A Zuithoff, Yanda R van Rood, André J P M Smout, Bas L A M Weusten, Peter J Whorwell, Niek J de Wit
Journal: The Lancet. Gastroenterology & hepatology (2018)
Predicting Treatment Response Based on RNA Expression in Large Datasets
Authors: Aaron S. Mansfield, Jin Jen
Journal: Clinical Cancer Research (2018)

Abstract PD-L1 expression levels derived from &amp;gt;16,000 samples guided the selection of tumor types likely to benefit from pembrolizuamb monotherapy in clinical trials. Although not fail-proof, FDA approvals for most of the prioritized indications speak to the power of RNA expression profiling and the value of large genomic datasets. See related article by Ayers et al., p. 1564
Concern about NHS is key factor in shift in views on Brexit
Authors: Ingrid Torjesen
Journal: BMJ (2018)

Concern about the NHS is a key factor in driving “leavers” to want to back “remain” in any new referendum on Brexit, results of a YouGov poll indicate.

The YouGov survey of about 8000 UK citizens was carried out on behalf of the People’s Vote Campaign in early September. It found that, although only a small proportion of people had changed their views since the 2016 referendum, views about the NHS were closely linked to views about Brexit and to voting intentions …
The red leg dilemma: a scoping review of the challenges of diagnosing lower‐limb cellulitis
Authors: M. Patel, S.I. Lee, K.S. Thomas, J. Kai
Journal: British Journal of Dermatology (2018)

Background Presentations of suspected lower-limb cellulitis are commonly misdiagnoses, resulting in avoidable antibiotic prescribing or hospital admissions. Understanding the challenges posed in diagnosing cellulitis may help enhance future care. Objectives To examine and map out the challenges and facilitators identified by patients and health professionals in diagnosing lower-limb cellulitis. Methods A scoping systematic review was performed in MEDLINE and Embase in October 2017. Thematic analysis was used to identify key themes. Quantitative data were summarized by narrative synthesis. Results Three themes were explored: (i) clinical case reports of misdiagnosis, (ii) service development and (iii) diagnostic aids. Forty-seven different pathologies were misdiagnosed, including seven malignancies. Two different services have been piloted to reduce the misdiagnosis rates of lower-limb cellulitis and save costs. Four studies have looked at biochemical markers, imaging and a scoring tool to aid diagnosis. Conclusions This review highlights the range of alternative pathologies that can be misdiagnosed as cellulitis, and emerging services and diagnostic aids developed to minimize misdiagnosis. Future work should focus on gaining a greater qualitative understanding of the diagnostic challenges from the perspective of patients and clinicians.