bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exogenous Activation of Invariant Natural Killer T Cells by α-Galactosylceramide Reduces Pneumococcal Outgrowth and Dissemination Postinfluenza
Authors: Barthelemy Adeline , Ivanov Stoyan , Hassane Maya , Fontaine Josette , Heurtault Béatrice , Frisch Benoit , Faveeuw Christelle , Paget Christophe , Trottein François 
Published: November 2016

ABSTRACT

Influenza A virus infection can predispose to potentially devastating secondary bacterial infections. Invariant natural killer T (iNKT) cells are unconventional, lipid-reactive T lymphocytes that exert potent immunostimulatory functions. Using a mouse model of postinfluenza invasive secondary pneumococcal infection, we sought to establish whether α-galactosylceramide (α-GalCer [a potent iNKT cell agonist that is currently in clinical development]) could limit bacterial superinfection. Our results highlighted the presence of a critical time window during which α-GalCer treatment can trigger iNKT cell activation and influence resistance to postinfluenza secondary pneumococcal infection. Intranasal treatment with α-GalCer during the acute phase (on day 7) of influenza virus H3N2 and H1N1 infection failed to activate (gamma interferon [IFN-γ] and interleukin-17A [IL-17A]) iNKT cells; this effect was associated with a strongly reduced number of conventional CD103
+
dendritic cells in the respiratory tract. In contrast, α-GalCer treatment during the early phase (on day 4) or during the resolution phase (day 14) of influenza was associated with lower pneumococcal outgrowth and dissemination. Less intense viral-bacterial pneumonia and a lower morbidity rate were observed in superinfected mice treated with both α-GalCer (day 14) and the corticosteroid dexamethasone. Our results open the way to alternative (nonantiviral/nonantibiotic) iNKT-cell-based approaches for limiting postinfluenza secondary bacterial infections.

IMPORTANCE
Despite the application of vaccination programs and antiviral drugs, influenza A virus (IAV) infection is responsible for widespread morbidity and mortality (500,000 deaths/year). Influenza infections can also result in sporadic pandemics that can be devastating: the 1918 pandemic led to the death of 50 million people. Severe bacterial infections are commonly associated with influenza and are significant contributors to the excess morbidity and mortality of influenza. Today’s treatments of secondary bacterial (pneumococcal) infections are still not effective enough, and antibiotic resistance is a major issue. Hence, there is an urgent need for novel therapies. In the present study, we set out to evaluate the efficacy of α-galactosylceramide (α-GalCer)—a potent agonist of invariant NKT cells that is currently in clinical development—in a mouse model of postinfluenza, highly invasive pneumococcal pneumonia. Our data indicate that treatment with α-GalCer reduces susceptibility to superinfections and, when combined with the corticosteroid dexamethasone, reduces viral-bacterial pneumonia.
Oral Administration of Astrovirus Capsid Protein Is Sufficient To Induce Acute Diarrhea
In Vivo
Authors: Meliopoulos Victoria A. , Marvin Shauna A. , Freiden Pamela , Moser Lindsey A. , Nighot Prashant , Ali Rizwana , Blikslager Anthony , Reddivari Muralidhar , Heath Richard J. , Koci Matthew D. , Schultz-Cherry Stacey 
Published: November 2016

ABSTRACT

The disease mechanisms associated with the onset of astrovirus diarrhea are unknown. Unlike other enteric virus infections, astrovirus infection is not associated with an inflammatory response or cellular damage.
In vitro
studies in differentiated Caco-2 cells demonstrated that human astrovirus serotype 1 (HAstV-1) capsid protein alone disrupts the actin cytoskeleton and tight junction complex, leading to increased epithelial barrier permeability. In this study, we show that oral administration of purified recombinant turkey astrovirus 2 (TAstV-2) capsid protein results in acute diarrhea in a dose- and time-dependent manner in turkey poults. Similarly to that induced by infectious virus, TAstV-2 capsid-induced diarrhea was independent of inflammation or histological changes but was associated with increased intestinal barrier permeability, as well as redistribution of sodium hydrogen exchanger 3 (NHE3) from the membrane to the cytoplasm of the intestinal epithelium. Unlike other viral enterotoxins that have been identified, astrovirus capsid induces diarrhea after oral administration, reproducing the natural route of infection and demonstrating that ingestion of intact noninfectious capsid protein may be sufficient to provoke acute diarrhea. Based on these data, we hypothesize that the astrovirus capsid acts like an enterotoxin and induces intestinal epithelial barrier dysfunction.

IMPORTANCE
Acute gastroenteritis, with its sequela diarrhea, is one of the most important causes of childhood morbidity and mortality worldwide. A variety of infectious agents cause gastroenteritis, and in many cases, an enterotoxin produced by the agent is involved in disease manifestations. Although we commonly think of bacteria as a source of toxins, at least one enteric virus, rotavirus, produces a protein with enterotoxigenic activity during viral replication. In these studies, we demonstrate that oral administration of the turkey astrovirus 2 (TAstV-2) structural (capsid) protein induces acute diarrhea, increases barrier permeability, and causes relocalization of NHE3 in the small intestine, suggesting that rotavirus may not be alone in possessing enterotoxigenic activity.
Evaluation of clinicians' knowledge and practices regarding medical radiological exposure: findings from a mixed-methods investigation (survey and qualitative study)
Authors: Lumbreras B , Vilar J , González-Álvarez I , Guilabert M , Parker L A , Pastor-Valero M , Domingo M L , Fernández-Lorente M F , Hernández-Aguado I 
Published: November 2016

ObjectivesTo assess the impact of initiatives aiming to increase clinician awareness of radiation exposure; to explore the challenges they face when communicating with patients; to study what they think is the most appropriate way of communicating the long-term potential risks of medical radiological exposure to patients.DesignA quantitative and qualitative evaluation through a survey and focal groups.SettingSan Juan Hospital and Dr Peset Hospital (Southeast Spain) and clinicians from Spanish scientific societies.ParticipantsThe surveys were answered (a) in person (216: all the radiologists (30), urologists (14) and surgeons (44) working at both participant hospitals; a sample of general practitioners from the catchment area of one hospital (45), and a consecutive sample of radiologists attending a scientific meeting (60)) or (b) electronically through Spanish scientific societies (299: radiologists (45), pneumologists (123), haematologists (75) and surgeons (40)). Clinicians were not randomly selected and thus the results are limited by the diligence of the individuals filling out the survey.Primary and secondary outcome measuresClinicians' knowledge and practices regarding medical radiological exposure, and what they considered most appropriate for communicating information to patients.ResultsNearly 80% of the clinicians surveyed had never heard of the European recommendations. Fewer than 20% of the clinicians surveyed identified correctly the radiation equivalence dose of intravenous urography or barium enema. It was reported by 31.7% that they inform patients about the long-term potential risks of ionising radiation. All participants agreed that the most appropriate way to present information is a table with a list of imaging tests and their corresponding radiation equivalence dose in terms of chest X-rays and background radiation exposure.ConclusionsMedical radiological exposure is frequently underestimated and rarely explained to patients. With a clear understanding of medical radiological exposure and proper communication tools, clinicians will be able to accurately inform patients.
Prospective Register Of patients undergoing repeated OFfice and Ambulatory Blood Pressure Monitoring (PROOF-ABPM): protocol for an observational cohort study
Authors: Sheppard James P , Martin Una , Gill Paramjit , Stevens Richard , McManus Richard J 
Published: November 2016

IntroductionThe diagnosis and management of hypertension depends on accurate measurement of blood pressure (BP) in order to target antihypertensive treatment appropriately. Most BP measurements take place in a clinic setting, but it has long been recognised that readings taken out-of-office (via home or ambulatory monitoring) estimate true underlying BP more accurately. Recent studies have shown that the change in clinic BP over multiple readings is a significant predictor of the difference between clinic and out-of-office BP. Used in combination with patient characteristics, this change has been shown to accurately predict a patient's out-of-office BP level. The present study proposes to collect real-life BP data to prospectively validate this new prediction tool in routine clinical practice.Methods and analysisA prospective, multicentre observational cohort design will be used, recruiting patients from primary and secondary care. All patients attending participating centres for ambulatory BP monitoring will be eligible to participate. Anonymised clinical data will be collected from all eligible patients, who will be invited to give informed consent to permit identifiable data to be collected for data linkage to external outcome registries. Descriptive statistics will be used to calculate the sensitivity, specificity, positive and negative predictive values of the out-of-office BP prediction tool. Area under the receiver operator characteristic curve statistics will be used to examine model performance.Ethics and disseminationEthical approval for this study has been obtained from the National Research. Ethics Service Committee South Central—Oxford A (reference; 15/SC/0184), and site-specific R&D approval has been acquired from the relevant NHS trusts. All findings will be presented at relevant conferences and published in peer-reviewed journals, on the study website and disseminated in lay and social media where appropriate.
Do acute myocardial infarction and stroke mortality vary by distance to hospitals in Switzerland? Results from the Swiss National Cohort Study
Authors: Berlin Claudia , Panczak Radoslaw , Hasler Rebecca , Zwahlen Marcel 
Published: November 2016

ObjectiveSwitzerland has mountains and valleys complicating the access to a hospital and critical care in case of emergencies. Treatment success for acute myocardial infarction (AMI) or stroke depends on timely treatment. We examined the relationship between distance to different hospital types and mortality from AMI or stroke in the Swiss National Cohort (SNC) Study.Design and settingThe SNC is a longitudinal mortality study of the census 2000 population of Switzerland. For 4.5 million Swiss residents not living in a nursing home and older than 30 years in the year 2000, we calculated driving time and straight-line distance from their home to the nearest acute, acute with emergency room, central and university hospital (in total 173 hospitals). On the basis of quintiles, we used multivariable Cox proportional hazard models to estimate HRs of AMI and stroke mortality for driving time distance groups compared to the closest distance group.ResultsOver 8 years, 19 301 AMI and 21 931 stroke deaths occurred. Mean driving time to the nearest acute hospital was 6.5 min (29.7 min to a university hospital). For AMI mortality, driving time to a university hospital showed the strongest association among the four types of hospitals with a hazard ratio (HR) of 1.19 (95% CI 1.10 to 1.30) and 1.10 (95% CI 1.01 to 1.20) for men and women aged 65+ years when comparing the highest quintile with the lowest quintile of driving time. For stroke mortality, the association with university hospital driving time was less pronounced than for AMI mortality and did not show a clear incremental pattern with increasing driving time. There was no association with driving time to the nearest hospital.ConclusionsThe increasing AMI mortality with increasing driving time to the nearest university hospital but not to any nearest hospital reflects a complex interplay of many factors along the care pathway.
Disease activity indices in coeliac disease: systematic review and recommendations for clinical trials
Authors: Hindryckx Pieter , Levesque Barrett G , Holvoet Tom , Durand Serina , Tang Ceen-Ming , Parker Claire , Khanna Reena , Shackelton Lisa M , D'Haens Geert , Sandborn William J , Feagan Brian G , Lebwohl Benjamin , Leffler Daniel A , Jairath Vipul 
Published: November 2016

ObjectiveAlthough several pharmacological agents have emerged as potential adjunctive therapies to a gluten-free diet for coeliac disease, there is currently no widely accepted measure of disease activity used in clinical trials. We conducted a systematic review of coeliac disease activity indices to evaluate their operating properties and potential as outcome measures in registration trials.DesignMEDLINE, EMBASE and the Cochrane central library were searched from 1966 to 2015 for eligible studies in adult and/or paediatric patients with coeliac disease that included coeliac disease activity markers in their outcome measures. The operating characteristics of histological indices, patient-reported outcomes (PROs) and endoscopic indices were evaluated for content and construct validity, reliability, responsiveness and feasibility using guidelines proposed by the US Food and Drug Administration (FDA).ResultsOf 19 123 citations, 286 studies were eligible, including 24 randomised-controlled trials. Three of five PROs identified met most key evaluative criteria but only the Celiac Disease Symptom Diary (CDSD) and the Celiac Disease Patient-Reported Outcome (CeD PRO) have been approved by the FDA. All histological and endoscopic scores identified lacked content validity. Quantitative morphometric histological analysis had better reliability and responsiveness compared with qualitative scales. Endoscopic indices were infrequently used, and only one index demonstrated responsiveness to effective therapy.ConclusionsCurrent best evidence suggests that the CDSD and the CeD PRO are appropriate for use in the definition of primary end points in coeliac disease registration trials. Morphometric histology should be included as a key secondary or co-primary end point. Further work is needed to optimise end point configuration to inform efficient drug development.
Abstract A013: Favorable changes in tumor microenvironment following intravenous dosing with live attenuated Listeria monocytogenes-based immunotherapy
Authors: Deng Weiwen , Tsujikawa Takahiro , Nair Nitya , Hudson Thomas , Liu Weiqun , Rae Chris S. , Lemmens Edward E. , Desbien Anthony W. , Hanson William , Lauer Peter , Coussens Lisa M. , Brockstedt Dirk G. , Dubensky Thomas W. , Leong Meredith L. 
Published: November 2016

Abstract
Modification of the tumor microenvironment (TME) to promote immune-mediated tumor cell destruction is considered to be an essential step for effective immunotherapy. We are evaluating recombinant live-attenuated, double deleted Listeria monocytogenes (LADD) as an immunotherapy platform for the treatment of cancer in several clinical trials in diverse indications. One LADD strain, known as CRS-207, has been engineered to express the tumor-associated antigen mesothelin and is being tested in pancreatic, ovarian and mesothelioma malignancies. Using multi-dimensional immunohistochemistry of paired biopsies from three patients with mesothelioma, we demonstrate the recruitment and expansion of effector tumor-infiltrating lymphocytes, including CD8+ T cells, mature DCs, CD163− macrophages and NK cells, following two prime infusions of CRS-207. In several different syngeneic mouse tumor models, we demonstrate that treatment with LADD engineered to express endogenous tumor antigens also induced significant changes in the TME that were consistent with changes observed in cancer patients, including enhanced CD8+ T cell effector function, recruitment of critical antigen presenting cells and reduction of regulatory T cells, and these changes correlated with significant therapeutic benefit in the mouse. LADD-induced changes to the TME were required for synergistic therapeutic antitumor efficacy combined with immune checkpoint blockade, including targeting MC38 tumor-specific neoantigens. Together, these findings demonstrate that intravenous administration of recombinant LADD therapy induces favorable changes in the tumor microenvironment in mice and humans with promise for effective outcomes in human clinical trials.
Citation Format: Weiwen Deng, Takahiro Tsujikawa, Nitya Nair, Thomas Hudson, Weiqun Liu, Chris S. Rae, Edward E. Lemmens, Anthony W. Desbien, William Hanson, Peter Lauer, Lisa M. Coussens, Dirk G. Brockstedt, Thomas W. Dubensky, Jr., Meredith L. Leong. Favorable changes in tumor microenvironment following intravenous dosing with live attenuated Listeria monocytogenes-based immunotherapy [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A013.
Abstract A025: Association of functionally distinct ERAP1 variants in HPV positive cancer
Authors: Reeves Emma , King Emma , Elliott Tim , Thomas Gareth , James Edward 
Published: November 2016

Abstract
Human papillomavirus (HPV) infection accounts for 5% cancers worldwide, with cervical carcinoma and squamous cell carcinoma of the head and neck (SCCHN) being most common. HPV can enable immune evasion, with 50% of HPV+ SCCHN having reduced pMHC I expression, correlating with fewer tumor infiltrating lymphocytes (TIL) and a worse clinical outcome. Polymorphisms in the endoplasmic reticulum aminopeptidase1 (ERAP1), a key component of antigen processing, trimming N-terminally extended peptides for MHC I, are associated with prognosis and outcome in cervical carcinoma. We have previously demonstrated ERAP1 to be highly polymorphic, forming distinct allotypes with functional differences. Here we investigate the contribution of ERAP1 in the pathogenesis of SCCHN. We identified a number of novel ERAP1 allotype pairs (both chromosomal copies) from an HPV+ SCCHN cohort. Assessment of trimming function revealed a range of abilities to generate the model epitope SIINFEHL from individual amino acid or AIVMK precursors. Furthermore, the ability to generate HPV-16 E6/E7 specific epitopes also demonstrated varying trimming phenotypes. Interestingly, the overall ability to generate the final epitopes (model and HPV) in TILLOW patients was poor, whereas TILHIGH patients were able to generate these epitopes efficiently. This reveals ERAP1 gene sequence and function stratifies with TIL levels and prognosis, suggesting that the successful presentation of HPV-16 E6/E7 epitopes at the cell surface depends on the ERAP1 allotype pairs expressed within an individual. Furthermore, the allotype pairs correlate with levels of tumor infiltrate, suggesting ERAP1 activity as an indicator of prognosis in HPV+ SCCHN patients.
Citation Format: Emma Reeves, Emma King, Tim Elliott, Gareth Thomas, Edward James. Association of functionally distinct ERAP1 variants in HPV positive cancer [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A025.
Abstract A037: The Agenus Immunogenic Mutation platform (AIM™) generates synthesis-ready blueprints for the AutoSynVax™ vaccine patient-specific neo-antigen vaccine
Authors: Uduman Mohamed , Karapetyan Armen , Khattar Mithun , Tanne Antoine , Morin Benjamin , Zelin Justin , Craig Sandra , Shiwen Shiwen , Joshi Bishnu , Findeis Mark A. , Wilson Nicholas , Drouin Elise , Yang Amy , Raizer Jeffrey , Goldberg John , Buell Jennifer , Stein Robert , Castle John , Levey Daniel L. 
Published: November 2016

Abstract
Agenus is clinically testing Prophage™, an individualized tumor vaccine which uses heat-shock proteins endogenously complexed to neo-antigens harvested from the patient's own tumor. Agenus' genomics and bioinformatics unit rapidly identifies potentially immunogenic neo-antigens in the patient's tumor for use in immunomonitoring. However, in cases such as when the tumor mass is insufficient to generate the Prophage vaccine, we plan to treat patients with an individualized synthetic neo-antigen vaccine, AutoSynVax™ vaccine, combined with QS21 Stimulon® adjuvant and optionally immunomodulatory antibodies. In a murine model, we have demonstrated tumor control after treatment with our synthetic vaccine.
The majority of mutations in human tumors are unique to the individual tumor, necessitating the rapid identification of mutations using next generation sequencing and bioinformatics. Further, the number of candidate immunogens presented on a tumor can range from a handful to hundreds. Accurately identifying tumor mutations; determining their impact, expression and translation; and predicting ability to bind patient-specific HLA class I and II molecules and elicit an immune response (immunogenicity) is complex, particularly in the context of clinical trials.
The AutoSynVax™ vaccine platform leverages AIM™, the Agenus Immunogenic Mutation workflow, to generate a synthesis-ready blueprint for optimal immunogenic patient-specific neo-antigen vaccines. AIM™ comprises a robust and efficient approach to computational vaccinology designed to generate an immunogenic candidate blueprint, agnostic to vaccine format, followed by a format-specific blueprint ready for vaccine synthesis and manufacture.
Citation Format: Mohamed Uduman, Armen Karapetyan, Mithun Khattar, Antoine Tanne, Benjamin Morin, Justin Zelin, Sandra Craig, Shiwen Shiwen, Bishnu Joshi, Mark A. Findeis, Nicholas Wilson, Elise Drouin, Amy Yang, Jeffrey Raizer, John Goldberg, Jennifer Buell, Robert Stein, John Castle, Daniel L. Levey. The Agenus Immunogenic Mutation platform (AIM™) generates synthesis-ready blueprints for the AutoSynVax™ vaccine patient-specific neo-antigen vaccine [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A037.