bluuebunny/crossref_metadata_2025_split huggingface dataset:
Critical Role for the Adenosine Pathway in Controlling Simian Immunodeficiency Virus-Related Immune Activation and Inflammation in Gut Mucosal Tissues
Authors: He Tianyu , Brocca-Cofano Egidio , Gillespie Delbert G. , Xu Cuiling , Stock Jennifer L. , Ma Dongzhu , Policicchio Benjamin B. , Raehtz Kevin D. , Rinaldo Charles R. , Apetrei Cristian , Jackson Edwin K. , Macatangay Bernard J. C. , Pandrea Ivona 
Published: July 2015

ABSTRACT

The role of the adenosine (ADO) pathway in human immunodeficiency virus type 1/simian immunodeficiency virus (HIV-1/SIV) infection remains unclear. We compared SIVsab-induced changes of markers related to ADO production (CD39 and CD73) and breakdown (CD26 and adenosine deaminase) on T cells from blood, lymph nodes, and intestine collected from pigtailed macaques (PTMs) and African green monkeys (AGMs) that experience different SIVsab infection outcomes. We also measured ADO and inosine (INO) levels in tissues by mass spectrometry. Finally, we assessed the suppressive effect of ADO on proinflammatory cytokine production after T cell receptor stimulation. The baseline level of both CD39 and CD73 coexpression on regulatory T cells and ADO levels were higher in AGMs than in PTMs. Conversely, high INO levels associated with dramatic increases in CD26 expression and adenosine deaminase activity were observed in PTMs during chronic SIV infection. Immune activation and inflammation markers in the gut and periphery inversely correlated with ADO and directly correlated with INO.
Ex vivo
administration of ADO significantly suppressed proinflammatory cytokine production by T cells in both species. In conclusion, the opposite dynamics of ADO pathway-related markers and contrasting ADO/INO levels in species with divergent proinflammatory responses to SIV infection support a key role of ADO in controlling immune activation/inflammation in nonprogressive SIV infections. Changes in ADO levels predominately occurred in the gut, suggesting that the ADO pathway may be involved in sparing natural hosts of SIVs from developing SIV-related gut dysfunction. Focusing studies of the ADO pathway on mucosal sites of viral replication is warranted.

IMPORTANCE
The mechanisms responsible for the severe gut dysfunction characteristic of progressive HIV and SIV infection in humans and macaques are not completely elucidated. We report that ADO may play a key role in controlling immune activation/inflammation in nonprogressive SIV infections by limiting SIV-related gut inflammation. Conversely, in progressive SIV infection, significant degradation of ADO occurs, possibly due to an early increase of ADO deaminase complexing protein 2 (CD26) and adenosine deaminase. Our study supports therapeutic interventions to offset alterations of this pathway during progressive HIV/SIV infections. These potential approaches to control chronic immune activation and inflammation during pathogenic SIV infection may prevent HIV disease progression.
Fungal Biofilms:
In Vivo
Models for Discovery of Anti-Biofilm Drugs
Authors: Nett Jeniel E. , R. Andes David 
Published: July 2015

ABSTRACT

During infection, fungi frequently transition to a biofilm lifestyle, proliferating as communities of surface-adherent aggregates of cells. Phenotypically, cells in a biofilm are distinct from free-floating cells. Their high tolerance of antifungals and ability to withstand host defenses are two characteristics that foster resilience. Biofilm infections are particularly difficult to eradicate, and most available antifungals have minimal activity. Therefore, the discovery of novel compounds and innovative strategies to treat fungal biofilms is of great interest. Although many fungi have been observed to form biofilms, the most well-studied is
Candida albicans
. Animal models have been developed to simulate common
Candida
device-associated infections, including those involving vascular catheters, dentures, urinary catheters, and subcutaneous implants. Models have also reproduced the most common mucosal biofilm infections: oropharyngeal and vaginal candidiasis. These models incorporate the anatomical site, immune components, and fluid dynamics of clinical niches and have been instrumental in the study of drug resistance and investigation of novel therapies. This chapter describes the significance of fungal biofilm infections, the animal models developed for biofilm study, and how these models have contributed to the development of new strategies for the eradication of fungal biofilm infections.
Long-term pulmonary function in children with recessive polycystic kidney disease
Authors: Jahnukainen Timo , Kirjavainen Turkka , Luoto Topi , Ylinen Elisa , Linkosalo Laura , Arikoski Pekka , Pakarinen Mikko , Jalanko Hannu 
Published: July 2015

BackgroundNeonatal autosomal-recessive polycystic kidney disease (ARPKD) is associated with pulmonary hypoplasia and severe respiratory distress. There is no published information on long-term lung function in ARPKD survivors.MethodsPulmonary function tests, including spirometry and diffusion capacity, were performed in a nationwide cohort of Finnish paediatric patients with ARPKD. The annual incidence of respiratory infections and the need for permanent asthma medication were also evaluated in this population.ResultsPulmonary function in 11 children surviving the neonatal period was good when measured after a median follow-up time of 10.4 years (range 5.4–16.1 years). None of the patients required oxygen supplementation, and only one patient had asthma. Patients who had received ventilator therapy during infancy had significantly lower maximal instantaneous forced expiratory flow (MEF%) (66%; 43–93% vs 105%; 63–110%; p=0.048) and forced expiratory volume/forced vital capacity (0.76; 0.7–0.81 vs 0.89; 0.77–0.91; p=0.03) than patients without a history of mechanical ventilation, suggesting tendency for airway obstruction in the former group of patients. The frequency of respiratory infections did not differ from Finnish paediatric population in general.ConclusionsThe results of pulmonary function tests were within reference values for most patients with ARPKD, which suggested good long-term lung prognosis. Lung function tests should be considered for patients with ARPKD with a history of mechanical ventilation during infancy.
Emergency supply of prescription-only medicines to patients by community pharmacists: a mixed methods evaluation incorporating patient, pharmacist and GP perspectives
Authors: Morecroft Charles W , Mackridge Adam J , Stokes Elizabeth C , Gray Nicola J , Wilson Sarah E , Ashcroft Darren M , Mensah Noah , Pickup Graham B 
Published: July 2015

ObjectiveTo evaluate and inform emergency supply of prescription-only medicines by community pharmacists (CPs), including how the service could form an integral component of established healthcare provision to maximise adherence.DesignMixed methods. 4 phases: prospective audit of emergency supply requests for prescribed medicines (October–November 2012 and April 2013); interviews with CPs (February–April 2013); follow-up interviews with patients (April–May 2013); interactive feedback sessions with general practice teams (October–November 2013).Setting22 community pharmacies and 6 general practices in Northwest England.Participants27 CPs with experience of dealing with requests for emergency supplies; 25 patients who received an emergency supply of a prescribed medicine; 58 staff at 6 general practices.ResultsClinical audit in 22 pharmacies over two 4-week periods reported that 526 medicines were requested by 450 patients. Requests peaked over a bank holiday and around weekends. A significant number of supplies were made during practice opening hours. Most requests were for older patients and for medicines used in long-term conditions. Difficulty in renewing repeat medication (forgetting to order, or prescription delays) was the major reason for requests. The majority of medicines were ‘loaned’ in advance of a National Health Service (NHS) prescription. Interviews with CPs and patients indicated that continuous supply had a positive impact on medicines adherence, removing the need to access urgent care. General practice staff were surprised and concerned by the extent of emergency supply episodes.ConclusionsCPs regularly provide emergency supplies to patients who run out of their repeat medication, including during practice opening hours. This may aid adherence. There is currently no feedback loop, however, to general practice. Patient care and interprofessional communication may be better served by the introduction of a formally structured and funded NHS emergency supply service from community pharmacies, with ongoing optimisation of repeat prescribing.
Split-mouth and parallel-arm trials to compare pain with intraosseous anaesthesia delivered by the computerised Quicksleeper system and conventional infiltration anaesthesia in paediatric oral healthcare: protocol for a randomised controlled trial
Authors: Smaïl-Faugeron Violaine , Muller-Bolla Michèle , Sixou Jean-Louis , Courson Frédéric 
Published: July 2015

IntroductionLocal anaesthesia is commonly used in paediatric oral healthcare. Infiltration anaesthesia is the most frequently used, but recent developments in anaesthesia techniques have introduced an alternative: intraosseous anaesthesia. We propose to perform a split-mouth and parallel-arm multicentre randomised controlled trial (RCT) comparing the pain caused by the insertion of the needle for the injection of conventional infiltration anaesthesia, and intraosseous anaesthesia by the computerised QuickSleeper system, in children and adolescents.Methods and analysisInclusion criteria are patients 7–15 years old with at least 2 first permanent molars belonging to the same dental arch (for the split-mouth RCT) or with a first permanent molar (for the parallel-arm RCT) requiring conservative or endodontic treatment limited to pulpotomy. The setting of this study is the Department of Paediatric Dentistry at 3 University dental hospitals in France. The primary outcome measure will be pain reported by the patient on a visual analogue scale concerning the insertion of the needle and the injection/infiltration. Secondary outcomes are latency, need for additional anaesthesia during the treatment and pain felt during the treatment. We will use a computer-generated permuted-block randomisation sequence for allocation to anaesthesia groups. The random sequences will be stratified by centre (and by dental arch for the parallel-arm RCT). Only participants will be blinded to group assignment. Data will be analysed by the intent-to-treat principle. In all, 160 patients will be included (30 in the split-mouth RCT, 130 in the parallel-arm RCT).Ethics and disseminationThis protocol has been approved by the French ethics committee for the protection of people (Comité de Protection des Personnes, Ile de France I) and will be conducted in full accordance with accepted ethical principles. Findings will be reported in scientific publications and at research conferences, and in project summary papers for participants.Trial registration numberClinicalTrials.govNCT02084433.
Reducing and managing faecal incontinence in people with advanced dementia who are resident in care homes: protocol for a realist synthesis
Authors: Goodman Claire , Rycroft Malone Jo , Norton Christine , Harari Danielle , Harwood Rowan , Roe Brenda , Russell Bridget , Fader Mandy , Buswell Marina , Drennan Vari M , Bunn Frances 
Published: July 2015

IntroductionFaecal incontinence (FI) is the involuntary loss of liquid or solid stool that is a social or hygienic problem. The prevalence of FI in residents of care homes is high, but it is not an inevitable consequence of old age or dementia. There is good evidence on risk factors, but few studies provide evidence about effective interventions. There is a need to understand how, why, and in what circumstances particular programmes to reduce and manage FI are effective (or not) for people with dementia. The purpose of this review is to identify which (elements of the) interventions could potentially be effective, and examine the barriers and facilitators to the acceptability, uptake and implementation of interventions designed to address FI in people with dementia who are resident in care homes.Methods and analysisA realist synthesis approach to review the evidence will be used which will include studies on continence, person-centred care, implementation research in care homes, workforce and research on care home culture. An iterative four-stage approach is planned. Phase 1: development of an initial programme theory or theories that will be ‘tested’ through a first scoping of the literature and consultation with five stakeholder groups (care home providers, user representatives, academics and practice educators, clinicians with a special interest in FI and continence specialists). Phase 2: a systematic search and analysis of published and unpublished evidence to test and develop the programme theories identified in phase 1. Phase 3: validation of programme theory/ies with a purposive sample of participants from phase 1.Ethics and disseminationThe overall protocol does not require ethical review. The University research ethics committee will review interviews conducted as part of phase 1 and 3. The final fourth phase will synthesise and develop recommendations for practice and develop testable hypotheses for further research.
A research protocol for developing a Point-Of-Care Key Evidence Tool ‘POCKET’: a checklist for multidimensional evidence reporting on point-of-care in vitro diagnostics
Authors: Huddy Jeremy R , Ni Melody , Mavroveli Stella , Barlow James , Williams Doris-Ann , Hanna George B 
Published: July 2015

IntroductionPoint-of-care in vitro diagnostics (POC-IVD) are increasingly becoming widespread as an acceptable means of providing rapid diagnostic results to facilitate decision-making in many clinical pathways. Evidence in utility, usability and cost-effectiveness is currently provided in a fragmented and detached manner that is fraught with methodological challenges given the disruptive nature these tests have on the clinical pathway. The Point-of-care Key Evidence Tool (POCKET) checklist aims to provide an integrated evidence-based framework that incorporates all required evidence to guide the evaluation of POC-IVD to meet the needs of policy and decisionmakers in the National Health Service (NHS).Methods and analysisA multimethod approach will be applied in order to develop the POCKET. A thorough literature review has formed the basis of a robust Delphi process and validation study. Semistructured interviews are being undertaken with POC-IVD stakeholders, including industry, regulators, commissioners, clinicians and patients to understand what evidence is required to facilitate decision-making. Emergent themes will be translated into a series of statements to form a survey questionnaire that aims to reach a consensus in each stakeholder group to what needs to be included in the tool. Results will be presented to a workshop to discuss the statements brought forward and the optimal format for the tool. Once assembled, the tool will be field-tested through case studies to ensure validity and usability and inform refinement, if required. The final version will be published online with a call for comments. Limitations include unpredictable sample representation, development of compromise position rather than consensus, and absence of blinding in validation exercise.Ethics and disseminationThe Imperial College Joint Research Compliance Office and the Imperial College Hospitals NHS Trust R&D department have approved the protocol. The checklist tool will be disseminated through a PhD thesis, a website, peer-reviewed publication, academic conferences and formal presentations.
How social inequalities impact the course of treatment and care for patients with type 2 diabetes mellitus: study protocol for a qualitative cross-sectional study from the patient's perspective
Authors: Baumann Amelie , Schröder Sara L , Fink Astrid 
Published: July 2015

IntroductionStudies from various scientific disciplines have demonstrated that socioeconomic inequalities in type 2 diabetes mellitus negatively affect groups with a low socioeconomic status. Furthermore, socioeconomic inequalities also exist in terms of access to, and utilisation and perceived quality of, diabetological care. The aim of this qualitative study, which focuses on the patient's perspective, is to provide insights into the ways socioeconomic inequalities impact the course of treatment and care of patients with type 2 diabetes mellitus. The study aims to develop an understanding of how socioeconomic inequalities in care arise.Methods and analysisA cross-sectional qualitative study will be conducted using a sample of about 20 patients with type 2 diabetes mellitus aged 18 and older. Patients will be recruited successively from the University Hospital in Halle/Saale, Germany, a general practitioner's office, and in a specialised diabetological practice. The patients will be interviewed personally once, using semistructured qualitative interviews. All interviews will be recorded, transcribed, and analysed based on Grounded Theory.Ethics and disseminationAll interviewees will receive comprehensive written information about the study and sign a declaration of consent prior to the interview. The study will comply rigorously with data protection legislation. The research team has obtained the approval of the Ethical Review Committee at the MLU Halle-Wittenberg, Germany. The results of the study will be published in high-quality, peer-reviewed international journals, presented at several congresses and used for developing follow-up research projects.Trial registration numberThis study has been registered with the German Clinical Trials Register and assigned DRKS00007847.
Small Molecule Inhibition of MDM2–p53 Interaction Augments Radiation Response in Human Tumors
Authors: Werner Lauryn R. , Huang Shyhmin , Francis David M. , Armstrong Eric A. , Ma Fang , Li Chunrong , Iyer Gopal , Canon Jude , Harari Paul M. 
Published: July 2015

AbstractMDM2–p53 interaction and downstream signaling affect cellular response to DNA damage. AMG 232 is a potent small molecule inhibitor that blocks the interaction of MDM2 and p53. We examined the capacity of AMG 232 to augment radiation response across a spectrum of human tumor cell lines and xenografts. AMG 232 effectively inhibited proliferation and enhanced radiosensitivity via inhibition of damage repair signaling. Combined AMG 232 and radiation treatment resulted in the accumulation of γH2AX-related DNA damage and induction of senescence with promotion of apoptotic and/or autophagic cell death. Several molecules involved in senescence, autophagy, and apoptosis were specifically modulated following the combined AMG 232/radiation treatment, including FoxM1, ULK-1, DRAM, and BAX. In vivo xenograft studies confirmed more potent antitumor and antiangiogenesis efficacy with combined AMG 232/radiation treatment than treatment with drug or radiation alone. Taken together, these data identify the capacity of AMG 232 to augment radiation response across a variety of tumor types harboring functional p53. Mol Cancer Ther; 14(9); 1994–2003. ©2015 AACR.
Small Molecule Inhibition of MERTK Is Efficacious in Non–Small Cell Lung Cancer Models Independent of Driver Oncogene Status
Authors: Cummings Christopher T. , Zhang Weihe , Davies Kurtis D. , Kirkpatrick Gregory D. , Zhang Dehui , DeRyckere Deborah , Wang Xiaodong , Frye Stephen V. , Earp H. Shelton , Graham Douglas K. 
Published: July 2015

Abstract
Treatment of non–small cell lung cancer (NSCLC) has been transformed by targeted therapies directed against molecular aberrations specifically activated within an individual patient's tumor. However, such therapies are currently only available against a small number of such aberrations, and new targets and therapeutics are needed. Our laboratory has previously identified the MERTK receptor tyrosine kinase (RTK) as a potential drug target in multiple cancer types, including NSCLC. We have recently developed UNC2025—the first-in-class small molecule inhibitor targeting MERTK with pharmacokinetic properties sufficient for clinical translation. Here, we utilize this compound to further validate the important emerging biologic functions of MERTK in lung cancer pathogenesis, to establish that MERTK can be effectively targeted by a clinically translatable agent, and to demonstrate that inhibition of MERTK is a valid treatment strategy in a wide variety of NSCLC lines independent of their driver oncogene status, including in lines with an EGFR mutation, a KRAS/NRAS mutation, an RTK fusion, or another or unknown driver oncogene. Biochemically, we report the selectivity of UNC2025 for MERTK, and its inhibition of oncogenic downstream signaling. Functionally, we demonstrate that UNC2025 induces apoptosis of MERTK-dependent NSCLC cell lines, while decreasing colony formation in vitro and tumor xenograft growth in vivo in murine models. These findings provide further evidence for the importance of MERTK in NSCLC, and demonstrate that MERTK inhibition by UNC2025 is a feasible, clinically relevant treatment strategy in a wide variety of NSCLC subtypes, which warrants further investigation in clinical trials. Mol Cancer Ther; 14(9); 2014–22. ©2015 AACR.
Histone Deacetylase Inhibitors Inhibit Rhabdomyosarcoma by Reactive Oxygen Species–Dependent Targeting of Specificity Protein Transcription Factors
Authors: Hedrick Erik , Crose Lisa , Linardic Corinne M. , Safe Stephen 
Published: July 2015

AbstractThe two major types of rhabdomyosarcoma (RMS) are predominantly diagnosed in children, namely embryonal (ERMS) and alveolar (ARMS) RMS, and patients are treated with cytotoxic drugs, which results in multiple toxic side effects later in life. Therefore, development of innovative chemotherapeutic strategies is imperative, and a recent genomic analysis suggested the potential efficacy of reactive oxygen species (ROS)–inducing agents. Here, we demonstrate the efficacy of the potent histone deacetylase (HDAC) inhibitors, panobinostat and vorinostat, as agents that inhibit RMS tumor growth in vivo, induce apoptosis, and inhibit invasion of RD and Rh30 RMS cell lines. These effects are due to epigenetic repression of cMyc, which leads to decreased expression of cMyc-regulated miRs-17, -20a, and -27a; upregulation of ZBTB4, ZBTB10, and ZBTB34; and subsequent downregulation of Sp transcription factors. We also show that inhibition of RMS cell growth, survival and invasion, and repression of Sp transcription factors by the HDAC inhibitors are independent of histone acetylation but reversible after cotreatment with the antioxidant glutathione. These results show a novel ROS-dependent mechanism of antineoplastic activity for panobinostat and vorinostat that lies outside of their canonical HDAC-inhibitory activity and demonstrates the potential clinical utility for treating RMS patients with ROS-inducing agents. Mol Cancer Ther; 14(9); 2143–53. ©2015 AACR.