bluuebunny/crossref_metadata_2025_split huggingface dataset:
Accuracy and cost-effectiveness of dynamic contrast-enhanced CT in the characterisation of solitary pulmonary nodules—the SPUtNIk study
Authors: Qureshi N R , Rintoul R C , Miles K A , George S , Harris S , Madden J , Cozens K , Little L A , Eichhorst K , Jones J , Moate P , McClement C , Pike L , Sinclair D , Wong W L , Shekhdar J , Eaton R , Shah A , Brindle L , Peebles C , Banerjee A , Dizdarevic S , Han S , Poon F W , Groves A M , Kurban L , Frew A J , Callister M E , Crosbie P , Gleeson F V , Karunasaagarar K , Kankam O , Gilbert F J 
Published: October 2016

IntroductionSolitary pulmonary nodules (SPNs) are common on CT. The most cost-effective investigation algorithm is still to be determined. Dynamic contrast-enhanced CT (DCE-CT) is an established diagnostic test not widely available in the UK currently.Methods and analysisThe SPUtNIk study will assess the diagnostic accuracy, clinical utility and cost-effectiveness of DCE-CT, alongside the current CT and 18-flurodeoxyglucose-positron emission tomography) (18FDG-PET)-CT nodule characterisation strategies in the National Health Service (NHS). Image acquisition and data analysis for18FDG-PET-CT and DCE-CT will follow a standardised protocol with central review of 10% to ensure quality assurance. Decision analytic modelling will assess the likely costs and health outcomes resulting from incorporation of DCE-CT into management strategies for patients with SPNs.Ethics and disseminationApproval has been granted by the South West Research Ethics Committee. Ethics reference number 12/SW/0206. The results of the trial will be presented at national and international meetings and published in an Health Technology Assessment (HTA) Monograph and in peer-reviewed journals.Trial registration numberISRCTN30784948; Pre-results.
UK end-of-life care services in dementia, initiatives and sustainability: results of a national online survey
Authors: Amador Sarah , Goodman Claire , Robinson Louise , Sampson Elizabeth L 
Published: October 2016

BackgroundPeople living and dying with non-cancer diagnoses, including dementia, have poorer access to generalist and specialist palliative care than people with cancer, and experience worse outcomes in terms of pain and symptom control, and quality and experience of care. In the UK, the National Council for Palliative Care (NCPC) ran a national survey of services for end-of-life care for people with dementia (2008) in which 16 services were identified, and reported on case studies and examples of good practice. We updated the NCPC survey to review progress in previously identified services, identify factors that lead to sustainable services and identify new initiatives in this area of care.MethodsAn online survey was developed and piloted before use. Initiatives were contacted via targeted (N=63) and open call invitations. The survey was made up of 5 sections. Quantitative data were analysed using descriptive statistics.Results15 services responded. They engaged in a wide range of activities predominately providing direct care (80%) and workforce development/advisory or educational activities (87%). Results suggest that sustainability of services is reliant on clinicians with a leadership role and wider system support through funding mechanisms and a minimum level of integration within normal service provision.ConclusionsRecent initiatives are largely built on the expertise of the nursing profession (with or without input from medical consultants), and driven mainly by the charity and hospice sector. This has generated a potential new model of care provision in end of life dementia care, ‘Hospice-enabled Dementia Care’.
Molecular classification of Crohn's disease reveals two clinically relevant subtypes
Authors: Weiser Matthew , Simon Jeremy M , Kochar Bharati , Tovar Adelaide , Israel Jennifer W , Robinson Adam , Gipson Gregory R , Schaner Matthew S , Herfarth Hans H , Sartor R Balfour , McGovern Dermot P B , Rahbar Reza , Sadiq Timothy S , Koruda Mark J , Furey Terrence S , Sheikh Shehzad Z 
Published: October 2016

ObjectiveThe clinical presentation and course of Crohn's disease (CD) is highly variable. We sought to better understand the cellular and molecular mechanisms that guide this heterogeneity, and characterise the cellular processes associated with disease phenotypes.DesignWe examined both gene expression and gene regulation (chromatin accessibility) in non-inflamed colon tissue from a cohort of adult patients with CD and control patients. To support the generality of our findings, we analysed previously published expression data from a large cohort of treatment-naïve paediatric CD and control ileum.ResultsWe found that adult patients with CD clearly segregated into two classes based on colon tissue gene expression—one that largely resembled the normal colon and one where certain genes showed expression patterns normally specific to the ileum. These classes were supported by changes in gene regulatory profiles observed at the level of chromatin accessibility, reflective of a fundamental shift in underlying molecular phenotypes. Furthermore, gene expression from the ilea of a treatment-naïve cohort of paediatric patients with CD could be similarly subdivided into colon-like and ileum-like classes. Finally, expression patterns within these CD subclasses highlight large-scale differences in the immune response and aspects of cellular metabolism, and were associated with multiple clinical phenotypes describing disease behaviour, including rectal disease and need for colectomy.ConclusionsOur results strongly suggest that these molecular signatures define two clinically relevant forms of CD irrespective of tissue sampling location, patient age or treatment status.
Human oral microbiome and prospective risk for pancreatic cancer: a population-based nested case-control study
Authors: Fan Xiaozhou , Alekseyenko Alexander V , Wu Jing , Peters Brandilyn A , Jacobs Eric J , Gapstur Susan M , Purdue Mark P , Abnet Christian C , Stolzenberg-Solomon Rachael , Miller George , Ravel Jacques , Hayes Richard B , Ahn Jiyoung 
Published: October 2016

ObjectiveA history of periodontal disease and the presence of circulating antibodies to selected oral pathogens have been associated with increased risk of pancreatic cancer; however, direct relationships of oral microbes with pancreatic cancer have not been evaluated in prospective studies. We examine the relationship of oral microbiota with subsequent risk of pancreatic cancer in a large nested case–control study.DesignWe selected 361 incident adenocarcinoma of pancreas and 371 matched controls from two prospective cohort studies, the American Cancer Society Cancer Prevention Study II and the National Cancer Institute Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. From pre-diagnostic oral wash samples, we characterised the composition of the oral microbiota using bacterial 16S ribosomal RNA (16S rRNA) gene sequencing. The associations between oral microbiota and risk of pancreatic cancer, controlling for the random effect of cohorts and other covariates, were examined using traditional and L1-penalised least absolute shrinkage and selection operator logistic regression.ResultsCarriage of oral pathogens,Porphyromonas gingivalisandAggregatibacter actinomycetemcomitans, were associated with higher risk of pancreatic cancer (adjusted OR for presence vs absence=1.60 and 95% CI 1.15 to 2.22; OR=2.20 and 95% CI 1.16 to 4.18, respectively). PhylumFusobacteriaand its genusLeptotrichiawere associated with decreased pancreatic cancer risk (OR per per cent increase of relative abundance=0.94 and 95% CI 0.89 to 0.99; OR=0.87 and 95% CI 0.79 to 0.95, respectively). Risks related to these phylotypes remained after exclusion of cases that developed within 2 years of sample collection, reducing the likelihood of reverse causation in this prospective study.ConclusionsThis study provides supportive evidence that oral microbiota may play a role in the aetiology of pancreatic cancer.
PIK3CAandAKT1mutations in hidradenoma papilliferum
Authors: Goto Keisuke , Maeda Daichi , Kudo-Asabe Yukitsugu , Hibiya Takashi , Hayashi Akimasa , Fukayama Masashi , Ohashi Kenichi , Goto Akiteru 
Published: October 2016

AimsHidradenoma papilliferum (HP) is a benign vulvar neoplasm that arises from anogenital mammary-like glands, and its morphology is similar to mammary intraductal papilloma. The aim of this study was to investigate oncogenic mutations involved in the tumourigenesis of HP. We focused specifically onPIK3CAandAKT1mutations, which are both reported to be detected in 33% of mammary intraductal papillomas.MethodsIn total, seven HP cases were analysed. Clinicopathological analyses and immunohistochemistry for oestrogen receptor, p63, smooth muscle actin (SMA), p53 and β-catenin were performed. Furthermore,PIK3CA,AKT1, BRAFandKRAShot spot mutations were examined by Sanger sequencing.ResultsMorphologically, all HPs had a papillary and tubular architecture with a biphasic pattern of epithelial and myoepithelial cells. Immunohistochemistry revealed that oestrogen receptor expression was restricted to epithelial cells, whereas p63 and SMA were exclusively expressed in myoepithelial cells. The patterns of p53 and β-catenin immunostaining suggested wild-type genotypes. Direct sequencing revealed the presence of somaticPIK3CAmutations (Ex9. c.1633G>A, p.E545K and Ex20. c.3140A>G, p.H1047R) in two of the HPs and anAKT1(c.49G>A, p.E17K) mutation in one.BRAFandKRASmutations were not found in any of the HP cases.ConclusionsPIK3CAandAKT1are frequently mutated in HP tumours (29% and 14%, respectively). PIK3CA/AKT1 pathway alterations in HP further support the hypothesis that HP is the vulvar (anogenital mammary-like gland) analogue of breast intraductal papilloma.
Coiling of wide-necked carotid artery aneurysms assisted by a temporary bridging device (Comaneci): preliminary experience
Authors: Fischer S , Weber A , Carolus A , Drescher F , Götz F , Weber W 
Published: October 2016

BackgroundEndovascular treatment of wide-necked aneurysms remains challenging without the use of adjunctive devices to preserve the parent artery.ObjectiveTo present our initial experience with a temporary bridging device, the Comaneci (Rapid Medical, Israel). The compliant remodeling mesh protects the parent artery during coil occlusion without flow arrest in the distal vasculature. Permanent dual antiplatelet therapy is not required since the device is fully removed at the end of the procedure.MethodsAll intracranial aneurysms treated by coil occlusion with the Comaneci device between December 2014 and November 2015 were included. Angiographic and clinical results were retrospectively analysed, including follow-up examinations. All aneurysms were unruptured.Results18 aneurysms of the internal carotid artery were included. Successful coil occlusion assisted by the Comaneci device as intended was possible in 14 cases (77.8%). Insufficient coverage of the aneurysmal neck was observed in four cases (22.2%), with modification of the treatment to stent-assisted coiling or remodeling. One clinically relevant complication occurred (5.6%).ConclusionsOur initial experience shows that use of the Comaneci device is straightforward for the treatment of selected wide-necked aneurysms. Further studies with long-term follow-up data are needed to identify the significance of the presented technique in the neurointerventional armamentarium.
High prevalence of antithyroid peroxidase and antiparietal cell antibodies among patients with type 1 diabetes mellitus attending a tertiary diabetes centre in South Africa
Authors: Paruk Imran M , Ganie Yasmeen , Maharaj Sureka , Pirie Fraser J , Naidoo Vasudevan G , Nkwanyana Ntombifikile M , Dinnematin Hilary L , Ramdial Pratistadevi K , Motala Ayesha A 
Published: October 2016

ABSTRACTObjectiveData on the prevalence of autoimmune thyroid disease (AITD) and gastric autoimmunity in type 1 diabetes mellitus (T1DM) in Africa are limited. The aim of this study was to assess the prevalence of antithyroid peroxidase (TPO-A) and antiparietal cell antibody (PCA) in patients with T1DM at a tertiary diabetes clinic in Durban, South Africa.Research design and methodsThis was a cross-sectional observational study among subjects attending the adult T1DM clinic at Inkosi Albert Luthuli Hospital. Information about history and clinical examination was collected. Blood tests included glutamic acid decarboxylase antibody (GADA), TPO-A, PCA, vitamin B12, folate, ferritin, thyroid stimulating hormone (TSH), free thyroxine, lipids and HbA1c.ResultsA total of 202 (M:F, 90:112) patients were recruited. The ethnic composition was African (black) (56.4%; n=114), Indian (31.7%; n=64), white (4.5%; n=9) and coloured (mixed race) (7.4%; n=15). Mean age and mean duration of diabetes were 26.4±11.4 and 10.7±9.1 years, respectively. Mean body mass index was 21.6±6.3 kg/m2. GADA was positive in 63.37% (n=128). The prevalence of TPO-A was 18.9% (n=39) and PCA 8.9% (n=17). The prevalence of overt hypothyroidism, subclinical hypothyroidism and Graves’ disease was 10.9%, 2.5% and 1.5%, respectively; vitamin B12 deficiency was noted in 3.5% (n=7) and iron deficiency in 19.3% (n=39).ConclusionsAmong patients with T1DM in this study, there was a high prevalence of coexistent AITD and gastric autoimmunity. Screening for hypothyroidism and thyroid autoimmunity should be undertaken in all patients at initial presentation. However, to assess the feasibility and optimal timing of subsequent testing in the African setting with limited resources, more collaborative research with longitudinal studies is required.
MicroRNAs interfere with DNA methylation in rheumatoid arthritis synovial fibroblasts
Authors: Gaur Niharika , Karouzakis Emmanuel , Glück Selene , Bagdonas Edvardas , Jüngel Astrid , Michel Beat A , Gay Renate E , Gay Steffen , Frank-Bertoncelj Mojca , Neidhart Michel 
Published: October 2016

BackgroundThe DNA of rheumatoid arthritis synovial fibroblasts (RASF) is globally hypomethylated; this contributes to an aggressive behaviour. In an attempt to remethylate these cells, we supplemented with methyl donors. We investigated the possible interference of microRNAs (miRs).Material and methodsRASF were treated with L-methionine or betaine. Transcripts of de novo methyltransferases (DNMTs) and miRs were measured by real-time PCR, and a transcription PCR array was performed. Levels of homocysteine, matrix metalloproteinase-1 (MMP-1) and global DNA methylation were determined. Transfection with lipofectamine was performed with specific pre-miRs and anti-miRs, such as miR29 and let7f.ResultsL-methionine was more efficient to increase DNA methylation than betaine. This was associated with a reduced expression of DNMT3A mRNA in betaine-treated RASF. Betaine increases the expression of miR29 in RASF which targets DNMT3A, thereby limiting the remethylation process. Nevertheless, betaine inhibited the expression of multiple transcription factors, decreased the release of MMP-1, biosynthesis of homocysteine and cell migration.ConclusionAlterations in cellular miRs profiles, in particular the upregulation of miR29, which targets DNMT3A, may limit the efficiency of betaine if it is used as DNA remethylating agent. However, L-methionine also has similar impact on miR29 expression. On the other hand, betaine has multiple other beneficial effects on the activated phenotype of RASF; it is not excluded that the effect of betaine on DNMT3A is, at least in part, indirect. Clinical trials with betaine could be promising.
Lysyl Oxidase Is a Strong Determinant of Tumor Cell Colonization in Bone
Authors: Reynaud Caroline , Ferreras Laura , Di Mauro Paola , Kan Casina , Croset Martine , Bonnelye Edith , Pez Floriane , Thomas Clémence , Aimond Géraldine , Karnoub Antoine E. , Brevet Marie , Clézardin Philippe 
Published: October 2016

Abstract
Lysyl oxidase (LOX) is a secreted copper-dependent amine oxidase whose primary function is to drive collagen crosslinking and extracellular matrix stiffness. LOX in colorectal cancer synergizes with hypoxia-inducible factor-1 (HIF-1) to promote tumor progression. Here we investigated whether LOX/HIF1 endows colorectal cancer cells with full competence for aggressive colonization in bone. We show that a high LOX expression in primary tumors from patients with colorectal cancer was associated with poor clinical outcome, irrespective of HIF-1. In addition, LOX was expressed by tumor cells in the bone marrow from colorectal cancer patients with bone metastases. In vivo experimental studies show that LOX overexpression in colorectal cancer cells or systemic delivery of the conditioned medium from LOX-overexpressing colorectal cancer cells promoted tumor cell dissemination in the bone marrow and enhanced osteolytic lesion formation, irrespective of HIF-1. Conversely, silencing or pharmacologic inhibition of LOX activity blocked dissemination of colorectal cancer cells in the bone marrow and tumor-driven osteolytic lesion formation. In vitro, tumor-secreted LOX supported the attachment and survival of colorectal cancer cells to and in the bone matrix, and inhibited osteoblast differentiation. LOX overexpression in colorectal cancer cells also induced a robust production of IL6. In turn, both LOX and IL6 were acting in concert to promote RANKL-dependent osteoclast differentiation, thereby creating an imbalance between bone resorption and bone formation. Collectively, our findings show that LOX supports colorectal cancer cell dissemination in the bone marrow and they reveal a novel mechanism through which LOX-driven IL6 production by colorectal cancer cells impairs bone homeostasis. Cancer Res; 77(2); 268–78. ©2016 AACR.
The Stem Cell Factor HMGA2 Is Expressed in Non-HPV–Associated Head and Neck Squamous Cell Carcinoma and Predicts Patient Survival of Distinct Subsites
Authors: Günther Kathrin , Foraita Ronja , Friemel Juliane , Günther Frauke , Bullerdiek Jörn , Nimzyk Rolf , Markowski Dominique Nadine , Behrens Thomas , Ahrens Wolfgang 
Published: October 2016

Abstract
Background: The transcription factor high-mobility AT-hook 2 (HMGA2) is involved in stem cell renewal and is expressed in many tumor tissues. Head and neck squamous cell carcinomas (HNSCC) comprise tumors of the upper aerodigestive tract and are characterized by high recurrence rates that represent a challenge to patient management. The study addresses the potential of HMGA2 as a molecular biomarker for HNSCC patient survival.
Methods: Patients with HNSCC of the larynx, pharynx, tonsils, or oral cavity were recruited in a hospital-based case–control study (n = 202). Quantitative expression of HMGA2 in tumor tissues was measured by RT-PCR. In a 6- to 10-year follow-up, secondary cancers, vital status, and cause of death were ascertained. The HR and 95% confidence intervals (CI) for overall, tumor-specific, and progression-free survival were estimated by Cox proportional hazards with HMGA2 expression level as the independent variable.
Results: High HMGA2 expression in tumor tissues of HNSCC patients was significantly correlated with negative HPV status (P = 0.01), and associated with shorter overall survival time. In Cox regression modeling, HMGA2 expression yielded a risk increase for overall and tumor-specific death in subsets of HNSCC patients, that is, laryngeal cancer patients (overall survival: HR = 4.00; 95% CI, 1.18–13.62) and in oral cancer patients (tumor-specific survival: HR = 2.88; 95% CI, 1.06–7.84), but not in patients with pharyngeal and tonsillar HNSCC.
Conclusions: HMGA2 expression is associated with a risk increase for adverse outcomes in patients with HNSCC of the larynx and oral cavity.
Impact: The understanding of stem cell signaling in HNSCC may offer new strategies for cancer treatment. Cancer Epidemiol Biomarkers Prev; 26(2); 197–205. ©2016 AACR.
Toxicity and Efficacy Probability Interval Design for Phase I Adoptive Cell Therapy Dose-Finding Clinical Trials
Authors: Li Daniel H. , Whitmore James B. , Guo Wentian , Ji Yuan 
Published: October 2016

Abstract
Recent trials of adoptive cell therapy (ACT), such as the chimeric antigen receptor (CAR) T-cell therapy, have demonstrated promising therapeutic effects for cancer patients. A main issue in the product development is to determine the appropriate dose of ACT. Traditional phase I trial designs for cytotoxic agents explicitly assume that toxicity increases monotonically with dose levels and implicitly assume the same for efficacy to justify dose escalation. ACT usually induces rapid responses, and the monotonic dose–response assumption is unlikely to hold due to its immunobiologic activities. We propose a toxicity and efficacy probability interval (TEPI) design for dose finding in ACT trials. This approach incorporates efficacy outcomes to inform dosing decisions to optimize efficacy and safety simultaneously. Rather than finding the maximum tolerated dose (MTD), the TEPI design is aimed at finding the dose with the most desirable outcome for safety and efficacy. The key features of TEPI are its simplicity, flexibility, and transparency, because all decision rules can be prespecified prior to trial initiation. We conduct simulation studies to investigate the operating characteristics of the TEPI design and compare it to existing methods. In summary, the TEPI design is a novel method for ACT dose finding, which possesses superior performance and is easy to use, simple, and transparent. Clin Cancer Res; 23(1); 13–20. ©2016 AACR.
FCGR Polymorphisms Influence Response to IL2 in Metastatic Renal Cell Carcinoma
Authors: Erbe Amy K. , Wang Wei , Goldberg Jacob , Gallenberger Mikayla , Kim KyungMann , Carmichael Lakeesha , Hess Dustin , Mendonca Eneida A. , Song Yiqiang , Hank Jacquelyn A. , Cheng Su-Chun , Signoretti Sabina , Atkins Michael , Carlson Alexander , Mier James W. , Panka David J. , McDermott David F. , Sondel Paul M. 
Published: October 2016

AbstractPurpose: Fc-gamma receptors (FCGRs) are expressed on immune cells, bind to antibodies, and trigger antibody-induced cell-mediated antitumor responses when tumor-reactive antibodies are present. The affinity of the FCGR/antibody interaction is variable and dependent upon FCGR polymorphisms. Prior studies of patients with cancer treated with immunotherapy indicate that FCGR polymorphisms can influence antitumor response for certain immunotherapies that act via therapeutically administered mAbs or via endogenous tumor-reactive antibodies induced from tumor antigen vaccines. The previously published “SELECT” trial of high-dose aldesleukin (HD-IL2) for metastatic renal cell carcinoma resulted in an objective response rate of 25%. We evaluated the patients in this SELECT trial to determine whether higher-affinity FCGR polymorphisms are associated with outcome.Experimental Design: SNPs in FCGR2A, FCGR3A, and FCGR2C were analyzed, individually and in combination, for associations between genotype and clinical outcome.Results: When higher-affinity genotypes for FCGR2A, FCGR3A, and FCGR2C were considered together, they were associated with significantly increased tumor shrinkage and prolonged survival in response to HD-IL2.Conclusions: Although associations of higher-affinity FCGR genotype with clinical outcome have been demonstrated with mAb therapy and with idiotype vaccines, to our knowledge, this is the first study to show associations of FCGR genotypes with outcome following HD-IL2 treatment. We hypothesize that endogenous antitumor antibodies may engage immune cells through their FCGRs, and HD-IL2 may enhance antibody-induced tumor destruction, or antibody-enhanced tumor antigen presentation, via augmented activation of innate or adaptive immune responses; this FCGR-mediated immune activity would be augmented through immunologically favorable FCGRs. Clin Cancer Res; 23(9); 2159–68. ©2016 AACR.