bluuebunny/crossref_metadata_2025_split huggingface dataset:
Understanding poor health behaviours as predictors of different types of hospital admission in older people: findings from the Hertfordshire Cohort Study
Authors: Syddall Holly E , Westbury Leo D , Simmonds Shirley J , Robinson Sian , Cooper Cyrus , Sayer Avan Aihie 
Published: October 2015

BackgroundRates of hospital admission are increasing, particularly among older people. Poor health behaviours cluster but their combined impact on risk of hospital admission among older people in the UK is unknown.Methods2997 community-dwelling men and women (aged 59–73) participated in the Hertfordshire Cohort Study (HCS). We scored (from 0 to 4) number of poor health behaviours engaged in at baseline (1998–2004) out of: current smoking, high weekly alcohol, low customary physical activity and poor diet. We linked HCS with Hospital Episode Statistics and mortality data to 31/03/2010 and analysed associations between the score and risk of different types of hospital admission: any; elective; emergency; long stay (>7 days); 30-day readmission (any, or emergency).Results32%, 40%, 20% and 7% of men engaged in 0, 1, 2 and 3/4 poor health behaviours; corresponding percentages for women 51%, 38%, 9%, 2%. 75% of men (69% women) experienced at least one hospital admission. Among men and women, increased number of poor health behaviours was strongly associated (p<0.01) with greater risk of long stay and emergency admissions, and 30-day emergency readmissions. Hazard ratios (HRs) for emergency admission for 3/4 poor health behaviours in comparison with none were: men, 1.37 (95% CI 1.11 to 1.69); women, 1.84 (95% CI 1.22 to 2.77). Associations were unaltered by adjustment for age, body mass index and comorbidity.ConclusionsClustered poor health behaviours are associated with increased risk of hospital admission among older people in the UK. Lifecourse interventions to reduce number of poor health behaviours could have substantial beneficial impact on health and use of healthcare in later life.
Improving Researcher Homepage Classification with Unlabeled Data
Authors: Gollapalli Sujatha Das , Caragea Cornelia , Mitra Prasenjit , Giles C. Lee 
Published: October 2015

A classifier that determines if a webpage is relevant to a specified set of topics comprises a key component for focused crawling. Can a classifier that is tuned to perform well on training datasets continue to filter out irrelevant pages in the face of changing content on the Web? We investigate this question in the context of identifying researcher homepages. We show experimentally that classifiers trained on existing datasets of academic homepages underperform on “non-homepages” present on current-day academic websites. As an alternative to obtaining labeled datasets to retrain classifiers for the new content, in this article we ask the following question: “How can we effectively use the unlabeled data readily available from academic websites to improve researcher homepage classification?”

We design novel URL-based features and use them in conjunction with content-based features for representing homepages. Within the co-training framework, these sets of features can be treated as complementary views enabling us to effectively use unlabeled data and obtain remarkable improvements in homepage identification on the current-day academic websites. We also propose a novel technique for “learning a conforming pair of classifiers” that
mimics
co-training. Our algorithm seeks to minimize a loss (objective) function quantifying the difference in predictions from the two views afforded by co-training. We argue that this loss formulation provides insights for understanding co-training and can be used even in the absence of a validation dataset.

Our next set of findings pertains to the evaluation of other state-of-the-art techniques for classifying homepages. First, we apply feature selection (FS) and feature hashing (FH) techniques independently and in conjunction with co-training to academic homepages. FS is a well-known technique for removing redundant and unnecessary features from the data representation, whereas FH is a technique that uses hash functions for efficient encoding of features. We show that FS can be effectively combined with co-training to obtain further improvements in identifying homepages. However, using hashed feature representations, a performance degradation is observed possibly due to feature collisions.
Finally, we evaluate other semisupervised algorithms for homepage classification. We show that although several algorithms are effective in using information from the unlabeled instances, co-training that explicitly harnesses the feature split in the underlying instances outperforms approaches that combine content and URL features into a single view.
A wait-free multi-producer multi-consumer ring buffer
Authors: Feldman Steven , Dechev Damian 
Published: October 2015

The ring buffer is a staple data structure used in many algorithms and applications. It is highly desirable in high-demand use cases such as multimedia, network routing, and trading systems. This work presents a new ring buffer design that is, to the best of our knowledge, the only array-based first-in-first-out ring buffer to provide wait-freedom. Wait-freedom guarantees that each thread completes its operation within a finite number of steps. This property is desirable for real-time and mission critical systems.
This work is an extension and refinement of our earlier work. We have improved and expanded algorithm descriptions and pseudo-code, and we have performed all new performance evaluations.
In contrast to other concurrent ring buffer designs, our implementation includes new methodology to prevent thread starvation and livelock from occurring.
Prevalence of Pathogenic Mutations in Cancer Predisposition Genes among Pancreatic Cancer Patients
Authors: Hu Chunling , Hart Steven N. , Bamlet William R. , Moore Raymond M. , Nandakumar Kannabiran , Eckloff Bruce W. , Lee Yean K. , Petersen Gloria M. , McWilliams Robert R. , Couch Fergus J. 
Published: October 2015

Abstract
The prevalence of germline pathogenic mutations in a comprehensive panel of cancer predisposition genes is not well-defined for patients with pancreatic ductal adenocarcinoma (PDAC). To estimate the frequency of mutations in a panel of 22 cancer predisposition genes, 96 patients unselected for a family history of cancer who were recruited to the Mayo Clinic Pancreatic Cancer patient registry over a 12-month period were screened by next-generation sequencing. Fourteen pathogenic mutations in 13 patients (13.5%) were identified in eight genes: four in ATM, two in BRCA2, CHEK2, and MSH6, and one in BARD1, BRCA1, FANCM, and NBN. These included nine mutations (9.4%) in established pancreatic cancer genes. Three mutations were found in patients with a first-degree relative with PDAC, and 10 mutations were found in patients with first- or second-degree relatives with breast, pancreas, colorectal, ovarian, or endometrial cancers. These results suggest that a substantial proportion of patients with PDAC carry germline mutations in predisposition genes associated with other cancers and that a better understanding of pancreatic cancer risk will depend on evaluation of families with broad constellations of tumors. These findings highlight the need for recommendations governing germline gene-panel testing of patients with pancreatic cancer. Cancer Epidemiol Biomarkers Prev; 25(1); 207–11. ©2015 AACR.
MAPK Activation Predicts Poor Outcome and the MEK Inhibitor, Selumetinib, Reverses Antiestrogen Resistance in ER-Positive High-Grade Serous Ovarian Cancer
Authors: Hew Karina E. , Miller Philip C. , El-Ashry Dorraya , Sun Jun , Besser Alexandra H. , Ince Tan A. , Gu Mengnan , Wei Zhi , Zhang Gao , Brafford Patricia , Gao Wei , Lu Yiling , Mills Gordon B. , Slingerland Joyce M. , Simpkins Fiona 
Published: October 2015

AbstractPurpose: Although 67% of high-grade serous ovarian cancers (HGSOC) express the estrogen receptor (ER), most fail antiestrogen therapy. Because MAPK activation is frequent in ovarian cancer, we investigated if estrogen regulates MAPK and if MEK inhibition (MEKi) reverses antiestrogen resistance.Experimental Design: Effects of MEKi (selumetinib), antiestrogen (fulvestrant), or both were assayed in ER-positive HGSOC in vitro and in xenografts. Response biomarkers were investigated by gene expression microarray and reverse phase protein array (RPPA). Genes differentially expressed in two independent primary HGSOC datasets with high versus low pMAPK by RPPA were used to generate a “MAPK-activated gene signature.” Gene signature components that were reversed by MEKi were then identified.Results: High intratumor pMAPK independently predicts decreased survival (HR, 1.7; CI &gt; 95%,1.3–2.2; P = 0.0009) in 408 HGSOC from The Cancer Genome Atlas. A differentially expressed “MAPK-activated” gene subset was also prognostic. “MAPK-activated genes” in HGSOC differ from those in breast cancer. Combined MEK and ER blockade showed greater antitumor effects in xenografts than monotherapy. Gene set enrichment analysis and RPPA showed that dual therapy downregulated DNA replication and cell-cycle drivers, and upregulated lysosomal gene sets. Selumetinib reversed expression of a subset of “MAPK-activated genes” in vitro and/or in xenografts. Three of these genes were prognostic for poor survival (P = 0.000265) and warrant testing as a signature predictive of MEKi response.Conclusions: High pMAPK is independently prognostic and may underlie antiestrogen failure. Data support further evaluation of fulvestrant and selumetinib in ER-positive HGSOC. The MAPK-activated HGSOC signature may help identify MEK inhibitor responsive tumors. Clin Cancer Res; 22(4); 935–47. ©2015 AACR.
Well-Differentiated Neuroendocrine Tumors with a Morphologically Apparent High-Grade Component: A Pathway Distinct from Poorly Differentiated Neuroendocrine Carcinomas
Authors: Tang Laura H. , Untch Brian R. , Reidy Diane L. , O'Reilly Eileen , Dhall Deepti , Jih Lily , Basturk Olca , Allen Peter J. , Klimstra David S. 
Published: October 2015

Abstract
Purpose: Most well-differentiated neuroendocrine tumors (WD-NET) of the enteropancreatic system are low-intermediate grade (G1, G2). Elevated proliferation demonstrated by either a brisk mitotic rate (&gt;20/10 high power fields) or high Ki-67 index (&gt;20%) defines a group of aggressive neoplasms designated as high-grade (G3) neuroendocrine carcinoma (NEC). High-grade NEC is equated with poorly differentiated NEC (PD-NEC) and is associated with a dismal outcome. Progression of WD-NETs to a high-grade neuroendocrine neoplasm very rarely occurs and their clinicopathologic and molecular features need to be characterized.
Experimental Design: We investigated 31 cases of WD-NETs with evidence of a component of a high-grade neoplasm. The primary sites included pancreas, small bowel, bile duct, and rectum. Histopathology of the cases was retrospectively reviewed and selected IHC and gene mutation analyses performed.
Results: The high-grade component occurred either within the primary tumor (48%) or at metastatic sites (52%). The clinical presentation, radiographic features, biomarkers, and the genotype of these WD-NETs with high-grade component remained akin to those of G1–G2 WD-NETs. The median disease-specific survival (DSS) was 55 months (16–119 months), and 2-year and 5-year DSS was 88% and 49%, respectively—significantly better than that of a comparison group of true PD-NEC (DSS 11 months).
Conclusions: Mixed grades can occur in WD-NETs, which are distinguished from PD-NECs by their unique phenotype, proliferative indices, and the genotype. This phenomenon of mixed grade in WD-NET provides additional evidence to the growing recognition that the current WHO G3 category contains both WD-NETs as well as PD-NECs. Clin Cancer Res; 22(4); 1011–7. ©2015 AACR.
Abstract B03: Pin1 is required for sustained B cell proliferation upon oncogenic activation of Myc
Authors: D'Artista Luana , Piontini Andrea , Kress Theresia , Morelli Marco , Verrecchia Alessandro , Doni Mirko , Campaner Stefano , Amati Bruno 
Published: October 2015

Abstract
The c-myc proto-oncogene is activated by translocation in Burkitt's lymphoma, where it is also frequently subject to secondary mutations. Substitutions in codon 58, in particular, stabilize the Myc protein and augment its oncogenic potential. In wild-type Myc, phosphorylation of Ser 62 primes phosphorylation of Thr 58, providing a landing pad for the peptidyl prolyl-isomerase Pin1, which in turn promotes Ser 62 dephosphorylation and Myc degradation. However, genetic data are missing to address whether Pin1 influences Myc-induced lymphomagenesis. Here, we show that genetic ablation of Pin1 in Eµ-myc transgenic mice starkly reduced lymphoma onset and penetrance. In pre-malignant Pin1 deficient B cells, the proliferative response to Myc was selectively impaired, while Myc-induced apoptosis was intact. This phenotype was not the result of deregulated levels of Ser 62 phosphorylation in the Pin1-/- background. Similar results were observed in Pin1-/- mouse embryo fibroblasts (MEFs), where prolonged Myc activation inhibited proliferation. In either B cells or MEFs, loss of Pin1 did not affect mitogen-induced cell cycle entry, an effect that relies on endogenous Myc activity. Thus, our data unravel the existence of a synthetic-lethal interaction between deletion of Pin1 and oncogenic activation of Myc. Myc-induced oncogenic stress is linked to the induction of the Arf/p53 pathway, which is critical for tumor suppression in Eµ-myc mice. The selective pressure to inactivate Arf/p53 axis was preserved in Eµ-myc Pin1-/- lymphomas. In the absence of Arf or p53, the Pin1 deletion no longer reduced Myc-induced tumorigenesis or proliferation. Thus the proliferative arrest of pre-tumoral Eµ-myc Pin1-/- B cells required an active ARF-p53 dependent cytostatic response. Our data demonstrate that Pin1 is required to support the oncogenic activity of Myc in B cells and warrant further assessment of Pin1 as a therapeutic target in Myc-dependent malignancies.
Citation Format: Luana D'Artista, Andrea Piontini, Theresia Kress, Marco Morelli, Alessandro Verrecchia, Mirko Doni, Stefano Campaner, Bruno Amati. Pin1 is required for sustained B cell proliferation upon oncogenic activation of Myc. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr B03.
Abstract B28: Determining the apoptotic mechanisms of bromodomain and extraterminal (BET) inhibitors
Authors: Lasorsa Elena , Ellis Leigh 
Published: October 2015

Abstract
Inhibitors of the bromodomain and extraterminal domain family (BETi), represent a novel class of targeted therapy to treat aggressive B-cell lymphomas. Specifically, BETi are shown to inhibit proliferation and induce apoptosis in lymphoma cells arising from Myc transgenic mice. However, the underlying apoptotic mechanisms are still not well understood. Dissecting apoptotic mechanisms required by BETi could provide strong rationale on how to best utilize BETi to treat patients with aggressive B-cell lymphomas.
It was the primary purpose of this study to delineate the molecular mechanisms underlying BETi induced apoptosis. Secondly, by determining critical apoptotic proteins/pathways, investigate the potential of BETi in novel combination therapy strategies. For this, we conducted in vitro studies utilizing primary and compound mutant lymphomas derived from the Eµ-myc murine model of B-cell lymphoma. The BETi IBET762 was used to treat lymphomas, and over all cell death, apoptosis, mitochondria damage, cell cycle distribution were assessed by flow cytometry. Protein expression of Myc, bromodomain 3 and 4 (BRD 3 and BRD4), Bcl-2 and activated caspase 3 were assessed by western blot.
IBET762 induces apoptosis in Eµ-myc lymphomas in a time and dose dependent manner at low nanomolar concentrations. Apoptosis was dependent on the intrinsic apoptotic pathway, but independent of p53 or p19arf. Loss of apoptosome function delayed the kinetics of BETi mediated cell death. Analysis of BRD3, BRD4, Bcl-2 and Myc protein expression is ongoing. Because apoptosis induction by BETi was blocked by the overexpression of Bcl-2, we tested the efficacy of the small molecule Bcl-2 inhibitor, ABT-263. Combining low dose ABT-263 with IBET762 resulted in induction of apoptosis in Eµ-myc/Bcl-2 lymphomas.
These data indicate mitochondrial damage to be critical for BETi mediated apoptosis. Finally, our current studies will provide vision and strong rationale on how best to apply BET inhibitors to the clinic to provide maximum benefit to patients with aggressive B-cell lymphomas.
Citation Format: Elena Lasorsa, Leigh Ellis. Determining the apoptotic mechanisms of bromodomain and extraterminal (BET) inhibitors. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr B28.
Identification and Functional Characterization of a Novel
CACNA1C
-Mediated Cardiac Disorder Characterized by Prolonged QT Intervals With Hypertrophic Cardiomyopathy, Congenital Heart Defects, and Sudden Cardiac Death
Authors: Boczek Nicole J. , Ye Dan , Jin Fang , Tester David J. , Huseby April , Bos J. Martijn , Johnson Aaron J. , Kanter Ronald , Ackerman Michael J. 
Published: October 2015

Background—

A portion of sudden cardiac deaths can be attributed to structural heart diseases, such as hypertrophic cardiomyopathy (HCM) or cardiac channelopathies such as long-QT syndrome (LQTS); however, the underlying molecular mechanisms are distinct. Here, we identify a novel
CACNA1C
missense mutation with mixed loss-of-function/gain-of-function responsible for a complex phenotype of LQTS, HCM, sudden cardiac death, and congenital heart defects.

Methods and Results—

Whole exome sequencing in combination with Ingenuity variant analysis was completed on 3 affected individuals and 1 unaffected individual from a large pedigree with concomitant LQTS, HCM, and congenital heart defects and identified a novel CACNA1C mutation, p.Arg518Cys, as the most likely candidate mutation. Mutational analysis of exon 12 of
CACNA1C
was completed on 5 additional patients with a similar phenotype of LQTS plus a personal or family history of HCM-like phenotypes and identified 2 additional pedigrees with mutations at the same position, p.Arg518Cys/His. Whole cell patch clamp technique was used to assess the electrophysiological effects of the identified mutations in Ca
V
1.2 and revealed a complex phenotype, including loss of current density and inactivation in combination with increased window and late current.

Conclusions—
Through whole exome sequencing and expanded cohort screening, we identified a novel genetic substrate p.Arg518Cys/His-CACNA1C, in patients with a complex phenotype including LQTS, HCM, and congenital heart defects annotated as cardiac-only Timothy syndrome. Our electrophysiological studies, identification of mutations at the same amino acid position in multiple pedigrees, and cosegregation with disease in these pedigrees provide evidence that p.Arg518Cys/His is the pathogenic substrate for the observed phenotype.
Decrement Evoked Potential Mapping
Authors: Jackson Nicholas , Gizurarson Sigfus , Viswanathan Karthik , King Benjamin , Massé Stephane , Kusha Marjan , Porta-Sanchez Andreu , Jacob John Roshan , Khan Fakhar , Das Moloy , Ha Andrew C.T. , Pashaei Ali , Vigmond Edward , Downar Eugene , Nanthakumar Kumaraswamy 
Published: October 2015

Background—
Substrate-based mapping for ventricular tachycardia (VT) ablation is hampered by its inability to determine critical sites of the VT circuit. We hypothesized that those potentials, which delay with a decremental extrastimulus (decrement evoked potentials or DEEPs), are more likely to colocalize with the diastolic pathways of VT circuits.

Methods and Results—

DEEPs were identified in intraoperative left ventricular maps from 6 patients with ischemic cardiomyopathy (total 9 VTs) and were compared with late potential (LP) and activation maps of the diastolic pathway for each VT. Mathematical modeling was also used to further validate and elucidate the mechanisms of DEEP mapping. All patients demonstrated regions of DEEPs and LPs. The mean endocardial surface area of these potentials was 18±4% and 21±6%, respectively (
P
=0.13). The mean sensitivity for identifying the diastolic pathway in VT was 50±23% for DEEPs and 36±32% for LPs (
P
=0.31). The mean specificity was 43±23% versus 20±8% for DEEP and LP mapping, respectively (
P
=0.031). The electrograms that displayed the greatest decrement in each case had a sensitivity and specificity for the VT isthmus of 29±10% and 95±1%, respectively. Mathematical modeling studies recapitulated DEEPs at the VT isthmus and demonstrated their role in VT initiation with a critical degree of decrement.

Conclusions—
In this preliminary study, DEEP mapping was more specific than LP mapping for identifying the critical targets of VT ablation. The mechanism of DEEPs relates to conduction velocity restitution magnified by zigzag conduction within scar channels.
Jupiter’s Unearthly Jets: A New Turbulent Model Exhibiting Statistical Steadiness without Large-Scale Dissipation*
Authors: Thomson Stephen I. , McIntyre Michael E. 
Published: October 2015

Abstract
A longstanding mystery about Jupiter has been the straightness and steadiness of its weather-layer jets, quite unlike terrestrial strong jets with their characteristic unsteadiness and long-wavelength meandering. The problem is addressed in two steps. The first is to take seriously the classic Dowling–Ingersoll (DI) 1½-layer scenario and its supporting observational evidence, pointing toward deep, massive, zonally symmetric zonal jets in the underlying dry-convective layer. The second is to improve the realism of the model stochastic forcing used to represent the effects of Jupiter’s moist convection, as far as possible within the 1½-layer dynamics of the DI scenario. The real moist convection should be strongest in the belts where the interface to the deep flow is highest and coldest and should generate cyclones as well as anticyclones, with the anticyclones systematically stronger. The new model forcing reflects these insights. Also, it acts quasi frictionally on large scales to produce statistically steady turbulent weather-layer regimes without any need for explicit large-scale dissipation, and with weather-layer jets that are approximately straight thanks to the influence of the deep jets, allowing shear stability despite nonmonotonic potential vorticity gradients when the Rossby deformation length scale is not too large. Moderately strong forcing produces chaotic vortex dynamics and realistic belt–zone contrasts in the model’s convective activity, through an eddy-induced sharpening and strengthening of the weather-layer jets relative to the deep jets, tilting the interface between them. Weak forcing, for which the only jet-sharpening mechanism is the passive, Kelvin shearing of vortices (as in the zonostrophic instability mechanism), produces unrealistic belt–zone contrasts.