bluuebunny/crossref_metadata_2025_split huggingface dataset:
Defect of CARD9 Leads to Impaired Accumulation of Gamma Interferon-Producing Memory Phenotype T Cells in Lungs and Increased Susceptibility to Pulmonary Infection with Cryptococcus neoformans
Authors: Yamamoto Hideki , Nakamura Yuri , Sato Ko , Takahashi Yurie , Nomura Toshiki , Miyasaka Tomomitsu , Ishii Keiko , Hara Hiromitsu , Yamamoto Natsuo , Kanno Emi , Iwakura Yoichiro , Kawakami Kazuyoshi 
Published: January 2014

ABSTRACTCaspase recruitment domain-containing protein 9 (CARD9) is an adaptor molecule signal that is critical for NF-κB activation and is triggered through C-type lectin receptors (CLRs), which are pattern recognition receptors that recognize carbohydrate structures. Previous studies have reported thatCryptococcus neoformans, a fungal pathogen that causes meningoencephalitis in AIDS patients, is recognized through some CLRs, such as mannose receptors or DC-SIGN. However, the role of CARD9 in the host defense against cryptococcal infection remains to be elucidated. In the present study, we analyzed the role of CARD9 in the host defense against pulmonary infection withC. neoformans. CARD9 gene-disrupted (knockout [KO]) mice were highly susceptible to this infection, as shown by the reduced fungal clearance in the infected lungs of CARD9 KO mice, compared to that in wild-type (WT) mice. Gamma interferon (IFN-γ) production was strongly reduced in CARD9 KO mice during the innate-immunity phase of infection. Reduced IFN-γ synthesis was due to impaired accumulation of NK and memory phenotype T cells, which are major sources of IFN-γ innate-immunity-phase production; a reduction in the accumulation of these cells was correlated with reduced CCL4, CCL5, CXCL9, and CXCL10 synthesis. However, differentiation of Th17 cells, but not of Th1 cells, was impaired at the adaptive-immunity phase in CARD9 KO mice compared to WT mice, although there was no significant difference in the infection susceptibility between interleukin 17A (IL-17A) KO and WT mice. These results suggest that CARD9 KO mice are susceptible toC. neoformansinfection probably due to the reduced accumulation of IFN-γ-expressing NK and memory phenotype T cells at the early stage of infection.
Elucidating the Genetic Basis of Crystalline Biofilm Formation in Proteus mirabilis
Authors: Holling N. , Lednor D. , Tsang S. , Bissell A. , Campbell L. , Nzakizwanayo J. , Dedi C. , Hawthorne J. A. , Hanlon G. , Ogilvie L. A. , Salvage J. P. , Patel B. A. , Barnes L. M. , Jones B. V. 
Published: January 2014

ABSTRACT

Proteus mirabilis
forms extensive crystalline biofilms on urethral catheters that occlude urine flow and frequently complicate the management of long-term-catheterized patients. Here, using random transposon mutagenesis in conjunction with
in vitro
models of the catheterized urinary tract, we elucidate the mechanisms underpinning the formation of crystalline biofilms by
P. mirabilis
. Mutants identified as defective in blockage of urethral catheters had disruptions in genes involved in nitrogen metabolism and efflux systems but were unaffected in general growth, survival in bladder model systems, or the ability to elevate urinary pH. Imaging of biofilms directly on catheter surfaces, along with quantification of levels of encrustation and biomass, confirmed that the mutants were attenuated specifically in the ability to form crystalline biofilms compared with that of the wild type. However, the biofilm-deficient phenotype of these mutants was not due to deficiencies in attachment to catheter biomaterials, and defects in later stages of biofilm development were indicated. For one blocking-deficient mutant, the disrupted gene (encoding a putative multidrug efflux pump) was also found to be associated with susceptibility to fosfomycin, and loss of this system or general inhibition of efflux pumps increased sensitivity to this antibiotic. Furthermore, homologues of this system were found to be widely distributed among other common pathogens of the catheterized urinary tract. Overall, our findings provide fundamental new insight into crystalline biofilm formation by
P. mirabilis
, including the link between biofilm formation and antibiotic resistance in this organism, and indicate a potential role for efflux pump inhibitors in the treatment or prevention of
P. mirabilis
crystalline biofilms.
Stratified medicine in European Medicines Agency licensing: a systematic review of predictive biomarkers
Authors: Malottki Kinga , Biswas Mousumi , Deeks Jonathan J , Riley Richard D , Craddock Charles , Johnson Philip , Billingham Lucinda 
Published: January 2014

ObjectivesStratified medicine is often heralded as the future of clinical practice. Key part of stratified medicine is the use of predictive biomarkers, which identify patient subgroups most likely to benefit (or least likely to experience harm) from an intervention. We investigated how many and what predictive biomarkers are currently included in European Medicines Agency (EMA) licensing.SettingEMA licensing.ParticipantsIndications and contraindications of all drugs considered by the EMA and published in 883 European Public Assessment Reports and Pending Decisions.Primary and secondary outcome measuresData were collected on: the type of the biomarker, whether it selected a subgroup of patients based on efficacy or toxicity, therapeutic area, marketing status, date of licensing decision, date of inclusion of the biomarker in the indication or contraindication and on orphan designation.Results49 biomarker–indication–drug (B-I-D) combinations were identified over 16 years, which included 37 biomarkers and 41 different drugs. All identified biomarkers were molecular. Six drugs (relating to 10 B-I-D combinations) had an orphan designation at the time of licensing. The identified B-I-D combinations were mainly used in cancer and HIV treatment, and also in hepatitis C and three other indications (cystic fibrosis, hyperlipoproteinaemia type I and methemoglobinaemia). In 45 B-I-D combinations, biomarkers were used as predictive of drug efficacy and in four of drug toxicity. It appeared that there was an increase in the number of B-I-D combinations introduced each year; however, the numbers were too small to identify any trends.ConclusionsGiven the large body of literature documenting research into potential predictive biomarkers and extensive investment into stratified medicine, we identified relatively few predictive biomarkers included in licensing. These were also limited to a small number of clinical areas. This might suggest a need for improvement in methods of translation from laboratory findings to clinical practice.
An analysis of the learning curve to achieve competency at colonoscopy using the JETS database
Authors: Ward Stephen Thomas , Mohammed Mohammed A , Walt Robert , Valori Roland , Ismail Tariq , Dunckley Paul 
Published: January 2014

ObjectiveThe number of colonoscopies required to reach competency is not well established. The primary aim of this study was to determine the number of colonoscopies trainees need to perform to attain competency, defined by a caecal intubation rate (CIR) ≥90%. As competency depends on completion, we also investigated trainee factors that were associated with colonoscopy completion.DesignThe Joint Advisory Group on GI Endoscopy in the UK has developed a trainee e-portfolio from which colonoscopy data were retrieved. Inclusion criteria were all trainees who had performed a total of ≥20 colonoscopies and had performed ≤50 colonoscopies prior to submission of data to the e-portfolio. The primary outcome measure was colonoscopy completion. The number of colonoscopies required to achieve CIR ≥90% was calculated by the moving average method and learning curve cumulative summation (LC-Cusum) analysis. To determine factors which determine colonoscopy completion, a mixed effect logistic regression model was developed which allowed for nesting of patients within trainees and nesting of patients within hospitals, with various patient, trainee and training factors entered as fixed effects.Results297 trainees undertook 36 730 colonoscopies. By moving average analysis, the cohort of trainees reached a CIR of 90% at 233 procedures. By LC-Cusum analysis, 41% of trainees were competent after 200 procedures. Of the trainee factors, the number of colonoscopies, intensity of training and previous flexible sigmoidoscopy experience were significant factors associated with colonoscopy completion.ConclusionsThis is the largest study to date investigating the number of procedures required to achieve competency in colonoscopy. The current training certification benchmark in the UK of 200 procedures does not appear to be an inappropriate minimum requirement. The LC-Cusum chart provides real time feedback on individual learning curves for trainees. The association of training intensity and flexible sigmoidoscopy experience with colonoscopy completion could be exploited in training programmes.
Interaction of stratigraphic and sedimentological heterogeneities with flow in carbonate ramp reservoirs: impact of fluid properties and production strategy
Authors: Fitch P. J. R. , Jackson M. D. , Hampson G. J. , John C. M. 
Published: January 2014

It is well known that heterogeneities in carbonate reservoirs impact fluid flow during production. However, few studies have examined the impact of the same heterogeneities on flow behaviour with different fluid properties and production scenarios. We use integrated flow simulation and experimental design techniques to investigate the relative, first-order impact of stratigraphic and sedimentological heterogeneities on simulated recovery in carbonate ramp reservoirs. Two production strategies are compared, which promote dominance of either horizontal or vertical flow.
We find that the modelled geology is more important than the simulated fluid properties and production scenarios over the ranges tested. Of the heterogeneities modelled here, rock properties and stratigraphic heterogeneities that control reservoir architecture and the spatial distribution of environment of deposition (EOD) belts are important controls on recovery regardless of the production strategy. The presence of cemented hardground surfaces becomes the key control on oil recovery in displacements dominated by vertical flow. Permeability anisotropy is of low importance for all production strategies. The impacts of stratigraphic heterogeneities on recovery factor and water breakthrough are more strongly influenced by fluid properties and well spacing in displacements dominated by vertical flow. These results help to streamline the reservoir modelling process, by identifying key heterogeneities, and to optimize production strategies.
Effect of strain geometry on the petrophysical properties of plastically deformed aggregates: experiments on Solnhofen limestone
Authors: Llana-Fúnez Sergio , Rutter Ernest H. 
Published: January 2014

Abstract

Specimens of Solnhofen limestone were deformed under conditions where calcite deforms plastically using four experimental configurations: extension, torsion, direct shear and axisymmetric shortening. All experiments were run on dry specimens at the same temperature (600 °C), confining pressure (200 MPa) and comparable strain rates (
c.
10
−4
s
−1
). The different experimental settings and the heterogeneity of deformation within some of the specimens provided a large range of strain geometries. They allowed locally imposed strain geometries to be related to the crystallographic preferred orientation (CPO) patterns of calcite and the orientation of the shape fabric of calcite grains. CPO in calcite was measured using electron back-scattered diffraction (EBSD) in scanning electron microscopy. The development of CPO during deformation under the dominance of intracrystalline plasticity contains information about the strain geometry accumulated in rocks in 3D, although in nature the strain geometry can be modified by dynamic recrystallization that was not seen in the experiments. The different CPO patterns have a significant effect on the velocity structure of the deformed aggregates. Seismic properties inferred from CPO show that the orientation of the fastest
V

p

wave aligns with principal strain directions that are not equivalent in different strain geometries.
Communication costs of Strassen's matrix multiplication
Authors: Ballard Grey , Demmel James , Holtz Olga , Schwartz Oded 
Published: January 2014

Algorithms have historically been evaluated in terms of the number of arithmetic operations they performed. This analysis is no longer sufficient for predicting running times on today's machines. Moving data through memory hierarchies and among processors requires much more time (and energy) than performing computations. Hardware trends suggest that the relative costs of this communication will only increase. Proving lower bounds on the communication of algorithms and finding algorithms that attain these bounds are therefore fundamental goals. We show that the communication cost of an algorithm is closely related to the graph expansion properties of its corresponding computation graph.
Matrix multiplication is one of the most fundamental problems in scientific computing and in parallel computing. Applying expansion analysis to Strassen's and other fast matrix multiplication algorithms, we obtain the first lower bounds on their communication costs. These bounds show that the current sequential algorithms are optimal but that previous parallel algorithms communicate more than necessary. Our new parallelization of Strassen's algorithm is communication-optimal and outperforms all previous matrix multiplication algorithms.<!-- END_PAGE_1 -->
Document Score Distribution Models for Query Performance Inference and Prediction
Authors: Cummins Ronan 
Published: January 2014

Modelling the distribution of document scores returned from an information retrieval (IR) system in response to a query is of both theoretical and practical importance. One of the goals of modelling document scores in this manner is the inference of document relevance. There has been renewed interest of late in modelling document scores using parameterised distributions. Consequently, a number of hypotheses have been proposed to constrain the mixture distribution from which document scores could be drawn.
In this article, we show how a standard performance measure (i.e., average precision) can be inferred from a document score distribution using labelled data. We use the accuracy of the inference of average precision as a measure for determining the usefulness of a particular model of document scores. We provide a comprehensive study which shows that certain mixtures of distributions are able to infer average precision more accurately than others. Furthermore, we analyse a number of mixture distributions with regard to the recall-fallout convexity hypothesis and show that the convexity hypothesis is practically useful.
Consequently, based on one of the best-performing score-distribution models, we develop some techniques for query-performance prediction (QPP) by automatically estimating the parameters of the document score-distribution model when relevance information is unknown. We present experimental results that outline the benefits of this approach to query-performance prediction.
ATDC/TRIM29 Phosphorylation by ATM/MAPKAP Kinase 2 Mediates Radioresistance in Pancreatic Cancer Cells
Authors: Wang Lidong , Yang Huibin , Palmbos Phillip L. , Ney Gina , Detzler Taylor Ann , Coleman Dawn , Leflein Jacob , Davis Mary , Zhang Min , Tang Wenhua , Hicks J. Kevin , Helchowski Corey M. , Prasad Jayendra , Lawrence Theodore S. , Xu Liang , Yu Xiaochun , Canman Christine E. , Ljungman Mats , Simeone Diane M. 
Published: January 2014

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by therapeutic resistance for which the basis is poorly understood. Here, we report that the DNA and p53-binding protein ATDC/TRIM29, which is highly expressed in PDAC, plays a critical role in DNA damage signaling and radioresistance in pancreatic cancer cells. Ataxia-telangiectasia group D-associated gene (ATDC) mediated resistance to ionizing radiation in vitro and in vivo in mouse xenograft assays. ATDC was phosphorylated directly by MAPKAP kinase 2 (MK2) at Ser550 in an ATM-dependent manner. Phosphorylation at Ser-550 by MK2 was required for the radioprotective function of ATDC. Our results identify a DNA repair pathway leading from MK2 and ATM to ATDC, suggesting its candidacy as a therapeutic target to radiosensitize PDAC and improve the efficacy of DNA-damaging treatment. Cancer Res; 74(6); 1778–88. ©2014 AACR.
Rare Coding Variants and Breast Cancer Risk: Evaluation of Susceptibility Loci Identified in Genome-Wide Association Studies
Authors: Zhang Yanfeng , Long Jirong , Lu Wei , Shu Xiao-Ou , Cai Qiuyin , Zheng Ying , Li Chun , Li Bingshan , Gao Yu-Tang , Zheng Wei 
Published: January 2014

Abstract
Background: To date, common genetic variants in approximately 70 loci have been identified for breast cancer via genome-wide association studies (GWAS). It is unknown whether rare variants in these loci are also associated with breast cancer risk.
Methods: We investigated rare missense/nonsense variants with minor allele frequency (MAF) ≤5% located in flanking 500 kb of each of the index single-nucleotide polymorphism (SNP) in 67 GWAS loci. Included in the study were 3,472 cases and 3,595 controls from the Shanghai Breast Cancer Study. Both single marker and gene-based analyses were conducted to investigate the associations.
Results: Single marker analyses identified 38 missense variants being associated with breast cancer risk at P &lt; 0.05 after adjusting for the index SNP. SNP rs146217902 in the EDEM1 gene and rs200340088 in the EFEMP2 gene were only observed in 8 cases (P = 0.004 for both). SNP rs200995432 in the EFEMP2 gene was associated with increased risk with an OR of 6.2 [95% confidence interval (CI), 1.4–27.6; P = 6.2 × 10−3]. SNP rs80358978 in the BRCA2 gene was associated with 16.5-fold elevated risk (95% CI, 2.2–124.5; P = 2.2 × 10−4). Gene-based analyses suggested eight genes associated with breast cancer risk at P &lt; 0.05, including the EFEMP2 gene (P = 0.002) and the FBXO18 gene (P = 0.008).
Conclusion: Our results identified associations of several rare coding variants neighboring common GWAS loci with breast cancer risk. Further investigation of these rare variants and genes would help to understand the biologic mechanisms underlying the associations.
Impact: Independent studies with larger sample size are warranted to clarify the relationship between these rare variants and breast cancer risk. Cancer Epidemiol Biomarkers Prev; 23(4); 622–8. ©2014 AACR.
Prevalence and Characteristics of MUTYH-Associated Polyposis in Patients with Multiple Adenomatous and Serrated Polyps
Authors: Guarinos Carla , Juárez Miriam , Egoavil Cecilia , Rodríguez-Soler María , Pérez-Carbonell Lucía , Salas Ramón , Cubiella Joaquín , Rodríguez-Moranta Francisco , de-Castro Luisa , Bujanda Luis , Serradesanferm Anna , Nicolás-Pérez David , Herráiz Maite , Fernández-Bañares Fernando , Herreros-de-Tejada Alberto , Aguirre Elena , Balmaña Judith , Rincón María-Luisa , Pizarro Angeles , Polo-Ortiz Francisco , Castillejo Adela , Alenda Cristina , Payá Artemio , Soto José-Luis , Jover Rodrigo 
Published: January 2014

Abstract
Purpose: The present study aimed to determine the prevalence of MUTYH mutations in patients with multiple colonic polyps and to explore the best strategy for diagnosing MUTYH-associated polyposis (MAP) in these patients.
Experimental Design: This study included 405 patients with at least 10 colonic polyps each. All cases were genetically tested for the three most frequent MUTYH mutations. Whole-gene analysis was performed in heterozygous patients and in 216 patients lacking the three most frequent mutations. Polyps from 56 patients were analyzed for the KRAS-Gly12Cys and BRAF V600E somatic mutations.
Results: Twenty-seven (6.7%) patients were diagnosed with MAP, of which 40.8% showed serrated polyps. The sensitivity of studying only the three common variants was 74.1%. Of 216 patients without any monoallelic mutation in common variants, whole-gene analysis revealed biallelic pathogenic mutation in only one. G396D mutation was associated with serrated lesions and older age at diagnosis. There was a strong association between germinal MUTYH mutation and KRAS Gly12Cys somatic mutation in polyps. BRAF V600E mutation was found in 74% of serrated polyps in MUTYH-negative patients and in none of the polyps of MAP patients.
Conclusions: We observed a low frequency of MUTYH mutations among patients with multiple adenomatous and serrated polyps. The MAP phenotype frequently included patients with serrated polyps, especially when G396D mutation was involved. Our results show that somatic molecular markers of polyps can be useful in identifying MAP cases and support the need for the complete MUTYH gene analysis only in patients heterozygous for recurrent variants. Clin Cancer Res; 20(5); 1158–68. ©2014 AACR.
A Functional Germline Variant in GLI1 Implicates Hedgehog Signaling in Clinical Outcome of Stage II and III Colon Carcinoma Patients
Authors: Szkandera Joanna , Pichler Martin , Absenger Gudrun , Stotz Michael , Weissmueller Melanie , Samonigg Hellmut , Asslaber Martin , Lax Sigurd , Leitner Gerhard , Winder Thomas , Renner Wilfried , Gerger Armin 
Published: January 2014

Abstract
Purpose: Cumulating evidence indicates that germline variants in the Wnt, Notch, and Hedgehog pathways are involved in colon carcinoma progression and metastasis. We investigated germline polymorphisms in a comprehensive panel of Wnt, Notch, and Hedgehog pathway genes to predict time to recurrence (TTR) and overall survival in patients with stage II and III colon carcinoma.
Experimental Design: A total of 742 consecutively collected patients with stage II and III colon carcinoma were included in this retrospective study. Genomic DNA was analyzed for 18 germline polymorphisms in Wnt, Notch, and Hedgehog pathway genes (SFRP, DKK 2 and 3, AXIN2, APC, MYC, TCF7L2, NOTCH2, and GLI1) by TaqMan 5′-exonuclease assays.
Results: In univariate analysis, the homozygous mutant variant of GLI1 rs2228226 G&gt;C was significantly associated with decreased TTR in a recessive genetic model after adjustment for multiple testing [HR = 2.35; confidence interval (95% CI), 1.48–3.74; P &lt; 0.001] and remained significant in multivariate analysis including clinical stage, lymphovascular-, vascular-, and perineural-invasion (HR = 2.43; CI 95%, 1.52–3.87; P &lt; 0.001). In subanalyses, the association was limited to patients with surgery alone (HR = 3.21; CI 95%, 1.59–6.49; P = 0.001), in contrast with patients with adjuvant chemotherapy (HR = 0.82; CI 95%, 0.35–1.95; P = 0.657). When the subgroup of patients with “high-risk” GLI1 rs2228226 C/C genotype was analyzed, no benefit of adjuvant 5-fluorouracil–based chemotherapy could be found.
Conclusion: This is the first study identifying GLI1 rs2228226 G&gt;C as an independent prognostic marker in patients with stage II and III colon carcinoma. Prospective studies are warranted to validate our findings. Clin Cancer Res; 20(6); 1687–97. ©2014 AACR.