bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inferring the kinetics of stochastic gene expression from single-cell RNA-sequencing data
Authors: Kim Jong Kyoung , Marioni John C 
Published: January 2013

Abstract
Background
Genetically identical populations of cells grown in the same environmental condition show substantial variability in gene expression profiles. Although single-cell RNA-seq provides an opportunity to explore this phenomenon, statistical methods need to be developed to interpret the variability of gene expression counts.

Results
We develop a statistical framework for studying the kinetics of stochastic gene expression from single-cell RNA-seq data. By applying our model to a single-cell RNA-seq dataset generated by profiling mouse embryonic stem cells, we find that the inferred kinetic parameters are consistent with RNA polymerase II binding and chromatin modifications. Our results suggest that histone modifications affect transcriptional bursting by modulating both burst size and frequency. Furthermore, we show that our model can be used to identify genes with slow promoter kinetics, which are important for probabilistic differentiation of embryonic stem cells.

Conclusions
We conclude that the proposed statistical model provides a flexible and efficient way to investigate the kinetics of transcription.
Prognostic Nomogram for Intrahepatic Cholangiocarcinoma After Partial Hepatectomy
Authors: Wang Yizhou , Li Jun , Xia Yong , Gong Renyan , Wang Kui , Yan Zhenlin , Wan Xuying , Liu Guanghua , Wu Dong , Shi Lehua , Lau Wanyee , Wu Mengchao , Shen Feng 
Published: January 2013

Purpose This study aimed to establish an effective prognostic nomogram for intrahepatic cholangiocarcinoma (ICC) after partial hepatectomy. Patients and Methods The nomogram was based on a retrospectively study on 367 patients who underwent partial hepatectomy for ICC at the Eastern Hepatobiliary Surgery Hospital from 2002 to 2007. The predictive accuracy and discriminative ability of the nomogram were determined by concordance index (C-index) and calibration curve and compared with five currently used staging systems on ICC. The results were validated using bootstrap resampling and a prospective study on 82 patients operated on from 2007 to 2008 at the same institution. Results On multivariate analysis of the primary cohort, independent factors for survival were serum carcinoembryonic antigen, CA 19-9, tumor diameter and number, vascular invasion, lymph node metastasis, direct invasion, and local extrahepatic metastasis, which were all selected into the nomogram. The calibration curve for probability of survival showed good agreement between prediction by nomogram and actual observation. The C-index of the nomogram for predicting survival was 0.74 (95% CI, 0.71 to 0.77), which was statistically higher than the C-index values of the following systems: American Joint Committee on Cancer (AJCC) seventh edition (0.65), AJCC sixth edition (0.65), Nathan (0.64), Liver Cancer Study Group of Japan (0.64), and Okabayashi (0.67; P < .001 for all). It was also higher (0.74) in predicting survival for the mass-forming type of ICC (P < .001). In the validation cohort, the nomogram discrimination was superior to the five other staging systems (C-index: 0.75 v 0.60 to 0.63; P < .001 for all). Conclusion The proposed nomogram resulted in more-accurate prognostic prediction for patients with ICC after partial hepatectomy.
Postinduction Dexamethasone and Individualized Dosing of Escherichia Coli L-Asparaginase Each Improve Outcome of Children and Adolescents With Newly Diagnosed Acute Lymphoblastic Leukemia: Results From a Randomized Study—Dana-Farber Cancer Institute ALL Consortium Protocol 00-01
Authors: Vrooman Lynda M. , Stevenson Kristen E. , Supko Jeffrey G. , O'Brien Jane , Dahlberg Suzanne E. , Asselin Barbara L. , Athale Uma H. , Clavell Luis A. , Kelly Kara M. , Kutok Jeffery L. , Laverdière Caroline , Lipshultz Steven E. , Michon Bruno , Schorin Marshall , Relling Mary V. , Cohen Harvey J. , Neuberg Donna S. , Sallan Stephen E. , Silverman Lewis B. 
Published: January 2013

Purpose We assessed the toxicity and efficacy of dexamethasone and a novel dosing method of Escherichia coli L-asparaginase (EC-Asnase) in children and adolescents with newly diagnosed acute lymphoblastic leukemia (ALL). Patients and Methods Patients achieving complete remission (CR) on Dana-Farber Cancer Institute ALL Consortium Protocol 00-01 were eligible for random assignment to 1) dexamethasone or prednisone, administered as 5-day pulses, every 3 weeks, and 2) weekly EC-Asnase, administered as a 25,000 IU/m2 fixed dose (FD) or individualized dose (ID) starting at 12,500-IU/m2, adjusted every 3 weeks based on nadir serum asparaginase activity (NSAA) determinations. Results Between 2000 and 2004, 492 evaluable patients (ages 1 to 18 years) enrolled; 473 patients (96%) achieved CR. Four hundred eight patients (86%) participated in the corticosteroid randomization and 384 patients (81%) in the EC-Asnase randomization. With 4.9 years of median follow-up, dexamethasone was associated with superior 5-year event-free survival (EFS; 90% v 81% for prednisone; P = .01) but higher rates of infection (P = .03) and, in older children, higher cumulative incidence of osteonecrosis (P = .02) and fracture (P = .06). ID EC-Asnase had superior 5-year EFS (90% v 82% for FD; P = .04), but did not reduce the frequency of asparaginase-related toxicity. Multivariable analysis identified both dexamethasone and ID EC-Asnase as independent predictors of favorable EFS. Conclusion There was no overall difference in skeletal toxicity by corticosteroid type; dexamethasone was associated with more infections and, in older children, increased incidence of osteonecrosis and fracture. There was no difference in asparaginase-related toxicity by EC-Asnase dosing method. Dexamethasone and ID EC-Asnase were each associated with superior EFS. Monitoring NSAA during treatment with EC-Asnase may be an effective strategy to improve outcome in pediatric ALL.
Exemestane Versus Anastrozole in Postmenopausal Women With Early Breast Cancer: NCIC CTG MA.27—A Randomized Controlled Phase III Trial
Authors: Goss Paul E. , Ingle James N. , Pritchard Kathleen I. , Ellis Matthew J. , Sledge George W. , Budd G. Thomas , Rabaglio Manuela , Ansari Rafat H. , Johnson David B. , Tozer Richard , D'Souza David P. , Chalchal Haji , Spadafora Silvana , Stearns Vered , Perez Edith A. , Liedke Pedro E.R. , Lang Istvan , Elliott Catherine , Gelmon Karen A. , Chapman Judy-Anne W. , Shepherd Lois E. 
Published: January 2013

Purpose In patients with hormone-dependent postmenopausal breast cancer, standard adjuvant therapy involves 5 years of the nonsteroidal aromatase inhibitors anastrozole and letrozole. The steroidal inhibitor exemestane is partially non–cross-resistant with nonsteroidal aromatase inhibitors and is a mild androgen and could prove superior to anastrozole regarding efficacy and toxicity, specifically with less bone loss. Patients and Methods We designed an open-label, randomized, phase III trial of 5 years of exemestane versus anastrozole with a two-sided test of superiority to detect a 2.4% improvement with exemestane in 5-year event-free survival (EFS). Secondary objectives included assessment of overall survival, distant disease–free survival, incidence of contralateral new primary breast cancer, and safety. Results In the study, 7,576 women (median age, 64.1 years) were enrolled. At median follow-up of 4.1 years, 4-year EFS was 91% for exemestane and 91.2% for anastrozole (stratified hazard ratio, 1.02; 95% CI, 0.87 to 1.18; P = .85). Overall, distant disease–free survival and disease-specific survival were also similar. In all, 31.6% of patients discontinued treatment as a result of adverse effects, concomitant disease, or study refusal. Osteoporosis/osteopenia, hypertriglyceridemia, vaginal bleeding, and hypercholesterolemia were less frequent on exemestane, whereas mild liver function abnormalities and rare episodes of atrial fibrillation were less frequent on anastrozole. Vasomotor and musculoskeletal symptoms were similar between arms. Conclusion This first comparison of steroidal and nonsteroidal classes of aromatase inhibitors showed neither to be superior in terms of breast cancer outcomes as 5-year initial adjuvant therapy for postmenopausal breast cancer by two-way test. Less toxicity on bone is compatible with one hypothesis behind MA.27 but requires confirmation. Exemestane should be considered another option as up-front adjuvant therapy for postmenopausal hormone receptor–positive breast cancer.
Contactin 4, -5 and -6 differentially regulate neuritogenesis while they display identical PTPRG binding sites
Authors: Mercati Oriane , Danckaert Anne , André-Leroux Gwénaëlle , Bellinzoni Marco , Gouder Laura , Watanabe Kazutada , Shimoda Yasushi , Grailhe Régis , De Chaumont Fabrice , Bourgeron Thomas , Cloëz-Tayarani Isabelle 
Published: January 2013

Summary
The neural cell-adhesion molecules contactin 4, contactin 5 and contactin 6 are involved in brain development, and disruptions in contactin genes may confer increased risk for autism spectrum disorders (ASD). We describe a co-culture of rat cortical neurons and HEK293 cells overexpressing and delivering the secreted forms of rat contactin 4–6. We quantified their effects on the length and branching of neurites. Contactin 4–6 effects were different depending on the contactin member and duration of co-culture. At 4 days in culture, contactin 4 and -6 increased the length of neurites, while contactin 5 increased the number of roots. Up to 8 days in culture, contactin 6 progressively increased the length of neurites while contactin 5 was more efficient on neurite branching. We studied the molecular sites of interaction between human contactin 4, -5 or -6 and the human Protein Tyrosine Phosphatase Receptor Gamma (PTPRG), a contactin partner, by modeling their 3D structures. As compared to contactin 4, we observed differences in the Ig2 and Ig3 domains of contactin 5 and -6 with the appearance of an omega loop that could adopt three distinct conformations. However, interactive residues between human contactin 4–6 and PTPRG were strictly conserved. We did not observe any differences in PTPRG binding on contactin 5 and -6 either. Our data suggest that the differential contactin effects on neurite outgrowth do not result from distinct interactions with PTPRG. A better understanding of the contactin cellular properties should help elucidate their roles in ASD.
On Implications of Demand Censoring in the Newsvendor Problem
Authors: Besbes Omar , Muharremoglu Alp 
Published: January 2013

We consider a repeated newsvendor problem in which the decision maker (DM) does not have access to the underlying demand distribution. The goal of this paper is to characterize the implications of demand censoring on performance. To that end, we compare the benchmark setting in which the DM has access to demand observations to a setting in which the DM may only rely on sales data. We measure performance in terms of regret: the difference between the cumulative costs of a policy and the optimal cumulative costs with knowledge of the demand distribution. Through upper and lower bounds, we characterize the optimal magnitude of the worst-case regret for the two settings, enabling one to isolate the implications of demand censoring. In particular, the results imply that the exploration–exploitation trade-off introduced by demand censoring is fundamentally different in the continuous and discrete demand cases, and that active exploration plays a much stronger role in the latter case. We further establish that in the discrete demand case, the need for active exploration almost disappears as soon as a lost sales indicator (that records whether demand was censored or not) becomes available, in addition to the censored demand samples. This paper was accepted by Gérard P. Cachon, stochastic models and simulation.
Exposure to Alcohol Advertisements and Teenage Alcohol-Related Problems
Authors: Grenard Jerry L. , Dent Clyde W. , Stacy Alan W. 
Published: January 2013

OBJECTIVE:
This study used prospective data to test the hypothesis that exposure to alcohol advertising contributes to an increase in underage drinking and that an increase in underage drinking then leads to problems associated with drinking alcohol.

METHODS:
A total of 3890 students were surveyed once per year across 4 years from the 7th through the 10th grades. Assessments included several measures of exposure to alcohol advertising, alcohol use, problems related to alcohol use, and a range of covariates, such as age, drinking by peers, drinking by close adults, playing sports, general TV watching, acculturation, parents’ jobs, and parents’ education.

RESULTS:
Structural equation modeling of alcohol consumption showed that exposure to alcohol ads and/or liking of those ads in seventh grade were predictive of the latent growth factors for alcohol use (past 30 days and past 6 months) after controlling for covariates. In addition, there was a significant total effect for boys and a significant mediated effect for girls of exposure to alcohol ads and liking of those ads in 7th grade through latent growth factors for alcohol use on alcohol-related problems in 10th grade.

CONCLUSIONS:
Younger adolescents appear to be susceptible to the persuasive messages contained in alcohol commercials broadcast on TV, which sometimes results in a positive affective reaction to the ads. Alcohol ad exposure and the affective reaction to those ads influence some youth to drink more and experience drinking-related problems later in adolescence.
Nine-Year Follow-up of a Home-Visitation Program: A Randomized Trial
Authors: Fergusson David M. , Boden Joseph M. , Horwood L. John 
Published: January 2013

OBJECTIVE:
To evaluate the extent to which a home-visitation program (Early Start) had benefits for child abuse, child behavior, and parental- and family-level benefits to the 9-year follow-up.

METHODS:
A randomized controlled trial in which 220 families receiving Early Start were contrasted with a control series of 223 families not receiving the program. Families were enrolled in the program for up to 5 years. Outcomes were assessed at 6 months, annually from 1 year to 6 years, and at 9 years after trial entry.

RESULTS:
Comparisons between the Early Start and control series showed that families in the Early Start program showed significant (P &lt; .05) benefits in reduced risk of hospital attendance for unintentional injury, lower risk of parent-reported harsh punishment, lower levels of physical punishment, higher parenting competence scores, and more positive child behavioral adjustment scores. Effect sizes (Cohen’s “d”) ranged from 0.13 to 0.29 (median = 0.25). There were no significant differences (all P values &gt; .05) between the Early Start and control series on a range of measures of parental behavior and family outcomes, including maternal depression, parental substance use, intimate partner violence, adverse economic outcomes, and life stress.

CONCLUSIONS:
The Early Start program was associated with small to moderate benefits in a range of areas relating to child abuse, physical punishment, child behavior, and parenting competence. There was little evidence to suggest that the Early Start program had benefits that extended to the level of parents or family overall.
Guidance on Management of Asymptomatic Neonates Born to Women With Active Genital Herpes Lesions
Authors: Kimberlin David W. , Baley Jill ,   COMMITTEE ON INFECTIOUS DISEASES,   COMMITTEE ON FETUS AND NEWBORN, Brady Michael T. , Byington Carrie L. , Davies H. Dele , Edwards Kathryn M. , Glode Mary P. , Jackson Mary Anne , Keyserling Harry L. , Maldonado Yvonne A. , Murray Dennis L. , Orenstein Walter A. , Schutze Gordon E. , Willoughby Rodney E. , Zaoutis Theoklis E. , Papile Lu-Ann , Bhutani Vinod K. , Carlo Waldemar A. , Cummings James , Kumar Praveen , Polin Richard A. , Tan Rosemarie C. , Wang Kasper S. , Watterberg Kristi L. 
Published: January 2013

This Clinical Report was retired March 2022.
Herpes simplex virus (HSV) infection of the neonate is uncommon, but genital herpes infections in adults are very common. Thus, although treating an infant with neonatal herpes is a relatively rare occurrence, managing infants potentially exposed to HSV at the time of delivery occurs more frequently. The risk of transmitting HSV to an infant during delivery is determined in part by the mother’s previous immunity to HSV. Women with primary genital HSV infections who are shedding HSV at delivery are 10 to 30 times more likely to transmit the virus to their newborn infants than are women with recurrent HSV infection who are shedding virus at delivery. With the availability of commercial serological tests that reliably can distinguish type-specific HSV antibodies, it is now possible to determine the type of maternal infection and, thus, further refine management of infants delivered to women who have active genital HSV lesions. The management algorithm presented herein uses both serological and virological studies to determine the risk of HSV transmission to the neonate who is delivered to a mother with active herpetic genital lesions and tailors management accordingly. The algorithm does not address the approach to asymptomatic neonates delivered to women with a history of genital herpes but no active lesions at delivery.
Analysis of Regional Timelines To Set Up a Global Phase III Clinical Trial in Breast Cancer: The Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Experience
Authors: Metzger-Filho Otto , de Azambuja Evandro , Bradbury Ian , Saini Kamal S. , Bines José , Simon Sergio D. , Van Dooren Veerle , Aktan Gursel , Pritchard Kathleen I. , Wolff Antonio C. , Smith Ian , Jackisch Christian , Lang Istvan , Untch Michael , Boyle Frances , Xu Binghe , Baselga Jose , Perez Edith A. , Piccart-Gebhart Martine 
Published: January 2013

Abstract

Learning Objectives
Discuss methods for improving the efficiency of global clinical trials. Explain the need for national regulatory authorities and collaborative cancer groups to initiate efforts to quicken the activation process in their countries. Describe the activation process of phase III studies and its complex and heterogeneous regulation across different geographic and economic regions.

Purpose.
This study measured the time taken for setting up the different facets of Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO), an international phase III study being conducted in 44 participating countries.

Methods.
Time to regulatory authority (RA) approval, time to ethics committee/institutional review board (EC/IRB) approval, time from study approval by EC/IRB to first randomized patient, and time from first to last randomized patient were prospectively collected in the ALTTO study. Analyses were conducted by grouping countries into either geographic regions or economic classes as per the World Bank's criteria.

Results.
South America had a significantly longer time to RA approval (median: 236 days, range: 21–257 days) than Europe (median: 52 days, range: 0–151 days), North America (median: 26 days, range: 22–30 days), and Asia-Pacific (median: 62 days, range: 37–75 days). Upper-middle economies had longer times to RA approval (median: 123 days, range: 21–257 days) than high-income (median: 47 days, range: 0–112 days) and lower-middle income economies (median: 57 days, range: 37–62 days). No significant difference was observed for time to EC/IRB approval across the studied regions (median: 59 days, range 0–174 days). Overall, the median time from EC/IRB approval to first recruited patient was 169 days (range: 26–412 days).

Conclusion.
This study highlights the long time intervals required to activate a global phase III trial. Collaborative research groups, pharmaceutical industry sponsors, and regulatory authorities should analyze the current system and enter into dialogue for optimizing local policies. This would enable faster access of patients to innovative therapies and enhance the efficiency of clinical research.
Construction and Use of Environmental Management Accounting Systems with the REA Business Ontology
Authors: Weigand Hans , Elsas Philip 
Published: January 2013

ABSTRACT
Environmental Management Accounting is rapidly evolving from an ethical side-issue into a core business concern. However, traditional management accounting methods and currently available tools provide only limited support. Resource-Event-Agent (REA) is a well-known business ontology that offers a rigorous axiomatic basis for accounting and auditing. The paper demonstrates that on the basis of an extension of REA, it is possible to develop integrated modeling solutions and tools for environmental management accounting and assurance. The focus is on physical resource flow modeling (internal and external).
Renal Glucose Handling
Authors: Ferrannini Ele , Veltkamp Stephan A. , Smulders Ronald A. , Kadokura Takeshi 
Published: January 2013

OBJECTIVE
Ipragliflozin, a sodium-glucose cotransporter 2 inhibitor, stimulates glycosuria and lowers glycemia in patients with type 2 diabetes (T2DM). The objective of this study was to assess the pharmacodynamics of ipragliflozin in T2DM patients with impaired renal function.

RESEARCH DESIGN AND METHODS
Glycosuria was measured before and after a single ipragliflozin dose in 8 nondiabetic subjects and 57 T2DM patients (age 62 ± 9 years, fasting glucose 133 ± 39 mg/dL, mean ± SD) with normal renal function (assessed as the estimated glomerular filtration rate [eGFR]) (eGFR1 ≥90 mL · min–1 · 1.73 m−2), mild (eGFR2 ≥60 to &lt;90), moderate (eGFR3 ≥30 to &lt;60), or severe reduction in eGFR (eGFR4 ≤15 to &lt;30).

RESULTS
Ipragliflozin significantly increased urinary glucose excretion in each eGFR class (P &lt; 0.0001). However, ipragliflozin-induced glycosuria declined (median [IQR]) across eGFR class (from 46 mg/min [33] in eGFR1 to 8 mg/min [7] in eGFR4, P &lt; 0.001). Ipragliflozin-induced fractional glucose excretion (excretion/filtration) was 39% [27] in the T2DM patients (pooled data), similar to that of the nondiabetic subjects (37% [17], P = ns). In bivariate analysis of the pooled data, ipragliflozin-induced glycosuria was directly related to eGFR and fasting glucose (P &lt; 0.0001 for both, r2 = 0.55), predicting a decrement in 24-h glycosuria of 15 g for each 20 mL/min decline in eGFR and an increase of 7 g for each 10 mg/dL increase in glucose above fasting normoglycemia.

CONCLUSIONS
In T2DM patients, ipragliflozin increases glycosuria in direct, linear proportion to GFR and degree of hyperglycemia, such that its amount can be reliably predicted in the individual patient. Although absolute glycosuria decreases with declining GFR, the efficiency of ipragliflozin action (fractional glucose excretion) is maintained in patients with severe renal impairment.
Analysis of inter-quark interactions in classical chromodynamics
Authors: Darewych Jurij , Duviryak Askold 
Published: January 2013

Abstract
The QCD gluon equation of motion is solved approximately by means of a Green function. This solution is used to reformulate the Lagrangian of QCD such that the gluon propagator appears directly in the interaction terms of the Lagrangian. The nature of the interactions is discussed. A coordinate-space form of the interactions is presented and analyzed in the static, non-relativistic case.