bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antitumor Activity of a Duocarmycin Analogue Rationalized to Be Metabolically Activated by Cytochrome P450 1A1 in Human Transitional Cell Carcinoma of the Bladder
Authors: Sutherland Mark , Gill Jason H. , Loadman Paul M. , Laye Jonathan P. , Sheldrake Helen M. , Illingworth Nicola A. , Alandas Mohammed N. , Cooper Patricia A. , Searcey Mark , Pors Klaus , Shnyder Steve D. , Patterson Laurence H. 
Published: October 2012

AbstractWe identify cytochrome P450 1A1 (CYP1A1) as a target for tumor-selective drug development in bladder cancer and describe the characterization of ICT2700, designed to be metabolized from a prodrug to a potent cytotoxin selectively by CYP1A1. Elevated CYP1A1 expression was shown in human bladder cancer relative to normal human tissues. RT112 bladder cancer cells, endogenously expressing CYP1A1, were selectively chemosensitive to ICT2700, whereas EJ138 bladder cells that do not express CYP1A1 were significantly less responsive. Introduction of CYP1A1 into EJ138 cells resulted in 75-fold increased chemosensitivity to ICT2700 relative to wild-type EJ138. Negligible chemosensitivity was observed in ICT2700 in EJ138 cells expressing CYP1A2 or with exposure of EJ138 cells to CYP1B1- or CYP3A4-generated metabolites of ICT2700. Chemosensitivity to ICT2700 was also negated in EJ138-CYP1A1 cells by the CYP1 inhibitor α-naphthoflavone. Furthermore, ICT2700 did not induce expression of the AhR-regulated CYP1 family, indicating that constitutive CYP1A1 expression is sufficient for activation of ICT2700. Consistent with the selective activity by CYP1A1 was a time and concentration-dependent increase in γ-H2AX protein expression, indicative of DNA damage, associated with the activation of ICT2700 in RT112 but not EJ138 cells. In mice-bearing CYP1A1-positive and negative isogenic tumors, ICT2700 administration resulted in an antitumor response only in the CYP1A1-expressing tumor model. This antitumor response was associated with detection of the CYP1A1-activated metabolite in tumors but not in the liver. Our findings support the further development of ICT2700 as a tumor-selective treatment for human bladder cancers. Mol Cancer Ther; 12(1); 27–37. ©2012 AACR.
EDSS variability before randomization may limit treatment discovery in primary progressive MS
Authors: Zhang Jiameng , Waubant Emmanuelle , Cutter Gary , Wolinsky Jerry S , Glanzman Robert 
Published: October 2012

Background: Baseline Expanded Disability Status Scale (EDSS) is usually based on a single measurement. Here we evaluated whether using a baseline EDSS derived from two pre-treatment measurements improves the detection of progression events and the ability to demonstrate a therapeutic effect in delaying MS disability progression. Methods: Real data from OLYMPUS, a phase II/III randomized, placebo-controlled trial of rituximab in patients with primary progressive multiple sclerosis (PPMS), as well as simulated data were analyzed. Several definitions of baseline EDSS were used to capture sustained disability progression (SDP) events. Variations in the EDSS were estimated by linear mixed-effect models. Results: Selecting the higher of two baseline EDSS scores lowered the number of SDP events in both treatment groups, so decreasing sensitivity, and reduced the number of false SDP events, so increasing specificity. Conversely, selecting the lower of two baseline scores increased sensitivity but decreased specificity. Increased power (~7% based on the simulation study) was observed when the average of screening and Week 0 EDSS scores was used for baseline. Conclusion: Baseline EDSS derived from two pre-treatment EDSS measurements may enhance the ability of detecting a therapeutic effect in slowing disability progression in PPMS. This strategy could be implemented in future clinical trials of patients with MS.
Behaviorally based adherence program for pediatric patients treated with positive airway pressure
Authors: Harford Kelli-Lee , Jambhekar Supriya , Com Gulnur , Pruss Kristi , Kabour Marianne , Jones Kaitlin , Ward Wendy L. 
Published: October 2012

Objectives: Positive Airway Pressure (PAP) devices are being increasingly used in pediatric populations for problems including Obstructive Sleep Apnea. There is limited literature regarding pediatric adherence with PAP treatment or successful interventions that improve adherence. This paper describes a clinical program for pediatric PAP users which was designed to improve adherence of patients prescribed PAP therapy and involves intensive assessment and behavioral intervention. Method: The design and implementation of the program is described, including the purpose, goals, programmatic structure, clinical content, type and training of personnel, strengths and limitations and financial concerns as well as the challenges with the development and application of the program’s protocol. Results: Preliminary outcome data show short-term improvements in consistent usage for many of the patients. Conclusions: The program shows some promise and provides a framework for future program development and research.
Self-perception in a clinical sample of gender variant children
Authors: Rijn Anouk Balleur-van , Steensma Thomas D , Kreukels Baudewijntje PC , Cohen-Kettenis Peggy T 
Published: October 2012

Background: Gender variance (GV) in childhood has a negative impact on the self-concept of children in the general population and can lead to mental health problems and even suicidal ideation in adulthood. This study explored the self-concept of clinically referred gender variant children and examined potential risk factors. Method: The Self-Perception Profile for Children was administered to 147 children, who were referred to a gender identity clinic. Their parents completed the Child Behaviour Checklist and the Gender Identity Questionnaire to assess the degree of GV. Results: The referred children were at risk of developing a negative self-concept; more specifically gender variant girls had low scores on ‘global self-worth’, ‘physical appearance’ and ‘behavioural conduct’ compared to Dutch norms for girls. Gender variant boys had low scores on ‘global self-worth’, ‘scholastic competence’, ‘athletic competence’ and ‘physical appearance’ compared to Dutch norms for boys. Within the group of referred children, sex differences, but no age effects, were found. The referred girls felt more competent than the referred boys on ‘athletic competence’ and ‘scholastic functioning’. For both boys and girls poor peer relations had a significant negative relationship with self-concept and more GV was related to a lower global self-worth. Conclusions: Clinically referred gender variant children seemed vulnerable to developing a negative self-concept. Poor peer relations and extreme GV might be mediating variables. Interventions might focus on enhancing acceptance of the environment and improving social skills of gender variant children.
Participant characteristics and study features associated with high retention rates in a longitudinal investigation of type 1 diabetes mellitus
Authors: Kramer John R , Bayless Margaret L , Lorenzi Gayle M , Ziegler Georgia K , Larkin Mary E , Lackaye Mary E , Harth Judith , Diminick Lisa J , Anderson Karen L , Braffett Barbara H , Cleary Patricia A ,   The DCCT/EDIC Study Group
Published: October 2012

Background The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study has sustained an extraordinarily high level of participant involvement for over two decades. Purpose In order to identify specific characteristics of EDIC that contributed most strongly to retention, study-designed questionnaires were distributed to 1334 participants. Methods Confidential questionnaires were completed during EDIC Years 15–17. Participants were classified as Completely Adherent (completed all visits), Partly Adherent (missed >1 visit or major portion of a visit), or Inactive (did not participate for >5 years). Questionnaire items addressed specific aspects of clinic visits, evaluation procedures, staff–participant relationships, and medical/health-care support provided by EDIC. Results The most commonly cited reasons for continuing participation were Cutting Edge Tests to assess diabetes complications (79.3%), Annual Evaluations (67.7%), a desire to Help Others (65.2%), and Better Care for Diabetes (61.6%). Women chose Cutting Edge Tests as their first or second most important reason significantly more often than men, whereas men chose Better Care for Diabetes more frequently. Individuals with at least three diabetes-related complications were more likely than those with fewer complications to choose Annual Evaluations as their first or second reason for continued involvement. Limitations The small proportion of individuals who discontinued participation restricted our ability to identify factors associated with suspended involvement. In addition, our analysis is limited to a cohort with type 1 diabetes followed in an observational study after an average participation time of 6.5 years in a randomized trial. Conclusions The primary reasons identified by respondents for their long-term commitment are consistent with shorter-term studies and underscore the importance of expert medical care, supportive staff–participant relationships, and involvement with clinically and scientifically meaningful research.
SOCS3 promotes interleukin-17 expression of human T cells
Authors: Kleinsteuber Katja , Heesch Kerrin , Schattling Stefanie , Sander-Juelch Claudia , Mock Ulrike , Riecken Kristoffer , Fehse Boris , Fleischer Bernhard , Jacobsen Marc 
Published: October 2012

AbstractSOCS3 is a feedback regulator of cytokine signaling that affects T-cell polarization. Human tuberculosis is accompanied by increased SOCS3 expression in T cells, and this may influence susceptibility against Mycobacterium tuberculosis. Because the role of SOCS3 in human T-cell function is not well defined, we characterized cytokine expression and proliferation of human T cells with differential SOCS3 expression in the present study. We established a flow cytometry–based method for SOCS3 protein quantification and detected higher SOCS3 levels induced by M tuberculosis specific T-cell activation and a transient decrease of SOCS3 expression in the presence of mycobacteria-infected macrophages. Notably increased SOCS3 expression was detected in IL-17–expressing T-cell clones and in CD161+ T helper type 17 cells ex vivo. Ectopic SOCS3 expression in primary CD4+ T cells by lentiviral transduction induced increased IL-17 production but diminished proliferation and viability. Recombinant IL-7 inhibited SOCS3 expression and reduced IL-17–expressing T-cell proportions. We concluded that higher SOCS3 expression in human T cells favors T helper type 17 cells. Therefore, increased SOCS3 expression in human tuberculosis may reflect polarization toward IL-17–expressing T cells as well as T-cell exhaustion marked by reduced proliferation.
A phase 1 trial of the anti-KIR antibody IPH2101 in patients with relapsed/refractory multiple myeloma
Authors: Benson Don M. , Hofmeister Craig C. , Padmanabhan Swaminathan , Suvannasankha Attaya , Jagannath Sundar , Abonour Rafat , Bakan Courtney , Andre Pascale , Efebera Yvonne , Tiollier Jérôme , Caligiuri Michael A. , Farag Sherif S. 
Published: October 2012

Abstract
Natural killer (NK) cells elicit cytotoxicity against multiple myeloma (MM); however, MM cells express HLA class I molecules as ligands to NK cell inhibitory killer immunoglobulin-like receptors (KIRs) as a means of immunoevasion. KIR-ligand mismatch may improve outcomes in allogeneic transplantation for MM. Extrapolating on this concept, we conducted a phase 1 trial of IPH2101, an anti-KIR antibody, in patients with relapsed/refractory MM. IPH2101 was administered intravenously every 28 days in 7 dose–escalated cohorts (0.0003-3 mg/kg) for up to 4 cycles. Pharmacokinetic, pharmacodynamic, and correlative immunologic studies were completed. A total of 32 patients were enrolled. The biologic endpoint of full KIR2D occupancy across the dosing cycle was achieved without dose-limiting toxicity or maximally tolerated dose. One severe adverse event was noted. Pharmacokinetic and pharmacodynamic findings approximated preclinical predictions, and IPH2101 enhanced ex vivo patient–derived NK cell cytotoxicity against MM. No objective responses were seen. No evidence of autoimmunity was observed. These findings suggest that IPH2101 is safe and tolerable at doses that achieve full inhibitory KIR saturation, and this approach warrants further development in MM. This trial was registered at www.clinicaltrials.gov as #NCT00552396.
Evolution of major histocompatibility complex class I and class II genes in the brown bear
Authors: Kuduk Katarzyna , Babik Wiesław , Bojarska Katarzyna , Śliwińska Ewa B , Kindberg Jonas , Taberlet Pierre , Swenson Jon E , Radwan Jacek 
Published: October 2012

AbstractBackgroundMajor histocompatibility complex (MHC) proteins constitute an essential component of the vertebrate immune response, and are coded by the most polymorphic of the vertebrate genes. Here, we investigated sequence variation and evolution of MHC class I and class II DRB, DQA and DQB genes in the brown bearUrsus arctosto characterise the level of polymorphism, estimate the strength of positive selection acting on them, and assess the extent of gene orthology and trans-species polymorphism inUrsidae.ResultsWe found 37 MHC class I, 16 MHC class II DRB, four DQB and two DQA alleles. We confirmed the expression of several loci: three MHC class I, two DRB, two DQB and one DQA. MHC class I also contained two clusters of non-expressed sequences. MHC class I and DRB allele frequencies differed between northern and southern populations of the Scandinavian brown bear. The rate of nonsynonymous substitutions (dN) exceeded the rate of synonymous substitutions (dS) at putative antigen binding sites of DRB and DQB loci and, marginally significantly, at MHC class I loci. Models of codon evolution supported positive selection at DRB and MHC class I loci. Both MHC class I and MHC class II sequences showed orthology to gene clusters found in the giant pandaAiluropoda melanoleuca.ConclusionsHistorical positive selection has acted on MHC class I, class II DRB and DQB, but not on the DQA locus. The signal of historical positive selection on the DRB locus was particularly strong, which may be a general feature of caniforms. The presence of MHC class I pseudogenes may indicate faster gene turnover in this class through the birth-and-death process. South–north population structure at MHC loci probably reflects origin of the populations from separate glacial refugia.
Comparison of gait in progressive supranuclear palsy, Parkinson’s disease and healthy older adults
Authors: Egerton Thorlene , Williams David R , Iansek Robert 
Published: October 2012

Abstract

Background
Progressive supranuclear palsy and Parkinson’s disease have characteristic clinical and neuropathologic profiles, but also share overlapping clinical features. This study aimed to analyze the gait of people with progressive supranuclear palsy (n=19) and compare it with people with Parkinson’s disease (n=20) and healthy older adults (n=20).

Methods
Gait was recorded at self-selected preferred, fast, very fast, slow and very slow speeds. Stride length was normalized to leg length. Linear regression analyses were carried out between cadence and stride length. Other gait variables were compared for each participant’s ‘walk’ which had stride length closest to 1.4.

Results
All groups showed a strong linear relationship between stride length and cadence with no difference between groups (p>0.05). The intercept between cadence and stride length was lowest in the progressive supranuclear palsy group and highest for older adults (p<0.001). The progressive supranuclear palsy group had higher cadence than older adults (p>0.05), and greater step width and greater double support phase compared with the other two groups (p<0.05).

Conclusions
The temporal-spatial gait characteristics of progressive supranuclear palsy and Parkinson’s disease are largely similar, with similar disruption to scaling of stride length. The additional findings of increased step width and double support percentage suggest increased severity of gait abnormality compared to Parkinson’s disease, despite similar disease duration. The findings are consistent with the clinical features of greater instability and more rapid disease progression in progressive supranuclear palsy compared to Parkinson’s disease and implicates the early pathological involvement of brain regions involved in gait control.
Cost-effectiveness of a 21-gene recurrence score assay versus Canadian clinical practice in women with early-stage estrogen- or progesterone-receptor-positive, axillary lymph-node negative breast cancer
Authors: Hannouf Malek B , Xie Bin , Brackstone Muriel , Zaric Gregory S 
Published: October 2012

Abstract

Background
A 21-gene recurrence score (RS) assay may inform adjuvant systematic treatment decisions in women with early stage breast cancer. We sought to investigate the cost effectiveness of using the RS-assay versus current clinical practice (CCP) in women with early-stage estrogen- or progesterone-receptor-positive, axilliary lymph-node negative breast cancer (ER+/ PR + LN- ESBC) from the perspective of the Canadian public healthcare system.

Methods
We developed a Markov model to project the lifetime clinical and economic consequences of ESBC. We evaluated adjuvant therapy separately in post- and pre-menopausal women with ER+/ PR + LN- ESBC. We assumed that the RS-assay would reclassify pre- and post-menopausal women among risk levels (low, intermediate and high) and guide adjuvant systematic treatment decisions. The model was parameterized using 7 year follow up data from the Manitoba Cancer Registry, cost data from Manitoba administrative databases, and secondary sources. Costs are presented in 2010 CAD. Future costs and benefits were discounted at 5%.

Results
The RS-assay compared to CCP generated cost-savings in pre-menopausal women and had an ICER of $60,000 per QALY gained in post-menopausal women. The cost effectiveness was most sensitive to the proportion of women classified as intermediate risk by the RS-assay who receive adjuvant chemotherapy and the risk of relapse in the RS-assay model.

Conclusions
The RS-assay is likely to be cost effective in the Canadian healthcare system and should be considered for adoption in women with ER+/ PR + LN- ESBC. However, ongoing assessment and validation of the assay in real-world clinical practice is warranted.
Physicians' Perceptions on the usefulness of contextual information for prioritizing and presenting alerts in computerized physician order entry systems
Authors: Jung Martin , Riedmann Daniel , Hackl Werner O , Hoerbst Alexander , Jaspers Monique W , Ferret Laurie , Lawton Kitta , Ammenwerth Elske 
Published: October 2012

Abstract

Background
One possible approach towards avoiding alert overload and alert fatigue in Computerized Physician Order Entry (CPOE) systems is to tailor their drug safety alerts to the context of the clinical situation. Our objective was to identify the perceptions of physicians on the usefulness of clinical context information for prioritizing and presenting drug safety alerts.

Methods
We performed a questionnaire survey, inquiring CPOE-using physicians from four hospitals in four European countries to estimate the usefulness of 20 possible context factors.

Results
The 223 participants identified the ‘ severity of the effect’ and the ‘clinical status of the patient’ as the most useful context factors. Further important factors are the ‘complexity of the case’ and the ‘risk factors of the patient’.

Conclusions
Our findings confirm the results of a prior, comparable survey inquiring CPOE researchers. Further research should focus on implementing these context factors in CPOE systems and on subsequently evaluating their impact.
Proteomic analysis reveals the diversity and complexity of membrane proteins in chickpea (Cicer arietinum L.)
Authors: Jaiswal Dinesh Kumar , Ray Doel , Subba Pratigya , Mishra Poonam , Gayali Saurabh , Datta Asis , Chakraborty Subhra , Chakraborty Niranjan 
Published: October 2012

Abstract

Background
Compartmentalization is a unique feature of eukaryotes that helps in maintaining cellular homeostasis not only in intra- and inter-organellar context, but also between the cells and the external environment. Plant cells are highly compartmentalized with a complex metabolic network governing various cellular events. The membranes are the most important constituents in such compartmentalization, and membrane-associated proteins play diverse roles in many cellular processes besides being part of integral component of many signaling cascades.

Results
To obtain valuable insight into the dynamic repertoire of membrane proteins, we have developed a proteome reference map of a grain legume, chickpea, using two-dimensional gel electrophoresis. MALDI-TOF/TOF and LC-ESI-MS/MS analysis led to the identification of 91 proteins involved in a variety of cellular functions viz., bioenergy, stress-responsive and signal transduction, metabolism, protein synthesis and degradation, among others. Significantly, 70% of the identified proteins are putative integral membrane proteins, possessing transmembrane domains.

Conclusions
The proteomic analysis revealed many resident integral membrane proteins as well as membrane-associated proteins including those not reported earlier. To our knowledge, this is the first report of membrane proteome from aerial tissues of a crop plant. The findings may provide a better understanding of the biochemical machinery of the plant membranes at the molecular level that might help in functional genomics studies of different developmental pathways and stress-responses.
Differences in lifestyle behaviors, dietary habits, and familial factors among normal-weight, overweight, and obese Chinese children and adolescents
Authors: Guo Xiaofan , Zheng Liqiang , Li Yang , Yu Shasha , Sun Guozhe , Yang Hongmei , Zhou Xinghu , Zhang Xingang , Sun Zhaoqing , Sun Yingxian 
Published: October 2012

Abstract

Background
Pediatric obesity has become a global public health problem. Data on the lifestyle behaviors, dietary habits, and familial factors of overweight and obese children and adolescents are limited. The present study aims to compare health-related factors among normal-weight, overweight, and obese Chinese children and adolescents.

Methods
We conducted a cross-sectional study consisted of 4262 children and adolescents aged 5–18 years old from rural areas of the northeast China. Anthropometric measurements and self-reported information on health-related variables, such as physical activities, sleep duration, dietary habits, family income, and recognition of weight status from the views of both children and parents, were collected by trained personnel.

Results
The prevalence rates of overweight and obesity were 15.3 and 6.4%, respectively. Compared to girls, boys were more commonly overweight (17.5% vs. 12.9%) and obese (9.5% vs. 3.1%). Approximately half of the parents with an overweight or obese child reported that they failed to recognize their child’s excess weight status, and 65% of patients with an overweight child reported that they would not take measures to decrease their child’s body weight. Obese children and adolescents were more likely to be nonsnackers [odds ratio (OR): 1.348; 95% confidence interval (CI): 1.039–1.748] and to have a family income of 2000 CNY or more per month (OR: 1.442; 95% CI: 1.045–1.99) and less likely to sleep longer (≥7.5 h) (OR: 0.475; 95% CI: 0.31–0.728) than the normal-weight participants.

Conclusions
Our study revealed a high prevalence of overweight and obesity in a large Chinese pediatric population. Differences in sleep duration, snacking, family income, and parental recognition of children’s weight status among participants in different weight categories were observed, which should be considered when planning prevention and treatment programs for pediatric obesity.