bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular mechanism of the camptothecin resistance of Glu710Gly topoisomerase IB mutant analyzed in vitro and in silico
Authors: Tesauro Cinzia , Morozzo della Rocca Blasco , Ottaviani Alessio , Coletta Andrea , Zuccaro Laura , Arnò Barbara , D'Annessa Ilda , Fiorani Paola , Desideri Alessandro 
Published: September 2013

Abstract

Background
DNA topoisomerases are key enzymes that modulate the topological state of DNA through the breaking and rejoining of DNA strands. Human topoisomerase IB can be inhibited by several compounds that act through different mechanisms, including clinically used drugs, such as the derivatives of the natural compound camptothecin that reversibly bind the covalent topoisomerase-DNA complex, slowing down the religation of the cleaved DNA strand, thus inducing cell death. Three enzyme mutations, which confer resistance to irinotecan in an adenocarcinoma cell line, were recently identified but the molecular mechanism of resistance was unclear.

Methods
The three resistant mutants have been investigated in S. cerevisiae model system following their viability in presence of increasing amounts of camptothecin. A systematical analysis of the different catalytic steps has been made for one of these mutants (Glu710Gly) and has been correlated with its structural-dynamical properties studied by classical molecular dynamics simulation.

Results
The three mutants display a different degree of camptothecin resistance in a yeast cell viability assay. Characterization of the different steps of the catalytic cycle of the Glu710Gly mutant indicated that its resistance is related to a high religation rate that is hardly affected by the presence of the drug. Analysis of the dynamic properties through simulation indicate that the mutant displays a much lower degree of correlation in the motion between the different protein domains and that the linker almost completely loses its correlation with the C-terminal domain, containing the active site tyrosine.

Conclusions
These results indicate that a fully functional linker is required to confer camptothecin sensitivity to topoisomerase I since the destabilization of its structural-dynamical properties is correlated to an increase of religation rate and drug resistance.
Associations between smoking, components of metabolic syndrome and lipoprotein particle size
Authors: Slagter Sandra N , van Vliet-Ostaptchouk Jana V , Vonk Judith M , Boezen H Marike , Dullaart Robin PF , Kobold Anneke C Muller , Feskens Edith J , van Beek André P , van derKlauw Melanie M , Wolffenbuttel Bruce HR 
Published: September 2013

Abstract

Background
The clustering of metabolic and cardiovascular risk factors is known as metabolic syndrome (MetS). The risk of having MetS is strongly associated with increased adiposity and can be further modified by smoking behavior. Apolipoproteins (apo) associated with low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C) may be altered in MetS. This study aimed to examine the association between smoking and the following parameters: MetS and its components, levels of apolipoproteins and estimated lipoprotein particle size, separately for men and women, and in different body mass index (BMI) classes.

Methods
We included 24,389 men and 35,078 women aged between 18 and 80 years who participated in the LifeLines Cohort Study between December 2006 and January 2012; 5,685 men and 6,989 women were current smokers. Participants were categorized into three different body mass index (BMI) classes (BMI <25; BMI 25 to 30; BMI ≥30 kg/m2). MetS was defined according to the National Cholesterol Education Program’s Adult Treatment Panel III (NCEP:ATPIII) criteria. Blood pressure, anthropometric and lipid measurements were rigorously standardized, and the large sample size enabled a powerful estimate of quantitative changes. The association between smoking and the individual MetS components, and apoA1 and apoB, was tested with linear regression. Logistic regression was used to examine the effect of smoking and daily tobacco smoked on risk of having MetS. All models were age adjusted and stratified by sex and BMI class.

Results
Prevalence of MetS increased with higher BMI levels. A total of 64% of obese men and 42% of obese women had MetS. Current smoking was associated with a higher risk of MetS in both sexes and all BMI classes (odds ratio 1.7 to 2.4 for men, 1.8 to 2.3 for women, all P values <0.001). Current smokers had lower levels of HDL cholesterol and apoA1, higher levels of triglycerides and apoB, and higher waist circumference than non-smokers (all P <0.001). Smoking had no consistent association with blood pressure or fasting blood glucose. In all BMI classes, we found a dose-dependent association of daily tobacco consumption with MetS prevalence as well as with lower levels of HDL cholesterol, higher triglyceride levels and lower ratios of HDL cholesterol/apoA1 and, only in those with BMI <30, LDL cholesterol/apoB (all P <0.001).

Conclusions
Smoking is associated with an increased prevalence of MetS, independent of sex and BMI class. This increased risk is mainly related to lower HDL cholesterol, and higher triglycerides and waist circumference. In addition, smoking was associated with unfavorable changes in apoA1 and apoB, and in lipoprotein particle size.
Please see related commentary: http://www.biomedcentral.com/1741-7015/11/196.
A culturally adapted lifestyle intervention addressing a Middle Eastern immigrant population at risk of diabetes, the MEDIM (impact of Migration and Ethnicity on Diabetes In Malmö): study protocol for a randomized controlled trial
Authors: Saha Sanjib , Leijon Matti , Gerdtham Ulf , Sundquist Kristina , Sundquist Jan , Arvidsson Daniel , Bennet Louise 
Published: September 2013

AbstractBackgroundStudies have shown that lifestyle interventions are effective in preventing or delaying the onset of type 2 diabetes in high-risk patients. However, research on the effectiveness of lifestyle interventions in high-risk immigrant populations with different cultural and socioeconomic backgrounds is scarce. The aim was to design a culturally adapted lifestyle intervention for an immigrant population and to evaluate its effectiveness and cost-effectiveness.Methods/designIn this randomized controlled trial, 308 participants (born in Iraq, living in Malmö, Sweden and at high risk of type 2 diabetes) will be allocated to either a culturally adapted intervention or a control group. The intervention will consist of 10 group counseling sessions focusing on diet, physical activity and behavioral change over 6 months, and the offer of exercise sessions. Cultural adaptation includes gender-specific exercise sessions, and counseling by a health coach community member. The control group will receive the information about healthy lifestyle habits provided by the primary health care center. The primary outcome is change in fasting glucose level. Secondary outcomes are changes in body mass index, insulin sensitivity, physical activity, food habits and health-related quality of life. Measurements will be taken at baseline, after 3 and 6 months. Data will be analyzed by the intention-to-treat approach. The cost-effectiveness during the trial period and over the longer term will be assessed by simulation modeling from patient, health care and societal perspectives.DiscussionThis study will provide a basis to measure the effectiveness of a lifestyle intervention designed for immigrants from the Middle East in terms of improvement in glucose metabolism, and will also assess its cost-effectiveness. Results from this trial may help health care providers and policy makers to adapt and implement lifestyle interventions suitable for this population group that can be conducted in the community.Trial registrationClinicalTrials.gov,NCT01420198
Tumor volume is an independent prognostic indicator of local control in nasopharyngeal carcinoma patients treated with intensity-modulated radiotherapy
Authors: Feng Mei , Wang Weidong , Fan Zixuan , Fu Binyu , Li Jie , Zhang Shichuan , Lang Jinyi 
Published: September 2013

Abstract

Background
To retrospectively analyze whether primary tumor volume and primary nodal volume could be considered independent prognostic factors for nasopharyngeal carcinoma treated with intensity-modulated radiation therapy.

Methods
Three hundred sixty-three consecutive nasopharyngeal carcinoma (NPC) patients who were stage I-IVa+b and treated with intensity-modulated radiotherapy (IMRT) in our center from October 2003 to October 2005 were analyzed retrospectively. The predictive ability of gender, age, T and N stage, combined chemotherapy, primary tumor and nodal volume for the 5-year local control (LC), distant-metastasis free survival (DMFS) and overall survival (OS) rate were investigated. Primary tumor and nodal volume were measured based on registration of magnetic resonance imaging (MRI) with contrast-enhanced computed tomography (CT) images. The Kaplan–Meier method was used for survival analysis, the log-rank test was used for univariate analyses and the Cox proportional hazard model was used for multivariate prognostic analyses.

Results
The mean value of primary tumor and nodal volume were 31.5 ml and 9.7 ml. The primary tumor and nodal volume were respectively divided into four groups for analysis (primary tumor volume: TV1≤20 ml, 20<TV2≤30 ml, 30<TV3≤40 ml, TV4>40 ml; primay nodal volume: NV1≤5 ml, 5<NV2≤10 ml, 10<NV3≤20 ml, NV4>20 ml). In univariate analysis, the 5-year LC and DMFS rate for TV4 was significantly decreased compared to the other groups (LC: p<0.001, DMFS: p=0.001), the 5-year OS rate for TV3 and TV4 were significantly decreased compared to other two subgroups (p=0.002) and the 5-year regional control (RC), DMFS and OS rate for NV3 and NV4 were significantly less than NV1 and NV2 (RC: p=0.002, DMFS: p=0.01, OS: p=0.014). Multivariate analysis showed that TV>40 ml was an adverse prognostic factor for the 5-year local regional control (LRC) rate (RR 2.454, p=0.002). Primary nodal volume had no statistical significance in predicting 5-year LRC, DMFS and OS rate in multivariate analysis.

Conclusions
Primary tumor volume could predict LRC rate of NPC patients, and the primary tumor volume of 40 ml may be the cut-off. Primary nodal volume may have predictive significance, but more data are needed. These factors should be considered in the TNM staging system of NPC for better estimates of prognosis.
Healthy ageing and depletion of intracellular glutathione influences T cell membrane thioredoxin-1 levels and cytokine secretion
Authors: Carilho Torrao Rita Barreto Duarte , Dias Irundika HK , Bennett Stuart J , Dunston Christopher R , Griffiths Helen R 
Published: September 2013

AbstractBackgroundDuring ageing an altered redox balance has been observed in both intracellular and extracellular compartments, primarily due to glutathione depletion and metabolic stress. Maintaining redox homeostasis is important for controlling proliferation and apoptosis in response to specific stimuli for a variety of cells. For T cells, the ability to generate specific response to antigen is dependent on the oxidation state of cell surface and cytoplasmic protein-thiols. Intracellular thiols are maintained in their reduced state by a network of redox regulating peptides, proteins and enzymes such as glutathione, thioredoxins and thioredoxin reductase. Here we have investigated whether any relationship exists between age and secreted or cell surface thioredoxin-1, intracellular glutathione concentration and T cell surface thioredoxin 1 (Trx-1) and how this is related to interleukin (IL)-2 production.ResultsHealthy older adults have reduced lymphocyte surface expression and lower circulating plasma Trx-1 concentrations. Using buthionine sulfoximine to deplete intracellular glutathione in Jurkat T cells we show that cell surface Trx-1 is lowered, secretion of Trx-1 is decreased and the response to the lectin phytohaemagglutinin measured as IL-2 production is also affected. These effects are recapitulated by another glutathione depleting agent, diethylmaleate.ConclusionTogether these data suggest that a relationship exists between the intracellular redox compartment and Trx-1 proteins. Loss of lymphocyte surface Trx-1 may be a useful biomarker of healthy ageing.
Splice variants of zinc finger protein 695 mRNA associated to ovarian cancer
Authors: Juárez-Méndez Sergio , Zentella-Dehesa Alejandro , Villegas-Ruíz Vanessa , Pérez-González Oscar Alberto , Salcedo Mauricio , López-Romero Ricardo , Román-Basaure Edgar , Lazos-Ochoa Minerva , Montes de Oca-Fuentes Víctor Edén , Vázquez-Ortiz Guelaguetza , Moreno José 
Published: September 2013

AbstractBackgroundStudies of alternative mRNA splicing (AS) in health and disease have yet to yield the complete picture of protein diversity and its role in physiology and pathology. Some forms of cancer appear to be associated to certain alternative mRNA splice variants, but their role in the cancer development and outcome is unclear.MethodsWe examined AS profiles by means of whole genome exon expression microarrays (Affymetrix GeneChip 1.0) in ovarian tumors and ovarian cancer-derived cell lines, compared to healthy ovarian tissue. Alternatively spliced genes expressed predominantly in ovarian tumors and cell lines were confirmed by RT-PCR.ResultsAmong several significantly overexpressed AS genes in malignant ovarian tumors and ovarian cancer cell lines, the most significant one was that of the zinc finger protein ZNF695, with two previously unknown mRNA splice variants identified in ovarian tumors and cell lines. The identity of ZNF695 AS variants was confirmed by cloning and sequencing of the amplicons obtained from ovarian cancer tissue and cell lines.ConclusionsAlternative ZNF695 mRNA splicing could be a marker of ovarian cancer with possible implications on its pathogenesis.
Global differences in specific histone H3 methylation are associated with overweight and type 2 diabetes
Authors: Jufvas Åsa , Sjödin Simon , Lundqvist Kim , Amin Risul , Vener Alexander V , Strålfors Peter 
Published: September 2013

Abstract

Background
Epidemiological evidence indicates yet unknown epigenetic mechanisms underlying a propensity for overweight and type 2 diabetes. We analyzed the extent of methylation at lysine 4 and lysine 9 of histone H3 in primary human adipocytes from 43 subjects using modification-specific antibodies.

Results
The level of lysine 9 dimethylation was stable, while adipocytes from type 2 diabetic and non-diabetic overweight subjects exhibited about 40% lower levels of lysine 4 dimethylation compared with cells from normal-weight subjects. In contrast, trimethylation at lysine 4 was 40% higher in adipocytes from overweight diabetic subjects compared with normal-weight and overweight non-diabetic subjects. There was no association between level of modification and age of subjects.

Conclusions
The findings define genome-wide molecular modifications of histones in adipocytes that are directly associated with overweight and diabetes, and thus suggest a molecular basis for existing epidemiological evidence of epigenetic inheritance.
Influence of subcutaneous specific immunotherapy on drug costs in children sufferingfrom allergic asthma
Authors: Reinhold Thomas , Ostermann Julia , Thum‐Oltmer Susanne , Brüggenjürgen Bernd 
Published: September 2013

AbstractBackgroundSubcutaneous specific immunotherapy (SCIT) is an effective treatment attenuatingthe progression of allergic asthma. To date, there is a lack of studiesinvestigating the economic consequences of SCIT on health care expenditures.MethodsA health‐economic piggy‐back analysis of SCIT was conducted based on a RCT thatenrolled 65 children and adolescents with allergic asthma. Patients were allocatedinto two groups: A group receiving SCIT with a high‐dose hypoallergenic house dustmite preparation plus asthma medication and a control group receiving only asthmamedication. For both groups asthma control was achieved before the start of the SCIT treatment and was maintained during the study. Both, costs andcost‐effectiveness of SCIT with the high‐dose hypoallergenic house dust mitepreparation were investigated based on total medication costs, incrementalmedication costs and treatment effects (measured as lung function), respectively. A bootstrap analysis was performed to validate the results.ResultsA steady decline in medication costs could be observed in the SCIT group one yearafter treatment start compared to the control group. This cost trend becamestatistically significant 3 years after SCIT started. The calculated potentialsavings in the SCIT group correlated with an improved lung function. Thedistribution of the bootstrap results revealed that the probability of SCIT havinga superior effectiveness compared to the control group is around 90%.ConclusionSCIT with a high‐dose hypoallergenic preparation received by children andadolescents suffering from mite induced allergic asthma reduces the allergicmedication intake and has cost‐saving effects. Additional costs associated withSCIT may be completely compensated by drug cost savings 4 years after end of SCIT. Additionally, SCIT is superior compared to routine care as measured by the lungfunction that improved in SCIT‐treated patients. Trial registration: (EudraCT no.2004 – 003892 – 35).
pPCV, a versatile vector for cloning PCR products
Authors: Janner Christiane R , Brito Ana Lívia P , Moraes Lidia Maria P , Reis Viviane CB , Torres Fernando AG 
Published: September 2013

Abstract
The efficiency of PCR product cloning depends on the nature of the DNA polymerase employed because amplicons may have blunt-ends or 3′ adenosines overhangs. Therefore, for amplicon cloning, available commercial vectors are either blunt-ended or have a single 3′ overhanging thymidine. The aim of this work was to offer in a single vector the ability to clone both types of PCR products. For that purpose, a minimal polylinker was designed to include restriction sites for Eco RV and Xcm I which enable direct cloning of amplicons bearing blunt-ends or A-overhangs, respectively, still offering blue/white selection. When tested, the resulting vector, pPCV, presented high efficiency cloning of both types of amplicons.
Informed choice about breast cancer prevention: randomized controlled trial of an online decision aid intervention
Authors: Korfage Ida J , Fuhrel-Forbis Andrea , Ubel Peter A , Zikmund-Fisher Brian J , Greene Sarah M , McClure Jennifer B , Smith Dylan M , Hensley Alford Sharon , Fagerlin Angela 
Published: September 2013

Abstract
Introduction
Tamoxifen and raloxifene are chemopreventive drugs that can reduce women's relative risk of primary breast cancer by 50%; however, most women eligible for these drugs have chosen not to take them. The reasons for low uptake may be related to women's knowledge or attitudes towards the drugs. We aimed to examine the impact of an online breast cancer chemoprevention decision aid (DA) on informed intentions and decisions of women at high risk of breast cancer.

Methods
We conducted a randomized clinical trial, assessing the effect of a DA about breast cancer chemoprevention on informed choices about chemoprevention. Women (n = 585), 46- to 74-years old old, completed online baseline, post-test, and three-month follow-up questionnaires. Participants were randomly assigned to either an intervention group, a standard control group that answered questions about chemoprevention at baseline, or a three-month control group that did not answer questions about chemoprevention at baseline . The main outcome measures were whether women's intentions and decisions regarding chemoprevention drugs were informed, and whether women who viewed the DA were more likely to make informed decisions than women who did not view the DA, using a dichotomous composite variable 'informed choice' (yes/no) to classify informed decisions as those reflecting sufficient knowledge and concordance between a woman's decision and relevant attitudes.

Results
Analyses showed that more intervention than standard control participants (52.7% versus 5.9%) made informed decisions at post-test, P <0.001. At the three-month follow-up, differences in rates of informed choice between intervention (16.9%) and both control groups (11.8% and 8.0%) were statistically non-significant, P = 0.067.

Conclusions
The DA increased informed decision making about breast cancer chemoprevention, although the impact on knowledge diminished over time. This study was not designed to determine how much knowledge decision makers must retain over time. Examining informed decisions increases understanding of the impact of DAs. A standard for defining and measuring sufficient knowledge for informed decisions is needed.

Trial registration
ClinicalTrials.gov: NCT00967824
MR appearance of paraganglioma of the cauda equina: Case reports
Authors: Taira H. , Takasita M. , Yoshida S. , Takita C. , Tsumura H. , Torisu T. 
Published: September 2013

Purpose: To investigate the value of MR imaging for preoperative diagnosis of paraganglioma of the cauda equina. Material and Methods: A retrospective review of 2 cases of paraganglioma of the cauda equina examined with MR imaging was undertaken. Features assessed included the homogeneity of the lesions, presence or absence of serpiginous flow void and thin hypointense margins. Results: In case 1, the tumor was hyperintense on the postcontrast examination and serpiginous flow void suggested vessels in the upper pole of the tumor. In case 2, the tumor was encapsulated by a thin hypointense margin on both T1- and T2-weighted images, which suggested hemosiderin. Conclusion: The MR appearance may be of great value in the preoperative diagnosis of paraganglioma of the cauda equina.
High-resolution MR imaging of the knee at 3 T
Authors: Niitsu M. , Nakai T. , Ikeda K. , Tang G.-Y. , Yoshioka H. , Itai Y. 
Published: September 2013

Purpose: To examine the practical feasibility of using a 3.0-T MR unit to obtain high-quality, high-resolution images of the knee joint. Material and Methods: One human cadaveric and 5 porcine knees were imaged with the 3.0-T unit. Sets of T1-weighted spin echo images were obtained with in-plane resolution of 0.195 × 0.39 mm and an acquisition time of approximately 5 min. Two porcine knees were also imaged with the 1.0-T unit with an identical imaging protocol and the signal-to-noise (S/N) ratios were measured on images at 3 T and 1 T. Results: The 3-T MR system provided detailed delineation of the knees. Deep layers of the medial collateral ligament and associated fine fibers beneath the medial and lateral collateral ligament were demarcated. We observed precise demonstration of the tibial attachment of the anterior cruciate ligament, irregularity of the meniscal free edge, and conjoint tendon formation together with the lateral collateral ligament and the biceps femoris tendon. Compared to the 1-T unit, the S/N ratio with the 3-T unit was increased by a factor of 1.39 to 1.72. Conclusion: Due to the potential advantage of obtaining detailed images, the 3-T MR system suggests a practical utility for fine demonstration of the knee morphology.