bluuebunny/crossref_metadata_2025_split huggingface dataset:
Surrogacy assessment using principal stratification with multivariate normal and Gaussian copula models
Authors: Taylor Jeremy MG , Conlon Anna SC , Elliott Michael R 
Published: December 2014

Background The validation of intermediate markers as surrogate markers ( S) for the true outcome of interest ( T) in clinical trials offers the possibility for trials to be run more quickly and cheaply by using the surrogate endpoint in place of the true endpoint. Purpose Working within a principal stratification framework, we propose causal quantities to evaluate surrogacy using a Gaussian copula model for an ordinal surrogate and time-to-event final outcome. The methods are applied to data from four colorectal cancer clinical trials, where S is tumor response and T is overall survival. Methods For the Gaussian copula model, a Bayesian estimation strategy is used and, as some parameters are not identifiable from the data, we explore the use of informative priors that are consistent with reasonable assumptions in the surrogate marker setting to aid in estimation. Results While there is some bias in the estimation of the surrogacy quantities of interest, the estimation procedure does reasonably well at distinguishing between poor and good surrogate markers. Limitations Some of the parameters of the proposed model are not identifiable from the data, and therefore, assumptions must be made in order to aid in their estimation. Conclusions The proposed quantities can be used in combination to provide evidence about the validity of S as a surrogate marker for T.
A case of chronic anorexia nervosa with child-bearing by in vitro fertilization necessitating comprehensive team support
Authors: Toki Shigeru , Hashimoto Eri , Masuda Masayuki , Machino Akihiko , Yamawaki Shigeto 
Published: December 2014

Lesson Generalists should be aware of the issues surrounding pregnancy in patients with anorexia nervosa and discuss well with patients and their families before in vitro fertilization.
Characterizing heterogeneity in leukemic cells using single-cell gene expression analysis
Authors: Saadatpour Assieh , Guo Guoji , Orkin Stuart H , Yuan Guo-Cheng 
Published: December 2014

Abstract
Background
A fundamental challenge for cancer therapy is that each tumor contains a highly heterogeneous cell population whose structure and mechanistic underpinnings remain incompletely understood. Recent advances in single-cell gene expression profiling have created new possibilities to characterize this heterogeneity and to dissect the potential intra-cancer cellular hierarchy.

Results
Here, we apply single-cell analysis to systematically characterize the heterogeneity within leukemic cells using the MLL-AF9 driven mouse model of acute myeloid leukemia. We start with fluorescence-activated cell sorting analysis with seven surface markers, and extend by using a multiplexing quantitative polymerase chain reaction approach to assay the transcriptional profile of a panel of 175 carefully selected genes in leukemic cells at the single-cell level. By employing a set of computational tools we find striking heterogeneity within leukemic cells. Mapping to the normal hematopoietic cellular hierarchy identifies two distinct subtypes of leukemic cells; one similar to granulocyte/monocyte progenitors and the other to macrophage and dendritic cells. Further functional experiments suggest that these subtypes differ in proliferation rates and clonal phenotypes. Finally, co-expression network analysis reveals similarities as well as organizational differences between leukemia and normal granulocyte/monocyte progenitor networks.

Conclusions
Overall, our single-cell analysis pinpoints previously uncharacterized heterogeneity within leukemic cells and provides new insights into the molecular signatures of acute myeloid leukemia.
Transcriptome-wide signatures of tumor stage in kidney renal clear cell carcinoma: connecting copy number variation, methylation and transcription factor activity
Authors: Liu Qi , Su Pei-Fang , Zhao Shilin , Shyr Yu 
Published: December 2014

Abstract
Background
Comparative analysis of expression profiles between early and late stage cancers can help to understand cancer progression and metastasis mechanisms and to predict the clinical aggressiveness of cancer. The observed stage-dependent expression changes can be explained by genetic and epigenetic alterations as well as transcription dysregulation. Unlike genetic and epigenetic alterations, however, activity changes of transcription factors, generally occurring at the post-transcriptional or post-translational level, are hard to detect and quantify.

Methods
Here we developed a statistical framework to infer the activity changes of transcription factors by simultaneously taking into account the contributions of genetic and epigenetic alterations to mRNA expression variations.

Results
Applied to kidney renal clear cell carcinoma (KIRC), the model underscored the role of methylation as a significant contributor to stage-dependent expression alterations and identified key transcription factors as potential drivers of cancer progression.

Conclusions
Integrating copy number, methylation, and transcription factor activity signatures to explain stage-dependent expression alterations presented a precise and comprehensive view on the underlying mechanisms during KIRC progression.
Computational investigation of inhibitory mechanism of flavonoids as bovine serum albumin anti-glycation agents
Authors: Johari Anahita , Moosavi-Movahedi Ali Akbar , Amanlou Massoud 
Published: December 2014

Abstract

Background
Glycation of serum albumin and its consequence products were considered as an important factor in drug distribution and diabetic complications, therefore finding the glycation inhibitors and their inhibitory mechanisms became a valuable field of study. In this work, bovine serum albumin (BSA) became a subject as a model protein for analyzing the inhibitory mechanism of flavonoids, known as natural BSA glycation inhibitors in the early stage of glycation.

Methods
Firstly, for theoretical study, the three-dimensional model of BSA structure was generated by homology modeling and refined through molecular dynamic simulation. Secondly, several validation methods (statistical assessment methods and also neural network methods) by simultaneous docking study were employed for insurance about accuracy of our simulation. Then docking studies were performed for visualizing the relation between flavonoids’ binding sites and BSA glycation sites besides, the correlation analyzes between calculated binding energy and reported experimental inhibitory IC50 values of the flavonoids set, was considered to explore their molecular inhibitory mechanism.

Results
The quality assessment methods and simultaneous docking studies on interaction of quercetin (as the most studied flavonoids) with BSA and Human serum albumin (HAS), confirm the accuracy of simulation and the second stage of docking results which were in close agreement with experimental observations, suggest that the potential residues in flavonoids binding sites (which were place neighbor of tryptophan 212 within 5Ǻ) cannot be considered as one of glycation sites.

Conclusions
Based on the results, flavonoids don’t participate in inhibitory interference mechanism, and also, the differentiation between complexes of flavonoids with BSA and HSA could destroy the speculation of using them as an exchangeable model protein in study of serum albumin and flavonoids interactions.
Hydroxylation index of omeprazole in relation to CYP2C19 polymorphism and sex in a healthy Iranian population
Authors: Payan Maryam , Rouini Mohammad Reza , Tajik Nader , Ghahremani Mohammad Hossein , Tahvilian Reza 
Published: December 2014

AbstractBackgroundPolymorphism ofCYP2C19gene is one of the important factors in pharmacokinetics of CYP2C19 substrates. Omeprazole is a proton pump inhibitor which is mainly metabolized by cytochrome P450 2C19 (CYP2C19). The aim of present study was to assess omeprazole hydroxylation index as a measure of CYP2C19 activity considering new variant allele (CYP2C19*17) in Iranian population and also to see if this activity is sex dependent.MethodsOne hundred and eighty healthy unrelated Iranian individuals attended in this study. Blood samples for genotyping and phenotyping were collected 3 hours after administration of 20 mg omeprazole orally. Genotyping of2C19variant alleles*2,*3and*17was performed by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and semi-nested PCR methods. Plasma concentrations of omeprazole and hydroxyomeprazole were determined by high performance liquid chromatography (HPLC) technique and hydxroxylation index (HI) (omeprazole/ hydroxyomeprazole) was calculated.ResultsTheCYP2C19*17was the most common variant allele in the studied population (21.6%). Genotype frequencies ofCYP2C19*17*17,*1*17, and*2*17were 5.5%, 28.8% and 3.3% respectively. The lowest and the highest median omeprazole HI was observed in*17*17and*2*2genotypes respectively (0.36 vs. 13.09). The median HI of omeprazole in subjects homozygous forCYP2C19*1was 2.16-fold higher than individuals homozygous forCYP2C19*17(P < 0.001) and the median HI ofCYP2C19*1*17genotype was 1.98-fold higher thanCYP2C19 *17*17subjects (P < 0.001). However, subjects withCYP2C19*2*17(median HI: 1.74) andCYP2C19*1*2(median HI: 1.98) genotypes and alsoCYP2C19*1*17(median HI: 0.71) andCYP2C19*1*1(mean HI: 0.78) did not show any significantly different enzyme activity. In addition, no statistically significant difference was found between women and men in distribution ofCYP2C19genotypes. Furthermore, the hydroxylation index of Omeprazole was not different between women and men in the studied population.ConclusionOur data point out the importance ofCYP2C19*2andCYP2C19*17variant alleles in metabolism of omeprazole and therefore CYP2C19 activity. Regarding the high frequency ofCYP2C19*17in Iranian population, the importance of this new variant allele in metabolism of CYP2C19 substrates shall be considered.
Impaired T cell function in argininosuccinate synthetase deficiency
Authors: Tarasenko Tatyana N , Gomez-Rodriguez Julio , McGuire Peter J 
Published: December 2014

Abstract
ASS1 is a cytosolic enzyme that plays a role in the conversion of citrulline to arginine. In human and mouse tissues, ASS1 protein is found in several components of the immune system, including the thymus and T cells. However, the role of ASS1 in these tissues remains to be defined. Considerable attention has been focused recently on the role of metabolism in T cell differentiation and function. Based on the expression of ASS1 in the immune system, we hypothesized that ASS1 deficiency would result in T cell defects. To evaluate this question, we characterized immune function in hypomorphic fold/fold mice. Analysis of splenic T cells by flow cytometry showed a marked reduction in T cell numbers with normal expression of activation surface markers. Gene therapy correction of liver ASS1 to enhance survival resulted in a partial recovery of splenic T cells for characterization. In vitro and in vivo studies demonstrated the persistence of the ASS1 enzyme defect in T cells and abnormal T cell differentiation and function. Overall, our work suggests that ASS1 plays a role in T cell function, and deficiency produces primary immune dysfunction. In addition, these data suggest that patients with ASS1 deficiency (citrullinemia type I) may have T cell dysfunction.
Student perception about working in rural United States/Canada after graduation: a study in an offshore Caribbean medical school
Authors: Shankar P Ravi , Dubey Arun K , Nandy Atanu , Herz Burton L , Little Brian W 
Published: December 2014

Introduction: Rural residents of the United States (US) and Canada face problems in accessing healthcare. International medical graduates (IMGs) play an important role in delivering rural healthcare. IMGs from Caribbean medical schools have the highest proportion of physicians in primary care. Xavier University School of Medicines admits students from the US, Canada and other countries to the undergraduate medical (MD) course and also offers a premedical program. The present study was conducted to obtain student perception about working in rural US/Canada after graduation. Methods: The study was conducted among premedical and preclinical undergraduate medical (MD) students during October 2014. The questionnaire used was modified from a previous study. Semester of study, gender, nationality, place of residence and occupation of parents were noted. Information about whether students plan to work in rural US/Canada after graduation, possible reasons why doctors are reluctant to work in rural areas, how the government can encourage rural practice, possible problems respondents anticipate while working in rural areas were among the topics studied.Results: Ninety nine of the 108 students (91.7%) participated. Forty respondents were in favor of working in rural US/Canada after graduation. Respondents mentioned good housing, regular electricity, water supply, telecommunication facilities, and schools for education of children as important conditions to be fulfilled. The government should provide higher salaries to rural doctors, help with loan repayment, and provide opportunities for professional growth. Potential problems mentioned were difficulty in being accepted by the rural community, problems in convincing patients to follow medical advice, lack of exposure to rural life among the respondents, and cultural issues.Conclusions: About 40% of respondents would consider working in rural US/Canada. Conditions required to be fulfilled have been mentioned above. Graduates from Caribbean medical schools have a role in addressing rural physician shortage. Similar studies in other offshore Caribbean medical schools are required as Caribbean IMGs make an important contribution to the rural US and Canadian health workforce.
Improving pressure ulcer risk assessment and management using the Waterlow scale at a London teaching hospital
Authors: Mahalingam S. , Gao L. , Nageshwaran S. , Vickers C. , Bottomley T. , Grewal P. 
Published: December 2014

Objective: Pressure ulcers (PUs) cost the National Health Service (NHS) up to 4% of its health care expenditure. Arising from this are also clinical negligence claims, where inadequate risk assessment has been cited as one of the principal drawbacks in the prevention of PUs. This two-cycle audit aims to examine the consistency and accuracy of risk assessment of patients, and demonstrates how simple focused interventions can improve the quality of care provided. Method: The Waterlow pressure ulcer risk assessment tool was employed to assess inpatients during a 6-month period at a London teaching hospital. Patients were risk assessed, and examined to detect PUs and to determine the type of mattress. We compared our findings with clinical (nursing and medical) documentation. Interventions were made through questionnaires given to staff, educational sessions, presentations and posters addressing where improvements could be made in risk stratifying patients. A repeat audit was carried out 24 months later and the results from both cycles were compared. Statistical analysis was carried out using Fisher's exact and the Student's T-test. Results: In total 100 in-patients were assessed in each cycle with a mean age of 71.4 years in cycle 1 and 70.1 years in cycle 2. A nursing Waterlow score was recorded for 81% of patients in cycle 1 and 100% in cycle 2 (p<0.05). In cycle 1, the average nursing score was significantly lower than that from the study (mean 13.7 versus 17.1, median 14.0 versus 18.0; p<0.05), but after intervention this had reduced to a minimal difference (mean 8.5 versus 9.0, median 8.0 versus 9.0, p=0.08). Conclusion: Nursing scores recorded in the notes were lower than the study scores in cycle 1, primarily from a failure to appropriately assess certain categories of the Waterlow scale. These differences reduced after focused education of staff. Our results suggest that targeted interventions tailored towards nursing and medical staff can result in improvements in the risk assessment for prevention and subsequent management of PUs. However, it also highlights the need for increased input from the entire multidisciplinary team in order to reduce the morbidity caused by PUs. Declaration of interest: The authors have no conflict of interest. No funding was received for this study.
Behavior of Aberrant Chromosome Configurations in Drosophila melanogaster Female Meiosis I
Authors: Gilliland William D , Colwell Eileen M , Lane Fiona M , Snouffer Ashley A 
Published: December 2014

Abstract
One essential role of the first meiotic division is to reduce chromosome number by half. Although this is normally accomplished by segregating homologous chromosomes from each other, it is possible for a genome to have one or more chromosomes that lack a homolog (such as compound chromosomes), or have chromosomes with multiple potential homologs (such as in XXY females). These configurations complete meiosis but engage in unusual segregation patterns. In Drosophila melanogaster females carrying two compound chromosomes, the compounds can accurately segregate from each other, a process known as heterologous segregation. Similarly, in XXY females, when the X chromosomes fail to cross over, they often undergo secondary nondisjunction, where both Xs segregate away from the Y. Although both of these processes have been known for decades, the orientation mechanisms involved are poorly understood. Taking advantage of the recent discovery of chromosome congression in female meiosis I, we have examined a number of different aberrant chromosome configurations. We show that these genotypes complete congression normally, with their chromosomes bioriented at metaphase I arrest at the same rates that they segregate, indicating that orientation must be established during prometaphase I before congression. We also show that monovalent chromosomes can move out on the prometaphase I spindle, but the dot 4 chromosomes appear required for this movement. Finally, we show that, similar to achiasmate chromosomes, heterologous chromosomes can be connected by chromatin threads, suggesting a mechanism for how heterochromatic homology establishes these unusual biorientation patterns.
A Rapid One-Generation Genetic Screen in aDrosophilaModel to Capture Rhabdomyosarcoma Effectors and Therapeutic Targets
Authors: Galindo Kathleen A , Endicott Tiana R , Avirneni-Vadlamudi Usha , Galindo Rene L 
Published: December 2014

AbstractRhabdomyosarcoma (RMS) is an aggressive childhood malignancy of neoplastic muscle-lineage precursors that fail to terminally differentiate into syncytial muscle. The most aggressive form of RMS, alveolar-RMS, is driven by misexpression of the PAX-FOXO1 oncoprotein, which is generated by recurrent chromosomal translocations that fuse either the PAX3 or PAX7 gene to FOXO1. The molecular underpinnings of PAX-FOXO1−mediated RMS pathogenesis remain unclear, however, and clinical outcomes poor. Here, we report a new approach to dissect RMS, exploiting a highly efficient Drosophila PAX7-FOXO1 model uniquely configured to uncover PAX-FOXO1 RMS genetic effectors in only one generation. With this system, we have performed a comprehensive deletion screen against the Drosophila autosomes and demonstrate that mutation of Mef2, a myogenesis lynchpin in both flies and mammals, dominantly suppresses PAX7-FOXO1 pathogenicity and acts as a PAX7-FOXO1 gene target. Additionally, we reveal that mutation of mastermind, a gene encoding a MEF2 transcriptional coactivator, similarly suppresses PAX7-FOXO1, further pointing toward MEF2 transcriptional activity as a PAX-FOXO1 underpinning. These studies show the utility of the PAX-FOXO1 Drosophila system as a robust one-generation (F1) RMS gene discovery platform and demonstrate how Drosophila transgenic conditional expression models can be configured for the rapid dissection of human disease.
Age-Related Changes in Nanoparticle Albumin-Bound Paclitaxel Pharmacokinetics and Pharmacodynamics: Influence of Chronological Versus Functional Age
Authors: Hurria Arti , Blanchard M. Suzette , Synold Timothy W. , Mortimer Joanne , Chung Cathie T. , Luu Thehang , Katheria Vani , Rotter Arnold J. , Wong Carol , Choi Anthony , Feng Tao , Ramani Rupal , Doan Caroline M. , Brown Jaycen , Somlo George 
Published: December 2014

Abstract

Purpose.
This study evaluated age-related changes in pharmacokinetic and pharmacodynamic parameters of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) in patients with metastatic breast cancer.

Methods.
Forty patients received nab-paclitaxel (100 mg/m2 weekly for 3 weeks followed by a 1-week break) as first- or second-line chemotherapy. Blood samples were collected for analysis, and response was assessed every two cycles. Planned statistical analyses included linear regression to examine the relationship between age and pharmacokinetic variables (ln clearance [CL] and ln area under the curve [AUC]) and two-sided two-sample t tests to evaluate age differences in pharmacodynamic variables. The association between chemotherapy toxicity risk scores and pharmacokinetic and pharmacodynamic variables including grade ≥3 toxicity were examined post hoc.

Results.
Of 40 patients enrolled, 39 (98%) were evaluable (mean age: 60 years; range: 30–81 years). A partial response was achieved in 31%, and 38% had stable disease. There was a borderline positive association between age and 24-hour ln AUC (slope = 0.011; SE = 0.006; p = .055). Grade 3 toxicity was experienced by 26% (8% hematologic, 18% nonhematologic). There were no differences in age based on the presence of grade 3 toxicity (p = .75), dose reductions (p = .38), or dose omissions (p = .15). A significant association was noted between chemotherapy toxicity risk score category and presence of grade 3 toxicity (toxicity rate by risk score category: low, 5 of 30 patients; medium, 3 of 6 patients; high, 2 of 3 patients; p = .041).

Conclusion.
A borderline significant relationship exists between age and 24-hour AUC, but no differences were noted for pharmacodynamic variables (grade 3 toxicity, dose reductions, or dose omissions) based on age. There is an association between toxicity risk score and grade ≥3 chemotherapy toxicity and pharmacokinetic variables. The treatment is well tolerated across all age groups.
FORMAÇÃO DO PREÇO DE VENDA PARA MICROS E PEQUENAS EMPRESAS
Authors: Pereira Fábio Henrique 
Published: December 2014

A formação do preço de venda em épocas passadas foi considerada como fator secundário para a gestão empresarial, porém com o passar dos tempos detectou-se a necessidade de se conhecer mais profundamente esta ferramenta que nos dias atuais é de extrema importância para a tomada de decisões gerenciais. Em virtude disto viu-se a necessidade de se conhecer a fundo e detalhadamente todos os fatores pertinentes à operacionalização da empresa, bem como estar sempre atento sobre as oscilações existentes no mercado e as exigências e necessidades do consumidor. Acredita-se que as micros e pequenas empresas são as mais carentes de suportes e subsídios em relação à formação do preço de venda em virtude muitas vezes da pouca ou nenhuma capacidade técnica de seus dirigentes aliada a falta de um suporte e auxílio mais especializado nesta área. O presente trabalho aborda primeiramente todos os pontos que julgamse importantes analisar para que se possa formar correta e conscientemente o preço de venda dos produtos ou serviços oferecidos ao mercado consumidor. Estes pontos abordados no presente trabalho referem-se a uma análise detalhada do Mercado consumidor onde está localizada a empresa, bem como os fatores que integram a metodologia de se formar o preço de venda, analisando-se posteriormente as estratégias de preços mais comuns utilizadas por empresas e concorrências na luta por um melhor posicionamento no mercado em que atuam. Finalizando o trabalho, realizou-se uma aplicação prática em uma micro empresa enfatizando-se algumas situações que poderão ser encontradas no dia-dia de sua operacionalização.