bluuebunny/crossref_metadata_2025_split huggingface dataset:
A signature of epithelial-mesenchymal plasticity and stromal activation in primary tumor modulates late recurrence in breast cancer independent of disease subtype
Authors: Cheng Qing , Chang Jeffrey T , Gwin William R , Zhu Jun , Ambs Stefan , Geradts Joseph , Lyerly H Kim 
Published: July 2014

Abstract
Introduction
Despite improvements in adjuvant therapy, late systemic recurrences remain a lethal consequence of both early- and late-stage breast cancer. A delayed recurrence is thought to arise from a state of tumor dormancy, but the mechanisms that govern tumor dormancy remain poorly understood.

Methods
To address the features of breast tumors associated with late recurrence, but not confounded by variations in systemic treatment, we compiled breast tumor gene expression data from 4,767 patients and established a discovery cohort consisting of 743 lymph node-negative patients who did not receive systemic neoadjuvant or adjuvant therapy. We interrogated the gene expression profiles of the 743 tumors and identified gene expression patterns that were associated with early and late disease recurrence among these patients. We applied this classification to a subset of 46 patients for whom expression data from microdissected tumor epithelium and stroma was available, and identified a distinct gene signature in the stroma and also a corresponding tumor epithelium signature that predicted disease recurrence in the discovery cohort. This tumor epithelium signature was then validated as a predictor for late disease recurrence in the entire cohort of 4,767 patients.

Results
We identified a novel 51-gene signature from microdissected tumor epithelium associated with late disease recurrence in breast cancer independent of the molecular disease subtype. This signature correlated with gene expression alterations in the adjacent tumor stroma and describes a process of epithelial to mesenchymal transition (EMT) and tumor-stroma interactions.

Conclusions
Our findings suggest that an EMT-related gene signature in the tumor epithelium is related to both stromal activation and escape from disease dormancy in breast cancer. The presence of a late recurrence gene signature in the primary tumor also suggests that intrinsic features of this tumor regulate the transition of disseminated tumor cells into a dormant phenotype with the ability to outgrowth as recurrent disease.
Tumor homologous recombination deficiency assays: another step closer to clinical application?
Authors: Stecklein Shane R , Sharma Priyanka 
Published: July 2014

AbstractInherited and acquired defects in homologous recombination, a phenotype termed ‘BRCAness’, may lend to therapeutic exploitation in breast cancer. To this end, development and clinical evaluation of platforms to identify signatures of BRCAness are of immense interest. In this issue of Breast Cancer Research, Vollebergh and colleagues report that a BRCA-like array comparative genomic hybridization (aCGH) genomic instability signature is associated with benefit from high-dose cyclophosphamide-thiotepa-carboplatin chemotherapy. We discuss the strengths and weaknesses of this study and consider the clinical significance and applicability of this aCGH BRCAness signature in the context of other existing homologous recombination deficiency detection platforms.
Cancer/stroma interplay via cyclooxygenase-2 and indoleamine 2,3-dioxygenase promotes breast cancer progression
Authors: Chen Jing-Yi , Li Chien-Feng , Kuo Cheng-Chin , Tsai Kelvin K , Hou Ming-Feng , Hung Wen-Chun 
Published: July 2014

Abstract
Introduction
Expression of indoleamine 2,3-dioxygenase (IDO) in primary breast cancer increases tumor growth and metastasis. However, the clinical significance of stromal IDO and the regulation of stromal IDO are unclear.

Methods
Metabolomics and enzyme-linked immunosorbent assay (ELISA) were used to study the effect of cyclooxygenase-2 (COX-2)-overexpressing breast cancer cells on IDO expression in co-cultured human breast fibroblasts. Biochemical inhibitors and short-hairpin RNA (shRNA) were used to clarify how prostaglandin E2 (PGE2) upregulates IDO expression. Associations of stromal IDO with clinicopathologic parameters were tested in tumor specimens. An orthotopic animal model was used to examine the effect of COX-2 and IDO inhibitors on tumor growth.

Results
Kynurenine, the metabolite generated by IDO, increases in the supernatant of fibroblasts co-cultured with COX-2-overexpressing breast cancer cells. PGE2 released by cancer cells upregulates IDO expression in fibroblasts through an EP4/signal transducer and activator of transcription 3 (STAT3)-dependent pathway. Conversely, fibroblast-secreted kynurenine promotes the formation of the E-cadherin/Aryl hydrocarbon receptor (AhR)/S-phase kinase-associated protein 2 (Skp2) complex, resulting in degradation of E-cadherin to increase breast cancer invasiveness. The enhancement of motility of breast cancer cells induced by co-culture with fibroblasts is suppressed by the IDO inhibitor 1-methyl-tryptophan. Pathological analysis demonstrates that upregulation of stromal IDO is a poor prognosis factor and is associated with of COX-2 overexpression. Co-expression of cancer COX-2 and stromal IDO predicts a worse disease-free and metastasis-free survival. Finally, COX-2 and IDO inhibitors inhibit tumor growth in vivo.

Conclusion
Integration of metabolomics and molecular and pathological approaches reveals the interplay between cancer and stroma via COX-2, and IDO promotes tumor progression and predicts poor patient survival.
Nutritional status modulates box C/D snoRNP biogenesis by regulated subcellular relocalization of the R2TP complex
Authors: Kakihara Yoshito , Makhnevych Taras , Zhao Liang , Tang Weiwen , Houry Walid A 
Published: July 2014

Abstract
Background
Box C/D snoRNPs, which are typically composed of box C/D snoRNA and the four core protein components Nop1, Nop56, Nop58, and Snu13, play an essential role in the modification and processing of pre-ribosomal RNA. The highly conserved R2TP complex, comprising the proteins Rvb1, Rvb2, Tah1, and Pih1, has been shown to be required for box C/D snoRNP biogenesis and assembly; however, the molecular basis of R2TP chaperone-like activity is not yet known.

Results
Here, we describe an unexpected finding in which the activity of the R2TP complex is required for Nop58 protein stability and is controlled by the dynamic subcellular redistribution of the complex in response to growth conditions and nutrient availability. In growing cells, the complex localizes to the nucleus and interacts with box C/D snoRNPs. This interaction is significantly reduced in poorly growing cells as R2TP predominantly relocalizes to the cytoplasm. The R2TP-snoRNP interaction is mainly mediated by Pih1.

Conclusions
The R2TP complex exerts a novel regulation on box C/D snoRNP biogenesis that affects their assembly and consequently pre-rRNA maturation in response to different growth conditions.
Effects of CoQ10 Supplementation on Lipid Profiles and Glycemic Control in Patients with Type 2 Diabetes: a randomized, double blind, placebo-controlled trial
Authors: Zahedi Hoda , Eghtesadi Shahryar , Seifirad Soroush , Rezaee Neshat , Shidfar Farzad , Heydari Iraj , Golestan Banafsheh , Jazayeri Shima 
Published: July 2014

Abstract
Background
Low grade inflammation and oxidative stress are the key factors in the pathogenesis and development of diabetes and its complications. Coenzyme Q10 (CoQ10) is known as an antioxidant and has a vital role in generation of cellular energy providing. This study was undertaken to evaluate the effects of CoQ10 supplementation on lipid profiles and glycemic controls in patients with diabetes.

Methods
Fifty patients with diabetes were randomly allocated into two groups to receive either 150 mg CoQ10 or placebo daily for 12 weeks. Before and after supplementation, fasting venous blood samples were collected and lipid profiles containing triglyceride, total cholesterol, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) and glycemic indices comprising of fasting plasma glucose (FPG), insulin and hemoglobin A1C (HbA1C) were measured. Insulin resistance was calculated using HOMA-IR index.

Results
Forty patients completed the study. After intervention FPG and HbA1C were significantly lower in the CoQ10 group compared to the placebo group, but there were no significant differences in serum insulin and HOMA-IR between the two groups. Although total cholesterol did not change in the Q10 group after supplementation, triglyceride and HDL-C significantly decreased and LDL-C significantly increased in the CoQ10 group.

Conclusion
The present study showed that treatment with Q10 may improve glycemic control with no favorable effects on lipid profiles in type 2 patients with diabetes.

Trial registration
IRCT registry number: IRCT138806102394N1
Foxa1 and Foxa2 Regulate α-Cell Differentiation, Glucagon Biosynthesis, and Secretion
Authors: Heddad Masson Mounia , Poisson Caroline , Guérardel Audrey , Mamin Aline , Philippe Jacques , Gosmain Yvan 
Published: July 2014

AbstractThe Forkhead box A transcription factors are major regulators of glucose homeostasis. They show both distinct and redundant roles during pancreas development and in adult mouse β-cells. In vivo ablation studies have revealed critical implications of Foxa1 on glucagon biosynthesis and requirement of Foxa2 in α-cell terminal differentiation. In order to examine the respective role of these factors in mature α-cells, we used small interfering RNA (siRNA) directed against Foxa1 and Foxa2 in rat primary pancreatic α-cells and rodent α-cell lines leading to marked decreases in Foxa1 and Foxa2 mRNA levels and proteins. Both Foxa1 and Foxa2 control glucagon gene expression specifically through the G2 element. Although we found that Foxa2 controls the expression of the glucagon, MafB, Pou3f4, Pcsk2, Nkx2.2, Kir6.2, and Sur1 genes, Foxa1 only regulates glucagon gene expression. Interestingly, the Isl1 and Gipr genes were not controlled by either Foxa1 or Foxa2 alone but by their combination. Foxa1 and Foxa2 directly activate and bind the promoter region the Nkx2.2, Kir6.2 and Sur1, Gipr, Isl1, and Pou3f4 genes. We also demonstrated that glucagon secretion is affected by the combined effects of Foxa1 and Foxa2 but not by either one alone. Our results indicate that Foxa1 and Foxa2 control glucagon biosynthesis and secretion as well as α-cell differentiation with both common and unique target genes.
Neurokinin B Induces c-fos Transcription via Protein Kinase C and Activation of Serum Response Factor and Elk-1 in Immortalized GnRH Neurons
Authors: Glidewell-Kenney Christine A. , Trang Crystal , Shao Paul P. , Gutierrez-Reed Navarre , Uzo-Okereke Adaku M. , Coss Djurdjica , Mellon Pamela L. 
Published: July 2014

AbstractMutations in neurokinin B (NKB) and its receptor, NK3R, were identified in human patients with hypogonadotropic hypogonadism, a disorder characterized by lack of puberty and infertility. Further studies have suggested that NKB acts at the level of the hypothalamus to control GnRH neuron activity, either directly or indirectly. We recently reported that treatment with senktide, a NK3R agonist, induced GnRH secretion and expression of c-fos mRNA in GT1-7 cells. Here, we map the responsive region in the murine c-fos promoter to between −400 and −200 bp, identify the signal transducer and activator of transcription (STAT) (−345) and serum response element (−310) sites as required for induction, a modulatory role for the Ets site (−318), and show that induction is protein kinase C dependent. Using gel shift and Gal4 assays, we further show that phosphorylation of Elk-1 leads to binding to DNA in complex with serum response factor at serum response element and Ets sites within the c-fos promoter. Thus, we determine molecular mechanisms involved in NKB regulation of c-fos induction, which may play a role in modulation of GnRH neuron activation.
Adipose Tissue μ-Crystallin Is a Thyroid Hormone-Binding Protein Associated With Systemic Insulin Sensitivity
Authors: Serrano Marta , Moreno Maria , Ortega Francisco José , Xifra Gemma , Ricart Wifredo , Moreno-Navarrete José María , Fernández-Real José Manuel 
Published: July 2014

Background:Circulating thyroid hormones have been described to be intrinsically associated with insulin sensitivity in healthy subjects. μ-Crystallin is a nicotinamide adenine dinucleotide phosphate-dependent thyroid hormone-binding protein that has been shown to bind T3 in the cytoplasm. We aimed to study μ-Crystallin expression in adipose tissue and in muscle in association with insulin action and thyroid function.Methods:μ-Crystallin gene expression was studied in 81 visceral and 75 sc adipose tissue samples and in 26 muscle samples from a cohort of subjects with a wide spectrum of adiposity (cohort 1). μ-Crystallin was also evaluated in 30 morbidly obese subjects in whom insulin action was evaluated using euglycemic clamp (cohort 2) and in 22 sc adipose tissue samples obtained before and after bariatric surgery-induced weight loss (cohort 3). μ-Crystallin was also evaluated during differentiation of human adipocytes. μ-Crystallin was overexpressed in human sc adipocytes using lentiviruses.Results:μ-Crystallin gene expression was 2.6- to 3-fold higher in sc vs visceral adipose tissue in direct association with the expression of thyroid hormone receptor α 1 in cohort 1 and cohort 2. Visceral, but not sc, adipose tissue μ-Crystallin was positively associated with the serum T3/T4 ratio in cohort 1 and with insulin sensitivity in cohort 2. In fact, μ-Crystallin gene expression was significantly decreased in visceral adipose tissue (−43%) and in muscle (−26%) in subjects with impaired fasting glucose and type 2 diabetes. Weight loss did not result in significant sc adipose tissue μ-Crystallin changes. μ-Crystallin overexpression led to increased insulin-induced Ser473Akt phosphorylation in sc adipocytes. During differentiation of adipocytes, μ-Crystallin gene expression decreased in both visceral (P = .006) and sc (P = .003) adipocytes from obese subjects.Conclusion:Visceral, but not sc, adipose tissue μ-Crystallin is an adipose tissue factor linked to parameters of thyroid hormone action (T3/T4 ratio) and might mediate the interaction of thyroid function and insulin sensitivity.
5-Hydroxymethylcytosine Promotes Proliferation of Human Uterine Leiomyoma: A Biological Link to a New Epigenetic Modification in Benign Tumors
Authors: Navarro Antonia , Yin Ping , Ono Masanori , Monsivais Diana , Moravek Molly B. , Coon John S. , Dyson Matthew T. , Wei Jian-Jun , Bulun Serdar E. 
Published: July 2014

Context:
Uterine leiomyoma, or fibroids, represent the most common benign tumors of the female reproductive tract. A newly discovered epigenetic modification, 5-hydroxymethylation (5-hmC), and its regulators, the TET (Ten Eleven Translocation) enzymes, were implicated in the pathology of malignant tumors; however, their roles in benign tumors, including uterine fibroids, remain unknown.

Objective:
To determine the role of 5-hmC and TET proteins in the pathogenesis of leiomyoma using human uterine leiomyoma and normal matched myometrial tissues and primary cells.

Design:
5-hmC levels were determined by ELISA and immunofluorescent staining in matched myometrial and leiomyoma tissues. TET expression was analyzed by quantitative RT-PCR and immunoblotting. TET1 or TET3 were silenced or inhibited by small interfering RNA or 2-hydroxyglutarate to study their effects on 5-hmC content and cell proliferation.

Results:
We demonstrated significantly higher 5-hmC levels in the genomic DNA of leiomyoma tissue compared to normal myometrial tissue. The increase in 5-hmC levels was associated with the up-regulation of TET1 or TET3 mRNA and protein expression in leiomyoma tissue. TET1 or TET3 knockdown significantly reduced 5-hmC levels in leiomyoma cells and decreased cell proliferation. Treatment with 2-hydroxyglutarate, a competitive TET enzyme inhibitor, significantly decreased both 5-hmC content and cell proliferation of leiomyoma cells.

Conclusion:
An epigenetic imbalance in the 5-hmC content of leiomyoma tissue, caused by up-regulation of the TET1 and TET3 enzymes, might lead to discovery of new therapeutic targets in leiomyoma.
Efficient Algorithms for Solving Several Problems in Teaching Programming
Authors: Дмитриев  , Dmitriev Vladislav 
Published: July 2014

Both at school and at higher educational institutions the priority generally is given to standard mathematical problems, which in most cases seem
to have quite evident solutions. However some of these problems can be solved in more optimal ways, which are often not been found at all. Based
on a range of examples the paper considers how to seek and apply efficient algorithms when solving a specific class of problems in the course of
programming teaching. The algorithm efficiency is meant that the program (as far as the current problem specifications require) meets requirements
of minimal memory use and certain speed of algorithms. The author has successfully used the problems discussed in the paper for running the distant
programming competition among students of physical-mathematical and engineering profiles. Source codes for the programs discussed are indicated
in terms of C++ programming language.
Development of High School Students’ Research Potential in Full-time School
Authors: Макотрова  , Makotrova Galina 
Published: July 2014

The paper presents ideas on how to develop research potential of upperclassmen, attending full-time school, based on ideological principles of recently
introduced Federal State Educational Standard. Special attention is given to methods, designed to realize ideas of subjectivity and subjectness in
developing senior high school students’ research qualities based on use of advanced information and communication technologies in the context of
close interrelation of class and extracurricular activities.
The results of research aimed at identifying psychological predictors of impulsive and restrictive behaviours in a population of females suffering from anorexia or bulimia nervosa. (the author’s own research report)
Authors: Izydorczyk Bernadetta 
Published: July 2014

Aim of the studyThe results of research aimed at identifying psychological predictors of impulsive and restrictive behaviours in a population of females suffering from anorexia or bulimia.Subject or material and methodsEating Disorder Inventory (EDI) devised by D. Garner.
Clinical group:90 Polish females with bulimia and anorexia, A control group: 121 women, who exhibited no eating disorders.ResultsAnalysis of the data gathered as a result of this research demonstrated that the females comprising the clinical sample, who exhibited symptoms of bulimia or anorexia displayed inappropriate levels of all emotional and cognitive characteristics. Statistically significant differences were observed between the clinical and control subjects in terms of the variables investigated in the study.DiscussionThe data analysis revealed that low interoceptive awareness proved to be a significant predictor of impulsive and restrictive behaviours in anorexia and bulimia. Perfectionism and body dissatisfaction were found to be significant determinants of restrictive behaviours. Where as, such variables as a tendency towards bulimia and body dissatisfaction emerged as predictive factors for the symptoms of bulimia and bulimia type anorexia.ConclusionsPossibility that a psychological diagnosis of the emotional and cognitive characteristics displayed by females diagnosed with anorexia or bulimia nervosa is likely to facilitate the process of detecting the symptoms which are typical of the particular types of eating disorders, and thus it is a tool that can be useful at the initial stage of treatment, which involves establishing appropriate psychological interventions aimed at eliminating impulsive and restrictive behaviours developed in patients diagnosed with the aforementioned eating disorders
Increasing the health, activity and participation levels of people attending day centres
Authors: Hurley Michael V , Dudziec Magdalena , Kennedy Bernadette , Anderson Liezl , Jackson Iris , Koskela Sian , Gallagher William , Jones Fiona 
Published: July 2014

Background: Day centres can enable people with mild-to-moderate physical and mental health conditions to continue living at home, delaying their move into residential care. ‘Access to Wellbeing’ is a programme designed to help day centres improve service users’ health and participation in meaningful physical, mental and social activities. This paper documents the programme and people's experiences of its implementation. Methods: This study used a retrospective observational design, and studied a day centre that caters for 40 disabled and/or frail adults daily. The Access to Wellbeing programme development started with a structured assessment of the day centre to identify aspects of the environment and working practices that impeded physical activity. Service users were interviewed to understand their needs, abilities and interests, and establish meaningful activities to improve their health and wellbeing. Alterations to organisational structures, the physical environment and work practices were instigated to increase opportunities for physical activity and involvement. Shortly after implementation of the Access to Wellbeing programme in a day centre, semi-structured interviews were conducted with three day centre staff and three members of the community rehabilitation team exploring their experiences of the programme and its implementation. Findings: Despite staff's initial scepticism about the programme and concerns about their increased workload, and its effect on their relationship and interaction with service users, the programme was successfully implemented. The programme increased service users’ physical health and wellbeing, and satisfaction with the service, and improved staff motivation and job satisfaction. A committed team working together was the most important factor determining successful implementation. Few additional resources were required. Conclusions: A holistic programme that aims to improve meaningful activities can be implemented in day centres. These programmes can bring wide-ranging benefits to service users health, wellbeing and participation, and staff motivation job satisfaction and productivity.
Using programme theory to evaluate delivery of health services: A methodology accessible to clinicians
Authors: Schuurs Sarita , Amsters Delena , Bayliss Carey , Maugham Lucy , Mason Oliver , Slattery Peter 
Published: July 2014

Background: With healthcare providers experiencing increasing demand to evaluate clinical service delivery, it is necessary to explore evaluation methodologies that can accommodate the complexities and contextual factors in health-care systems and human systems in general. Methodologies must also be comprehensible to clinicians. Programme theory is one such methodology. Content: This paper presents a brief description of programme theory methodology and a case study of the use of this approach in a custom wheelchair seating service for people with spinal cord injury. Conclusions: Programme theory is a useful methodology for examining how a service operates and whether it achieves what it sets out to do. It is essential that clinicians challenge and test their assumptions about their services and act on information obtained in order to continuously improve service delivery.