bluuebunny/crossref_metadata_2025 huggingface dataset:
Dysregulated methylation at imprinted genes in prostate tumor tissue detected by methylation microarray
Authors: Jacobs Daniel I , Mao Yingying , Fu Alan , Kelly William Kevin , Zhu Yong
Published: August 2013

Background

Imprinting is an important epigenetic regulator of gene expression that is often disrupted in cancer. While loss of imprinting (LOI) has been reported for two genes in prostate cancer (IGF2andTFPI2), disease-related changes in methylation across all imprinted gene regions has not been investigated.

Methods

Using an Illumina Infinium Methylation Assay, we analyzed methylation of 396 CpG sites in the promoter regions of 56 genes in a pooled sample of 12 pairs of prostate tumor and adjacent normal tissue. Selected LOI identified from the array was validated using the Sequenom EpiTYPER assay for individual samples and further confirmed by expression data from publicly available datasets.

Results

Methylation significantly increased in 52 sites and significantly decreased in 17 sites across 28 unique genes (P < 0.05), and the strongest evidence for loss of imprinting was demonstrated in tumor suppressor genesDLK1,PLAGL1,SLC22A18,TP73, andWT1. Differential expression of these five genes in prostate tumor versus normal tissue using array data from a publicly available database were consistent with the observed LOI patterns, andWT1hypermethylation was confirmed using quantitative DNA methylation analysis.

Conclusions

Together, these findings suggest a more widespread dysregulation of genetic imprinting in prostate cancer than previously reported and warrant further investigation.
Dual solutions of stagnation-point flow of a nanofluid over a stretching surface
Authors: Kameswaran Peri K , Sibanda Precious , RamReddy Chetteti , Murthy Prabhala VSN
Published: August 2013

The paper discusses the effects of homogeneous-heterogeneous reactions on stagnation-point flow of a nanofluid over a stretching or shrinking sheet. The model presented describes mass transfer in copper-water and silver-water nanofluids. The governing system of equations is solved numerically, and the study shows that dual solutions exist for certain suction/injection, stretching/shrinking and magnetic parameter values. Comparison of the numerical results is made with previously published results for special cases.
Functional Val66Met polymorphism of Brain-derived neurotrophic factor in type 2 diabetes with depression in Han Chinese subjects
Authors: Zhou Jian-Xin , Li He-Chao , Bai Xue-Jun , Chang Bao-Cheng , Li Chun-Jun , Sun Pei , Chen Li-Ming
Published: August 2013

Background

Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of major depression. Individuals with type 2 diabetes (T2DM) have a high prevalence of major depression and low levels of BDNF. We therefore explored whether the BDNF Val66Met polymorphism is associated with co-morbid depression and whether depression affects the serum levels of BDNF in a Han Chinese subjects with T2DM.

Methods

A Total of 296 T2DM patients and 70 healthy volunteers (Health control, HC group) were recruited in this study. T2DM patients were divided into two subgroups: depressive diabetes group (DDM group, n = 64) and non-depressive diabetes group (NDDM group, n = 232), according to the presence or the absence of depression assessed by Center for Epidemiologic Studies Depression Scale (CES-D) and Patient Health Questionnaire-9 (PHQ-9). Val66Met polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP). Serum BDNF levels were measured by ELISA kit.

Results

In this study, 21.6% (64/296) patients with T2DM had depression. The BDNF Val66Met genotype distributions were statistically different among the three groups (χ2 = 7.39, p < 0.05). DDM group carried the highest frequencies of Met allele (53.9%) compared to HC group (39.3%) and NDDM group (38.8%). Subjects with Met/Met had lowest serum BDNF levels (76.59 ± 5.12 pg/ml, F = 7.39, p < 0.05) compared to subjects with Val/Met (79.04 ± 5.19 pg/ml) and Val/Val (83.83 ± 3.97 pg/ml). Within T2DM group, it was also observed that the serum BDNF levels in DDM group were significantly lower than those in NDDM group (76.67 ± 5.35 vs. 79.84 ± 3.97 pg/ml, p < 0.05). In type 2 diabetes subjects, BDNF serum levels were significant correlations with genotypes (r = −0.346, p < 0.01), depression scores (r = −0.486, p < 0.01) and HbA1c (r = −0.168, p < 0.05). After adjustment for gender, HbA1c, BMI and numbers of complications, BDNF Val/Met genotype distributions (OR = 2.105, p < 0.05) and decreased serum BDNF levels (OR = 0.835, p < 0.01) were independently associated with depression in T2DM.

Conclusions

The BDNF Val66Met polymorphism might be implicated in the pathogenesis of depression in T2DM by decreasing serum BDNF levels in Han Chinese Subjects.
The detection of oral pre- malignant lesions with an autofluorescence based imaging system (VELscopeTM) – a single blinded clinical evaluation
Authors: Hanken Henning , Kraatz Juliane , Smeets Ralf , Heiland Max , Blessmann Marco , Eichhorn Wolfgang , Clauditz Till Sebastian , Gröbe Alexander , Kolk Andreas , Rana Madiha
Published: August 2013

Objective

The disease specific five-year survival rate especially for patients with advanced oral cancer has not improved significantly over the period of time. The most effective way of combating this dilemma is an early detection, diagnosis and eradication of early-stage lesions and their precursors. The use of VELscope® using an autofluorescence as a diagnostic tool might be useful in early detection of oral malignant lesions.

Materials and methods

120 patients with suspicious oral premalignant lesions were examined with two examination methods. They were randomly divided into two groups. Group 1 was examined conventional with white-light and group 2 was examined additionally to the white-light-examination with an autofluorescence visualization device, VELscope®. Biopsies were obtained from all suspicious areas identified in both examination groups (n = 52). The diagnostic strategies were compared regarding sensitivity and specificity.

Results

Based upon the result, use of the VELscope® leads to a higher sensitivity (22.0%), but regarding specificity the additional use of the VELscope® is inferior (8.4%).

Conclusion

The VELscope device is a simple, non-invasive test of the oral mucosa, which can help the experienced clinician to find oral precursor malignant lesions.
Online solid phase extraction liquid chromatography tandem mass spectrometry (SPE-LC-MS/MS) method for the determination of sucralose in reclaimed and drinking waters and its photo degradation in natural waters from South Florida
Authors: Batchu Sudha Rani , Quinete Natalia , Panditi Venkata R , Gardinali Piero R
Published: August 2013

Background

Sucralose has gained popularity as a low calorie artificial sweetener worldwide. Due to its high stability and persistence, sucralose has shown widespread occurrence in environmental waters, at concentrations that could reach up to several μg/L. Previous studies have used time consuming sample preparation methods (offline solid phase extraction/derivatization) or methods with rather high detection limits (direct injection) for sucralose analysis. This study described a faster and sensitive analytical method for the determination of sucralose in environmental samples.

Results

An online SPE-LC–MS/MS method was developed, being capable to quantify sucralose in 12 minutes using only 10 mL of sample, with method detection limits (MDLs) of 4.5 ng/L, 8.5 ng/L and 45 ng/L for deionized water, drinking and reclaimed waters (1:10 diluted with deionized water), respectively. Sucralose was detected in 82% of the reclaimed water samples at concentrations reaching up to 18 μg/L. The monthly average for a period of one year was 9.1 ± 2.9 μg/L. The calculated mass loads per capita of sucralose discharged through WWTP effluents based on the concentrations detected in wastewaters in the U. S. is 5.0 mg/day/person. As expected, the concentrations observed in drinking water were much lower but still relevant reaching as high as 465 ng/L. In order to evaluate the stability of sucralose, photodegradation experiments were performed in natural waters. Significant photodegradation of sucralose was observed only in freshwater at 254 nm. Minimal degradation (<20%) was observed for all matrices under more natural conditions (350 nm or solar simulator). The only photolysis product of sucralose identified by high resolution mass spectrometry was a de-chlorinated molecule at m/z 362.0535, with molecular formula C12H20Cl2O8.

Conclusions

Online SPE LC-APCI/MS/MS developed in the study was applied to more than 100 environmental samples. Sucralose was frequently detected (>80%) indicating that the conventional treatment process employed in the sewage treatment plants is not efficient for its removal. Detection of sucralose in drinking waters suggests potential contamination of surface and ground waters sources with anthropogenic wastewater streams. Its high resistance to photodegradation, minimal sorption and high solubility indicate that sucralose could be a good tracer of anthropogenic wastewater intrusion into the environment.
A 19-year-old man with sickle cell disease presenting with spinal infarction: a case report
Authors: Edwards April , Clay E Leila Jerome , Jewells Valerie , Adams Stacie , Crawford Regina D , Redding-Lallinger Rupa
Published: August 2013

Introduction

Vasculopathy of the large vessels commonly occurs in sickle cell disease, and as a result cerebral infarction is a well characterized complication of this condition. However, spinal infarction appears to be rare. Spinal infarct is infrequent in the non-sickle cell population as well, and accounts for only about 1 percent of all central nervous system infarcts.

Case presentation

In the present work, we report the case of a 19-year-old African-American man with sickle cell disease who experienced an anterior spinal infarct and subsequent quadriplegia. He was incidentally noted to be a heterozygote for factor V Leiden. We also reviewed the literature and found two previous cases of spinal cord infarction and sickle hemoglobin. Our literature search did not demonstrate that heterozygocity for factor V Leiden plays an important role in spinal cord infarction.

Conclusions

The paucity of cases associated with sickle hemoglobin does not allow us to postulate any particular risk factors with sickle cell disease that might predispose patients to spinal cord infarction. Our patient’s case raises the question as to whether spinal cord infarction is being missed in individuals with sickle cell disease and neurologic symptoms.
Cloning and biochemical characterization of an endo-1,4-β-mannanase from the coffee berry borer hypothenemus hampei
Authors: Aguilera-Gálvez Carolina , Vásquez-Ospina Juan J , Gutiérrez-Sanchez Pablo , Acuña-Zornosa Ricardo
Published: August 2013

Background

The study of coffee polysaccharides-degrading enzymes from the coffee berry borerHypothenemus hampei,has become an important alternative in the identification for enzymatic inhibitors that can be used as an alternative control of this dangerous insect. We report the cloning, expression and biochemical characterization of a mannanase gene that was identified in the midgut of the coffee berry borer and is responsible for the degradation of the most abundant polysaccharide in the coffee bean.

Methods

The amino acid sequence of HhMan was analyzed by multiple sequence alignment comparisons with BLAST (Basic Local Alignment Search Tool) and CLUSTALW. APichia pastorisexpression system was used to express the recombinant form of the enzyme. The mannanase activity was quantified by the 3,5-dinitrosalicylic (DNS) and the hydrolitic properties were detected by TLC.

Results

An endo-1,4-β-mannanase from the digestive tract of the insectHypothenemus hampeiwas cloned and expressed as a recombinant protein in thePichia pastorissystem. This enzyme is 56% identical to the sequence of an endo-β-mannanase fromBacillus circulansthat belongs to the glycosyl hydrolase 5 (GH5) family. The purified recombinant protein (rHhMan) exhibited a single band (35.5 kDa) by SDS-PAGE, and its activity was confirmed by zymography. rHhMan displays optimal activity levels at pH 5.5 and 30°C and can hydrolyze galactomannans of varying mannose:galactose ratios, suggesting that the enzymatic activity is independent of the presence of side chains such as galactose residues. The enzyme cannot hydrolyze manno-oligosaccharides such as mannobiose and mannotriose; however, it can degrade mannotetraose, likely through a transglycosylation reaction. The Kmand kcatvalues of this enzyme on guar gum were 2.074 mg ml-1and 50.87 s-1, respectively, which is similar to other mannanases.

Conclusion

This work is the first study of an endo-1,4-β-mannanase from an insect using this expression system. Due to this enzyme’s importance in the digestive processes of the coffee berry borer, this study may enable the design of inhibitors against endo-1,4-β-mannanase to decrease the economic losses stemming from this insect.
Molecular characterization of Trichinella spiralis aminopeptidase and its potential as a novel vaccine candidate antigen against trichinellosis in BALB/c mice
Authors: Zhang Ya Lan , Wang Zhong Quan , Li Ling Ge , Cui Jing
Published: August 2013

Background

Trichinella spiralis is an intracellular parasite that can cause a serious threat to human health by causing trichinellosis. The aminopeptidase (AP) was found in the proteins produced by T. spiralis infective larvae after in vitro co-culture with intestinal epithelial cells, but its characteristics and function are unknown. The purpose of this study was to identify the T. spiralis aminopeptidase (TsAP) and to investigate its potential as a vaccine candidate antigen against T. spiralis infection.

Methods

T. spiralis aminopeptidase (TsAP) gene encoding a 54.7 kDa protein was cloned and expressed in Escherichia coli, and purified recombinant TsAP protein was used to immunize BALB/c mice. The antibodies obtained were used to determine where TsAP was localized in the parasite. Transcription and expression of TsAP in different developmental stages of T. spiralis were observed by RT-PCR and Immunofluorescence test (IFT). The immune protection of recombinant TsAP protein against T. spiralis infection in BALB/c mice was evaluated.

Results

Anti-TsAP antibodies recognized the native protein migrating at 54.7 kDa by Western blotting of the crude antigens from muscle larvae. Transcription and expression of TsAP gene was observed in different developmental stages (adult worms, newborn larvae, pre-encapsulated larvae and muscle larvae). TsAP appears to be a cytoplasmic protein located primarily at the cuticle and internal organs of this parasite. After a challenge infection with T. spiralis infective larvae, mice immunized with the recombinant TsAP protein displayed a 38.1% reduction in adult worm burden and 59.1% reduction in muscle larval burden.

Conclusions

In this study, T. spiralis aminopeptidase (TsAP) was first characterized and will help reveal its potential biological functions. TsAP is a novel potential vaccine candidate antigen that merits further investigation.
Treeline dynamics in response to climate change in the Min Mountains, southwestern China
Authors: Zhao Zhi-Jiang , Shen Guo-Zhen , Tan Liu-Yi , Kang Dong-Wei , Wang Meng-Jun , Kang Wen , Guo Wen-Xia , Zeppel Melanie JB , Yu Qiang , Li Jun-Qing
Published: August 2013

Background

Abies faxonianais the dominant plant species of the forest ecosystem on the eastern edge of Qinghai-Tibet Plateau, where the treeline is strongly defined by climate. The tree-ring chronologies and age structure ofAbies faxonianawere developed in the treeline ecotones on the northwestern and southeastern aspects of the Min Mountains in the Wanglang Nature Reserve to examine the treeline dynamics of recent decades in response to climate change.

Results

On the northwestern aspect, correlation analysis showed that the radial growth was significantly and positively correlated with precipitation in current January and monthly mean temperature in current April, but significantly and negatively correlated with monthly mean temperature in previous August. On the southeastern aspect, the radial growth was significantly negatively correlated with monthly mean temperature in previous July and August.

Conclusions

The different responses of radial growth to climatic variability on both the aspects might be mainly due to the micro-environmental conditions. The recruitment benefited from the warm temperature in current April, July and September on the northwestern aspect. The responses of radial growth and recruitment to climatic variability were similar on the northwestern slope. Recruitment was greatly restricted by competition with dense bamboos on the southeastern aspect.
Micronutrient fortification of food and its impact on woman and child health: a systematic review
Authors: Das Jai K , Salam Rehana A , Kumar Rohail , Bhutta Zulfiqar A
Published: August 2013

Background

Vitamins and minerals are essential for growth and metabolism. The World Health Organization estimates that more than 2 billion people are deficient in key vitamins and minerals. Groups most vulnerable to these micronutrient deficiencies are pregnant and lactating women and young children, given their increased demands. Food fortification is one of the strategies that has been used safely and effectively to prevent vitamin and mineral deficiencies.

Methods

A comprehensive search was done to identify all available evidence for the impact of fortification interventions. Studies were included if food was fortified with a single, dual or multiple micronutrients and impact of fortification was analyzed on the health outcomes and relevant biochemical indicators of women and children. We performed a meta-analysis of outcomes using Review Manager Software version 5.1.

Results

Our systematic review identified 201 studies that we reviewed for outcomes of relevance. Fortification for children showed significant impacts on increasing serum micronutrient concentrations. Hematologic markers also improved, including hemoglobin concentrations, which showed a significant rise when food was fortified with vitamin A, iron and multiple micronutrients. Fortification with zinc had no significant adverse impact on hemoglobin levels. Multiple micronutrient fortification showed non-significant impacts on height for age, weight for age and weight for height Z-scores, although they showed positive trends. The results for fortification in women showed that calcium and vitamin D fortification had significant impacts in the post-menopausal age group. Iron fortification led to a significant increase in serum ferritin and hemoglobin levels in women of reproductive age and pregnant women. Folate fortification significantly reduced the incidence of congenital abnormalities like neural tube defects without increasing the incidence of twinning. The number of studies pooled for zinc and multiple micronutrients for women were few, though the evidence suggested benefit. There was a dearth of evidence for the impact of fortification strategies on morbidity and mortality outcomes in women and children.

Conclusion

Fortification is potentially an effective strategy but evidence from the developing world is scarce. Programs need to assess the direct impact of fortification on morbidity and mortality.
Elevated oleic acid serum concentrations in patients suffering from alcohol dependence
Authors: Teubert Annekatrin , Thome Johannes , Büttner Andreas , Richter Jörg , Irmisch Gisela
Published: August 2013

Background

Alcohol-induced damages such as brain atrophy and fatty liver are closely related to a disturbed lipid metabolism. In animal models, a linkage between chronic alcohol consumption and changes in fatty acid (FA) composition in various organs and cells is well known and there is some indication that this phenomenon could be linked to behavioural alterations associated with alcohol addiction such as craving. However, the influence of ethanol on secretory FA has not been investigated so far. In this study, we therefore aimed at investigating whether there is a significant change of serum FA composition in patients suffering from alcohol dependence. We compared patients before and after treatment (detoxication) with control individuals who did not suffer from addiction. The roles of age, the duration and intensity of alcohol use and lifestyles were considered.

Methods

Serum FA was measured in 73 male ethanol dependent patients before and after alcohol withdrawal in an in-patient setting. Additionally, of this group, 45 patients were matched with 45 healthy male volunteers as controls.

Results

We found significant differences in the FA composition before and after detoxication as well as between patients and controls. After detoxication, the values changed towards the ones in healthy controls. The main finding during acute alcohol use was an increased oleic acid concentration above the level of the linoleic acid concentration.

Conclusions

An elevated oleic/linoleic acid ratio seems to be a state marker for acute alcohol use and may be a relevant trait marker during detoxification and possibly the subsequent therapeutic measures. The results of this pilot study need to be replicated in a larger study also including female patients. Further, the specificity of this potential biomarker needs to be determined.
Optimization of preparation of chitosan-coated iron oxide nanoparticles for biomedical applications by chemometrics approaches
Authors: Honary Soheila , Ebrahimi Pouneh , Rad Hossein Asgari , Asgari Mahsa
Published: August 2013

Functionalized magnetic nanoparticles are used in several biomedical applications, such as drug delivery, magnetic cell separation, and magnetic resonance imaging. Size and surface properties of iron oxide nanoparticles are the two important factors which could dramatically affect the nanoparticle efficiency as well as their stability. In this study, the chemometrics approach was applied to optimize the coating process of iron oxide nanoparticles. To optimize the size of nanoparticles, the effect of two experimental parameters on size was investigated by means of multivariate analysis. The factors considered were chitosan molecular weight and chitosan-to-tripolyphosphate concentration ratio. The experiments were performed according to face-centered cube central composite response surface design. A second-order regression model was obtained which characterized by both descriptive and predictive abilities. The method was optimized with respect to the percent of Z average diameter’s increasing after coating as response. It can be concluded that experimental design provides a suitable means of optimizing and testing the robustness of iron oxide nanoparticle coating method.
Transcriptomic signatures in cartilage ageing
Authors: Peffers Mandy Jayne , Liu Xuan , Clegg Peter David
Published: August 2013

Introduction

Age is an important factor in the development of osteoarthritis. Microarray studies provide insight into cartilage aging but do not reveal the full transcriptomic phenotype of chondrocytes such as small noncoding RNAs, pseudogenes, and microRNAs. RNA-Seq is a powerful technique for the interrogation of large numbers of transcripts including nonprotein coding RNAs. The aim of the study was to characterise molecular mechanisms associated with age-related changes in gene signatures.

Methods

RNA for gene expression analysis using RNA-Seq and real-time PCR analysis was isolated from macroscopically normal cartilage of the metacarpophalangeal joints of eight horses; four young donors (4 years old) and four old donors (>15 years old). RNA sequence libraries were prepared following ribosomal RNA depletion and sequencing was undertaken using the Illumina HiSeq 2000 platform. Differentially expressed genes were defined using Benjamini-Hochberg false discovery rate correction with a generalised linear model likelihood ratio test (P < 0.05, expression ratios ± 1.4 log2 fold-change). Ingenuity pathway analysis enabled networks, functional analyses and canonical pathways from differentially expressed genes to be determined.

Results

In total, the expression of 396 transcribed elements including mRNAs, small noncoding RNAs, pseudogenes, and a single microRNA was significantly different in old compared with young cartilage (± 1.4 log2 fold-change, P < 0.05). Of these, 93 were at higher levels in the older cartilage and 303 were at lower levels in the older cartilage. There was an over-representation of genes with reduced expression relating to extracellular matrix, degradative proteases, matrix synthetic enzymes, cytokines and growth factors in cartilage derived from older donors compared with young donors. In addition, there was a reduction in Wnt signalling in ageing cartilage.

Conclusion

There was an age-related dysregulation of matrix, anabolic and catabolic cartilage factors. This study has increased our knowledge of transcriptional networks in cartilage ageing by providing a global view of the transcriptome.
Pharmacologic reversion of epigenetic silencing of the PRKD1promoter blocks breast tumor cell invasion and metastasis
Authors: Borges Sahra , Döppler Heike , Perez Edith A , Andorfer Cathy A , Sun Zhifu , Anastasiadis Panos Z , Thompson E Aubrey , Geiger Xochiquetzal J , Storz Peter
Published: August 2013

Introduction

DNA methylation-induced silencing of genes encoding tumor suppressors is common in many types of cancer, but little is known about how such epigenetic silencing can contribute to tumor metastasis. The PRKD1 gene encodes protein kinase D1 (PKD1), a serine/threonine kinase that is expressed in cells of the normal mammary gland, where it maintains the epithelial phenotype by preventing epithelial-to-mesenchymal transition.

Methods

The status of PRKD1 promoter methylation was analyzed by reduced representation bisulfite deep sequencing, methylation-specific PCR (MSP-PCR) and in situ MSP-PCR in invasive and noninvasive breast cancer lines, as well as in humans in 34 cases of “normal” tissue, 22 cases of ductal carcinoma in situ, 22 cases of estrogen receptor positive, HER2-negative (ER+/HER2-) invasive lobular carcinoma, 43 cases of ER+/HER2- invasive ductal carcinoma (IDC), 93 cases of HER2+ IDC and 96 cases of triple-negative IDC. A reexpression strategy using the DNA methyltransferase inhibitor decitabine was used in vitro in MDA-MB-231 cells as well as in vivo in a tumor xenograft model and measured by RT-PCR, immunoblotting and immunohistochemistry. The effect of PKD1 reexpression on cell invasion was analyzed in vitro by transwell invasion assay. Tumor growth and metastasis were monitored in vivo using the IVIS Spectrum Pre-clinical In Vivo Imaging System.

Results

Herein we show that the gene promoter of PRKD1 is aberrantly methylated and silenced in its expression in invasive breast cancer cells and during breast tumor progression, increasing with the aggressiveness of tumors. Using an animal model, we show that reversion of PRKD1 promoter methylation with the DNA methyltransferase inhibitor decitabine restores PKD1 expression and blocks tumor spread and metastasis to the lung in a PKD1-dependent fashion.

Conclusions

Our data suggest that the status of epigenetic regulation of the PRKD1 promoter can provide valid information on the invasiveness of breast tumors and therefore could serve as an early diagnostic marker. Moreover, targeted upregulation of PKD1 expression may be used as a therapeutic approach to reverse the invasive phenotype of breast cancer cells.
Estrogen receptor negative/progesterone receptor positive breast cancer is not a reproducible subtype
Authors: Hefti Marco M , Hu Rong , Knoblauch Nicholas W , Collins Laura C , Haibe-Kains Benjamin , Tamimi Rulla M , Beck Andrew H
Published: August 2013

Introduction

Estrogen receptor (ER) and progesterone receptor (PR) testing are performed in the evaluation of breast cancer. While the clinical utility of ER as a predictive biomarker to identify patients likely to benefit from hormonal therapy is well-established, the added value of PR is less well-defined. The primary goals of our study were to assess the distribution, inter-assay reproducibility, and prognostic significance of breast cancer subtypes defined by patterns of ER and PR expression.

Methods

We integrated gene expression microarray (GEM) and clinico-pathologic data from 20 published studies to determine the frequency (n = 4,111) and inter-assay reproducibility (n = 1,752) of ER/PR subtypes (ER+/PR+, ER+/PR-, ER-/PR-, ER-/PR+). To extend our findings, we utilized a cohort of patients from the Nurses’ Health Study (NHS) with ER/PR data recorded in the medical record and assessed on tissue microarrays (n = 2,011). In both datasets, we assessed the association of ER and PR expression with survival.

Results

In a genome-wide analysis, progesterone receptor was among the least variable genes in ER- breast cancer. The ER-/PR+ subtype was rare (approximately 1 to 4%) and showed no significant reproducibility (Kappa = 0.02 and 0.06, in the GEM and NHS datasets, respectively). The vast majority of patients classified as ER-/PR+ in the medical record (97% and 94%, in the GEM and NHS datasets) were re-classified by a second method. In the GEM dataset (n = 2,731), progesterone receptor mRNA expression was associated with prognosis in ER+ breast cancer (adjusted P <0.001), but not in ER- breast cancer (adjusted P = 0.21). PR protein expression did not contribute significant prognostic information to multivariate models considering ER and other standard clinico-pathologic features in the GEM or NHS datasets.

Conclusion

ER-/PR+ breast cancer is not a reproducible subtype. PR expression is not associated with prognosis in ER- breast cancer, and PR does not contribute significant independent prognostic information to multivariate models considering ER and other standard clinico-pathologic factors. Given that PR provides no clinically actionable information in ER+ breast cancer, these findings question the utility of routine PR testing in breast cancer.
Genome-wide analyses of Shavenbaby target genes reveals distinct features of enhancer organization
Authors: Menoret Delphine , Santolini Marc , Fernandes Isabelle , Spokony Rebecca , Zanet Jennifer , Gonzalez Ignacio , Latapie Yvan , Ferrer Pierre , Rouault Hervé , White Kevin P , Besse Philippe , Hakim Vincent , Aerts Stein , Payre Francois , Plaza Serge
Published: August 2013

Background

Developmental programs are implemented by regulatory interactions between Transcription Factors (TFs) and their target genes, which remain poorly understood. While recent studies have focused on regulatory cascades of TFs that govern early development, little is known about how the ultimate effectors of cell differentiation are selected and controlled. We addressed this question during late Drosophila embryogenesis, when the finely tuned expression of the TF Ovo/Shavenbaby (Svb) triggers the morphological differentiation of epidermal trichomes.

Results

We defined a sizeable set of genes downstream of Svb and used in vivo assays to delineate 14 enhancers driving their specific expression in trichome cells. Coupling computational modeling to functional dissection, we investigated the regulatory logic of these enhancers. Extending the repertoire of epidermal effectors using genome-wide approaches showed that the regulatory models learned from this first sample are representative of the whole set of trichome enhancers. These enhancers harbor remarkable features with respect to their functional architectures, including a weak or non-existent clustering of Svb binding sites. The in vivo function of each site relies on its intimate context, notably the flanking nucleotides. Two additional cis-regulatory motifs, present in a broad diversity of composition and positioning among trichome enhancers, critically contribute to enhancer activity.

Conclusions

Our results show that Svb directly regulates a large set of terminal effectors of the remodeling of epidermal cells. Further, these data reveal that trichome formation is underpinned by unexpectedly diverse modes of regulation, providing fresh insights into the functional architecture of enhancers governing a terminal differentiation program.
Treatment of child anxiety disorders via guided parent-delivered cognitive–behavioural therapy: Randomised controlled trial
Authors: Thirlwall Kerstin , Cooper Peter J. , Karalus Jessica , Voysey Merryn , Willetts Lucy , Creswell Cathy
Published: August 2013

Background

Promising evidence has emerged of clinical gains using guided self-help cognitive–behavioural therapy (CBT) for child anxiety and by involving parents in treatment; however, the efficacy of guided parent-delivered CBT has not been systematically evaluated in UK primary and secondary settings.

Aims

To evaluate the efficacy of low-intensity guided parent-delivered CBT treatments for children with anxiety disorders.

Method

A total of 194 children presenting with a current anxiety disorder, whose primary carer did not meet criteria for a current anxiety disorder, were randomly allocated to full guided parent-delivered CBT (four face-to-face and four telephone sessions) or brief guided parent-delivered CBT (two face-to-face and two telephone sessions), or a wait-list control group (trial registration: ISRCTN92977593). Presence and severity of child primary anxiety disorder (Anxiety Disorders Interview Schedule for DSM-IV, child/parent versions), improvement in child presentation of anxiety (Clinical Global Impression –Improvement scale), and change in child anxiety symptoms (Spence Children's Anxiety Scale, child/parent version and Child Anxiety Impact scale, parent version) were assessed at post-treatment and for those in the two active treatment groups, 6 months post-treatment.

Results

Full guided parent-delivered CBT produced superior diagnostic outcomes compared with wait-list at post-treatment, whereas brief guided parent-delivered CBT did not: at post-treatment, 25 (50%) of those in the full guided CBT group had recovered from their primary diagnosis, compared with 16 (25%) of those on the wait-list (relative risk (RR) 1.85, 95% CI 1.14–2.99); and in the brief guided CBT group, 18 participants (39%) had recovered from their primary diagnosis post-treatment (RR = 1.56, 95% CI 0.89–2.74). Level of therapist training and experience was unrelated to child outcome.

Conclusions

Full guided parent-delivered CBT is an effective and inexpensive first-line treatment for child anxiety.
Seismic Resistance Evaluation of Traditional Ottoman Timber-Frame Hımış Houses: Frame Loadings and Material Tests
Authors: Aktaş Yasemin Didem , Akyüz Uğurhan , Türer Ahmet , Erdil Barış , Güçhan Neriman Şahin
Published: August 2013

Traditional Ottoman timber-frame houses (“ hımış”) form the major part of the cultural heritage structures in Turkey. There are many studies in the literature regarding the seismic performance of hımış houses, which claim that these structures have an inherent seismically resistant property. However, these studies lack a quantitative engineering approach and are based on observations made after contemporary earthquakes. This study presents the results of the seismic resistance evaluation of traditional Ottoman houses, made by means of reverse cyclic frame tests conducted on six yellow pine and two fir frames with and without infill (brick and adobe) or cladding ( bağdadi and şamdolma). The experimental study, which was intended to differentiate the effects of infill materials, frame geometry, and timber type, has revealed that frames with bağdadi cladding and adobe infill resulted in the best and worst structural performances, respectively, while high ductility and good energy dissipation capacity characteristics were determined.
An Anomaly in the Equivalent Linearization Approach for the Estimation of Inelastic Response
Authors: Khose Vijay Namdev , Singh Yogendra
Published: August 2013

The estimation of inelastic displacement is an essential step in displacement-based design. Estimation of inelastic response using response spectra is a simpler and attractive alternative to nonlinear dynamic analysis. A number of methods based on different approaches are now available to estimate nonlinear response from design spectra. Equivalent linearization is one of the widely used approaches for this purpose. The approach is known to yield reasonably accurate results. However, an anomaly in the approach is observed, which results in significantly non-conservative estimates of inelastic displacement, particularly in displacement-controlled spectral range. This paper illustrates the anomaly using displacement modification factors and numerical examples of oscillators of different periods and ductility. The results from the equivalent linearization approach have been compared with the results of nonlinear dynamic analysis and yield spectrum approach.
Seismic Reliability Assessment of Aging Highway Bridge Networks with Field Instrumentation Data and Correlated Failures, II: Application
Authors: Rokneddin Keivan , Ghosh Jayadipta , Dueñas-Osorio Leonardo , Padgett Jamie E.
Published: August 2013

The bridge reliability in networks (BRAN) methodology introduced in the companion paper is applied to evaluate the reliability of part of the highway bridge network in South Carolina under a selected seismic scenario. The case study demonstrates Bayesian updating of deterioration parameters across bridges after spatial interpolation of data acquired from limited instrumented bridges. The updated deterioration parameters inform aging bridge seismic fragility curves through multi-dimensional integration of parameterized fragility models, which are utilized to derive bridge failure probabilities. The paper establishes the correlation structure among bridge failures from three information sources to generate realizations of bridge failures for network-level reliability assessments by Monte Carlo analysis. Positive correlations improve the reliability of the case study network, as predicted from network topology. The benefits of the BRAN methodology are highlighted in its applicability to large networks, while addressing some of the existing gaps in bridge network reliability and prioritization studies.
Application of an Urban Fire Simulation Model
Authors: Li Sizheng , Davidson Rachel
Published: August 2013

Computer models that simulate post-earthquake urban fires can be useful for improving understanding of the phenomenon, estimating risk, evaluating the relative effectiveness of possible risk reduction measures, and identifying areas for further study. A model's usefulness, however, depends on its credibility, which can be difficult to establish. In this paper, we describe two efforts to build the credibility of the recently developed urban fire simulation (UFS) model—comparing it to the widely used Hamada model and applying it to the 2007 Grass Valley, CA fire. The model produces results that are similar in character and magnitude to those from the Hamada model for simplified conditions, and in the Grass Valley case, that compare well to observations in terms of timing, spatial pattern, and modes of spread. The comparisons also highlight the challenges in validation of urban fire models and suggest some areas for future study.
Observed Performance of Residential Masonry Veneer Construction in the 2010/2011 Canterbury Earthquake Sequence
Authors: Dizhur Dmytro , Moon Lisa , Ingham Jason
Published: August 2013

Following the 2010/2011 Canterbury, New Zealand earthquakes, a detailed door-to-door survey was conducted in the Christchurch region to establish the earthquake performance of lightweight timber-framed residential dwellings with a masonry veneer external cladding system. The post-earthquake survey involved documenting the condition of dwellings in areas that had experienced different levels of earthquake shaking, allowing comparison between the performance of different veneer systems and different shaking intensities. In total, just fewer than 1,100 residential dwellings were inspected throughout the wider Christchurch area. The survey included parameters such as level of veneer damage, type of veneer damage, observed crack widths, and level of repair required. It is concluded that based on observed earthquake performance at the shaking intensities matching or exceeding ultimate limit state loading, the post-1996 veneer fixing details performed satisfactorily and continued use of the detail is recommended without further modification.
An Energy-Based Approach to the Generalized Optimal Locations of Viscous Dampers in Two-Way Asymmetrical Buildings
Authors: Lin Jui-Liang , Bui Manh-Tien , Tsai Keh-Chyuan
Published: August 2013

This paper proposes a simple approach to the generalized optimal locations of linear viscous dampers in elastic two-way asymmetrical buildings under bi-directional ground excitations. The control target used in this optimization process is to maximize the average dissipation rate of the overall strain energy of the two-way asymmetrical building under the ground excitation of two bi-directional unit impulses. The proposed control target, referred to as the smeared damping ratio, is an intrinsic property of the building system. Two advantages of the proposed approach appeal to engineering practice. First, the proposed approach does not require a complicated optimization algorithm. Second, due to the employment of an intrinsic property rather than a certain response parameter as the target performance index, the optimal damper locations resulting from the proposed approach are generalized, which are independent on the characteristics of input ground motions.
Ground Motion Record Selection Based on Broadband Spectral Compatibility
Authors: Smerzini Chiara , Galasso Carmine , Iervolino Iunio , Paolucci Roberto
Published: August 2013

The increasing interest in performance-based earthquake engineering has promoted research on the improvement of hazard-consistent seismic input definition and on advanced criteria for strong motion record selection to perform nonlinear time history analyses. Within the ongoing research activities to improve the representation of seismic actions and to develop tools as a support for engineering practice, this study addresses the selection of displacement-spectrum-compatible real ground motions, with special reference to Italy. This involved (1) the definition of specific target displacement spectra for Italian sites, constrained—both at long and short periods—by results of probabilistic seismic hazard analyses; (2) the compilation of a high-quality strong ground motion database; and (3) the development of a software tool for computer-aided displacement-based record selection. Application examples show that sets of unscaled, or lightly scaled, accelerograms with limited record-to-record spectral variability can also easily be obtained when a broadband spectral compatibility is required.
Evaluating the Reliability of Phones as Seismic Monitoring Instruments
Authors: Dashti Shideh , Bray Jonathan D. , Reilly Jack , Glaser Steven , Bayen Alexandre , Mari Ervasti
Published: August 2013

Emergency responders must “see” the effects of an earthquake clearly and rapidly for effective response. This paper presents a novel use of cell phone and information technology to measure ground motion intensity parameters. The phone sensor is an imperfect device and has a limited operational range. Thus, shake table tests were performed to evaluate their reliability as seismic monitoring instruments. Representative handheld devices, either rigidly connected to the table or free to move, measured shaking intensity parameters well. Bias in 5%-damped spectral accelerations measured by phones was less than 0.05 and 0.2 [log(g)] during one-dimensional (1-D) and three-dimensional (3-D) shaking in frequencies ranging from 1 Hz to 10 Hz. They did tend to overestimate the Arias Intensity, but this error declined for stronger motions with larger signal-to-noise ratios. With these ubiquitous measurement devices, a more accurate and rapid portrayal of the damage distribution during an earthquake can be provided.
Postnatal Expression of BRAFV600E Does Not Induce Thyroid Cancer in Mouse Models of Thyroid Papillary Carcinoma
Authors: Shimamura Mika , Nakahara Mami , Orim Florence , Kurashige Tomomi , Mitsutake Norisato , Nakashima Masahiro , Kondo Shinji , Yamada Masanobu , Taguchi Ryo , Kimura Shioko , Nagayama Yuji
Published: August 2013

The mutant BRAF (BRAFV600E) is the most common genetic alteration in papillary thyroid carcinomas (PTCs). The oncogenicity of this mutation has been shown by some genetically engineered mouse models. However, in these mice, BRAFV600E is expressed in all the thyroid cells from the fetal periods, and suppresses thyroid function, thereby leading to TSH elevation, which by itself promotes thyroid tumorigenesis. To overcome these problems, we exploited 2 different approaches, both of which allowed temporally and spatially restricted expression of BRAFV600E in the thyroid glands. First, we generated conditional transgenic mice harboring the loxP-neoR-loxP-BRAFV600E-internal ribosome entry site-green fluorescent protein sequence [Tg(LNL-BRAFV600E)]. The double transgenic mice (LNL-BRAFV600E;TPO-Cre) were derived from a high expressor line of Tg(LNL-BRAFV600E) mice and TPO-Cre mice; the latter expresses Cre DNA recombinase under the control of thyroid-specific thyroid peroxidase (TPO) promoter and developed PTC-like lesions in early life under normal serum TSH levels due to mosaic recombination. In contrast, injection of adenovirus expressing Cre under the control of another thyroid-specific thyroglobulin (Tg) promoter (Ad-TgP-Cre) into the thyroids of LNL-BRAFV600E mice did not induce tumor formation despite detection of BRAFV600E and pERK in a small fraction of thyroid cells. Second, postnatal expression of BRAFV600E in a small number of thyroid cells was also achieved by injecting the lentivirus expressing loxP-green fluorescent protein-loxP-BRAFV600E into the thyroids of TPO-Cre mice; however, no tumor development was again observed. These results suggest that BRAFV600E does not appear to induce PTC-like lesions when expressed in a fraction of thyroid cells postnatally under normal TSH concentrations.
GPER Deficiency in Male Mice Results in Insulin Resistance, Dyslipidemia, and a Proinflammatory State
Authors: Sharma Geetanjali , Hu Chelin , Brigman Jonathan L. , Zhu Gang , Hathaway Helen J. , Prossnitz Eric R.
Published: August 2013

Estrogen is an important regulator of metabolic syndrome, a collection of abnormalities including obesity, insulin resistance/glucose intolerance, hypertension, dyslipidemia, and inflammation, which together lead to increased risk of cardiovascular disease and diabetes. The role of the G protein-coupled estrogen receptor (GPER/GPR30), particularly in males, in these pathologies remains unclear. We therefore sought to determine whether loss of GPER contributes to aspects of metabolic syndrome in male mice. Although 6-month-old male and female GPER knockout (KO) mice displayed increased body weight compared with wild-type littermates, only female GPER KO mice exhibited glucose intolerance at this age. Weight gain in male GPER KO mice was associated with increases in both visceral and sc fat. GPER KO mice, however, exhibited no differences in food intake or locomotor activity. One-year-old male GPER KO mice displayed an abnormal lipid profile with higher cholesterol and triglyceride levels. Fasting blood glucose levels remained normal, whereas insulin levels were elevated. Although insulin resistance was evident in GPER KO male mice from 6 months onward, glucose intolerance was pronounced only at 18 months of age. Furthermore, by 2 years of age, a proinflammatory phenotype was evident, with increases in the proinflammatory and immunomodulatory cytokines IL-1β, IL-6, IL-12, TNFα, monocyte chemotactic protein-1, interferon γ-induced protein 10, and monokine induced by interferon gamma and a concomitant decrease in the adipose-specific cytokine adiponectin. In conclusion, our study demonstrates for the first time that in male mice, GPER regulates metabolic parameters associated with obesity and diabetes.