bluuebunny/crossref_metadata_2025 huggingface dataset:
The Athlete Biological Passport: an integral element of innovative strategies in antidoping
Authors: Vernec Alan R
Published: March 2014

Concern for the health of athletes and integrity of sport resulted in the banning of specific substances although many years passed before analytical testing took place. Soon doping control programmes became synonymous with urine tests and adverse analytical findings. This system has its limits due to the detection window of prohibited substances, the timing of sample collections and the sophistication of some doping regimens. There have been a number of situations where these limits were demonstrated by athletes who proclaimed innocence based on passing their analytical tests only to later confess to doping. New strategies were called for to protect clean athletes. In the current World Anti-Doping Code, there are eight means to an Anti-Doping Rule Violation (ADRV). Article 2.2 states that the use of a prohibited substance may be established by any reliable means including witness statements, documentary evidence or evaluations of longitudinal profiling. In 2006, the World Anti-Doping Agency (WADA) with the support of some International Federations (IFs) gathered a group of experts to develop a harmonised programme on longitudinal profiling, or serial analysis of indirect biomarkers of doping, that was both scientifically and legally robust. This culminated in the WADA Athlete Biological Passport (ABP) Operating Guidelines and Technical Documents, published in 2009. The ABP is a paradigm that infers the use of prohibited substance (or method) by the monitoring of discriminant biomarkers over time. The haematological module detects blood manipulation by the use of erythropoietic stimulating agents or via blood transfusions. The steroidal module aims to identify endogenous anabolic androgenic steroids when administered exogenously and other indirect steroid doping substances or methods. Other ABP modules (endocrine, ‘omics’) are being developed. The termpassport, first coined in 2000, is now defined in the ABP Guidelines as the longitudinal profile and all other relevant information including training, competitions and information derived from investigations. In the 2015 World Anti-Doping Code, investigations or enquiries gathered from other sources will play an even more prominent role.
Effects of life satisfaction and psychache on risk for suicidal behaviour: a cross-sectional study based on data from Chinese undergraduates
Authors: You Zhiqi , Song Juanjuan , Wu Caizhi , Qin Ping , Zhou Zongkui
Published: March 2014

Objectives

To examine predictive power of psychache and life satisfaction on risks for suicidal ideation and suicide attempt among young people.

Design

A cross-sectional study.

Setting

Data were collected from an online survey in Wuhan, China.

Participants

5988 university students from six universities were selected by a stratified cluster sampling method.

Primary and secondary outcome measures

Suicidal ideation and suicide attempt at some point of the students’ lifetime were the outcomes of interest.

Results

Students with suicidal ideation or attempted suicide reported a lower level of life satisfaction and high degree of psychache than counterparts without suicidal ideation or attempt. Regression analyses indicated that life satisfaction and psychache were significantly associated with the risk of suicidal ideation and the risk of suicidal attempt. Though psychache showed a relatively stronger predictive power than life satisfaction, the effect of the two factors remained significant when they were individually adjusted for personal demographic characteristics. However, when the two factors were included in the model simultaneously to adjust for each other, psychache could fully explain the association between life satisfaction and suicidal attempt. Life satisfaction remained to contribute unique variance in the statistical prediction of suicidal ideation.

Conclusions

Psychache and life satisfaction both have a significant predictive power on risk for suicidal behaviour, and life satisfaction could relieve the predictive power of psychache when suicidal behaviour is just starting. Shneidman's theory that psychache is the pre-eminent psychological cause of suicide is perhaps applicable only to a more serious form of suicidal behaviour.
Rationale and cross-sectional study design of the Research on Obesity and type 2 Diabetes among African Migrants: the RODAM study
Authors: Agyemang Charles , Beune Erik , Meeks Karlijn , Owusu-Dabo Ellis , Agyei-Baffour Peter , Aikins Ama de-Graft , Dodoo Francis , Smeeth Liam , Addo Juliet , Mockenhaupt Frank P , Amoah Stephen K , Schulze Matthias B , Danquah Ina , Spranger Joachim , Nicolaou Mary , Klipstein-Grobusch Kerstin , Burr Tom , Henneman Peter , Mannens Marcel M , van Straalen Jan P , Bahendeka Silver , Zwinderman A H , Kunst Anton E , Stronks Karien
Published: March 2014

Introduction

Obesity and type 2 diabetes (T2D) are highly prevalent among African migrants compared with European descent populations. The underlying reasons still remain a puzzle. Gene–environmental interaction is now seen as a potential plausible factor contributing to the high prevalence of obesity and T2D, but has not yet been investigated. The overall aim of theResearch onObesity andDiabetes amongAfricanMigrants (RODAM) project is to understand the reasons for the high prevalence of obesity and T2D among sub-Saharan Africans in diaspora by (1) studying the complex interplay between environment (eg, lifestyle), healthcare, biochemical and (epi)genetic factors, and their relative contributions to the high prevalence of obesity and T2D; (2) to identify specific risk factors within these broad categories to guide intervention programmes and (3) to provide a basic knowledge for improving diagnosis and treatment.

Methods and analysis

RODAM is a multicentre cross-sectional study among homogenous sub-Saharan African participants (ie, Ghanaians) aged >25 years living in rural and urban Ghana, the Netherlands, Germany and the UK (http://rod-am.eu/). Standardised data on the main outcomes, genetic and non-genetic factors are collected in all locations. The aim is to recruit 6250 individuals comprising five subgroups of 1250 individuals from each site. In Ghana, Kumasi and Obuasi (urban stratum) and villages in the Ashanti region (rural stratum) are served as recruitment sites. In Europe, Ghanaian migrants are selected through the municipality or Ghanaian organisations registers.

Ethics and dissemination

Ethical approval has been obtained in all sites. This paper gives an overview of the rationale, conceptual framework and methods of the study. The differences across locations will allow us to gain insight into genetic and non-genetic factors contributing to the occurrence of obesity and T2D and will inform targeted intervention and prevention programmes, and provide the basis for improving diagnosis and treatment in these populations and beyond.
Clinical, angiographic and radiographic outcome differences among mechanical thrombectomy devices: initial experience of a large-volume center
Authors: Kass-Hout Tareq , Kass-Hout Omar , Sun Chung-Huan Johnny , Kass-Hout Taha , Belagaje Samir , Anderson Aaron , Frankel Michael , Gupta Rishi , Nogueira Raul
Published: March 2014

Background and purpose

Higher reperfusion rates have been established with endovascular treatment of acute ischemic stroke (AIS). There are limited data on the comparative performance of mechanical thrombectomy devices.

Methods

A retrospective single-center analysis was undertaken of all consecutive patients who underwent thrombectomy using Merci, Penumbra or stent retrievers (SR) from September 2010 to November 2012. Baseline characteristics, rates of successful recanalization (modified Thrombolysis in Cerebral Infarction (mTICI) score 2b–3), symptomatic intracerebral hemorrhage (sICH), final infarct volume, 90-day mortality and independent functional outcomes at 90 days were compared across the three devices.

Results

Our cohort included 287 patients. There were mild imbalances in baseline characteristics with trends towards higher National Institutes of Health Stroke Scale (NIHSS) score in patients in the Merci group (SR=18 vs Merci=21 vs Penumbra=19, p=0.06) and lower Alberta Stroke Program Early CT Score (ASPECTS) in patients in the SR group (>7: SR=51% vs Merci=61% vs Penumbra=62%, p=0.12). On univariate analysis there were no differences in the rate of sICH (SR=7% vs Merci=7% vs Penumbra=6%, p=0.921) and infarct volume (SR=61.5 mL vs Merci=69.5 mL vs Penumbra=59.2 mL, p=0.621). Trends towards better functional outcomes were found with Penumbra and SR vs Merci (41% vs 36% vs 25%, respectively, p=0.079). Complete or near complete reperfusion (mTICI 2b–3) was higher in the SR and Penumbra groups than in the Merci group (86% vs 78% vs 70%, respectively, p=0.027). Binary logistic regression showed that SR was an independent predictor of good functional outcome (OR 2.27, 95% CI 1.018 to 5.048; p=0.045).

Conclusions

Although our initial data confirm the superiority of SR technology over the Merci device, there was no significant difference in near complete/complete reperfusion, final infarct volumes or clinical outcomes between SR and Penumbra thromboaspiration.
Endovascular coiling versus parent artery occlusion for treatment of cavernous carotid aneurysms: a meta-analysis
Authors: Turfe Zaahir A , Brinjikji Waleed , Murad Mohammad H , Lanzino Giuseppe , Cloft Harry J , Kallmes David F
Published: March 2014

Background and purpose

Endosaccular coil embolization and parent artery occlusion (PAO) are established endovascular techniques for treatment of cavernous carotid aneurysms. We performed a systematic review of published series on endovascular treatment of cavernous carotid aneurysms to determine outcomes and complications associated with endovascular coiling and PAO of cavernous carotid artery aneurysms.

Methods

In September 2013, we conducted a computerized search of MEDLINE and EMBASE for reports on endovascular treatment of intracranial cavernous carotid aneurysms from January 1990 to August 2013. Comparisons were made in periprocedural complications and outcomes between coiling and PAO patients who did not receive bypass. Event rates were pooled across studies using random effects meta-analysis.

Results

20 studies with 509 patients and 515 aneurysms were included in this systematic review. Aneurysm occlusion rates at >3 months after operation were significantly higher in the PAO without bypass group (93.0%, 95% CI 86.0 to 97.0) compared with the coiling group (67.0%, 95% CI 55.0 to 77.0) (p<0.01). Retreatment rates were significantly lower in the PAO without bypass group (6.0%, 95% CI 2.0 to 12.0) compared with the coiling group (18.0%, 95% CI 12.0 to 26.0) (p=0.01). Coiling patients had a similar morbidity rate (3.0%, 95% CI 2.0 to 6.0) compared with PAO without bypass patients (7.0%, 95% CI 3.0 to 12.0) (p=0.13). Coiling patients had a similar mortality rate (0.0%, 95% CI 0.0 to 6.0) compared with PAO without bypass patients (4.0%, 95% CI 1.0 to 9.0) (p=0.68).

Conclusions

Evidence from non-comparative studies suggests that traditional endovascular options are highly effective in treating cavernous sinus aneurysms. PAO is associated with a higher rate of complete occlusion. Periprocedural morbidity and mortality rates are not negligible, especially in patients receiving PAO.
Rheology of Non-Brownian Suspensions
Authors: Denn Morton M. , Morris Jeffrey F.
Published: March 2014

Suspensions of non-Brownian particles are commonly encountered in applications in a large number of industries. These suspensions exhibit nonlinear flow behavior, even in Newtonian suspending fluids under conditions where inertial effects can be ignored and linearity would normally be expected. We review the observed rheological behavior, emphasizing concentrated suspensions of spheres in Newtonian fluids, and we examine both particle-level and continuum approaches to describing the nonlinear behavior. Particle-particle nonhydrodynamic interactions appear to be important in concentrated suspensions. Continuum descriptions are not yet adequate to describe the observed behavior.
Dynamics of Colloidal Glasses and Gels
Authors: Joshi Yogesh M.
Published: March 2014

Many household and industrially important soft colloidal materials, such as pastes, concentrated suspensions and emulsions, foams, slurries, inks, and paints, are very viscous and do not flow over practical timescales until sufficient stress is applied. This behavior originates from restricted mobility of the constituents arrested in disordered structures of varying length scales, termed colloidal glasses and gels. Usually these materials are thermodynamically out of equilibrium, which induces a time-dependent evolution of the structure and the properties. This review presents an overview of the rheological behavior of this class of materials. We discuss the experimental observations and theoretical developments regarding the microstructure of these materials, emphasizing the complex coupling between the deformation field and nonequilibrium structures in colloidal glasses and gels, which leads to a rich array of rheological behaviors with profound implications for various industrial processes and products.
Impact Origin of the Moon?
Authors: Asphaug Erik
Published: March 2014

Earth formed in a series of giant impacts, and the last one made the Moon. This idea, an edifice of post-Apollo science, can explain the Moon's globally melted silicate composition, its lack of water and iron, and its anomalously large mass and angular momentum. But the theory is seriously called to question by increasingly detailed geochemical analysis of lunar rocks. Lunar samples should be easily distinguishable from Earth, because the Moon derives mostly from the impacting planet, in standard models of the theory. But lunar rocks are the same as Earth in O, Ti, Cr, W, K, and other species, to measurement precision. Some regard this as a repudiation of the theory; others say it wants a reformation. Ideas put forward to salvage or revise it are evaluated, alongside their relationships to past models and their implications for planet formation and Earth.
What Do We Know About Short- and Long-Term Effects of Early-Life Exposure to Pollution?
Authors: Currie Janet , Zivin Joshua Graff , Mullins Jamie , Neidell Matthew
Published: March 2014

Evidence shows that pollution exposure early in life is detrimental to near-term health, and an increasing body of evidence suggests that early-childhood health influences health and human capital outcomes later in life. This article reviews the economic research that brings these two literatures together. We begin with a conceptual model that highlights the core relationships across the life cycle. We then review the literature concerned with such estimates, focusing particularly on identification strategies to mitigate concerns regarding endogenous exposure. The nascent empirical literature provides both direct and indirect evidence that early-childhood exposure to pollution significantly impacts later-life outcomes. We discuss the potential policy implications of these long-lasting effects and conclude with a number of promising avenues for future research.
Skeletal muscle abnormalities and exercise intolerance in older patients with heart failure and preserved ejection fraction
Authors: Kitzman Dalane W. , Nicklas Barbara , Kraus William E. , Lyles Mary F. , Eggebeen Joel , Morgan Timothy M. , Haykowsky Mark
Published: March 2014

Heart failure (HF) with preserved ejection fraction (HFPEF) is the most common form of HF in older persons. The primary chronic symptom in HFPEF is severe exercise intolerance, and its pathophysiology is poorly understood. To determine whether skeletal muscle abnormalities contribute to their severely reduced peak exercise O2 consumption (V̇o2), we examined 22 older HFPEF patients (70 ± 7 yr) compared with 43 age-matched healthy control (HC) subjects using needle biopsy of the vastus lateralis muscle and cardiopulmonary exercise testing to assess muscle fiber type distribution and capillarity and peak V̇o2. In HFPEF versus HC patients, peak V̇o2 (14.7 ± 2.1 vs. 22.9 ± 6.6 ml·kg−1·min−1, P < 0.001) and 6-min walk distance (454 ± 72 vs. 573 ± 71 m, P < 0.001) were reduced. In HFPEF versus HC patients, the percentage of type I fibers (39.0 ± 11.4% vs. 53.7 ± 12.4%, P < 0.001), type I-to-type II fiber ratio (0.72 ± 0.39 vs. 1.36 ± 0.85, P = 0.001), and capillary-to-fiber ratio (1.35 ± 0.32 vs. 2.53 ± 1.37, P = 0.006) were reduced, whereas the percentage of type II fibers was greater (61 ± 11.4% vs. 46.3 ± 12.4%, P < 0.001). In univariate analyses, the percentage of type I fibers ( r = 0.39, P = 0.003), type I-to-type II fiber ratio ( r = 0.33, P = 0.02), and capillary-to-fiber ratio ( r = 0.59, P < 0.0001) were positively related to peak V̇o2. In multivariate analyses, type I fibers and the capillary-to-fiber ratio remained significantly related to peak V̇o2. We conclude that older HFPEF patients have significant abnormalities in skeletal muscle, characterized by a shift in muscle fiber type distribution with reduced type I oxidative muscle fibers and a reduced capillary-to-fiber ratio, and these may contribute to their severe exercise intolerance. This suggests potential new therapeutic targets in this difficult to treat disorder.
Testosterone induces apoptosis in vascular smooth muscle cells via extrinsic apoptotic pathway with mitochondria-generated reactive oxygen species involvement
Authors: Lopes Rheure Alves Moreira , Neves Karla Bianca , Pestana Cezar Rangel , Queiroz André Lima , Zanotto Camila Ziliotto , Chignalia Andréia Z. , Valim Yara Maria , Silveira Leonardo R. , Curti Carlos , Tostes Rita C.
Published: March 2014

Testosterone exerts both beneficial and harmful effects on the cardiovascular system. Considering that testosterone induces reactive oxygen species (ROS) generation and ROS activate cell death signaling pathways, we tested the hypothesis that testosterone induces apoptosis in vascular smooth muscle cells (VSMCs) via mitochondria-dependent ROS generation. Potential mechanisms were addressed. Cultured VSMCs were stimulated with testosterone (10−7mol/l) or vehicle (2–12 h) in the presence of flutamide (10−5mol/l), CCCP (10−6mol/l), mimetic manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP; 3 × 10−5mol/l), Z-Ile-Glu(O-ME)-Thr-Asp(O-Me) fluoromethyl ketone (Z-IETD-FMK; 10−5mol/l), or vehicle. ROS were determined with lucigenin and dichlorodihydrofluorescein; apoptosis, with annexin V and calcein; O2consumption, with a Clark-type electrode, and procaspases, caspases, cytochrome c, Bax, and Bcl-2 levels by immunoblotting. Testosterone induced ROS generation (relative light units/mg protein, 2 h; 162.6 ± 16 vs. 100) and procaspase-3 activation [arbitrary units, (AU), 6 h; 166.2 ± 19 vs. 100]. CCCP, MnTMPyP, and flutamide abolished these effects. Testosterone increased annexin-V fluorescence (AU, 197.6 ± 21.5 vs. 100) and decreased calcein fluorescence (AU, 34.4 ± 6.4 vs. 100), and O2consumption (nmol O2/min, 18.6 ± 2.0 vs. 34.4 ± 3.9). Testosterone also reduced Bax-to-Bcl-2 ratio but not cytochrome- c release from mitochondria. Moreover, testosterone (6 h) induced cleavage of procaspase 8 (AU, 161.1 ± 13.5 vs. 100) and increased gene expression of Fas ligand (2ΔΔCt, 3.6 ± 1.2 vs. 0.7 ± 0.5), and TNF-α (1.7 ± 0.4 vs. 0.3 ± 0.1). CCCP, MnTMPyP, and flutamide abolished these effects. These data indicate that testosterone induces apoptosis in VSMCs via the extrinsic apoptotic pathway with the involvement of androgen receptor activation and mitochondria-generated ROS.
Paternal low protein diet affects adult offspring cardiovascular and metabolic function in mice
Authors: Watkins Adam J. , Sinclair Kevin D.
Published: March 2014

Although the association between maternal periconceptional diet and adult offspring health is well characterised, our understanding of the impact of paternal nutrition at the time of conception on offspring phenotype remains poorly defined. Therefore, we determined the effect of a paternal preconception low protein diet (LPD) on adult offspring cardiovascular and metabolic health in mice. Male C57BL/6 mice were fed either normal protein diet (NPD; 18% casein) or LPD (9% casein) for 7 wk before mating. At birth, a reduced male-to-female ratio ( P = 0.03) and increased male offspring weight ( P = 0.009) were observed in litters from LPD compared with NPD stud males with no differences in mean litter size. LPD offspring were heavier than NPD offspring at 2 and 3 wk of age ( P < 0.02). However, no subsequent differences in body weight were observed. Adult male offspring derived from LPD studs developed relative hypotension (decreased by 9.2 mmHg) and elevated heart rate ( P < 0.05), whereas both male and female offspring displayed vascular dysfunction and impaired glucose tolerance relative to NPD offspring. At cull (24 wk), LPD males had elevated adiposity ( P = 0.04), reduced heart-to-body weight ratio ( P = 0.04), and elevated circulating TNF-α levels ( P = 0.015) compared with NPD males. Transcript expression in offspring heart and liver tissue was reduced for genes involved in calcium signaling ( Adcy, Plcb, Prkcb) and metabolism ( Fto) in LPD offspring ( P < 0.03). These novel data reveal the impact of suboptimal paternal nutrition on adult offspring cardiovascular and metabolic homeostasis, and provide some insight into the underlying regulatory mechanisms.
Human airway epithelia express catalytically active NEU3 sialidase
Authors: Lillehoj Erik P. , Hyun Sang Won , Feng Chiguang , Zhang Lei , Liu Anguo , Guang Wei , Nguyen Chinh , Sun Wenji , Luzina Irina G. , Webb Tonya J. , Atamas Sergei P. , Passaniti Antonino , Twaddell William S. , Puché Adam C. , Wang Lai-Xi , Cross Alan S. , Goldblum Simeon E.
Published: March 2014

Sialic acids on glycoconjugates play a pivotal role in many biological processes. In the airways, sialylated glycoproteins and glycolipids are strategically positioned on the plasma membranes of epithelia to regulate receptor-ligand, cell-cell, and host-pathogen interactions at the molecular level. We now demonstrate, for the first time, sialidase activity for ganglioside substrates in human airway epithelia. Of the four known mammalian sialidases, NEU3 has a substrate preference for gangliosides and is expressed at mRNA and protein levels at comparable abundance in epithelia derived from human trachea, bronchi, small airways, and alveoli. In small airway and alveolar epithelia, NEU3 protein was immunolocalized to the plasma membrane, cytosolic, and nuclear subcellular fractions. Small interfering RNA-induced silencing of NEU3 expression diminished sialidase activity for a ganglioside substrate by >70%. NEU3 immunostaining of intact human lung tissue could be localized to the superficial epithelia, including the ciliated brush border, as well as to nuclei. However, NEU3 was reduced in subepithelial tissues. These results indicate that human airway epithelia express catalytically active NEU3 sialidase.
MET Is a Potential Target across All Papillary Renal Cell Carcinomas: Result from a Large Molecular Study of pRCC with CGH Array and Matching Gene Expression Array
Authors: Albiges Laurence , Guegan Justine , Le Formal Audrey , Verkarre Virginie , Rioux-Leclercq Nathalie , Sibony Mathilde , Bernhard Jean-Christophe , Camparo Philippe , Merabet Zahira , Molinie Vincent , Allory Yves , Orear Cedric , Couvé Sophie , Gad Sophie , Patard Jean-Jacques , Escudier Bernard
Published: March 2014

Purpose: Papillary renal cell carcinomas (pRCC) are the most common nonclear cell RCC subtype. Germline mutations of the MET oncogene at 7q31 have been detected in patients with hereditary type I pRCC and in 13% of sporadic type I pRCC. Recent report of MET inhibition strengthened the role of c-Met inhibition across pRCC.

Experimental Design: We collected 220 frozen samples of sporadic pRCC through the French RCC Network and quality controlled for percentage of malignant cells >70%. Gene expression was assessed on 98 pRCC using human whole-genome Agilent 8 × 60K arrays. Copy number alterations were analyzed using Agilent Human 2 × 400K and 4× 180K array for type II pRCC and comparative genomic microarray analysis method for type I pRCC. MET gene sequencing was performed on type I pRCC.

Results: MET expression level was high across all pRCC. We identified copy number alterations (gain) in 46% of type II pRCC and in 81% of type I pRCC. Correlation between DNA copy number alterations and mRNA expression level was highly significant. Eleven somatic mutations of MET gene were identified amongst 51 type I pRCC (21.6%), including 4 new mutations. We validated LRRK2 cokinase as highly correlated to MET expression.

Conclusion: The present report expands the role of MET activation as a potential target across all pRCC subtypes. These data support investigating MET inhibitors in pRCC in correlation with MET activation status. Clin Cancer Res; 20(13); 3411–21. ©2014 AACR.
Regulation of Colorectal Carcinoma Stemness, Growth, and Metastasis by an miR-200c-Sox2–Negative Feedback Loop Mechanism
Authors: Lu Yan-Xia , Yuan Li , Xue Xiao-Lei , Zhou Min , Liu Yan , Zhang Chao , Li Jing-Ping , Zheng Lin , Hong Min , Li Xue-Nong
Published: March 2014

Purpose: To elucidate a novel mechanism of miR-200c in the regulation of stemness, growth, and metastasis in colorectal carcinoma (CRC).

Experimental Design: Quantitative reverse transcription PCR was used to quantify miR-200c expression in CRC cell lines and tissues. A luciferase assay was adopted for the target evaluation. The functional effects of miR-200c in CRC cells were assessed by its forced or inhibited expression using lentiviruses.

Results: MiR-200c was statistically lower in CRC clinical specimens and highly metastatic CRC cell lines compared with their counterparts. Sox2 was validated as a target for miR-200c. The knockdown of miR-200c significantly enhanced proliferation, migration, and invasion in CRC cell lines, whereas the upregulation of miR-200c exhibited an inverse effect. Moreover, rescue of Sox2 expression could abolish the effect of the upregulation of miR-200c. In addition, the reduction of miR-200c increased the expression of CRC stem cell markers and the sphere-forming capacity of CRC cell lines. Further study has shown that miR-200c and Sox2 reciprocally control their expression through a feedback loop. MiR-200c suppresses the expression of Sox2 to block the activity of the phosphoinositide 3-kinase (PI3K)–AKT pathway.

Conclusion: Our findings indicate that miR-200c regulates Sox2 expression through a feedback loop and is associated with CRC stemness, growth, and metastasis. Clin Cancer Res; 20(10); 2631–42. ©2014 AACR.
A Signature Predicting Poor Prognosis in Gastric and Ovarian Cancer Represents a Coordinated Macrophage and Stromal Response
Authors: Busuttil Rita A. , George Joshy , Tothill Richard W. , Ioculano Kylie , Kowalczyk Adam , Mitchell Catherine , Lade Stephen , Tan Patrick , Haviv Izhak , Boussioutas Alex
Published: March 2014

Purpose: Gene-expression profiling has revolutionized the way we think about cancer and confers the ability to observe the synchronous expression of thousands of genes. The use of putative genome-level expression profiles has allowed biologists to observe the complex interactions of genes that constitute recognized biologic pathways. We used gastric and ovarian datasets to identify gene-expression signatures and determine any functional significance.

Experimental Design: Microarray data of 94-tumor and 45-benign samples derived from patients with gastric cancer were interrogated using Hierarchical Ordered Partitioning and Collapsing Hybrid analysis identifying clusters of coexpressed genes. Clusters were further characterized with respect to biologic significance, gene ontology, and ability to discriminate between normal and tumor tissue. Tumor tissues were separated into epithelial and stromal compartments and immunohistochemical analysis performed to further elucidate specific cell lineages expressing genes contained in the signature.

Results: We identified a “stromal-response” expression signature, highly enriched for inflammatory, extracellular matrix, cytokine, and growth factor proteins. The majority of genes in the signature are expressed in the tumor-associated stroma but were absent in associated premalignant conditions. In gastric cancer, this module almost perfectly differentiates tumor from nonmalignant gastric tissue and hence can be regarded as a highly tumor-specific gene-expression signature.

Conclusions: We show that these genes are consistently coexpressed across a range of independent gastric datasets as well as other cancer types suggesting a conserved functional role in cancer. In addition, we show that this signature can be a surrogate marker for M2 macrophage activity and has significant prognostic implications in gastric and ovarian high-grade serous cancer. Clin Cancer Res; 20(10); 2761–72. ©2014 AACR.
Minimal Residual Disease in Breast Cancer: In Blood Veritas
Authors: Siravegna Giulia , Bardelli Alberto
Published: March 2014

A blood-based molecular test might direct recommendations for systemic therapies in patients with early-stage breast cancer undergoing surgery with curative intent. A new study suggests that droplet digital PCR (ddPCR) can be used to detect cancer-specific DNA alterations in plasma with sensitivity suitable for monitoring minimal residual disease. Clin Cancer Res; 20(10); 2505–7. ©2014 AACR.
Epithelial-to-Mesenchymal Transition Mediates Docetaxel Resistance and High Risk of Relapse in Prostate Cancer
Authors: Marín-Aguilera Mercedes , Codony-Servat Jordi , Reig Òscar , Lozano Juan José , Fernández Pedro Luis , Pereira María Verónica , Jiménez Natalia , Donovan Michael , Puig Pere , Mengual Lourdes , Bermudo Raquel , Font Albert , Gallardo Enrique , Ribal María José , Alcaraz Antonio , Gascón Pere , Mellado Begoña
Published: March 2014

Molecular characterization of radical prostatectomy specimens after systemic therapy may identify a gene expression profile for resistance to therapy. This study assessed tumor cells from patients with prostate cancer participating in a phase II neoadjuvant docetaxel and androgen deprivation trial to identify mediators of resistance. Transcriptional level of 93 genes from a docetaxel-resistant prostate cancer cell lines microarray study was analyzed by TaqMan low-density arrays in tumors from patients with high-risk localized prostate cancer (36 surgically treated, 28 with neoadjuvant docetaxel + androgen deprivation). Gene expression was compared between groups and correlated with clinical outcome. VIM, AR and RELA were validated by immunohistochemistry. CD44 and ZEB1 expression was tested by immunofluorescence in cells and tumor samples. Parental and docetaxel-resistant castration-resistant prostate cancer cell lines were tested for epithelial-to-mesenchymal transition (EMT) markers before and after docetaxel exposure. Reversion of EMT phenotype was investigated as a docetaxel resistance reversion strategy. Expression of 63 (67.7%) genes differed between groups (P < 0.05), including genes related to androgen receptor, NF-κB transcription factor, and EMT. Increased expression of EMT markers correlated with radiologic relapse. Docetaxel-resistant cells had increased EMT and stem-like cell markers expression. ZEB1 siRNA transfection reverted docetaxel resistance and reduced CD44 expression in DU-145R and PC-3R. Before docetaxel exposure, a selected CD44+ subpopulation of PC-3 cells exhibited EMT phenotype and intrinsic docetaxel resistance; ZEB1/CD44+ subpopulations were found in tumor cell lines and primary tumors; this correlated with aggressive clinical behavior. This study identifies genes potentially related to chemotherapy resistance and supports evidence of the EMT role in docetaxel resistance and adverse clinical behavior in early prostate cancer. Mol Cancer Ther; 13(5); 1270–84. ©2014 AACR.
Contribution of p53 to Metastasis
Authors: Powell Emily , Piwnica-Worms David , Piwnica-Worms Helen
Published: March 2014

The tumor suppressor p53 is lost or mutated in about half of all human cancers, and in those tumors in which it is wild-type, mechanisms exist to prevent its activation. p53 loss not only prevents incipient tumor cells from undergoing oncogene-induced senescence and apoptosis, but also perturbs cell-cycle checkpoints. This enables p53-deficient tumor cells with DNA damage to continue cycling, creating a permissive environment for the acquisition of additional mutations. Theoretically, this could contribute to the evolution of a cancer genome that is conducive to metastasis. Importantly, p53 loss also results in the disruption of pathways that inhibit metastasis, and transcriptionally defective TP53 mutants are known to gain additional functions that promote metastasis. Here, we review the evidence supporting a role for p53 loss or mutation in tumor metastasis, with an emphasis on breast cancer.

Significance: The metastatic potential of tumor cells can be positively influenced by loss of p53 or expression of p53 gain-of-function mutants. Understanding the mechanisms by which p53 loss and mutation promote tumor metastasis is crucial to understanding the biology of tumor progression and how to appropriately apply targeted therapies. Cancer Discov; 4(4); 405–14. ©2014 AACR.
Near-Infrared II Fluorescence for Imaging Hindlimb Vessel Regeneration With Dynamic Tissue Perfusion Measurement
Authors: Hong Guosong , Lee Jerry C. , Jha Arshi , Diao Shuo , Nakayama Karina H. , Hou Luqia , Doyle Timothy C. , Robinson Joshua T. , Antaris Alexander L. , Dai Hongjie , Cooke John P. , Huang Ngan F.
Published: March 2014

Background—

Real-time vascular imaging that provides both anatomic and hemodynamic information could greatly facilitate the diagnosis of vascular diseases and provide accurate assessment of therapeutic effects. Here, we have developed a novel fluorescence-based all-optical method, named near-infrared II (NIR-II) fluorescence imaging, to image murine hindlimb vasculature and blood flow in an experimental model of peripheral arterial disease, by exploiting fluorescence in the NIR-II region (1000–1400 nm) of photon wavelengths.

Methods and Results—

Because of the reduced photon scattering of NIR-II fluorescence compared with traditional NIR fluorescence imaging and thus much deeper penetration depth into the body, we demonstrated that the mouse hindlimb vasculature could be imaged with higher spatial resolution than in vivo microscopic computed tomography. Furthermore, imaging during 26 days revealed a significant increase in hindlimb microvascular density in response to experimentally induced ischemia within the first 8 days of the surgery (
P
<0.005), which was confirmed by histological analysis of microvascular density. Moreover, the tissue perfusion in the ischemic hindlimb could be quantitatively measured by the dynamic NIR-II method, revealing the temporal kinetics of blood flow recovery that resembled microbead-based blood flowmetry and laser Doppler blood spectroscopy.

Conclusions—

The penetration depth of millimeters, high spatial resolution, and fast acquisition rate of NIR-II imaging make it a useful imaging tool for murine models of vascular disease.
Loss of MicroRNA-155 Protects the Heart From Pathological Cardiac Hypertrophy
Authors: Seok Hee Young , Chen Jinghai , Kataoka Masaharu , Huang Zhan-Peng , Ding Jian , Yan Jinglu , Hu Xiaoyun , Wang Da-Zhi
Published: March 2014

Rationale:

In response to mechanical and pathological stress, adult mammalian hearts often undergo mal-remodeling, a process commonly characterized as pathological hypertrophy, which is associated with upregulation of fetal genes, increased fibrosis, and reduction of cardiac dysfunction. The molecular pathways that regulate this process are not fully understood.

Objective:

To explore the function of microRNA-155 (miR-155) in cardiac hypertrophy and remodeling.

Methods and Results:

Our previous work identified miR-155 as a critical microRNA that repressed the expression and function of the myocyte enhancer factor 2A. In this study, we found that miR-155 is expressed in cardiomyocytes and that its expression is reduced in pressure overload–induced hypertrophic hearts. In mouse models of cardiac hypertrophy, miR-155 null hearts suppressed cardiac hypertrophy and cardiac remodeling in response to 2 independent pathological stressors, transverse aortic restriction and an activated calcineurin transgene. Most importantly, loss of miR-155 prevents the progress of heart failure and substantially extends the survival of calcineurin transgenic mice. The function of miR-155 in hypertrophy is confirmed in isolated cardiomyocytes. We identified jumonji, AT rich interactive domain 2 (Jarid2) as an miR-155 target in the heart. miR-155 directly represses Jarid2, whose expression is increased in miR-155 null hearts. Inhibition of endogenous Jarid2 partially rescues the effect of miR-155 loss in isolated cardiomyocytes.

Conclusions:

Our studies uncover miR-155 as an inducer of pathological cardiomyocyte hypertrophy and suggest that inhibition of endogenous miR-155 might have clinical potential to suppress cardiac hypertrophy and heart failure.
Counseling African Americans to Control Hypertension
Authors: Ogedegbe Gbenga , Tobin Jonathan N. , Fernandez Senaida , Cassells Andrea , Diaz-Gloster Marleny , Khalida Chamanara , Pickering Thomas , Schwartz Joseph E.
Published: March 2014

Background—

Data are limited on the implementation of evidence-based multilevel interventions targeted at blood pressure (BP) control in hypertensive blacks who receive care in low-resource primary care practices.

Methods and Results—

Counseling African Americans to Control Hypertension is a cluster-randomized clinical trial in which 30 community health centers were randomly assigned to the intervention condition (IC) or usual care (UC). Patients at the IC sites received patient education, home BP monitoring, and monthly lifestyle counseling, whereas physicians attended monthly hypertension case rounds and received feedback on their patients’ home BP readings and chart audits. Patients and physicians at the UC sites received printed patient education material and hypertension treatment guidelines, respectively. The primary outcome was BP control, and secondary outcomes were mean changes in systolic and diastolic BPs at 12 months, assessed with an automated BP device. A total of 1059 patients (mean age, 56 years; 28% men, 59% obese, and 36% with diabetes mellitus) were enrolled. The BP control rate was similar in both groups (IC=49.3% versus UC=44.5%; odds ratio, 1.21 [95% confidence interval, 0.90–1.63];
P
=0.21). In prespecified subgroup analyses, the intervention was associated with greater BP control in patients without diabetes mellitus (IC=54.0% versus UC=44.7%; odds ratio, 1.45 [confidence interval, 1.02–2.06]); and small-sized community health centers (IC=51.1% versus UC=39.6%; odds ratio, 1.45 [confidence interval, 1.04–2.45]).

Conclusions—

A practice-based, multicomponent intervention was no better than UC in improving BP control among hypertensive blacks. Future research on the implementation of behavioral modification strategies for hypertension control in low-resource settings should focus on the development of more efficient and tailored interventions in this high-risk population.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00233220.
Proteomic Analysis Implicates Translationally Controlled Tumor Protein as a Novel Mediator of Occlusive Vascular Remodeling in Pulmonary Arterial Hypertension
Authors: Lavoie Jessie R. , Ormiston Mark L. , Perez-Iratxeta Carol , Courtman David W. , Jiang Baohua , Ferrer Elisabet , Caruso Paola , Southwood Mark , Foster William S. , Morrell Nicholas W. , Stewart Duncan J.
Published: March 2014

Background—

Pulmonary arterial hypertension (PAH) is a lethal disease characterized by excessive proliferation of pulmonary vascular endothelial cells (ECs). Hereditary PAH (HPAH) is often caused by mutations in the bone morphogenetic protein receptor type 2 gene (
BMPR2
). However, the mechanisms by which these mutations cause PAH remain unclear. Therefore, we screened for dysregulated proteins in blood-outgrowth ECs of HPAH patients with
BMPR2
mutations compared with healthy control subjects.

Methods and Results—

A total of 416 proteins were detected with 2-dimensional PAGE in combination with liquid chromatography/tandem mass spectrometry analysis, of which 22 exhibited significantly altered abundance in blood-outgrowth ECs from patients with HPAH. One of these proteins, translationally controlled tumor protein (TCTP), was selected for further study because of its well-established role in promoting tumor cell growth and survival. Immunostaining showed marked upregulation of TCTP in lungs from patients with HPAH and idiopathic PAH, associated with remodeled vessels of complex lesions. Increased TCTP expression was also evident in the SU5416 rat model of severe and irreversible PAH, associated with intimal lesions, colocalizing with proliferating ECs and the adventitia of remodeled vessels but not in the vascular media. Furthermore, silencing of TCTP expression increased apoptosis and abrogated the hyperproliferative phenotype of blood-outgrowth ECs from patients with HPAH, raising the possibility that TCTP may be a link in the emergence of apoptosis-resistant, hyperproliferative vascular cells after EC apoptosis.

Conclusion—

Proteomic screening identified TCTP as a novel mediator of endothelial prosurvival and growth signaling in PAH, possibly contributing to occlusive pulmonary vascular remodeling triggered by EC apoptosis.
Reshaping International Fisheries Development: Assimilating the Treaty on Fisheries between the Governments of Certain Pacific Island States and the United States under the PNA Vessel Day Scheme (VDS)
Authors: Aqorau Transform
Published: March 2014

Abstract

Since June 1988, Pacific Island States and the United States have co-operated in fisheries management, conservation and development through the Treaty on Fisheries between the Governments of Certain Pacific Island States and the Government of the United States. The renegotiation of the Treaty has presented challenges. The Treaty worked perfectly under an open and unrestricted access regime. However, changes instituted by Pacific Island States and the Commission for the Conservation and Management of Highly Migratory Fish Stocks in the Western and Central Pacific have tested the utility of the Treaty. This article discusses these changes, and these challenges, including the implications of the Vessel Day Scheme. The article concludes that having unimpeded multiple-zone access is inimical to a rights-based system such as the purse-seine Vessel Day Scheme.
Voluntary Guidelines for Flag State Performance: A New Tool to Conquer IUU Fishing
Authors: Erikstein Karine , Swan Judith
Published: March 2014

Abstract

Within the framework of the Food and Agriculture Organization of the United Nations (fao), Voluntary Guidelines for Flag State Performance were adopted by the fao Technical Consultation on Flag State Performance on 8 February 2013. The Guidelines, which focus on the role of the flag State in combating illegal, unreported and unregulated (iuu) fishing and build on existing international law, constitute a ground-breaking international instrument. They set out criteria and procedures for the assessment of flag State performance, as well as provisions on cooperation between flag States and coastal States, compliance and cooperation with, and assistance to, developing countries. The Guidelines were adopted as a response to the lack of effective control by many flag States over their fishing and fishing-related vessels, mindful that flag States may generally be said to have the primary responsibility for preventing, deterring and eliminating iuu fishing.1 The Guidelines are a robust and comprehensive tool for enhancing international fisheries governance.
Green Investment after Rio 2012
Authors: Viñuales Jorge E.
Published: March 2014

Abstract

This article analyses the relevance of investment and investment law in the environmental policy agenda post-Rio 2012. It is intended as a call for the mainstreaming of investment and investment law considerations in future negotiations concerning the environment.
Protection and Preservation of the Marine Environment as a Goal for Achieving Sustainable Development on the Rio+20 Agenda
Authors: Oanta Gabriela A.
Published: March 2014

Abstract

The United Nations Convention on Sustainable Development, held in Rio de Janeiro between 20 and 22 June 2012, represented an excellent opportunity for learning the current state of the international community’s commitment to sustainable development. Undoubtedly, without sustainable seas and oceans it is impossible to talk about sustainability on our planet. Seas and oceans enjoy a privileged position within the global ecosystem as they represent 72% of the Earth’s surface area, accounting for 90% of the habitat of all life, and are a major source of economic, social and environmental resources. Hence the special interest in an effective protection of the global marine ecosystem, which is gravely threatened by a variety of factors, of which illegal, unreported and unregulated fishing is one. The present article will be divided into two parts. The first of these will study the goal of protecting the marine environment as part of the Rio+20 agenda, whilst the second will analyse illegal, unreported and unregulated fishing from a legal point of view, with particular attention being paid to the most significant challenges presented by this global scourge.
Scramble, Scurry and Dash: The Correlation between Motion Event Encoding and Manner Verb Lexicon Size in Indo-European
Authors: Verkerk Annemarie
Published: March 2014

In recent decades, much has been discovered about the different ways in which people can talk about motion (Talmy, 1985, 1991; Slobin, 1996, 1997, 2004). Slobin (1997) has suggested that satellite-framed languages typically have a larger and more diverse lexicon of manner of motion verbs (such as run, fly, and scramble) when compared to verb-framed languages. Slobin (2004) has claimed that larger manner of motion verb lexicons originate over time because codability factors increase the accessibility of manner in satellite-framed languages. In this paper I investigate the dependency between the use of the satellite-framed encoding construction and the size of the manner verb lexicon. The data used come from 20 Indo-European languages. The methodology applied is a range of phylogenetic comparative methods adopted from biology, which allow for an investigation of this dependency while taking into account the shared history between these 20 languages. The results provide evidence that Slobin’s hypothesis was correct, and indeed there seems to be a relationship between the use of the satellite-framed construction and the size of the manner verb lexicon.