bluuebunny/crossref_metadata_2025_split huggingface dataset:
Appearance of the Novel Activating F1174S ALK Mutation in Neuroblastoma Correlates with Aggressive Tumor Progression and Unresponsiveness to Therapy
Authors: Martinsson Tommy , Eriksson Therese , Abrahamsson Jonas , Caren Helena , Hansson Magnus , Kogner Per , Kamaraj Sattu , Schönherr Christina , Weinmar Joel , Ruuth Kristina , Palmer Ruth H. , Hallberg Bengt 
Published: November 2010

Abstract
Mutations in the kinase domain of the ALK kinase have emerged recently as important players in the genetics of the childhood tumor neuroblastoma. Here, we report the appearance of a novel ALK mutation in neuroblastoma, correlating with aggressive tumor behavior. Analyses of genomic DNA from biopsy samples initially showed ALK sequence to be wild type. However, during disease progression, mutation of amino acid F1174 to a serine within the ALK kinase domain was observed, which correlated with aggressive neuroblastoma progression in the patient. We show that mutation of F1174 to serine generates a potent gain-of-function mutant, as observed in 2 independent systems. First, PC12 cell lines expressing ALKF1174S display ligand-independent activation of ALK and further downstream signaling activation. Second, analysis of ALKF1174S in Drosophila models confirms that the mutation mediates a strong, rough eye phenotype upon expression in the developing eye. Thus, we report a novel ALKF1174S mutation that displays ligand-independent activity in vivo, correlating with rapid and treatment-resistant tumor growth. The study also shows that initial screening in the first tumor biopsy of a patient may not be sufficient and that further molecular analysis, in particular in tumor progression and/or tumor relapse, is warranted for better understanding of the treatment of neuroblastoma patients. Cancer Res; 71(1); 98–105. ©2011 AACR.
Long-Term Improvement in Postinfarct Left Ventricular Global and Regional Contractile Function Is Mediated by Embryonic Stem Cell–Derived Cardiomyocytes
Authors: Qiao Hui , Zhang Hualei , Yamanaka Satoshi , Patel Vickas V. , Petrenko Nataliya B. , Huang Bin , Muenz Larry R. , Ferrari Victor A. , Boheler Kenneth R. , Zhou Rong 
Published: November 2010

Background—
Pluripotent stem cells represent one promising source for cellular cardiomyoplasty. In this study, we used cardiac magnetic resonance to examine the ability of highly enriched cardiomyocytes (CMs) derived from murine embryonic stem cells (ESC) to form grafts and improve contractile function of infarcted rat hearts.

Methods and Results—
Highly enriched ESC-CMs were obtained by inducing cardiac differentiation of ESCs stably expressing a cardiac-restricted puromycin resistance gene. At the time of transplantation, enriched ESC-CMs expressed cardiac-specific markers and markers of developing CMs, but only 6% of them were proliferating. A growth factor–containing vehicle solution or ESC-CMs (5 to 10 million) suspended in the same solution was injected into athymic rat hearts 1 week after myocardial infarction. Initial infarct size was measured by cardiac magnetic resonance 1 day after myocardial infarction. Compared with vehicle treatment, treatment with ESC-CMs improved global systolic function 1 and 2 months after injection and significantly increased contractile function in initially infarcted areas and border zones. Immunohistochemistry confirmed successful engraftment and the persistence of α-actinin–positive ESC-CMs that also expressed α-smooth muscle actin. Connexin-43–positive sites were observed between grafted ESC-CMs but only rarely between grafted and host CMs. No teratomas were observed in any of the animals.

Conclusions—
Highly enriched and early-stage ESC-CMs were safe, formed stable grafts, and mediated a long-term recovery of global and regional myocardial contractile function after infarction.
OMEGA, a Randomized, Placebo-Controlled Trial to Test the Effect of Highly Purified Omega-3 Fatty Acids on Top of Modern Guideline-Adjusted Therapy After Myocardial Infarction
Authors: Rauch Bernhard , Schiele Rudolf , Schneider Steffen , Diller Frank , Victor Norbert , Gohlke Helmut , Gottwik Martin , Steinbeck Gerhard , Del Castillo Ulrike , Sack Rudolf , Worth Heinrich , Katus Hugo , Spitzer Wilhelm , Sabin Georg , Senges Jochen ,   for the OMEGA Study Group
Published: November 2010

Background—
There is no randomized, double-blind trial testing the prognostic effect of highly purified omega-3 fatty acids in addition to current guideline-adjusted treatment of acute myocardial infarction.

Methods and Results—

OMEGA is a randomized, placebo-controlled, double-blind, multicenter trial testing the effects of omega-3-acid ethyl esters-90 (1 g/d for 1 year) on the rate of sudden cardiac death in survivors of acute myocardial infarction, if given in addition to current guideline-adjusted treatment. Secondary end points were total mortality and nonfatal clinical events. Patients (n=3851; female, 25.6%; mean age, 64.0 years) were randomized in 104 German centers 3 to 14 days after acute myocardial infarction from October 2003 until June 2007. Acute coronary angiography was performed in 93.8% and acute percutaneous coronary intervention in 77.8% of all patients. During a follow-up of 365 days, the event rates were (omega and control groups) as follows: sudden cardiac death, 1.5% and 1.5% (
P
=0.84); total mortality, 4.6% and 3.7% (
P
=0.18); major adverse cerebrovascular and cardiovascular events, 10.4% and 8.8% (
P
=0.1); and revascularization in survivors, 27.6% and 29.1% (
P
=0.34).

Conclusions—
Guideline-adjusted treatment of acute myocardial infarction results in a low rate of sudden cardiac death and other clinical events within 1 year of follow-up, which could not be shown to be further reduced by the application of omega-3 fatty acids.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00251134.
Effect of strength and balance training in children with Down’s syndrome: a randomized controlled trial
Authors: Gupta Sukriti , Rao Bhamini krishna , Kumaran SD 
Published: November 2010

Objective: The aim of the study was to determine the effect of exercise training on strength and balance in children with Down’s syndrome. Design: Randomized controlled trial. Setting: Rehabilitation school for special children. Subjects and intervention: Twenty-three children were randomized to intervention and control group. The intervention group ( n =  12) underwent progressive resistive exercises for lower limbs and balance training for six weeks. The control group continued their regular activities followed at school. Outcome measure: A handheld dynamometer was used to measure the lower limb muscle strength. Balance was assessed by the balance subscale of Bruininks Oseretsky Test of Motor Proficiency (BOTMP). Results: Following the training, the children in the intervention group showed a statistically significant improvement ( P <  0.05) in the lower limb strength of all the muscle groups assessed. The strength of knee extensors was 12.12  lbs in the control group versus 18.4  lbs in the experimental group; in hip flexors it was 12.34  lbs in the control group versus 16.66  lbs in the experimental group post-intervention. The balance of the children also improved significantly with an improvement in scores of the balance subscale of BOTMP (19.50 in the experimental group versus 9.00 in the control group, P =  0.001). Conclusion: This study suggests that a specific exercise training programme may improve the strength and balance in children with Down’s syndrome
Validated instruments used to measure attitudes of healthcare students and professionals towards patients with physical disability: a systematic review
Authors: Lam Wai Yim , Gunukula Sameer K , McGuigan Denise , Isaiah New , Symons Andrew B , Akl Elie A 
Published: November 2010

AbstractBackgroundInstruments to detect changes in attitudes towards people with disabilities are important for evaluation of training programs and for research. While we were interested in instruments specific for medical students, we aimed to systematically review the medical literature for validated survey instruments used to measure attitudes of healthcare students and professionals towards patients with physical disability.MethodsWe electronically searched Medline, EMBASE, PsycINFO, Health and Psychosocial Instruments. We included papers reporting on the development and/or validation of survey instruments to measure attitudes of healthcare students and professionals towards patients with physical disability. We excluded papers in which the attitudes were not measured in a provider-patient context. Two reviewers carried out titles and abstracts screening, full texts screening, and data abstraction in a duplicate and independent manner using standardized and pilot tested forms.ResultsWe identified seven validated survey instruments used for healthcare students and professionals. These instruments were originally developed for the following target populations: general population (n = 4); dental students (n = 1); nursing students (n = 1); and rehabilitation professionals (n = 1). The types of validity reported for these instruments were content validity (n = 3), criterion-related validity (n = 1), construct validity (n = 2), face validity (n = 1), discriminant validity (n = 1), and responsiveness (n = 1). The most widely validated and used tool (ATDP) was developed in the late 1960s while the most recent instrument was developed in the early 1990s.ConclusionOf the seven identified validated instruments, less than half were specifically designed for healthcare students and professionals and none for medical students. There is a need to develop and validate a contemporary instrument specifically for medical students.
Admixture mapping of end stage kidney disease genetic susceptibility using estimated mutual information ancestry informative markers
Authors: Shlush Liran I , Bercovici Sivan , Wasser Walter G , Yudkovsky Guennady , Templeton Alan , Geiger Dan , Skorecki Karl 
Published: November 2010

Abstract

Background
The question of a genetic contribution to the higher prevalence and incidence of end stage kidney disease (ESKD) among African Americans (AA) remained unresolved, until recent findings using admixture mapping pointed to the association of a genomic locus on chromosome 22 with this disease phenotype. In the current study we utilize this example to demonstrate the utility of applying a multi-step admixture mapping approach.

Methods
A multi-step case only admixture mapping study, consisted of the following steps was designed: 1) Assembly of the sample dataset (ESKD AA); 2) Design of the estimated mutual information ancestry informative markers (n = 2016) screening panel 3); Genotyping the sample set whose size was determined by a power analysis (n = 576) appropriate for the initial screening panel; 4) Inference of local ancestry for each individual and identification of regions with increased AA ancestry using two different ancestry inference statistical approaches; 5) Enrichment of the initial screening panel; 6) Power analysis of the enriched panel 7) Genotyping of additional samples. 8) Re-analysis of the genotyping results to identify a genetic risk locus.

Results
The initial screening phase yielded a significant peak using the ADMIXMAP ancestry inference program applying case only statistics. Subgroup analysis of 299 ESKD patients with no history of diabetes yielded peaks using both the ANCESTRYMAP and ADMIXMAP ancestry inference programs. The significant peak was found on chromosome 22. Genotyping of additional ancestry informative markers on chromosome 22 that took into account linkage disequilibrium in the ancestral populations, and the addition of samples increased the statistical significance of the finding.

Conclusions
A multi-step admixture mapping analysis of AA ESKD patients replicated the finding of a candidate risk locus on chromosome 22, contributing to the heightened susceptibility of African Americans to develop non-diabetic ESKD, and underscores the importance of using mutual information and multiple ancestry inference approaches to achieve a robust analysis, using relatively small datasets of "affected" only individuals. The current study suggests solutions to some limitations of existing admixture mapping methodologies, such as considerations regarding the distribution of ancestry information along the genome and its effects on power calculations and sample size.
The prevalence of thyroid disorders during early pregnancy in China: the benefits of universal screening in the first trimester of pregnancy
Authors: Wang Weiwei , Teng Weiping , Shan Zhongyan , Wang Sen , Li Jianxin , Zhu Lin , Zhou Jin , Mao Jinyuan , Yu Xiaohui , Li Jia , Chen Yanyan , Xue Haibo , Fan Chenling , Wang Hong , Zhang Hongmei , Li Chenyang , Zhou Weiwei , Gao Bo , Shang Tao , Zhou Jiaren , Ding Bin , Ma Ying , Wu Ying , Xu Hui , Liu Wei 
Published: November 2010

ContextMaternal thyroid disorders during early pregnancy can influence pregnancy outcome and fetal development. The recent Endocrine Society Clinical Practice Guideline recommends a case-finding approach in which pregnant women who are at high risk for developing thyroid disease are tested.ObjectiveThe purpose of this study was to use the first trimester-specific reference intervals of thyroid-related hormones to explore the prevalence of thyroid dysfunction during early pregnancy and to analyze effectiveness of different screening strategies.DesignA multicenter cohort study.MethodA total of 2899 pregnant women were enrolled in this study during their first trimester of gestation. Levels of TSH, free thyroxine, free triiodothyronine, and thyroid peroxidase antibodies (TPOAb) were measured and thyroid disorders of pregnant women were diagnosed based on the first trimester-specific reference intervals.ResultsThe prevalence of hypothyroidism was significantly higher in the high-risk group than in the non-high-risk group (10.9 vs 7.0%, χ2=7.1, P=0.008). The prevalence of hyperthyroidism was not significantly different between the high-risk group and the non-high-risk group (2.7 vs 1.6%, χ2=2.27, P=0.13). Elevated levels of TPOAb and a personal history of thyroid disease increased the risk of thyroid dysfunction.ConclusionsA case-finding strategy for screening thyroid function in the high-risk group would miss about 81.6% pregnant women with hypothyroidism and 80.4% pregnant women with hyperthyroidism.
One Hundred Years of Pleiotropy: A Retrospective
Authors: Stearns Frank W 
Published: November 2010

AbstractPleiotropy is defined as the phenomenon in which a single locus affects two or more distinct phenotypic traits. The term was formally introduced into the literature by the German geneticist Ludwig Plate in 1910, 100 years ago. Pleiotropy has had an important influence on the fields of physiological and medical genetics as well as on evolutionary biology. Different approaches to the study of pleiotropy have led to incongruence in the way that it is perceived and discussed among researchers in these fields. Furthermore, our understanding of the term has changed quite a bit since 1910, particularly in light of modern molecular data. This review traces the history of the term “pleiotropy” and reevaluates its current place in the field of genetics.
Genetic Evidence That Polysumoylation Bypasses the Need for a SUMO-Targeted Ub Ligase
Authors: Mullen Janet R , Das Mukund , Brill Steven J 
Published: November 2010

Abstract
Saccharomyces cerevisiae cells lacking the Slx5–Slx8 SUMO-targeted Ub ligase display increased levels of sumoylated and polysumoylated proteins, and they are inviable in the absence of the Sgs1 DNA helicase. One explanation for this inviability is that one or more sumoylated proteins accumulate to toxic levels in sgs1Δslx5Δ cells. To address this possibility, we isolated a second-site suppressor of sgs1Δslx5Δ synthetic lethality and identified it as an allele of the ULP2 SUMO isopeptidase. The suppressor, ulp2–D623H, behaved like the ulp2Δ allele in its sensitivity to heat, DNA replication stress, and DNA damage. Surprisingly, deletion of ULP2, which is known to promote the accumulation of poly-SUMO chains, suppressed sgs1Δslx5Δ synthetic lethality and the slx5Δ sporulation defect. Further, ulp2Δ's growth sensitivities were found to be suppressed in ulp2Δslx5Δ double mutants. This mutual suppression indicates that SLX5–SLX8 and ULP2 interact antagonistically. However, the suppressed strain sgs1Δslx5Δulp2–D623H displayed even higher levels of sumoylated proteins than the corresponding double mutants. Thus, sgs1Δslx5Δ synthetic lethality cannot be due simply to high levels of bulk sumoylated proteins. We speculate that the loss of ULP2 suppresses the toxicity of the sumoylated proteins that accumulate in slx5Δ–slx8Δ cells by permitting the extension of poly-SUMO chains on specific target proteins. This additional modification might attenuate the activity of the target proteins or channel them into alternative pathways for proteolytic degradation. In support of this latter possibility we find that the WSS1 isopeptidase is required for suppression by ulp2Δ.
Noninvasive MR characterization of structural and functional components of reperfused infarct
Authors: Saeed Maythem , Martin Alastair J. , Saloner David , Do Loi , Wilson Mark 
Published: November 2010

Background: Left ventricular (LV) remodeling is a highly complex phenomenon that starts soon after infarction and progresses to extensive regional and global architectural changes over time. Purpose: To noninvasively comprehensively characterize transient (edema, hemorrhage, microvascular obstruction (MO)) and persistent structural (infarct size) components of reperfused infarct up to 10 weeks and to determine their relation to LV function. Material and Methods: Farm pigs were used for the study. Under fluoroscopy the left anterior descending (LAD) coronary artery was occluded for 90 min. MR imaging was performed at 3 days ( n=14 pigs), 5 weeks ( n=10), and 10 weeks ( n=6) after reperfusion. The following MR imaging sequences were used: (i) cine; (ii) T2-weighted turbo spin echo; (iii) T2*-weighted turbo spin echo; (iv) tagged; (v) phase-contrast velocity-encoded; (vi) first-pass perfusion; and (vii) delayed contrast-enhanced (DE-MR imaging). After imaging, animals were euthanized at 3 days ( n=4), 5 weeks ( n=4), and 10 weeks ( n=6) and hearts were stained with triphenyltetrazolium chloride to define acute, subacute, and scar infarct and interstitial hemorrhage. Results: T2, T2*, and DE-MR imaging demonstrated transient interstitial edema, interstitial hemorrhage, and MO, respectively. MO was observed in 85% of animals and 60% of these showed hemorrhages. Cine, tagged, and phase-contrast velocity-encoded images documented the persistent impairment in 3D strain of infarcted segments, which on first-pass perfusion showed persistent perfusion deficit. MR imaging demonstrated the progressive increase in LV volumes and decreased ejection fraction over time. The changes in LV between 5 and 10 weeks were not related to the presence of interstitial edema, interstitial hemorrhage, MO or increase in infarct size. Conclusion: The various MR sequences described in this study allowed the demonstration of transient and persistent components of reperfused infarct. The progressive deterioration of global LV function was not related to the transient reperfusion components (edema, hemorrhage or MO) or change in infarct size. The results imply that MR imaging has the potential to identify progressive deterioration of LV function unrelated to reperfusion injury components or infarct size.
Increased B7-H1 Expression on Dendritic Cells Correlates with Programmed Death 1 Expression on T Cells in Simian Immunodeficiency Virus-Infected Macaques and May Contribute to T Cell Dysfunction and Disease Progression
Authors: Xu Huanbin , Wang Xiaolei , Pahar Bapi , Moroney-Rasmussen Terri , Alvarez Xavier , Lackner Andrew A. , Veazey Ronald S. 
Published: November 2010

Abstract
Suppression of dendritic cell (DC) function in HIV-1 infection is thought to contribute to inhibition of immune responses and disease progression, but the mechanism of this suppression remains undetermined. Using the rhesus macaque model, we show B7-H1 (programmed death [PD]-L1) is expressed on lymphoid and mucosal DCs (both myeloid DCs and plasmacytoid DCs), and its expression significantly increases after SIV infection. Meanwhile, its receptor, PD-1, is upregulated on T cells in both peripheral and mucosal tissues and maintained at high levels on SIV-specific CD8+ T cell clones in chronic infection. However, both B7-H1 and PD-1 expression in SIV controllers was similar to that of controls. Expression of B7-H1 on both peripheral myeloid DCs and plasmacytoid DCs positively correlated with levels of PD-1 on circulating CD4+ and CD8+ T cells, viremia, and declining peripheral CD4+ T cell levels in SIV-infected macaques. Importantly, blocking DC B7-H1 interaction with PD-1+ T cells could restore SIV-specific CD4+ and CD8+ T cell function as evidenced by increased cytokine secretion and proliferative capacity. Combined, the results indicate that interaction of B7-H1–PD-1 between APCs and T cells correlates with impairment of CD4+ Th cells and CTL responses in vivo, and all are associated with disease progression in SIV infection. Blockade of this pathway may have therapeutic implications for HIV-infected patients.
Organic and Inorganic Blocking Layers for Solution‐Processed Colloidal PbSe Nanocrystal Infrared Photodetectors
Authors: Sarasqueta Galileo , Choudhury Kaushik Roy , Subbiah Jegadesan , So Franky 
Published: November 2010

AbstractA PbSe solution‐processed nanocrystal‐based infrared photodetector incorporating carrier blocking layers is demonstrated, and significant reduction of dark current is achieved. Detectivity values close to 1012 Jones are achieved by using poly[(9,9′‐dioctylfluorenyl‐2,7‐diyl)‐co‐(4,4′‐(N‐(4‐sec‐butyl))diphenylamine)] (TFB) and ZnO nanocrystals (NC) as the electron blocker and hole blocker, respectively. An improvement in lifetime is also observed in the devices with the ZnO NCs hole blocking layer.
Chemically Stable Pr and Y Co‐Doped Barium Zirconate Electrolytes with High Proton Conductivity for Intermediate‐Temperature Solid Oxide Fuel Cells
Authors: Fabbri Emiliana , Bi Lei , Tanaka Hidehiko , Pergolesi Daniele , Traversa Enrico 
Published: November 2010

AbstractA chemically stable and highly proton‐conductive electrolyte is developed by partially substituting the Zr site of Y‐doped barium zirconate (BZY) with 10 mol% of Pr. Compared to BZY, BaZr0.7Pr0.1Y0.2O3‐δ (BZPY) shows improved sinterability as revealed by dilatometric measurements and scanning electron microscopy (SEM) analysis. Dense samples are obtained after sintering at 1500˚C for 8 h. Moreover, BZPY shows good chemical stability in the wide range of fuel‐cell operating conditions. The larger density and the enhanced grain growth, compared to BZY, allow the volume content of grain boundaries, which generally show a high resistance for proton transport, to be reduced and, thus, a high proton conductivity can be achieved in the temperature range of interest for practical applications (above 10−2 Scm−1 at 600˚C). The good sinterability, chemical stability, and high conductivity of the BZPY electrolyte enabled the fabrication of single‐cell prototypes based on a thin BZPY membrane by a simple and cost‐saving co‐pressing method. Electrochemical impedance spectroscopy (EIS) analysis performed during fuel‐cell tests under open‐circuit conditions confirms the good electrical performance of BZPY as electrolyte material. To improve the present fuel‐cell performance adapted cathode materials for this BZPY electrolyte need to be developed.