bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular Diagnostics in Embryonal Brain Tumors
Authors: Eberhart Charles G. 
Published: December 2010

AbstractEmbryonal brain tumors are a heterogeneous group of neoplasms united by the presence of poorly differentiated stem‐like cells. Molecular details are increasingly being used to separate them into biologically and clinically meaningful groups. For medulloblastoma, integrated mRNA expression profiling and DNA analysis by a number of research groups defines 4–6 distinctive molecular variants. A subset with prominent Wnt activity is associated with good clinical outcomes and classic histology. Medulloblastomas showing a Hedgehog gene expression signature are frequently of the desmoplastic/nodular subtype. Interestingly, Hedgehog activity is found in tumors arising either in infants or older teenagers and adults. The association of clinically aggressive medulloblastoma with MYC expression, large cell/anaplastic change and high levels of photoreceptor differentiation transcripts has also been noted in several studies. Immunohistochemical analysis of just one or two genes per molecular medulloblastoma variant may be sufficient for accurate classification, and this would be of great practical utility if validated. Advances have also been made in the classification of central nervous system (CNS) Primitive Neuroectodermal Tumors (PNET), as several groups have identified an amplicon at chromosome 19q13.41–42, which appears to define a unique PNET subtype associated with prominent true rosettes, young age and very poor outcomes.
The Use of Global Profiling in Biomarker Development for Gliomas
Authors: Sulman Erik P. , Aldape Ken 
Published: December 2010

AbstractThe diffuse gliomas are a heterogeneous group of malignancies with highly variable outcomes and diagnosis is largely based on the histological appearance of the tumors. Tumor classification according to cello type and grade provides some prognostic information. However, the diversity of gliomas, within tumor type and grade categories, has made prognostic determinations based purely on clinicopathologic variables difficult. There is an increasing body of data suggesting a significant amount of molecular diversity accounts for the heterogeneity of clinical observations, such as response to treatment and time to progression. The last decade has witnessed an explosive advance in our knowledge of the molecular genetics of brain tumors, due in large part to the availability of high‐throughput profiling techniques, including new sequencing methodologies as well as multidimensional profiling by the Cancer Genome Atlas project. The large amount of data generated by these efforts has enabled the identification of prognostic and predictive factors and helping to identify pathways that are driving tumor growth. Identification of biomarkers, especially when coupled to clinical trials of newer targeted therapies, will enable better patient stratification and individualization of treatment.
Invasion of human aortic endothelial cells by oral viridans group streptococci and induction of inflammatory cytokine production
Authors: Nagata E. , de Toledo A. , Oho T. 
Published: December 2010

SummaryOral viridans group streptococci are the major commensal bacteria of the supragingival oral biofilm and have been detected in human atheromatous plaque. Atherosclerosis involves an ongoing inflammatory response, reportedly involving chronic infection caused by multiple pathogens. The aim of this study was to examine the invasion of human aortic endothelial cells (HAECs) by oral viridans group streptococci and the subsequent cytokine production by viable invaded HAECs. The invasion of HAECs by bacteria was examined using antibiotic protection assays and was visualized by confocal scanning laser microscopy. The inhibitory effects of catalase and cytochalasin D on the invasion of HAECs were also examined. The production of cytokines by invaded or infected HAECs was determined using enzyme‐linked immunosorbent assays, and a real‐time polymerase chain reaction method was used to evaluate the expression of cytokine messenger RNA. The oral streptococci tested were capable of invading HAECs. The number of invasive bacteria increased with the length of the co‐culture period. After a certain co‐culture period, some organisms were cytotoxic to the HAECs. Catalase and cytochalasin D inhibited the invasion of HAECs by the organism. HAECs invaded by Streptococcus mutans Xc, Streptococcus gordonii DL1 (Challis), Streptococcus gordonii ATCC 10558 and Streptococcus salivarius ATCC 13419 produced more cytokine(s) (interleukin‐6, interleukin‐8, monocyte chemoattractant protein‐1) than non‐invaded HAECs. The HAECs invaded by S. mutans Xc produced the largest amounts of cytokines, and the messenger RNA expression of cytokines by invaded HAECs increased markedly compared with that by non‐invaded HAECs. These results suggest that oral streptococci may participate in the pathogenesis of atherosclerosis.
Changing attitudes towards euthanasia among medical students in Austria: Table 1
Authors: Stronegger Willibald J , Schmölzer Christin , Rásky Éva , Freidl Wolfgang 
Published: December 2010

BackgroundIn most European countries the attitudes regarding the acceptability of active euthanasia have clearly changed in the population since World War II. Therefore, it is interesting to know which trends in attitudes prevail among the physicians of the future.MethodsThe present study analyses trends in the attitudes towards active euthanasia in medical students at the Medical University of Graz, Austria. The survey was conducted over a period of 9 years, enabling us to investigate trends regarding both attitudes and underlying motives.ResultsAcceptance of active euthanasia increased from 16.3% to 29.1% to 49.5% in the periods from 2001 to 2003/04 to 2008/09.ConclusionsThe survey period from 2001 to 2009 reveals a massive change in medical students' attitudes towards active euthanasia under medical supervision. Ethical convictions of medical doctors seem to fall back behind a higher valuation of the autonomy of the patient.
Eribulin Induces Irreversible Mitotic Blockade: Implications of Cell-Based Pharmacodynamics for In vivo Efficacy under Intermittent Dosing Conditions
Authors: Towle Murray J. , Salvato Kathleen A. , Wels Bruce F. , Aalfs Kimberley K. , Zheng Wanjun , Seletsky Boris M. , Zhu Xiaojie , Lewis Bryan M. , Kishi Yoshito , Yu Melvin J. , Littlefield Bruce A. 
Published: December 2010

Abstract
Eribulin (E7389), a mechanistically unique microtubule inhibitor in phase III clinical trials for cancer, exhibits superior efficacy in vivo relative to the more potent compound ER-076349, a fact not explained by different pharmacokinetic properties. A cell-based pharmacodynamic explanation was suggested by observations that mitotic blockade induced by eribulin, but not ER-076349, is irreversible as measured by a flow cytometric mitotic block reversibility assay employing full dose/response treatment. Cell viability 5 days after drug washout established relationships between mitotic block reversibility and long-term cell survival. Similar results occurred in U937, Jurkat, HL-60, and HeLa cells, ruling out cell type–specific effects. Studies with other tubulin agents suggest that mitotic block reversibility is a quantifiable, compound-specific characteristic of antimitotic agents in general. Bcl-2 phosphorylation patterns parallel eribulin and ER-076349 mitotic block reversibility patterns, suggesting persistent Bcl-2 phosphorylation contributes to long-term cell-viability loss after eribulin's irreversible blockade. Drug uptake and washout/retention studies show that [3H]eribulin accumulates to lower intracellular levels than [3H]ER-076349, yet is retained longer and at higher levels. Similar findings occurred with irreversible vincristine and reversible vinblastine, pointing to persistent cellular retention as a component of irreversibility. Our results suggest that eribulin's in vivo superiority derives from its ability to induce irreversible mitotic blockade, which appears related to persistent drug retention and sustained Bcl-2 phosphorylation. More broadly, our results suggest that compound-specific reversibility characteristics of antimitotic agents contribute to interactions between cell-based pharmacodynamics and in vivo pharmacokinetics that define antitumor efficacy under intermittent dosing conditions. Cancer Res; 71(2); 496–505. ©2011 AACR.
ROS and CHOP Are Critical for Dibenzylideneacetone to Sensitize Tumor Cells to TRAIL through Induction of Death Receptors and Downregulation of Cell Survival Proteins
Authors: Prasad Sahdeo , Yadav Vivek R. , Ravindran Jayaraj , Aggarwal Bharat B. 
Published: December 2010

Abstract
Because tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively kills tumor cells, it is being tested in cancer patients. Unfortunately, patients develop resistance to the cytokine, therefore, agents that can sensitize cells to TRAIL are urgently needed. In this study, we investigated whether dibenzylideneacetone (DBA) can sensitize cancer cells to TRAIL and potentiates TRAIL-induced apoptosis. As indicated by accumulation of the membrane phospholipid phosphatidylserine, DNA breaks, intracellular esterase activity, and activation of caspase-8, -9, and -3, we concluded that DBA potentiated TRAIL-induced apoptosis in colon cancer cells. DBA also converted TRAIL resistant-cells to TRAIL-sensitive. When examined for the mechanism, we found that DBA decreased the expression of antiapoptotic proteins and decoy recptor-2 and increased proapoptotic proteins. DBA also induced both death receptor (DR)-5 and DR4. Knockdown of DR5 and DR4 by small interfering RNA (SiRNA) reduced the sensitizing effect of DBA on TRAIL-induced apoptosis. In addition, DBA increased the expression of CHOP proteins. Knockdown of CHOP by siRNA decreased the induction of DBA-induced DR5 expression and apoptosis. Induction of receptors by DBA, however, was p53-independent, as deletion of p53 had no effect on receptor induction. We observed that DBA-induced induction of DR5 and DR4 was mediated through generation of reactive oxygen species (ROS), as N-acetylcysteine blocked the induction of death receptors and suppression of cell survival proteins by DBA. Overall, our results show that DBA potentiates TRAIL-induced apoptosis through downregulation of cell survival proteins and upregulation of death receptors via activation of ROS and CHOP mediated pathways. Cancer Res; 71(2); 538–49. ©2010 AACR.
The Tumor Suppressor Protein Menin Inhibits AKT Activation by Regulating Its Cellular Localization
Authors: Wang Yan , Ozawa Atsushi , Zaman Shadia , Prasad Nijaguna B. , Chandrasekharappa Settara C. , Agarwal Sunita K. , Marx Stephen J. 
Published: December 2010

Abstract
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder associated mainly with tumors of multiple endocrine organs. Mutations in the MEN1 gene that encodes for the menin protein are the predominant cause for hereditary MEN1 syndrome. Though menin is a tumor suppressor, its molecular mechanism of action has not been defined. Here, we report that menin interacts with AKT1 in vitro and in vivo. Menin downregulates the level of active AKT and its kinase activity. Through interaction with AKT1, menin suppresses both AKT1-induced proliferation and antiapoptosis in nonendocrine and endocrine cells. Confocal microscopy analysis revealed that menin regulates AKT1 in part by reducing the translocation of AKT1 from the cytoplasm to the plasma membrane during growth factor stimulation. Our findings may be generalizable to other cancers, insofar as we found that loss of menin expression was also associated with AKT activation in a mouse model of pancreatic islet adenoma. Together, our results suggest menin as an important novel negative regulator of AKT kinase activity. Cancer Res; 71(2); 371–82. ©2010 AACR.
Role of Shear Stress in Endothelial Cell Morphology and Expression of Cyclooxygenase Isoforms
Authors: Potter Claire M.F. , Lundberg Martina H. , Harrington Louise S. , Warboys Christina M. , Warner Timothy D. , Berson R. Eric , Moshkov Alexey V. , Gorelik Julia , Weinberg Peter D. , Mitchell Jane A. 
Published: December 2010

Objective—The goal of this study was to examine the effect of chronic heterogeneous shear stress, applied using an orbital shaker, on endothelial cell morphology and the expression of cyclooxygenases 1 and 2.Methods and Results—Porcine aortic endothelial cells were plated on fibronectin-coated Transwell plates. Cells were cultured for up to 7 days either under static conditions or on an orbital shaker that generated a wave of medium inducing shear stress over the cells. Cells were fixed and stained for the endothelial surface marker CD31 or cyclooxygenases 1 and 2.En faceconfocal microscopy and scanning ion conductance microscopy were used to show that endothelial cells were randomly oriented at the center of the well, aligned with shear stress nearer the periphery, and expressed cyclooxygenase-1 under all conditions. Lipopolysaccharide induced cyclooxygenase-2 and the production of 6-keto-prostaglandin F1αin all cells.Conclusion—Cyclooxygenase-1 is expressed in endothelial cells cultured under chronic shear stress of high or low directionality.
Transforming Growth Factor-β Signaling Pathway in Patients With Kawasaki Disease
Authors: Shimizu Chisato , Jain Sonia , Davila Sonia , Hibberd Martin L. , Lin Kevin O. , Molkara Delaram , Frazer Jeffrey R. , Sun Shelly , Baker Annette L. , Newburger Jane W. , Rowley Anne H. , Shulman Stanford T. , Davila Sonia , Burgner David , Breunis Willemijn B. , Kuijpers Taco W. , Wright Victoria J. , Levin Michael , Eleftherohorinou Hariklia , Coin Lachlan , Popper Stephen J. , Relman David A. , Fury Wen , Lin Calvin , Mellis Scott , Tremoulet Adriana H. , Burns Jane C. 
Published: December 2010

Background—
Transforming growth factor (TGF)-β is a multifunctional peptide that is important in T-cell activation and cardiovascular remodeling, both of which are important features of Kawasaki disease (KD). We postulated that variation in TGF-β signaling might be important in KD susceptibility and disease outcome.

Methods and Results—

We investigated genetic variation in 15 genes belonging to the TGF-β pathway in a total of 771 KD subjects of mainly European descent from the United States, the United Kingdom, Australia, and the Netherlands. We analyzed transcript abundance patterns using microarray and reverse transcriptase–polymerase chain reaction for these same genes, and measured TGF-β2 protein levels in plasma. Genetic variants in
TGFB2
,
TGFBR2
, and
SMAD3
and their haplotypes were consistently and reproducibly associated with KD susceptibility, coronary artery aneurysm formation, aortic root dilatation, and intravenous immunoglobulin treatment response in different cohorts. A
SMAD3
haplotype associated with KD susceptibility replicated in 2 independent cohorts and an intronic single nucleotide polymorphism in a separate haplotype block was also strongly associated (A/G, rs4776338) (
P
=0.000022; odds ratio, 1.50; 95% confidence interval, 1.25 to 1.81). Pathway analysis using all 15 genes further confirmed the importance of the TGF-β pathway in KD pathogenesis. Whole-blood transcript abundance for these genes and TGF-β2 plasma protein levels changed dynamically over the course of the illness.

Conclusions—

These studies suggest that genetic variation in the TGF-β pathway influences KD susceptibility, disease outcome, and response to therapy, and that aortic root and coronary artery
Z
scores can be used for phenotype/genotype analyses. Analysis of transcript abundance and protein levels further support the importance of this pathway in KD pathogenesis.
Quality of Care for In-Hospital Stroke
Authors: Cumbler Ethan , Murphy Paul , Jones William J. , Wald Heidi L. , Kutner Jean S. , Smith Don B. 
Published: December 2010

Background and Purpose—
Approximately 4% to 17% of all adult strokes have onset in the hospital. Previous research indicates significant in-hospital evaluation delays and lower adherence to some measures of quality care compared to out-of-hospital strokes.

Methods—
Quality of care for in-hospital ischemic strokes compared to stroke with out-of-hospital onset was examined using cohort analysis of a statewide stroke database maintained by the Colorado Stroke Alliance.

Results—

One-hundred sixteen in-hospital strokes were compared to 4946 out-of-hospital strokes. Patients with in-hospital strokes were significantly more likely to have history of coronary artery disease (36.7% vs 26.5%;
P
=0.02), and in-hospital strokes were more severe (NIHSS score 9.5 vs 7.0;
P
=0.01). Time to brain imaging was not significantly different (54 minutes vs 43 minutes;
P
=0.13) between groups. Patients with in-hospital stroke were significantly more likely to have documentation of stroke education (90.4% vs 73.1%;
P
=0.0002) and assessment for rehabilitation (67.7% vs 45.2%;
P
<0.0001). Total deficit-free care defined as adherence to all Get With the Guidelines Stroke (GWTG-Stroke) measures was better for in-hospital strokes compared to strokes in the community (52.8% vs 32.3%;
P
<0.0001).

Conclusions—
Adherence to GWTG-Stroke performance measures was better for in-hospital strokes in this statewide registry. Variability in reporting by participating hospitals suggests in-hospital strokes are under-recognized or under-reported. In-hospital stroke evaluation times remain more than twice the recommended benchmark of 25 minutes, representing an opportunity for process improvement.
Association Between Obesity and Mortality After Acute First-Ever Stroke
Authors: Vemmos Konstantinos , Ntaios George , Spengos Konstantinos , Savvari Paraskevi , Vemmou Anastasia , Pappa Theodora , Manios Efstathios , Georgiopoulos George , Alevizaki Maria 
Published: December 2010

Background and Purpose—
Limited data exist concerning obesity and survival in patients after acute stroke. The objective of this study was to investigate the association between obesity and survival in patients with acute first-ever stroke.

Methods—

Patients were prospectively investigated based on a standard diagnostic protocol over a period of 16 years. Evaluation was performed on admission, at 7 days, at 1, 3, and 6 months after discharge, and yearly thereafter for up to 10 years after stroke. The study patients were divided into 3 groups according to body mass index (BMI): normal weight (<25 kg/m
2
), overweight (25–29.9 kg/m
2
), and obese (≥30 kg/m
2
). Overall survival during follow-up was the primary end point. The secondary end point was the overall composite cardiovascular events over the study period.

Results—

Based on our inclusion criteria, 2785 patients were recruited. According to BMI, 1138 (40.9%) patients were of normal weight, 1113 (41.0%) were overweight, and 504 (18.1%) were obese. NIHSS score on admission (mean, 11.28±8.65) was not different among the study groups. Early (first week) survival in obese (96.4%; 95% CI, 94.8%–97.9%) and overweight patients (92.8%; 95% CI, 91.2%–94.4%) was significantly higher compared to that of normal-weight patients (90.2%; 95% CI, 88.4%–92.0%). Similarly, 10-year survival was 52.5% (95% CI, 46.4%–58.6%) in obese, 47.4% (95% CI, 43.5%–51.3%) in overweight, and 41.5% (95% CI, 39.7%–45.0%) in normal-weight patients (log-rank test=17.7;
P
<0.0001). Overweight (HR, 0.82; 95% CI, 0.71–0.94) and obese patients (HR, 0.71; 95% CI, 0.59–0.86) had a significantly lower risk of 10-year mortality compared to normal-weight patients after adjusting for all confounding variables.

Conclusions—
Based on BMI estimation, obese and overweight stroke patients have significantly better early and long-term survival rates compared to those with normal BMI.
Comparative Effectiveness of Hemostatic Therapy in Experimental Warfarin-Associated Intracerebral Hemorrhage
Authors: Illanes Sergio , Zhou Wei , Schwarting Sönke , Heiland Sabine , Veltkamp Roland 
Published: December 2010

Background and Purpose—
Intracerebral hemorrhage associated with oral anticoagulants has a poor prognosis. Current treatment guidelines are based on case series and plausibility only, and a common consensus on effective hemostatic therapy is missing. We compared the effectiveness of diverse hemostatic approaches in a mouse model of warfarin-associated intracerebral hemorrhage.

Methods—
Male C57BL/6 mice received anticoagulant treatment with warfarin (0.4 mg/kg for 3 days). Intracerebral hemorrhage was induced by striatal injection of collagenase, and 30 minutes later, mice received an intravenous injection of saline (200 μL n=15), prothrombin complex concentrate (100 U/kg, n=10), fresh-frozen plasma (200 μL, n=13), recombinant human Factor VII activated (3.5 mg/kg, n=8 and 10 mg/kg, n=8), or tranhexamic acid (400 mg/kg, n=12). Intracerebral hemorrhage volume was quantified on T2-weighted images after 24 hours.

Results—

Mean hematoma volumes were 7.4±1.8 mm
3
in the nonwarfarin controls and 21.9±5.0 mm
3
in the warfarin group receiving saline. Prothrombin complex concentrate (7.5±2.3 mm
3
) and fresh-frozen plasma (8.7±2.1) treatment resulted in significantly smaller hematoma volume compared with saline. Recombinant human Factor VII activated (10 mg/kg: 14.7±3.4; 3.5 mg/kg: 15.0±6.8 mm
3
) and tranexamic acid (16.2±4.1 mm
3
) were less effective. Water content in the hemorrhagic hemisphere was similar in all groups except for tranexamic acid in which it was significantly increased.

Conclusions—
Prothrombin complex concentrate and fresh-frozen plasma effectively prevent hematoma growth in murine warfarin-associated intracerebral hemorrhage, whereas Factor VIIa was less effective. Tranexamic acid exacerbates perihematoma edema in this mouse warfarin-associated intracerebral hemorrhage model.
Analyzing the Impacts of Frequency and Severity of Forest Fire on the Recovery of Disturbed Forest using Landsat Time Series and EO-1 Hyperion in the Southern Brazilian Amazon
Authors: Numata Izaya , Cochrane Mark A. , Galvão Lênio S. 
Published: December 2010

Abstract
Estimation of fire impacts and forest recovery using remote sensing is difficult because of the heterogeneity of fire history (frequency, severity, and time since last fire) across burned forest landscapes. The authors analyzed impacts of fire frequency and severity within recovering forests in the Amazon region using remote sensing. A multispectral Landsat time series dataset was used to reconstruct the fire history from 1990 to 2002 in a portion of Mato Grosso, Brazil. Five narrowband vegetation indices were then calculated from a hyperspectral Earth Observing One (EO-1) Hyperion image for spectral analysis of physiological characteristics of fire-disturbed forests and their recovery. A total of 30% of the forests burned during the study period, with 72% burned once, 24% burned twice, and less than 4% burned three times. In terms of severity, 70% of burned forest was lightly burned, 21.1% was moderately burned, and 9.1% was severely burned. Analyses of spectral indices [normalized difference vegetation index (NDVI), carotenoid reflectance index (CRI), and photochemical reflectance index (PRI)] showed that those related to canopy greenness and pigment contents can discriminate between burned forests and undisturbed forest for the first 3 years after forest fire, whereas the effectiveness of canopy water content indices [normalized difference water index (NDWI) and normalized difference infrared index (NDII)] varied from 1 to 3 years, depending on the fire severity. Despite the relatively low signal-to-noise ratios of Hyperion imagery, we show that narrowband-derived indices provide useful information for monitoring degraded forests beyond what is currently possible with Landsat. This illustrates the great potential for environmental monitoring using satellite-borne hyperspectral sensors, such as the Hyperspectral Infrared Imager (HyspIRI), which have better signal-to-noise ratios.