bluuebunny/crossref_metadata_2025_split huggingface dataset:
A First Step toward Personalized Medicine in Osteosarcoma: Pharmacogenetics as Predictive Marker of Outcome after Chemotherapy-Based Treatment
Authors: Hagleitner Melanie M. , Coenen Marieke J.H. , Gelderblom Hans , Makkinje Remco R. , Vos Hanneke I. , de Bont Eveline S.J.M. , van der Graaf Winette T.A. , Schreuder H.W. Bart , Flucke Uta , van Leeuwen Frank N. , Hoogerbrugge Peter M. , Guchelaar Henk-Jan , te Loo Dunja M.W.M 
Published: April 2015

Abstract
Purpose: Overall survival in patients with osteosarcoma is only 60%. Poor response to chemotherapy is the dominant risk factor for poor survival. Pharmacogenetic research can offer possibilities to optimize treatment and improve outcome. We applied a pathway-based approach to evaluate the cumulative effect of genes involved in the metabolism of cisplatin and doxorubicin in relationship to clinical outcome.
Experimental Design: We included 126 patients with osteosarcoma. To comprehensively assess common genetic variation in the 54 genes selected, linkage disequilibrium (LD; r2 = 0.8)–based tag-single nucleotide polymorphisms (SNP) strategy was used. A final set of 384 SNPs was typed using Illumina Beadarray platform. SNPs significantly associated with 5-year progression-free survival (PFS) were replicated in another 64 patients with osteosarcoma.
Results: We identified five variants in FasL, MSH2, ABCC5, CASP3, and CYP3A4 that were associated with 5-year PFS. Risk stratification based on the combined effects of the risk alleles showed a significant improvement of 5-year PFS. Patients that carried no or only one risk allele had a 5-year PFS of 100% compared with a 5-year PFS of 84.4% for carriers of two or three risk alleles, 66.7% PFS if a patient carried four to five alleles, and a 5-year PFS of 41.8% for patients with &gt;5 risk alleles (P &lt; 0.001).
Conclusions: We identified several genes that showed association with PFS in patients with osteosarcoma. These pharmacogenetic risk factors might be useful to predict treatment outcome and to stratify patients immediately after diagnosis and offer the possibility to improve treatment and outcome. Clin Cancer Res; 21(15); 3436–41. ©2015 AACR.
Multimerin-1 (MMRN1) as Novel Adverse Marker in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group
Authors: Laszlo George S. , Alonzo Todd A. , Gudgeon Chelsea J. , Harrington Kimberly H. , Gerbing Robert B. , Wang Yi-Cheng , Ries Rhonda E. , Raimondi Susana C. , Hirsch Betsy A. , Gamis Alan S. , Meshinchi Soheil , Walter Roland B. 
Published: April 2015

AbstractPurpose: Exploratory gene expression array analyses suggested multimerin-1 (MMRN1) to be a predictive biomarker in acute myelogenous leukemia (AML). Following up on these studies, we evaluated the role of MMRN1 expression as outcome predictor in two recent Children's Oncology Group trials.Experimental Design: We retrospectively quantified MMRN1 expression in 183 participants of AAML03P1 and 750 participants of AAML0531 by reverse-transcriptase PCR and correlated expression levels with disease characteristics and clinical outcome.Results: In AAML03P1, the highest quartile of MMRN1 expression (expression ≥0.5 relative to β-glucuronidase; n = 45) was associated with inferior event-free survival (EFS; P &lt; 0.002) and higher relapse risk (P &lt; 0.004). In AAML0531, in which we quantified MMRN1 mRNA for validation, patients with relative MMRN1 expression ≥0.5 (n = 160) less likely achieved remission (67% vs. 77%, P = 0.006), and more frequently had minimal residual disease (43% vs. 24%, P = 0.001) after one induction course. They had inferior overall survival (OS; 44% ± 9% vs. 69% ± 4% at 5 years; P &lt; 0.001) and EFS (32% ± 8% vs. 54% ± 4% at 5 years; P &lt; 0.001) and higher relapse risk (57% ± 10% vs. 35% ± 5% at 5 years; P &lt; 0.001). These differences were partly attributable to the fact that patients with high MMRN1 expression less likely had cytogenetic/molecular low-risk disease (P &lt; 0.001) than those with low MMRN1 expression. Nevertheless, after multivariable adjustment, high MMRN1 expression remained statistically significantly associated with shorter OS (HR, 1.57; 95% confidence interval, 1.17–2.12; P = 0.003) and EFS (HR, 1.34; 1.04–1.73; P = 0.025), and higher relapse risk (HR, 1.40; 1.01–1.94; P = 0.044).Conclusions: Together, our studies identify MMRN1 expression as a novel biomarker that may refine AML risk stratification. Clin Cancer Res; 21(14); 3187–95. ©2015 AACR.
The Impact of Macrophage- and Microglia-Secreted TNFα on Oncolytic HSV-1 Therapy in the Glioblastoma Tumor Microenvironment
Authors: Meisen W. Hans , Wohleb Eric S. , Jaime-Ramirez Alena Cristina , Bolyard Chelsea , Yoo Ji Young , Russell Luke , Hardcastle Jayson , Dubin Samuel , Muili Kamaldeen , Yu Jianhua , Caligiuri Michael , Godbout Jonathan , Kaur Balveen 
Published: April 2015

AbstractPurpose: Oncolytic herpes simplex viruses (oHSV) represent a promising therapy for glioblastoma (GBM), but their clinical success has been limited. Early innate immune responses to viral infection reduce oHSV replication, tumor destruction, and efficacy. Here, we characterized the antiviral effects of macrophages and microglia on viral therapy for GBM.Experimental Design: Quantitative flow cytometry of mice with intracranial gliomas (±oHSV) was used to examine macrophage/microglia infiltration and activation. In vitro coculture assays of infected glioma cells with microglia/macrophages were used to test their impact on oHSV replication. Macrophages from TNFα-knockout mice and blocking antibodies were used to evaluate the biologic effects of TNFα on virus replication. TNFα blocking antibodies were used to evaluate the impact of TNFα on oHSV therapy in vivo.Results: Flow-cytometry analysis revealed a 7.9-fold increase in macrophage infiltration after virus treatment. Tumor-infiltrating macrophages/microglia were polarized toward a M1, proinflammatory phenotype, and they expressed high levels of CD86, MHCII, and Ly6C. Macrophages/microglia produced significant amounts of TNFα in response to infected glioma cells in vitro and in vivo. Using TNFα-blocking antibodies and macrophages derived from TNFα-knockout mice, we discovered TNFα-induced apoptosis in infected tumor cells and inhibited virus replication. Finally, we demonstrated the transient blockade of TNFα from the tumor microenvironment with TNFα-blocking antibodies significantly enhanced virus replication and survival in GBM intracranial tumors.Conclusions: The results of these studies suggest that FDA approved TNFα inhibitors may significantly improve the efficacy of oncolytic virus therapy. Clin Cancer Res; 21(14); 3274–85. ©2015 AACR.
1α,25-Dihydroxyvitamin D3 Inhibits Esophageal Squamous Cell Carcinoma Progression by Reducing IL6 Signaling
Authors: Chen Ping-Tsung , Hsieh Ching-Chuan , Wu Chun-Te , Yen Tzu-Chen , Lin Paul-Yang , Chen Wen-Cheng , Chen Miao-Fen 
Published: April 2015

AbstractThe aim of this study was to highlight the role of 1α,25-dihydroxyvitamin D3 (calcitriol) in esophageal squamous cell carcinoma (SCC). The human esophageal SCC cell lines CE81T and TE2 were selected for cellular and animal experiments to investigate the changes in tumor behavior after calcitriol supplementation and the underlying mechanisms. Moreover, we evaluated the relationship between calcitriol supplementation, myeloid-derived suppressor cell (MDSC) recruitment, IL6 levels, and tumor progression by a 4-nitroquinoline 1-oxide (4-NQO)–induced esophageal tumor animal model. In this study, we demonstrated that calcitriol supplementation inhibited aggressive tumor behavior both in vitro and in vivo. The underlying changes included increased cell death, a lower degree of epithelial–mesenchymal transition, and inhibited IL6 signaling. In the 4-NQO–induced esophageal tumor animal model, increased IL6 and MDSC recruitment were linked with invasive esophageal tumors. Supplementation with calcitriol attenuated the level of IL6, the induction of MDSCs, and the incidence of 4-NQO–induced invasive tumors. Moreover, the IL6-induced changes in C57 mice, including augmented MDSC recruitment, increased levels of ROS and p-Stat3 in MDSCs, and higher suppressive function of MDSCs in T-cell proliferation, which were abrogated by calcitriol supplementation. On the basis of our results, we concluded that calcitriol abrogated the IL6-induced aggressive tumor behavior and MDSC recruitment to inhibit esophageal tumor promotion. Therefore, we suggest that supplementation with vitamin D3 may be a promising strategy for the prevention and treatment of esophageal SCC. Mol Cancer Ther; 14(6); 1365–75. ©2015 AACR.
Acute and Chronic Performance Evaluation of a Novel Epicardial Pacing Lead Placed by Percutaneous Subxiphoid Approach in a Canine Model
Authors: John Roy M. , Morgan Kevin , Brennecke Lucas H. , Benser Michael E. , Jais Pierre 
Published: April 2015

Background—
Endovascularly implanted leads risk vascular injury and endocarditis, and can be difficult to locate in desired positions for LV pacing. We evaluated the acute and long-term stability, electric performance and histopathology of a percutaneously placed intrapericardial lead (IPL).

Methods and Results—

Twelve adult mongrel dogs underwent defibrillator implants incorporating IPLs. Successful uncomplicated percutaneous implantation of an IPL was achieved in all. Early fluoroscopic shift noted with 3 of 6 of the initial version IPL-1 was not seen with the modified IPL-2. Mean±95% confidence interval bipolar capture threshold at 0.5-ms pulse width for the IPL increased from 0.69±0.14 V at implant to 1.50±0.34 V (
P
=0.003) at 12 weeks. The 12-week thresholds were higher for IPL compared with right ventricular endocardial leads (0.75±0.33 V;
P
=0.001) but not different compared with coronary sinus leads (1.33±0.58 V;
P
=0.994). IPL impedance increased from 742±46 Ω at implant to 1066±207 Ω at 12 weeks (
P
=0.007). R-wave amplitude at 12 weeks was 8.37±1.52 mV. There was no important phrenic nerve stimulation from IPL pacing. Histopathology in 8 animals showed adequate adhesion of the electrodes or mesh to the epicardium without damage to underlying vasculature. There was no evidence for late pericardial inflammation or effusion.

Conclusions—
The IPL demonstrated adequate stability of position and acceptable electric parameters without chronic pericardial inflammation in this canine model and offers a potential alternative to endocardial pacing leads.
Feasibility of Combined Unipolar and Bipolar Voltage Maps to Improve Sensitivity of Endomyocardial Biopsy
Authors: Casella Michela , Pizzamiglio Francesca , Dello Russo Antonio , Carbucicchio Corrado , Al-Mohani Ghaliah , Russo Eleonora , Notarstefano Pasquale , Pieroni Maurizio , D’Amati Giulia , Sommariva Elena , Giovannardi Marta , Carnevali Andrea , Riva Stefania , Fassini Gaetano , Tundo Fabrizio , Santangeli Pasquale , Di Biase Luigi , Bolognese Leonardo , Natale Andrea , Tondo Claudio 
Published: April 2015

Background—
Endomyocardial biopsy (EMB) has a low sensitivity. Electroanatomic voltage mapping (EVM) is effective in guiding EMB thanks to its ability in identifying and locating low-voltage regions. The analysis of unipolar EVM can correlate with epicardial pathological involvement. We evaluated the unipolar EVM in EMB areas to determine whether it can increase EMB sensitivity in diagnosing epicardial diseases.

Methods and Results—

We performed endocardial bipolar EVM-guided EMBs in 29 patients and we analyzed unipolar EVM at withdrawal sites. Eighty myocardial samples were collected (mean, 2.8±0.9; median, 3 fragments per patient) and 60 were suitable for histological analysis. Ten specimens (17%) were collected from an area with discordant normal bipolar/low-voltage unipolar EVM and they were diagnostic or suggestive for arrhythmogenic right ventricular dysplasia/cardiomyopathy in 6 patients, for myocarditis and sarcoidosis in 1 patient each. Six samples (10%) were collected from an area with discordant low-voltage bipolar/normal unipolar EVM and they showed nonspecific features. The sensitivity of unipolar EVMs for a diagnostic biopsy finding EMB was significantly higher compared with bipolar EVMs analyzed according to samples (
P
<0.01) and patients (
P
=0.008). The specificity of unipolar EMB was better than bipolar EMB when analyzed for all samples (
P
=0.0014) but the difference did not reach statistical significance when analyzed by patient (
P
=0.083). The diagnostic yield was 63.3% for the bipolar and 83.3% for the unipolar EVM.

Conclusions—
These findings suggest that use of a combined bipolar/unipolar map may be able to improve the diagnostic yield of endomyocardial ventricular biopsy.
Access and Non–Access Site Bleeding After Percutaneous Coronary Intervention and Risk of Subsequent Mortality and Major Adverse Cardiovascular Events
Authors: Kwok Chun Shing , Khan Muhammad A. , Rao Sunil V. , Kinnaird Tim , Sperrin Matt , Buchan Iain , de Belder Mark A. , Ludman Peter F. , Nolan James , Loke Yoon K. , Mamas Mamas A. 
Published: April 2015

Background—
The prognostic impact of site-specific major bleeding complications after percutaneous coronary intervention (PCI) has yielded conflicting data. The aim of this study is to provide an overview of site-specific major bleeding events in contemporary PCI and study their impact on mortality and major adverse cardiovascular event outcomes.

Methods and Results—
We conducted a meta-analysis of PCI studies that evaluated site-specific periprocedural bleeding complications and their impact on major adverse cardiovascular events and mortality outcomes. A systematic search of MEDLINE and Embase was conducted to identify relevant studies and random effects meta-analysis was used to estimate the risk of adverse outcomes with site-specific bleeding complications. Twenty-five relevant studies including 2 400 645 patients that underwent PCI were identified. Both non–access site (risk ratio [RR], 4.06; 95% confidence interval [CI], 3.21–5.14) and access site (RR, 1.71; 95% CI, 1.37–2.13) related bleeding complications were independently associated with an increased risk of periprocedural mortality. The prognostic impact of non–access site–related bleeding events on mortality related to the source of anatomic bleeding, for example, gastrointestinal RR, 2.78; 95% CI, 1.25 to 6.18; retroperitoneal RR, 5.87; 95% CI, 1.63 to 21.12; and intracranial RR, 22.71; 95% CI, 12.53 to 41.15.

Conclusions—
The prognostic impact of bleeding complications after PCI varies according to anatomic source and severity. Non–access site-related bleeding complications have a similar prevalence to those from the access site but are associated with a significantly worse prognosis partly related to the severity of the bleed. Clinicians should minimize the risk of major bleeding complications during PCI through judicious use of bleeding avoidance strategies irrespective of the access site used.
High-Sensitivity Cardiac Troponin I and B-Type Natriuretic Peptide as Predictors of Vascular Events in Primary Prevention
Authors: Everett Brendan M. , Zeller Tanja , Glynn Robert J. , Ridker Paul M , Blankenberg Stefan 
Published: April 2015

Background—
Cardiac troponin and B-type natriuretic peptide (BNP) concentrations are associated with adverse cardiovascular outcome in primary prevention populations. Whether statin therapy modifies this association is poorly understood.

Methods and Results—

We measured high-sensitivity cardiac troponin I (hsTnI) in 12 956 and BNP in 11 076 participants without cardiovascular disease in the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial before randomization to rosuvastatin 20 mg/d or placebo. Nearly 92% of participants had detectable circulating hsTnI, and 2.9% of men and 4.1% of women had levels above proposed sex-specific reference limits of 36 and 15 ng/L, respectively. hsTnI concentrations in the highest tertile were associated with a first major cardiovascular event (adjusted hazard ratio [aHR], 2.19; 95% confidence interval, 1.56–3.06;
P
for trend <0.001). BNP levels in the highest tertile were also associated a first cardiovascular event (aHR, 1.94; 95% confidence interval, 1.41–2.68;
P
for trend <0.001). The risk of all-cause mortality was elevated for the highest versus the lowest tertiles of hsTnI (aHR, 2.61; 95% confidence interval, 1.81–3.78;
P
for trend <0.001) and BNP (aHR, 1.45; 95% confidence interval, 1.03–2.04;
P
for trend 0.02). Rosuvastatin was equally effective in preventing a first cardiovascular event across categories of hsTnI (aHR range, 0.50–0.60) and BNP (aHR range, 0.42–0.67) with no statistically significant evidence of interaction (
P
for interaction=0.53 and 0.20, respectively).

Conclusions—
In a contemporary primary prevention population, baseline cardiac troponin I and BNP were associated with the risk of vascular events and all-cause mortality. The benefits of rosuvastatin were substantial and consistent regardless of baseline hsTnI or BNP concentrations.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00239681.
Growth Hormone–Releasing Hormone Agonists Reduce Myocardial Infarct Scar in Swine With Subacute Ischemic Cardiomyopathy
Authors: Bagno Luiza L. , Kanashiro‐Takeuchi Rosemeire M. , Suncion Viky Y. , Golpanian Samuel , Karantalis Vasileios , Wolf Ariel , Wang Bo , Premer Courtney , Balkan Wayne , Rodriguez Jose , Valdes David , Rosado Marcos , Block Norman L. , Goldstein Peter , Morales Azorides , Cai Ren‐Zhi , Sha Wei , Schally Andrew V. , Hare Joshua M. 
Published: April 2015

Background

Growth hormone–releasing hormone agonists (
GHRH
‐As) stimulate cardiac repair following myocardial infarction (
MI
) in rats through the activation of the
GHRH
signaling pathway within the heart. We tested the hypothesis that the administration of
GHRH
‐As prevents ventricular remodeling in a swine subacute
MI
model.

Methods and Results

Twelve female Yorkshire swine (25 to 30 kg) underwent transient occlusion of the left anterior descending coronary artery (
MI
). Two weeks post
MI
, swine were randomized to receive injections of either 30 μg/kg
GHRH
‐A (
MR
‐409) (
GHRH
‐A group; n=6) or vehicle (placebo group; n=6). Cardiac magnetic resonance imaging and pressure–volume loops were obtained at multiple time points. Infarct, border, and remote (noninfarcted) zones were assessed for GHRH receptor by immunohistochemistry. Four weeks of
GHRH
‐A treatment resulted in reduced scar mass (
GHRH
‐A: −21.9±6.42%;
P
=0.02; placebo: 10.9±5.88%;
P
=0.25; 2‐way
ANOVA
;
P
=0.003), and scar size (percentage of left ventricular mass) (
GHRH
‐A: −38.38±4.63;
P
=0.0002; placebo: −14.56±6.92;
P
=0.16; 2‐way
ANOVA
;
P
=0.02). This was accompanied by improved diastolic strain. Unlike in rats, this reduced infarct size in swine was not accompanied by improved cardiac function as measured by serial hemodynamic pressure–volume analysis.
GHRH
receptors were abundant in cardiac tissue, with a greater density in the border zone of the
GHRH
‐A group compared with the placebo group.

Conclusions

Daily subcutaneous administration of
GHRH
‐A is feasible and safe in a large animal model of subacute ischemic cardiomyopathy. Furthermore,
GHRH
‐A therapy significantly reduced infarct size and improved diastolic strain, suggesting a local activation of the
GHRH
pathway leading to the reparative process.
Trends in Door-to-Thrombolysis Time in the Safe Implementation of Stroke Thrombolysis Registry
Authors: Strbian Daniel , Ahmed Niaz , Wahlgren Nils , Lees Kennedy R. , Toni Danilo , Roffe Christine , Surakka Ida L. , Tatlisumak Turgut 
Published: April 2015

Background and Purpose—
Shorter delays between symptom onset and treatment translate into better outcomes after ischemic stroke thrombolysis. There are considerable intercenter variations in treatment delivery. We analyzed the trends of door-to-needle times (DNTs) in the Safe Implementation of Thrombolysis in Stroke registry between 2003 and 2011.

Methods—
We extracted from the Safe Implementation of Thrombolysis in Stroke registry (n=45 079) year of treatment, center code, DNT, sex, age, National Institutes of Health Stroke Scale, and comorbidity. For each center, the year they joined the registry and the annual volume of patients were determined (<5, 5–24, 25–49, 50–74, 75–99, and ≥100 patients/y).

Results—
DNT was not available for 720 (1.6%) patients. The overall mean (SD) DNT was 73 (37) minutes with a median (interquartile range) of 67 (47–91) minutes. The DNT was 65 (46–90), 68 (50–92), and 72 (51–98) minutes for centers joined early (2003–2005), later (2006–2009), and recently (2009–2011), respectively. Center volume had more robust effect on DNT than year of treatment, and the shortest DNTs were seen in centers with volumes ≥100 patients/y. Earlier enrollment period was also associated with shorter delays.

Conclusions—
Centers that joined the registry earlier and those with high annual volume achieved shorter DNT than centers that joined later and low-volume centers. However, in most of the centers, DNT did not change much during the registry period. A multicenter project aiming to reduce DNT is warranted.
Effect of Public Awareness Campaigns on Calls to Ambulance Across Australia
Authors: Bray Janet E. , Straney Lahn , Barger Bill , Finn Judith 
Published: April 2015

Background and Purpose—
The National Stroke Foundation of Australia has run 12 public awareness campaigns since 2004. Campaign exposure and funding has varied annually and regionally during this time. The aim of this study was to measure the effect of campaigns on calls to ambulance for stroke across Australia in exposed regions (paid or pro bono advertising).

Methods—
All ambulance services in Australia provided monthly ambulance dispatch data between January 2003 and June 2014. We performed multivariable regression to measure the effect of campaign exposure on the volume of stroke-related emergency calls, after controlling for confounders.

Results—
The final model indicated that 11 of the 12 National Stroke Foundation campaigns were associated with increases in the volume of stroke-related calls (varying between 1% and 9.9%) in regions with exposure to advertising. This increase lasted ≈3 months, with an additional 10.2% relative increase in the volume of the calls in regions with paid advertising. We found no significant additional effect of the campaigns on stroke calls where ambulance services are publicly funded.

Conclusions—
The National Stroke Foundation stroke awareness campaigns are associated with increases to calls to ambulance for stroke in regions receiving advertising and promotion. Research is now required to examine whether this increased use in ambulance is for appropriate emergencies.
The Amundsen Sea Low: Variability, Change, and Impact on Antarctic Climate
Authors: Raphael M. N. , Marshall G. J. , Turner J. , Fogt R. L. , Schneider D. , Dixon D. A. , Hosking J. S. , Jones J. M. , Hobbs W. R. 
Published: April 2015

Abstract
The Amundsen Sea low (ASL) is a climatological low pressure center that exerts considerable influence on the climate of West Antarctica. Its potential to explain important recent changes in Antarctic climate, for example, in temperature and sea ice extent, means that it has become the focus of an increasing number of studies. Here, the authors summarize the current understanding of the ASL, using reanalysis datasets to analyze recent variability and trends, as well as ice-core chemistry and climate model projections, to examine past and future changes in the ASL, respectively. The ASL has deepened in recent decades, affecting the climate through its influence on the regional meridional wind field, which controls the advection of moisture and heat into the continent. Deepening of the ASL in spring is consistent with observed West Antarctic warming and greater sea ice extent in the Ross Sea. Climate model simulations for recent decades indicate that this deepening is mediated by tropical variability while climate model projections through the twenty-first century suggest that the ASL will deepen in some seasons in response to greenhouse gas concentration increases.