bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of practices and morbidities affecting the mortality of very low birth weight infants using a multilevel logistic analysis: clinical trial or standardisation?
Authors: Kusuda Satoshi , Fujimura Masanori , Uchiyama Atsushi , Nakanishi Hidehiko , Totsu Satsuki ,   for Neonatal Research Network, Japan
Published: August 2013

ObjectivesTo determine the feasibility of clinical trials of newly developed treatments or standardisation of existing practices to further improve outcomes among very low birth weight (VLBW) infants, a nationwide database was analysed with a two-dimensional approach using two multivariate logistic models.DesignRetrospective observational analysis.SettingLevel III perinatal centres in Japan.Participants15 920 VLBW infants admitted at 38 participating centres from 2003 through 2010.Outcome measuresClinical information for the infants was collected until discharge from the centres. A multivariate logistic model identified practices and morbidities associated with mortality. Then, those which were significantly associated with mortality were analysed using a multilevel logistic model. The residues calculated by the multilevel analysis were used as an indicator of centre variation.ResultsAmong practices, antenatal steroids and intubation at birth showed relatively high centre variations (0.9 and 0.8) and favourable ORs (0.7 and 0.5) for mortality, while caesarean section showed a low centre variation (0.4) and a favourable OR (0.8). Sepsis and air leak showed high centre variations (0.4 and 0.4) and high ORs (3.8 and 3.4) among morbidities. Pulmonary haemorrhage, persistent pulmonary hypertension of the newborn, and intraventricular haemorrhage showed moderate variations (0.2, 0.3 and 0.2, respectively) and high ORs (5.6, 4.1 and 2.9, respectively). In contrast, necrotising enterocolitis showed the lowest variation (0.1) and a high OR (4.9).ConclusionsThe two-dimensional approach has clearly demonstrated the importance of clinical trial or standardisation. The practices and morbidities with low centre variations and high ORs for mortality must be improved through clinical trials of newly introduced techniques, while standardisation must be considered for practices and morbidities with a high centre variation.Trial registrationThe database was registered as UMIN000006961.
High-sensitivity cardiac troponin T is an independent predictor of inhospital mortality in emergency department patients with suspected infection: a prospective observational derivation study
Authors: de Groot Bas , Verdoorn Ruben C W , Lameijer Joost , van der Velden Jolanda 
Published: August 2013

IntroducionTo assess the prognostic and discriminative accuracy of high-sensitivity cardiac troponin T (hs-cTnT) for prediction of inhospital mortality in emergency department (ED) patients with suspected infection.MethodsProspective observational derivation study in ED patients with suspected infection. Prognostic performance of hs-cTnT (divided in four quartiles because of non-linearity) for prediction of inhospital mortality was assessed using multivariable logistic regression, correcting for predisposition, infection, response and organ failure (PIRO) score as a measure of illness severity and quality of ED treatment as quantified by the number of ‘Surviving Sepsis Campaign’ goals achieved. Discriminative power of hs-cTnT was assessed by receiver operator characteristics with area under the curve (AUC) analysis.ResultsHs-cTnT (median (IQR) was 57 (25–90) ng/L (n=23) in non-survivors, significantly higher than the 15 (7–28) ng/L in survivors (n=269, p<0.001). Additionally, the lowest quartile of hs-cTnT was a perfect predictor of survival because zero death occurred. Therefore, the second quartile was used as a reference category in the multivariable logistic regression analysis showing that hs-cTnT was an independent predictor of inhospital mortality: Corrected ORs were 2.2 (95% CI 0.4 to 12.1) and 5.8 (1.2 to 27.3) for the 3rd and 4th quartile compared with the 2nd hs-cTnT quartile. The AUCs of hs-TnT was 0.81 (0.74 to 0.88), similar to the AUC of 0.78 (0.68 to 0.87) of the PIRO score (p>0.05). Overall negative predictive value of hs-cTnT was 99%.ConclusionsIn ED patients with suspected infection, the routinely used biomarker hs-cTnT is an independent predictor of inhospital mortality with excellent discriminative performance. Future studies should focus on the additional value of hs-cTnT to existing risk stratification tools.
Economic conditions and health behaviours during the ‘Great Recession’
Authors: Nandi Arijit , Charters Thomas J , Strumpf Erin C , Heymann Jody , Harper Sam 
Published: August 2013

BackgroundThe adoption of healthier behaviours has been hypothesised as a mechanism to explain empirical findings of population health improvements during some economic downturns.MethodsWe estimated the effect of the local unemployment rate on health behaviours using pooled annual surveys from the 2003–2010 Behavioral Risk Factor Surveillance Surveys, as well as population-based telephone surveys of the US adult general population. Analyses were based on approximately 1 million respondents aged 25 years or older living in 90 Metropolitan Statistical Areas and Metropolitan Divisions (MMSAs). The primary exposure was the quarterly MMSA-specific unemployment rate. Outcomes included alcohol consumption, smoking status, attempts to quit smoking, body mass index, overweight/obesity and past-month physical activity or exercise.ResultsThe average unemployment rate across MMSAs increased from a low of 4.5% in 2007 to a high of 9.3% in 2010. In multivariable models accounting for individual-level sociodemographic characteristics and MMSA and quarter fixed effects, a one percentage-point increase in the unemployment rate was associated with 0.15 (95% CI −0.31 to 0.01) fewer drinks consumed in the past month and a 0.14 (95% CI −0.28 to 0.00) percentage-point decrease in the prevalence of past-month heavy drinking; these effects were driven primarily by men. Changes in the unemployment rate were not consistently associated with other health behaviours. Although individual-level unemployment status was associated with higher levels of alcohol consumption, smoking and obesity, the MMSA-level effects of the recession were largely invariant across employment groups.ConclusionsOur results do not support the hypothesis that health behaviours mediate the effects of local-area economic conditions on mortality.
Zircon U–Pb and Hf – isotopes from the eastern part of the Sveconorwegian Orogen, SW Sweden: implications for the growth of Fennoscandia
Authors: Petersson Andreas , Scherstén Anders , Andersson Jenny , Möller Charlotte 
Published: August 2013

Abstract

Current models for the growth of Fennoscandia, including the eastern part of the Sveconorwegian Province, are largely based on U–Pb data and do not discriminate between juvenile and reworked crust. Here we present new combined U–Pb and Hf isotopic data, from the Eastern Segment and the Idefjorden terrane of the Sveconorwegian Province, and suggest a revised model of crustal growth. Most of the crystalline basement in this part of the shield formed by mixing of a 2.1–1.9 Ga juvenile component and Archaean crust. Archaean reworking decreases between 1.9 and 1.7 Ga and a mixed Svecofennian crustal reservoir is generated. Succeeding magmatism between 1.7 and 1.4 Ga indicates reworking of this reservoir with little or no crust generation. At
c.
1.2 Ga, an influx of juvenile magma is recorded by granite to quartz-syenite magmatism with mildly depleted (ε
Hf 1.18 Ga
of
c.
3) signatures. The amount of recycled crust in the 1.9–1.7 Ga arc system is in contrast to previously proposed models for the growth of the southwestern part of the Fennoscandian Shield. This model agrees with long-term subduction along the western margin of Fennoscandia, but suggests substantial reworking of existing crust and decreasing amounts of <1.9 Ga crustal growth.

Supplementary material:

The analytical method, U–Pb SIMS table, U–Pb LA-SF-ICP-MS table and Lu–Hf table are available at
www.geolsoc.org.uk/SUP18648
EGFR-Activating Mutations Correlate with a Fanconi Anemia–like Cellular Phenotype That Includes PARP Inhibitor Sensitivity
Authors: Pfäffle Heike N. , Wang Meng , Gheorghiu Liliana , Ferraiolo Natalie , Greninger Patricia , Borgmann Kerstin , Settleman Jeffrey , Benes Cyril H. , Sequist Lecia V. , Zou Lee , Willers Henning 
Published: August 2013

Abstract
In patients with lung cancer whose tumors harbor activating mutations in the EGF receptor (EGFR), increased responses to platinum-based chemotherapies are seen compared with wild-type cancers. However, the mechanisms underlying this association have remained elusive. Here, we describe a cellular phenotype of cross-linker sensitivity in a subset of EGFR-mutant lung cancer cell lines that is reminiscent of the defects seen in cells impaired in the Fanconi anemia pathway, including a pronounced G2–M cell-cycle arrest and chromosomal radial formation. We identified a defect downstream of FANCD2 at the level of recruitment of FAN1 nuclease and DNA interstrand cross-link (ICL) unhooking. The effect of EGFR mutation was epistatic with FANCD2. Consistent with the known role of FANCD2 in promoting RAD51 foci formation and homologous recombination repair (HRR), EGFR-mutant cells also exhibited an impaired RAD51 foci response to ICLs, but not to DNA double-strand breaks. EGFR kinase inhibition affected RAD51 foci formation neither in EGFR-mutant nor wild-type cells. In contrast, EGFR depletion or overexpression of mutant EGFR in wild-type cells suppressed RAD51 foci, suggesting an EGFR kinase-independent regulation of DNA repair. Interestingly, EGFR-mutant cells treated with the PARP inhibitor olaparib also displayed decreased FAN1 foci induction, coupled with a putative block in a late HRR step. As a result, EGFR-mutant lung cancer cells exhibited olaparib sensitivity in vitro and in vivo. Our findings provide insight into the mechanisms of cisplatin and PARP inhibitor sensitivity of EGFR-mutant cells, yielding potential therapeutic opportunities for further treatment individualization in this genetically defined subset of lung cancer. Cancer Res; 73(20); 6254–63. ©2013 AACR.
mRNA Splicing Variants: Exploiting Modularity to Outwit Cancer Therapy
Authors: Dehm Scott M. 
Published: August 2013

Abstract
Systemic cancer therapy has traditionally exploited vulnerabilities in cancer cells, a strategy which has become more precise with the identification and targeting of driver oncogenes. However, persistent tumor growth due to primary (de novo) or secondary (acquired) resistance limits therapeutic efficacy for many patients. Alternative splicing is important for increasing the diversity of the cellular proteome, and is a process frequently deregulated during cancer development and progression. In cancer cells, diverse splicing alterations have been identified that eliminate protein domains or enzymatic activities required for efficacy of cancer therapies, promote gain of novel signaling functions that circumvent cancer therapies, and uncouple signaling pathways from upstream regulatory points that are blocked by cancer therapies. The mechanisms underlying these splicing changes range from stable alterations in gene sequence/structure to deregulation of splicing regulatory factors. In this review, the role of splice variants in cancer therapy resistance will be discussed, with examples of how mechanistic understanding of these processes has led to the development of novel strategies for therapy resensitization. Cancer Res; 73(17); 5309–14. ©2013 AACR.
FOXO Transcription Factors Control E2F1 Transcriptional Specificity and Apoptotic Function
Authors: Shats Igor , Gatza Michael L. , Liu Beiyu , Angus Steven P. , You Lingchong , Nevins Joseph R. 
Published: August 2013

Abstract
The transcription factor E2F1 is a key regulator of proliferation and apoptosis but the molecular mechanisms that mediate these cell fate decisions remain unclear. Here, we identify FOXO transcription factors as E2F1 target genes that act in a feed-forward regulatory loop to reinforce gene induction of multiple apoptotic genes. We found that E2F1 forms a complex with FOXO1 and FOXO3. RNAi-mediated silencing of FOXO impaired E2F1 binding to the promoters of cooperative target genes. A FOXO3 mutant insensitive to inactivation by survival kinases rescued the inhibitory effect of growth factor signaling on E2F1-mediated transcription and apoptosis. The E2F1/FOXO axis is frequently blocked in cancer, as evidenced by the specific downregulation of the FOXO-dependent E2F1 transcriptional program in multiple cancer types and by the association of a reduced E2F1/FOXO transcriptional program with poor prognosis. HDAC and phosphoinositide 3-kinase (PI3K) inhibitors were identified as specific activators of E2F1/FOXO transcription, acting to enhance E2F1-induced apoptosis in a FOXO3-dependent manner. Notably, combining the histone deacetylase inhibitor vorinostat with a PI3K inhibitor led to enhanced FOXO-dependent apoptosis. Collectively, our results identify E2F1/FOXO cooperation as a regulatory mechanism that places E2F1 apoptotic activity under the control of survival signaling. Therapeutic reactivation of this tumor suppressive mechanism may offer a novel broad-acting therapy for cancer. Cancer Res; 73(19); 6056–67. ©2013 AACR.
Novel Oncogenic PDGFRA Mutations in Pediatric High-Grade Gliomas
Authors: Paugh Barbara S. , Zhu Xiaoyan , Qu Chunxu , Endersby Raelene , Diaz Alexander K. , Zhang Junyuan , Bax Dorine A. , Carvalho Diana , Reis Rui M. , Onar-Thomas Arzu , Broniscer Alberto , Wetmore Cynthia , Zhang Jinghui , Jones Chris , Ellison David W. , Baker Suzanne J. 
Published: August 2013

Abstract
The outcome for children with high-grade gliomas (HGG) remains dismal, with a 2-year survival rate of only 10% to 30%. Diffuse intrinsic pontine glioma (DIPG) comprise a subset of HGG that arise in the brainstem almost exclusively in children. Genome-wide analyses of copy number imbalances previously showed that platelet-derived growth factor receptor α (PDGFRA) is the most frequent target of focal amplification in pediatric HGGs, including DIPGs. To determine whether PDGFRA is also targeted by more subtle mutations missed by copy number analysis, we sequenced all PDGFRA coding exons from a cohort of pediatric HGGs. Somatic-activating mutations were identified in 14.4% (13 of 90) of nonbrainstem pediatric HGGs and 4.7% (2 of 43) of DIPGs, including missense mutations and in-frame deletions and insertions not previously described. Forty percent of tumors with mutation showed concurrent amplification, whereas 60% carried heterozygous mutations. Six different mutations impacting different domains all resulted in ligand-independent receptor activation that was blocked by small molecule inhibitors of PDGFR. Expression of mutants in p53-null primary mouse astrocytes conferred a proliferative advantage in vitro and generated HGGs in vivo with complete penetrance when implanted into brain. The gene expression signatures of these murine HGGs reflected the spectrum of human diffuse HGGs. PDGFRA intragenic deletion of exons 8 and 9 were previously shown in adult HGG, but were not detected in 83 nonbrainstem pediatric HGG and 57 DIPGs. Thus, a distinct spectrum of mutations confers constitutive receptor activation and oncogenic activity to PDGFRα in childhood HGG. Cancer Res; 73(20); 6219–29. ©2013 AACR.
Pralatrexate Pharmacology and Clinical Development
Authors: Marchi Enrica , Mangone Michael , Zullo Kelly , O'Connor Owen A. 
Published: August 2013

Abstract
Folates are well known to be essential for many cellular processes, including cellular proliferation. As a consequence, antifolates, the fraudulent mimics of folic acid, have been shown to be potent therapeutic agents in many cancers. Over the past several decades, efforts to improve on this class of drugs have met with little success. Recently, one analog specifically designed to have high affinity for the reduced folate carrier, which efficiently internalizes natural folates and antifolates, has been shown to be very active in T-cell lymphoma. Pralatrexate, approved by the U.S. Food and Drug Administration in 2009, is highly active across many lymphoid malignancies, including chemotherapy-resistant T-cell lymphoma. Emerging combination studies have now shown that pralatrexate is highly synergistic with gemcitabine, histone deacetylase inhibitors like romidepsin and bortezomib. These insights are leading to a number of novel phase I and II combination studies which could challenge existing regimens like CHOP, and improve the outcome of patients with T-cell lymphoma Clin Cancer Res; 19(24); 6657–61. ©2013 AACR.
MiR-335 Inhibits Small Cell Lung Cancer Bone Metastases via IGF-IR and RANKL Pathways
Authors: Gong Meng , Ma Junrong , Guillemette Ryan , Zhou Mingliang , Yang Yan , Yang Yujing , Hock Janet M. , Yu Xijie 
Published: August 2013

Abstract
Small cell lung cancer (SCLC) is a rapidly progressing, incurable cancer that frequently spreads to bone. New insights are needed to identify therapeutic targets to prevent or retard SCLC metastatic progression. Human SCLC SBC-5 cells in mouse xenograft models home to skeletal and nonskeletal sites, whereas human SCLC SBC-3 cells only pervade nonskeletal sites. Because microRNAs (miRNA) often act as tumor regulators, we investigated their role in preclinical models of SCLC. miRNA expression profiling revealed selective and reduced expression of miRNA (miR)-335 and miR-29a in SBC-5 cells, compared with SBC-3 cells. In SBC-5 cells, miR-335 expression correlated with bone osteolytic lesions, whereas miR-29a expression did not. Overexpression of miR-335 in SBC-5 cells significantly reduced cell migration, invasion, proliferation, colony formation, and osteoclast induction in vitro. Importantly, in miR-335 overexpressing SBC-5 cell xenografts (n = 10), there were minimal osteolytic lesions in the majority of mice and none in three mice. Expression of RANK ligand (RANKL) and insulin-like growth factor-I receptor (IGF-IR), key mediators of bone metastases, were elevated in SBC-5 as compared with SBC-3 cells. Mechanistically, overexpression of miR-335 in SBC-5 cells reduced RANKL and IGF-IR expression. In conclusion, loss of miR-335 promoted SCLC metastatic skeletal lesions via deregulation of IGF-IR and RANKL pathways and was associated with metastatic osteolytic skeletal lesions.
Implications: These preclinical findings establish a need to pursue the role of miR-335 in human SCLC with metastatic skeletal disease. Mol Cancer Res; 12(1); 101–10. ©2013 AACR.
Cost-effectiveness impact of rivaroxaban versus new and existing prophylaxis for the prevention of venous thromboembolism after total hip or knee replacement surgery in France, Italy and Spain
Authors: Monreal Manuel , Folkerts Kerstin , Imberti Davide , Brosa Max , Diamantopoulos Alex 
Published: August 2013

SummaryVenous thromboembolism (VTE) has a significant impact on healthcare costs but is largely preventable with anticoagulant prophylaxis using low-molecular-weight heparins (LMWHs), such as enoxaparin or dalteparin. Rivaroxaban and dabigatran etexilate are two new oral anticoagulants (NOACs) both compared with enoxaparin in separate trials. A decision analytic model with a healthcare and national payer perspective over a five-year time horizon was used to evaluate the cost-effectiveness of the NOACs for VTE prophylaxis after total hip replacement (THR) or total knee replacement (TKR) in France, Italy and Spain. Efficacy and safety data were obtained from randomised controlled trials of rivaroxaban vs enoxaparin and an indirect statistical comparison for rivaroxaban vs dabigatran. Rivaroxaban demonstrated dominance across all comparisons, indications and countries. In THR, total per-patient costs were reduced by up to €160 in the enoxaparin comparison and €115 in the dabigatran comparison, respectively. In addition, quality-adjusted life-years (QALYs) were increased by up to 0.0011 and 0.0012 in each comparison, respectively. Similarly, total costs were reduced in TKR by up to €137 and €28 in the enoxaparin and dabigatran comparisons, respectively. The total number of QALYs was increased by up to 0.0014 in the enoxaparin comparison and 0.0005 in the dabigatran comparison. The results were driven by costs since the incremental benefits were minimal. Rivaroxaban use could result in substantial healthcare cost savings and improved quality of life. The results are applicable across three European countries with differing healthcare systems so, potentially, could be generalised to a much wider population.
Functional responses and molecular mechanisms involved in histone-mediated platelet activation
Authors: Romaniuk Marìa Albertina , Fondevila Carlos , Negrotto Soledad , Carestia Agostina , Rivadeneyra Leonardo , Schattner Mirta 
Published: August 2013

SummaryHistones are highly alkaline proteins found in cell nuclei and they can be released by either dying or inflammatory cells. The recent observations that histones are major components of neutrophil extracellular traps and promote platelet aggregation and platelet-dependent thrombin generation have shown that these proteins are potent prothrombotic molecules. Because the mechanism(s) of platelet activation by histones are not completely understood, we explored the ability of individual recombinant human histones H1, H2A, H2B, H3 and H4 to induce platelet activation as well as the possible molecular mechanisms involved. All histones were substrates for platelet adhesion and spreading and triggered fibrinogen binding, aggregation, von Willebrand factor release, P-selectin and phosphatidylserine (PS) exposure and the formation of platelet-leukocyte aggregates; however, H4 was the most potent. Histone-mediated fibrinogen binding, P-selectin and PS exposure and the formation of mixed aggregates were potentiated by thrombin. Histones induced the activation of ERK, Akt, p38 and NFkB. Accordingly, histone-induced platelet activation was significantly impaired by pretreatment of platelets with inhibitors of ERK (U 0126), PI3K/Akt (Ly 294002), p38 (SB 203580) and NFkB (BAY 11–7082 and Ro 106–9920). Preincubation of platelets with either aspirin or dexamethasone markedly decreased fibrinogen binding and the adhesion mediated by histones without affecting P-selectin exposure. Functional platelet responses induced by H3 and H4, but not H1, H2A and H2B, were partially mediated through interaction with Toll-like receptors –2 and –4. Our data identify histones as important triggers of haemostatic and proinflammatory platelet responses, and only haemostatic responses are partially inhibited by anti-inflammatory drugs.