bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of lifestyle-related factors with circadian onset patterns of acute myocardial infarction: a prospective observational study in Japan
Authors: Edahiro Ryuya , Sakata Yasuhiko , Nakatani Daisaku , Suna Shinichiro , Usami Masaya , Matsumoto Sen , Hara Masahiko , Kitamura Tetsuhisa , Sato Hiroshi , Yamashita Shizuya , Nanto Shinsuke , Hikoso Shungo , Sakata Yasushi , Hori Masatsugu , Hamasaki Toshimitsu , Komuro Issei ,   on behalf of the OACIS Investigators
Published: June 2014

ObjectiveThe onset of acute myocardial infarction (AMI) shows characteristic circadian variations involving a definite morning peak and a less-defined night-time peak. However, the factors influencing the circadian patterns of AMI onset and their influence on morning and night-time peaks have not been fully elucidated.Design, setting and participantsAn analysis of patients registered between 1998 and 2008 in the Osaka Acute Coronary Insufficiency Study, which is a prospective, multicentre observational study of patients with AMI in the Osaka region of Japan. The present study included 7755 consecutive patients with a known time of AMI onset.Main outcomes and measuresA mixture of two von Mises distributions was used to examine whether a circadian pattern of AMI had uniform, unimodal or bimodal distribution, and the likelihood ratio test was then used to select the best circadian pattern among them. The hierarchical likelihood ratio test was used to identify factors affecting the circadian patterns of AMI onset. The Kaplan-Meier method was used to estimate survival curves of 1-year mortality according to AMI onset time.ResultsThe overall population had a bimodal circadian pattern of AMI onset characterised by a high and sharp morning peak and a lower and less-defined night-time peak (bimodal p<0.001). Although several lifestyle-related factors had a statistically significant association with the circadian patterns of AMI onset, serum triglyceride levels had the most prominent association with the circadian patterns of AMI onset. Patients with triglyceride ≥150 mg/dL on admission had only one morning peak in the circadian pattern of AMI onset during weekdays, with no peaks detected on weekends, whereas all other subgroups had two peaks throughout the week.ConclusionsThe circadian pattern of AMI onset was characterised by bimodality. Notably, several lifestyle-related factors, particularly serum triglyceride levels, had a strong relation with the circadian pattern of AMI onset.Trial registration numberUMIN000004575.
Marital status and survival after oesophageal cancer surgery: a population-based nationwide cohort study in Sweden
Authors: Brusselaers Nele , Mattsson Fredrik , Johar Asif , Wikman Anna , Lagergren Pernilla , Lagergren Jesper , Ljung Rickard 
Published: June 2014

ObjectivesA beneficial effect of being married on survival has been shown for several cancer types, but is unclear for oesophageal cancer. The objective of this study was to clarify the potential influence of the marital status on the overall and disease-specific survival after curatively intended treatment of oesophageal cancer using a nationwide population-based design, taking into account the known major prognostic variables.DesignProspective, population-based cohort.SettingAll Swedish hospitals performing surgery for oesophageal cancer during 2001–2005.ParticipantsThis study included 90% of all patients with oesophageal or junctional cancer who underwent surgical resection in Sweden in 2001–2005, with follow-up until death or the end of the study period (2012).Primary and secondary outcome measuresCox regression was used to estimate associations between the marital status and the 5-year overall and disease-specific mortality, expressed as HRs with 95% CIs, with adjustment for sex, age, tumour stage, histological type, complications, comorbidities and annual surgeon volume.ResultsOf all 606 included patients (80.4% men), 55.1% were married, 9.2% were remarried, 22.6% were previously married and 13% were never married. Compared with the married patients, the never married (HR 1.02, 95% CI 0.77 to 1.35), previously married (HR 0.90, 95% CI 0.71 to 1.15) and remarried patients (HR 0.79, 95% CI 0.55 to 1.13) had no increased overall 5-year mortality. The corresponding HRs for disease-specific survival, and after excluding the initial 90 days of surgery, were similar to the HRs for the overall survival.ConclusionsThis study showed no evidence of a better 5-year survival in married patients compared with non-married patients undergoing surgery for oesophageal cancer.
Mitigating errors caused by interruptions during medication verification and administration: interventions in a simulated ambulatory chemotherapy setting
Authors: Prakash Varuna , Koczmara Christine , Savage Pamela , Trip Katherine , Stewart Janice , McCurdie Tara , Cafazzo Joseph A , Trbovich Patricia 
Published: June 2014

BackgroundNurses are frequently interrupted during medication verification and administration; however, few interventions exist to mitigate resulting errors, and the impact of these interventions on medication safety is poorly understood.ObjectiveThe study objectives were to (A) assess the effects of interruptions on medication verification and administration errors, and (B) design and test the effectiveness of targeted interventions at reducing these errors.MethodsThe study focused on medication verification and administration in an ambulatory chemotherapy setting. A simulation laboratory experiment was conducted to determine interruption-related error rates during specific medication verification and administration tasks. Interventions to reduce these errors were developed through a participatory design process, and their error reduction effectiveness was assessed through a postintervention experiment.ResultsSignificantly more nurses committed medication errors when interrupted than when uninterrupted. With use of interventions when interrupted, significantly fewer nurses made errors in verifying medication volumes contained in syringes (16/18; 89% preintervention error rate vs 11/19; 58% postintervention error rate; p=0.038; Fisher's exact test) and programmed in ambulatory pumps (17/18; 94% preintervention vs 11/19; 58% postintervention; p=0.012). The rate of error commission significantly decreased with use of interventions when interrupted during intravenous push (16/18; 89% preintervention vs 6/19; 32% postintervention; p=0.017) and pump programming (7/18; 39% preintervention vs 1/19; 5% postintervention; p=0.017). No statistically significant differences were observed for other medication verification tasks.ConclusionsInterruptions can lead to medication verification and administration errors. Interventions were highly effective at reducing unanticipated errors of commission in medication administration tasks, but showed mixed effectiveness at reducing predictable errors of detection in medication verification tasks. These findings can be generalised and adapted to mitigate interruption-related errors in other settings where medication verification and administration are required.
A new clinical cut-off of cytokeratin 19 mRNA copy number in sentinel lymph node better identifies patients eligible for axillary lymph node dissection in breast cancer
Authors: Deambrogio Cristina , Castellano Isabella , Paganotti Alessia , Zorini Elisabetta Omodeo , Corsi Fabio , Bussone Riccardo , Franchini Roberto , Antona Jlenia , Miglio Umberto , Sapino Anna , Antonacci Concetta , Boldorini Renzo 
Published: June 2014

AimsCytokeratin 19 (CK19) mRNA copy number predicts the probability of tumour load in axillary lymph nodes (ALN) and can help in decision-making regarding the axillary dissection. The purpose of this study was to define a new cut-off of CK19 mRNA copy number using the one-step nucleic acid amplification (OSNA) assay on metastatic sentinel lymph nodes (SLN) in order to identify cases at risk of having one or more positive ALN.Methods1296 SLN from 1080 patients were analysed with the OSNA assay. 194 patients with positive SLN underwent ALN dissection and the mean value of CK19 copy number (320 000) of their SLN was set as initial cut-off. Receiver operative characteristics curve identify a best cut-off of 7700 (sensitivity 78%, specificity 57%). A comparison between our and the traditional cut-off (5000) was performed.ResultsThe cut-off of 7700 successfully identifies patients with positive ALN (p=0.001, false- negative cases: 17%). In the range between 5000 and 7700, one patient with positive ALN would not undergo axillary dissection, whereas eight patients with negative ALN would be correctly identified.ConclusionsWe suggest that the level of CK19 mRNA copy number could be the only parameter to consider in the intraoperative management of the axilla.
Drivers of inequality in disability-free expectancy at birth and age 85 across space and time in Great Britain
Authors: Wohland Pia , Rees Phil , Gillies Clare , Alvanides Seraphim , Matthews Fiona E , O'Neill Vikki , Jagger Carol 
Published: June 2014

BackgroundAlthough mortality and health inequalities at birth have increased both geographically and in socioeconomic terms, little is known about inequalities at age 85, the fastest growing sector of the population in Great Britain (GB).AimTo determine whether trends and drivers of inequalities in life expectancy (LE) and disability-free life expectancy (DFLE) at age 85 between 1991 and 2001 are the same as those at birth.MethodsDFLE at birth and age 85 for 1991 and 2001 by gender were calculated for each local authority in GB using the Sullivan method. Regression modelling was used to identify area characteristics (rurality, deprivation, social class composition, ethnicity, unemployment, retirement migration) that could explain inequalities in LE and DFLE.ResultsSimilar to values at birth, LE and DFLE at age 85 both increased between 1991 and 2001 (though DFLE increased less than LE) and gaps across local areas widened (and more for DFLE than LE). The significantly greater increases in LE and DFLE at birth for less-deprived compared with more-deprived areas were still partly present at age 85. Considering all factors, inequalities in DFLE at birth were largely driven by social class composition and unemployment rate, but these associations appear to be less influential at age 85.ConclusionsInequalities between areas in LE and DFLE at birth and age 85 have increased over time though factors explaining inequalities at birth (mainly social class and unemployment rates) appear less important for inequalities at age 85.
An Inducible Hepatocellular Carcinoma Model for Preclinical Evaluation of Antiangiogenic Therapy in Adult Mice
Authors: Runge Anja , Hu Junhao , Wieland Matthias , Bergeest Jan-Philip , Mogler Carolin , Neumann André , Géraud Cyrill , Arnold Bernd , Rohr Karl , Komljenovic Dorde , Schirmacher Peter , Goerdt Sergij , Augustin Hellmut G. 
Published: June 2014

Abstract
The limited availability of experimental tumor models that faithfully mimic the progression of human tumors and their response to therapy remains a major bottleneck to the clinical translation and application of novel therapeutic principles. To address this challenge in hepatocellular carcinoma (HCC), one of the deadliest and most common cancers in the world, we developed and validated an inducible model of hepatocarcinogenesis in adult mice. Tumorigenesis was triggered by intravenous adenoviral delivery of Cre recombinase in transgenic mice expressing the hepatocyte-specific albumin promoter, a loxP-flanked stop cassette, and the SV40 large T-antigen (iAST). Cre recombinase–mediated excision of the stop cassette led to a transient viral hepatitis and resulted in multinodular tumorigenesis within 5 to 8 weeks. Tumor nodules with histologic characteristics of human HCC established a functional vasculature by cooption, remodeling, and angiogenic expansion of the preexisting sinusoidal liver vasculature with increasing signs of vascular immaturity during tumor progression. Treatment of mice with sorafenib rapidly resulted in the induction of vascular regression, inhibition of tumor growth, and enhanced overall survival. Vascular regression was characterized by loss of endothelial cells leaving behind avascular type IV collagen–positive empty sleeves with remaining pericytes. Sorafenib treatment led to transcriptional changes of Igf1, Id1, and cMet over time, which may reflect the emergence of potential escape mechanisms. Taken together, our results established the iAST model of inducible hepatocarcinogenesis as a robust and versatile preclinical model to study HCC progression and validate novel therapies. Cancer Res; 74(15); 4157–69. ©2014 AACR.
Transient Ablation of Regulatory T cells Improves Antitumor Immunity in Colitis-Associated Colon Cancer
Authors: Pastille Eva , Bardini Katrin , Fleissner Diana , Adamczyk Alexandra , Frede Annika , Wadwa Munisch , von Smolinski Dorthe , Kasper Stefan , Sparwasser Tim , Gruber Achim D. , Schuler Martin , Sakaguchi Shimon , Roers Axel , Müller Werner , Hansen Wiebke , Buer Jan , Westendorf Astrid M. 
Published: June 2014

AbstractRegulatory T cells (Treg) are supportive to cancer development in most tissues, but their role in colitis-associated colon cancer (CAC) remains unclear. In this study, we investigated the role of CD4+Foxp3+ Treg in a mouse model of CAC and in patients with colon cancer. These Treg were increased strongly in number in a mouse model of CAC and in the peripheral blood of patients with colon cancer, exhibiting an activated phenotype as defined by elevated expression of GARP, CD103, CTLA-4, and IL10, along with an increased suppressive effect on the proliferation and Th1 cytokine expression of CD4+CD25− responder T cells ex vivo. Transient ablation of CD4+Foxp3+ Treg during tumor development in the CAC model suppressed tumor outgrowth and distribution, accompanied by an increased number of CD8+IFNγ/granzyme B-producing effector T cells. Conversely, inactivation of IL10 in Treg did not elevate the antitumor response but instead further boosted tumor development. Our results establish a tumor-promoting function for Treg during CAC formation, but they also suggest that a selective, transient ablation of Treg can evoke antitumor responses, with implications for immunotherapeutic interventions in patients with CAC. Cancer Res; 74(16); 4258–69. ©2014 AACR.
A Regulatory Loop Involving miR-22, Sp1, and c-Myc Modulates CD147 Expression in Breast Cancer Invasion and Metastasis
Authors: Kong Ling-Min , Liao Cheng-Gong , Zhang Yang , Xu Jing , Li Yu , Huang Wan , Zhang Yi , Bian Huijie , Chen Zhi-Nan 
Published: June 2014

AbstractBreast cancer is the most common cancer in women for which the metastatic process is still poorly understood. CD147 is upregulated in breast cancer and has been associated with tumor progression, but little is known about its regulatory mechanisms. In this study, we demonstrated that CD147 was overexpressed in breast cancer tissues and cell lines, and the high expression correlated with tumor invasion and metastasis. We also found that the transcription factors Sp1 and c-Myc could bind to the CD147 promoter and enhance its expression. The CD147 mRNA has a 748-bp 3′-untranslated region (UTR) with many miRNA target sites, suggesting possible regulation by miRNAs. We discovered that miR-22 repressed CD147 expression by directly targeting the CD147 3′UTR. We also determined that miR-22 could indirectly participate in CD147 modulation by downregulating Sp1 expression. miR-22 could form an autoregulatory loop with Sp1, which repressed miR-22 transcription by binding to the miR-22 promoter. Together with the c-Myc–mediated inhibition of miR-22 expression, our investigation identified a miR-22/Sp1/c-Myc network that regulates CD147 gene transcription. In addition, miR-22 overexpression suppressed breast cancer cell invasion, metastasis, and proliferation by targeting CD147 in vitro and in vivo. Furthermore, we found that miR-22 was significantly downregulated in breast cancer tissues and that its expression was inversely correlated with the tumor–node–metastasis stage and lymphatic metastasis in patients. Our study provides the first evidence that an miR-22/Sp1/c-Myc network regulates CD147 upregulation in breast cancer and that miR-22 represses breast cancer invasive and metastatic capacities. Cancer Res; 74(14); 3764–78. ©2014 AACR.
Hippo Coactivator YAP1 Upregulates SOX9 and Endows Esophageal Cancer Cells with Stem-like Properties
Authors: Song Shumei , Ajani Jaffer A. , Honjo Soichiro , Maru Dipen M. , Chen Qiongrong , Scott Ailing W. , Heallen Todd R. , Xiao Lianchun , Hofstetter Wayne L. , Weston Brian , Lee Jeffrey H. , Wadhwa Roopma , Sudo Kazuki , Stroehlein John R. , Martin James F. , Hung Mien-Chie , Johnson Randy L. 
Published: June 2014

Abstract
Cancer stem cells (CSC) are purported to initiate and maintain tumor growth. Deregulation of normal stem cell signaling may lead to the generation of CSCs; however, the molecular determinants of this process remain poorly understood. Here we show that the transcriptional coactivator YAP1 is a major determinant of CSC properties in nontransformed cells and in esophageal cancer cells by direct upregulation of SOX9. YAP1 regulates the transcription of SOX9 through a conserved TEAD binding site in the SOX9 promoter. Expression of exogenous YAP1 in vitro or inhibition of its upstream negative regulators in vivo results in elevated SOX9 expression accompanied by the acquisition of CSC properties. Conversely, shRNA-mediated knockdown of YAP1 or SOX9 in transformed cells attenuates CSC phenotypes in vitro and tumorigenicity in vivo. The small-molecule inhibitor of YAP1, verteporfin, significantly blocks CSC properties in cells with high YAP1 and a high proportion of ALDH1+. Our findings identify YAP1-driven SOX9 expression as a critical event in the acquisition of CSC properties, suggesting that YAP1 inhibition may offer an effective means of therapeutically targeting the CSC population. Cancer Res; 74(15); 4170–82. ©2014 AACR.
Molecular Pathways: The Basis for Rational Combination Using MEK Inhibitors in KRAS-Mutant Cancers
Authors: Okumura Shunsuke , Jänne Pasi A. 
Published: June 2014

Abstract
Mutations in RAS oncogenes are frequently observed in human cancers, and the mutations result in activation of the RAS–RAF–MEK–ERK pathway, leading to cell proliferation and survival. The pathway is, therefore, a potent therapeutic target in the RAS-mutant cancers. MEK inhibitors can specifically block the pathway and are one of the key types of drugs for the treatment of the RAS-mutant cancers. As RAS proteins activate other downstream signaling proteins in addition to the RAS–RAF–MEK–ERK pathway, combination therapeutic approaches with MEK inhibitors are also being evaluated. Moreover, MEK inhibitors can arrest cancer cells in G1 phase and repress prosurvival Bcl2 family proteins such as MCL1 and BCL2/BCLXL, and increase expression of Bim, a proapoptotic BH3-only family protein. This mechanism may explain the efficacy of the combination of MEK inhibitors with cytotoxic agents or other targeted inhibitors. A better understanding of the pathway will help us with development of rational combinations for the treatment of the RAS-mutant cancers. Clin Cancer Res; 20(16); 4193–9. ©2014 AACR.
Essential Role of Aldehyde Dehydrogenase 1A3 for the Maintenance of Non–Small Cell Lung Cancer Stem Cells Is Associated with the STAT3 Pathway
Authors: Shao Chunli , Sullivan James P. , Girard Luc , Augustyn Alexander , Yenerall Paul , Rodriguez-Canales Jaime , Liu Hui , Behrens Carmen , Shay Jerry W. , Wistuba Ignacio I. , Minna John D. 
Published: June 2014

AbstractPurpose: Lung cancer stem cells (CSC) with elevated aldehyde dehydrogenase (ALDH) activity are self-renewing, clonogenic, and tumorigenic. The purpose of our study is to elucidate the mechanisms by which lung CSCs are regulated.Experimental Design: A genome-wide gene expression analysis was performed to identify genes differentially expressed in the ALDH+ versus ALDH− cells. RT-PCR, Western blot analysis, and Aldefluor assay were used to validate identified genes. To explore the function in CSCs, we manipulated their expression followed by colony and tumor formation assays.Results: We identified a subset of genes that were differentially expressed in common in ALDH+ cells, among which ALDH1A3 was the most upregulated gene in ALDH+ versus ALDH− cells. shRNA-mediated knockdown of ALDH1A3 in non–small cell lung cancer (NSCLC) resulted in a dramatic reduction in ALDH activity, clonogenicity, and tumorigenicity, indicating that ALDH1A3 is required for tumorigenic properties. In contrast, overexpression of ALDH1A3 by itself it was not sufficient to increase tumorigenicity. The ALDH+ cells also expressed more activated STAT3 than ALDH− cells. Inhibition of STAT3 or its activator EZH2 genetically or pharmacologically diminished the level of ALDH+ cells and clonogenicity. Unexpectedly, ALDH1A3 was highly expressed in female, never smokers, well-differentiated tumors, or adenocarcinoma. ALDH1A3 low expression was associated with poor overall survival.Conclusions: Our data show that ALDH1A3 is the predominant ALDH isozyme responsible for ALDH activity and tumorigenicity in most NSCLCs, and that inhibiting either ALDH1A3 or the STAT3 pathway are potential therapeutic strategies to eliminate the ALDH+ subpopulation in NSCLCs. Clin Cancer Res; 20(15); 4154–66. ©2014 AACR.
Polymorphisms of Asparaginase Pathway and Asparaginase-Related Complications in Children with Acute Lymphoblastic Leukemia
Authors: Ben Tanfous Mohsen , Sharif-Askari Bahram , Ceppi Francesco , Laaribi Haithem , Gagné Vincent , Rousseau Julie , Labuda Malgorzata , Silverman Lewis B. , Sallan Stephen E. , Neuberg Donna , Kutok Jeffery L. , Sinnett Daniel , Laverdière Caroline , Krajinovic Maja 
Published: June 2014

AbstractPurpose: Asparaginase (ASNase) is a standard and critical component in the therapy of childhood acute lymphoblastic leukemia (ALL), but it is also associated with several toxicities.Experimental design: We recently reported the results of an association study between ASNase pathway genes and event-free survival (EFS) in childhood patients with ALL. The same polymorphisms were interrogated here in relation to allergies, pancreatitis, and thrombotic events following treatment with E. coli ASNase.Results: Among patients of the discovery group, allergies, and pancreatitis were more frequent in individuals who are homozygous for the triple-repeat allele (3R) of the asparagine synthetase (ASNS) gene, resulting in remarkably higher risk of these toxicities associated with 3R3R genotype [OR for allergies, 14.6; 95% confidence interval (CI), 3.6–58.7; P &lt; 0.0005 and OR for pancreatitis, 8.6; 95% CI, 2.0–37.3; P = 0.01]. In contrast, the ASNS haplotype *1 harboring double-repeat (2R) allele had protective effect against these adverse reactions (P ≤ 0.01). The same haplotype was previously reported to confer reduction in EFS. The risk effect of 3R3R genotype was not replicated in the validation cohort, whereas the protective effect of haplotype *1 against allergies was maintained (P ≤ 0.002). Analysis with additional polymorphisms in ASNS locus in lymphoblastoid cell lines showed that haplotype *1 is diversified in several subtypes of which one was associated with reduced in vitro sensitivity to ASNase (rs10486009, P = 0.01) possibly explaining an association seen in clinical setting.Conclusions: This finding might have implication for treatment individualization in ALL and other cancers using asparagine depletion strategies. Clin Cancer Res; 21(2); 329–34. ©2014 AACR.See related commentary by Avramis, p. 230