bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mortality of babies enrolled in a community-based support programme: CONI PLUS (Care of Next Infant Plus)
Authors: Waite Alison J , Coombs Robert C , McKenzie Angela , Daman-Willems Charlotte , Cohen Marta C , Campbell Michael J , Carpenter Robert G 
Published: January 2015

ObjectiveTo report mortality in babies enrolled on a community-based programme, Care of Next Infant Plus (CONI PLUS), which primarily supports parents anxious because of previous sudden unexpected death in infancy (SUDI) in their extended family or following an apparent life threatening event (ALTE) in their baby.DesignProspective observational study from 1996 to 2010 in the UK.ResultsOf 6487 babies enrolled, 37 died (5.7 per 1000). There were 2789 (43.0%) SUDI related babies of whom, six died suddenly and unexpectedly (2.15 per 1000). Four babies were sharing a sofa at night or a bed with parent(s) who smoked or had consumed alcohol. Of the 1882 (29.0%) babies enrolled following an ALTE, five died suddenly and unexpectedly (2.66 per 1000): four unexplained and one due to infection. None occurred while sharing a sleep surface, and at least three died during the day. The remaining 1816 (28%) babies were enrolled for other reasons. Seven died suddenly and unexpectedly (3.85 per 1000), two were unexplained and none associated with bed sharing.ConclusionsThe number of SUDI deaths in babies enrolled on CONI PLUS is higher than expected from UK averages. Deaths in babies enrolled because of family history of SUDI were mostly associated with inappropriate sharing of a sleep surface at night and mostly outside the peak age range for sudden infant death. The opposite is true for those enrolled following an ALTE. The number of deaths is small but findings suggest a different mechanism for death in these two groups.
NSAIDs, statins, low-dose aspirin and PPIs, and the risk of oesophageal adenocarcinoma among patients with Barrett's oesophagus: a population-based case–control study
Authors: Masclee Gwen M C , Coloma Preciosa M , Spaander Manon C W , Kuipers Ernst J , Sturkenboom Miriam C J M 
Published: January 2015

ObjectivesNon-steroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), low-dose aspirin and statins may decrease the risk of oesophageal adenocarcinoma (OAC) among patients with Barrett's oesophagus (BO). However, previous studies did not adequately address bias and confounding. Our objective was to estimate the risk of OAC among patients with BO exposed to NSAIDs, statins and PPIs.DesignCase–control study nested within a BO cohort.SettingTwo primary care databases (the UK and the Netherlands (NL)).ParticipantsCases were adults ≥18 years of age with OAC or high-grade dysplasia (HGD) diagnosis ≥1 year after BO diagnosis. Controls were matched on age, sex, year of BO diagnosis and database.ExposureDrug use was assessed from BO diagnosis until matching date.Outcome measureAdjusted ORs with 95% CI were calculated by conditional logistic regression.ResultsWithin the BO cohort (n=15 134), 45 OAC (UK: 40, NL: 5) and 12 HGD cases (NL: 12) were identified. ORa for OAC during NSAID use was 1.2 (95% CI 0.6 to 2.5) and during statin use for >3 years 0.5 (95% CI 0.1 to 1.7). When including HGD cases (n=57), ORa for NSAID use was 0.9 (95% CI 0.5 to 1.8) and for statin use >3 years 0.5 (95% CI 0.1 to 1.7). Higher doses of statins showed lower estimates for OAC and HGD, though not statistically significant. Low-dose aspirin and PPIs did not significantly decrease the risk of OAC and HGD.ConclusionsIn this population-based nested case–control study, use of NSAIDs, PPIs, low-dose aspirin or statins did not reduce the risk of HGD and OAC among patients with BO. These findings indicate that for an unselected group of patients with BO chemoprevention by use of drugs to reduce progression to HGD and OAC should not be directly considered as routine care.
A history of diabetes but not hyperglycaemia during exacerbation of obstructive lung disease has impact on long-term mortality: a prospective, observational cohort study
Authors: Koskela Heikki O , Salonen Päivi H , Romppanen Jarkko , Niskanen Leo 
Published: January 2015

ObjectiveHyperglycaemia is very common during exacerbations of asthma and chronic obstructive pulmonary disease (COPD). However, its clinical significance is not clear. The objective of the present study was to assess whether exacerbation-associated hyperglycaemia affects long-term mortality in these patients.DesignA prospective, observational cohort study.SettingA single hospital in eastern Finland.Participants153 consecutive patients who were hospitalised due to mild to moderate obstructive lung disease exacerbation (110 with asthma and 43 with COPD) and who survived at least 30 days.InterventionsPlasma glucose levels were recorded seven times during the first day on the ward. Several possible confounders were also recorded. The median follow-up time was 6 years and 2 months.ResultsDuring the follow-up, 57 (37%) of the patients died. Previously diagnosed diabetes was strongly associated with elevated mortality (adjusted HR (aHR) 3.03 (1.28 to 7.18). The highest fasting glucose value (aHR 1.10 (1.01 to 1.20) per 1 mmol/L) and the highest postprandial glucose value ((aHR 1.07 (1.00 to 1.16)) were also associated with late mortality. However, the associations between highest glucose values and mortality vanished when the diagnosis of diabetes was included in the same model. Within the patients without diabetes, neither fasting (aHR 0.92 (0.42 to 2.02)) nor postprandial ((aHR 1.04 (0.50 to 2.12)) hyperglycaemia was associated with late mortality. There were no statistically significant differences in the underlying causes of death between the patients with and without diabetes.ConclusionA history of diabetes but not hyperglycaemia during exacerbation of obstructive lung disease has impact on long-term mortality.
Influenza vaccination rates for hospitalised patients: a multiyear quality improvement effort
Authors: Cohen Emily Suzanne , Ogrinc Greg , Taylor Tom , Brown Christine , Geiling James 
Published: January 2015

BackgroundInfluenza vaccination is the most effective method for preventing influenza virus infection. Adult hospitalised patients form a particularly high-risk group for severe influenza given their advanced age and comorbidities. We sought to improve the influenza vaccination rates of hospitalised patients at the White River Junction Veterans Affairs Medical Center.MethodsThe improvement effort started in 2007 when our baseline vaccination rate was about 60%. An interprofessional team analysed the influenza vaccination process for hospitalised patients. During the course of six influenza seasons, eight Plan-Do-Study-Act cycles were used including a hospital-wide flu campaign, embedded orders in the electronic medical record (EMR) to facilitate ordering vaccinations by providers, daily reminders from ward clerks and standing orders for influenza vaccination on discharge. The measure was the monthly percentage of patients discharged from the hospital with an up-to-date influenza vaccination.ResultsThe percentage of veterans discharged with an up-to-date influenza vaccination increased to over 80% in February 2009 and has remained high.ConclusionsAlthough we are confident that our local efforts helped to improve the vaccination rate, external factors such as the 2009 H1N1 pandemic and universal vaccination may have primed our system to respond more readily to the implemented changes. Understanding all of the relevant factors that lead to vaccination uptake can be applied to future hospital influenza vaccination campaigns. In addition, our work demonstrates that an interprofessional approach is still required to apply the functionality of the EMR effectively.
Chemotherapy-Induced miRNA-29c/Catenin-δ Signaling Suppresses Metastasis in Gastric Cancer
Authors: Wang Yuxuan , Liu Changzheng , Luo Min , Zhang Zhengyi , Gong Jianan , Li Jingjing , You Lei , Dong Lei , Su Rui , Lin Haishuang , Ma Yanni , Wang Fang , Wang Yi , Chen Jie , Zhang Junwu , Jia Hongyan , Kong Yan , Yu Jia 
Published: January 2015

Abstract
Chemotherapy has improved the survival of patients with gastric cancer by unknown mechanisms. In this study, we showed that cisplatin and docetaxel used in gastric cancer treatment increase the expression of miRNA-29 (miR-29) family members and decrease the expression of their oncogenic targets, mediating a significant part of the efficacious benefits of these chemotherapeutic agents. In particular, patients with gastric cancer who experienced recurrences after chemotherapy tended to exhibit low levels of miR-29c expression in their tumors, suggesting that miR-29c activation may contribute to the chemotherapeutic efficacy. Enforced expression of miR-29s in gastric cancer cells inhibited cell invasion in vitro and in vivo by directly targeting catenin-δ (CTNND1). Drug treatment suppressed gastric cancer cell invasion by restoring miR-29c–mediated suppression of catenin-δ and RhoA signaling. In parallel, drug treatment also activated several tumor-suppressive miRNAs, thereby decreasing expression of their oncogenic effector targets. Overall, our findings defined a global mechanism for understanding the efficacious effects of cytotoxic chemotherapy in gastric cancer. Cancer Res; 75(7); 1332–44. ©2015 AACR.
Prostaglandin E2 Inhibits p53 in Human Breast Adipose Stromal Cells: A Novel Mechanism for the Regulation of Aromatase in Obesity and Breast Cancer
Authors: Wang Xuyi , Docanto Maria M. , Sasano Hironobu ,   Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, Lo Camden , Simpson Evan R. , Brown Kristy A. 
Published: January 2015

Abstract
Obesity is a risk factor for postmenopausal breast cancer and the majority of these cancers are estrogen dependent. Aromatase converts androgens into estrogens and its increased expression in breast adipose stromal cells (ASC) is a major driver of estrogen receptor–positive breast cancer. In particular, obesity-associated and tumor-derived factors, such as prostaglandin E2 (PGE2), have been shown to drive the expression of aromatase by stimulating the activity of the proximal promoter II (PII). The tumor-suppressor p53 is a key regulator of cell-cycle arrest and apoptosis and is frequently mutated in breast cancer. Mutations in p53 are rare in tumor-associated ASCs. Therefore, it was hypothesized that p53 is regulated by PGE2 and involved in the PGE2-mediated regulation of aromatase. Results demonstrate that PGE2 causes a significant decrease in p53 transcript and nuclear protein expression, as well as phosphorylation at Ser15 in primary human breast ASCs. Stabilization of p53 with RITA leads to a significant decrease in the PGE2-stimulated aromatase mRNA expression and activity, and PII activity. Interaction of p53 with PII was demonstrated and this interaction is decreased in the presence of PGE2. Moreover, mutation of the identified p53 response element leads to an increase in the basal activity of the promoter. Immunofluorescence on clinical samples demonstrates that p53 is decreased in tumor-associated ASCs compared with ASCs from normal breast tissue, and that there is a positive association between perinuclear (inactive) p53 and aromatase expression in these cells. Furthermore, aromatase expression is increased in breast ASCs from Li–Fraumeni patients (germline TP53 mutations) compared with non-Li–Fraumeni breast tissue. Overall, our results demonstrate that p53 is a negative regulator of aromatase in the breast and its inhibition by PGE2 provides a novel mechanism for aromatase regulation in obesity and breast cancer. Cancer Res; 75(4); 645–55. ©2015 AACR.
Emerging Links between E2F Control and Mitochondrial Function
Authors: Benevolenskaya Elizaveta V. , Frolov Maxim V. 
Published: January 2015

Abstract
The family of E2F transcription factors is the key downstream target of the retinoblastoma tumor suppressor protein (pRB), which is frequently inactivated in human cancer. E2F is best known for its role in cell-cycle regulation and triggering apoptosis. However, E2F binds to thousands of genes and, thus, could directly influence a number of biologic processes. Given the plethora of potential E2F targets, the major challenge in the field is to identify specific processes in which E2F plays a functional role and the contexts in which a particular subset of E2F targets dictates a biologic outcome. Recent studies implicated E2F in regulation of expression of mitochondria-associated genes. The loss of such regulation results in severe mitochondrial defects. The consequences become evident during irradiation-induced apoptosis, where E2F-deficient cells are insensitive to cell death despite induction of canonical apoptotic genes. Thus, this novel function of E2F may have a major impact on cell viability, and it is independent of induction of apoptotic genes. Here, we discuss the implications of these findings in cancer biology. Cancer Res; 75(4); 619–23. ©2015 AACR.
Evolutionary Action Score ofTP53Identifies High-Risk Mutations Associated with Decreased Survival and Increased Distant Metastases in Head and Neck Cancer
Authors: Neskey David M. , Osman Abdullah A. , Ow Thomas J. , Katsonis Panagiotis , McDonald Thomas , Hicks Stephanie C. , Hsu Teng-Kuei , Pickering Curtis R. , Ward Alexandra , Patel Ameeta , Yordy John S. , Skinner Heath D. , Giri Uma , Sano Daisuke , Story Michael D. , Beadle Beth M. , El-Naggar Adel K. , Kies Merrill S. , William William N. , Caulin Carlos , Frederick Mitchell , Kimmel Marek , Myers Jeffrey N. , Lichtarge Olivier 
Published: January 2015

AbstractTP53 is the most frequently altered gene in head and neck squamous cell carcinoma, with mutations occurring in over two-thirds of cases, but the prognostic significance of these mutations remains elusive. In the current study, we evaluated a novel computational approach termed evolutionary action (EAp53) to stratify patients with tumors harboring TP53 mutations as high or low risk, and validated this system in both in vivo and in vitro models. Patients with high-risk TP53 mutations had the poorest survival outcomes and the shortest time to the development of distant metastases. Tumor cells expressing high-risk TP53 mutations were more invasive and tumorigenic and they exhibited a higher incidence of lung metastases. We also documented an association between the presence of high-risk mutations and decreased expression of TP53 target genes, highlighting key cellular pathways that are likely to be dysregulated by this subset of p53 mutations that confer particularly aggressive tumor behavior. Overall, our work validated EAp53 as a novel computational tool that may be useful in clinical prognosis of tumors harboring p53 mutations. Cancer Res; 75(7); 1527–36. ©2015 AACR.
GOLPH3 Links the Golgi, DNA Damage, and Cancer
Authors: Buschman Matthew D. , Rahajeng Juliati , Field Seth J. 
Published: January 2015

Abstract
GOLPH3 is the first example of an oncogene that functions in secretory trafficking at the Golgi. The discovery of GOLPH3′s roles in both cancer and Golgi trafficking raises questions about how GOLPH3 and the Golgi contribute to cancer. Our recent investigation of the regulation of GOLPH3 revealed a surprising response by the Golgi upon DNA damage that is mediated by DNA-PK and GOLPH3. These results provide new insight into the DNA damage response with important implications for understanding the cellular response to standard cancer therapeutic agents. Cancer Res; 75(4); 624–7. ©2015 AACR.
Loss of SOD3 (EcSOD) Expression Promotes an Aggressive Phenotype in Human Pancreatic Ductal Adenocarcinoma
Authors: O'Leary Brianne R. , Fath Melissa A. , Bellizzi Andrew M. , Hrabe Jennifer E. , Button Anna M. , Allen Bryan G. , Case Adam J. , Altekruse Sean , Wagner Brett A. , Buettner Garry R. , Lynch Charles F. , Hernandez Brenda Y. , Cozen Wendy , Beardsley Robert A. , Keene Jeffery , Henry Michael D. , Domann Frederick E. , Spitz Douglas R. , Mezhir James J. 
Published: January 2015

Abstract
Purpose: Pancreatic ductal adenocarcinoma (PDA) cells are known to produce excessive amounts of reactive oxygen species (ROS), particularly superoxide, which may contribute to the aggressive and refractory nature of this disease. Extracellular superoxide dismutase (EcSOD) is an antioxidant enzyme that catalyzes the dismutation of superoxide in the extracellular environment. This study tests the hypothesis that EcSOD modulates PDA growth and invasion by modifying the redox balance in PDA.
Experimental Design: We evaluated the prognostic significance of EcSOD in a human tissue microarray (TMA) of patients with PDA. EcSOD overexpression was performed in PDA cell lines and animal models of disease. The impact of EcSOD on PDA cell lines was evaluated with Matrigel invasion in combination with a superoxide-specific SOD mimic and a nitric oxide synthase (NOS) inhibitor to determine the mechanism of action of EcSOD in PDA.
Results: Loss of EcSOD expression is a common event in PDA, which correlated with worse disease biology. Overexpression of EcSOD in PDA cell lines resulted in decreased invasiveness that appeared to be related to reactions of superoxide with nitric oxide. Pancreatic cancer xenografts overexpressing EcSOD also demonstrated slower growth and peritoneal metastasis. Overexpression of EcSOD or treatment with a superoxide-specific SOD mimic caused significant decreases in PDA cell invasive capacity.
Conclusions: These results support the hypothesis that loss of EcSOD leads to increased reactions of superoxide with nitric oxide, which contributes to the invasive phenotype. These results allow for the speculation that superoxide dismutase mimetics might inhibit PDA progression in human clinical disease. Clin Cancer Res; 21(7); 1741–51. ©2015 AACR.
Cleaved NOTCH1 Expression Pattern in Head and Neck Squamous Cell Carcinoma Is Associated with NOTCH1 Mutation, HPV Status, and High-Risk Features
Authors: Rettig Eleni M. , Chung Christine H. , Bishop Justin A. , Howard Jason D. , Sharma Rajni , Li Ryan J. , Douville Christopher , Karchin Rachel , Izumchenko Evgeny , Sidransky David , Koch Wayne , Califano Joseph , Agrawal Nishant , Fakhry Carole 
Published: January 2015

Abstract
The Notch pathway is frequently altered in head and neck squamous cell carcinomas (HNSCC); however, the clinical significance of NOTCH1 dysregulation is poorly understood. This study was designed to characterize expression of the transcriptionally active NOTCH1 intracellular domain (NICD1) in HNSCCs and evaluate its association with NOTCH1 mutation status and clinical parameters. IHC for NICD1 was performed on 79 previously sequenced archival HNSCCs with known NOTCH1 mutation status. Three distinct immunohistochemical staining patterns were identified: positive/peripheral (47%), positive/nonperipheral (34%), and negative (19%). NICD1 expression was associated with NOTCH1 mutation status (P &lt; 0.001). Most NOTCH1–wild-type tumors were peripheral (55%), whereas mutated NOTCH1 tumors were most commonly negative (47%). Nonperipheral tumors were more likely than peripheral tumors to have extracapsular spread [adjusted odds ratio (aOR), 16.01; 95% confidence interval (CI), 1.92–133.46; P = 0.010] and poor differentiation (aOR, 5.27; 95% CI, 0.90–30.86; P = 0.066). Negative staining tumors tended to be poorly differentiated (aOR, 24.71; 95% CI, 1.53–399.33; P = 0.024) and were less likely to be human papillomavirus (HPV) positive (aOR, 0.043; 95% CI, 0.001–1.59; P = 0.087). NOTCH1 mutagenesis was significantly associated with HPV status, with NOTCH1–wild-type tumors more likely to be HPV positive than NOTCH1-mutated tumors (aOR, 19.06; 95% CI, 1.31–276.15; P = 0.031). TP53 disruptive mutations were not associated with NICD1 expression or NOTCH1 mutation. In conclusion, NICD1 is expressed in three distinct patterns in HNSCC that are significantly associated with high-risk features. These findings further support a dual role for NOTCH1 as both tumor suppressor and oncogene in HNSCC. Further research is necessary to clarify the role of NOTCH1 in HNSCC and understand the clinical and therapeutic implications therein. Cancer Prev Res; 8(4); 287–95. ©2015 AACR.
Resiquimod as an Immunologic Adjuvant for NY-ESO-1 Protein Vaccination in Patients with High-Risk Melanoma
Authors: Sabado Rachel Lubong , Pavlick Anna , Gnjatic Sacha , Cruz Crystal M. , Vengco Isabelita , Hasan Farah , Spadaccia Meredith , Darvishian Farbod , Chiriboga Luis , Holman Rose Marie , Escalon Juliet , Muren Caroline , Escano Crystal , Yepes Ethel , Sharpe Dunbar , Vasilakos John P. , Rolnitzsky Linda , Goldberg Judith D. , Mandeli John , Adams Sylvia , Jungbluth Achim , Pan Linda , Venhaus Ralph , Ott Patrick A. , Bhardwaj Nina 
Published: January 2015

Abstract
The Toll-like receptor (TLR) 7/8 agonist resiquimod has been used as an immune adjuvant in cancer vaccines. We evaluated the safety and immunogenicity of the cancer testis antigen NY-ESO-1 given in combination with Montanide (Seppic) with or without resiquimod in patients with high-risk melanoma. In part I of the study, patients received 100 μg of full-length NY-ESO-1 protein emulsified in 1.25 mL of Montanide (day 1) followed by topical application of 1,000 mg of 0.2% resiquimod gel on days 1 and 3 (cohort 1) versus days 1, 3, and 5 (cohort 2) of a 21-day cycle. In part II, patients were randomized to receive 100-μg NY-ESO-1 protein plus Montanide (day 1) followed by topical application of placebo gel [(arm A; n = 8) or 1,000 mg of 0.2% resiquimod gel (arm B; n = 12)] using the dosing regimen established in part I. The vaccine regimens were generally well tolerated. NY-ESO-1–specific humoral responses were induced or boosted in all patients, many of whom had high titer antibodies. In part II, 16 of 20 patients in both arms had NY-ESO-1–specific CD4+ T-cell responses. CD8+ T-cell responses were only seen in 3 of 12 patients in arm B. Patients with TLR7 SNP rs179008 had a greater likelihood of developing NY-ESO-1–specific CD8+ responses. In conclusion, NY-ESO-1 protein in combination with Montanide with or without topical resiquimod is safe and induces both antibody and CD4+ T-cell responses in the majority of patients; the small proportion of CD8+ T-cell responses suggests that the addition of topical resiquimod to Montanide is not sufficient to induce consistent NY-ESO-1–specific CD8+ T-cell responses. Cancer Immunol Res; 3(3); 278–87. ©2015 AACR.
Tyrosine Kinase Receptor B Protects Against Coronary Artery Disease and Promotes Adult Vasculature Integrity by Regulating Ets1-Mediated VE-Cadherin Expression
Authors: Jiang Hong , Huang Shuhong , Li Xinyun , Li Xian , Zhang Yun , Chen Zhe-Yu 
Published: January 2015

Objective—
Tyrosine kinase receptor B (TrkB) is a high-affinity receptor for brain-derived neurotrophic factor. In addition to its nervous system functions, TrkB is also expressed in the cardiovascular system. However, the association of TrkB and coronary artery disease (CAD) remains unknown. We investigated the role of TrkB in the development of CAD and its mechanism.

Approach and Results—

We performed a case–control study in 2 independent cohort of Chinese subjects and found –69C>G polymorphisms of TrkB gene significantly associated with CAD. TrkB –69C homozygotes, which corresponded to decreased TrkB expression by luciferase reporter assay, showed increased risk for CAD. Immunofluorescence analysis revealed that TrkB was expressed in the aortic endothelium in atherosclerotic lesions in humans and ApoE
–/–
mice. TrkB knockdown in the aortic endothelium resulted in vascular leakage in ApoE
–/–
mice. Mechanistic studies showed that TrkB regulated vascular endothelial cadherin (VE-cadherin) expression through induction and activation of Ets1 transcriptional factor. Importantly, TrkB activation attenuated proatherosclerotic factors induced-endothelial hyperpermeability in human vascular endothelial cells.

Conclusions—
Our data demonstrate that TrkB protects endothelial integrity during atherogenesis by promoting Ets1-mediated VE-cadherin expression and plays a previously unknown protective role in the development of CAD.