bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Role of Protein Kinase A Regulation of the E6 PDZ-Binding Domain during the Differentiation-Dependent Life Cycle of Human Papillomavirus Type 18
Authors: Delury Craig P. , Marsh Elizabeth K. , James Claire D. , Boon Siaw Shi , Banks Lawrence , Knight Gillian L. , Roberts Sally 
Published: June 2013

ABSTRACT
Human papillomavirus (HPV) E6 proteins of high-risk alpha types target a select group of PSD95/DLG1/ZO1 (PDZ) domain-containing proteins by using a C-terminal PDZ-binding motif (PBM), an interaction that can be negatively regulated by phosphorylation of the E6 PBM by protein kinase A (PKA). Here, we have mutated the canonical PKA recognition motif that partially overlaps with the E6 PBM in the HPV18 genome (E6153PKA) and compared the effect of this mutation on the HPVl8 life cycle in primary keratinocytes with the wild-type genome and with a second mutant genome that lacks the E6 PBM (E6ΔPDZ). Loss of PKA recognition of E6 was associated with increased growth of the genome-containing cells relative to cells carrying the wild-type genome, and upon stratification, a more hyperplastic phenotype, with an increase in the number of S-phase competent cells in the upper suprabasal layers, while the opposite was seen with the E6ΔPDZ genome. Moreover, the growth of wild-type genome-containing cells was sensitive to changes in PKA activity, and these changes were associated with increased phosphorylation of the E6 PBM. In marked contrast to E6ΔPDZ genomes, the E6153PKA mutation exhibited no deleterious effects on viral genome amplification or expression of late proteins. Our data suggest that the E6 PBM function is differentially regulated by phosphorylation in the HPV18 life cycle. We speculate that perturbation of protein kinase signaling pathways could lead to changes in E6 PBM function, which in turn could have a bearing on tumor promotion and progression.
Interferon Regulatory Factor 4 Is Activated through c-Src-Mediated Tyrosine Phosphorylation in Virus-Transformed Cells
Authors: Wang Ling , Ning Shunbin 
Published: June 2013

ABSTRACT
The importance of the oncogenic transcription factor interferon regulatory factor 4 (IRF4) in hematological malignancies has been increasingly recognized. We have previously identified the B cell integration cluster (BIC), the gene encoding miR-155, as the first microRNA (miRNA)-encoding gene transcriptionally targeted by IRF4 in virus-transformed cancer cells. Activation of IRFs is prerequisite for their functions. However, how IRF4 is activated in cancer is an open question. Our phosphoproteome profiling has identified several tyrosine phosphorylation sites on IRF4 in Epstein-Barr virus (EBV)-transformed cells. Further, we show here that c-Src dramatically stimulates IRF4 phosphorylation and activity and that Y61 and Y124 are two key sites responding to c-Src-mediated activation. Consistently, c-Src is constitutively expressed and active in EBV-transformed cells. However, c-Src is unlikely to be a direct kinase for IRF4. Furthermore, we have a polyclonal antibody specific to phospho-IRF4(Y121/124) developed in rabbit. We have further shown that inhibition of c-Src activity reduces p-IRF4(Y121/124) and significantly represses transcription of the IRF4 target BIC in EBV-transformed cells. Our results therefore, for the first time, demonstrate that IRF4 is phosphorylated and activated through a c-Src-mediated pathway in virus-transformed cells. These findings will improve our understanding of IRF4 in neoplasia and will provide profound insights into the interaction of oncogenic viruses with IRF4 in the development of hematological malignancies.
Chronic traumatic encephalopathy in sport: a systematic review
Authors: Gardner Andrew , Iverson Grant L , McCrory Paul 
Published: June 2013

ObjectiveTo provide a critical review of chronic traumatic encephalopathy (CTE) by considering the range of clinical presentations, neuropathology and the strength of evidence for CTE as a distinct syndrome.Data sourcesSeven electronic databases were searched using a combination of MeSH terms and key words to identify relevant articles.Review methodsSpecific inclusion and exclusion criteria were used to select studies for review. Data extracted where present included study population, exposure/outcome measures, clinical data, neurological examination findings, cognitive assessment, investigation results and neuropathology results.ResultsThe data from 158 published case studies were reviewed. Critical differences between the older descriptions of CTE (the ‘classic’ syndrome) and the recent descriptions (the ‘modern’ syndrome) exist in the age of onset, natural history, clinical features, pathological findings and diagnostic criteria, which suggests that modern CTE is a different syndrome. The methodology of the current studies does not allow determination of aetiology or risk factors.ConclusionsThe clinicopathological differences between the ‘classic’ CTE syndrome and the ‘modern’ syndrome suggest that the new syndrome needs a different nomenclature. Further research is required to clearly define the clinical phenotype of the modern CTE syndrome and establish the underlying aetiology. Future research needs to address these issues through large-scale, prospective clinicopathological studies.
National trends in hospital-acquired preventable adverse events after major cancer surgery in the USA
Authors: Sukumar Shyam , Roghmann Florian , Trinh Vincent Q , Sammon Jesse D , Gervais Mai-Kim , Tan Hung-Jui , Ravi Praful , Kim Simon P , Hu Jim C , Karakiewicz Pierre I , Noldus Joachim , Sun Maxine , Menon Mani , Trinh Quoc-Dien 
Published: June 2013

ObjectivesWhile multiple studies have demonstrated variations in the quality of cancer care in the USA, payers are increasingly assessing structure-level and process-level measures to promote quality improvement. Hospital-acquired adverse events are one such measure and we examine their national trends after major cancer surgery.DesignRetrospective, cross-sectional analysis of a weighted-national estimate from the Nationwide Inpatient Sample (NIS) undergoing major oncological procedures (colectomy, cystectomy, oesophagectomy, gastrectomy, hysterectomy, lung resection, pancreatectomy and prostatectomy). The Agency for Healthcare Research and Quality Patient Safety Indicators (PSIs) were utilised to identify trends in hospital-acquired adverse events.SettingSecondary and tertiary care, US hospitals in NISParticipantsA weighted-national estimate of 2 508 917 patients (>18 years, 1999–2009) from NIS.Primary outcome measuresHospital-acquired adverse events.Results324 852 patients experienced ≥1-PSI event (12.9%). Patients with ≥1-PSI experienced higher rates of in-hospital mortality (OR 19.38, 95% CI 18.44 to 20.37), prolonged length of stay (OR 4.43, 95% CI 4.31 to 4.54) and excessive hospital-charges (OR 5.21, 95% CI 5.10 to 5.32). Patients treated at lower volume hospitals experienced both higher PSI eventsandfailure-to-rescue rates. While a steady increase in the frequency of PSI events after major cancer surgery has occurred over the last 10 years (estimated annual % change (EAPC): 3.5%, p<0.001), a concomitant decrease in failure-to-rescue rates (EAPC −3.01%) and overall mortality (EAPC −2.30%) was noted (all p<0.001).ConclusionsOver the past decade, there has been a substantial increase in the national frequency of potentially avoidable adverse events after major cancer surgery, with a detrimental effect on numerous outcome-level measures. However, there was a concomitant reduction in failure-to-rescue rates and overall mortality rates. Policy changes to improve the increasing burden of specific adverse events, such as postoperative sepsis, pressure ulcers and respiratory failure, are required.
Reprogramming the Chromatin Landscape: Interplay of the Estrogen and Glucocorticoid Receptors at the Genomic Level
Authors: Miranda Tina B. , Voss Ty C. , Sung Myong-Hee , Baek Songjoon , John Sam , Hawkins Mary , Grøntved Lars , Schiltz R. Louis , Hager Gordon L. 
Published: June 2013

Abstract
Cross-talk between estrogen receptors (ER) and glucocorticoid receptors (GR) has been shown to contribute to the development and progression of breast cancer. Importantly, the ER and GR status in breast cancer cells is a significant factor in determining the outcome of the disease. However, mechanistic details defining the cellular interactions between ER and GR are poorly understood. We investigated genome-wide binding profiles for ER and GR upon coactivation and characterized the status of the chromatin landscape. We describe a novel mechanism dictating the molecular interplay between ER and GR. Upon induction, GR modulates access of ER to specific sites in the genome by reorganization of the chromatin configuration for these elements. Binding to these newly accessible sites occurs either by direct recognition of ER response elements or indirectly through interactions with other factors. The unveiling of this mechanism is important for understanding cellular interactions between ER and GR and may represent a general mechanism for cross-talk between nuclear receptors in human disease. Cancer Res; 73(16); 5130–9. ©2013 AACR.
Acquired Resistance to Anti-VEGF Therapy in Glioblastoma Is Associated with a Mesenchymal Transition
Authors: Piao Yuji , Liang Ji , Holmes Lindsay , Henry Verlene , Sulman Erik , de Groot John F. 
Published: June 2013

Abstract
Purpose: Antiangiogenic therapy reduces vascular permeability and delays progression but may ultimately promote an aggressive treatment-resistant phenotype. The aim of the present study was to identify mechanisms responsible for glioblastoma resistance to antiangiogenic therapy.
Experimental Design: Glioma stem cell (GSC) NSC11 and U87 cell lines with acquired resistance to bevacizumab were developed from orthotopic xenografts in nude mice treated with bevacizumab. Genome-wide analyses were used to identify changes in tumor subtype and specific factors associated with resistance.
Results: Mice with established parental NSC11 and U87 cells responded to bevacizumab, whereas glioma cell lines derived at the time of acquired resistance to anti-VEGF therapy were resistant to bevacizumab and did not have prolongation of survival compared with untreated controls. Gene expression profiling comparing anti-VEGF therapy-resistant cell lines to untreated controls showed an increase in genes associated with a mesenchymal origin, cellular migration/invasion, and inflammation. Gene-set enrichment analysis showed that bevacizumab-treated tumors showed a highly significant correlation to published mesenchymal gene signatures. Mice bearing resistant tumors showed significantly greater infiltration of myeloid cells in NSC11- and U87-resistant tumors. Invasion-related genes were also upregulated in both NSC11 and U87 resistant cells which had higher invasion rates in vitro compared with their respective parental cell lines.
Conclusions: Our studies identify multiple proinflammatory factors associated with resistance and identify a proneural to mesenchymal transition in tumors resistant to antiangiogenic therapy. Clin Cancer Res; 19(16); 4392–403. ©2013 AACR.
β-Mannosylceramide Activates Type I Natural Killer T Cells to Induce Tumor Immunity without Inducing Long-Term Functional Anergy
Authors: O'Konek Jessica J. , Kato Shingo , Takao Satomi , Izhak Liat , Xia Zheng , Illarionov Petr , Besra Gurdyal S. , Terabe Masaki , Berzofsky Jay A. 
Published: June 2013

Abstract
Purpose: Most studies characterizing antitumor properties of invariant natural killer T (iNKT) cells have used the agonist, α-galactosylceramide (α-GalCer). However, α-GalCer induces strong, long-lasting anergy of iNKT cells, which could be a major detriment for clinical therapy. A novel iNKT cell agonist, β-mannosylceramide (β-ManCer), induces strong antitumor immunity through a mechanism distinct from that of α-GalCer. The objective of this study was to determine whether β-ManCer induces anergy of iNKT cells.
Experimental Design: Induction of anergy was determined by ex vivo analysis of splenocytes from mice pretreated with iNKT cell agonists as well as in the CT26 lung metastasis in vivo tumor model.
Results: β-ManCer activated iNKT cells without inducing long-term anergy. The transience of anergy induction correlated with a shortened duration of PD-1 upregulation on iNKT cells activated with β-ManCer, compared with α-GalCer. Moreover, whereas mice pretreated with α-GalCer were unable to respond to a second glycolipid stimulation to induce tumor protection for up to 2 months, mice pretreated with β-ManCer were protected from tumors by a second stimulation equivalently to vehicle-treated mice.
Conclusions: The lack of long-term functional anergy induced by β-ManCer, which allows for a second dose to still give therapeutic benefit, suggests the strong potential for this iNKT cell agonist to succeed in settings where α-GalCer has failed. Clin Cancer Res; 19(16); 4404–11. ©2013 AACR.
Sulindac Selectively Inhibits Colon Tumor Cell Growth by Activating the cGMP/PKG Pathway to Suppress Wnt/β-Catenin Signaling
Authors: Li Nan , Xi Yaguang , Tinsley Heather N. , Gurpinar Evrim , Gary Bernard D. , Zhu Bing , Li Yonghe , Chen Xi , Keeton Adam B. , Abadi Ashraf H. , Moyer Mary P. , Grizzle William E. , Chang Wen-Chi , Clapper Margie L. , Piazza Gary A. 
Published: June 2013

Abstract
Nonsteroidal anti-inflammatory drugs (NSAID) display promising antineoplastic activity for colorectal and other cancers, but toxicity from COX inhibition limits their long-term use for chemoprevention. Previous studies have concluded that the basis for their tumor cell growth inhibitory activity does not require COX inhibition, although the underlying mechanism is poorly understood. Here, we report that the NSAID sulindac sulfide inhibits cyclic guanosine 3′,5′-monophosphate phosphodiesterase (cGMP PDE) activity to increase intracellular cGMP levels and activate cGMP-dependent protein kinase (PKG) at concentrations that inhibit proliferation and induce apoptosis of colon tumor cells. Sulindac sulfide did not activate the cGMP/PKG pathway, nor affect proliferation or apoptosis in normal colonocytes. Knockdown of the cGMP-specific PDE5 isozyme by siRNA and PDE5-specific inhibitors tadalafil and sildenafil also selectively inhibited the growth of colon tumor cells that expressed high levels of PDE5 compared with colonocytes. The mechanism by which sulindac sulfide and the cGMP/PKG pathway inhibits colon tumor cell growth involves the transcriptional suppression of β-catenin to inhibit Wnt/β-catenin T-cell factor transcriptional activity, leading to downregulation of cyclin D1 and survivin. These observations suggest that safer and more efficacious sulindac derivatives can be developed for colorectal cancer chemoprevention by targeting PDE5 and possibly other cGMP-degrading isozymes. Mol Cancer Ther; 12(9); 1848–59. ©2013 AACR.
A Prospective Analysis of Body Size during Childhood, Adolescence, and Adulthood and Risk of Non-Hodgkin Lymphoma
Authors: Bertrand Kimberly A. , Giovannucci Edward , Zhang Shumin M. , Laden Francine , Rosner Bernard , Birmann Brenda M. 
Published: June 2013

AbstractThe etiology of non-Hodgkin lymphoma (NHL) is poorly understood. Obesity is associated with inflammation, a cytokine milieu conducive to lymphocyte proliferation, and has been associated with NHL risk in some epidemiologic studies. To prospectively examine NHL risk in relation to adult and earlier life obesity, we documented 635 incident NHL diagnoses among 46,390 men in the Health Professionals Follow-up Study and 1,254 diagnoses among 116,794 women in the Nurses' Health Study over 22 to 32 years of follow-up. Using multivariable Cox proportional hazards models, we estimated cohort-specific incidence rate ratios (RR) and 95% confidence intervals (CI) for risk of NHL and major histologic subtypes associated with cumulative average middle and young adult (ages, 18–21 years) body mass index (BMI) and adolescent and childhood somatotype. NHL risk was modestly increased in men (but not women) with a cumulative average middle adult BMI ≥ 30 kg/m2 (vs. 15–22.9 kg/m2; RR, 1.28; 95% CI, 0.92–1.77; Ptrend = 0.05). In meta-analyses across cohorts, higher young adult BMI was associated with increased risk of all NHL (pooled RR per 5 kg/m2, 1.19; 95% CI, 1.05–1.37), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma (all Ptrend ≤ 0.02). Adolescent somatotype was also positively associated with all NHL, DLBCL, and follicular lymphoma in pooled analyses (all Ptrend ≤ 0.03), whereas childhood somatotype was positively associated with NHL overall among women only (Ptrend &lt; 0.01). These findings in two large prospective cohorts provide novel evidence that larger body size in childhood, adolescence, and young adulthood predicts increased risk of NHL, and particularly of DLBCL and follicular lymphoma. Cancer Prev Res; 6(8); 864–73. ©2013 AACR.
Body mass index, a major confounder to insulin resistance association with unprovoked venous thromboembolism
Authors: Moreuil Claire De , Kerspern Hélène , Le Moigne Emmanuelle , Mottier Dominique , Tromeur Cécile , Carre Jean-Luc , Le Gal Grégoire , Lacut Karine , Delluc Aurélien 
Published: June 2013

SummaryShared risk factors help explain the association between venous thromboembolism (VTE) and atherothrombosis. The potential association between insulin resistance and VTE has been poorly evaluated. Thus, we aimed to assess the association between insulin resistance and VTE in the EDITH hospital-based case-control study. Between May 2000 and December 2004, 677 patients with unprovoked VTE and their age- and sex-matched controls were included. Fasting glycaemia and insulinaemia were measured and insulin resistance was estimated with the homeostasis model assessment of insulin resistance (HOMAIR) equation. The association between HOMA-IR and VTE was determined in non-diabetic patients in a quintile-based analysis. A total of 590 non-diabetic cases (median age 73.0 years, 255 men) and 581 non-diabetic controls (median age 72.0 years, 247 men) were analysed. There was a trend for a higher median level of HOMA-IR index in cases than in controls (1.21 [interquartile range 0.84-2.10] vs 1.19 [interquartile range 0.72-2.02], p=0.08). The unadjusted analysis showed an increased risk of unprovoked VTE associated with increasing HOMA-IR (odds ratio [OR] 1.53; 95% confidence interval [CI] 1.00-2.34 for the highest quintile of HOMA-IR compared with the first quintile). Adjustment for lipid lowering drugs and antiplatelet agents use slightly modified the association (OR 1.51; 95% CI 0.97-2.34). When body mass index was added in the adjusted model, HOMA-IR was no longer associated with VTE (OR 1.08; 95% CI 0.67-1.73). Our results highlight the role of body mass index in the association between cardiovascular risk factors and VTE.
Impact of intravenous heparin on quantification of circulating microRNAs in patients with coronary artery disease
Authors: Kaudewitz Dorothee , Lee Regent , Willeit Peter , McGregor Reuben , Markus Hugh S. , Kiechl Stefan , Zampetaki Anna , Storey Robert F. , Channon Keith M. , Mayr Manuel 
Published: June 2013

SummaryMicroRNAs are small non-coding RNAs that are detectable in plasma and serum. Circulating levels of microRNAs have been measured in various studies related to cardiovascular disease. Heparin is a potential confounder of microRNA measurements due to its known interference with polymerase chain reactions. In this study, platelet-poor plasma was obtained from patients undergoing cardiac catheterisation for diagnostic coronary angiography, or for percutaneous coronary intervention, both before and after heparin administration. Heparin had pronounced effects on the assessment of the exogenous C. elegans spike-in control (decrease by approx. 3 cycles), which disappeared 6 hours after the heparin bolus. Measurements of endogenous microRNAs were less sensitive to heparin medication. Normalisation of individual microRNAs with the average cycle threshold value of all microRNAs provided a suitable alternative to normalisation with exogenous C. elegans spike-in control in this setting. Thus, both the timing of blood sampling relative to heparin dosing and the normalisation procedure are critical for reliable microRNA measurements in patients receiving intravenous heparin. This has to be taken into account when designing studies to investigate the relation of circulating microRNAs to acute cardiovascular events or coronary intervention.
Francisco de Vitoria’s Unexpected Transformations and Reinterpretations for International Law
Authors: del Moral Ignacio de la Rasilla 
Published: June 2013

Abstract
A review of some of the legacies of Vitoria for international legal scholarship accompanies, in the first part, a retrospective gaze at the first third of the Twentieth century, in order to examine how the founder of the American Society of International Law, James Brown Scott, contributed to (re)establish Vitoria as the father of international law in the inter-war years. The second part provides a genealogy of the critical front of the Vitorian revival in international law today. Special attention is, then, paid to some of the intellectual building-blocks and programmatic tenets which have inspired a Third World Approaches to International Law (TWAIL) anti-imperial narrative of the international legal order along with a TWAIL’s re-interpretation and re-contextualisation of the works of the sixteenth century’s Prima professor of Sacred Theology at the University of Salamanca. The conclusion reflects on the lasting legacy of the Spanish Classics in the American tradition of international law.
The Interface between Non-governmental Organisations and the Human Rights Committee
Authors: Lintel Ida , Ryngaert Cedric 
Published: June 2013

Abstract
Non-governmental organisations (NGOs) are participating increasingly in the multifaceted work of the Human Rights Committee (HRC), which monitors the implementation of the International Covenant on Civil and Political Rights (ICCPR). In particular, they have supplied shadow reports, provided input for the Committee’s general comments, and have supported individuals filing communications with the Committee. In so doing, they have eroded the central role of the State in the various HRC procedures, have enriched the sources on which the HRC can draw, and have contributed considerably to the effectiveness and legitimacy of the Committee’s work. Still, some improvements can be made to NGOs’ participation, such as the introduction of greater transparency in NGO reporting and increased cooperation and coordination between the various NGOs.
The “Reservations Dialogue” as a Constitution-Making Process
Authors: Yahyaoui Krivenko Ekaterina 
Published: June 2013

Abstract
The article proposes a new reading of the reservations regime to human rights treaties. The practice developed by states in relation to the reservations regime is analysed and presented as a constitution-making process. This new vision is based on the notion of the reservations dialogue as presented and developed by the Special Rapporteur of the International Law Commission on reservations to treaties. However, the article also proposes a wide reading of the practice of the reservations dialogue using examples from the Convention on the Elimination of All Forms of Discrimination against Women. Based on this analysis, the author formulates some proposals as to a more adequate development of the reservations dialogue and the reservations regime. A development which will favour the formation of inclusive international human rights as a basis for a future international constitution accepted as legitimate by all members of the international community.