bluuebunny/crossref_metadata_2025_split huggingface dataset:
PI3K Pathway Activation Provides a Novel Therapeutic Target for Pediatric Ependymoma and Is an Independent Marker of Progression-Free Survival
Authors: Rogers Hazel A. , Mayne Cerys , Chapman Rebecca J. , Kilday John-Paul , Coyle Beth , Grundy Richard G. 
Published: September 2013

AbstractPurpose: Currently, there are few effective adjuvant therapies for pediatric ependymoma outside confocal radiation, and prognosis remains poor. The phosphoinositide 3-kinase (PI3K) pathway is one of the most commonly activated pathways in cancer. PI3Ks transduce signals from growth factors and cytokines, resulting in the phosphorylation and activation of AKT, which in turn induces changes in cell growth, proliferation, and apoptosis.Experimental Design: PI3K pathway status was analyzed in ependymoma using gene expression data and immunohistochemical analysis of phosphorylated AKT (P-AKT). The effect of the PI3K pathway on cell proliferation was investigated by immunohistochemical analysis of cyclin D1 and Ki67, plus in vitro functional analysis. To identify a potential mechanism of PI3K pathway activation, PTEN protein expression and the mutation status of PI3K catalytic subunit α-isoform gene (PIK3CA) was investigated.Results: Genes in the pathway displayed significantly higher expression in supratentorial than in posterior fossa and spinal ependymomas. P-AKT protein expression, indicating pathway activation, was seen in 72% of tumors (n = 169) and P-AKT expression was found to be an independent marker of a poorer progression-free survival. A significant association between PI3K pathway activation and cell proliferation was identified, suggesting that pathway activation was influencing this process. PTEN protein loss was not associated with P-AKT staining and no mutations were identified in PIK3CA.Conclusions: Our results suggest that the PI3K pathway could act as a biomarker, not only identifying patients with a worse prognosis but also those that could be treated with therapies targeted against the pathway, a strategy potentially effective in a high percentage of ependymoma patients. Clin Cancer Res; 19(23); 6450–60. ©2013 AACR.
A Genetically Engineered Oncolytic Adenovirus Decoys and Lethally Traps Quiescent Cancer Stem–like Cells in S/G2/M Phases
Authors: Yano Shuya , Tazawa Hiroshi , Hashimoto Yuuri , Shirakawa Yasuhiro , Kuroda Shinji , Nishizaki Masahiko , Kishimoto Hiroyuki , Uno Futoshi , Nagasaka Takeshi , Urata Yasuo , Kagawa Shunsuke , Hoffman Robert M. , Fujiwara Toshiyoshi 
Published: October 2013

Abstract
Purpose: Because chemoradiotherapy selectively targets proliferating cancer cells, quiescent cancer stem–like cells are resistant. Mobilization of the cell cycle in quiescent leukemia stem cells sensitizes them to cell death signals. However, it is unclear that mobilization of the cell cycle can eliminate quiescent cancer stem–like cells in solid cancers. Thus, we explored the use of a genetically-engineered telomerase-specific oncolytic adenovirus, OBP-301, to mobilize the cell cycle and kill quiescent cancer stem–like cells.
Experimental Design: We established CD133+ cancer stem–like cells from human gastric cancer MKN45 and MKN7 cells. We investigated the efficacy of OBP-301 against quiescent cancer stem–like cells. We visualized the treatment dynamics of OBP-301 killing of quiescent cancer stem–like cells in dormant tumor spheres and xenografts using a fluorescent ubiquitination cell-cycle indicator (FUCCI).
Results: CD133+ gastric cancer cells had stemness properties. OBP-301 efficiently killed CD133+ cancer stem–like cells resistant to chemoradiotherapy. OBP-301 induced cell-cycle mobilization from G0–G1 to S/G2/M phases and subsequent cell death in quiescent CD133+ cancer stem–like cells by mobilizing cell-cycle–related proteins. FUCCI enabled visualization of quiescent CD133+ cancer stem–like cells and proliferating CD133− non–cancer stem–like cells. Three-dimensional visualization of the cell-cycle behavior in tumor spheres showed that CD133+ cancer stem–like cells maintained stemness by remaining in G0–G1 phase. We showed that OBP-301 mobilized quiescent cancer stem–like cells in tumor spheres and xenografts into S/G2/M phases where they lost viability and cancer stem–like cell properties and became chemosensitive.
Conclusion: Oncolytic adenoviral infection is an effective mechanism of cancer cell killing in solid cancer and can be a new therapeutic paradigm to eliminate quiescent cancer stem–like cells. Clin Cancer Res; 19(23); 6495–505. ©2013 AACR.
A Drug Repositioning Approach Identifies Tricyclic Antidepressants as Inhibitors of Small Cell Lung Cancer and Other Neuroendocrine Tumors
Authors: Jahchan Nadine S. , Dudley Joel T. , Mazur Pawel K. , Flores Natasha , Yang Dian , Palmerton Alec , Zmoos Anne-Flore , Vaka Dedeepya , Tran Kim Q.T. , Zhou Margaret , Krasinska Karolina , Riess Jonathan W. , Neal Joel W. , Khatri Purvesh , Park Kwon S. , Butte Atul J. , Sage Julien 
Published: September 2013

Abstract
Small cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer with high mortality. We used a systematic drug repositioning bioinformatics approach querying a large compendium of gene expression profiles to identify candidate U.S. Food and Drug Administration (FDA)–approved drugs to treat SCLC. We found that tricyclic antidepressants and related molecules potently induce apoptosis in both chemonaïve and chemoresistant SCLC cells in culture, in mouse and human SCLC tumors transplanted into immunocompromised mice, and in endogenous tumors from a mouse model for human SCLC. The candidate drugs activate stress pathways and induce cell death in SCLC cells, at least in part by disrupting autocrine survival signals involving neurotransmitters and their G protein–coupled receptors. The candidate drugs inhibit the growth of other neuroendocrine tumors, including pancreatic neuroendocrine tumors and Merkel cell carcinoma. These experiments identify novel targeted strategies that can be rapidly evaluated in patients with neuroendocrine tumors through the repurposing of approved drugs.
Significance: Our work shows the power of bioinformatics-based drug approaches to rapidly repurpose FDA-approved drugs and identifies a novel class of molecules to treat patients with SCLC, a cancer for which no effective novel systemic treatments have been identified in several decades. In addition, our experiments highlight the importance of novel autocrine mechanisms in promoting the growth of neuroendocrine tumor cells. Cancer Discov; 3(12); 1364–77. ©2013 AACR.
See related commentary by Wang and Byers, p. 1333
This article is highlighted in the In This Issue feature, p. 1317
Activation of the PD-1 Pathway Contributes to Immune Escape in EGFR-Driven Lung Tumors
Authors: Akbay Esra A. , Koyama Shohei , Carretero Julian , Altabef Abigail , Tchaicha Jeremy H. , Christensen Camilla L. , Mikse Oliver R. , Cherniack Andrew D. , Beauchamp Ellen M. , Pugh Trevor J. , Wilkerson Matthew D. , Fecci Peter E. , Butaney Mohit , Reibel Jacob B. , Soucheray Margaret , Cohoon Travis J. , Janne Pasi A. , Meyerson Matthew , Hayes D. Neil , Shapiro Geoffrey I. , Shimamura Takeshi , Sholl Lynette M. , Rodig Scott J. , Freeman Gordon J. , Hammerman Peter S. , Dranoff Glenn , Wong Kwok-Kin 
Published: September 2013

Abstract
The success in lung cancer therapy with programmed death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between EGF receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, CTL antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. We observed decreased CTLs and increased markers of T-cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T-cell function and lowering the levels of tumor-promoting cytokines. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non–small cell lung cancer cell lines with activated EGFR. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape and mechanistically link treatment response to PD-1 inhibition.
Significance: We show that autochthonous EGFR-driven lung tumors inhibit antitumor immunity by activating the PD-1/PD-L1 pathway to suppress T-cell function and increase levels of proinflammatory cytokines. These findings indicate that EGFR functions as an oncogene through non–cell-autonomous mechanisms and raise the possibility that other oncogenes may drive immune escape. Cancer Discov; 3(12); 1355–63. ©2013 AACR.
See related commentary by Rech and Vonderheide, p. 1330
This article is highlighted in the In This Issue feature, p. 1317
Repetitive Myocardial Ischemia Promotes Coronary Growth in the Adult Mammalian Heart
Authors: Lavine Kory J. , Kovacs Attila , Weinheimer Carla , Mann Douglas L. 
Published: October 2013

Background
Coronary artery disease and ischemic cardiomyopathy represent the leading cause of heart failure and continue to grow at exponential rates. Despite widespread availability of coronary bypass surgery and percutaneous coronary intervention, subsequent ischemic events and progression to heart failure continue to be common occurrences. Previous studies have shown that a subgroup of patients develop collateral blood vessels that serve to connect patent and occluded arteries and restore perfusion to ischemic territories. The presence of coronary collaterals has been correlated with improved clinical outcomes; however, the molecular mechanisms governing this process remain largely unknown.

Methods and Results
To date, no mouse models of coronary arterial growth have been described. Using a closed‐chest model of myocardial ischemia, we have demonstrated that brief episodes of repetitive ischemia are sufficient to promote the growth of both large coronary arteries and the microvasculature. Induction of large coronary artery and microvascular growth resulted in improvements in myocardial perfusion after prolonged ischemia and protected from subsequent myocardial infarction. We further show that repetitive ischemia did not lead to increased expression of classic proangiogenic factors but instead resulted in activation of the innate immune system and recruitment of macrophages to growing blood vessels.

Conclusions
These studies describe a novel model of coronary angiogenesis and implicate the cardiac macrophage as a potential mediator of ischemia‐driven coronary growth.
Response of North Atlantic Ocean Circulation to Atmospheric Weather Regimes
Authors: Barrier Nicolas , Cassou Christophe , Deshayes Julie , Treguier Anne-Marie 
Published: October 2013

Abstract
A new framework is proposed for investigating the atmospheric forcing of North Atlantic Ocean circulation. Instead of using classical modes of variability, such as the North Atlantic Oscillation (NAO) or the east Atlantic pattern, the weather regimes paradigm was used. Using this framework helped avoid problems associated with the assumptions of orthogonality and symmetry that are particular to modal analysis and known to be unsuitable for the NAO. Using ocean-only historical and sensitivity experiments, the impacts of the four winter weather regimes on horizontal and overturning circulations were investigated. The results suggest that the Atlantic Ridge (AR), negative NAO (NAO−), and positive NAO (NAO+) regimes induce a fast (monthly-to-interannual time scales) adjustment of the gyres via topographic Sverdrup dynamics and of the meridional overturning circulation via anomalous Ekman transport. The wind anomalies associated with the Scandinavian blocking regime (SBL) are ineffective in driving a fast wind-driven oceanic adjustment. The response of both gyre and overturning circulations to persistent regime conditions was also estimated. AR causes a strong, wind-driven reduction in the strengths of the subtropical and subpolar gyres, while NAO+ causes a strengthening of the subtropical gyre via wind stress curl anomalies and of the subpolar gyre via heat flux anomalies. NAO− induces a southward shift of the gyres through the southward displacement of the wind stress curl. The SBL is found to impact the subpolar gyre only via anomalous heat fluxes. The overturning circulation is shown to spin up following persistent SBL and NAO+ and to spin down following persistent AR and NAO− conditions. These responses are driven by changes in deep water formation in the Labrador Sea.
Combined Tibial Tubercle Osteotomy With Medial Opening Wedge High Tibial Osteotomy Minimizes Changes in Patellar Height
Authors: Longino P. David , Birmingham Trevor B. , Schultz William J. , Moyer Rebecca F. , Giffin J. Robert 
Published: September 2013

Background: Medial opening wedge high tibial osteotomy (HTO) for the treatment of varus gonarthrosis can be associated with inadvertent decreases in patellar height. Hypothesis: Decreases in patellar height observed after medial opening wedge HTO can be minimized with the addition of a tibial tubercle osteotomy (TTO). Study Design: Cohort study; Level of evidence, 3. Methods: Twenty-nine patients undergoing medial opening wedge HTO with a concurrent TTO were matched with 29 controls who previously underwent medial opening wedge HTO without a TTO. Both groups had substantial varus malalignment (mean mechanical axis angle, −10° ± 3°) requiring large corrections. Measurements of patellar height and posterior tibial slope were calculated from standing lateral radiographs and compared preoperatively and 6 months postoperatively. Patellar height measures included the Blackburne-Peel index, Caton-Deschamps index, Miura-Kawamura index, Insall-Salvati ratio, and modified Insall-Salvati ratio. Results: The changes in the Blackburne-Peel, Caton-Deschamps, and Miura-Kawamura indices were significantly less in the HTO/TTO group versus the HTO group. There were 3 of 29 (10%) new cases that met the radiographic criteria for patella infera in the HTO/TTO group versus 11 of 29 (38%) new cases of patella infera found postoperatively in the HTO group, suggesting an absolute risk reduction of 28% with TTO. The changes in the Blackburne-Peel and Caton-Deschamps indices were correlated to a larger preoperative varus deformity in the coronal plane ( r = 0.52 and r = 0.41, respectively). Conclusion: The addition of a TTO when performing a medial opening wedge HTO minimizes the decreases in patellar height associated with the procedure.
Comparative Analysis of Empiric Antimicrobial Treatments for Skin and Soft Tissue Infections in Newly Hospitalized Patients
Authors: Yazdani Cyrus , Hanna Nancy 
Published: September 2013

Purpose: Intravenous vancomycin is the standard empiric treatment for complicated skin and soft tissue infections (SSTIs) due to its coverage against methicillin-resistant Staphylococcus aureus (MRSA). The objective of this study was to compare the hospital length of stay (LOS) between vancomycin-treated patients and patients receiving newer anti-MRSA agents. The study also aimed to identify factors associated with therapy change in patients receiving vancomycin on admission. Methods: Electronic medical records were used to conduct this retrospective cohort study. The LOS was compared among 5 groups of adult patients with admission diagnoses for SSTI who were initiated on linezolid, daptomycin, ceftaroline, tigecycline, or vancomycin. Survival analysis was used to identify factors associated with therapy change from vancomycin to another study medication. Results: Vancomycin was prescribed in 1046 (92%) admissions. Although none of the between-group differences in LOS reached statistical significance, there was a trend toward shorter LOS in vancomycin-treated patients compared to linezolid-treated patients ( P = .059). Coagulopathy was independently associated with increased likelihood of therapy change from vancomycin (hazard ratio = 4.71; P <.001). Conclusions: In the treatment of SSTI, newer agents result in LOS comparable to vancomycin. In patients initiated on vancomycin, therapy change was associated with longer LOS. Coagulopathy was independently associated with increased probability of therapy change.
The Luhmannian approach to exclusion/inclusion and its relevance to Social Work
Authors: Schirmer Werner , Michailakis Dimitris 
Published: September 2013

Summary Although the concept of social exclusion is central to the academic discipline of social work, there is not much theoretical clarity about what it actually means. For instance, exclusion is used as a synonym for poverty, marginalization, detachment, unemployment, or solitude. We argue that the systems-theoretical framework developed by the German social theorist Niklas Luhmann (1927–1997) provides the conceptual tools to understand inclusion and exclusion in a theoretically adequate way that is highly relevant to Social Work. Since there is scarcely any literature on Luhmann's work in the field of social work not written in German, this article aims to provide a systematic introduction to the Luhmannian theory of society with respect to the distinction of inclusion/exclusion and its relation to social work to an English-speaking audience . Findings After a presentation of some basic concepts, it will be argued that exclusion is not a problem per se nor is inclusion always and per se unproblematic. The Luhmannian approach suggests that inclusion and exclusion are operations of social systems that treat human beings as relevant addresses for communication. Against that background, systems theory gives a clear and accurate description of what social work can (and cannot) do in terms of inclusion/exclusion. Applications The main purpose of social work is exclusion management. Exclusion management involves working on the social addresses of individuals with the aim of improving their attractiveness for other social systems, a (re)orientation towards being includable. It appears in three forms: exclusion prevention, inclusion mediation, and exclusion administration.
Patients’ attitudes and perceptions of two health-related quality-of-life questionnaires used to collect patient-reported outcome measures in the English National Health Service: A qualitative study of patients undergoing cardiac interventions
Authors: Matata Bashir M , Hinder Susan , Steele Sharon , Gibbons Elizabeth , Jackson Mark 
Published: September 2013

Objectives: To explore patients’ views on the EuroQol-5D and Coronary Revascularisation Outcome Questionnaire, tools currently used for collecting patient-reported outcome measures in the English National Health Service. The key questions were as follows: (1) whether patients consider them sensitive enough to detect change in their health after cardiovascular disease interventions and (2) whether they consider the health-related quality-of-life questions as meaningful. Methods: Data were collected on patients’ views using focus groups. We held four focus groups selecting participants on the basis of their baseline and follow-up EuroQol-5D scores. Data were analysed using framework analysis and grounded theory. Results: Focus group participants confirmed that they had derived substantial health benefits from their cardiac interventions despite the lack of measurable effects on the EuroQol-5D scores. Participants felt that the EuroQol-5D questionnaire was limited because of the following reasons: Their health fluctuates from day to day. They had difficulty assessing their general health status on the visual analogue scale. They felt that the Coronary Revascularisation Outcome Questionnaire was limited because of the following reasons: They did not understand the clinical terms used. The impact of tiredness on their quality of life was not captured. They were unable to distinguish between the effects of their heart condition and other health issues. Additionally, neither questionnaire considers the adjustments people have made to their domestic arrangements to improve their health-related quality of life. Conclusion: This study provides evidence that the two questionnaires do not capture some aspects of health that patients consider important. Furthermore, the presence of co-morbidities masks the symptoms relating to the heart disease and the effect of their cardiac interventions. Future work on patient-reported outcome measures should consider developing new questionnaires that address these major concerns.
Camel Streptococcus agalactiae populations are associated with specific disease complexes and acquired the tetracycline resistance gene tetM via a Tn916-like element
Authors: Fischer Anne , Liljander Anne , Kaspar Heike , Muriuki Cecilia , Fuxelius Hans-Henrik , Bongcam-Rudloff Erik , de Villiers Etienne P , Huber Charlotte A , Frey Joachim , Daubenberger Claudia , Bishop Richard , Younan Mario , Jores Joerg 
Published: October 2013

Abstract
Camels are the most valuable livestock species in the Horn of Africa and play a pivotal role in the nutritional sustainability for millions of people. Their health status is therefore of utmost importance for the people living in this region. Streptococcus agalactiae, a Group B Streptococcus (GBS), is an important camel pathogen. Here we present the first epidemiological study based on genetic and phenotypic data from African camel derived GBS. Ninety-two GBS were characterized using multilocus sequence typing (MLST), capsular polysaccharide typing and in vitro antimicrobial susceptibility testing. We analysed the GBS using Bayesian linkage, phylogenetic and minimum spanning tree analyses and compared them with human GBS from East Africa in order to investigate the level of genetic exchange between GBS populations in the region. Camel GBS sequence types (STs) were distinct from other STs reported so far. We mapped specific STs and capsular types to major disease complexes caused by GBS. Widespread resistance (34%) to tetracycline was associated with acquisition of the tetM gene that is carried on a Tn916-like element, and observed primarily among GBS isolated from mastitis. The presence of tetM within different MLST clades suggests acquisition on multiple occasions. Wound infections and mastitis in camels associated with GBS are widespread and should ideally be treated with antimicrobials other than tetracycline in East Africa.