bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alternative Lengthening of Telomeres in Primary Pancreatic Neuroendocrine Tumors Is Associated with Aggressive Clinical Behavior and Poor Survival
Authors: Kim Joo Young , Brosnan-Cashman Jacqueline A. , An Soyeon , Kim Sung Joo , Song Ki-Byung , Kim Min-Sun , Kim Mi-Ju , Hwang Dae Wook , Meeker Alan K. , Yu Eunsil , Kim Song Cheol , Hruban Ralph H. , Heaphy Christopher M. , Hong Seung-Mo 
Published: September 2016

AbstractPurpose: Alternative lengthening of telomeres (ALT), a telomerase-independent telomere maintenance mechanism, is strongly associated with ATRX and DAXX alterations and occurs frequently in pancreatic neuroendocrine tumors (PanNET).Experimental Design: In a Korean cohort of 269 surgically resected primary PanNETs and 19 sporadic microadenomas, ALT status and nuclear ATRX and DAXX protein expression were assessed and compared with clinicopathologic factors.Results: In PanNETs, ALT or loss of ATRX/DAXX nuclear expression was observed in 20.8% and 19.3%, respectively, whereas microadenomas were not altered. ALT-positive PanNETs displayed a significantly higher grade, size, and pT classification (all, P &lt; 0.001). ALT also strongly correlated with lymphovascular (P &lt; 0.001) and perineural invasion (P = 0.001) and the presence of lymph node (P &lt; 0.001) and distant metastases (P = 0.002). Furthermore, patients with ALT-positive primary PanNETs had a shorter recurrence-free survival [HR = 3.38; 95% confidence interval (CI), 1.83–6.27; P &lt; 0.001]. Interestingly, when limiting to patients with distant metastases, those with ALT-positive primary tumors had significantly better overall survival (HR = 0.23; 95% CI, 0.08–0.68; P = 0.008). Similarly, tumors with loss of ATRX/DAXX expression were significantly associated with ALT (P &lt; 0.001), aggressive clinical behavior, and reduced recurrence-free survival (P &lt; 0.001). However, similar to ALT, when limiting to patients with distant metastases, loss of ATRX/DAXX expression was associated with better overall survival (P = 0.003).Conclusions: Both primary ALT-positive and ATRX/DAXX-negative PanNETs are independently associated with aggressive clinicopathologic behavior and displayed reduced recurrence-free survival. In contrast, ALT activation and loss of ATRX/DAXX are both associated with better overall survival in patients with metastases. Therefore, these biomarkers may be used as prognostic markers depending on the context of the disease. Clin Cancer Res; 23(6); 1598–606. ©2016 AACR.
AZ1366: An Inhibitor of Tankyrase and the Canonical Wnt Pathway that Limits the Persistence of Non–Small Cell Lung Cancer Cells Following EGFR Inhibition
Authors: Scarborough Hannah A. , Helfrich Barbara A. , Casás-Selves Matias , Schuller Alwin G. , Grosskurth Shaun E. , Kim Jihye , Tan Aik-Choon , Chan Daniel C. , Zhang Zhiyong , Zaberezhnyy Vadym , Bunn Paul A. , DeGregori James 
Published: September 2016

Abstract
Purpose: The emergence of EGFR inhibitors such as gefitinib, erlotinib, and osimertinib has provided novel treatment opportunities in EGFR-driven non–small cell lung cancer (NSCLC). However, most patients with EGFR-driven cancers treated with these inhibitors eventually relapse. Recent efforts have identified the canonical Wnt pathway as a mechanism of protection from EGFR inhibition and that inhibiting tankyrase, a key player in this pathway, is a potential therapeutic strategy for the treatment of EGFR-driven tumors.
Experimental Design: We performed a preclinical evaluation of tankyrase inhibitor AZ1366 in combination with multiple EGFR-inhibitors across NSCLC lines, characterizing its antitumor activity, impingement on canonical Wnt signaling, and effects on gene expression. We performed pharmacokinetic and pharmacodynamic profiling of AZ1366 in mice and evaluated its therapeutic activity in an orthotopic NSCLC model.
Results: In combination with EGFR inhibitors, AZ1366 synergistically suppressed proliferation of multiple NSCLC lines and amplified global transcriptional changes brought about by EGFR inhibition. Its ability to work synergistically with EGFR inhibition coincided with its ability to modulate the canonical Wnt pathway. Pharmacokinetic and pharmacodynamic profiling of AZ1366-treated orthotopic tumors demonstrated clinically relevant serum drug levels and intratumoral target inhibition. Finally, coadministration of an EGFR inhibitor and AZ1366 provided better tumor control and improved survival for Wnt-responsive lung cancers in an orthotopic mouse model.
Conclusions: Tankyrase inhibition is a potent route of tumor control in EGFR-dependent NSCLC with confirmed dependence on canonical Wnt signaling. These data strongly support further evaluation of tankyrase inhibition as a cotreatment strategy with EGFR inhibition in an identifiable subset of EGFR-driven NSCLC. Clin Cancer Res; 23(6); 1531–41. ©2016 AACR.
Prognostic Utility of a New mRNA Expression Signature of Gleason Score
Authors: Sinnott Jennifer A. , Peisch Sam F. , Tyekucheva Svitlana , Gerke Travis , Lis Rosina , Rider Jennifer R. , Fiorentino Michelangelo , Stampfer Meir J. , Mucci Lorelei A. , Loda Massimo , Penney Kathryn L. 
Published: September 2016

Abstract
Purpose: Gleason score strongly predicts prostate cancer mortality; however, scoring varies among pathologists, and many men are diagnosed with intermediate-risk Gleason score 7. We previously developed a 157-gene signature for Gleason score using a limited gene panel. Using a new whole-transcriptome expression dataset, we verified the previous signature's performance and developed a new Gleason signature to improve lethal outcome prediction among men with Gleason score 7.
Experimental Design: We generated mRNA expression data from prostate tumor tissue from men in the Physicians' Health Study and Health Professionals Follow-Up Study (N = 404) using the Affymetrix Human Gene 1.0 ST microarray. The Prediction Analysis for Microarrays method was used to develop a signature to distinguish high (≥8) versus low (≤6) Gleason score. We evaluated the signature's ability to improve prediction of lethality among men with Gleason score 7, adjusting for 3 + 4/4 + 3 status, by quantifying the area under the receiver operating characteristic (ROC) curve (AUC).
Results: We identified a 30-gene signature that best distinguished Gleason score ≤6 from ≥8. The AUC to predict lethal disease among Gleason score 7 men was 0.76 [95% confidence interval (CI), 0.67–0.84] compared with 0.68 (95% CI, 0.59–0.76) using 3 + 4/4 + 3 status alone (P = 0.0001). This signature was a nonsignificant (P = 0.09) improvement over our previous signature (AUC = 0.72).
Conclusions: Our new 30-gene signature improved prediction of lethality among men with Gleason score 7. This signature can potentially become a useful prognostic tool for physicians to improve treatment decision making. Clin Cancer Res; 23(1); 81–87. ©2016 AACR.
See related commentary by Yin et al., p. 6
Improved Efficacy of Neoadjuvant Compared to Adjuvant Immunotherapy to Eradicate Metastatic Disease
Authors: Liu Jing , Blake Stephen J. , Yong Michelle C.R. , Harjunpää Heidi , Ngiow Shin Foong , Takeda Kazuyoshi , Young Arabella , O'Donnell Jake S. , Allen Stacey , Smyth Mark J. , Teng Michele W.L. 
Published: September 2016

Abstract
Immunotherapy has recently entered a renaissance phase with the approval of multiple agents for the treatment of cancer. Immunotherapy stands ready to join traditional modalities, including surgery, chemotherapy, radiation, and hormone therapy, as a pillar of cancer treatment. Although immunotherapy has begun to have success in advanced cancer treatment, its scheduling and efficacy with surgery to treat earlier stages of cancer and prevent distant metastases have not been systematically examined. Here, we have used two models of spontaneously metastatic breast cancers in mice to illustrate the significantly greater therapeutic power of neoadjuvant, compared with adjuvant, immunotherapies in the context of primary tumor resection. Elevated and sustained peripheral tumor-specific immune responses underpinned the outcome, and blood sampling of tumor-specific CD8+ T cells immediately prior to and post surgery may provide a predictor of outcome. These data now provide a strong rationale to extensively test and compare neoadjuvant immunotherapy in humans.
Significance: We demonstrate the significantly greater therapeutic efficacy of neoadjuvant, compared with adjuvant, immunotherapies to eradicate distant metastases following primary tumor resection. Elevated and sustained peripheral tumor-specific immune responses underpinned the outcome, and blood sampling of tumor-specific CD8+ T cells immediately prior to and post surgery may provide a predictor of outcome. Cancer Discov; 6(12); 1382–99. ©2016 AACR.
See related commentary by Melero et al., p. 1312.
This article is highlighted in the In This Issue feature, p. 1293
Pharmacological Targeting of Plasminogen Activator Inhibitor-1 Decreases Vascular Smooth Muscle Cell Migration and Neointima Formation
Authors: Ji Yan , Weng Zhen , Fish Philip , Goyal Neha , Luo Mao , Myears Samantha P. , Strawn Tammy L. , Chandrasekar Bysani , Wu Jianbo , Fay William P. 
Published: September 2016

Objective—
Plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor that promotes and inhibits cell migration, plays a complex and important role in adverse vascular remodeling. Little is known about the effects of pharmacological PAI-1 inhibitors, an emerging drug class, on migration of vascular smooth muscle cells (SMCs) and endothelial cells (ECs), crucial mediators of vascular remodeling. We investigated the effects of PAI-039 (tiplaxtinin), a specific PAI-1 inhibitor, on SMC and EC migration in vitro and vascular remodeling in vivo.

Approach and Results—
PAI-039 inhibited SMC migration through collagen gels, including those supplemented with vitronectin and other extracellular matrix proteins, but did not inhibit migration of PAI-1-deficient SMCs, suggesting that its antimigratory effects were PAI-1-specific and physiologically relevant. However, PAI-039 did not inhibit EC migration. PAI-039 inhibited phosphorylation and nuclear translocation of signal transducers and activators of transcription-1 in SMCs, but had no discernable effect on signal transducer and activator of transcription-1 signaling in ECs. Expression of low-density lipoprotein receptor–related protein 1, a motogenic PAI-1 receptor that activates Janus kinase/signal transducers and activators of transcription-1 signaling, was markedly lower in ECs than in SMCs. Notably, PAI-039 significantly inhibited intimal hyperplasia and inflammation in murine models of adverse vascular remodeling, but did not adversely affect re-endothelialization after endothelium-denuding mechanical vascular injury.

Conclusions—
PAI-039 inhibits SMC migration and intimal hyperplasia, while having no inhibitory effect on ECs, which seems to be because of differences in PAI-1-dependent low-density lipoprotein receptor–related protein 1/Janus kinase/signal transducer and activator of transcription-1 signaling between SMCs and ECs. These findings suggest that PAI-1 may be an important therapeutic target in obstructive vascular diseases characterized by neointimal hyperplasia.
Facilitators and inhibitors in developing professional values in nursing students
Authors: Shafakhah Mahnaz , Molazem Zahra , Khademi Mojgan , Sharif Farkhondeh 
Published: September 2016

Background: Values are the basis of nursing practice, especially in making decisions about complicated ethical issues. Despite their key role in nursing, little information exists on the factors affecting their development and manifestation in nursing students. Objective: This study identifies and describes the facilitators and inhibitors of the development and manifestation of professional values based on the experiences of nursing students and instructors and nurses. Research design: Data were collected through 29 semi-structured interviews and two focus group interviews in 2013–2015 and were analyzed using the conventional content analysis method of Elo and Kyngäs. Participants and research context: In total, 18 nursing undergraduates, five nursing instructors, and five nurses from Shiraz University of Medical Sciences and one of the teaching hospitals in Shiraz were selected through purposive sampling. Ethical considerations: The research was approved by the Ethics Committee of Shiraz University of Medical Sciences and the teaching hospital examined. Findings: The findings consisted of two categories: personal and environmental factors. Personal factors consisted of the two subcategories of personal stimuli (work experience and past relationships, inner beliefs and acting on values, belief in God and a divine worldview) and personal inhibitors (the lack of professional motivation and enthusiasm, negative emotions). Environmental factors consisted of the two subcategories of environmental stimuli (cooperation, order and discipline) and environmental inhibitors (unfavorable work environment, society’s negative attitude toward nursing, the violation of rights). Discussion and conclusion: Given the impact of personal and environmental factors on the development and manifestation of professional values in nursing students, it is upon the education authorities to take account of them in their planning, and nursing managers are also recommended to further address these factors in their development of a proper work environment, provision of standard facilities and removal of barriers.
Ethics support in community care makes a difference for practice
Authors: Magelssen Morten , Gjerberg Elisabeth , Lillemoen Lillian , Førde Reidun , Pedersen Reidar 
Published: September 2016

Background: Through the Norwegian ethics project, ethics activities have been implemented in the health and care sector in more than 200 municipalities. Objectives: To study outcomes of the ethics activities and examine which factors promote and inhibit significance and sustainability of the activities. Research design: Two online questionnaires about the municipal ethics activities. Participants and research context: A total of 137 municipal contact persons for the ethics project answered the first survey (55% response rate), whereas 217 ethics facilitators responded to the second survey (33% response rate). Ethical considerations: Based on informed consent, the study was approved by the Data Protection Official of the Norwegian Social Science Data Services. Findings: Around half of the respondents found the ethics project to have been highly significant for daily professional practice. Outcomes include better handling of ethical challenges, better employee cooperation, better service quality, and better relations to patients and next of kin. Factors associated with sustainability and/or significance of the activities were sufficient support from stakeholders, sufficient available time, and ethics facilitators having sufficient knowledge and skills in ethics and access to supervision. Discussion: This study shows that ethics initiatives can be both sustainable and significant for practice. There is a need to create regional or national structures for follow-up and develop more comprehensive ethics training for ethics facilitators. Conclusion: It is both possible and potentially important to implement clinical ethics support activities in community health and care services systematically on a large scale. Future ethics initiatives in the community sector should be designed in light of documented promoting and inhibiting factors.
Apples and Pears
Authors: Reyneke Roelof P. 
Published: September 2016

Purpose: To investigate how an adventure-based activity could help facilitate dialogue and enable a safe process where students could engage in a difficult topic such as diversity without feeling threatened. Method: A qualitative study was used in which 89 social work students who took part in diversity training gave permission that their manuscripts be used for documentary analysis. Content analysis was used to analyze the data in order to determine if and how the adventure-based activity contributed to the facilitation of dialogue. Results: It was found that the activity contributed to changing the attitude and knowledge of social work students. It opened up new perspectives and allowed students to discuss diversity without fear. Conclusion: The use of adventure activities is an effective strategy to facilitate dialogue between students.
Relationship of Prolonged Operative Time and Comorbidities With Complications After Geriatric Ankle Fractures
Authors: Aigner René , Salomia Constantin , Lechler Philipp , Pahl Roman , Frink Michael 
Published: September 2016

Background: The incidence of geriatric ankle fractures has increased during the last few decades. In contrast to younger patients, increased complication rates have been observed. Thus, the goal of the present study was to identify risk factors for perioperative complications following open reduction and internal fixation of geriatric ankle fractures. Methods: Two hundred thirty-seven patients over the age of 65 years (mean, 72.5 ± 6.1 years) treated for ankle fractures in our institution between 2004 and 2014 were included. Complications associated with operative treatment as well as complications requiring revision surgery were analyzed. In a multivariate analysis, risk factors were determined. Results: In 68 patients (28.7%), 74 complications were documented. The most common complications were impaired wound healing and operative site infections. The multivariate analysis revealed that the operative time was the only independent risk factor for the development of a complication. The operative time as well as the presence of an open fracture represented risk factors for needing revision surgery. Comorbidities did not influence the development of complications. Conclusion: The operative management of geriatric ankle fractures was associated with a high complication rate. In the present study, the operative time was the only modifiable factor for the development of a complication that required revision surgery. During preoperative preparation, we believe that perfusion of the affected limb should be optimized to reduce the incidence of wound complications. Level of Evidence: Level III, retrospective cohort study.
The effect of telepsychiatric modalities on reduction of readmissions in psychiatric settings: A systematic review
Authors: Koblauch Henrik , Reinhardt Sasha M , Lissau Waltraut , Jensen Pia-Lis 
Published: September 2016

Introduction Telepsychiatric modalities are used widely in the treatment of many mental illnesses. It has also been proposed that telepsychiatric modalities could be a way to reduce readmissions. The purpose of the study was to conduct a systematic review of the literature on the effects of telepsychiatric modalities on readmissions in psychiatric settings. Methods We conducted a systematic literature search in MEDLINE, CINAHL, Embase, Cochrane, PsycINFO and Joanna Briggs databases in October 2015. Inclusion criteria were (a) patients with a psychiatric diagnosis, (b) telepsychiatric interventions and (c) an outcome related to readmission. Results The database search identified 218 potential studies, of which eight were eligible for the review. Studies were of varying quality and there was a tendency towards low-quality studies (five studies) which found positive outcomes regarding readmission, whereas the more methodological sound studies (three studies) found no effect of telepsychiatric modalities on readmission rates. Discussion Previous studies have proven the effectiveness of telepsychiatric modalities in the treatment of various mental illnesses. However, in the present systematic review we were unable to find an effect of telepsychiatric modalities on the rate of readmission. Some studies found a reduced rate of readmissions, but the poor methodological quality make the findings questionable. At the present time there is no evidence to support the use of telepsychiatry due to heterogeneous interventions, heterogeneous patient groups and lack of high-quality studies.
Using Qualitative Research to Overcome the Shortcomings of Systematic Reviews When Designing of a Self-Management Intervention for Advanced Cancer Pain
Authors: Flemming Kate , Closs S. José , Hughes Nicholas D. , Bennett Michael I. 
Published: September 2016

Objectives: To identify the key components for a self-management intervention for advanced cancer pain using evidence drawn from systematic reviews of complex interventions and syntheses of qualitative research. Methods: Evidence from up-to-date systematic reviews was prioritized. Searches were initially undertaken to identify the systematic reviews of effectiveness in Cinahl, Medline, Embase, PsycInfo, and the Cochrane Database of systematic reviews from 2009 to June 2014, using validated search terms. Subsequent searches to identify the qualitative systematic reviews were undertaken in Cinahl, Medline, Embase, and PsycInfo from 2009 to January 2015. The results of the two sets of reviews were integrated using methods based on constant comparative techniques. Results: Four systematic reviews examining interventions for the self-management of advanced cancer pain were identified. Although each review recommended some attributes of a pain management intervention, it was not possible to determine the essential key components. Subsequent searches for qualitative evidence syntheses identified three reviews. These were integrated with the effectiveness reviews. The integration identified key components for a self-management intervention including individualized approaches to care, the importance of addressing patients’ knowledge, skills, and attitudes toward pain management, and the significance of team approaches and inter-disciplinary working in the management of pain. Conclusion: Implementing the findings from systematic reviews of complex interventions is often hindered by a lack of understanding of important contextual components of care, often provided by qualitative research. Using both types of data to provide answers for practice demonstrates the benefits of incorporating qualitative research in reviews of complex interventions by ensuring the strengths of qualitative and quantitative research are combined and that their respective weaknesses are overcome.