bluuebunny/crossref_metadata_2025_split huggingface dataset:
PAK1 Is a Novel Therapeutic Target in Tyrosine Kinase Inhibitor–Resistant Lung Adenocarcinoma Activated by the PI3K/AKT Signaling Regardless of EGFR Mutation
Authors: Wu De-Wei , Wu Tzu-Chin , Chen Chih-Yi , Lee Huei 
Published: May 2016

Abstract
Purpose: EGFR mutation as a biomarker has documented that EGFR-mutant patients will derive clinical benefit from tyrosine kinase inhibitor (TKI) treatment. Unfortunately, most patients show TKI resistance and tumor recurrence after therapy. Therefore, we expected that an adjuvant biomarker other than EGFR mutation is needed for predicting TKI resistance.
Experimental Design: Molecular manipulations were performed to verify whether TKI resistance mediated by p21-activated kinase (PAK1) could be through increasing Mcl-1 protein stability via the PI3K/AKT/C/EBP-β/miR-145 cascade. Xenograft mouse models were used to confirm the mechanistic action of PAK1 on TKI resistance. Forty-six tumor tissues from patients with lung adenocarcinoma who received TKI therapy were collected to evaluate PAK1 and E-cadherin mRNA expressions by real-time PCR. The association of PAK1 and E-cadherin mRNA expressions with tumor response to TKI treatment and outcomes was evaluated.
Results: We demonstrate that PAK1 confers TKI resistance in EGFR-mutant cells as well as in EGFR–wild-type cells. Mechanistically, the positive feedback loop of PAK1/PI3K/AKT/C/EBP-β/miR-145 cascades persistently activates the PI3K/AKT signaling pathway to protect Mcl-1 degradation by Fbw7, which results, in turn, in TKI resistance and cell invasion via epithelial-to-mesenchymal transition due to a decrease in E-cadherin expression. The mechanism underlying the cell model is further confirmed in xenograft tumors. Among patients, high-PAK1 or low–E-cadherin tumors more commonly exhibited an unfavorable response to TKI and poorer outcome compared with low-PAK1 or low–E-cadherin tumors.
Conclusions: The combination of TKI with AKT inhibitor might confer TKI sensitivity and in turn improve outcomes in patients with lung adenocarcinoma who harbored high PAK1 mRNA–expressing tumors. Clin Cancer Res; 22(21); 5370–82. ©2016 AACR.
Immune-Derived PD-L1 Gene Expression Defines a Subgroup of Stage II/III Colorectal Cancer Patients with Favorable Prognosis Who May Be Harmed by Adjuvant Chemotherapy
Authors: Dunne Philip D. , McArt Darragh G. , O'Reilly Paul G. , Coleman Helen G. , Allen Wendy L. , Loughrey Maurice , Van Schaeybroeck Sandra , McDade Simon , Salto-Tellez Manuel , Longley Daniel B. , Lawler Mark , Johnston Patrick G. 
Published: May 2016

Abstract
A recent phase II study of patients with metastatic colorectal carcinoma showed that mismatch repair gene status was predictive of clinical response to PD-1–targeting immune checkpoint blockade. Further examination revealed strong correlation between PD-L1 protein expression and microsatellite instability (MSI) in stage IV colorectal carcinoma, suggesting that the amount of PD-L1 protein expression could identify late-stage patients who might benefit from immunotherapy. To assess whether the clinical associations between PD-L1 gene expression and MSI identified in metastatic colorectal carcinoma are also present in stage II/III colorectal carcinoma, we used in silico analysis to elucidate the cell types expressing the PD-L1 gene. We found a statistically significant association of PD-L1 gene expression with MSI in early-stage colorectal carcinoma (P &lt; 0.001) and show that, unlike in non–colorectal carcinoma tumors, PD-L1 is derived predominantly from the immune infiltrate. We demonstrate that PD-L1 gene expression has positive prognostic value in the adjuvant disease setting (PD-L1low vs. PD-L1high HR = 9.09; CI, 2.11–39.10). PD-L1 gene expression had predictive value, as patients with high PD-L1 expression appear to be harmed by standard-of-care treatment (HR = 4.95; CI, 1.10–22.35). Building on the promising results from the metastatic colorectal carcinoma PD-1–targeting trial, we provide compelling evidence that patients with PD-L1high/MSI/immunehigh stage II/III colorectal carcinoma should not receive standard chemotherapy. This conclusion supports the rationale to clinically evaluate this patient subgroup for PD-1 blockade treatment. Cancer Immunol Res; 4(7); 582–91. ©2016 AACR.
Obstructive Sleep Apnea and Cardiovascular Events After Percutaneous Coronary Intervention
Authors: Lee Chi-Hang , Sethi Rishi , Li Ruogu , Ho Hee-Hwa , Hein Thet , Jim Man-Hong , Loo Germaine , Koo Chieh-Yang , Gao Xiao-Fei , Chandra Sharad , Yang Xiao-Xiao , Furlan Sofia F. , Ge Zhen , Mundhekar Ajeya , Zhang Wei-Wei , Uchôa Carlos Henrique G. , Kharwar Rajiv Bharat , Chan Po-Fun , Chen Shao-Liang , Chan Mark Y. , Richards Arthur Mark , Tan Huay-Cheem , Ong Thun-How , Roldan Glenn , Tai Bee-Choo , Drager Luciano F. , Zhang Jun-Jie 
Published: May 2016

Background—
There is a paucity of data from large cohort studies examining the prognostic significance of obstructive sleep apnea (OSA) in patients with coronary artery disease. We hypothesized that OSA predicts subsequent major adverse cardiac and cerebrovascular events (MACCEs) in patients undergoing percutaneous coronary intervention.

Methods and Results—

The Sleep and Stent Study was a prospective, multicenter registry of patients successfully treated with percutaneous coronary intervention in 5 countries. Between December 2011 and April 2014, 1748 eligible patients were prospectively enrolled. The 1311 patients who completed a sleep study within 7 days of percutaneous coronary intervention formed the cohort for this analysis. Drug-eluting stents were used in 80.1% and bioresorbable vascular scaffolds in 6.3% of the patients, and OSA, defined as an apnea-hypopnea index of ≥15 events per hour, was found in 45.3%. MACCEs, a composite of cardiovascular mortality, nonfatal myocardial infarction, nonfatal stroke, and unplanned revascularization, occurred in 141 patients during the median follow-up of 1.9 years (interquartile range, 0.8 years). The crude incidence of an MACCEs was higher in the OSA than the non-OSA group (3-year estimate, 18.9% versus 14.0%;
p
=0.001). Multivariate Cox regression analysis indicated that OSA was a predictor of MACCEs, with an adjusted hazard ratio of 1.57 (95% confidence interval, 1.10–2.24;
P
=0.013), independently of age, sex, ethnicity, body mass index, diabetes mellitus, and hypertension.

Conclusions—
OSA is independently associated with subsequent MACCEs in patients undergoing percutaneous coronary intervention. Evaluation of therapeutic approaches to mitigate OSA-associated risk is warranted.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01306526.
Galectin‐3 and Risk of Heart Failure and Death in Blacks and Whites
Authors: McEvoy John W. , Chen Yuan , Halushka Marc K. , Christenson Eric , Ballantyne Christie M. , Blumenthal Roger S. , Christenson Robert H. , Selvin Elizabeth 
Published: May 2016

Background

The association between galectin‐3 and heart failure (
HF
) or death is well established for white, but not for black, adults.

Methods and Results

Galectin‐3 was measured in 1809 participants (1375 white, 434 black), enrolled in a substudy of the Atherosclerosis Risk in Communities (
ARIC
) observational cohort during 2004–2005. We used Cox proportional hazard models to estimate the adjusted association between galectin‐3 and outcomes. Analyses were conducted overall and by race category. Median (interquartile range) galectin‐3 levels were 13.4 (11.2–16.4) and 14.8 (12–17.6) ng/mL, in white and black participants, respectively. In the sample overall, galectin‐3 was not independently associated with
HF
or death over a maximum of 7.9 years. However, in race‐stratified analyses, galectin‐3 was independently associated with a composite of
HF
or death among whites (eg, hazard ratio 2.2, 95%
CI
1.2–3.9, comparing Q4 versus Q1); but not among blacks (hazard ratio of 0.8 [0.4–1.8] for Q4 versus Q1, race interaction
P
=0.03). Associations between galectin‐3 and both outcomes analyzed individually also demonstrated similar racial differences. Furthermore, results were qualitatively similar with galectin‐3 modeled as a continuous exposure. In addition, galectin‐3 improved discrimination for the composite of
HF
or death among whites (increase in Harrell's C statistic from 0.729 to 0.735 [difference of +0.006],
P
=0.049), but not among blacks (0.696 to 0.695 [difference of −0.001],
P
=0.814).

Conclusions

In contrast to whites, galectin‐3 may have limited prognostic utility for predicting
HF
and death in blacks. While our results require replication, they could reflect racial differences in the processes by which galectin‐3 mediates disease.
Science–Policy Interplay: Improvement of Air Quality from 2008 to 2014 in Beijing and the Scientific Approach to Achieve APEC Blue
Authors: Wang Zhanshan , Li Yunting , Chen Tian , Zhang Dawei , Li Lingjun , Liu Baoxian , Li Jinxiang , Sun Feng , Pan Libo 
Published: May 2016

Abstract
The Beijing government has made great effort to solve the air pollution problem in recent years. In this paper, the major air pollution control measures and the air quality improvement from 2008 to 2014 in Beijing were represented. With the implementation of a series of unconventional and high–air pollutant reduction measures in Beijing and the surrounding area, good air quality during both the 2008 Olympic Games and the 2014 Asia–Pacific Economic Cooperation (APEC) conference was guaranteed. Notably, a new scientific approach was applied to formulate air pollution control policy during the APEC conference. In addition to the established measures, two periods of enhanced and targeted reduction measures were implemented according to the forecast in advance. Finally, suggestions for improving air quality in Beijing were offered on the basis of the monitoring results and analyses during the APEC conference.
Self-rated confidence and on-road driving performance among older adults
Authors: Riendeau Julie A. , Maxwell Hillary , Patterson Loretta , Weaver Bruce , Bédard Michel 
Published: May 2016

Background. Driver confidence can be measured through concepts such as driving frequency, situational avoidance, and self-perceptions. However, it is not clear how well confidence aligns with actual driving performance. Purpose. We examined the relationship between subjective measures of confidence in driving ability and on-road performance. Method. We report findings from two studies. The first compared scores from the Older and Wiser Driver Questionnaire to an on-road driving evaluation. The second looked at the Day and Night Driving Comfort Scales and Driving Habits and Intentions Questionnaire in relation to an on-road driving evaluation. Findings. No measures of confidence in driving ability were related to on-road driving performance. Implications. Confidence in driving ability bears little relationship to on-road performance. Future research should examine approaches to foster a better match between self-assessments and actual abilities among drivers.
Cooperation in Human-Agent Systems to Support Resilience
Authors: Chiou Erin K. , Lee John D. 
Published: May 2016

Objective: This study uses a dyadic approach to understand human-agent cooperation and system resilience. Background: Increasingly capable technology fundamentally changes human-machine relationships. Rather than reliance on or compliance with more or less reliable automation, we investigate interaction strategies with more or less cooperative agents. Method: A joint-task microworld scenario was developed to explore the effects of agent cooperation on participant cooperation and system resilience. To assess the effects of agent cooperation on participant cooperation, 36 people coordinated with a more or less cooperative agent by requesting resources and responding to requests for resources in a dynamic task environment. Another 36 people were recruited to assess effects following a perturbation in their own hospital. Results: Experiment 1 shows people reciprocated the cooperative behaviors of the agents; a low-cooperation agent led to less effective interactions and less resource sharing, whereas a high-cooperation agent led to more effective interactions and greater resource sharing. Experiment 2 shows that an initial fast-tempo perturbation undermined proactive cooperation—people tended to not request resources. However, the initial fast tempo had little effect on reactive cooperation—people tended to accept resource requests according to cooperation level. Conclusion: This study complements the supervisory control perspective of human-automation interaction by considering interdependence and cooperation rather than the more common focus on reliability and reliance. Application: The cooperativeness of automated agents can influence the cooperativeness of human agents. Design and evaluation for resilience in teams involving increasingly autonomous agents should consider the cooperative behaviors of these agents.
A systematic review of the compression regimes used in randomised clinical trials following endovenous ablation
Authors: El-Sheikha Joseph , Carradice Daniel , Nandhra Sandip , Leung Clement , Smith George E , Wallace Tom , Campbell Bruce , Chetter Ian C 
Published: May 2016

Objectives There is insufficient evidence to inform guidelines on the optimal compression strategy following ablation for varicose veins. This study aimed to identify the practice of key opinion leaders performing randomised clinical trials involving endovenous ablation. Method A systematic review of MEDLINE/EMBASE/CENTRAL was performed identifying the compression strategies used in randomised clinical trials where at least one comparator arm underwent endovenous ablation. Results Thirty-four randomised clinical trials were identified. At least 14 different compression products were used, with at least 6 different pressures in 7 different regimes with durations from 2 to 84 days. There was no evidence of any convergence of practice over time. Conclusions A lack of evidence as to the optimal strategy for compression has resulted in a marked variation in clinical practice. There is no suggestion that this variation is becoming less over time indicating that experience is not helping to form a consensus and, therefore, further research is required.
Impact of prior mammograms on combined reading of digital mammography and digital breast tomosynthesis
Authors: Kim Won Hwa , Chang Jung Min , Koo Hye Ryoung , Seo Mirinae , Bae Min Sun , Lee Joongyub , Moon Woo Kyung 
Published: May 2016

Background Although digital breast tomosynthesis (DBT) is an emerging technique yielding higher sensitivity and specificity compared to digital mammography (DM) alone, relative contribution of prior mammograms on the interpretation of DBT combined with DM has not been investigated. Purpose To retrospectively compare the diagnostic performances of DM, DM + DBT, and DM + DBT with prior mammograms. Material and Methods Three breast radiologists independently reviewed images of 116 patients with 24 cancers in the sequential order of DM, DM + DBT, and DM + DBT with prior mammograms using Breast Imaging Reporting and Data System (BI-RADS) assessment categories. Results The average areas under the receiver operating characteristic curve (AUC) of DM, DM + DBT, and DM + DBT with prior mammograms were 0.712, 0.777, and 0.816, respectively. Adding prior mammograms did not significantly affect the AUC of DM + DBT ( P = 0.108), whereas adding DBT significantly increased the AUC of DM ( P = 0.009). Sensitivity for DM, DM + DBT, and DM + DBT with prior mammograms was 58.3%, 69.4%, and 69.4%, and specificities were 84.1%, 85.9%, and 93.8%, respectively. Addition of DBT significantly increased the sensitivity ( P = 0.0090) of DM. Prior mammograms significantly improved the specificity of DM + DBT ( P = 0.0004), whereas adding prior mammogram did not affect sensitivity of DM + DBT ( P = 1.000). Conclusion DBT significantly increases the overall sensitivity and diagnostic performance of DM. Prior mammograms significantly increase the specificity of DM + DBT but have no significant effect on sensitivity and overall diagnostic performance.
Outcome of primary percutaneous stent-revascularization in patients with atherosclerotic acute mesenteric ischemia
Authors: Forbrig Robert , Renner Philipp , Kasprzak Piotr , Dahlke Marc-H , Müller-Wille René , Stroszczynski Christian , Heiss Peter 
Published: May 2016

Background Patients with acute mesenteric ischemia (AMI) often exhibit severe co-morbidities and significant surgical risks, leading to high perioperative morbidity. Purpose To investigate the feasibility of primary percutaneous stent-revascularization (PPSR) in atherosclerotic AMI and its impact on patients’ outcome. Material and Methods Retrospective analysis of 19 consecutive patients (7 women, 12 men; median age, 69 years) with AMI caused by atherosclerotic, non-embolic stenoses/occlusions of the splanchnic arteries and PPSR. Alternative minimally invasive techniques were excluded. Clinical characteristics including the Charlson Comorbidity Index adjusted by age (CCIa) and symptom duration, technical and clinical success of PPSR, clinical course, 30-day mortality, and follow-up were evaluated and compared to literature data for surgical approaches. Technical success was defined as residual stenosis of <30% in diameter. Clinical success was defined as resolution of symptoms of AMI and/or normalization of serum lactate after sole PPSR. Results The majority of patients presented with severe co-morbidities (CCIa >4 in 17 of 19 patients, 89%). Median symptom duration was 50 h. Technical and clinical success rates of PPSR were 95% (21 of 22 arteries) and 53% (10 of 19 patients). Seven patients underwent subsequent laparotomy with bowel resection in four cases. Thirty-day mortality was 42% (8 of 19 patients). Conclusion In our study population of patients with atherosclerotic AMI, severe co-morbidities, prolonged acute symptoms, and significant perioperative risks PPSR of splanchnic stenoses were technically feasible and the clinical outcome was acceptable.
Long-term clinical and radiological outcome of endovascular embolization of pancreatitis-related pseudoaneurysms
Authors: Vander Mijnsbrugge Ward , Laleman Wim , Van Steenbergen Werner , Heye Sam , Verslype Chris , Maleux Geert 
Published: May 2016

Background Long-term outcome after embolization of pancreatitis-induced pseudoaneurysm is not yet determined. Purpose To assess the long-term efficacy and patients’ overall survival after embolization of pancreatitis-induced pseudoaneurysm. Material and Methods Patients referred for endovascular treatment of a pancreatitis-induced pseudoaneurysm between January 1998 and January 2014 were analyzed. Embolization procedures were performed by transcatheter techniques using different types of embolic agents. Demographic, technical-radiological, and clinical data were collected. Results Thirty-four patients were identified with a pancreatitis-induced pseudoaneurysm; the underlying disease was acute (n = 13; 38%) or chronic (n = 21; 62%) pancreatitis; seven patients (20.6%) had active bleeding when embolized, while in the remaining 27 patients (79.4%) the pseudoaneurysm was not bleeding. In all 34 patients, successful endovascular exclusion of the pseudoaneurysm was obtained after the first attempt. Minor complications occurred in 11 patients (30%); no major complications were noted. A new pseudoaneurysm on a different vessel was identified during follow-up in three patients (9%). In another patient (3%), the excluded pseudoaneurysm reopened during follow-up. All four recurrences occurred within the first 5 months after embolization. Long-term follow-up (mean, 6.6 years; range, 4 months–16 years) revealed estimated survival rates of 94%, 89%, and 75% after 2, 5, and 10 years respectively, without pseudoaneurysm-related death. Conclusion Catheter-directed embolization of pancreatitis-induced pseudoaneurysms is relatively safe and effective. Recurrence or new pseudoaneurysm formation was low and occurred within the first 6 months after embolization. Overall survival is high, with no pseudoaneurysm-related deaths.
Quantification of inflammatory activity in patients with Crohn’s disease using diffusion weighted imaging (DWI) in MR enteroclysis and MR enterography
Authors: Stanescu-Siegmund Nora , Nimsch Yessica , Wunderlich Arthur P , Wagner Martin , Meier Reinhard , Juchems Markus S , Beer Meinrad , Schmidt Stefan A 
Published: May 2016

Background Individual studies have demonstrated the potential of diffusion-weighted magnetic resonance imaging (DWI-MRI) for identifying inflamed bowel segments. However, these studies were conducted with rather small patient cohorts and in most cases by means of MR enterography only. Purpose To demonstrate the feasibility of detecting inflamed bowel segments in a large collective of patients with Crohn’s disease using DWI in MR enteroclysis and MR enterography and to compare the results of both techniques, also considering clinical parameters by means of the Harvey-Bradshaw Index (HBI). Material and Methods Ninety-six patients underwent MRI enteroclysis and 35 patients MR enterography, both with additional DWI. The HBI as well as apparent diffusion coefficients (ADC) in areas of inflamed and normal bowel wall were determined. Thus resulting in 208 bowel segments that were visualized and subsequently statistically analyzed. Results There were no significant differences in ADC values in MR enteroclysis and MR enterography ( P = 0.383 in inflammation, P = 0.223 in normal wall). Areas of inflammation showed statistically highly significant lower ADC values than areas of normal bowel wall ( P < 0.001). An ADC threshold of 1.56 × 10–3 mm2/s can distinguish between normal and inflamed bowel segments with a sensitivity of 97.4% and a specificity of 99.2%. A highly significant correlation could be shown between ADC and HBI values ( P = 0.001). Conclusion DWI-MRI facilitates recognition of inflamed bowel segments in patients with Crohn’s disease and the ADC values show an excellent correlation to the HBI. There were no significant differences in ADC values in MR enteroclysis and MR enterography. An ADC threshold of 1.56 × 10–3 mm2/s differentiates between normal and inflamed bowel wall.
Towards improved migraine management: Determining potential trigger factors in individual patients
Authors: Peris Francesc , Donoghue Stephen , Torres Ferran , Mian Alec , Wöber Christian 
Published: May 2016

BackgroundCertain chronic diseases such as migraine result in episodic, debilitating attacks for which neither cause nor timing is well understood. Historically, possible triggers were identified through analysis of aggregated data from populations of patients. However, triggers common in populations may not be wholly responsible for an individual’s attacks. To explore this hypothesis we developed a method to identify individual ‘potential trigger’ profiles and analysed the degree of inter-individual variation.MethodsWe applied N = 1 statistical analysis to a 326-migraine-patient database from a study in which patients used paper-based diaries for 90 days to track 33 factors (potential triggers or premonitory symptoms) associated with their migraine attacks. For each patient, univariate associations between factors and migraine events were analysed using Cox proportional hazards models.ResultsWe generated individual factor-attack association profiles for 87% of the patients. The average number of factors associated with attacks was four per patient: Factor profiles were highly individual and were unique in 85% of patients with at least one identified association.ConclusionAccurate identification of individual factor-attack profiles is a prerequisite for testing which are true triggers and for development of trigger avoidance or desensitisation strategies. Our methodology represents a necessary development toward this goal.