bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer
Authors: Chou Angela , Froio Danielle , Nagrial Adnan M , Parkin Ashleigh , Murphy Kendelle J , Chin Venessa T , Wohl Dalia , Steinmann Angela , Stark Rhys , Drury Alison , Walters Stacey N , Vennin Claire , Burgess Andrew , Pinese Mark , Chantrill Lorraine A , Cowley Mark J , Molloy Timothy J , Waddell Nicola , Johns Amber , Grimmond Sean M , Chang David K , Biankin Andrew V , Sansom Owen J , Morton Jennifer P , Grey Shane T , Cox Thomas R , Turchini John , Samra Jaswinder , Clarke Stephen J , Timpson Paul , Gill Anthony J , Pajic Marina 
Published: October 2017

ObjectiveExtensive molecular heterogeneity of pancreatic ductal adenocarcinoma (PDA), few effective therapies and high mortality make this disease a prime model for advancing development of tailored therapies. The p16-cyclin D-cyclin-dependent kinase 4/6-retinoblastoma (RB) protein (CDK4) pathway, regulator of cell proliferation, is deregulated in PDA. Our aim was to develop a novel personalised treatment strategy for PDA based on targeting CDK4.DesignSensitivity to potent CDK4/6 inhibitor PD-0332991 (palbociclib) was correlated to protein and genomic data in 19 primary patient-derived PDA lines to identify biomarkers of response. In vivo efficacy of PD-0332991 and combination therapies was determined in subcutaneous, intrasplenic and orthotopic tumour models derived from genome-sequenced patient specimens and genetically engineered model. Mechanistically, monotherapy and combination therapy were investigated in the context of tumour cell and extracellular matrix (ECM) signalling. Prognostic relevance of companion biomarker, RB protein, was evaluated and validated in independent PDA patient cohorts (>500 specimens).ResultsSubtype-specific in vivo efficacy of PD-0332991-based therapy was for the first time observed at multiple stages of PDA progression: primary tumour growth, recurrence (second-line therapy) and metastatic setting and may potentially be guided by a simple biomarker (RB protein). PD-0332991 significantly disrupted surrounding ECM organisation, leading to increased quiescence, apoptosis, improved chemosensitivity, decreased invasion, metastatic spread and PDA progression in vivo. RB protein is prevalent in primary operable and metastatic PDA and may present a promising predictive biomarker to guide this therapeutic approach.ConclusionThis study demonstrates the promise of CDK4 inhibition in PDA over standard therapy when applied in a molecular subtype-specific context.
Rethinking safety in numbers: are intersections with more crossing pedestrians really safer?
Authors: Xu Pengpeng , Xie Siqi , Dong Ni , Wong Sze Chun , Huang Helai 
Published: October 2017

ObjectiveTo advance the interpretation of the ‘safety in numbers’ effect by addressing the following three questions. How should the safety of pedestrians be measured, as the safety of individual pedestrians or as the overall safety of road facilities for pedestrians? Would intersections with large numbers of pedestrians exhibit a favourable safety performance? Would encouraging people to walk be a sound safety countermeasure?MethodsWe selected 288 signalised intersections with 1003 pedestrian crashes in Hong Kong from 2010 to 2012. We developed a Bayesian Poisson-lognormal model to calculate two common indicators related to pedestrian safety: the expected crash rate per million crossing pedestrians and the expected excess crash frequency. The ranking results of these two indicators for the selected intersections were compared.ResultsWe confirmed a significant positive association between pedestrian volumes and pedestrian crashes, with an estimated coefficient of 0.21. Although people who crossed at intersections with higher pedestrian volumes experienced a relatively lower crash risk, these intersections may still have substantial potential for crash reduction.ConclusionsConclusions on the safety in numbers effect based on a cross-sectional analysis should be reached with great caution. The safety of individual pedestrians can be measured based on the crash risk, whereas the safety of road facilities for pedestrians should be determined by the environmental hazards of walking. Intersections prevalent of pedestrians do not always exhibit favourable safety performance. Relative to increasing the number of pedestrians, safety strategies should focus on reducing environmental hazards and removing barriers to walking.
Endovascular treatment for cerebral vasospasm following aneurysmal subarachnoid hemorrhage: predictors of outcome and retreatment
Authors: Sokolowski Jennifer D , Chen Ching-Jen , Ding Dale , Buell Thomas J , Raper Daniel M , Ironside Natasha , Taylor Davis G , Starke Robert M , Liu Kenneth 
Published: October 2017

ObjectiveAlthough endovascular therapy has been widely adopted for the treatment of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH), its effect on clinical outcomes remains incompletely understood. The aims of this retrospective cohort study are to evaluate the outcomes of endovascular intervention for post-aSAH vasospasm and identify predictors of functional independence at discharge and repeat endovascular vasospasm treatment.MethodsWe assessed the baseline and outcomes data for patients with aSAH who underwent endovascular vasospasm treatment at our institution, including intra-arterial (IA) vasodilator infusion and angioplasty. Statistical analyses were performed to determine factors associated with good outcome at discharge (modified Rankin Scale 0–2) and repeat endovascular vasospasm treatment.ResultsThe study cohort comprised 159 patients with a mean age of 52 years. Good outcome was achieved in 17% of patients at discharge (26/150 patients), with an in-hospital mortality rate of 22% (33/150 patients). In the multivariate analysis, age (OR 0.895; p=0.009) and positive smoking status (OR 0.206; p=0.040) were negative independent predictors of good outcome. Endovascular retreatment was performed in 34% (53/156 patients). In the multivariate analysis, older age (OR 0.950; p=0.004), symptomatic vasospasm (OR 0.441; p=0.046), initial treatment with angioplasty alone (OR 0.096; p=0.039), and initial treatment with combined IA vasodilator infusion and angioplasty (OR 0.342; p=0.026) were negative independent predictors of retreatment.ConclusionWe found a modest rate of functional independence at discharge in patients with aSAH who underwent endovascular vasospasm treatment. Older patients and smokers had worse functional outcomes at discharge. Initial use of angioplasty appears to decrease the need for subsequent retreatment.
miR-20a Regulates FAS Expression in Osteosarcoma Cells by Modulating FAS Promoter Activity and Can be Therapeutically Targeted to Inhibit Lung Metastases
Authors: Yang Yuanzheng , Huang Gangxiong , Zhou Zhichao , Fewell Jason G. , Kleinerman Eugenie S. 
Published: October 2017

Abstract
The metastatic potential of osteosarcoma cells is inversely correlated to cell surface FAS expression. Downregulation of FAS allows osteosarcoma cells to escape FAS ligand–mediated apoptosis when they enter a FAS ligand–positive microenvironment such as the lung. We have previously demonstrated that miR-20a, encoded by the miR-17-92 cluster, downregulates FAS expression in osteosarcoma. We further demonstrated an inverse correlation between FAS expression and miR-20a expression. However, the mechanism of FAS regulation by miR-20a was still unclear. The purpose of the current study was to evaluate the mechanism of FAS regulation by miR-20a in vitro and test the effect of targeting miR-20a in vivo. We investigated whether miR-20a's downregulation of FAS was mediated by binding to the 3′-untranslated region (3′-UTR) of FAS mRNA with the consequent induction of mRNA degradation or translational suppression. We identified and mutated two miR-20a binding sites on the FAS mRNA 3′-UTR. Using luciferase reporter assays, we demonstrated that miR-20a did not bind to either the wild-type or mutated FAS 3′-UTR. In contrast, overexpression of miR-20a resulted in downregulation of FAS promoter activity. Similarly, the inhibition of miR-20a increased FAS promoter activity. The critical region identified on the FAS promoter was between −240 bp and −150 bp. Delivery of anti-miR-20a in vivo using nanoparticles in mice with established osteosarcoma lung metastases resulted in upregulation of FAS and tumor growth inhibition. Taken together, our data suggest that miR-20a regulates FAS expression through the modulation of the FAS promoter and that targeting miR-20a using anti-miR-20a has therapeutic potential. Mol Cancer Ther; 17(1); 130–9. ©2017 AACR.
Reversible Transgene Expression Reduces Fratricide and Permits 4-1BB Costimulation of CAR T Cells Directed to T-cell Malignancies
Authors: Mamonkin Maksim , Mukherjee Malini , Srinivasan Madhuwanti , Sharma Sandhya , Gomes-Silva Diogo , Mo Feiyan , Krenciute Giedre , Orange Jordan S. , Brenner Malcolm K. 
Published: October 2017

AbstractT cells expressing second-generation chimeric antigen receptors (CARs) specific for CD5, a T-cell surface marker present on normal and malignant T cells, can selectively kill tumor cells. We aimed to improve this killing by substituting the CD28 costimulatory endodomain (28.z) with 4-1BB (BB.z), as 28.z CD5 CAR T cells rapidly differentiated into short-lived effector cells. In contrast, 4-1BB costimulation is known to promote development of the central memory subpopulation. Here, we found BB.z CD5 CAR T cells had impaired growth compared with 28.z CD5.CAR T cells, due to increased T-cell–T-cell fratricide. We demonstrate that TRAF signaling from the 4-1BB endodomain upregulated the intercellular adhesion molecule 1, which stabilized the fratricidal immunologic synapse between CD5 CAR T cells. As the surviving BB.z CD5 CAR T cells retained the desired central memory phenotype, we aimed to circumvent the 4-1BB–mediated toxicity using a regulated expression system that reversibly inhibits CAR expression. This system minimized CAR signaling and T-cell fratricide during in vitro expansion in the presence of a small-molecule inhibitor, and restored CAR expression and antitumor function of transduced T cells in vivo. These studies reveal a mechanism by which 4-1BB costimulation impairs expansion of CD5 CAR T cells and offer a solution to mitigate this toxicity. Cancer Immunol Res; 6(1); 47–58. ©2017 AACR.
Characterization of Gadolinium Contrast Enhancement of Radiofrequency Ablation Lesions in Predicting Edema and Chronic Lesion Size
Authors: Ghafoori Elyar , Kholmovski Eugene G. , Thomas Sam , Silvernagel Josh , Angel Nathan , Hu Nan , Dosdall Derek J. , MacLeod Rob , Ranjan Ravi 
Published: October 2017

Background
Magnetic resonance imaging (MRI) has been used to acutely visualize radiofrequency ablation lesions, but its accuracy in predicting chronic lesion size is unknown. The main goal of this study was to characterize different areas of enhancement in late gadolinium enhancement MRI done immediately after ablation to predict acute edema and chronic lesion size.

Methods and Results

In a canine model (n=10), ventricular radiofrequency lesions were created using ThermoCool SmartTouch (Biosense Webster) catheter. All animals underwent MRI (late gadolinium enhancement and T2-weighted edema imaging) immediately after ablation and after 1, 2, 4, and 8 weeks. Edema, microvascular obstruction, and enhanced volumes were identified in MRI and normalized to chronic histological volume. Immediately after contrast administration, the microvascular obstruction region was 3.2±1.1 times larger than the chronic lesion volume in acute MRI. Even 60 minutes after contrast administration, edema was 8.7±3.31 times and the enhanced area 6.14±2.74 times the chronic lesion volume. Exponential fit to the microvascular obstruction volume was found to be the best predictor of chronic lesion volume at 26.14 minutes (95% prediction interval, 24.35–28.11 minutes) after contrast injection. The edema volume in late gadolinium enhancement correlated well with edema volume in T2-weighted MRI with an
R
2
of 0.99.

Conclusion
Microvascular obstruction region on acute late gadolinium enhancement images acquired 26.1 minutes after contrast administration can accurately predict the chronic lesion volume. We also show that T1-weighted MRI images acquired immediately after contrast injection accurately shows edema resulting from radiofrequency ablation.
Impaired Fasting Glucose Is the Major Determinant of the 20‐Year Mortality Risk Associated With Metabolic Syndrome in Nondiabetic Patients With Stable Coronary Artery Disease
Authors: Younis Arwa , Goldkorn Ronen , Goldenberg Ilan , Geva Diklah , Tzur Boaz , Mazu Anna , Younis Anan , Fisman Zvi , Tannenbaum Alexander , Klempfner Robert 
Published: October 2017

Background
We wanted to explore the association of metabolic syndrome (MetS) versus its individual components with 20‐year all‐cause mortality among patients with stable coronary artery disease.

Methods and Results

The cohort comprised 12 403 nondiabetic patients with stable coronary artery disease who were enrolled in the Bezafibrate Infarction Prevention Registry between February 1990 and October 1992 and followed up through December 2014. The study cohort was divided into 4 groups: patients without MetS or impaired fasting glucose (
IFG
), patients with
IFG
but without MetS, patients with MetS but without
IFG
, and patients with both MetS and
IFG
. Kaplan‐Meier survival analysis showed that at 20 years of follow‐up, the rates of all‐cause mortality were the highest among patients with both MetS and
IFG
(66%). Patients with
IFG
without MetS experienced a significantly higher mortality rate compared with those with MetS without
IFG
(61% versus 56%; log‐rank
P
<0.001). Multivariable Cox proportional hazard analysis showed that the final Cox model demonstrated that the additive effect of MetS (hazard ratio, 1.13; 95% confidence interval, 1.1–1.16;
P
=0.02) and
IFG
(hazard ratio, 1.54; 95% confidence interval, 1.46–1.62;
P
<0.001) on 20 years mortality was nonsignificant (hazard ratio, 1.01; 95% confidence interval, 0.93–1.11;
P
=0.69).
IFG
was associated with the most pronounced increase in mortality risk among the individual components (hazard ratio, 1.22; 95% confidence interval, 1.14–1.3;
P
<0.001).

Conclusions

Our findings suggest that
IFG
alone is a major independent predictor of long‐term mortality among patients with stable coronary artery disease versus other components of the MetS.
Endothelial Progenitor Cell Biology and Vascular Recovery Following Transradial Cardiac Catheterization
Authors: Mitchell Andrew , Fujisawa Takeshi , Mills Nicholas L. , Brittan Mairi , Newby David E. , Cruden Nicholas L. M. 
Published: October 2017

Background
Transradial catheterization is associated with radial artery injury and vasomotor dysfunction and represents an accessible model of acute vascular injury in humans. We characterized vascular injury and functional recovery to understand the role of circulating endothelial progenitor cells in vascular repair.

Methods and Results

In 50 patients (aged 64±10 years, 70% male) undergoing transradial cardiac catheterization, radial artery injury was assessed by optical coherence tomography and examination of explanted vascular sheaths. Flow‐ and nitrate‐mediated dilatation of the radial artery was assessed in both arms at baseline, at 24 hours, and at 1, 4, and 12 weeks. Circulating endothelial progenitor cell populations were quantified using flow cytometry. Late endothelial outgrowth colonies were isolated and examined in vitro. Optical coherence tomography identified macroscopic injury in 12 of 50 patients (24%), but endothelial cells (1.9±1.2×10
4
cells) were isolated from all arterial sheaths examined. Compared with the noncatheterized radial artery, flow‐mediated vasodilatation was impaired in the catheterized artery at 24 hours (9.9±4.6% versus 4.1±3.1%,
P
<0.0001) and recovered by 12 weeks (8.1±4.9% versus 10.1±4.9%,
P
=0.09). Although the number of
CD
133
+
cells increased 24 hours after catheterization (
P
=0.02), the numbers of
CD
34
+
cells and endothelial outgrowth colonies were unchanged. Migration of endothelial cells derived from endothelial outgrowth colonies correlated with arterial function before catheterization but was not related to recovery of function following injury.

Conclusions
Transradial cardiac catheterization causes endothelial denudation, vascular injury, and vasomotor dysfunction that recover over 12 weeks. Recovery of vascular function does not appear to be dependent on the mobilization or function of endothelial progenitor cells.

Clinical Trial Registration

URL
:
https://www.clinicaltrials.gov
. Unique identifier:
NCT
02147119.
Comparative Risk of Cardiovascular Outcomes Between Topical and Oral Nonselective NSAIDs in Taiwanese Patients With Rheumatoid Arthritis
Authors: Lin Tzu‐Chieh , Solomon Daniel H. , Tedeschi Sara K. , Yoshida Kazuki , Kao Yang Yea‐Huei 
Published: October 2017

Background

Topical
NSAID
s have less systemic absorption than oral
NSAID
s. We examined the risk of cardiovascular events associated with nonselective topical NSAIDs versus oral NSAIDs among patients with rheumatoid arthritis in Taiwan.

Methods and Results

We conducted a retrospective cohort study that included patients with incident rheumatoid arthritis who were newly starting therapy with nonselective topical NSAIDs or oral NSAIDs. We used the Taiwan National Health Insurance Research Database (
NHIRD
). The first date patients received either type of
NSAID
was defined as the index date.
NSAID
exposures continued until there was a treatment gap of >30 days. The main outcome was composite cardiovascular events, including myocardial infarction, unstable angina, heart failure, stroke, or revascularization. Follow‐up was censored at treatment discontinuation, switch or addition of other
NSAID
category, cardiovascular outcome, death, or the end of the study. Propensity score weighted Cox regression models were used to compare the risk of cardiovascular events between topical NSAIDs and oral NSAIDs. There were 10 758 and 78 056 treatment episodes for topical and oral
NSAID
s identified. After weighting by propensity score, the cohorts were well balanced over all covariates. The crude cardiovascular event rate was 1.87 per 100 person‐years for topical
NSAID
s and 2.14 per 100 person‐years for oral
NSAID
s. Results of propensity score weighted Cox regression found the topical NSAID group had 36% lower risk for cardiovascular events compared with the oral NSAID group (hazard ratio, 0.64; 95% confidence interval, 0.43–0.95).

Conclusions

We found topical NSAID users experienced a reduced risk of cardiovascular events compared with oral NSAID users. If future studies with a larger sample size and longer follow‐up confirm these results,
NSAID
prescribing might change accordingly.
Gender Differences in the Reporting of Vocal Fatigue in Teachers as Quantified by the Vocal Fatigue Index
Authors: Hunter Eric J. , Banks Russell E. 
Published: October 2017

Objectives: Occupational voice users report higher instances of vocal health problems. Women, who are more likely than men to report voice problems, are the largest members of some occupational voice users, such as teachers. While a common complaint among this population is vocal fatigue, it has been difficult to quantify. Therefore, the goal of this study is to quantify vocal fatigue generally in school teachers and investigate any related gender differences. Methods: Six hundred forty (518 female, 122 male) teachers were surveyed using an online questionnaire consisting in part of the Vocal Fatigue Index (VFI), an index specifically designed to quantify vocal fatigue. Results: Compared to vocally healthy adults, the teachers surveyed were 3 times as likely to report vocal tiredness or vocal avoidance and over 3 times as likely to report physical voice discomfort. Additionally, female teachers were more likely to have scores approaching those with dysphonia. Conclusions: The VFI quantified elevated levels of vocal fatigue in teachers, with a significant prevalence of symptoms reported among females compared to males. Further, because the VFI indicated elevated complaints (between normal and dysphonic) in a population likely to be elevated, the VFI might be used to identify early indications of voice problems and/or track recovery.
Bipolar Radiofrequency Ablation (Coblation) of External Auditory Canal Lymphatic Malformation and Other Soft Stenoses
Authors: Gu Alex , Bauman Nancy M. 
Published: October 2017

Introduction: Soft tissue occlusion of the external auditory canal (EAC) can cause intense pruritis, recurrent foul smelling otorrhea, recurrent otitis externa, and conductive hearing loss. Occlusion of the EAC can be challenging to treat as the area is prone to circumferential scarring. Methods: We describe the novel use of serial bipolar radiofrequency ablation (coblation) to treat 3 children with complete EAC occlusion from congenital and acquired conditions including lymphedema (1), microcystic lymphatic malformation (1), and venolymphatic malformation (1). Results: Patients underwent a mean of 3 procedures with postoperative EAC stenting (7 days) and antibiotic and steroid aural preparations (10 days). Otologic symptoms resolved in all patients, and their EACs remained patent 14 months after last procedure (range, 4-32 months). One patient experienced a pinpoint tympanic membrane perforation that healed spontaneously 2 weeks later. Conclusions: Coblation of soft tissue stenosis of the EAC can be an effective treatment for this problematic condition.
A Mindful Approach to Diabetes Self-Management Education and Support for Veterans
Authors: DiNardo Monica , Saba Shaddy , Greco Carol M. , Broyles Lauren , Terhorst Lauren , Chasens Eileen R. , Bair Brandi , Charron-Prochownik Denise , Cohen Susan 
Published: October 2017

Purpose The purpose of this study is to determine feasibility, satisfaction, and preliminary effects of Mindful Stress Reduction in Diabetes Education (Mind-STRIDE), a mindfulness-based intervention for veterans. Methods The study used a single-group pretest-posttest repeated-measures design. The 90-minute Mind-STRIDE training, adapted from Mindfulness Based Stress Reduction (MBSR), was provided as the final component of a half-day diabetes self-management education class at a Veterans Affairs (VA) outpatient diabetes clinic. Following initial training, participants were asked to practice mindfulness at home for 10 minutes each day during the 3-month study. Study recruitment and retention were calculated as rates. Veteran and diabetes educator satisfaction were assessed by rating scales and open-ended comments. Psychosocial-behavioral and metabolic outcomes were assessed at baseline and 3 months after initial training. Bivariate correlations were performed to describe relationships between mindfulness and other outcome variables. Gain scores and Wilcoxon matched-pair signed rank tests were used to assess pre to post changes; Cohen’s d was applied to estimate the magnitude of effects. Results Twenty-eight of 49 eligible veterans (57%) enrolled in the study. Of those, 11 veterans (39%) demonstrated participation in home practice, and 20 veterans (71%) completed the study. Overall, participants and diabetes educators were highly satisfied with the Mind-STRIDE intervention. Significant improvements were found in diabetes distress, diabetes self-efficacy, diabetes self-management behaviors, mindful-describing, and A1C. Conclusion Results suggest feasibility, satisfaction, and positive preliminary effects. Efficacy testing by randomized controlled trial with analysis of covariance structures is warranted.