bluuebunny/crossref_metadata_2025_split huggingface dataset:
Faster on-scene times associated with decreased mortality in Helicopter Emergency Medical Services (HEMS) transported trauma patients
Authors: Pham Hannah , Puckett Yana , Dissanaike Sharmila 
Published: October 2017

BackgroundThe ‘Golden Hour’ emphasizes the importance of rapidly providing definitive care to trauma patients. Dispatch time, defined as the time it takes the Helicopter Emergency Medical Service (HEMS) to dispatch from their base and reach the patient, and on-scene time, defined as the time spent with the patient prior to departure to a trauma center, can impact how quickly the patient will reach definitive care. We evaluated HEMS dispatch and on-scene times by investigating the survival rates among patients transported by air to a level 1 trauma center. We hypothesize that longer HEMS dispatch and on-scene times are associated with worse patient outcomes.MethodsA retrospective, single institution analysis was performed on patients transported by HEMS. Inclusion criteria were air transported patients aged 18 years and above admitted to a level 1 trauma center from January 1, 2005 to January 1, 2015. Total dispatch time and on-scene times were divided into five incremental groups and mortality data were analyzed. Mortality was defined as death during initial hospital admission. A Pearson’s correlation was used to analyze relationship between dispatch times, on-scene times, and mortality. Simple binary logistic regression was used to run a multivariate analysis on confounding variables of Injury Severity Score (ISS), gender, age, and Glasgow Coma Scale.ResultsThere was a strong positive linear correlation between HEMS on-scene time and mortality, R=0.962, p=0.038. Additionally, there was a positive trend between HEMS dispatch time and mortality. ISS was found to be a significant confounder of mortality in our cohort with on-scene times >20 min, with mortality increasing by 7.5% for every 0.1 increase in ISS score (p=0.01).ConclusionLonger HEMS on-scene and dispatch times appeared to be associated with increased mortality in trauma patients. However, those with higher ISS require longer on-scene times, increasing mortality. Regardless, efforts should focus on reducing on-scene and dispatch times.Level of evidence and study typeLevel III; Therapeutic/Care Management.
Carbohydrate restriction with postmeal walking effectively mitigates postprandial hyperglycemia and improves endothelial function in type 2 diabetes
Authors: Francois Monique E. , Myette-Cote Etienne , Bammert Tyler D. , Durrer Cody , Neudorf Helena , DeSouza Christopher A. , Little Jonathan P. 
Published: October 2017

Postprandial hyperglycemia has deleterious effects on endothelial function. Restricting carbohydrate intake and postmeal walking have each been shown to reduce postprandial hyperglycemia, but their combination and subsequent effects on endothelial function have not been investigated. Here, we sought to examine the effect of blunting postprandial hyperglycemia by following a low-carbohydrate diet, with or without postmeal walking exercise, on markers of vascular health in type 2 diabetes (T2D). In a randomized crossover design, individuals with T2D ( n = 11) completed three 4-day controlled diet interventions consisting of 1) low-carbohydrate diet alone (LC), 2) low-carbohydrate diet with 15-min postmeal walks (LC + Ex), and 3) low-fat control diet (CON). Fasting blood samples and brachial artery flow-mediated dilation (%FMD) were measured before and after each intervention. Total circulating microparticles (MPs), endothelial MPs, platelet MPs, monocyte-platelet aggregates, and adhesion molecules were assessed as biomarkers of vascular health. There was a significant condition × time interaction for %FMD ( P = 0.01), with post hoc tests revealing improved %FMD after LC + Ex (+0.8 ± 1.0%, P = 0.02), with no change after LC or CON. Endothelial MPs were significantly reduced with the LC diet by ~45% (from 99 ± 60 to 44 ± 31 MPs/μl, P = 0.02), with no change after LC + Ex or CON (interaction: P = 0.04). Total MPs were lower (main effect time: P = 0.02), whereas monocyte-platelet aggregates were higher (main effect time: P < 0.01) after all interventions. Plasma adhesion molecules and C-reactive protein were unaltered. Attenuating postprandial hyperglycemic excursions using a low-carbohydrate diet combined with postmeal walking appears to be an effective strategy to improve endothelial function in individuals with T2D.NEW & NOTEWORTHY Carbohydrate restriction and postmeal walking lower postprandial hyperglycemia in individuals with type 2 diabetes. Here, we show that the combination significantly improved endothelial function and that carbohydrate restriction alone reduced circulating endothelial microparticles in individuals with type 2 diabetes.Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/low-carb-diet-and-exercise-improve-endothelial-health/ .
Phase Ib/II Trial of NC-6004 (Nanoparticle Cisplatin) Plus Gemcitabine in Patients with Advanced Solid Tumors
Authors: Subbiah Vivek , Grilley-Olson Juneko E. , Combest Austin J. , Sharma Neelesh , Tran Richard H. , Bobe Iulian , Osada Atsushi , Takahashi Kazuhiro , Balkissoon Jaikrishna , Camp Aaron , Masada Atsuhiro , Reitsma Dirk J. , Bazhenova Lyudmila A. 
Published: October 2017

Abstract
Purpose: NC-6004, a novel cisplatin nanoparticle developed using micellar technology exhibits sustained release of cisplatin and selective distribution to tumors. Preclinical data demonstrated a favorable tolerability profile and preserved or improved antitumor activity compared with cisplatin across animal models. We evaluated the safety and tolerability of NC-6004 and gemcitabine using a Bayesian continual reassessment model (N-CRM) to determine the optimal dose.
Experimental Design: Patients with advanced solid tumors received NC-6004 at 60 to 180 mg/m2 on day 1 and gemcitabine at 1,250 mg/m2 on days 1 and 8 every 3 weeks. Dose escalation of NC-6004 began with a single patient run-in until a dose-limiting toxicity occurred at 180 mg/m2. Cohorts of four patients were enrolled at doses predicted by the N-CRM. The maximum tolerated dose (MTD) was defined as having the greatest probability of target toxicity &lt;25%. Quality of life was assessed using EORTC-QLQ-C30.
Results: Among 22 patients, the most common grade III/IV hematologic adverse events were leukopenia (68%) and thrombocytopenia (59%). Of 20 pretreated patients evaluable for response, half were previously exposed to a platinum agent. The MTD was 135 mg/m2. Nine patients were treated at the MTD with median treatment duration of 15 weeks (range, 3–50). Tumor shrinkage occurred in 11 (55%), partial responses in 3 (15%), and stable disease in 14 (70%). Most patients reported stable or improved EORTC QLQ-C30 scores.
Conclusions: Greater cisplatin equivalent doses were achieved with no clinically significant neuro-, oto-, or nephrotoxicity. These data demonstrate tolerability and promising activity of NC-6004 in combination with gemcitabine. Clin Cancer Res; 24(1); 43–51. ©2017 AACR.
RAD50 Expression Is Associated with Poor Clinical Outcomes after Radiotherapy for Resected Non–small Cell Lung Cancer
Authors: Wang Yifan , Gudikote Jayanthi , Giri Uma , Yan Jun , Deng Weiye , Ye Rui , Jiang Wen , Li Nan , Hobbs Brian P. , Wang Jing , Swisher Stephen G. , Fujimoto Junya , Wistuba Ignacio I. , Komaki Ritsuko , Heymach John V. , Lin Steven H. 
Published: October 2017

Abstract
Purpose: Although postoperative radiotherapy is often used to maintain local control after surgical resection and chemotherapy for locally advanced non–small cell lung cancer (NSCLC), both locoregional failure and distant metastasis remain problematic. The mechanisms of therapeutic resistance remain poorly understood.
Experimental Design: We used reverse-phase protein arrays (RPPA) to profile the baseline expression of 170 total and phosphorylated proteins in 70 NSCLC cell lines to categorize pathways that may contribute to radiation resistance. Significant markers identified by RPPA were further analyzed in tissue microarrays (TMA) of specimens from 127 patients with NSCLC who had received surgery before receiving postoperative radiotherapy. Cox regression analysis and log-rank tests were used to identify potential predictive factors. We then validated the biological function of the markers in NSCLC cell lines in vitro.
Results: Of the 170 proteins or phospho-proteins profiled, a subset of 12 proteins was found to correlate with radiation response parameters. TMA analysis of the 12 proteins showing the greatest differences in expression in the RPPA analysis demonstrated that RAD50 had the strongest correlation with distant relapse-free survival, locoregional relapse-free survival, and disease-free survival in patients with NSCLC. We confirmed that knockdown of RAD50 sensitized NSCLC cells to radiation and that upregulation of RAD50 increased radioresistance in in vitro experiments.
Conclusions: Upregulated RAD50 may be a predictor of radioresistance in patients with lung cancer who received radiotherapy. Clin Cancer Res; 24(2); 341–50. ©2017 AACR.
Cell-Cycle and DNA-Damage Response Pathway Is Involved in Leptomeningeal Metastasis of Non–Small Cell Lung Cancer
Authors: Fan Yun , Zhu Xuehua , Xu Yan , Lu Xuesong , Xu Yanjun , Wang Mengzhao , Xu Haiyan , Ding Jingyan , Ye Xin , Fang Luo , Huang Zhiyu , Gong Lei , Lu Hongyang , Mao Weimin , Hu Min 
Published: October 2017

Abstract
Purpose: Leptomeningeal metastasis (LM) is a detrimental complication of non–small cell lung cancer (NSCLC) and associated with poor prognosis. However, the underlying mechanisms of the metastasis process are still poorly understood.
Experimental Design: We performed next-generation panel sequencing of primary tumor tissue, cerebrospinal fluid (CSF), and matched normal controls from epidermal growth factor receptor (EGFR) mutation-positive NSCLC patients with LM.
Results: The status of EGFR-activating mutations was highly concordant between primary tumor and CSF. PIK3CA aberrations were high in these patients, implicating an association with LM risk. Intriguingly, low overlapping of somatic protein-changing variants was observed between paired CSF and primary lesions, exhibiting tumor heterogeneity and genetic divergence. Moreover, genes with CSF-recurrent genomic alterations were predominantly involved in cell-cycle regulation and DNA-damage response (DDR), suggesting a role of the pathway in LM development.
Conclusions: Our study has shed light on the genomic variations of NSCLC-LM, demonstrated genetic heterogeneity and divergence, uncovered involvement of cell-cycle and DDR pathway, and paved the way for potential therapeutic approaches to this unmet medical need. Clin Cancer Res; 24(1); 209–16. ©2017 AACR.
A Prognostic Bio-Model Based on SQSTM1 and N-Stage Identifies Nasopharyngeal Carcinoma Patients at High Risk of Metastasis for Additional Induction Chemotherapy
Authors: Yang Qi , Zhang Meng-Xia , Zou Xiong , Liu You-Ping , You Rui , Yu Tao , Jiang Rou , Zhang Yi-Nuan , Cao Jing-Yu , Hong Ming-Huang , Liu Qing , Guo Ling , Kang Tie-Bang , Zhu Xiao-Feng , Chen Ming-Yuan 
Published: October 2017

Abstract
Purpose: Metastasis is one of the most important causes of treatment failure in nasopharyngeal carcinoma (NPC). In T4 or N2-3 patients at high-risk of metastasis, concurrent chemoradiotherapy (CCRT) is inadequate and additional induction chemotherapy (IC) is controversial. There is a critical need to develop a better patient stratification to efficiently identify patients at high-risk of metastasis for additional IC. Recently, Sequestosome 1 (SQSTM1)/p62, an autophagy adaptor protein, was identified as one of the metastasis-related proteins in NPC. However, the mechanism by which SQSTM1 is involved in NPC metastasis was not investigated.
Experimental Design: The effect of SQSTM1 on cell migration and invasion was examined in vitro and in vivo. SQSTM1 expression was analyzed in clinical NPC samples using IHC. Luciferase reporter analyses were conducted to identify the effects of SQSTM1 on NF-κB transcriptional activity. A prediction bio-model was constructed by Cox analysis. Retrospective and prospective randomized clinical data were adopted to build and test the model, respectively.
Results: SQSTM1 mediated epithelial to mesenchymal transition (EMT) through the NF-κB pathway to promote NPC metastasis. Inhibiting SQSTM1 enhanced sensitivity to cisplatin in NPC cells. In NPC patients, high SQSTM1 expression was associated with increased risk of distant metastasis. Furthermore, we propose a prognostic bio-model based on SQSTM1 and N-stage to predict NPC metastasis. Most importantly, our prospective randomized study suggested that IC is beneficial for NPC patients with high metastasis risk.
Conclusions: The prognostic bio-model identifies NPC patients at high-risk of metastasis for additional IC. Clin Cancer Res; 24(3); 648–58. ©2017 AACR.
HMG-CoA Reductase Inhibition Delays DNA Repair and Promotes Senescence After Tumor Irradiation
Authors: Efimova Elena V. , Ricco Natalia , Labay Edwardine , Mauceri Helena J. , Flor Amy C. , Ramamurthy Aishwarya , Sutton Harold G. , Weichselbaum Ralph R. , Kron Stephen J. 
Published: October 2017

Abstract
Despite significant advances in combinations of radiotherapy and chemotherapy, altered fractionation schedules and image-guided radiotherapy, many cancer patients fail to benefit from radiation. A prevailing hypothesis is that targeting repair of DNA double strand breaks (DSB) can enhance radiation effects in the tumor and overcome therapeutic resistance without incurring off-target toxicities. Unrepaired DSBs can block cancer cell proliferation, promote cancer cell death, and induce cellular senescence. Given the slow progress to date translating novel DSB repair inhibitors as radiosensitizers, we have explored drug repurposing, a proven route to improving speed, costs, and success rates of drug development. In a prior screen where we tracked resolution of ionizing radiation-induced foci (IRIF) as a proxy for DSB repair, we had identified pitavastatin (Livalo), an HMG-CoA reductase inhibitor commonly used for lipid lowering, as a candidate radiosensitizer. Here, we report that pitavastatin and other lipophilic statins are potent inhibitors of DSB repair in breast and melanoma models both in vitro and in vivo. When combined with ionizing radiation, pitavastatin increased persistent DSBs, induced senescence, and enhanced acute effects of radiation on radioresistant melanoma tumors. shRNA knockdown implicated HMG-CoA reductase, farnesyl diphosphate synthase, and protein farnesyl transferase in IRIF resolution, DSB repair, and senescence. These data confirm on-target activity of statins, although via inhibition of protein prenylation rather than cholesterol biosynthesis. In light of prior studies demonstrating enhanced efficacy of radiotherapy in patients taking statins, this work argues for clinical evaluation of lipophilic statins as nontoxic radiosensitizers to enhance the benefits of image-guided radiotherapy. Mol Cancer Ther; 17(2); 407–18. ©2017 AACR.
See all articles in this MCT Focus section, “Developmental Therapeutics in Radiation Oncology.”
Patient and Spousal Health and Outcomes in Heart Failure
Authors: Dunlay Shannon M. , Roger Véronique L. , Weston Susan A. , Bangerter Lauren R. , Killian Jill M. , Griffin Joan M. 
Published: October 2017

Background:
A diagnosis of heart failure (HF) often requires a comprehensive lifestyle change to maintain disease stability. When patients with HF are married, the spouse frequently assumes the caregiving role. Our objectives were to describe the health of spouses of married patients with HF, and examine whether the health of a spouse impacts patient outcomes.

Methods and Results:

We identified 905 patients that were married at the time of incident HF diagnosis in Olmsted County, MN, from 2000 to 2012. Using Rochester Epidemiology Project resources, the patient and their spouse’s comprehensive longitudinal health histories were linked. Spousal health at patient HF diagnosis was assessed by comorbidity burden, self-reported difficulty with activities of daily living and prior hospitalizations. The associations of spousal health with patient outcomes and patient death with spousal outcomes were examined using Cox and Andersen–Gill models. Spouses of patients with HF were elderly (mean age, 71 years), often had comorbid conditions, and 16% had difficulty with ≥1 activities of daily living. After adjustment for patient age, sex, and comorbidity, there were no independent associations of spousal health and patient risk of death or hospitalization after HF diagnosis. However, the risk of hospitalization (adjusted hazard ratio, 1.34; 95% confidence interval, 1.11–1.60;
P
=0.002) and death (hazard ratio, 2.10; 95% confidence interval, 1.60–2.75;
P
<0.001) increased in the surviving spouse after patient death.

Conclusions:
We found no evidence that the health of a spouse impacts patient outcomes after HF diagnosis. However, after a patient with HF dies, their surviving spouse’s risk of hospitalization and death increases.
Dose-Dependent Effects of the Myosin Activator Omecamtiv Mecarbil on Cross-Bridge Behavior and Force Generation in Failing Human Myocardium
Authors: Mamidi Ranganath , Li Jiayang , Gresham Kenneth S. , Verma Sujeet , Doh Chang Yoon , Li Amy , Lal Sean , dos Remedios Cristobal G. , Stelzer Julian E. 
Published: October 2017

Background:
Omecamtiv mecarbil (OM) enhances systolic function in vivo by directly binding the myosin cross-bridges (XBs) in the sarcomere. However, the mechanistic details governing OM-induced modulation of XB behavior in failing human myocardium are unclear.

Methods and Results:

The effects of OM on steady state and dynamic XB behavior were measured in chemically skinned myocardial preparations isolated from human donor and heart failure (HF) left ventricle. HF myocardium exhibited impaired contractile function as evidenced by reduced maximal force, magnitude of XB recruitment (
P
df
), and a slowed rate of XB detachment (
k
rel
) at submaximal Ca
2+
activations. Ca
2+
sensitivity of force generation (pCa
50
) was higher in HF myocardium when compared with donor myocardium, both prior to and after OM incubations. OM incubation (0.5 and 1.0 μmol/L) enhanced force generation at submaximal Ca
2+
activations in a dose-dependent manner. Notably, OM induced a slowing in
k
rel
with 1.0 μmol/L OM but not with 0.5 μmol/L OM in HF myocardium. Additionally, OM exerted other differential effects on XB behavior in HF myocardium as evidenced by a greater enhancement in
P
df
and slowing in the time course of cooperative XB recruitment (
T
rec
), which collectively prolonged achievement of peak force development (
T
pk
), compared with donor myocardium.

Conclusions:
Our findings demonstrate that OM augments force generation but also prolongs the time course of XB transitions to force-bearing states in remodeled HF myocardium, which may extend the systolic ejection time in vivo. Optimal OM dosing is critical for eliciting enhanced systolic function without excessive prolongation of systolic ejection time, which may compromise diastolic filling.
Runx1 Deficiency Protects Against Adverse Cardiac Remodeling After Myocardial Infarction
Authors: McCarroll Charlotte S. , He Weihong , Foote Kirsty , Bradley Ashley , Mcglynn Karen , Vidler Francesca , Nixon Colin , Nather Katrin , Fattah Caroline , Riddell Alexandra , Bowman Peter , Elliott Elspeth B. , Bell Margaret , Hawksby Catherine , MacKenzie Scott M. , Morrison Liam J. , Terry Anne , Blyth Karen , Smith Godfrey L. , McBride Martin W. , Kubin Thomas , Braun Thomas , Nicklin Stuart A. , Cameron Ewan R. , Loughrey Christopher M. 
Published: October 2017

Background:
Myocardial infarction (MI) is a leading cause of heart failure and death worldwide. Preservation of contractile function and protection against adverse changes in ventricular architecture (cardiac remodeling) are key factors to limiting progression of this condition to heart failure. Consequently, new therapeutic targets are urgently required to achieve this aim. Expression of the Runx1 transcription factor is increased in adult cardiomyocytes after MI; however, the functional role of Runx1 in the heart is unknown.

Methods:

To address this question, we have generated a novel tamoxifen-inducible cardiomyocyte-specific
Runx1
-deficient mouse. Mice were subjected to MI by means of coronary artery ligation. Cardiac remodeling and contractile function were assessed extensively at the whole-heart, cardiomyocyte, and molecular levels.

Results:

Runx1
-deficient mice were protected against adverse cardiac remodeling after MI, maintaining ventricular wall thickness and contractile function. Furthermore, these mice lacked eccentric hypertrophy, and their cardiomyocytes exhibited markedly improved calcium handling. At the mechanistic level, these effects were achieved through increased phosphorylation of phospholamban by protein kinase A and relief of sarco/endoplasmic reticulum Ca
2+
-ATPase inhibition. Enhanced sarco/endoplasmic reticulum Ca
2+
-ATPase activity in Runx1-deficient mice increased sarcoplasmic reticulum calcium content and sarcoplasmic reticulum–mediated calcium release, preserving cardiomyocyte contraction after MI.

Conclusions:
Our data identified Runx1 as a novel therapeutic target with translational potential to counteract the effects of adverse cardiac remodeling, thereby improving survival and quality of life among patients with MI.