bluuebunny/crossref_metadata_2025 huggingface dataset:
Marine Aerosols and Clouds
Authors: Brooks Sarah D. , Thornton Daniel C.O.
Published: October 2017

The role of marine bioaerosols in cloud formation and climate is currently so uncertain that even the sign of the climate forcing is unclear. Marine aerosols form through direct emissions and through the conversion of gas-phase emissions to aerosols in the atmosphere. The composition and size of aerosols determine how effective they are in catalyzing the formation of water droplets and ice crystals in clouds by acting as cloud condensation nuclei and ice nucleating particles, respectively. Marine organic aerosols may be sourced both from recent regional phytoplankton blooms that add labile organic matter to the surface ocean and from long-term global processes, such as the upwelling of old refractory dissolved organic matter from the deep ocean. Understanding the formation of marine aerosols and their propensity to catalyze cloud formation processes are challenges that must be addressed given the major uncertainties associated with aerosols in climate models.
Evidence for Genetic Risk Contributing to Long-Term Adverse Treatment Effects in Childhood Cancer Survivors
Authors: Gramatges Maria Monica , Bhatia Smita
Published: October 2017

Survivors of childhood cancer are at increased risk for therapy-related morbidities and mortality. Although the demographic and clinical factors predicting the risk for long-term effects of cancer therapy are well known, the impact of genetic risk for specific late effects is less clearly defined. Here, we review the extant literature and recent research describing genetic modifiers to risk for the more common late effects of childhood cancer therapy. Results of this research support the need for clinical trials that attempt to further refine risk prediction by incorporating genetic testing into existing algorithms that are primarily based on clinical and demographic factors. Confirmation of genetic predisposition, as defined by reproducibility and prospective validation, would permit therapeutic modification and discussion of individualized survivor care plans even at initial cancer diagnosis.
New-Generation High-Potency and Designer Antibodies: Role in HIV-1 Treatment
Authors: Gama Lucio , Koup Richard A.
Published: October 2017

Broadly neutralizing antibodies (bNAbs) have been evaluated as promising agents in the fight against infectious diseases. HIV-1-specific bNAbs, in particular, have been tested in both preventive and therapeutic modalities. Multiple bNAbs have been isolated, characterized, and assessed in vitro and in vivo, but no single antibody appears to possess the breadth and potency that may be needed if it is to be used in the treatment of HIV-1 infection. With the technological advances of the past decades, novel and more effective bNAbs have been identified or engineered for higher neutralizing potency, greater breadth, and increased serum half-life. In this review, we discuss the development of a new generation of anti-HIV-1 bNAbs and their potential to be used clinically for treatment and prevention of HIV-1 infection.
Refinement of the Affordable Care Act: A Progressive Perspective
Authors: Carrasquillo Olveen , Mueller Michael
Published: October 2017

The Affordable Care Act (ACA) was the most significant expansion of health coverage since Medicare and Medicaid were enacted. The law resulted in approximately 13–20 million uninsured persons gaining coverage. Despite these gains, the ACA has numerous shortcomings. For progressives, the ACA was a unique opportunity to provide access to high-quality, comprehensive, equitable health coverage to all persons living in the United States. Using this perspective as our framework, in this review we highlight some of the limitations of the ACA and potential areas for refinement. We conclude that the ACA fell far short of the goal of achieving universal coverage and that the coverage made available through the ACA was not equitable. In addition, the ACA expanded coverage by building onto a highly fragmented, inefficient, and costly health system. Thus, it did little to control health costs. A more fiscally prudent approach would have been built upon more successful existing programs, such as a Medicare for All.
Advances in the Treatment of Context in Organizational Research
Authors: Johns Gary
Published: October 2017

Although scholars in the field of organizational behavior have raised concerns about a lack of contextual appreciation, there has been a recent embrace of contextual thinking in the organizational sciences. In this review, I discuss several recent theories and measures of context. The added value of a contextual approach is illustrated by how context can shape personality, how it affects the emergence of work designs, and how it benefits the study of organizational demography. Future research topics include context cue sensitivity, the way context is shaped, the mediators of context effects, and the breadth and limits of contextual impact. A recurrent theme is that although context enables a demarcation of what is distinctive about situations, it also permits integration across research areas and levels of analysis, identifying what they have in common as settings for organizational behavior.
Application of Microphysiological Systems to Enhance Safety Assessment in Drug Discovery
Authors: Ewart Lorna , Dehne Eva-Maria , Fabre Kristin , Gibbs Susan , Hickman James , Hornberg Ellinor , Ingelman-Sundberg Magnus , Jang Kyung-Jin , Jones David R. , Lauschke Volker M. , Marx Uwe , Mettetal Jerome T. , Pointon Amy , Williams Dominic , Zimmermann Wolfram-Hubertus , Newham Peter
Published: October 2017

Enhancing the early detection of new therapies that are likely to carry a safety liability in the context of the intended patient population would provide a major advance in drug discovery. Microphysiological systems (MPS) technology offers an opportunity to support enhanced preclinical to clinical translation through the generation of higher-quality preclinical physiological data. In this review, we highlight this technological opportunity by focusing on key target organs associated with drug safety and metabolism. By focusing on MPS models that have been developed for these organs, alongside other relevant in vitro models, we review the current state of the art and the challenges that still need to be overcome to ensure application of this technology in enhancing drug discovery.
Lymphatic Dysfunction, Leukotrienes, and Lymphedema
Authors: Jiang Xinguo , Nicolls Mark R. , Tian Wen , Rockson Stanley G.
Published: October 2017

The lymphatic system is essential for the maintenance of tissue fluid homeostasis, gastrointestinal lipid absorption, and immune trafficking. Whereas lymphatic regeneration occurs physiologically in wound healing and tissue repair, pathological lymphangiogenesis has been implicated in a number of chronic diseases such as lymphedema, atherosclerosis, and cancer. Insight into the regulatory mechanisms of lymphangiogenesis and the manner in which uncontrolled inflammation promotes lymphatic dysfunction is urgently needed to guide the development of novel therapeutics: These would be designed to reverse lymphatic dysfunction, either primary or acquired. Recent investigation has demonstrated the mechanistic role of leukotriene B4(LTB4) in the molecular pathogenesis of lymphedema. LTB4, a product of the innate immune response, is a constituent of the eicosanoid inflammatory mediator family of molecules that promote both physiological and pathological inflammation. Here we provide an overview of lymphatic development, the pathophysiology of lymphedema, and the role of leukotrienes in lymphedema pathogenesis.
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

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 <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

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

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

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

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.
Cell Type-Specific Chromatin Signatures Underline Regulatory DNA Elements in Human Induced Pluripotent Stem Cells and Somatic Cells
Authors: Zhao Ming-Tao , Shao Ning-Yi , Hu Shijun , Ma Ning , Srinivasan Rajini , Jahanbani Fereshteh , Lee Jaecheol , Zhang Sophia L. , Snyder Michael P. , Wu Joseph C.
Published: October 2017

Rationale:

Regulatory DNA elements in the human genome play important roles in determining the transcriptional abundance and spatiotemporal gene expression during embryonic heart development and somatic cell reprogramming. It is not well known how chromatin marks in regulatory DNA elements are modulated to establish cell type–specific gene expression in the human heart.

Objective:

We aimed to decipher the cell type–specific epigenetic signatures in regulatory DNA elements and how they modulate heart-specific gene expression.

Methods and Results:

We profiled genome-wide transcriptional activity and a variety of epigenetic marks in the regulatory DNA elements using massive RNA-seq (n=12) and ChIP-seq (chromatin immunoprecipitation combined with high-throughput sequencing; n=84) in human endothelial cells (CD31
+
CD144
+
), cardiac progenitor cells (Sca-1
+
), fibroblasts (DDR2
+
), and their respective induced pluripotent stem cells. We uncovered 2 classes of regulatory DNA elements: class I was identified with ubiquitous enhancer (H3K4me1) and promoter (H3K4me3) marks in all cell types, whereas class II was enriched with H3K4me1 and H3K4me3 in a cell type–specific manner. Both class I and class II regulatory elements exhibited stimulatory roles in nearby gene expression in a given cell type. However, class I promoters displayed more dominant regulatory effects on transcriptional abundance regardless of distal enhancers. Transcription factor network analysis indicated that human induced pluripotent stem cells and somatic cells from the heart selected their preferential regulatory elements to maintain cell type–specific gene expression. In addition, we validated the function of these enhancer elements in transgenic mouse embryos and human cells and identified a few enhancers that could possibly regulate the cardiac-specific gene expression.

Conclusions:

Given that a large number of genetic variants associated with human diseases are located in regulatory DNA elements, our study provides valuable resources for deciphering the epigenetic modulation of regulatory DNA elements that fine-tune spatiotemporal gene expression in human cardiac development and diseases.
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.
Diagnostic Accuracy of the Aortic Dissection Detection Risk Score Plus D-Dimer for Acute Aortic Syndromes
Authors: Nazerian Peiman , Mueller Christian , Soeiro Alexandre de Matos , Leidel Bernd A. , Salvadeo Sibilla Anna Teresa , Giachino Francesca , Vanni Simone , Grimm Karin , Oliveira Múcio Tavares , Pivetta Emanuele , Lupia Enrico , Grifoni Stefano , Morello Fulvio , Capretti Elisa , Castelli Matteo , Gualtieri Simona , Trausi Federica , Battista Stefania , Bima Paolo , Carbone Federica , Tizzani Maria , Veglio Maria G. , Badertscher Patrick , Boeddinghaus Jasper , Nestelberger Thomas , Twerenbold Raphael
Published: October 2017

Background:

Acute aortic syndromes (AASs) are rare and severe cardiovascular emergencies with unspecific symptoms. For AASs, both misdiagnosis and overtesting are key concerns, and standardized diagnostic strategies may help physicians to balance these risks. D-dimer (DD) is highly sensitive for AAS but is inadequate as a stand-alone test. Integration of pretest probability assessment with DD testing is feasible, but the safety and efficiency of such a diagnostic strategy are currently unknown.

Methods:

In a multicenter prospective observational study involving 6 hospitals in 4 countries from 2014 to 2016, consecutive outpatients were eligible if they had ≥1 of the following: chest/abdominal/back pain, syncope, perfusion deficit, and if AAS was in the differential diagnosis. The tool for pretest probability assessment was the aortic dissection detection risk score (ADD-RS, 0–3) per current guidelines. DD was considered negative (DD−) if <500 ng/mL. Final case adjudication was based on conclusive diagnostic imaging, autopsy, surgery, or 14-day follow-up. Outcomes were the failure rate and efficiency of a diagnostic strategy for ruling out AAS in patients with ADD-RS=0/DD− or ADD-RS ≤1/DD−.

Results:

A total of 1850 patients were analyzed. Of these, 438 patients (24%) had ADD-RS=0, 1071 patients (58%) had ADD-RS=1, and 341 patients (18%) had ADD-RS >1. Two hundred forty-one patients (13%) had AAS: 125 had type A aortic dissection, 53 had type B aortic dissection, 35 had intramural aortic hematoma, 18 had aortic rupture, and 10 had penetrating aortic ulcer. A positive DD test result had an overall sensitivity of 96.7% (95% confidence interval [CI], 93.6–98.6) and a specificity of 64% (95% CI, 61.6–66.4) for the diagnosis of AAS; 8 patients with AAS had DD−. In 294 patients with ADD-RS=0/DD−, 1 case of AAS was observed. This yielded a failure rate of 0.3% (95% CI, 0.1–1.9) and an efficiency of 15.9% (95% CI, 14.3–17.6) for the ADD-RS=0/DD− strategy. In 924 patients with ADD-RS ≤1/DD−, 3 cases of AAS were observed. This yielded a failure rate of 0.3% (95% CI, 0.1–1) and an efficiency of 49.9% (95% CI, 47.7–52.2) for the ADD-RS ≤1/DD− strategy.

Conclusions:

Integration of ADD-RS (either ADD-RS=0 or ADD-RS ≤1) with DD may be considered to standardize diagnostic rule out of AAS.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02086136.
Added Value of Vessel Wall Magnetic Resonance Imaging for Differentiation of Nonocclusive Intracranial Vasculopathies
Authors: Mossa-Basha Mahmud , Shibata Dean K. , Hallam Danial K. , de Havenon Adam , Hippe Daniel S. , Becker Kyra J. , Tirschwell David L. , Hatsukami Thomas , Balu Niranjan , Yuan Chun
Published: October 2017

Background and Purpose—

Our goal is to determine the added value of intracranial vessel wall magnetic resonance imaging (IVWI) in differentiating nonocclusive vasculopathies compared with luminal imaging alone.

Methods—

We retrospectively reviewed images from patients with both luminal and IVWI to identify cases with clinically defined intracranial vasculopathies: atherosclerosis (intracranial atherosclerotic disease), reversible cerebral vasoconstriction syndrome, and inflammatory vasculopathy. Two neuroradiologists blinded to clinical data reviewed the luminal imaging of defined luminal stenoses/irregularities and evaluated the pattern of involvement to make a presumed diagnosis with diagnostic confidence. Six weeks later, the 2 raters rereviewed the luminal imaging in addition to IVWI for the pattern of wall involvement, presence and pattern of postcontrast enhancement, and presumed diagnosis and confidence. Analysis was performed on per-lesion and per-patient bases.

Results—

Thirty intracranial atherosclerotic disease, 12 inflammatory vasculopathies, and 12 reversible cerebral vasoconstriction syndrome patients with 201 lesions (90 intracranial atherosclerotic disease, 64 reversible cerebral vasoconstriction syndrome, and 47 inflammatory vasculopathy lesions) were included. For both per-lesion and per-patient analyses, there was significant diagnostic accuracy improvement with luminal imaging+IVWI when compared with luminal imaging alone (per-lesion: 88.8% versus 36.1%;
P
<0.001 and per-patient: 96.3% versus 43.5%;
P
<0.001, respectively). There was substantial interrater diagnostic agreement for luminal imaging+IVWI (κ=0.72) and only slight agreement for luminal imaging (κ=0.04). Although there was a significant correlation for both luminal and IVWI pattern of wall involvement with diagnosis, there was a stronger correlation for IVWI finding of lesion eccentricity and intracranial atherosclerotic disease diagnosis than for luminal imaging (κ=0.69 versus 0.18;
P
<0.001).

Conclusions—

IVWI can significantly improve the differentiation of nonocclusive intracranial vasculopathies when combined with traditional luminal imaging modalities.
Oilseed radish/black oat subsidiary crops can help regulate plant-parasitic nematodes under non-inversion tillage in an organic wheat-potato rotation
Authors: Schmidt Jan H. , Finckh Maria R. , Hallmann Johannes
Published: October 2017

Soil conservation is one of the major challenges for agriculture in the 21st century. For this reason, non-inversion tillage systems including subsidiary crops have become popular over the last three decades in Europe. However, the adoption of new agricultural practices may change the diversity and abundance of certain pests and diseases. For example, plant-parasitic nematodes that are major threats towards cultivated plants may be promoted if good hosts, such as certain subsidiary crops and weeds, occur more frequently. The indigenous plant-parasitic nematode fauna under organic farming systems is already adapted to diverse crop rotations and usually dominated by nematodes with broad host ranges. These may be further enhanced in organic farming systems if non-inversion tillage is introduced, which generally increases the abundance and biomass of certain weeds. We evaluated the early effects of non-inversion tillage and subsidiary crops in an organic wheat-potato rotation on plant-parasitic nematodes in two field experiments in two successive years. The total densities of plant-parasitic nematodes increased from an initial 1260 nematodes (100 ml soil)−1 at the start of the experiment to 1850 and 1700 nematodes (100 ml soil)−1 after wheat under non-inversion and conventional tillage, respectively. Plant-parasitic nematode densities then decreased on average to 1100 and 560 nematodes (100 ml soil)−1 after subsidiary crops and potatoes, respectively. Parasitic nematode densities tended to be higher under non-inversion than conventional tillage, except where oilseed radish and black oats had been used as cover crops. For the latter, no differences between tillage treatments occurred. In the second experiment, about 1700 free-living nematodes (100 ml soil)−1 were found under conventional tillage without mulch while under reduced tillage with mulch their numbers were significantly higher at 3100 nematodes (100 ml soil)−1. We conclude that an appropriate choice of subsidiary crops can be an important management factor for the long term sustainability of non-inversion tillage systems.
Using Habits of Mind, Intelligent Behaviors, and Educational Theories to Create a Conceptual Framework for Developing Effective Teaching Dispositions
Authors: Altan Servet , Lane Jennie F. , Dottin Erskine
Published: October 2017

Despite the heated debates about dispositions in teacher education, most accrediting agencies continue to put dispositions among their priorities. The authors of the current article concur with the value of using Dewey to understand how habits can be clustered to better understand intelligent teaching dispositions. But, can we extend Dewey’s epistemology to learning theories in a manner that informs the making of teaching conduct more intelligent? To address this question, the authors applied qualitative content analysis to review the literature. Through a deductive approach, dispositions as Habits of Mind were related to educational theories using intelligent behaviors as the common denominator. The conclusion is that dispositions can be clustered around Habits of Mind that are related directly to educational learning theories vis-à-vis thoughtfulness, and to learning theories that support learning or mindfulness. Grounding dispositions as habits of mind in selected educational theories may guide and support the professional development of teaching dispositions.
Adolescent Dating Violence Victimization and Relationship Dissolution
Authors: Soller Brian , Copp Jennifer E. , Haynie Dana L. , Kuhlemeier Alena
Published: October 2017

We integrate literature on gender and adolescent friendships to examine the association between adolescent dating violence victimization (ADVV) and relationship dissolution. In particular, we test whether ADVV increases the hazard of relationship dissolution among adolescent romances, and whether a number of friendship dynamics alter the association between ADVV and relationship dissolution. Using discrete time event history models from 5,787 romantically involved youth from the National Longitudinal Study of Adolescent to Adult Health (Add Health), results indicated, on average, ADVV was not associated with the hazard of relationship dissolution for girls or boys. However, the positive effect of ADVV was stronger for girls who did not withdraw from their friendships over the course of their romantic relationships. This study highlights the importance of peer groups and gender in shaping youths’ decisions to exit abusive relationships.
Development of a Single-Session, Transdiagnostic Preventive Intervention for Young Adults at Risk for Emotional Disorders
Authors: Bentley Kate H. , Boettcher Hannah , Bullis Jacqueline R. , Carl Jenna R. , Conklin Laren R. , Sauer-Zavala Shannon , Pierre-Louis Catherine , Farchione Todd J. , Barlow David H.
Published: October 2017

Cognitive-behavioral prevention programs have demonstrated efficacy in reducing subclinical symptoms of anxiety and depression, and there is some evidence to suggest that they can lower the risk of future disorder onset. However, existing interventions tend to be relatively lengthy and target specific disorders or problem areas, both of which limit their potential for widespread dissemination. To address these limitations, we aimed to develop a single-session, transdiagnostic preventive intervention based on the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders for young adults at risk for developing anxiety and/or depressive disorders within a college setting. Results from this proof-of-concept study indicated that the intervention was viewed as highly satisfactory and acceptable. The intervention also was successful at delivering adaptive emotion management skills in its 2-hr workshop format. Future studies evaluating the efficacy of this novel transdiagnostic, emotion-focused prevention program are warranted.
Multivariate Hypothesis Testing Methods for Evaluating Significant Individual Change
Authors: Wang Chun , Weiss David J.
Published: October 2017

The measurement of individual change has been an important topic in both education and psychology. For instance, teachers are interested in whether students have significantly improved (e.g., learned) from instruction, and counselors are interested in whether particular behaviors have been significantly changed after certain interventions. Although classical test methods have been unable to adequately resolve the problems in measuring change, recent approaches for measuring change have begun to use item response theory (IRT). However, all prior methods mainly focus on testing whether growth is significant at the group level. The present research targets a key research question: Is the “change” in latent trait estimates for each individual significant across occasions? Many researchers have addressed this research question assuming that the latent trait is unidimensional. This research generalizes their earlier work and proposes four hypothesis testing methods to evaluate individual change on multiple latent traits: a multivariate Z-test, a multivariate likelihood ratio test, a multivariate score test, and a Kullback–Leibler test. Simulation results show that these tests hold promise of detecting individual change with low Type I error and high power. A real-data example from an educational assessment illustrates the application of the proposed methods.
Mid-Holocene palaeolimnological record of a Southern Hemisphere subtropical lake spanning the last ~6000 years: Lake Jennings, Fraser Island, Australia
Authors: Hembrow Sarah C , Taffs Kathryn H , Atahan Pia , Zawadzki Atun , Heijnis Henk , Parr Jeff
Published: October 2017

The study of climate mechanisms in the Southern Hemisphere during the Holocene remains an area of active research that lacks the spatial and temporal connectivity characteristic of Northern Hemisphere research. The subtropical/temperate climate transition zone of eastern Australia provides a unique location to investigate long-term environmental changes during the Holocene. Lake Jennings on Fraser Island was used to investigate climate change in this transition zone using palaeolimnological techniques. The beginning of the Lake Jennings record (~6000 to 3500 cal. yBP), is characterised by fluctuations in geochemical signals, an abundance of sponge spicules, and a lack of diatom species. Results suggest gradually increasing precipitation and water depth, which affect nutrient cycling. However, the biological functioning of the lake is difficult to interpret due to the absence of diatoms, possibly a result of turbidity, dissolution and/or predation by freshwater sponges. During the late Holocene, ~3500 cal. yBP to present, precipitation and water depth of the lake decreases to present day levels. Within this section of the core nutrient cycling changes, as indicated by the geochemical results, and a series of more intense wet and dry events took place before stabilising at present day levels. Other palaeoecological studies within the Southern Hemisphere have noted changes in geochemical and biological attributes within similar latitudes, confirming the notion of climate forced environmental change in aquatic ecosystems. This continuous ~6000 year record from Lake Jennings shows distinct changes in aquatic communities, confirming a trend of drying in subtropical eastern Australia through the late Holocene.
Crisis and post-crisis urban gardening initiatives from a Southern European perspective: The case of Barcelona
Authors: Calvet-Mir Laura , March Hug
Published: October 2017

Throughout the 20th century, urban gardening in central and northern Europe as well as in North America has received a great deal of academic attention. However, the recent proliferation of urban gardening in other geographies, such as southern Europe in the aftermath of the economic crisis of 2007–2008, remains underexplored. The economic crisis put on hold urban developments in many southern European cities, leaving idle plots of land waiting to be urbanized. The crisis also triggered radical political demands, such as those of the Indignados, as well as fuelling narratives revolving around social entrepreneurship and social innovation. Barcelona emerges as a laboratory of urban gardening initiatives in vacant lots mobilizing either radical urban demands or embedding new post-crisis rhetoric around social entrepreneurship. Through a combination of qualitative methods, including participant observation, a literature review, semi-structured interviews, informal conversations and field diaries, we present a characterization and evolution of the three most prominent urban gardening initiatives in the city of Barcelona (including 54 gardens at the end of 2016): the Network of Municipal Gardens (municipally led gardens for retired people); the Network of Communitarian Gardens (social movements); and the Empty Plots Plan (social entrepreneurial urban gardening). Subsequently, we discuss the different meanings of gardening in crisis/post-crisis Barcelona as well as the urban politics that each initiative articulates. Our results show that urban gardens within the city are an expression of different and non-exclusive meanings that explicitly or implicitly, in a context of crisis and post-crisis, mobilize notions of political gardening.
Core Practices in Music Teaching: A Delphi Expert Panel Survey
Authors: Millican J. Si , Forrester Sommer Helweh
Published: October 2017

The pedagogical content knowledge framework has been used to decipher the complexities of teaching by integrating subject matter knowledge with knowledge of teaching and knowledge of learners. Researchers in math, English, and history have modified this framework to identify core teaching practices within their disciplines. Core teaching practices are those that novices can begin to master and have a direct impact on student success. We developed a preliminary list of core practices in music using a Delphi panel approach. This panel of public school and college teachers with expertise in band, choir, orchestra, and elementary music found that modeling, sequencing instruction, and deconstructing musical concepts were core teaching practices that apply across a wide variety of teaching and learning contexts. The panel felt developing knowledge of and relationships with students was important for in-service teachers, but other practices should be developed first by novice teachers.