bluuebunny/crossref_metadata_2025 huggingface dataset:
Advantages and Adversities of the Weighted Toxicity Score
Authors: Vaishampayan Ulka
Published: July 2018

It is imperative to develop a comprehensive toxicity score that will capture, convey, and compare adverse events of agents that are therapeutic options for the same disease state. The weighted toxicity score tool is a valuable aid in the shared decision-making process of therapeutic choice between patients and providers. Clin Cancer Res; 24(20); 4918–20. ©2018 AACR.

See related article by Carbini et al., p. 4968
Clusterin, a Novel DEC1 Target, Modulates DNA Damage–Mediated Cell Death
Authors: Ming Xin , Bao Chenyi , Hong Tao , Yang Ying , Chen Xinbin , Jung Yong-Sam , Qian Yingjuan
Published: July 2018

Differentiated embryonic chondrocyte expressed gene 1 (DEC1, also known as Sharp2/Stra13/BHLHE40) is a basic helix–loop–helix transcription factor that plays an important role in circadian rhythms, cell proliferation, apoptosis, cellular senescence, hypoxia response, and epithelial-to-mesenchymal transition of tumor cells. Secretory clusterin (sCLU) is a cytoprotective protein that guards against genotoxic stresses. Here, clusterin (CLU) was identified as a novel target gene of DEC1 and suppresses DNA damage–induced cell death in tumor cells. Mechanistically, based on chromatin immunoprecipitation and luciferase assays, DEC1 binds to and activates the promoter of the CLU gene. DEC1 and DNA-damaging agents induce sCLU expression, whereas DEC1 knockdown decreases the expression of sCLU upon DNA damage. Moreover, the data demonstrate that DEC1 inhibits, whereas sCLU knockdown enhances, DNA damage–induced cell death in MCF7 breast cancer cells. Given that DEC1 and sCLU are frequently overexpressed in breast cancers, these data provide mechanistic insight into DEC1 as a prosurvival factor by upregulating sCLU to reduce the DNA damage–induced apoptotic response. Together, this study reveals sCLU as a novel target of DEC1 which modulates the sensitivity of the DNA damage response.

Implications: DEC1 and sCLU are frequently overexpressed in breast cancer, and targeting the sCLU-mediated cytoprotective signaling pathway may be a novel therapeutic approach. Mol Cancer Res; 16(11); 1641–51. ©2018 AACR.
Tumor Suppressor Activity of Selenbp1, a Direct Nkx2-1 Target, in Lung Adenocarcinoma
Authors: Caswell Deborah R. , Chuang Chen-Hua , Ma Rosanna K. , Winters Ian P. , Snyder Eric L. , Winslow Monte M.
Published: July 2018

The Nkx2-1 transcription factor promotes differentiation of lung epithelial lineages and suppresses malignant progression of lung adenocarcinoma. However, targets of Nkx2-1 that limit tumor growth and progression remain incompletely understood. Here, direct Nkx2-1 targets are identified whose expression correlates with Nkx2-1 activity in human lung adenocarcinoma. Selenium-binding protein 1 (Selenbp1), an Nkx2-1 effector that limits phenotypes associated with lung cancer growth and metastasis, was investigated further. Loss- and gain-of-function approaches demonstrate that Nkx2-1 is required and sufficient for Selenbp1 expression in lung adenocarcinoma cells. Interestingly, Selenbp1 knockdown also reduced Nkx2-1 expression and Selenbp1 stabilized Nkx2-1 protein levels in a heterologous system, suggesting that these genes function in a positive feedback loop. Selenbp1 inhibits clonal growth and migration and suppresses growth of metastases in an in vivo transplant model. Genetic inactivation of Selenbp1, using CRISPR/Cas9, also enhanced primary tumor growth in autochthonous lung adenocarcinoma mouse models. Collectively, these data demonstrate that Selenbp1 is a direct target of Nkx2-1, which inhibits lung adenocarcinoma growth in vivo.

Implications: Selenbp1 is an important suppressor of lung tumor growth that functions in a positive feedback loop with Nkx2-1, and whose loss is associated with worse patient outcome. Mol Cancer Res; 16(11); 1737–49. ©2018 AACR.
Circulating Tumor Microparticles Promote Lung Metastasis by Reprogramming Inflammatory and Mechanical Niches via a Macrophage-Dependent Pathway
Authors: Zhang Huafeng , Yu Yuandong , Zhou Li , Ma Jingwei , Tang Ke , Xu Pingwei , Ji Tiantian , Liang Xiaoyu , Lv Jiadi , Dong Wenqian , Zhang Tianzhen , Chen Degao , Xie Jing , Liu Yuying , Huang Bo
Published: July 2018

Despite the frequency of lung metastasis and its associated mortality, the mechanisms behind metastatic tumor cell survival and colonization in the lungs remain elusive. Here, we show that tumor cell–released microparticles (T-MPs) from the primary tumor site play a critical role in the metastatic process. The T-MPs remodeled the lung parenchyma via a macrophage-dependent pathway to create an altered inflammatory and mechanical response to tumor cell invasion. Mechanistically, we show that circulating T-MPs readily enter the lung parenchyma where they are taken up by local macrophages and induce CCL2 production. CCL2 recruits CD11b+Ly6Chigh inflammatory monocytes to the lungs where they mature into F4/80+CD11b+Ly6C− macrophages that not only produce IL6 but also trigger fibrin deposition. IL6 and the deposited fibrin facilitate the survival and growth of tumor-repopulating cells in the lungs by providing chemical and mechanical signals, respectively, thus setting the stage for lung metastasis. These data illustrate that T-MPs reprogram the lung microenvironment promoting metastasis. Cancer Immunol Res; 6(9); 1046–56. ©2018 AACR.
Improved Risk-Adjusted Survival for Melanoma Brain Metastases in the Era of Checkpoint Blockade Immunotherapies: Results from a National Cohort
Authors: Iorgulescu J. Bryan , Harary Maya , Zogg Cheryl K. , Ligon Keith L. , Reardon David A. , Hodi F. Stephen , Aizer Ayal A. , Smith Timothy R.
Published: July 2018

The successes of checkpoint blockade immunotherapy (CBI) and BRAFV600-targeted therapy trials have generated substantial promise for revolutionizing the management of patients with advanced melanoma. However, because early clinical trials of CBIs and BRAFV600-targeted therapy either excluded or included disproportionately fewer cases of melanoma brain metastases (MBMs), the survival benefit of these novel therapies for MBM remains unknown. We, therefore, evaluated the characteristics, management, and overall survival (OS) of patients who presented with cutaneous MBMs during 2010 to 2015 using the National Cancer Database, which comprises 70% of all newly diagnosed U.S. cancers. OS was analyzed with risk-adjusted proportional hazards and compared by Kaplan–Meier techniques. We found that 2,753 (36%) of patients presenting with stage 4 melanoma had MBMs. Following the 2011 FDA approvals for CBI and BRAFV600-targeted therapy, MBM patients demonstrated a 91% relative increase in 4-year OS to 14.1% from 7.4% preapproval (P < 0.001). Postapproval, the proportion of MBM patients who received CBI rose from 10.5% in 2011 to 34.0% in 2015 (P < 0.001). Initial CBI in MBM patients displayed an improved median and 4-year OS of 12.4 months (compared with 5.2 months; P < 0.001) and 28.1% (compared with 11.1%), respectively. These benefits were pronounced in MBM patients without extracranial metastases, in which CBI demonstrated improved median and 4-year OS of 56.4 months (compared with 7.7 months; P < 0.001) and 51.5% (compared with 16.9%), respectively. Using a large national cohort composed of a “real-life” MBM treatment population, we demonstrated the dramatic OS improvements associated with novel checkpoint blockade immunotherapies. Cancer Immunol Res; 6(9); 1039–45. ©2018 AACR.
Effects of Selenium in the Microcirculation of Fructose-Fed Hamsters
Authors: Castiglione Raquel Carvalho , Barros Carlos M.M.R. , Boa Beatriz C.S. , De Souza Maria das Graças C. , Bouskela Eliete
Published: July 2018

Background and Aims: Fructose intake is directly related to vascular dysfunction and it is a risk factor for the development of metabolic and cardiovascular diseases, such as obesity, diabetes, and hypertension. Selenium, a component of antioxidant enzymes, improves hyperglycemia and vascular function in diabetic animals. The aim of this study was to evaluate the effects of dietary selenium supplementation on microcirculatory and metabolic parameters of fructose-fed hamsters. Methods and Results: Male hamsters (Mesocricetus auratus) had their drinking water substituted or not by 10% fructose solution for 60 days, during which their microcirculatory function was evaluated in the cheek pouch preparation. Blood glucose and serum insulin levels were also tested. Microcirculatory responses to acetylcholine (an endothelium-dependent vasodilator) and to sodium nitroprusside (SNP, an endothelium-independent vasodilator), and macromolecular permeability increase induced by a 30-min ischemia/reperfusion (I/R) procedure, showed that endothelium-dependent and independent vasodilatation was significantly increased in animals that had high selenium supplementation, in both the control and fructose-fed groups. Selenium supplementation protected against plasma leakage induced by I/R in all control and fructose-fed groups. Conclusion: Our results indicate that dietary selenium supplementation reduces microvascular dysfunction by increasing endothelial-dependent and independent dilatation and reducing macromolecular permeability increase in fructose-fed animals.
The Six-Item Cognitive Impairment Test Is Associated with Adverse Outcomes in Acutely Hospitalized Older Patients: A Prospective Cohort Study
Authors: Lucke Jacinta A. , van der Mast Roos C.  , de Gelder Jelle , Heim Noor , de Groot Bas , Mooijaart Simon P. , Blauw Gerard J.
Published: July 2018

Aim: The study aim was to investigate whether cognitive impairment, measured by the Six-Item Cognitive Impairment Test (6-CIT), is an independent predictor of adverse outcomes in acutely hospitalized older patients. Methods: This was a prospective multicenter study including acutely hospitalized patients aged 70 years and older. Multivariable logistic regression was used to investigate whether impaired cognition (6-CIT ≥11 points) was an independent predictor of 90-day adverse outcome, a composite measure of functional decline and mortality. Secondary endpoints were hospital length of stay, new institutionalization, and in-hospital mortality. Results: In total, 196 (15.6%) of 1,252 included patients had a 6-CIT ≥11. Median age was 80 years (interquartile range 74–85). Patients with impaired cognition had higher rates of 90-day adverse outcome (41.7% compared to 30.3% in 1,056 not cognitively impaired patients, p = 0.009). Impaired cognition was a predictor of 90-day adverse outcome with a crude odds ratio (OR) of 1.64 (95% CI 1.13–2.39), but statistical significance was lost when fully corrected for possible confounders (OR 1.44, 95% CI 0.98–2.11). For all secondary outcomes, impaired cognition was an independent predictor. Conclusions: In the acute hospital setting, the 6-CIT is associated with 90-day adverse outcome and is an independent predictor of hospital length of stay, new institutionalization, and in-hospital mortality.
Expression of Endothelial Cell Injury Marker Cd146 Correlates with Disease Severity and Predicts the Renal Outcomes in Patients with Diabetic Nephropathy
Authors: Fan Ying , Fei Yang , Zheng Li , Wang Jiemin , Xiao Wenzhen , Wen Jiejun , Xu Yanping , Wang Yiyun , He Li , Guan Jian , Wei Jia , He John Cijiang , Wang Niansong
Published: July 2018

Background/Aims: Glomerular endothelial cell injury plays a crucial role in the development of diabetic nephropathy (DN). CD146, an endothelial marker, was shown to increase in chronic kidney disease (CKD), but its role in DN remains unknown. We aim to assess whether CD146 could be used to evaluate disease severity and predict renal outcomes in DN at early stages. Methods: 159 non-dialysis type 2-DN patients from 2008 to 2015 were enrolled to measure the plasma concentration of soluble CD146 (sCD146). 94 type 2 diabetes mellitus patients without DN and 100 healthy subjects were used as controls. The patients with CKD stage 1-3 were referred as early stage patients. Another independent cohort of 48 patients with biopsy-proved DN was used for the immunohistochemistry study of CD146. Renal outcomes were defined as doubling of serum creatinine, initiation of renal replacement therapy or death. Results: We found that plasma level of sCD146 was upregulated and associated with renal function in DN patients. sCD146 was proved to be a more optimal marker than urine albumin creatinine ratio to evaluate disease severity in these DN patients. The kidney expression of CD146 was co-localized with endothelial marker CD31 and increased in DN. CD146 staining in kidney was correlated with the severity of pathological changes in DN patients. Survival analysis suggested that both plasma and biopsy expression of CD146 were correlated with renal outcomes. Conclusions: CD146 is associated with kidney injury and could be a good marker to predict renal outcomes in patients with early stages of DN.
The Association Between Three Genetic Variants in MicroRNAs (Rs11614913, Rs2910164, Rs3746444) and Prostate Cancer Risk
Authors: Mi Yuanyuan , Ren Kewei , Zou Jiangang , Bai Yu  , Zhang Lifeng , Zuo Li , Okada Atsushi , Yasui Takahiro
Published: July 2018

Background/Aims: MicroRNAs (miRNAs) are a class of small non-coding RNA molecules which play a significant role in transcriptional and translational regulation. Published data on the association between the miRNA SNPs and prostate cancer (PCa) risk are somewhat inconclusive. Methods: We performed a meta-analysis of all available studies including 2,227 patients and 2,331 control subjects to evaluate the impact of three common genetic variants of microRNAs in prostate cancer risk. Odds ratios (ORs) with 95% confidence intervals (CIs) were utilized to investigate the strength of the association. Results: For miR-499 polymorphism, a significant association was observed between the rs3746444 A>G polymorphism and PCa risk in heterozygote comparison and dominant genetic model, in particular in Asian population subgroup. For miR-146a polymorphism, the rs2910164 CC genotype was associated with decreased PCa risk in Asian population in homozygote comparison. In addition, rs2910164 CC genotype had a weekly higher percentage value in subgroup of Gleason score < 7. Similar results were also indicated in localized prostate cancer in subgroup analysis by tumor stage. For miR-196a2 polymorphism, no association was observed between this variant and PCa risk in the overall group. However, in stratified analysis by ethnicity, we found that rs11614913 T allele was a risk factor for Asian PCa patients. Conclusions: Polymorphisms of miR-196a2 rs11614913, miR-146a rs2910164, and miR-499 rs3746444 may contribute to the risk for developing prostate cancer in Asian descendants. Moreover, miR-146a rs2910164 polymorphism was related to PCa prognosis.
High-Density Lipoprotein Particles, Cell-Cholesterol Efflux, and Coronary Heart Disease Risk
Authors: Asztalos Bela F. , Horvath Katalin V. , Schaefer Ernst J.
Published: July 2018

Objective—

The cell-cholesterol efflux capacity of HDL (high-density lipoprotein) is inversely associated with coronary heart disease risk. ABCA1 (ATP-binding cassette transporter A1) plays a crucial role in cholesterol efflux from macrophages to preβ-1-HDL. We tested the hypothesis that coronary heart disease patients have functionally abnormal preβ-1-HDL.

Approach and Results—

HDL cell-cholesterol efflux capacity via the ABCA1 and the SR-BI (scavenger receptor class B type I) pathways, HDL antioxidative capacity, apo (apolipoprotein) A-I-containing HDL particles, and inflammatory- and oxidative-stress markers were measured in a case-control study of 100 coronary heart disease cases and 100 sex-matched controls. There were significant positive correlations between ABCA1-dependent cholesterol efflux and the levels of small lipid-poor preβ-1 particles (
R
2
=0.535) and between SR-BI-dependent cholesterol efflux and the levels of large lipid-rich (α-1+α-2) HDL particles (
R
2
=0.712). Cases had significantly higher (87%) preβ-1 concentrations than controls, but the functionality of their preβ-1 particles (preβ-1 concentration normalized ABCA1–dependent efflux capacity) was significantly lower (−31%). Cases had significantly lower (−12%) mean concentration of large HDL particles, but the functionality of their particles (α-1+α-2 concentration normalized SR-BI–dependent efflux capacity) was significantly higher (22%) compared with that of controls. HDL antioxidative capacity was significantly lower (−16%) in cases than in controls. There were no significant correlations between either preβ-1 functionality or large HDL particle functionality with HDL antioxidative capacity or the concentrations of inflammatory- and oxidative-stress markers.

Conclusions—

HDL cell-cholesterol efflux capacity is significantly influenced by both the concentration and the functionality of specific HDL particles participating in cell-cholesterol efflux. Coronary heart disease patients have higher than normal preβ-1 concentrations with decreased functionality and lower than normal large HDL particle concentrations with enhanced functionality.
Thirty-Second Gold Standard Definition of Atrial Fibrillation and Its Relationship With Subsequent Arrhythmia Patterns
Authors: Steinberg Jonathan S. , O’Connell Heather , Li Shelby , Ziegler Paul D.
Published: July 2018

Background:

The Heart Rhythm Society consensus statement arbitrarily defines atrial fibrillation (AF) ablation failure as any episode ≥30 seconds. However, if brief AF events are not correlated to longer events, the rationale for this end point is questionable. We determined the impact of AF episode duration threshold on AF incidence and burden.

Methods:

Patients with a pacemaker in a prospective registry with device-detected AF and follow-up >30 days were analyzed. AF patterns were calculated for various AF duration thresholds (30 s; 2 and 6 minutes; 3.8, 5.5, and 24 hours) selected based on published consensus statements, established evidence of stroke risk, and device capabilities. Freedom from AF postdevice implant at each AF episode duration threshold was assessed, as was overall AF burden.

Results:

Among 615 patients with pacemaker (aged 72.0±11.8 years, 54.2% male, follow-up 3.7±2.2 years) with device-detected AF, 599 had ≥1 AF episode of ≥30 seconds duration (median, 22 episodes). At 12 months, freedom from AF was 25.5%, 30.1%, 34.6%, 52.6%, 56.5%, and 73.1% for duration thresholds of 30 seconds, 2 minutes, 6 minutes, 3.8 hours, 5.5 hours, and 24 hours, respectively. Of patients with a first episode of 30 seconds to 2 minutes, 35.8% were free from subsequent episode >2 minutes at 180 days. Median AF burden was significantly less for patients with first episodes between 30 seconds and 3.8 hours versus >3.8 hours (0.2% versus 9.5%, respectively;
P
<0.0001).

Conclusions:

Small differences in AF episode duration definition can significantly affect the perceived incidence of AF and impact reported outcomes, including AF ablation success. An initial AF episode of 30 seconds does not predict clinically meaningful AF patterns.
Lifetime Risk of Atrial Fibrillation by Race and Socioeconomic Status
Authors: Mou Liping , Norby Faye L. , Chen Lin Y. , O’Neal Wesley T. , Lewis Tené T. , Loehr Laura R. , Soliman Elsayed Z. , Alonso Alvaro
Published: July 2018

Background:

Limited information exists on the lifetime risk of atrial fibrillation (AF) in African Americans and by socioeconomic status.

Methods:

We studied 15 343 participants without AF at baseline from the ARIC (Atherosclerosis Risk in Communities) cohort recruited in 1987 to 1989 from 4 communities in the United States when they were 45 to 64 years of age. Participants have been followed through 2014. Incidence rates of AF were calculated dividing the number of new cases by person-years of follow-up. Lifetime risk of AF was estimated by a modified Kaplan-Meier method considering death as a competing risk. Participants’ family income and education were obtained at baseline.

Results:

We identified 2760 AF cases during a mean follow-up of 21 years. Lifetime risk of AF was 36% (95% confidence interval, 32%–38%) in white men, 30% (95% confidence interval, 26%–32%) in white women, 21% (95% confidence interval, 13%–24%) in African American men, and 22% (95% confidence interval, 16%–25%) in African American women. Regardless of race and sex, incidence rates of AF decreased from the lowest to the highest categories of income and education. In contrast, lifetime risk of AF increased in individuals with higher income and education in most sex-race groups. Cumulative incidence of AF was lower in those with higher income and education compared with their low socioeconomic status counterparts through earlier life but was reversed after age 80.

Conclusions:

Lifetime risk of AF in the ARIC cohort was ≈1 in 3 among whites and 1 in 5 among African Americans. Socioeconomic status was inversely associated with cumulative incidence of AF before the last decades of life.
Myocardial Scar and Mortality in Severe Aortic Stenosis
Authors: Musa Tarique A. , Treibel Thomas A. , Vassiliou Vassiliou S. , Captur Gabriella , Singh Anvesha , Chin Calvin , Dobson Laura E. , Pica Silvia , Loudon Margaret , Malley Tamir , Rigolli Marzia , Foley James R.J. , Bijsterveld Petra , Law Graham R. , Dweck Marc R. , Myerson Saul G. , McCann Gerry P. , Prasad Sanjay K. , Moon James C. , Greenwood John P.
Published: July 2018

Background:

Aortic valve replacement (AVR) for aortic stenosis is timed primarily on the development of symptoms, but late surgery can result in irreversible myocardial dysfunction and additional risk. The aim of this study was to determine whether the presence of focal myocardial scar preoperatively was associated with long-term mortality.

Methods:

In a longitudinal observational outcome study, survival analysis was performed in patients with severe aortic stenosis listed for valve intervention at 6 UK cardiothoracic centers. Patients underwent preprocedural echocardiography (for valve severity assessment) and cardiovascular magnetic resonance for ventricular volumes, function and scar quantification between January 2003 and May 2015. Myocardial scar was categorized into 3 patterns (none, infarct, or noninfarct patterns) and quantified with the full width at half-maximum method as percentage of the left ventricle. All-cause mortality and cardiovascular mortality were tracked for a minimum of 2 years.

Results:

Six hundred seventy-four patients with severe aortic stenosis (age, 75±14 years; 63% male; aortic valve area, 0.38±0.14 cm
2
/m
2
; mean gradient, 46±18 mm Hg; left ventricular ejection fraction, 61.0±16.7%) were included. Scar was present in 51% (18% infarct pattern, 33% noninfarct). Management was surgical AVR (n=399) or transcatheter AVR (n=275). During follow-up (median, 3.6 years), 145 patients (21.5%) died (52 after surgical AVR, 93 after transcatheter AVR). In multivariable analysis, the factors independently associated with all-cause mortality were age (hazard ratio [HR], 1.50; 95% CI, 1.11–2.04;
P
=0.009, scaled by epochs of 10 years), Society of Thoracic Surgeons score (HR, 1.12; 95% CI, 1.03–1.22;
P
=0.007), and scar presence (HR, 2.39; 95% CI, 1.40–4.05;
P
=0.001). Scar independently predicted all-cause (26.4% versus 12.9%;
P
<0.001) and cardiovascular (15.0% versus 4.8%;
P
<0.001) mortality, regardless of intervention (transcatheter AVR,
P
=0.002; surgical AVR,
P
=0.026 [all-cause mortality]). Every 1% increase in left ventricular myocardial scar burden was associated with 11% higher all-cause mortality hazard (HR, 1.11; 95% CI, 1.05–1.17;
P
<0.001) and 8% higher cardiovascular mortality hazard (HR, 1.08; 95% CI, 1.01–1.17;
P
<0.001).

Conclusions:

In patients with severe aortic stenosis, late gadolinium enhancement on cardiovascular magnetic resonance was independently associated with mortality; its presence was associated with a 2-fold higher late mortality.
Gastrin Protects Against Myocardial Ischemia/Reperfusion Injury via Activation of RISK (Reperfusion Injury Salvage Kinase) and SAFE (Survivor Activating Factor Enhancement) Pathways
Authors: Yang Xiaoli , Yue Rongchuan , Zhang Jun , Zhang Xiaoqun , Liu Yukai , Chen Caiyu , Wang Xinquan , Luo Hao , Wang Wei Eric , Chen Xiongwen , Wang Huixia Judy , Jose Pedro A. , Wang Hongyong , Zeng Chunyu
Published: July 2018

Background

Ischemia/reperfusion injury (IRI) is one of the most predominant complications of ischemic heart disease. Gastrin has emerged as a regulator of cardiovascular function, playing a key protective role in hypoxia. Serum gastrin levels are increased in patients with myocardial infarction, but the pathophysiogical significance of this finding is unknown. The purpose of this study was to determine whether and how gastrin protects cardiac myocytes from IRI.

Methods and Results

Adult male Sprague‐Dawley rats were used in the experiments. The hearts in living rats or isolated Langendorff‐perfused rat hearts were subjected to ischemia followed by reperfusion to induce myocardial IRI. Gastrin, alone or with an antagonist, was administered before the induction of myocardial IRI. We found that gastrin improved myocardial function and reduced the expression of myocardial injury markers, infarct size, and cardiomyocyte apoptosis induced by IRI. Gastrin increased the phosphorylation levels of
ERK
1/2 (extracellular signal‐regulated kinase 1/2), AKT (protein kinase B), and
STAT
3 (signal transducer and activator of transcription 3), indicating its ability to activate the
RISK
(reperfusion injury salvage kinase) and
SAFE
(survivor activating factor enhancement) pathways. The presence of inhibitors of
ERK
1/2,
AKT
, or
STAT
3 abrogated the gastrin‐mediated protection. The protective effect of gastrin was via CCK2R (cholecystokinin 2 receptor) because the
CCK
2R blocker
CI
988 prevented the gastrin‐mediated protection of the heart with IRI. Moreover, we found a negative correlation between serum levels of cardiac troponin I and gastrin in patients with unstable angina pectoris undergoing percutaneous coronary intervention, suggesting a protective effect of gastrin in human cardiomyocytes.

Conclusions

These results indicate that gastrin can reduce myocardial IRI by activation of the
RISK
and
SAFE
pathways.
Magnesium Sulfate–Mediated Vascular Relaxation and Calcium Channel Activity in Placental Vessels Different From Nonplacental Vessels
Authors: Tang Jiaqi , He Axin , Li Na , Chen Xueyi , Zhou Xiuwen , Fan Xiaorong , Liu Yanping , Zhang Mengshu , Qi Linglu , Tao Jianying , Sun Miao , Xu Zhice
Published: July 2018

Background

Magnesium sulfate (Mg
SO
4
) has been used as a common therapy for preeclampsia and eclampsia for many years. Mg
SO
4
decreases peripheral vascular resistance so as to reduce maternal blood pressure. Whether placental blood vessels react to Mg
SO
4
in the same patterns as that in maternal vessels is largely unknown.

Methods and Results

This study compared placental vessels (
PV
) versus nonplacental vessels (non‐
PV
) in human and animal models. Mg
SO
4
‐caused vascular dilation was significantly weaker in
PV
than that in non‐
PV
. Prostaglandin I
2
synthetase affected Mg
SO
4
‐mediated vasodilatation in
PV
, not in umbilical vessels, while cyclooxygenase did not influence Mg
SO
4
‐induced relaxation in both
PV
and non‐
PV
. Mg
2+
‐caused vasodilatation was mainly through calcium channels. In
PV
, calcium channel activities were significantly weaker in
PV
than that in non‐
PV
. Relative
mRNA
expression of

CACNA
1D

,

CACNB
2

, and

CACNB
3

was significantly higher in
PV
than those in umbilical vessels, despite the fact that the expression of

CACNA
1F

was less in
PV
. The contractile phenotype of smooth muscle cell marker (
CALD
1) was less and the synthetic phenotype (
MYH
10) was more in
PV
than that in
UV
.

Conclusions

These results demonstrated that
PV
were characterized by much weaker responses to Mg
SO
4
compared with nonplacental vessels. The difference was related to weaker calcium channel activity and minor contractile phenotype smooth muscle cells in
PV
, providing important information for further understanding treatments with Mg
SO
4
in preeclampsia.
Targeting Chemokine Receptor CXCR4 and Translocator Protein for Characterization of High-Risk Plaque in Carotid Stenosis Ex Vivo
Authors: Grosse Gerrit M. , Bascuñana Pablo , Schulz-Schaeffer Walter J. , Teebken Omke E. , Wilhelmi Mathias , Worthmann Hans , Ross Tobias L. , Wester Hans-Jürgen , Kropf Saskia , Derlin Thorsten , Bengel Frank M. , Bankstahl Jens P. , Weissenborn Karin
Published: July 2018

Background and Purpose—

This pilot study aims to demonstrate the feasibility of targeting molecular characteristics of high-risk atherosclerotic plaque in symptomatic and asymptomatic carotid stenosis (CS), that is, upregulation of the translocator protein (TSPO) and the chemokine receptor type 4 (CXCR4), by means of molecular imaging.

Methods—

In a translational setting, specimens of carotid plaques of patients with symptomatic and asymptomatic CS obtained by carotid endarterectomy were analyzed for the presence of TSPO and CXCR4 by autoradiography, using the positron emission tomography tracers
18
F-GE180 and
68
Ga-Pentixafor and evaluated by histopathology. In addition,
68
Ga-Pentixafor positron emission tomography/computed tomography was performed in a patient with high-grade CS.

Results—

Distinct patterns of upregulation of TSPO (
18
F-GE180 uptake) and CXCR4 (
68
Ga-Pentixafor uptake) were identified in carotid plaque by autoradiography. The spatial distribution was associated with specific histological hallmarks that are established features of high-risk plaque: TSPO upregulation correlated with activated macrophages infiltration, whereas CXCR4 upregulation also corresponded to areas of intraplaque hemorrhage.
68
Ga-Pentixafor uptake was significantly higher in plaques of symptomatic compared with asymptomatic CS. Clinical positron emission tomography revealed marked
68
Ga-Pentixafor uptake in carotid plaque of a patient with high-grade CS.

Conclusions—

Clinical imaging of molecular signatures of high-risk atherosclerotic plaque is feasible and may become a promising diagnostic tool for comprehensive characterization of carotid disease. This methodology provides a platform for future studies targeting carotid plaque.
The Travails of Democratization in Cameroon in the Context of Political Liberalisation since the 1990s
Authors: Fonchingong Charles C.
Published: July 2018

Nurturing Cameroon’s fledgling democracy is proving a herculean task against the backdrop of disintegrative forces: flawed electoral process, ethnicity, identity consciousness, clientelism, endemic corruption, regionalism and neopatrimonialism inherent in the state apparatus. The undercurrents on the interface of statehood in Cameroon’s democratization process from the ’90s are explored. There is an enormous gulf between the state and the masses with the elite playing a prominent role in political sloganeering and regionalism, leading to a heightened sense of exclusion. The bureaucratic ethos still remains largely centralised despite the discourses on decentralisation. The simmering Anglophone problem is still brushed aside. The paper illuminates on the disruption and fragmentation of national politics which has led to the emergence of identity and ethnic constructions in the search for belonging to the polity. The question of legitimacy and civic participation is largely distorted due to the disinterestedness of the populace in the state machinery. This is rendered more fluid by the manipulative tendencies of the regime, ruling elite and a fractured opposition. The fundamental question is whether Cameroon was adequately prepared for multiparty politics. Rekindling Cameroon’s botched democratic process hinges on the institutionalisation of consensus building, democratic accountability and participative governance.
Gender Differences in an Emerging Health Profession: Ghanaian Women as Itinerant Drug Vendors
Authors: Williamson David A. , Pillai Vijayan K. , Owusu Gertrude , Oppong Joseph R.
Published: July 2018

The analysis in this paper is based on a sample of 517 itinerant drug vendors (IDVs) who were interviewed in Ghana during the summer of 1997. IDVs are health care entrepreneurs who provide inexpensive services in medically underserved areas. We describe the differences between men and women IDVs in order to assess 1) their potential to improve health services and 2) the possibility that sex segregation may be lessened in this innovative new profession, allowing women to make a greater contribution to health services delivery. Results indicate that IDVs may be a relatively untapped health resource, but segregation remains strong, thus their full potential is hampered as it is in institutionalized biomedicine.
Attribution of Arctic Sea Ice Decline from 1953 to 2012 to Influences from Natural, Greenhouse Gas, and Anthropogenic Aerosol Forcing
Authors: Mueller B. L. , Gillett N. P. , Monahan A. H. , Zwiers F. W.
Published: July 2018

The paper presents results from a climate change detection and attribution study on the decline of Arctic sea ice extent in September for the 1953–2012 period. For this period three independently derived observational datasets and simulations from multiple climate models are available to attribute observed changes in the sea ice extent to known climate forcings. Here we direct our attention to the combined cooling effect from other anthropogenic forcing agents (mainly aerosols), which has potentially masked a fraction of greenhouse gas–induced Arctic sea ice decline. The presented detection and attribution framework consists of a regression model, namely, regularized optimal fingerprinting, where observations are regressed onto model-simulated climate response patterns (i.e., fingerprints). We show that fingerprints from greenhouse gas, natural, and other anthropogenic forcings are detected in the three observed records of Arctic sea ice extent. Beyond that, our findings indicate that for the 1953–2012 period roughly 23% of the greenhouse gas–induced negative sea ice trend has been offset by a weak positive sea ice trend attributable to other anthropogenic forcing. We show that our detection and attribution results remain robust in the presence of emerging nonstationary internal climate variability acting upon sea ice using a perfect model experiment and data from two large ensembles of climate simulations.
Asian Summer Precipitation over the Past 544 Years Reconstructed by Merging Tree Rings and Historical Documentary Records
Authors: Shi Hui , Wang Bin , Cook Edward R. , Liu Jian , Liu Fei
Published: July 2018

Sparse long-term Asian monsoon (AM) records have limited our ability to understand and accurately model low-frequency AM variability. Here we present a gridded 544-yr (from 1470 to 2013) reconstructed Asian summer precipitation (RAP) dataset by weighted merging of two complementary proxies including 453 tree-ring-width chronologies and 71 historical documentary records. The RAP dataset provides substantially improved data quality when compared with single-proxy-type reconstructions. Skillful reconstructions are obtained in East and North China, northern India and Pakistan, the Indochina Peninsula, midlatitude Asia, the Maritime Continent, and southern Japan. The RAP faithfully illustrates large-scale regional rainfall variability but has more uncertainties in representing small-scale local rainfall anomalies. The RAP reproduces a realistic climatology and captures well the year-to-year rainfall variability averaged over monsoon Asia, arid central Asia, and all of Asia during the twentieth century. It also shows a general agreement with other proxies (speleothems and ice cores) during the period of 1470–1920. The RAP captures the remarkably abrupt change during the 1600s recorded in the upwelling proxy over the Arabian Sea. Four major modes of variability of the Asian summer precipitation are identified with the long record of the RAP, including a biennial El Niño–Southern Oscillation (ENSO) mode, a low-frequency ENSO mode, a central Pacific El Niño–like decadal mode, and an interdecadal mode. In sum, the RAP provides a valuable dataset for study of the large-scale Asian summer precipitation variability, especially the decadal–centennial variability that is caused by external forcing and internal feedback processes within the Earth climate system.
Object-Based Verification of a Prototype Warn-on-Forecast System
Authors: Skinner Patrick S. , Wheatley Dustan M. , Knopfmeier Kent H. , Reinhart Anthony E. , Choate Jessica J. , Jones Thomas A. , Creager Gerald J. , Dowell David C. , Alexander Curtis R. , Ladwig Therese T. , Wicker Louis J. , Heinselman Pamela L. , Minnis Patrick , Palikonda Rabindra
Published: July 2018

An object-based verification methodology for the NSSL Experimental Warn-on-Forecast System for ensembles (NEWS-e) has been developed and applied to 32 cases between December 2015 and June 2017. NEWS-e forecast objects of composite reflectivity and 30-min updraft helicity swaths are matched to corresponding reflectivity and rotation track objects in Multi-Radar Multi-Sensor system data on space and time scales typical of a National Weather Service warning. Object matching allows contingency-table-based verification statistics to be used to establish baseline performance metrics for NEWS-e thunderstorm and mesocyclone forecasts. NEWS-e critical success index (CSI) scores of reflectivity (updraft helicity) forecasts decrease from approximately 0.7 (0.4) to 0.4 (0.2) over 3 h of forecast time. CSI scores decrease through the forecast period, indicating that errors do not saturate during the 3-h forecast. Lower verification scores for rotation track forecasts are primarily a result of a high-frequency bias. Comparison of different system configurations used in 2016 and 2017 shows an increase in skill for 2017 reflectivity forecasts, attributable mainly to improvements in the forecast initial conditions. A small decrease in skill in 2017 rotation track forecasts is likely a result of sample differences between 2016 and 2017. Although large case-to-case variation is present, evidence is found that NEWS-e forecast skill improves with increasing object size and intensity.
Platelet Membrane Γ-Glutamyl Transferase-Specific Activity and the Clinical Course of Acute Coronary Syndrome
Authors: Demirtaş Koray , Yayla Çağri , Sade Leyla Elif , Yildirir Aylin , Özin Mehmet Bülent , Haberal Ayşegül , Müderrisoğlu Ibrahim Haldun
Published: July 2018

γ-Glutamyl transferase (GGT) participates in oxidative and inflammatory reactions inside the atheroma plaque and platelets. We evaluated whether platelet membrane γ-glutamyl transferase (Plt-GGT) activity is a predictor of major adverse cardiac events (MACEs) during 3 months follow-up of patients with acute coronary syndrome (ACS; MACE-3M). We included 105 patients who were hospitalized consecutively with the diagnosis of ACS. Patients with an MACE-3M were older, more likely to have hypertension, hyperlipidemia, family history of coronary artery disease(CAD), thrombolysis in myocardial infarction (TIMI) risk score >4, higher Plt-GGT and serum GGT activities, serum C-reactive protein level, and lower left ventricular ejection fraction (LVEF) when compared to those without MACE-3M (all P values ≤.05). By receiver–operator characteristic (ROC) curve analysis, 265 mU/mg for Plt-GGT, 30 U/L for serum GGT, and 45% for LVEF were determined as cutoff values to discriminate MACEs. Platelet GGT activity >265 mU/mg, TIMI risk score >4, and family history of CAD were independent predictors of MACE-3M (all P values <.05). Platelet GGT activity was as an independent predictor for MACEs in patients with ACS during the 3 months follow-up.
Protecting Workers Abroad and Industries at Home: Rights-based Conditionality in Trade Preference Programs
Authors: Hafner-Burton Emilie M. , Mosley Layna , Galantucci Robert
Published: July 2018

A growing number of developed country governments link good governance, including human rights, to developing countries’ access to aid, trade, and investment. We consider whether governments enforce these conditions sincerely, in response to rights violations, or whether such conditions might instead be used as a veil for protectionist policies, motivated by domestic concerns about import competition. We do so via an examination of the world’s most important unilateral trade preference program, the US Generalized System of Preferences (GSP), which includes worker rights as one criterion for program access. We argue that the two-tiered structure of the GSP privileges some domestic interests at one level, while disadvantaging them at the other. Using a new data set on all US GSP beneficiary countries and sanctioning measures from 1986 to 2013, we demonstrate that labor rights outcomes play a role in the maintenance of country-level trade benefits and that import competition does not condition the application of rights-based criteria at this level. At the same, however, the US government does not consider worker rights in the elements (at the country-product level) of the program that have the greatest material impact. The result is a situation in which the US government talks somewhat sincerely at the country level in its rights-based conditionality, but its behavior at the country-product level cheapens this talk.
Amyotrophic Lateral Sclerosis and a “Death With Dignity”
Authors: Andersen Jennifer A.
Published: July 2018

The Oregon “Death With Dignity” Act (DWD Act) allows a terminally ill patient with 6 months to live to ask a physician for medication to end their life. To receive the medication, the DWD Act requires the patient to verbally request the prescription twice 2 weeks apart as well as in writing. Patients with amyotrophic lateral sclerosis have three main barriers to using DWD: (a) the ability to communicate their informed consent as the disease progresses further, (b) the possibility of dementia which may affect their decisional capacity, and (c) given the nature and speed of amyotrophic lateral sclerosis, limited time is available for patients to self-administer the prescription and may rush the time line for the death. This article reviews the current knowledge and addresses the need for adjustments to existing law and recommendations for states considering a DWD law.
Predictive Validity of the MAYSI-2 and PAI-A for Suicide-Related Behavior and Nonsuicidal Self-Injury Among Adjudicated Adolescent Offenders on Probation
Authors: Shaffer Catherine S. , Gulbransen Erik M. D. , Viljoen Jodi L. , Roesch Ronald , Douglas Kevin S.
Published: July 2018

This prospective study evaluated the ability of the MAYSI-2 and PAI-A to predict suicide-related behavior (SRB) and nonsuicidal self-injury (NSSI) among adjudicated adolescent offenders on probation. Predictive validity of the MAYSI-2 for SRB and NSSI has generally been postdictively examined among detained adolescents. In addition, no published studies have examined the predictive validity of the PAI-A for SRB and NSSI among adolescent offenders. Neither the MAYSI-2 nor PAI-A added incremental predictive validity above lifetime SRB or NSSI. However, several MAYSI-2 and PAI-A subscales were predictive of SRB or NSSI. With some exceptions, most recommended instrument cut-off scores differentiated between low-risk and high-risk youth. These findings suggest that the MAYSI-2 and PAI-A hold promise for evaluating SRB and NSSI among justice-involved youth. In addition, these findings contribute to more informed decisions regarding the use of these tools and can be used to inform SRB and NSSI prevention efforts.
Option Backdating Announcements and Information Advantage of Institutional Investors
Authors: Huang Wenli , Lu Hai , Wang Xiaolu
Published: July 2018

This article uses transaction-level fund trading data from the United States to study the information advantage of institutional investors. Our research design follows a two-step procedure. In the first step, we identify funds that sell shares in firms before their unexpected revelation of stock option backdating (BD) investigations, and thus establish fund–firm pairs of interest. In the second step, we focus on trading that takes place at other times and find that the funds are more likely to make correct trades before the earnings announcements of their paired firms and that their trading performance for paired firms is better in general. This superior performance, however, is more evident in the pre-BD-announcement period and for firms whose BD investigations are initiated internally. The results imply that although institutions have access to private information on certain firms, this advantage disappears after the BD revelation, possibly due to reduced information leakage.
Criticality: How Changes Preserve Stability in Self-Organizing Systems
Authors: Accard Philippe
Published: July 2018

Self-organizing systems are social systems which are immanently and constantly recreated by agents. In a self-organizing system, agents make changes while preserving stability. If they do not preserve stability, they push the system toward chaos and cannot recreate it. How changes preserve stability is thus a fundamental issue. In current works, changes preserve stability because agents’ ability to make changes is limited by interaction rules and power. However, how agents diffuse the changes throughout the system while preserving its stability has not been addressed in these works. We have addressed this issue by borrowing from a complex system theory neglected thus far in organization theories: self-organized criticality theory. We suggest that self-organizing systems are in critical states: agents have equivalent ability to make changes, and none are able to foresee or control how their changes diffuse throughout the system. Changes, then, diffuse unpredictably – they may diffuse to small or large parts of the system or not at all, and it is this unpredictable diffusion that preserves stability in the system over time. We call our theoretical framework self-organiz ing criticality theory. It presents a new treatment of change and stability and improves the understanding of self-organizing.
Community control as a relationship between a place-based population and institution: The case of a community land trust
Authors: Williams Olivia R
Published: July 2018

Community control is a concept used to identify and promote efforts at collective resource ownership as a response to heightened inequality and capital mobility. The term has been used widely in political and theoretical discourses since the 1960s, but there is no clear consensus on its definition or the practical possibilities of how it can be actualized, particularly in the contemporary era of neoliberal fiscal austerity. In this paper, a case study of Rondo Community Land Trust in Saint Paul, MN is used to theorize community control as an interaction between a place-based population and an institution with authority over a shared resource. The Rondo neighborhood’s history of displacement, impending threat of gentrification, and civic leadership inspired visions for a commercial land trust development by a neighborhood leader. Rondo Community Land Trust’s history as a neighborhood-based organization, its participatory board structure, and its need for organizational diversification, and relationships with funders and other nonprofit groups made it a receptive vehicle for the proposal. The resulting “community control” of the project development was a collaboration between Rondo Community Land Trust and a group of neighborhood property owners. Neighborhood residents favored their commercial land trust proposal over a developer-led proposal for the same lot. If the neighborhood residents had been more broadly mobilized, the level of community control may have been more participatory, but Rondo Community Land Trust’s capacity to initiate community organizing was limited, so the resulting community control was driven by key leaders in the neighborhood with the support of Rondo Community Land Trust.