bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploiting MCL1 Dependency with Combination MEK + MCL1 Inhibitors Leads to Induction of Apoptosis and Tumor Regression in KRAS-Mutant Non–Small Cell Lung Cancer
Authors: Nangia Varuna , Siddiqui Faria M. , Caenepeel Sean , Timonina Daria , Bilton Samantha J. , Phan Nicole , Gomez-Caraballo Maria , Archibald Hannah L. , Li Chendi , Fraser Cameron , Rigas Diamanda , Vajda Kristof , Ferris Lorin A. , Lanuti Michael , Wright Cameron D. , Raskin Kevin A. , Cahill Daniel P. , Shin John H. , Keyes Colleen , Sequist Lecia V. , Piotrowska Zofia , Farago Anna F. , Azzoli Christopher G. , Gainor Justin F. , Sarosiek Kristopher A. , Brown Sean P. , Coxon Angela , Benes Cyril H. , Hughes Paul E. , Hata Aaron N.
Published: September 2018

BH3 mimetic drugs, which inhibit prosurvival BCL2 family proteins, have limited single-agent activity in solid tumor models. The potential of BH3 mimetics for these cancers may depend on their ability to potentiate the apoptotic response to chemotherapy and targeted therapies. Using a novel class of potent and selective MCL1 inhibitors, we demonstrate that concurrent MEK + MCL1 inhibition induces apoptosis and tumor regression in KRAS-mutant non–small cell lung cancer (NSCLC) models, which respond poorly to MEK inhibition alone. Susceptibility to BH3 mimetics that target either MCL1 or BCL-xL was determined by the differential binding of proapoptotic BCL2 proteins to MCL1 or BCL-xL, respectively. The efficacy of dual MEK + MCL1 blockade was augmented by prior transient exposure to BCL-xL inhibitors, which promotes the binding of proapoptotic BCL2 proteins to MCL1. This suggests a novel strategy for integrating BH3 mimetics that target different BCL2 family proteins for KRAS-mutant NSCLC.

Significance:

Defining the molecular basis for MCL1 versus BCL-xL dependency will be essential for effective prioritization of BH3 mimetic combination therapies in the clinic. We discover a novel strategy for integrating BCL-xL and MCL1 inhibitors to drive and subsequently exploit apoptotic dependencies of KRAS-mutant NSCLCs treated with MEK inhibitors.

See related commentary by Leber et al., p. 1511.

This article is highlighted in the In This Issue feature, p. 1494
AMG 176, a Selective MCL1 Inhibitor, Is Effective in Hematologic Cancer Models Alone and in Combination with Established Therapies
Authors: Caenepeel Sean , Brown Sean P. , Belmontes Brian , Moody Gordon , Keegan Kathleen S. , Chui Danny , Whittington Douglas A. , Huang Xin , Poppe Leszek , Cheng Alan C. , Cardozo Mario , Houze Jonathan , Li Yunxiao , Lucas Brian , Paras Nick A. , Wang Xianghong , Taygerly Joshua P. , Vimolratana Marc , Zancanella Manuel , Zhu Liusheng , Cajulis Elaina , Osgood Tao , Sun Jan , Damon Leah , Egan Regina K. , Greninger Patricia , McClanaghan Joseph D. , Gong Jianan , Moujalled Donia , Pomilio Giovanna , Beltran Pedro , Benes Cyril H. , Roberts Andrew W. , Huang David C. , Wei Andrew , Canon Jude , Coxon Angela , Hughes Paul E.
Published: September 2018

The prosurvival BCL2 family member MCL1 is frequently dysregulated in cancer. To overcome the significant challenges associated with inhibition of MCL1 protein–protein interactions, we rigorously applied small-molecule conformational restriction, which culminated in the discovery of AMG 176, the first selective MCL1 inhibitor to be studied in humans. We demonstrate that MCL1 inhibition induces a rapid and committed step toward apoptosis in subsets of hematologic cancer cell lines, tumor xenograft models, and primary patient samples. With the use of a human MCL1 knock-in mouse, we demonstrate that MCL1 inhibition at active doses of AMG 176 is tolerated and correlates with clear pharmacodynamic effects, demonstrated by reductions in B cells, monocytes, and neutrophils. Furthermore, the combination of AMG 176 and venetoclax is synergistic in acute myeloid leukemia (AML) tumor models and in primary patient samples at tolerated doses. These results highlight the therapeutic promise of AMG 176 and the potential for combinations with other BH3 mimetics.

Significance:

AMG 176 is a potent, selective, and orally bioavailable MCL1 inhibitor that induces a rapid commitment to apoptosis in models of hematologic malignancies. The synergistic combination of AMG 176 and venetoclax demonstrates robust activity in models of AML at tolerated doses, highlighting the promise of BH3-mimetic combinations in hematologic cancers.

See related commentary by Leber et al., p. 1511.

This article is highlighted in the In This Issue feature, p. 1494
The Risk of Clonal Evolution of Granulocyte Colony-Stimulating Factor for Acquired Aplastic Anemia: A Systematic Review and Meta-Analysis
Authors: Ding Shao-xue , Chen Tong , Wang Ting , Liu Chun-yan , Lu Wen-li , Fu Rong
Published: September 2018

Objectives: This meta-analysis aimed to evaluate the risk of clonal evolution of granulocyte colony-stimulating factor (G-CSF) in acquired aplastic anemia (AA), and whether the use of G-CSF increases the occurrence of secondary malignant neoplasms, mainly myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) or paroxysmal nocturnal hemoglobinuria (PNH). Methods: Data were gathered from randomized controlled trials (RCTs) to evaluate the effect of G-CSF versus no G-CSF at the risk of developing the clonal complications of acquired AA. Electronic searches in PubMed, Embase, and the Cochrane Library were performed to identify studies up to 1 January 2017. Only RCTs performed on patients who were randomly assigned to receive G-CSF or not to receive G-CSF were included. Results: Four relevant trials that met the inclusion criteria were identified. In a pooled analysis, the G-CSF groups of AA patients were not associated with a statistically significant higher occurrence of secondary malignant neoplasm, mainly MDS and AML (relative risk [RR] 0.86; 95% confidence interval [CI] 0.34–2.19; 4 trials). No significant heterogeneity was found (p = 0.67, I2 = 0%). There was no statistically significant higher occurrence of PNH in the G-CSF groups with AA (RR 1.17; 95% CI 0.51–2.71; 4 trials) and no significant heterogeneity was found (p = 0.42, I2 = 0%). Conclusions: G-CSF for patients with AA is not associated with a higher occurrence of secondary malignant neoplasm, mainly MDS/AML, or PNH.
Influences of Surgical Volume on Perioperative and Oncological Outcomes Following Radical Prostatectomy
Authors: Pohle Margit , Magheli Ahmed , Fischer Tom , Ralla Bernhard , Miller Kurt , Hinz Stefan
Published: September 2018

Introduction: The purpose of this study was to evaluate whether the number of radical prostatectomies per hospital per year is associated with stage distribution, surgical techniques or quality related outcome in Germany. Materials and Methods: A German Internet-based database was analyzed. Hospitals were categorized according to their yearly radical prostatectomy (RP) volume. Patient’s characteristics, RP techniques, and outcome-related parameters were compared between the different hospital volume categories. Results: A total of 6,447 patients were analyzed. The highest rate of organ-confined disease and the lowest rate of extracapsular invasion have been demonstrated in very low-volume centres (72.6% <pT3, 27% pT ≥3). High-volume centres had the highest rate of open (92%) and robot-assisted RP approaches (5.5%). Regarding outcome, the lowest rate of positive surgical margins (11.7%) and the lowest intraoperative blood loss (3.3 g/dL) have been observed in high-volume centres. Conclusion: A higher number or RPs per year was associated with better outcome regarding quality-related parameters like surgical margin status and blood loss. However, the tumour stage distribution did not significantly differ between the low, intermediate and high-volume centres suggesting that till date the allocation of patients to the different centres is not triggered by the tumour risk classification.
Antihistamines: Recommended Dosage – Divergence between Clinical Practice and Guideline Recommendations
Authors: Manti Sara , Salpietro Carmelo , Cuppari Caterina
Published: September 2018

The updosing of second-generation antihistamines for chronic urticaria is based on inconsistent findings. Herein, we report data on the treatment of children with chronic spontaneous urticaria (CSU) unresponsive to single doses of second-generation H(1)-antihistamines in whom an increase in antihistamine was performed without improvement and with a high prevalence of adverse events. Thus, it appears that well-controlled, well-designed clinical trials are needed to clarify which nonsedating antihistamines should be used, in what dose, and for how long in patients not responding to the standard treatment, despite the improvement in health care that guidelines help to incorporate. Furthermore, a critical use of such guidelines should be done to improve the knowledge in CSU, especially in the pediatric population.
Cyclic Dimeric Guanosine Monophosphate: Activation and Inhibition of Innate Immune Response
Authors: Cui Tao , Cang Huaixing , Yang Baoqiang , He Zheng-Guo
Published: September 2018

Cyclic dimeric guanosine monophosphate (c-di-GMP) is a universally conserved second messenger that contributes to the pathogenicity of numerous bacterial species. In recent years, growing evidence has shown that bacterial extracellular c-di-GMP can interact with the innate immune system and regulate host immune responses. This review summarizes our current understanding on the dual roles of bacterial c-di-GMP in pathogen-host interaction: activation of the antibacterial innate immune response through the cytosolic surveillance pathway and inhibition of innate immune defense for iron restriction.
Chronic Stress May Not Be a Factor in the Behavioral Response to Chronic Lithium in ICR Mice
Authors: Shemesh Gil , Kara Nirit ,   Carmi, Einat Haim
Published: September 2018

Background: Lithium (Li) is the prototypic mood-stabilizing drug, but the individual response to Li is highly heterogeneous. Some evidence suggest interactions between Li and stress, and it is possible to hypothesize that lithium’s effects are modified by stress conditions. The current study examines the interaction between 2 chronic stressors, constant light (CL) and restrain and the behavioral responses to chronic Li in female and male mice. Methods: Female and male ICR mice were exposed to 3 weeks of either (1) CL; (2) daily restrain or (3) no stress control. One week after the start of the stress intervention, mice started chronic oral Li treatment or control. After 2 weeks of stress and Li, mice were tested in a number of behavioral tests including spontaneous activity, sweet solution preference, plus-maze and forced swim test. Results: There were no effects of stressors on behavior. Effects of Li were demonstrated in males but not females with no interactions between stress and Li. Conclusions: The behavioral effects of Li in this study were not affected by stress. The lack of effects of the stressors themselves on behavior suggests that the application of more intrusive stressors might be needed to further explore the issue.
New Beginnings: An Interactionist and Constructivist Approach to Early Moral Development
Authors: Dahl Audun
Published: September 2018

Orientations toward harming and helping others are central to morality. These orientations undergo major transformations in early life. This paper proposes an interactionist and constructivist approach to early moral development and discusses how children construct orientations toward harming and helping through everyday social interactions. A major developmental acquisition – typically evident by age 3 – is the ability to make judgments of right and wrong based on concerns with others’ welfare. The paper concludes by outlining issues for future research on the development of morality from infancy to childhood.
Association Between Preoperative Vitamin D Status and Short-Term Physical Performance after Total Hip Arthroplasty: A Prospective Study
Authors: Visser Edith , de Roos Nicole M. , Oosting Ellen , Endenburg Silvia C. , Dronkers Jaap J.
Published: September 2018

Background: Insufficient serum vitamin D concentrations (50–75 nmol/L) are prevalent in 40–65% of patients who require total hip arthroplasty (THA). This could impair physical recovery after surgery. This study investigated the association between preoperative vitamin D status and physical performance after THA. Additionally, postoperative changes in vitamin D concentrations were measured. Methods: We included 87 patients scheduled for elective THA and aged ≥65 years. Three groups were recruited: patients classified as vitamin D deficient (< 50 nmol/L, n = 23), insufficient (50–75 nmol/L, n = 32), or sufficient (> 75 nmol/L, n = 32). Serum 25-hydroxyvitamin D3 (25[OH]D3) concentration and physical performance were measured perioperatively. Linear mixed models were used to examine differences between groups. Results: Change in physical performance over time was not affected by preoperative vitamin D status. In contrast, for physical activity, both vitamin D (p = 0.021) and time (p < 0.001) effect was seen: from 80.2 ± 25.8 to 58.1 ± 17.8 min/day in the deficient group, 143.7 ± 19.8 to 92.9 ± 11.5 min/day in the insufficient group, and 108.1 ± 20.9 to 62.3 ± 12.9 min/day in the sufficient group. The Chair Stand Test, Timed Up and Go test, and 10-Meter Walking Test also improved significantly over time, but independent of vitamin D status. An increase in 25(OH)D3 concentration 6 weeks postoperatively was correlated with improved hip function (Pearson’s r = –0.471, p = 0.018). Overall, serum 25(OH)D3 declined with 32% one day after surgery (p < 0.001), to nearly return to baseline values 6 weeks later in all groups. Conclusion: Vitamin D status did not appear to affect physical recovery after THA. The drop in vitamin D after surgery deserves further investigation, but could possibly be explained by hemodilution.
Comparison of Ultrasound and Fluoroscopically Guided Percutaneous Transhepatic Biliary Drainage
Authors: Nennstiel Simon , Treiber Matthias , Faber Alexander , Haller Bernhard , von Delius Stefan , Schmid Roland M. , Neu Bruno
Published: September 2018

Background: Percutaneous transhepatic biliary drainage (PTBD) plays a significant role especially in the palliation of an endoscopically inaccessible biliary system. Since a standard technique of PTBD is not defined, we compared a fluoroscopically guided technique (F-PTBD) with an ultrasound (US-PTBD) guided approach. Patients and Methods: Procedure characteristics, success-rates and complication-rates of the different PTBD techniques were compared in patients who underwent PTBD between October 1, 2006, and ­December 31, 2014. Results: In 195 patients, 251 PTBDs (207 F-PTBDs, 44 US-PTBDs) were performed. F-PTBDs were mostly inserted from the right and US-PTBDs from the left. Patient age, gender and physical status were comparable in both techniques. There was no difference regarding overall procedure success (90%/86.4%), overall interventional complication rates (10.6%/9.1%), fluoroscopy times, intervention times or sedatives dosages. However, major complications were only encountered in F-PTBDs. There was a higher success rate for F-PTBD vs. US-PTBD from the right side (91.9 vs. 75%; p = 0.033) and a trend towards a higher success rate for US guidance from the left side (82.9 vs. 95.8%; p = 0.223). Conclusions: For drainage of the right biliary system F-PTBD seems superior over the US-PTBD technique used in this study. However, major complications can occur more frequently in F-PTBD.
Correlation of Vitamin D3 (Calcitriol) Serum Concentrations with Vitamin B12 and Folic Acid in Women Undergoing in vitro Fertilisation/Intracytoplasmatic Sperm Injection
Authors: Rogenhofer Nina , Mischitz Daniela , Mann Corinna , Gluderer Johanna , von Schönfeldt Viktoria , Jeschke Udo , Thaler Christian J.
Published: September 2018

Background: The important role of vitamin D3 in human health is well recognized. In this study, we measured serum concentrations of vitamin D3, vitamin B12 and B9 (folic acid) in 410 women undergoing in vitro fertilisation (IVF)/intracytoplasmatic sperm injection (ICSI) with dedicated focus on 3-month changes in consideration of patients’ BMI. Methods: Patients were of European origin and did not take any supplementation of D3. In preparing for pregnancy, patients took ≥4 weeks 400 µg folic acid combined with 9 µg vitamin B12 and 150 µg iodide as recommended. Results: We found a significant 3-month quartile change of D3 serum concentrations (p < 0.0001) with maximum levels in autumn and lowest in spring. D3 correlated significantly with B12 (p = 0.035, ρ = 0.102) and folic acid (p < 0.0001, ρ = 0.191). BMIs however showed a negative correlation with B12 (p = 0.031, ρ = –0.105) and folic acid (p = 0.012, ρ = –0.125). Conclusions: Our results suggest a model in which the sun exposure during summer months enables storage of D3 followed by a slow release as a major factor to maintain D3 levels throughout the year. Finally, our data indicate that B12 and folic acid uptake might be influenced by vitamin D receptor and D3, where D3 and the BMI appear to have an indirect relationship – via B12 and folic acid.
The Effectiveness of Tamoxifen in the Prevention of Recurrent Urethral Strictures Following Internal Urethrotomy
Authors: El-Shazly M. , Hodhod A. , Selim M. , El-Gharabawy M. , Badawy A. , El-sherif E. , Zanaty F. , Alhajeri F.
Published: September 2018

Abstract Objective: Tamoxifen was not used earlier in clinical practice to decrease the urethral re-stricture rate after visual internal urethrotomy (VIU). In this study, we are the first to report the use of Tamoxifen as an adjuvant therapy to decrease the re-fibrosis and stricture recurrence post-VIU. Patients and Methods: Between 2015 and 2017, 60 patients underwent VIU for post-traumatic bulbar urethral stricture ≤1 cm. They were randomly divided into 2 groups (30 patients each). The Tamoxifen group cases received Tamoxifen 10 mg twice daily for 6 months post-VIU. The control group did not receive any medications. All patients were evaluated using the IPSS score, uroflowmetry, and perineal ultrasonography preoperatively at 3 and 6 months. Results: At presentation, there was no significant difference between patients of both groups in terms of IPSS score, Qmax, stricture width, and length. At 6 months follow-up, the mean IPSS score for the Tamoxifen group was 12.3 (8–19) in comparison with 20 (12–26) in the control group (p < 0.001). The Tamoxifen group had mean Qmax 11.1 mL/s (9–14), while those of the control group had mean Qmax 8.2 mL/s (6–10; p < 0.001). Using perineal ultrasound, only stricture width showed to be significantly smaller in the Tamoxifen group (p = 0.001). Conclusion: Tamoxifen seemed to be effective in reducing the recurrence of urethral stricture post-VIU. There was a significant improvement of the clinical outcome regarding Qmax and IPSS score after Tamoxifen adjuvant therapy.
Predicting Dysphagia with National Institute of Health Stroke Scale: Distinction between Infra- and Supratentorial Region is Essential
Authors: Labeit Bendix , Mueller Hannah , Muhle Paul , Claus Inga , Warnecke Tobias , Dziewas Rainer , Suntrup-Krueger Sonja
Published: September 2018

Background: For the early detection of post-stroke dysphagia (PSD), valid screening parameters are crucial as part of a step-wise diagnostic procedure. This study examines the role of the National Institute of Health Stroke Scale (NIH-SS) as a potential low-threshold screening parameter. Methods: During a ten-year period, 687 newly admitted patients at University Hospital Muenster were included in a retrospective analysis, if they had ischemic or haemorrhagic stroke confirmed by neuroimaging and had received NIH-SS scoring and endoscopic swallowing evaluation upon admission. The NIH-SS score was correlated with dysphagia severity as measured by the validated 6-point fiberoptic endoscopic dysphagia severity score (FEDSS), and the ideal cut-off score to predict PSD, defined as FEDSS > 1, was calculated. Supra- and infratentorial strokes were analysed separately due to their differing role in the pathophysiology of neurogenic dysphagia. Results: NIH-SS and dysphagia severity show a significant positive correlation in the whole study population (R2 = 0.745) as well as in both analysed subgroups (R2 = 0.494 for supra- and R2 = 0.646 for infratentorial strokes, p < 0.0005, respectively). For supratentorial strokes, the ideal NIH-SS cut-off is > 9 (sensitivity 68.3%, specificity 61.5%, positive predictive value 89.7%, negative predictive value 28.4%). For infratentorial strokes, a lower ideal cut-off > 5 was calculated (sensitivity 67.4%, specificity 85.0%, positive predictive value 95.1%, negative predictive value 37.8%). Conclusions: NIH-SS may be used as an adjunct to predict dysphagia in acute stroke patients with moderate sensitivity and specificity. Differentiation between supra- and infratentorial regions is essential not to miss dysphagia in infratentorial stroke.
Aging and the Epidemiology of Epilepsy
Authors: Beghi Ettore , Giussani Giorgia
Published: September 2018

Background: Epilepsy is a chronic disorder affecting all ages but with a peak in the elderly. The association of epilepsy with age can be explained by the predominance of brain diseases with epileptogenic potential (mostly stroke and dementia) and by the effects of the aging process through a number of molecular mechanisms involving networks of neurons with focal or diffuse distribution. Summary: The prevalence of active epilepsy is 6.4 per 1,000 and the lifetime prevalence is 7.6 per 1,000. The prevalence tends to increase with age, with peaks in the oldest age groups and in socially deprived individuals. The incidence of epilepsy is 61.4 per 100,000 person-years. Epilepsy has a bimodal distribution according to age with peaks in the youngest individuals and in the elderly. The increased incidence of seizures and epilepsy in the elderly can be attributed to the increase of age-related and aging-related epileptogenic conditions. Key Messages: As the world population is steadily growing with parallel increase in the number of aged subjects, in the future, epilepsy will represent a huge burden for the society. Measures must thus be taken to prevent seizures and epilepsy through the reduction of preventable epileptogenic factors.
The Incidence Prognosis and Risk Factors of Cognitive Impairment in Maintenance Haemodialysis Patients
Authors: Lu Renhua , Xu Chenqi , Li Yan , Yu Ling , Shao Xinghua , Xie Kewei , Gu Jiaqi , Yu Zanzhe , Yan Yucheng , Guan Yangtai , Ni Zhaohui , Ronco Claudio , Gu Leyi
Published: September 2018

Objective: To investigate the incidence and the prognosis of cognitive impairment (CI) and to find out the risk factors associated with the outcome in maintenance haemodialysis (MHD) patients. Methods: Enrolled the patients who met the criteria as below: MHD (≥3 months) patients before July 2014, ≥18 years old and could carry on the cognitive function test (Montreal Cognitive Assessment [MoCA]). All enrolled patients were divided into 2 groups: CI group (MoCA < 26) and non-CI group (MoCA ≥26). All patients were followed up for 36 months. The incidence, demography data, medical history, haemodialysis data, laboratory examination and prognosis of CI in haemodialysis patients were prospectively compared and analyzed. Multivariate logistic regression analysis was used to investigate the risk factors of CI. Kaplan-Meier survival curve was used for survival analysis. Results: In the present study, 219 patients were enrolled. The ratio of male to female was 1.46: 1. Age was 60.07 ± 12.44 and dialysis vintage was 100.79 ± 70.23 months. One hundred thirteen patients’ MoCA scores were lower than 26 were divided into CI group. Education status (OR 3.428), post-dialysis diastolic pressure (OR 2.234) and spKt/V (OR 1.982) were independent risk factors for CI in MHD patients. During the follow-up period, 15 patients died (13.2%) in the CI group and 5 died (4.72%) in the non-CI group (p < 0.05). The Kaplan-Meier survival curve analysis showed that the survival rate of patients with CI was lower than that of non-CI group in MHD patients during 3 years follow-up (p = 0.046). Conclusion: CI is one of the most common complications in MHD patients. The mortality is high in patients who had CI. Education status, post-dialysis diastolic pressure and spKt/V are independent risk factors for CI in MHD patients.
Regulator of G Protein Signaling 6 Facilities Cardiac Hypertrophy by Activating Apoptosis Signal–Regulating Kinase 1–P38/c‐JUN N‐Terminal Kinase 1/2 Signaling
Authors: Huang Zhijun , Shu Jingxian , Jiang Weihong , Jiang Mengqing , Lu Yao , Dai Haijiang , Xu Nana , Yuan Hong , Cai Jingjing
Published: September 2018

Background

Regulator of G protein signaling 6 (
RGS
6) is an important member of the
RGS
family and produces pleiotropic regulatory effects on cardiac pathophysiology. However, the role of
RGS
6 protein in cardiomyocytes during angiotensin
II
– and pressure overload–induced cardiac hypertrophy remain unknown.

Methods and Results

Here, we used a genetic approach to study the regulatory role of
RGS
6 in cardiomyocytes during pathological cardiac hypertrophy.
RGS
6 expression was significantly increased in failing human hearts and in hypertrophic murine hearts. The extent of aortic banding–induced cardiac hypertrophy, dysfunction, and fibrosis in cardiac‐specific
RGS
6 knockout mice was alleviated, whereas the hearts of transgenic mice with cardiac‐specific
RGS
6 overexpression exhibited exacerbated responses to pressure overload. Consistent with these findings,
RGS
6 also facilitated an angiotensin
II
–induced hypertrophic response in isolated cardiomyocytes. According to the mechanistic studies,
RGS
6 mediated cardiac hypertrophy by directly interacting with apoptosis signal–regulating kinase 1, which further activates the P38‐c‐
JUN
N‐terminal kinase 1/2 signaling pathway.

Conclusions

Based on our findings,
RGS
6 aggravates cardiac hypertrophy, and the
RGS
6‐apoptosis signal–regulating kinase 1 pathway represents a potential therapeutic target to attenuate pressure overload–driven cardiac remodeling.
Effects of Coenzyme Q10 on Statin‐Induced Myopathy: An Updated Meta‐Analysis of Randomized Controlled Trials
Authors: Qu Hua , Guo Ming , Chai Hua , Wang Wen‐ting , Gao Zhu‐ye , Shi Da‐zhuo
Published: September 2018

Background

Previous studies have demonstrated a possible association between the induction of coenzyme Q10 (CoQ10) after statin treatment and statin‐induced myopathy. However, whether CoQ10 supplementation ameliorates statin‐induced myopathy remains unclear.

Methods and Results

PubMed,
EMBASE
, and Cochrane Library were searched to identify randomized controlled trials investigating the effect of CoQ10 on statin‐induced myopathy. We calculated the pooled weighted mean difference (
WMD
) using a fixed‐effect model and a random‐effect model to assess the effects of CoQ10 supplementation on statin‐associated muscle symptoms and plasma creatine kinase. The methodological quality of the studies was determined, according to the
Cochrane Handbook
. Publication bias was evaluated by a funnel plot, Egger regression test, and the Begg‐Mazumdar correlation test. Twelve randomized controlled trials with a total of 575 patients were enrolled; of them, 294 patients were in the CoQ10 supplementation group and 281 were in the placebo group. Compared with placebo, CoQ10 supplementation ameliorated statin‐associated muscle symptoms, such as muscle pain (
WMD
, −1.60; 95% confidence interval [
CI
], −1.75 to −1.44;
P
<0.001), muscle weakness (
WMD
, −2.28; 95%
CI
, −2.79 to −1.77;
P
=0.006), muscle cramp (
WMD
, −1.78; 95%
CI
, −2.31 to −1.24;
P
<0.001), and muscle tiredness (
WMD
, −1.75; 95%
CI
, −2.31 to −1.19;
P
<0.001), whereas no reduction in the plasma creatine kinase level was observed after CoQ10 supplementation (
WMD
, 0.09; 95%
CI
, −0.06 to 0.24;
P
=0.23).

Conclusions

CoQ10 supplementation ameliorated statin‐associated muscle symptoms, implying that CoQ10 supplementation may be a complementary approach to manage statin‐induced myopathy.
Comments on Penelope Maddy’s What Do Philosophers Do?
Authors: Stroud Barry
Published: September 2018

I here offer a discussion of some of Penelope Maddy’s responses to philosophical scepticism in her recent book, What Do Philosophers Do? Among other things, I suggest that philosophers who take an interest in human knowledge are not primarily concerned with whether anyone knows anything about the world, but rather with understanding how we know the things we do in the face of the difficulties that seem naturally to arise in the explanations they come up with.
Replies to Coliva, Leite, and Stroud
Authors: Maddy Penelope
Published: September 2018

Here I cast some doubt on Professor Coliva’s interpretive claim that Moore’s “Proof of an external world” is addressed to idealism, not skepticism, and explore the consequences for our understanding of the final paragraphs of the paper. In response to Professor Leite, I examine the disagreement between us on whether the global skeptical hypotheses can be refuted by ordinary evidence. Finally, after analyzing the logic of the skeptical argumentation, I attempt an answer to Professor Stroud’s question about the staying power of the representative theory of perception.
The Plain Inquirer’s Plain Evidence against the Global Skeptical Scenarios
Authors: Leite Adam
Published: September 2018

Penelope Maddy claims that we can have no evidence that we are not being globally deceived by an evil demon. However, Maddy’s Plain Inquirer holds that she has good evidence for a wide variety of claims about the world and her relation to it. She rejects the broadly Cartesian idea that she can’t be entitled to these claims, or have good evidence for them, or know them, unless she can provide a defense of them that starts from nowhere. She likewise rejects the more limited demand for a defense that makes use only of considerations that do not concern the world outside of her mind. She allows that some considerations about the world can be appealed to perfectly appropriately as fully adequate evidence in favor of other considerations about the world. So why can’t the Plain Inquirer rule out global skeptical hypotheses by producing evidence against them that depends upon other considerations about the world? Is there good reason for singling out global skeptical hypotheses such as I am not being deceived by an evil demon as requiring a different kind of treatment? Considerations about epistemic asymmetry and epistemic circularity, as well as Wittgensteinian considerations about the relation between evidence and the real-world and human background context, all lead to the conclusion that there is not.
A Call for the Evaluation of Web-Based Climate Data and Analysis Tools
Authors: VanderMolen Kristin , Wall Tamara U. , Daudert Britta
Published: September 2018

Researchers are producing an ever greater number of web-based climate data and analysis tools in support of natural resource research and management. Yet the apparent absence or underreporting of evaluation in the development of these applications has raised questions as to whether, by whom, and for what they are utilized, and, relatedly, whether they meet the rationale for their development. This paper joins recent efforts to address these questions by introducing one approach to evaluation—developmental evaluation—and reporting on its use in the evaluation of the Southwest Climate and Environmental Information Collaborative (SCENIC). A web interface under development at the Western Regional Climate Center, SCENIC provides access to climate data and analysis tools to environmental scientists in support of natural resource research and management in the southwestern United States. Evaluation findings highlight subtlety in the improvements necessary for ensuring a useful and usable application that could not have been ascertained in the absence of end-user feedback. We therefore urge researchers to systematically evaluate web-based climate data and analysis tools in the interest of ensuring their usefulness, usability, and fulfillment of the proposed rationale. In so doing, we recommend that researchers test and apply established evaluation frameworks, thereby engaging end users directly in the process of application development.
Short Warm-Side Temperature Distribution Tails Drive Hot Spots of Warm Temperature Extreme Increases under Near-Future Warming
Authors: Loikith Paul C. , Neelin J. David , Meyerson Joyce , Hunter Jacob S.
Published: September 2018

Regions of shorter-than-Gaussian warm-side temperature anomaly distribution tails are shown to occur in spatially coherent patterns in global reanalysis. Under such conditions, future warming may be manifested in more complex ways than if the underlying distribution were close to Gaussian. For example, under a uniform warm shift, the simplest prototype for future warming, a location with a short tail would experience a greater increase in extreme warm exceedances relative to a fixed threshold compared to if the distribution were Gaussian. The associated societal and environmental impacts make realistic representation of these short tails an important target for climate models. Global evaluation of the ability for a suite of global climate models (GCMs) contributing to phase 5 of the Coupled Model Intercomparison Project (CMIP5) suggests that most models approximately capture the principal observed coherent regions of short tails. This suggests the underlying dynamics and physics occur on scales resolved by the models, and helps build confidence in model simulations of extremes. Furthermore, most GCMs show more rapid future increases in exceedances of the historical 95th percentile in regions exhibiting short tails in the historical climate. These regions, where the ratio of exceedances projected by the GCM compared to that expected from a Gaussian sometimes exceeds 1.5, are termed hot spots. Prominent hot spots include western North America, Central America, a broad swath of northwestern Eurasia, and the Indochina Peninsula during boreal winter. During boreal summer, central and western Australia, parts of southern Africa, and portions of central South America are major hot spots.
Assembling Justice: Reviving Nonhuman Subjectivities to Examine Institutional Betrayal Around Sexual Misconduct
Authors: Gentile Katie
Published: September 2018

While some colleges have adopted bystander intervention and restorative justice practices to address sexual misconduct as a community issue, psychoanalytic institutes facing crises of sexual misconduct have typically relied on the tried-and-true tactic of identifying the neoliberal individual as the sole site of trouble. Successful strategies used in colleges can be applied to the psychoanalytic setting by focusing on institutional betrayal. This systemic, community-based approach decenters not only individual bodies but human subjectivities. Here institutions become not just containers for group or networked affect, as if affect itself emanates from individuals into an institution. Agency and affect emerge through networks, not individual bodies, and institutions are active agents in violent betrayal. Acknowledging the ways the nonhuman and the human co-emerge creates the space to hold the vitalities and agencies of both, including multiple potentialities for (re)traumatization, resistance, and transformation.
Emotional Regulation in Women with Chronic Fatigue Syndrome and Depression: Internal Representations and Adaptive Defenses
Authors: Bram Anthony D. , Gottschalk Kiley A. , Leeds William M.
Published: September 2018

Chronic fatigue syndrome (CFS) presents challenges in differential diagnosis and treatment. Complicating diagnosis is that its symptoms overlap with those of depression. This study applies psychoanalytic concepts to understand emotional regulation (ER) in women with CFS and/or depression. One hundred eighty-six women were assigned to four groups and compared: (a) CFS plus high er depression (CFS-HD); (b) CFS plus lower depression (CFS-LD); (c) depressive disorder (DD); and (d) healthy controls (HC). ER was operationalized by measures of capacity to form internal representations and adaptive defenses. The study’s premise was that difficulties metabolizing emotions psychologically would be associated with their greater somatic expression. Some support was found for the hypothesis that CFS participants would exhibit more impairment in representing emotions and in adaptive defenses compared to the DD and HC groups, but this held only for the CFS-HD group. Although CFS-LD participants were expected to be more purely somatizing than the CFS-HD group, they instead showed more sophisticated capacities for ER than that group and recalled less distressing early relationships, revealing more resilience. Still, however, we found support for somatization in some CFS sufferers: Within both the CFS-HD and the CFS-LD groups, weaknesses in representing emotions and in defensive functioning were associated with more severe physical symptoms. Clinically, the heterogeneity of CFS and those who suffer from it indicates the need for individual assessment and depression treatment.
The formation of young workers: The cultivation of the self as a subject of value to the contemporary labour force
Authors: Farrugia David
Published: September 2018

This article explores the practices through which young people cultivate themselves as subjects of value to the post-Fordist labour force. In this, the article goes beyond an existing emphasis on young people’s ‘transitions’ through employment, to a focus on the practices through which young people are formed as labouring subjects, and therefore on the relationship between youth subjectivities and post-Fordist labour force formation. Theoretically, the article builds upon increasingly influential suggestions in studies of post-Fordism that the formation of post-Fordist workers now takes place through the conversion of the whole of a subject’s life into the capacity for labour, including affective styles, modes of relationality, and characteristics usually not considered as productive dimensions of the self. In this context, the article shows that whilst young people form themselves as workers through practices that are not specific to institutionalised definitions of education and labour, these practices – and the modes of selfhood they aim to cultivate – vary in ways that contribute to classed divisions within post-Fordist societies. In this, the study of the formation of young workers offers a critical insight into the way that the formation of subjectivities intertwines with the disciplinary requirements of post-Fordist labour in their classed manifestations.
Collective Leadership Development: Emerging Themes From Urban, Suburban, and Rural High Schools
Authors: Eckert Jonathan
Published: September 2018

Purpose: Applying an analytic model to better understand collective leadership development, this study examines three high schools: one urban, one suburban, and one rural. Each school’s unique structure and context tests the model’s explanatory power. Research Methods: Using a multiple-case study design, data consisting of interviews with teachers and administrators ( n = 64), document analysis, and observations were collected from each of the three high schools to describe and explain variation in collective leadership development, practice, and student outcomes. Findings: Schools’ efforts to develop leadership are organized for cross-case analysis by model constructs. Variation between schools exists in collective leadership capacity, practice, and student outcomes. This variation is explained by antecedent factors that include principal support of teacher leadership, initial teacher capacity, school conditions, work design, and leadership development experiences. Specifically, catalytic principal support, relational trust, professional capital, and views of leadership as work enhance development. Moreover, because of the iterative nature of improvement captured by the model, improved collective leadership practice influences the antecedent constructs. Implications: This study has implications for how schools and districts understand collective leadership development efforts of administrators and teachers. The analytic model facilitates the examination of school contexts to understand the potential and relative success of development efforts.
Full-scale measurement on vibration performance of vehicle-mounted optical transceiver mast
Authors: Lei Yao , Wang Jinli , Zhang Lizhong
Published: September 2018

Background:

Mast is mainly used for assisting the communication-vehicle-mounted optical transceiver to obtain a coarse tracking of objects rapidly and accurately, especially when objects are communicating among different regions.

Methods:

This study first conducts a force analysis of a vehicle-mounted mast specialized for laser communication and then derives dynamic characteristics of the mast under wind load. In order to validate tracking precision and the stabilization of the optical transceiver, and examine the wind disturbance resistance of the mast, a series of field experiments were carried out.

Results and Conclusion:

Finally, the test errors were analyzed in detail, and the experimental results demonstrated that the tracking error of the vehicle-mounted optical transceiver is less than 80μrad which means the optical transceiver satisfies the system requirements in terms of precision. Furthermore, both theoretical analysis and experimental results revealed that designed mast satisfies the technical requirements of the vehicle-mounted laser communication, thus the feasibility of the mast in vehicle-mounted communication was validated.
Experimental study on shear-dominant fiber failure in CFRP laminates by out-of-plane shear loading
Authors: Yashiro Shigeki , Ogi Keiji
Published: September 2018

Understanding the shear behavior and resulting fiber failure of fiber-reinforced plastics is required for better prediction of their behavior during the machining process, but knowledge regarding the shear strength of fiber failure is limited. In this study, out-of-plane shear tests were conducted to observe the shear behavior of carbon fiber-reinforced plastic laminates subjected to high shear stress exceeding the shear strength of matrix failure. The longitudinal fibers in carbon fiber-reinforced plastic unidirectional laminates were cut by shear loading without severe internal damage and the maximum shear stress causing progressive fiber breaks was much higher than the shear strength of matrix failure. This result suggested the possibility of out-of-plane shearing as a machining method for fiber-reinforced plastics and shear tests were subsequently performed for carbon fiber-reinforced plastic cross-ply laminates. Delamination was generated by high shear stress to cut the reinforcing fibers, but the size of the remaining damage was small even in the thermoset carbon fiber-reinforced plastic laminates in which delamination likely occurs, without any optimization of the trimming conditions.
Syntactic Cues Take Precedence Over Distributional Cues in Native and Non-Native Speech Segmentation
Authors: Tremblay Annie , Spinelli Elsa , Coughlin Caitlin E. , Namjoshi Jui
Published: September 2018

This study investigates whether syntactic cues take precedence over distributional cues in native and non-native speech segmentation by examining native and non-native speech segmentation in potential French-liaison contexts. Native French listeners and English-speaking second-language learners of French completed a visual-world eye-tracking experiment. Half the stimuli contained the pivotal consonant /t/, a frequent word onset but infrequent liaison consonant, and half contained /z/, a frequent liaison consonant but rare word onset. In the adjective–noun condition (permitting liaison), participants heard a consonant-initial target (e.g., le petit tatoué; le fameux zélé) that was temporarily ambiguous at the segmental level with a vowel-initial competitor (e.g., le petit [t]athée; le fameux [z]élu); in the noun–adjective condition (not permitting liaison), they heard a consonant-initial target (e.g., le client tatoué; le Français zélé) that was not temporarily ambiguous with a vowel-initial competitor (e.g., le client [*t]athée; le Français [*z]élu). Growth-curve analyses revealed that syntactic context modulated both groups’ fixations (noun–adjective > adjective–noun), and pivotal consonant modulated both groups’ fixations (/t/ > /z/) only in the adjective–noun condition, with the effect of the consonant decreasing in more proficient French learners. These results suggest that syntactic cues override distributional cues in the segmentation of French words in potential liaison contexts.
Reframing the Environment in Neoliberal India: Introduction to the Theme
Authors: Rao Manisha
Published: September 2018

Contemporary discussions on environment emphasise the use and abuse of the environment in multiple ways and means. The collective mobilisations around environmental alteration, degradation and destruction signal the crises in the material bases of life based at the intersections of caste, class and gender. This process, it is argued, has begun on an unprecedented scale since the neoliberal turn in India. There is an emerging and significant process of appropriation of land and natural resources to help the ‘growth’ story. Marginalised groups and local communities are being sidelined from access and control of resources, whether it is land, water, forest or urban commons. There are increasing instances of land appropriation for the so-called ‘environmental’ ends. However, it involves new forms of valuation, commodification and markets for different aspects of nature being built across a range of actors and alliances, such as venture capitalists, traders and consultants, ecotourism companies, green activists and consumers who seem to have common interests. Hence, the attempt would be to unravel the underlying power relations that are hidden in the present discourse of ecological sustainability.
The Coloured Lens Effect: Disentangling the Contradictory Discourses within Watershed Policies
Authors: de Souza Arun
Published: September 2018

This proposed article seeks to analyse the Hariyali guidelines in order to show how a capitalistic, managerial and scientific rationale is used which presumes that nature in order to be valued must have a productive value. As a capitalist enterprise, nature is only useful if it serves the livelihood needs of the populace. All other values are elided in favour of one overarching idea of productivity for the market. This productivity is sought to be harnessed through the twin ideas of proper managerial and scientific principles. The ‘Watershed Users Association’ is premised on the principle of people being rational maximisers who will put aside their caste, gender, religious and class differences in order to transform the topographical watershed into a productive entrepreneurial community enterprise. On the ground, people of course manage to subvert and resist these processes even as they acquiesce in the larger development plan.
Dam, ‘Development’ and Popular Resistance in Northeast India
Authors: Sharma Chandan Kumar
Published: September 2018

The policy of the Government of India to turn its northeastern region, especially Arunachal Pradesh, into ‘India’s Future Powerhouse’ by generating massive hydel power from almost all its perennial rivers has led to widespread protests in the region. These protests are based on the apprehension that this new ‘development’ initiative of the government would spell disaster to the river ecosystem and the livelihood and cultural heritage of the people of the region. The protests are also informed by the fact that the region is seismically very active, geologically fragile and ecologically sensitive. The conflict between the government’s new logic of development in a region considered as a distant security frontier and the local people’s apprehensions and questions about the character of this development has unfolded a complex discourse entangled in the interplay of issues concerning development, environment, people’s rights and rule of law.