bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Tumor Suppressor CIC Directly Regulates MAPK Pathway Genes via Histone Deacetylation
Authors: Weissmann Simon , Cloos Paul A. , Sidoli Simone , Jensen Ole N. , Pollard Steven , Helin Kristian 
Published: May 2018

Abstract
Oligodendrogliomas are brain tumors accounting for approximately 10% of all central nervous system cancers. CIC is a transcription factor that is mutated in most patients with oligodendrogliomas; these mutations are believed to be a key oncogenic event in such cancers. Analysis of the Drosophila melanogaster ortholog of CIC, Capicua, indicates that CIC loss phenocopies activation of the EGFR/RAS/MAPK pathway, and studies in mammalian cells have demonstrated a role for CIC in repressing the transcription of the PEA3 subfamily of ETS transcription factors. Here, we address the mechanism by which CIC represses transcription and assess the functional consequences of CIC inactivation. Genome-wide binding patterns of CIC in several cell types revealed that CIC target genes were enriched for MAPK effector genes involved in cell-cycle regulation and proliferation. CIC binding to target genes was abolished by high MAPK activity, which led to their transcriptional activation. CIC interacted with the SIN3 deacetylation complex and, based on our results, we suggest that CIC functions as a transcriptional repressor through the recruitment of histone deacetylases. Independent single amino acid substitutions found in oligodendrogliomas prevented CIC from binding its target genes. Taken together, our results show that CIC is a transcriptional repressor of genes regulated by MAPK signaling, and that ablation of CIC function leads to increased histone acetylation levels and transcription at these genes, ultimately fueling mitogen-independent tumor growth.
Significance: Inactivation of CIC inhibits its direct repression of MAPK pathway genes, leading to their increased expression and mitogen-independent growth.
Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/15/4114/F1.large.jpg. Cancer Res; 78(15); 4114–25. ©2018 AACR.
Target-Based Screening against eIF4A1 Reveals the Marine Natural Product Elatol as a Novel Inhibitor of Translation Initiation with In Vivo Antitumor Activity
Authors: Peters Tara L. , Tillotson Joseph , Yeomans Alison M. , Wilmore Sarah , Lemm Elizabeth , Jiménez-Romero Carlos , Amador Luis A. , Li Lingxiao , Amin Amit D. , Pongtornpipat Praechompoo , Zerio Christopher J. , Ambrose Andrew J. , Paine-Murrieta Gillian , Greninger Patricia , Vega Francisco , Benes Cyril H. , Packham Graham , Rodríguez Abimael D. , Chapman Eli , Schatz Jonathan H. 
Published: May 2018

Abstract
Purpose: The DEAD-box RNA helicase eIF4A1 carries out the key enzymatic step of cap-dependent translation initiation and is a well-established target for cancer therapy, but no drug against it has entered evaluation in patients. We identified and characterized a natural compound with broad antitumor activities that emerged from the first target-based screen to identify novel eIF4A1 inhibitors.
Experimental Design: We tested potency and specificity of the marine compound elatol versus eIF4A1 ATPase activity. We also assessed eIF4A1 helicase inhibition, binding between the compound and the target including binding site mutagenesis, and extensive mechanistic studies in cells. Finally, we determined maximum tolerated dosing in vivo and assessed activity against xenografted tumors.
Results: We found elatol is a specific inhibitor of ATP hydrolysis by eIF4A1 in vitro with broad activity against multiple tumor types. The compound inhibits eIF4A1 helicase activity and binds the target with unexpected 2:1 stoichiometry at key sites in its helicase core. Sensitive tumor cells suffer acute loss of translationally regulated proteins, leading to growth arrest and apoptosis. In contrast to other eIF4A1 inhibitors, elatol induces markers of an integrated stress response, likely an off-target effect, but these effects do not mediate its cytotoxic activities. Elatol is less potent in vitro than the well-studied eIF4A1 inhibitor silvestrol but is tolerated in vivo at approximately 100× relative dosing, leading to significant activity against lymphoma xenografts.
Conclusions: Elatol's identification as an eIF4A1 inhibitor with in vivo antitumor activities provides proof of principle for target-based screening against this highly promising target for cancer therapy. Clin Cancer Res; 24(17); 4256–70. ©2018 AACR.
Scylax of Caryanda, pseudo-scylax, and the Paris Periplus: reconsidering the ancient tradition of a geographical text
Authors: Matijašić Ivan 
Published: May 2018

O Périplo, preservado no manuscrito Parisinus suppl. gr. 443 e erroneamente atribuído a Cílax de Carianda (sexto século a. C.), é o mais antigo espécime da periplografia grega antiga. Ele pertence ao quarto século antes de Cristo. No presente artigo, todos os testemunhos da tradição antiga tanto de Cílax quanto do Périplo de Paris são cuidadosamente avaliadas. O objetivo é determinar quando e por que o Périplo de Paris foi equivocadamente atribuído a Cílax e dissipar qualquer dúvida da suposta autoria deste trabalho geográfico antigo. A confusão, ou a falsificação deliberada, é evidente em Estrabão: ele sabia que a viagem de Cílax para o Oriente e, ao mesmo tempo estava familiarizado com o texto do Périplo de Paris, que ele atribui ao antigo navegador. Autores gregos e latinos da Época Imperial Romana conheciam o Périplo de Paris, mas muitos seguiam cegamente a atribuição equivocada a Cílax de Carianda. Quando Marciano de Heracleia no período Bizantino Antigo coletou seu corpus de geógrafos gregos antigos, ele também atribuiu o Périplo de Paris a Cílax, assim transmitindo o erro aos copistas do Paris. suppl. gr. 443.
Epicurus and aesthetic disinterestedness
Authors: Celkyte Aiste 
Published: May 2018

O desinteresse estético é um dos conceitos centrais da estética, e Jerome Stolnitz, o mais proeminente teórico do desinteresse no século XX, afirmou que (i) o envolvimento dos pensadores antigos com esta noção era superficial e pouco desenvolvido e, consequentemente, (ii) a emergência do desinteresse no século XVIII marca o nascimento da estética como disciplina. Neste artigo, pretendo usar os trabalhos existentes de Epicuro para mostrar que o filósofo antigo não apenas tinha conceitos similares, como também os usava de maneiras cuidadosas e complexas. Eu argumento que, no enquadramento teórico de Epicuro, as artes pertenciam a categoria dos desejos "meramente naturais", e esta classificação, combinada com aquilo que sabemos da rejeição de Epicuro da crítica da arte, mostra que ele tinha desenvolvido cuidadosamente razões que fundamentavam a ideia de que a arte deveria ser abordada terminalmente, ao invés de instrumentalmente. Por fim, eu comparo a noção de desinteresse estético com as visões de Epicuro acerca da arte e argumento que de muitas maneiras a última não é inferior a primeira, e que, portanto, deve pertencer a história da estética.
Taurine Reduces tPA (Tissue-Type Plasminogen Activator)-Induced Hemorrhage and Microvascular Thrombosis After Embolic Stroke in Rat
Authors: Jin Rong , Xiao Adam Y. , Liu Shan , Wang Min , Li Guohong 
Published: May 2018

Background and Purpose—
Taurine (2-aminoethansulfolic amino acid) exerts neuroprotective actions in experimental stroke. Here, we investigated the effect of taurine in combination with delayed tPA (tissue-type plasminogen activator) on embolic stroke.

Methods—
Rats subjected to embolic middle cerebral artery occlusion were treated with taurine (50 mg/kg) at 4 hours in combination with tPA (10 mg/kg) at 6 hours. Control groups consisted of ischemic rats treated with either taurine (50 mg/kg) or saline at 4 hours or tPA (10 mg/kg) alone at 2 or 6 hours after middle cerebral artery occlusion.

Results—
We found that combination treatment with taurine and tPA robustly reduced infarct volume and neurological deficits 3 days after stroke, whereas treatment with taurine alone had a less-significant protective effect. tPA alone at 6 hours had no effects on infarct volume but instead induced intracerebral hemorrhage. The combination treatment with taurine prevented tPA-associated hemorrhage and reduced intravascular deposition of fibrin/fibrinogen and platelets in downstream microvessels and hence improved microvascular patency. These protective effects are associated with profound inhibition of CD147 (cluster of differentiation 147)-dependent MMP-9 (matrix metalloproteinase-9) pathway in ischemic brain endothelium by taurine. Notably, targeted inhibition of CD147 by intracerebroventricular injection of the rat CD147 siRNA profoundly inhibited ischemia-induced and tPA-enhanced MMP-9 activity in ischemic brain endothelium and blocked tPA-induced cerebral hemorrhage. Finally, the combination treatment with taurine and tPA improved long-term outcome at least 45 days after stroke compared with saline-treated group.

Conclusions—
Our results suggest that taurine in combination with tPA may be a clinically feasible approach toward future attempts at combination stroke therapy.
Job-related burnout is associated with brain neurotransmitter levels in Chinese medical workers: a cross-sectional study
Authors: Yao Yongcheng , Zhao Shan , Zhang Yuhong , Tang Lixia , An Zhen , Lu Lingeng , Yao Sanqiao 
Published: May 2018

Objective The aim of the present study was to investigate the relationship between job burnout and neurotransmitter levels in medical staff. Methods A total of 80 medical staff were enrolled in the study and assessed for occupational burnout using the Maslach Burnout Inventory – General Survey (MBI-GS). The levels of neurotransmitters in the cerebral cortex were analysed using an SP03 encephalofluctuograph. Results The levels of the neurotransmitters γ-aminobutyric acid, 5-hydroxytryptamine (5-HT), norepinephrine (NE), glutamate, acetylcholine (Achl) and dopamine (DA) were significantly lower in men than in women. Medical staff with lower levels of exhaustion had significantly higher neurotransmitter levels than staff with moderate levels of exhaustion. However, there was no significant interaction between sex and exhaustion on neurotransmitter levels. Canonical correlation showed that exhaustion was positively associated with 5-HT and DA, but negatively associated with NE and Achl, regardless of age and sex. Conclusion Neurotransmitter levels in the cerebral cortex were associated with job-related burnout in medical staff. The findings suggest that long-term job-related burnout may lead to behavioural and psychiatric disorders.
A Brief History of Awareness of the Link Between Alcohol and Fetal Alcohol Spectrum Disorder
Authors: Brown Jasmine M. , Bland Roger , Jonsson Egon , Greenshaw Andrew J. 
Published: May 2018

Objective: Fetal alcohol spectrum disorder (FASD) is a medical term used to describe a range of mental and physical disabilities caused by maternal alcohol consumption. The role of alcohol as a teratogen and its effects on the cellular growth of the embryo and the fetus were not determined on scientific grounds until the late 1960s. However, the link between alcohol use during pregnancy and its harms to offspring might have been observed frequently over the many thousands of years during which alcohol has been available and used for social and other reasons. Methods and Results: Using sources ranging from the biblical Book of Judges (pre-1700) up until the first public health bulletin (1977), we seek to provide an overview of the academic debate around early historical accounts ostensibly attributed to the awareness of alcohol as a prenatal teratogen as well as to describe the social and political influences that sculpted developments leading to the public recognition of FASD. Conclusions: Our analysis provides a brief overview of the discourse regarding historical awareness of the detrimental effects of prenatal alcohol exposure on fetal development leading to the formal recognition of FASD as a distinct clinical entity. Further research will be required to fully appreciate the scientific, medical, and societal ills associated with prenatal alcohol exposure.
Practicing Communication Skills For Responding to Emotionally Charged Questions
Authors: Patell Rushad , Gutierrez Alejandra , Lee Natalie , Neuendorf Kathleen 
Published: May 2018

Objective: To assess the impact of a 1-hour communication skills workshop highlighting the “ask more and summarize technique” (AMST) to teach residents an effective way to respond to emotionally charged questions. Methods: From December 2015 to January 2017, residents on an inpatient oncology or palliative medicine rotation attended a mandatory 1-hour workshop on AMST involving a short introduction to the technique followed by skills practice. A survey (S1) was administered to the residents during the first session to assess their self-reported attitudes and practices. A follow-up survey (S2) was e-mailed at the end of the rotation to assess the usefulness of AMST. Results: Twenty-one participants completed S1, and 12 participants completed S2. A total of 62% (13/21) reported the workshop was “very useful.” There was a reported increased frequency of “summarizing back” between surveys ( P = .01). Addressing fear and anxiety (75%, 9/12) and responding to patients who were angry/upset (67%, 8/12) were the situations where AMST was found to be the most useful. Fifty-four percent of respondents (7/12) felt they could have used AMST more. Conclusion: A 1-hour communication skills workshop targeting residents on an inpatient oncology or palliative rotation increased the use of summary statements in challenging situations. Practice Implications: A short skills practice workshop can be incorporated into a busy clinical curriculum to achieve changes in trainee behaviors and attitudes.
Palliative care nursing involvement in end-of-life decision-making: Qualitative secondary analysis
Authors: Hernández-Marrero Pablo , Fradique Emília , Pereira Sandra Martins 
Published: May 2018

Background: Nurses are the largest professional group in healthcare and those who make more decisions. In 2014, the Committee on Bioethics of the Council of Europe launched the “Guide on the decision-making process regarding medical treatment in end-of-life situations” (hereinafter, Guide), aiming at improving decision-making processes and empowering professionals in making end-of-life decisions. The Guide does not mention nurses explicitly. Objectives: To analyze the ethical principles most valued by nurses working in palliative care when making end-of-life decisions and investigate if they are consistent with the framework and recommendations of the Guide; to identify what disputed/controversial issues are more frequent in these nurses’ current end-of-life care practices. Design: Qualitative secondary analysis. Participants/context: Three qualitative datasets including 32 interviews from previous studies with nurses working in palliative care in Portugal. Ethical consideration: Ethical approval was obtained from the Ethics Research Lab of the Instituto de Bioética (Ethics Research Lab of the Institute of Bioethics) (Ref.04.2015). Ethical procedures are thoroughly described. Findings: All participant nurses referred to autonomy as an ethical principle paramount in end-of-life decision-making. They were commonly involved in end-of-life decision-making. Palliative sedation and communication were the most mentioned disputed/controversial issues. Discussion: Autonomy was highly valued in end-of-life care and decision-making. Nurses expressed major concerns in assessing patients’ preferences, wishes, and promoting advance care planning. Nurses working in palliative care in Portugal were highly involved in end-of-life decision-making. These processes embraced a collective, inclusive approach. Palliative sedation was the most mentioned disputed issue, which is aligned with previous findings. Communication also emerged as a sensitive ethical issue; it is surprising, however, that only three nurses referred to it. Conclusion: While the Guide does not explicitly mention nurses in its content, this study shows that nurses working in palliative care in Portugal are involved in these processes. Further research is needed on nurses’ involvement and practices in end-of-life decision-making.
Economic Growth, Structural Change and Productive Employment Linkages in India
Authors: Aggarwal Aradhna 
Published: May 2018

This article presents a quantitative analysis of growth, structural change and employment linkages at the aggregate level and by sector under the state- and market-led regimes in India. The underlying objectives are: (a) to understand how economic liberalization has affected the economic and labour market structures, and linkages thereof; and (b) to analyse how these dynamics have affected the generation of productive employment in the economy. The analysis is based on Shapley decompositions. Our results suggest that the contribution of structural change in employment to growth declined drastically and secularly as the country transitioned to a high-growth regime driven by globalization. The sector-level analysis indicates that employment opportunities are not being created in high-productivity sectors and segments. Thus, despite a high-growth rate in GDP per capita and productivity-enhancing structural transformation in GDP, a vast population is still trapped in employment that cannot be qualified as productive employment. The study attributes it to trade-induced economic specialization accompanied with weakening of internal inter-sectoral linkages. The article makes a strong case for strategic government intervention to broad base structural change for generating productive employment, which is at the core of poverty reduction. JEL codes: E24, O14, O4
Remittances and Real Effective Exchange Rate
Authors: Dutta Ujjal Protim , Sengupta Partha Pratim 
Published: May 2018

Remittances in India have been growing rapidly since 1991. Most of the studies find that remittance has had a significant impact on real effective exchange rate (REER). It is imperative to evaluate the impact of a transfer such as remittance and aid on country’s competitiveness. This article is an attempt to investigate the impact of workers’ remittances and some selected macro-variables on REER of India using annual data from 1980–2015. The study conducted autoregressive distributive lag (ARDL) bound test co-integration approach to explore this long-run relationship. The ARDL bound test approach confirms significant long-run relationships among the selected variables at 1 per cent level of significance. In addition to this, the ARDL short-run error correction model implies that while REER may temporarily deviate from its long-run equilibrium, the deviations adjust towards the equilibrium level in the long run. JEL: F31, F35, F41
Depression, anxiety, and stress from substance-use disorder among family members in Iceland
Authors: Ólafsdóttir Jóna , Hrafnsdóttir Steinunn , Orjasniemi Tarja 
Published: May 2018

Aims: This research was designed to explore the extent to which the use of alcohol or drugs by one member of a family affects the psychosocial state of other family members. The study asks whether family members of substance abusers are more likely to report increased depression, anxiety and stress then the general population in Iceland? Are there significant differences between family members; e.g., spouses, parents, adult children and siblings by gender, age, education and income? Data and methods: The instrument used for this purpose is the Depression Anxiety Stress Scale (DASS), which is designed to measure those three related mental states. It was administered to 143 participants (111 women and 32 men) with ages ranging from 19–70 years on the first day of a four-week group therapy programme for relatives of substance use disorder (SUD) at The Icelandic National Centre for Addiction Treatment (SÁÁ) from August 2015 to April 2016. Thirty participants are adult children of a parent with SUD, 47 are a spouse, 56 are parents of a child with SUD and 10 are siblings. The subscales of the DASS for depression, anxiety, and stress were utilised to examine which family member – parent, child, partner, or sibling – presented the behaviour associated with SUD. Results: 36% or more of the respondents in all three subscales had average, serious, or very serious depression, anxiety, and/or stress. This is higher than in DASS studies of the general population in Iceland. However, the analysis indicates that it made little difference to the family’s wellbeing which family member was affected by SUD.
Long-term prospective observation suggests that glomerular hyperfiltration is associated with rapid decline in renal filtration function: A multiethnic study
Authors: Low Serena , Zhang Xiao , Wang Jiexun , Yeoh Lee Ying , Liu Yan Lun , Ang Keven Kue Loong , Tang Wern Ee , Kwan Pek Yee , Tavintharan Subramaniam , Sum Chee Fang , Lim Su Chi 
Published: May 2018

Aim: Glomerular hyperfiltration usually occurs early in development of kidney complications in diabetes. To understand hyperfiltration as a marker of renal disease progression in type 2 diabetes mellitus, we aimed to examine association between glomerular hyperfiltration (estimated glomerular filtration rate ⩾ 120 mL/min/1.73 m2) and rapid renal decline (annual estimated glomerular filtration rate loss ⩾ 3 mL/min/1.73 m2). Methods: This was a prospective cohort comprising 1014 patients with type 2 diabetes mellitus attending a Diabetes Centre of a regional hospital in 2002–2014. A separate prospective cohort, comprising 491 patients who attended Diabetes Centre or primary-care polyclinics, was used for validation. We performed binary mediation analysis to examine role of hyperfiltration on relationship between baseline haemoglobin A1c and rapid renal decline. Results: Among patients in discovery cohort, 5.2% had baseline hyperfiltration. Over mean follow-up of 6 years, 22.9% had rapid glomerular filtration rate decline. Baseline hyperfiltration was significantly associated with greater odds of rapid renal decline after adjusting for demographics, diabetes duration and clinical covariates (odds ratio: 2.57; 95% confidence interval: 1.21–5.46; p = 0.014). Similar finding was found in validation cohort (odds ratio: 2.98; 95% confidence interval: 1.06–8.42; p = 0.034). Hyperfiltration significantly accounted for 35.3% of association between increasing baseline haemoglobin A1c and rapid renal decline. Conclusion: Glomerular hyperfiltration is an independent risk factor of rapid renal decline. It mediates the association between increasing haemoglobin A1c and rapid renal decline.
The use of flow diverters to treat aneurysms of the posterior inferior cerebellar artery: Report of three cases
Authors: Bhogal Pervinder , Chudyk Jorge , Bleise Carlos , Lylyk Ivan , Henkes Hans , Lylyk Pedro 
Published: May 2018

Objective The objective of this study was to report our experience on the use of flow diverting stents placed within the posterior inferior cerebellar artery (PICA) as a treatment option for aneurysms of the PICA. Methods Three patients with aneurysms of the PICA, both ruptured and unruptured, underwent treatment of their aneurysms with placement of a single flow diverter in the PICA across the neck of the aneurysm. Adjunctive techniques such as coiling were not used. We present the angiographic and clinical follow-up data. Results The procedure was a technical success in all cases and there were no intraoperative complications. Follow-up data were available for two patients and this showed complete occlusion of the aneurysm with the PICA remaining patent. There was no evidence, either clinical or radiological, of medullary or pontine infarction. One patient died during the follow-up period from an unrelated medical illness (community acquired pneumonia). Conclusion Flow diverters can be successfully placed within the PICA to treat both ruptured and unruptured aneurysms, and they represent an alternative treatment option to endovascular coiling or microscopic neurosurgery.