bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of BUB1 Kinase by BAY 1816032 Sensitizes Tumor Cells toward Taxanes, ATR, and PARP Inhibitors In Vitro and In Vivo
Authors: Siemeister Gerhard , Mengel Anne , Fernández-Montalván Amaury E. , Bone Wilhelm , Schröder Jens , Zitzmann-Kolbe Sabine , Briem Hans , Prechtl Stefan , Holton Simon J. , Mönning Ursula , von Ahsen Oliver , Johanssen Sandra , Cleve Arwed , Pütter Vera , Hitchcock Marion , von Nussbaum Franz , Brands Michael , Ziegelbauer Karl , Mumberg Dominik 
Published: November 2018

Abstract

Purpose:
The catalytic function of BUB1 is required for chromosome arm resolution and positioning of the chromosomal passenger complex for resolution of spindle attachment errors and plays only a minor role in spindle assembly checkpoint activation. Here, we present the identification and preclinical pharmacologic profile of the first BUB1 kinase inhibitor with good bioavailability.

Experimental Design:
The Bayer compound library was screened for BUB1 kinase inhibitors and medicinal chemistry efforts to improve target affinity and physicochemical and pharmacokinetic parameters resulting in the identification of BAY 1816032 were performed. BAY 1816032 was characterized for kinase selectivity, inhibition of BUB1 signaling, and inhibition of tumor cell proliferation alone and in combination with taxanes, ATR, and PARP inhibitors. Effects on tumor growth in vivo were evaluated using human triple-negative breast xenograft models.

Results:
The highly selective compound BAY 1816032 showed long target residence time and induced chromosome mis-segregation upon combination with low concentrations of paclitaxel. It was synergistic or additive in combination with paclitaxel or docetaxel, as well as with ATR or PARP inhibitors in cellular assays. Tumor xenograft studies demonstrated a strong and statistically significant reduction of tumor size and excellent tolerability upon combination of BAY 1816032 with paclitaxel or olaparib as compared with the respective monotherapies.

Conclusions:
Our findings suggest clinical proof-of-concept studies evaluating BAY 1816032 in combination with taxanes or PARP inhibitors to enhance their efficacy and potentially overcome resistance.
FLI1 Exonic Circular RNAs as a Novel Oncogenic Driver to Promote Tumor Metastasis in Small Cell Lung Cancer
Authors: Li Lingyu , Li Wei , Chen Naifei , Zhao Haixin , Xu Guang , Zhao Yijing , Pan Xin , Zhang Xiaoying , Zhou Lei , Yu Dehai , Li Ailing , Hu Ji-Fan , Cui Jiuwei 
Published: November 2018

Abstract

Purpose:
The aberrantly upregulated Friend leukemia virus integration 1 (FLI1) is closely correlated with the malignant phenotype of small cell lung cancer (SCLC). It is interesting to note that the CRISPR gene knockout by Cas9 gRNAs that target the FLI1 coding region and the posttranscriptional knockdown by shRNAs that target the 3′ region of FLI1 mRNA yielded distinct antimetastasis effects in SCLC cells. This study attempts to examine if FLI1 exonic circular RNAs (FECR) function as a new malignant driver that determines the metastatic phenotype in SCLC.

Experimental Design:
The clinical relevance of FECRs was examined in 56 primary SCLC tissues and 50 non–small cell lung cancer (NSCLC) tissues. The prognostic value of FECRs was examined by measuring serum exosomal FECRs in a longitudinal cohort of patients with SCLC. The oncogenic activity of FECRs was investigated in both SCLC cell lines and animal xenograft studies. Finally, we explored the molecular mechanisms underlying these noncoding RNAs as a malignant driver.

Results:
Therapeutic comparison of CRISPR Cas9 knockout and shRNA knockdown of FLI1 identified FECRs as a new noncanonical malignant driver in SCLC. Using RNA FISH and quantitative PCR, we found that FECR1 (exons 4-2-3) and FECR2 (exons 5-2-3-4) were aberrantly upregulated in SCLC tissues (P &lt; 0.0001), and was positively associated with lymph node metastasis (P &lt; 0.01). Notably, serum exosomal FECR1 was associated with poor survival (P = 0.038) and clinical response to chemotherapy. Silencing of FECRs significantly inhibited the migration in two highly aggressive SCLC cell lines and reduced tumor metastasis in vivo. Mechanistically, we uncovered that FECRs sequestered and subsequently inactivated tumor suppressor miR584-3p, leading to the activation of the Rho Associated Coiled-Coil Containing Protein Kinase 1 gene (ROCK1).

Conclusions:
This study identifies FLI1 exonic circular RNAs as a new oncogenic driver that promotes tumor metastasis through the miR584–ROCK1 pathway. Importantly, serum exosomal FECR1 may serve as a promising biomarker to track disease progression of SCLC.
O Princípio da Euritmia nas Ciências Sociais e Humanas
Authors: Castro Paulo 
Published: November 2018

O Princípio da Euritmia é a afirmação de que os entes na natureza adoptam preferencialmente os comportamentos que preservam a sua integridade estrutural, estendendo a sua existência. Formulado no contexto de uma física não linear como alternativa ao paradigma de Niels Bohr, o Princípio surge como um dos desenvolvimentos fundamentais a partir das ideias de Louis de Broglie, no âmbito da chamada Escola de Lisboa. Reflecte-se sobre os conceitos de «Princípio», «Lei da Natureza» e «Emergência», tendo como objectivo estender o paradigma Eurítmico às Ciências Sociais e Humanas. Propõe-se um processo dinâmico descrevendo as escolhas de um agente social de acordo com uma instanciação possível do Princípio. Usando uma simulação computacional desse processo, estudam-se os comportamentos de dois agentes sociais em interacção com o meio, entre si e com a totalidade do sistema que compõem. Define-se autómato não linear como conceito operativo fundamental no entendimento dos fenómenos de Emergência.
A indagação da História nos manuscritos literários de Guimarães Rosa
Authors: Rodrigues Camila 
Published: November 2018

O objetivo deste artigo é problematizar as relações entre História e Literatura a partir da proposta metodológica pensada por Carlo Ginzburg, que sugere ao historiador que, ao invés de apenas analisar o produto literário final, ele concentre-se em suas fases preparatórias. Para problematizar isso foram consultados manuscritos de Guimarães Rosa como fontes primárias, e ali encontramos registro de certo questionamento da História. Nossos resultados sublinham a peculiaridade da perspectiva rosiana sobre o processo histórico, especialmente ao ressignificar o conflito entre os letrados e os iletrados, que é um dos mais violentos e silenciosos de nossa História Cultural até hoje.
In memory of Robert Campbell Dalgleish (1940–2009)
Authors: ZHANG ZHI-QIANG 
Published: November 2018

Dr Robert Campbell Dalgleish—Zootaxa’s editor for Phthiraptera and Siphonaptera—died suddenly of a heart attack on December 7th at his home in San Diego, California, USA. He was in contact with the editorial office when he accepted two manuscripts for Zootaxa in Nov. 2009 (Lareschi & Linardi 2009; Mound 2009). I was shocked and deeply saddened when I heard the news of his passing in December 2009.
Water Mass Transformation in the Greenland Sea during the Period 1986–2016
Authors: Brakstad Ailin , Våge Kjetil , Håvik Lisbeth , Moore G. W. K. 
Published: November 2018

AbstractHydrographic measurements from ships, autonomous profiling floats, and instrumented seals over the period 1986–2016 are used to examine the temporal variability in open-ocean convection in the Greenland Sea during winter. This process replenishes the deep ocean with oxygen and is central to maintaining its thermohaline properties. The deepest and densest mixed layers in the Greenland Sea were located within its cyclonic gyre and exhibited large interannual variability. Beginning in winter 1994, a transition to deeper (>500 m) mixed layers took place. This resulted in the formation of a new, less dense class of intermediate water that has since become the main product of convection in the Greenland Sea. In the preceding winters, convection was limited to <300-m depth, despite strong atmospheric forcing. Sensitivity studies, performed with a one-dimensional mixed layer model, suggest that the deeper convection was primarily the result of reduced water-column stability. While anomalously fresh conditions that increased the stability of the upper part of the water column had previously inhibited convection, the transition to deeper mixed layers was associated with increased near-surface salinities. Our analysis further suggests that the volume of the new class of intermediate water has expanded in line with generally increased depths of convection over the past 10–15 years. The mean export of this water mass from the Greenland Sea gyre from 1994 to present was estimated to be 0.9 ± 0.7 Sv (1 Sv ≡ 106m3s−1), although rates in excess of 1.5 Sv occurred in summers following winters with deep convection.
The speedboat vertebral fracture: a hazard of holiday watersports
Authors: Maempel JF , Maempel FZ 
Published: November 2018

Purpose The purpose of this study was to describe and characterise spinal fractures sustained by watercraft occupants due to splashdown of light watercraft when riding over uneven water surfaces. Methods A retrospective review of all patients presenting with these injuries to St Luke’s and Mater Dei state hospitals in Malta over a 10-year period was undertaken to determine patient demographics, the nature of spinal injuries sustained and the incidence of any associated extra-spinal injuries. Results Twenty-one patients (mean age 41.2 years) suffered 25 fractures. Injuries were seasonal, occurring exclusively between the months of May and October. One patient was local whilst 20 were from other countries. All fractures were Magerl type A fractures and occurred around the thoracolumbar junction. The L1 vertebra was most commonly affected (12 patients). Four patients sustained two vertebral fractures. There were no extra-spinal injuries. Conclusions Watercraft splashdown can transmit significant forces to occupants, resulting in Magerl type A vertebral fractures around the thoracolumbar junction. These injuries occur under compression. They are highly consistent in their morphology and localisation and should be excluded in individuals complaining of back pain after watercraft use. Almost all patients were from outside Malta and injuries were seasonal, providing opportunities for targeted injury prevention campaigns.
Euthanasia and assisted dying: what is the current position and what are the key arguments informing the debate?
Authors: Fontalis Andreas , Prousali Efthymia , Kulkarni Kunal 
Published: November 2018

Summary Assisted dying is a highly controversial moral issue incorporating both physician-assisted dying (PAD) and voluntary active euthanasia. End-of-life practices are debated in many countries, with assisted dying receiving different consideration across various jurisdictions. In this paper, we provide an analytic framework of the current position and the main arguments related to the rights and moral principles concerning assisted dying. Assisted dying proponents focus on the respect of autonomy, self-determination and forestalling suffering. On the other hand, concerns are raised regarding the interpretation of the constitutional right to life and balancing this with the premise of assisted dying, alongside the impacts of assisted dying on the doctor–patient relationship, which is fundamentally based on trust, mutual respect and the premise of ‘first do no harm’. Our review is underpinning the interpretation of constitutional rights and the Hippocratic Oath with the premise of assisted dying, alongside the impacts of assisted dying on the doctor–patient relationship. Most clinicians remain untrained in such decision making, with fears against crossing key ethical divides. Due to the increasing number of cases of assisted dying and lack of consensus, our review enables the integration of ethical and legal aspects and facilitates decision making.
Changes in periacetabular bone mineral density five years after resurfacing hip arthroplasty versus conventional total hip arthroplasty
Authors: Gerhardt Davey MJM , Smolders José MH , Roovers Elisabeth A , Rijnders Ton AJM , van Susante Job LC 
Published: November 2018

Introduction: We studied whether acetabular bone mineral density (BMD) is better preserved after resurfacing hip arthroplasty (RHA) versus small diameter metal-on-metal total hip arthroplasty (THA). Methods: This randomised controlled trial included 82 patients. BMD was measured in 5 periprosthetic regions of interest (ROI) with dual-energy absorptiometry (DEXA) preoperatively, at 3 and 6 months, 1, 2, 3 and 5 years postoperative. 34 RHA and 26 THA had a complete 5 years follow-up. 1 RHA and 1 THA were revised due to pseudotumour formation, 2 THA were revised because of recurrent dislocations and 1 RHA for avascular necrosis. Results: Overall an initial decrease in BMD was observed for both implants, stabilising after 2 years. 5 years after RHA a BMD change of +1% in upper cranial, –4% ( p < 0.01) in cranial, –8% ( p < 0.01) in craniomedial, –7% ( p < 0.01) in medial and +4% in caudal ROI compared to baseline values was seen. 5 years after THA a BMD change of –3% ( p = 0.01), –13% ( p < 0.01), –21% ( p < 0.01), –11% ( p < 0.01) and –2% for each respective ROI. The observed BMD decrease in different regions was structurally favouring the RHA-cup, with significantly higher levels in the cranial and craniomedial ROI. Conclusion: Acetabular BMD is better preserved behind a rigid press-fit convex cup in RHA compared to a titanium threaded cup in conventional THA in the cranial and craniomedial ROI. Despite of a theoretical higher stress-shielding behind the stiff acetabular component in RHA, compared to the more elastic threaded titanium THA-cup, bone depletion behind the RHA component does not seem to be of major concern. Registration: EudraCT (2006-005610-12)
Developing a risk-based composite neurologic outcome for a trial of hydroxyurea in young children with sickle cell disease
Authors: Casella James F , Adams Robert J , Brambilla Donald J , Strouse John J , Maier Pia , Dlugash Rachel , Avadhani Radhika , Vermillion Krista , Tonascia James , Voeks Jenifer H , Hanley Daniel F , Thompson Richard E , Lehmann Harold P 
Published: November 2018

Background Studies of interventions to prevent the many neurological complications of sickle cell disease must take into account multiple outcomes of variable severity, with limited sample size. The goals of the studies presented were to use investigator preferences across outcomes to determine an attitude-based weighting of relevant clinical outcomes and to establish a valid composite outcome for a clinical trial. Methods In Study 1, investigators were surveyed about their practice regarding hydroxyurea therapy and opinions about outcomes for the “Hydroxyurea to Prevent the Central Nervous System Complications of Sickle Cell Disease Trial” (HU Prevent), and their minimally acceptable relative risk reduction for the two outcome components, motor and neurocognitive deficits. In Study 2, HU Prevent investigators provided overall weights for these two components. In Study 3, they provided more granular rankings, ratings, and maximum number acceptable to harm. A weighted composite outcome, the Stroke Consequences Risk Score, was constructed that incorporates the major neurologic complications of sickle cell disease. The Stroke Consequences Risk Score represents the 3-year risk of suffering the adverse consequences of stroke. In Study 4, the results of the Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP2) and Silent Infarct Transfusion Trials were reanalyzed in light of the composite outcome. Results In total, 22 to 27 investigators participated per study. In Study 1, across three samplings between 2009 and 2015, the average minimally acceptable relative risk reduction ranged from 0.36 to 0.50, at or below the target effect size of 0.50. In 2015, 21 (91%) reported that a placebo-controlled trial is reasonable; 23 (100%), that it is ethical; and 22 (96%), that they would change their practice, if the results of the trial were positive. In Studies 2 and 3, the weight elicited for a cognitive decline (of 10 IQ points) from the overall assessment was 0.67 (and for motor deficit, the complementary 0.33); from ranking, 0.6; from rating, 0.58; and from maximal number acceptable to harm, 0.5. Using data from two major clinical trials, Study 4 demonstrated the same conclusions as the original trials using the Stroke Consequences Risk Score, with smaller p-values for both reanalyses. An assessment of acceptability was performed as well. Conclusion This set of studies provides the rationale, justification, and validation for the use of a weighted composite outcome and confirms the need for the phase III HU Prevent study. Surveys of investigators in multi-center studies can provide the basis of clinically meaningful outcomes that foster the translation of study results into practice while increasing the efficiency of a study.
Health literacy as a determinant, mediator and/or moderator of health: empirical models using the European Health Literacy Survey dataset
Authors: Pelikan Jürgen M. , Ganahl Kristin , Roethlin Florian 
Published: November 2018

Background/Research Question: In the health literacy (HL) discourse there is debate about the ways by which HL is impacting health. Three different, logically non-exclusive hypotheses are proposed: (a) HL as a specific, direct, social determinant of health; (b) HL as a mediator between other determinants and health; and (c) HL as a moderator of the effect of other determinants on health. Only few examples of empirically testing the mediator or moderator hypothesis exist. The data of the European Health Literacy Survey allow testing of the three hypotheses comparatively in parallel for functional and comprehensive HL. Methods: Data collection was based on multistage random samples of about 1000 European Union citizens aged 15 or older with Computer Assisted Personal Interviewing or Paper Assisted Personal Interviewing methodology in 2011 in eight Member States of the EU. Demographic and socio-economic indicators, a comprehensive (European Health Literacy Survey Q47) and a functional (Newest Vital Sign Test) health literacy measure and one self-assessed health variable were surveyed. Correlation analysis, multiple regression analysis and path analysis were performed. Results: Comprehensive HL (and to a much lesser degree functional HL) is a relevant predictor for self-assessed health. Also, comprehensive HL is only to a limited degree mediating the effects of other determinants on self-assessed health and only for age does HL partly moderate the effect on health. Explained variance and strength of effects vary considerably by national context. Conclusions/Implications: Comprehensive HL is a critical, direct determinant of health. Therefore comprehensive HL has a considerable potential for health promotion to improve population health and tackle the health gap. But comprehensive HL measurement should be standardised in every country to allow for designing adequate measures for the specific situation of the country and also for benchmarking. For better understanding of the causal structure of the impact of HL on health, longitudinal studies will be needed.
Prognostic value of D-dimer and markers of coagulation for stratification of abdominal aortic aneurysm growth
Authors: Sundermann Alexandra C. , Saum Keith , Conrad Kelsey A. , Russell Hannah M. , Edwards Todd L. , Mani Kevin , Björck Martin , Wanhainen Anders , Owens A. Phillip 
Published: November 2018

Abstract
Abdominal aortic aneurysm (AAA) is associated with high morbidity and mortality and is an established cause of unbalanced hemostasis. A number of hemostatic biomarkers have been associated with AAA; however, the utility of hemostatic biomarkers in AAA diagnosis and prognosis is unclear. The aim of the present study was to characterize the potential prognostic value of D-dimer and markers of altered hemostasis in a large cohort of patients with AAAs characterized by either fast or slow aneurysm growth (frequency matched for baseline diameter) and subaneurysmal dilations. We measured plasma concentrations of thrombin-antithrombin (TAT) complex, platelet factor 4 (PF4), and D-dimer in 352 patients with either fast-growing AAAs (&gt;2 mm/y), slow-growing AAAs (&lt;2 mm/y), subaneurysmal aortic dilations, or nonaneurysmal aortas. Plasma D-dimer and TAT were significantly elevated in both AAA and subaneurysmal dilation patients compared with controls. Individuals with D-dimer levels ≥500 ng/mL had 3.09 times the odds of subaneurysms, 6.23 times the odds of slow-growing AAAs, and 7.19 times the odds of fast-growing AAAs than individuals with D-dimer level &lt;500 ng/mL. However, no differences in D-dimer concentration were noted between fast- and slow-growing aneurysms. Plasma D-dimer and TAT were strong independent predictors of AAA growth rate with multivariate analysis revealing a 500-ng/mL increase in D-dimer or 1-µg/mL increase in TAT led to additional 0.21-mm and 0.24-mm changes in aortic diameter per year, respectively. Rising levels of plasma TAT, in addition to D-dimer, may predict disease progression and aneurysm growth in patients with AAA or subaneurysmal dilation.