bluuebunny/crossref_metadata_2025_split huggingface dataset:
An empirical model for educational simulation of cervical dilation in first-stage labor
Authors: Gefferie Silvano R. , Scholten Anouk W. J. , Wijlens Kim A. E. , Ferreira Bastos M. Luísa , van der Hout-van der Jagt M. Beatrijs , Zwart Hans , van Meurs Willem J. 
Published: June 2018

Abstract
Background
Several models for educational simulation of labor and delivery were published in the literature and incorporated into a commercially available training simulator (CAE Healthcare Lucina). However, the engine of this simulator does not include a model for the clinically relevant indicators: uterine contraction amplitude and frequency, and cervical dilation. In this paper, such a model is presented for the primigravida in normal labor.

Methods
The conceptual and mathematical models represent oxytocin release by the hypothalamus, oxytocin pharmacokinetics, and oxytocin effect on uterine contractions, cervical dilation, and (positive) feedback from cervical dilation to oxytocin release by the hypothalamus.

Results
Simulation results for cervical dilation are presented, together with target data for a normal primigravida. Corresponding oxytocin concentrations and amplitude and frequency of uterine contractions are also presented.

Conclusion
An original empirical model for educational simulation of oxytocin concentration, uterine contractions, and cervical dilation in first-stage labor is presented. Simulation results for cervical dilation match target data for a normal patient. The model forms a basis for taking into account more independent variables and patient profiles and can thereby considerably expand the range of training scenarios that can be simulated.
Pembrolizumab for Patients With Refractory or Relapsed Thymic Epithelial Tumor: An Open-Label Phase II Trial
Authors: Cho Jinhyun , Kim Hae Su , Ku Bo Mi , Choi Yoon-La , Cristescu Razvan , Han Joungho , Sun Jong-Mu , Lee Se-Hoon , Ahn Jin Seok , Park Keunchil , Ahn Myung-Ju 
Published: June 2018

PURPOSE Limited treatment options exist for patients with thymic epithelial tumor (TET) whose disease progresses after platinum-based chemotherapy. We conducted a phase II study of pembrolizumab in patients with TET to evaluate its efficacy and safety. METHODS Patients with histologically confirmed TET whose disease progressed after at least one line of platinum-based chemotherapy were eligible for the study. Patients were excluded if they had an active autoimmune disease requiring systemic treatment within the past year or documented history of clinically severe autoimmune disease. Patients received 200 mg of pembrolizumab intravenously every 3 weeks until tumor progression or unacceptable toxicity. The primary objective of response rate was assessed every 9 weeks by investigators. RESULTS Of 33 patients enrolled, 26 had thymic carcinoma and seven had thymoma. Of seven thymoma, two (28.6%; 95% CI, 8.2% to 64.1%) had partial response, and five (71.6%) had stable disease. Of 26 thymic carcinoma, five (19.2%; 95% CI, 8.5% to 37.9%) had partial response and 14 (53.8%) had stable disease. The median progression-free survival was 6.1 months for both groups. The most common adverse events of any grade included dyspnea (11; 33.3%), chest wall pain (10; 30.3%), anorexia (seven; 21.2%), and fatigue (seven; 21.2%). Five (71.4%) of seven patients with thymoma and four (15.4%) of 26 patients with thymic carcinoma reported grade ≥ 3 immune-related adverse events, including hepatitis (four; 12.1%), myocarditis (three; 9.1%), myasthenia gravis (two; 6.1%), thyroiditis (one; 3.0%), antineutrophil cytoplasmic antibody–associated rapidly progressive glomerulonephritis (one; 3.0%), colitis (one; 3.0%), and subacute myoclonus (one; 3.0%). CONCLUSIONS Pembrolizumab showed encouraging antitumor activity in patients with advanced TET. Given the high incidence of autoimmunity, additional studies are needed to identify those who can benefit from pembrolizumab without immune-related adverse events.
Epigenetic regulators Rbbp4 and Hdac1 are overexpressed in a zebrafish model of RB1 embryonal brain tumor, and are required for neural progenitor survival and proliferation
Authors: Schultz Laura E. , Haltom Jeffrey A. , Almeida Maira P. , Wierson Wesley A. , Solin Staci L. , Weiss Trevor J. , Helmer Jordan A. , Sandquist Elizabeth J. , Shive Heather R. , McGrail Maura 
Published: June 2018

ABSTRACT
In this study, we used comparative genomics and developmental genetics to identify epigenetic regulators driving oncogenesis in a zebrafish retinoblastoma 1 (rb1) somatic-targeting model of RB1 mutant embryonal brain tumors. Zebrafish rb1 brain tumors caused by TALEN or CRISPR targeting are histologically similar to human central nervous system primitive neuroectodermal tumors (CNS-PNETs). Like the human oligoneural OLIG2+/SOX10+ CNS-PNET subtype, zebrafish rb1 tumors show elevated expression of neural progenitor transcription factors olig2, sox10, sox8b and the receptor tyrosine kinase erbb3a oncogene. Comparison of rb1 tumor and rb1/rb1 germline mutant larval transcriptomes shows that the altered oligoneural precursor signature is specific to tumor tissue. More than 170 chromatin regulators were differentially expressed in rb1 tumors, including overexpression of chromatin remodeler components histone deacetylase 1 (hdac1) and retinoblastoma binding protein 4 (rbbp4). Germline mutant analysis confirms that zebrafish rb1, rbbp4 and hdac1 are required during brain development. rb1 is necessary for neural precursor cell cycle exit and terminal differentiation, rbbp4 is required for survival of postmitotic precursors, and hdac1 maintains proliferation of the neural stem cell/progenitor pool. We present an in vivo assay using somatic CRISPR targeting plus live imaging of histone-H2A.F/Z-GFP fusion protein in developing larval brain to rapidly test the role of chromatin remodelers in neural stem and progenitor cells. Our somatic assay recapitulates germline mutant phenotypes and reveals a dynamic view of their roles in neural cell populations. Our study provides new insight into the epigenetic processes that might drive pathogenesis in RB1 brain tumors, and identifies Rbbp4 and its associated chromatin remodeling complexes as potential target pathways to induce apoptosis in RB1 mutant brain cancer cells.
This article has an associated First Person interview with the first author of the paper.
P1 promoter-driven HNF4α isoforms are specifically repressed by β-catenin signaling in colorectal cancer cells
Authors: Babeu Jean-Philippe , Jones Christine , Geha Sameh , Carrier Julie C. , Boudreau François 
Published: June 2018

ABSTRACT
HNF4α is a key nuclear receptor for regulating gene expression in the gut. Although both P1 and P2 isoform classes of HNF4α are expressed in colonic epithelium, specific inhibition of P1 isoforms is commonly found in colorectal cancer. Previous studies have suggested that P1 and P2 isoforms might regulate different cellular functions. Despite these advances, it remains unclear whether these isoform classes are functionally divergent in the context of human biology. Here, the consequences of specific inhibition of P1 or P2 isoform expression was measured in a human colorectal cancer cell transcriptome. Results indicate that P1 isoforms were specifically associated with the control of cell metabolism, whereas P2 isoforms globally supported aberrant oncogenic signalization, promoting cancer cell survival and progression. P1 promoter-driven isoform expression was found to be repressed by β-catenin, one of the earliest oncogenic pathways to be activated during colon tumorigenesis. These findings identify a novel cascade by which the expression of P1 isoforms is rapidly shut down in the early stages of colon tumorigenesis, allowing a change in HNF4α-dependent transcriptome, thereby promoting colorectal cancer progression.
This article has an associated First Person interview with the first author of the paper.
Mutations that prevent methylation of cohesin render sensitivity to DNA damage in S. pombe
Authors: Sanyal Swastika , Molnarova Lucia , Richterova Judita , Huraiova Barbora , Benko Zsigmond , Polakova Silvia , Cipakova Ingrid , Sevcovicova Andrea , Gaplovska-Kysela Katarina , Mechtler Karl , Cipak Lubos , Gregan Juraj 
Published: June 2018

ABSTRACT
The canonical role of cohesin is to mediate sister chromatid cohesion. In addition, cohesin plays important roles in processes such as DNA repair and regulation of gene expression. Mounting evidence suggests that various post-translational modifications, including phosphorylation, acetylation and sumoylation regulate cohesin functions. Our mass spectrometry analysis of cohesin purified from Schizosaccharomyces pombe cells revealed that the cohesin subunit Psm1 is methylated on two evolutionarily conserved lysine residues, K536 and K1200. We found that mutations that prevent methylation of Psm1 K536 and K1200 render sensitivity to DNA-damaging agents and show positive genetic interactions with mutations in genes encoding the Mus81–Eme1 endonuclease. Yeast two-hybrid and co-immunoprecipitation assays showed that there were interactions between subunits of the cohesin and Mus81–Eme1 complexes. We conclude that cohesin is methylated and that mutations that prevent methylation of Psm1 K536 and K1200 show synthetic phenotypes with mutants defective in the homologous recombination DNA repair pathway.
Epigenetic alterations mediate iPSC-induced normalization of DNA repair gene expression and TNR stability in Huntington's disease cells
Authors: Mollica Peter A. , Zamponi Martina , Reid John A. , Sharma Deepak K. , White Alyson E. , Ogle Roy C. , Bruno Robert D. , Sachs Patrick C. 
Published: June 2018

ABSTRACT
Huntington's disease (HD) is a rare autosomal dominant neurodegenerative disorder caused by a cytosine-adenine-guanine (CAG) trinucleotide repeat (TNR) expansion within the HTT gene. The mechanisms underlying HD-associated cellular dysfunction in pluripotency and neurodevelopment are poorly understood. We had previously identified downregulation of selected DNA repair genes in HD fibroblasts relative to wild-type fibroblasts, as a result of promoter hypermethylation. Here, we tested the hypothesis that hypomethylation during cellular reprogramming to the induced pluripotent stem cell (iPSC) state leads to upregulation of DNA repair genes and stabilization of TNRs in HD cells. We sought to determine how the HD TNR region is affected by global epigenetic changes through cellular reprogramming and early neurodifferentiation. We find that early stage HD-affected neural stem cells (HD-NSCs) contain increased levels of global 5-hydroxymethylation (5-hmC) and normalized DNA repair gene expression. We confirm TNR stability is induced in iPSCs, and maintained in HD-NSCs. We also identify that upregulation of 5-hmC increases ten-eleven translocation 1 and 2 (TET1/2) protein levels, and show their knockdown leads to a corresponding decrease in the expression of select DNA repair genes. We further confirm decreased expression of TET1/2-regulating miR-29 family members in HD-NSCs. Our findings demonstrate that mechanisms associated with pluripotency induction lead to a recovery in the expression of select DNA repair gene and stabilize pathogenic TNRs in HD.
Wnt7b signalling through Frizzled-7 receptor promotes dendrite development by coactivating CaMKII and JNK
Authors: Ferrari María E. , Bernis María E. , McLeod Faye , Podpolny Marina , Coullery Romina P. , Casadei Inelia M. , Salinas Patricia C. , Rosso Silvana B. 
Published: June 2018

ABSTRACT
The formation of complex dendritic arbors is crucial for the assembly of functional networks as abnormal dendrite formation underlies several neurodevelopmental and psychiatric disorders. Many extracellular factors have been postulated as regulators of dendritic growth. Wnt proteins play a critical role in neuronal development and circuit formation. We previously demonstrated that Wnt7b acts through the scaffold protein dishevelled 1 (Dvl1) to modulate dendrite arborisation by activating a non-canonical Wnt signalling pathway. Here, we identify the seven-transmembrane frizzled-7 (Fz7, also known as FZD7) as the receptor for Wnt7b-mediated dendrite growth and complexity. Importantly, Fz7 is developmentally regulated in the intact hippocampus, and is localised along neurites and at dendritic growth cones, suggesting a role in dendrite formation and maturation. Fz7 loss-of-function studies demonstrated that Wnt7b requires Fz7 to promote dendritic arborisation. Moreover, in vivo Fz7 loss of function results in dendritic defects in the intact mouse hippocampus. Furthermore, our findings reveal that Wnt7b and Fz7 induce the phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and JNK proteins, which are required for dendritic development. Here, we demonstrate that Wnt7b–Fz7 signals through two non-canonical Wnt pathways to modulate dendritic growth and complexity.
Obstructive sleep apnea as an independent predictor of postoperative delirium and pain: protocol for an observational study of a surgical cohort
Authors: Strutz Patricia , Tzeng William , Arrington Brianna , Kronzer Vanessa , McKinnon Sherry , Ben Abdallah Arbi , Haroutounian Simon , Avidan Michael S. 
Published: June 2018

Introduction: Postoperative delirium and pain are common complications in adults, and are difficult both to prevent and treat. Obstructive sleep apnea (OSA) is prevalent in surgical patients, and has been suggested to be a risk factor for postoperative delirium and pain. OSA also might impact pain perception, and alter pain medication requirements. This protocol describes an observational study, with the primary aim of testing whether OSA is an independent predictor of postoperative complications, focusing on (i) postoperative incident delirium and (ii) acute postoperative pain severity. We secondarily hypothesize that compliance with prescribed treatment for OSA (typically continuous positive airway pressure or CPAP) might decrease the risk of delirium and the severity of pain. Methods and analysis: We will include data from patients who have been enrolled into three prospective studies: ENGAGES, PODCAST, and SATISFY-SOS. All participants underwent general anesthesia for a non-neurosurgical inpatient operation, and had a postoperative hospital stay of at least one day at Barnes Jewish Hospital in St. Louis, Missouri, from February 2013 to May 2018. Patients included in this study have been assessed for postoperative delirium and pain severity as part of the parent studies. In the current study, determination of delirium diagnosis will be based on the Confusion Assessment Method, and the Visual Analogue Pain Scale will be used for pain severity. Data on OSA diagnosis, OSA risk and compliance with treatment will be obtained from the preoperative assessment record. Other variables that are candidate risk factors for delirium and pain will also be extracted from this record. We will use logistic regression to test whether OSA independently predicts postoperative delirium and linear regression to assess OSAs relationship to acute pain severity. We will conduct secondary analyses with subgroups to explore whether these relationships are modified by compliance with OSA treatment.
The Impact of Online Product Reviews on Product Returns
Authors: Sahoo Nachiketa , Dellarocas Chrysanthos , Srinivasan Shuba 
Published: June 2018

Although many researchers in information systems and marketing have studied the effect of product reviews on sales, few have looked at their effect on product returns. We hypothesize that, by reducing product uncertainty, product reviews affect the probability of product returns. We elaborate this hypothesis starting with an analytical model that examines how changes in valence and precision of information from product reviews influence the purchase and return probabilities of risk-averse, but rational, consumers. We then empirically test our hypotheses using a transaction-level data set from a multichannel, multibrand North American specialty retailer. Harnessing different consumers’ purchases and returns of the same products, but with varying sets of product reviews over two years, we show that the availability of more reviews and the presence of more “helpful” reviews, as voted by consumers, lead to fewer product returns—after controlling for customer, product, and other context-related factors. Analyzing the purchase behavior of the consumers, we find that when fewer product reviews are available, consumers buy more substitutes in conjunction with a product, potentially to mitigate their uncertainty. Purchase of substitutes, in turn, leads to more product returns. Finally, leveraging a discontinuity in the displayed average ratings, we find that when products are shown with an average rating that is higher than the true rating, they are returned more often. These results support the predictions of our theoretical model—unbiased online reviews indeed help consumers make better purchase decisions, leading to lower product returns; biasing reviews upward results in more returns. The presence of online reviews has important cost implications for the firm beyond the cost of reprocessing the returns; we observe that when consumers return products, they are more likely to write online reviews and that these reviews are more negative than reviews that follow a nonreturned purchase. The online appendix is available at https://doi.org/10.1287/isre.2017.0736 .
Optimal Pricing and Inventory Planning with Charitable Donations
Authors: Chu Leon Yang , Li Guang , Rusmevichientong Paat 
Published: June 2018

Problem definition: This paper investigates firms’ optimal operational decisions and after-tax profits with regard to tax deduction for charitable donations. Academic/practical relevance: Motivated by the steady growth in noncash donations from U.S. companies, our work is the first to provide theoretical guidance on operational planning under tax deduction for both precommitted donations and end-of-season donations. Methodology: We analyze the impact of tax deduction for a profit-driven firm under a two-period price-markdown newsvendor model and characterize the firm’s optimal price and quantity decisions. Results: The firm’s optimal donation behavior is driven by two factors—fixed cost and demand uncertainty. Specifically, a positive fixed cost can induce precommitted donation during the regular selling season, and demand uncertainty can induce end-of-season donation during the clearance period. Managerial insights: The enhanced tax deduction that is designed to encourage charitable donations results in unexpected behavior by the firm. For example, the firm’s optimal clearance price can increase with the amount of leftover inventory, and the firm’s optimal after-tax profit can increase as the tax rate increases. While the value of the deduction is tied to the fair market value (and the price) of the product, surprisingly, the firm may find it more profitable to charge a lower price, because the lower price may scale up the demand uncertainty and consequently increase the expected tax subsidy under the enhanced tax deduction. Our analysis reveals important insights about the impact of the tax law on a monopolist’s optimal operational decisions and profit. The online appendix is available at https://doi.org/10.1287/msom.2017.0676 .
Chief Information Officer team evolution in university hospitals: interaction of the three ‘C’s (CIO, CCIO, CRIO)
Authors: Sridharan Shankar , Priestman Ward , Sebire Neil J. 
Published: June 2018

BackgroundThe Chief Information Officer (CIO) and Chief Clinical Information Officer (CCIO) are now established senior roles in hospital practice. With increasing emphasis on optimising use of routine health data for secondary purposes and research, additional skills are required as part of the senior information officer team, particularly in academic health care institutions.ObjectiveTo present the role of the Chief Research Information Officer (CRIO), as an emerging, and important, component of the senior information team.MethodWe review recent publications describing the composition of the senior information team, including CIO and CCIO roles, and discuss the development of the CRIO as a distinct component of the team, based on the published evidence and our experience.ResultsThe CRIO is emerging as an additional senior role in academic healthcare institutions, whose roles include leadership of the informatics strategy and optimisation of routine data collection systems for research data use, in addition to important aspects of research data governance. Such individuals should be senior clinicians with experience in informatics, in addition to having established research expertise and knowledge of research processes, governance and academic networks.ConclusionsThe CRIO is emerging as a distinct senior information leadership role in conjunction with the already established positions of CCIO and CIO, who together, can provide optimal oversight of digital activities across the organisation.
Kınık Höyük in South Cappadocia
Authors: d’Alfonso Lorenzo , Castellano Lorenzo 
Published: June 2018

AbstractThis note complements the preliminary comparative stratigraphy of excavated sites of Cilicia published in AoF 44/2 with the new stratigraphic data obtained at the ongoing excavation of Niğde Kınık Höyük, in South Cappadocia. South Cappadocia lies directly north of Cilicia beyond the Taurus mountains, and from Prehistory it has controlled the access from Cilicia to the Anatolian Plateau. The region knew periods of minor, and more intense, participation in the cultural developments experienced in Cilicia, and the note is intended to provide basic stratigraphic information to start the study of this relation in a more precise and comprehensive way. The note only adds the information for the site of Kınık Höyük, but it is a strong invitation to other colleagues working in Cappadocia to build a similar comparative stratigraphy.
Physicochemical properties of stabilized sewage sludge admixtures by modified steel slag
Authors: Zhu Xi , Li Fei , Zhang Jingdong , Wu Shengzhe 
Published: June 2018

Abstract
Cement stabilization is used extensively to solidify sludge. However, previous studies suggest that the organic acids in sludge can restrain the hydration processes of cementitious materials. This study presents a new binder (steel slag based materials) whose effectiveness of stabilization was investigated on sewage sludge. Several series of tests for solidified sludge were conducted including the moisture content, compressive strength, shear force, permeability, and toxicity characteristic leaching (TCLP). The result shows that the stabilization effect of physicochemical properties of stabilized sewage by S1* (content 90% steel slag) were better than that of cement. With 20% S1, the moisture content of the sludge could be reduced to 30% at 20+1°C for 7 days; The compressive strength was 74.5 kappa and the permeability coefficient was 5.03 × 10–5 (cm/s); The TCLP was below the limit value. The hydration products of paste and solidified sludge at 1, 3, 14, 28, and 90 days were analyzed by XRD, SEM, and energy spectroscopy to distinguish ettringite/iron ettringite in S1 solidified sludge. the result shows the Needle-like ettringite of S1 possess high iron content and may be Fe–Aft.