bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevention of relapses with levamisole as adjuvant therapy in children with a first episode of idiopathic nephrotic syndrome: study protocol for a double blind, randomised placebo-controlled trial (the LEARNS study)
Authors: Veltkamp Floor , Khan Djera H , Reefman Christa , Veissi Susan , van Oers Hedy A , Levtchenko Elena , Mathôt Ron A A , Florquin Sandrine , van Wijk Joanna A E , Schreuder Michiel F , Haverman Lotte , Bouts Antonia H M 
Published: August 2019

IntroductionIdiopathic nephrotic syndrome (INS) is characterised by a high relapse rate up to 80% after initial response to standard therapy with corticosteroids. Steroid toxicity is common and causes a great burden of disease that negatively influences the health-related quality of life (HRQoL). Recently, studies have shown that levamisole, an anthelminthic drug, significantly improves relapse-free survival in children with frequent relapses or steroid dependency. Compared with other steroid-sparing drugs, levamisole has relatively few side effects. We hypothesise that adding levamisole to standard therapy with corticosteroids in children with a first episode of INS will prevent relapses, decrease cumulative dosage of steroids used and improve HRQoL. This paper presents the study protocol for the LEARNS study (LEvamisole as Adjuvant therapy to Reduce relapses of Nephrotic Syndrome).Methods and analysisAn international, double-blind, placebo-controlled randomised trial will be conducted in 20 participating hospitals in the Netherlands and Belgium. Participants (n=92) with a first episode of INS, aged 2–16 years, who achieve remission after 4 weeks of oral prednisolone will be randomly assigned (1:1) to receive either levamisole 2.5 mg/kg alternate day or placebo added to prednisolone (18-week tapering schedule) for a total of 24 weeks. Follow-up will be until 2 years after first presentation. Additionally, parents and/or children will fill out five HRQoL questionnaires. Primary outcome of the LEARNS study is occurrence of relapses within 12 months after first presentation. Secondary outcomes include time to first relapse, cumulative steroid dose after 2 years, safety parameters and quality of life scores.Ethics and disseminationThe trial was approved by the Medical Ethical Committee. Results of the study will be published in a peer-reviewed journal.Trial registration numberNL6826, 2017-001025-41
A phase equilibrium investigation of selected source controls on the composition of melt batches generated by sequential melting of an average metapelite
Authors: Mayne Matthew J. , Stevens Gary , Moyen Jean-François 
Published: August 2019

Abstract

The ability of Rcrust software to conduct path-dependent phase equilibrium modelling with automated changing bulk compositions allows for a phase equilibrium approach to investigate an array of source controls for their effect on the bulk compositions of melts produced by sequential melting events. The following source controls of the rock system are considered: (1) initial magnesium and iron content; (2) initial sodium and calcium content; (3) pressure–temperature path followed by the system; and (4) threshold by which melt extractions in the system are triggered. These source controls are investigated in a water-restricted system and a water-in-excess system. The permutation of these cases resulted in 128 different modelled pressure–temperature bulk composition paths investigating the melting of an average pelite composition. The resultant melt compositions are compared to that of a natural granite dataset and provide a good fit for the incompatible elements Na
2
O and K
2
O with the allowance that granites most likely form as magmas consisting of melt and ferromagnesian-rich crystals. The fluid state of the system is shown to have the strongest control on melt compositions, with the pressure–temperature path having subordinate control on the volume and composition of melts produced.
Cardiac troponin-I phosphorylation underlies myocardial contractile dysfunction induced by hypothermia rewarming
Authors: Tveita Torkjel , Arteaga Grace M. , Han Young-Soo , Sieck Gary C. 
Published: August 2019

Rewarming the intact heart after a period of hypothermia is associated with reduced myocardial contractility, decreased Ca2+ sensitivity, and increased cardiac troponin-I (cTnI) phosphorylation. We hypothesized that hypothermia/rewarming (H/R) induces left ventricular (LV) contractile dysfunction due to phosphorylation of cTnI at Ser23/24. To test this hypothesis, the response of wild-type mice ( n = 7) to H/R was compared with transgenic (TG) mice expressing slow skeletal TnI (TG-ssTnI; n = 7) that lacks the Ser23/24 phosphorylation sites. Hypothermia was induced by surface cooling and maintained at 23–25°C for 3 h. Subsequently, the animals were rewarmed to 37°C. LV systolic and diastolic function was assessed using a 1.4 F pressure-volume Millar catheter introduced via the right carotid artery. At baseline conditions, there were no significant differences in LV systolic function between wild-type and TG-ssTnI mice, whereas measurements of diastolic function [isovolumic relaxation constant (τ) and end-diastolic pressure-volume relationship (EDPVR)] were significantly ( P < 0.05) reduced in TG-ssTnI animals. Immediately after rewarming, significant differences between groups were found in cardiac output (CO; wild-type 6.6 ± 0.7 vs. TG-ssTnI 8.8 ± 0.7 mL/min), stroke work (SW; wild-type 796 ± 112 vs. TG-ssTnI 1208 ± 67 mmHg/μL), and the preload recruited stroke work (PRSW; wild-type 38.3 ± 4.9 vs. TG-ssTnI 68.8 ± 8.2 mmHg). However, EDPVR and τ returned to control levels within 1 h in both groups. We conclude that H/R-induced LV systolic dysfunction results from phosphorylation of cTnI at Ser23/24. NEW & NOTEWORTHY Rewarming following a period of accidental hypothermia leads to a form of acute cardiac failure (rewarming shock), which is in part due to reduced sensitivity to Ca2+ activation of myocardial contraction. The results of the present study support the hypothesis that rewarming shock is due to phosphorylation of cardiac troponin I.
Patient-Derived Xenografts and Matched Cell Lines Identify Pharmacogenomic Vulnerabilities in Colorectal Cancer
Authors: Lazzari Luca , Corti Giorgio , Picco Gabriele , Isella Claudio , Montone Monica , Arcella Pamela , Durinikova Erika , Zanella Eugenia R. , Novara Luca , Barbosa Fabiane , Cassingena Andrea , Cancelliere Carlotta , Medico Enzo , Sartore-Bianchi Andrea , Siena Salvatore , Garnett Mathew J. , Bertotti Andrea , Trusolino Livio , Di Nicolantonio Federica , Linnebacher Michael , Bardelli Alberto , Arena Sabrina 
Published: August 2019

Abstract

Purpose:
Patient-derived xenograft (PDX) models accurately recapitulate the tumor of origin in terms of histopathology, genomic landscape, and therapeutic response, but some limitations due to costs associated with their maintenance and restricted amenability for large-scale screenings still exist. To overcome these issues, we established a platform of 2D cell lines (xeno-cell lines, XL), derived from PDXs of colorectal cancer with matched patient germline gDNA available.

Experimental Design:
Whole-exome and transcriptome sequencing analyses were performed. Biomarkers of response and resistance to anti-HER therapy were annotated. Dependency on the WRN helicase gene was assessed in MSS, MSI-H, and MSI-like XLs using a reverse genetics functional approach.

Results:
XLs recapitulated the entire spectrum of colorectal cancer transcriptional subtypes. Exome and RNA-seq analyses delineated several molecular biomarkers of response and resistance to EGFR and HER2 blockade. Genotype-driven responses observed in vitro in XLs were confirmed in vivo in the matched PDXs. MSI-H models were dependent upon WRN gene expression, while loss of WRN did not affect MSS XLs growth. Interestingly, one MSS XL with transcriptional MSI-like traits was sensitive to WRN depletion.

Conclusions:
The XL platform represents a preclinical tool for functional gene validation and proof-of-concept studies to identify novel druggable vulnerabilities in colorectal cancer.
Genetic Aberrations in the CDK4 Pathway Are Associated with Innate Resistance to PD-1 Blockade in Chinese Patients with Non-Cutaneous Melanoma
Authors: Yu Jiayi , Yan Junya , Guo Qian , Chi Zhihong , Tang Bixia , Zheng Bin , Yu Jinyu , Yin Ting , Cheng Zhiyuan , Wu Xiaowen , Yu Huan , Dai Jie , Sheng Xinan , Si Lu , Cui Chuanliang , Bai Xue , Mao Lili , Lian Bin , Wang Xuan , Yan Xieqia , Li Siming , Zhou Li , Flaherty Keith T. , Guo Jun , Kong Yan 
Published: August 2019

Abstract

Purpose:
PD-1 checkpoint blockade immunotherapy induces long and durable response in patients with advanced melanoma. However, only a subset of patients with melanoma benefit from this approach. The mechanism triggering the innate resistance of anti–PD-1 therapy remains unclear.
Experimental Design: Whole-exome sequencing (WES) and RNA sequencing (RNA-Seq) analyses were performed in a training cohort (n = 31) using baseline tumor biopsies of patients with advanced melanoma treated with the anti–PD-1 antibody. Copy-number variations (CNVs) for the genes CDK4, CCND1, and CDKN2A were assayed using a TaqMan copy-number assay in a validation cohort (n = 85). The effect of CDK4/6 inhibitors combined with anti–PD-1 antibody monotherapy was evaluated in PD-1–humanized mouse (C57BL/6-hPD-1) and humanized immune system (HIS) patient-derived xenograft (PDX) models.

Results:
WES revealed several significant gene copy-number gains in the patients of no clinical benefit cohort, such as 12q14.1 loci, which harbor CDK4. The association between CDK4 gain and innate resistance to anti–PD-1 therapy was validated in 85 patients with melanoma (P &lt; 0.05). RNA-Seq analysis of CDK4-normal cell lines and CDK4-normal tumors showed altered transcriptional output in TNFα signaling via NF-κB, inflammatory response, and IFNγ response gene set. In addition, CDK4/6 inhibitor (palbociclib) treatment increased PD-L1 protein levels and enhanced efficacy (P &lt; 0.05) in the C57BL/6-hPD-1 melanoma cell and the HIS PDX model.

Conclusions:
In summary, we discovered that genetic aberrations in the CDK4 pathway are associated with innate resistance to anti–PD-1 therapy in patients with advanced melanoma. Moreover, our study provides a strong rationale for combining CDK4/6 inhibitors with anti–PD-1 antibody for the treatment of advanced melanomas.
Genetic Characterization and Prognostic Relevance of Acquired Uniparental Disomies in Cytogenetically Normal Acute Myeloid Leukemia
Authors: Walker Christopher J. , Kohlschmidt Jessica , Eisfeld Ann-Kathrin , Mrózek Krzysztof , Liyanarachchi Sandya , Song Chi , Nicolet Deedra , Blachly James S. , Bill Marius , Papaioannou Dimitrios , Oakes Christopher C. , Giacopelli Brian , Genutis Luke K. , Maharry Sophia E. , Orwick Shelley , Archer Kellie J. , Powell Bayard L. , Kolitz Jonathan E. , Uy Geoffrey L. , Wang Eunice S. , Carroll Andrew J. , Stone Richard M. , Byrd John C. , de la Chapelle Albert , Bloomfield Clara D. 
Published: August 2019

AbstractPurpose:Uniparental disomy (UPD) is a way cancer cells duplicate a mutated gene, causing loss of heterozygosity (LOH). Patients with cytogenetically normal acute myeloid leukemia (CN-AML) do not have microscopically detectable chromosome abnormalities, but can harbor UPDs. We examined the prognostic significance of UPDs and frequency of LOH in patients with CN-AML.Experimental Design: We examined the frequency and prognostic significance of UPDs in a set of 425 adult patients with de novo CN-AML who were previously sequenced for 81 genes typically mutated in cancer. Associations of UPDs with outcome were analyzed in the 315 patients with CN-AML younger than 60 years.Results:We detected 127 UPDs in 109 patients. Most UPDs were large and typically encompassed all or most of the affected chromosome arm. The most common UPDs occurred on chromosome arms 13q (7.5% of patients), 6p (2.8%), and 11p (2.8%). Many UPDs significantly cooccurred with mutations in genes they encompassed, including 13q UPD with FLT3-internal tandem duplication (FLT3-ITD; P &lt; 0.001), and 11p UPD with WT1 mutations (P = 0.02). Among patients younger than 60 years, UPD of 11p was associated with longer overall survival (OS) and 13q UPD with shorter disease-free survival (DFS) and OS. In multivariable models that accounted for known prognostic markers, including FLT3-ITD and WT1 mutations, UPD of 13q maintained association with shorter DFS, and UPD of 11p maintained association with longer OS.Conclusions:LOH mediated by UPD is a recurrent feature of CN-AML. Detection of UPDs of 13q and 11p might be useful for genetic risk stratification of patients with CN-AML.
Are Muslims in Turkey Really ‘Green’?
Authors: Ugur Zeynep B. 
Published: August 2019

AbstractTheoretically, the teachings of Islam can promote environmentally conscious behavior. As the only Muslim majority country to take part in the International Social Science Survey (ISSP), we study indicators of environmental consciousness in Turkey using ISSP 2010. Among all ISSP 2010 participating countries, a cross-country comparison does not provide evidence to support the argument that Islamic religiosity promotes environmental consciousness. In an analysis of individual level data, our overall findings failed to discover a statistically significant relationship between religiosity and environmental consciousness. Yet, this gap between the teachings of Islam and practices of Muslims may be identified as an unexploited potential to foster environmental consciousness in Turkey through a well-articulated religious education that brings together the book of scripture and the book of nature.
An Objective Classification and Analysis of Upper-Level Coupling to the Great Plains Low-Level Jet over the Twentieth Century
Authors: Burrows D. Alex , Ferguson Craig R. , Campbell Matthew A. , Xia Geng , Bosart Lance F. 
Published: August 2019

AbstractLow-level jets (LLJ) around the world critically support the food, water, and energy security in regions that they traverse. For the purposes of development planning and weather and climate prediction, it is important to improve understanding of how LLJs interact with the land surface and upper-atmospheric flow, and collectively, how LLJs have and may change over time. This study details the development and application of a new automated, dynamical objective classification of upper-atmospheric jet stream coupling based on a merging of the Bonner–Whiteman vertical wind shear classification and the finite-amplitude local wave activity diagnostic. The classification approach is transferable globally, but applied here only for the Great Plains (GP) LLJ (GPLLJ). The analysis spans the period from 1901 to 2010, enabled by the ECMWF climate-quality, coupled Earth reanalysis of the twentieth century. Overall, statistically significant declines in total GPLLJ event frequency over the twentieth century are detected across the entire GP corridor and attributed to declines in uncoupled GPLLJ frequency. Composites of lower- and upper-atmospheric flow are shown to capture major differences in the climatological, coupled GPLLJ, and uncoupled GPLLJ synoptic environments. Detailed analyses for southern, central, and northern GP subregions further highlight synoptic differences between weak and strong GPLLJs and provide quantification of correlations between total, coupled, and uncoupled GPLLJ frequencies and relevant atmospheric anomalies. Because uncoupled GPLLJs tend to be associated with decreased precipitation and low-level wind speed and enhanced U.S. ridge strength, this finding may suggest that support for drought over the twentieth century has waned.
Using Near-Ground Storm Relative Helicity in Supercell Tornado Forecasting
Authors: Coffer Brice E. , Parker Matthew D. , Thompson Richard L. , Smith Bryan T. , Jewell Ryan E. 
Published: August 2019

Abstract
This study examines the possibility that supercell tornado forecasts could be improved by utilizing the storm-relative helicity (SRH) in the lowest few hundred meters of the atmosphere (instead of much deeper layers). This hypothesis emerges from a growing body of literature linking the near-ground wind profile to the organization of the low-level mesocyclone and thus the probability of tornadogenesis. This study further addresses the ramifications of near-ground SRH to the skill of the significant tornado parameter (STP), which is probably the most commonly used environmental indicator for tornadic thunderstorms. Using a sample of 20 194 severe, right-moving supercells spanning a 13-yr period, sounding-derived parameters were compared using forecast verification metrics, emphasizing a high probability of detection for tornadic supercells while minimizing false alarms. This climatology reveals that the kinematic components of environmental profiles are more skillful at discriminating significantly tornadic supercells from severe, nontornadic supercells than the thermodynamic components. The effective-layer SRH has by far the greatest forecast skill among the components of the STP, as it is currently defined. However, using progressively shallower layers for the SRH calculation leads to increasing forecast skill. Replacing the effective-layer SRH with the 0–500 m AGL SRH in the formulation of STP increases the number of correctly predicted events by 8% and decreases the number of missed events and false alarms by 18%. These results provide promising evidence that forecast parameters can still be improved through increased understanding of the environmental controls on the processes that govern tornado formation.
Pulse Lavage Fails to Significantly Reduce Bone Marrow Content in Osteochondral Allografts: A Histological and DNA Quantification Study
Authors: Ambra Luiz Felipe , de Girolamo Laura , Gomoll Andreas H. 
Published: August 2019

Background: Current clinical practice calls for pulse lavage of fresh osteochondral allografts (OCAs) to reduce immunogenicity; however, there is limited evidence of its effectiveness in reducing allogenic bone marrow elements. Purpose: To evaluate the effectiveness of pulse lavage in removing marrow elements from trabecular bone in fresh OCA transplantation. Study Design: Controlled laboratory study. Methods: The authors evaluated 48 fresh OCA plugs with 4 different common sizes (14- and 24-mm diameter, 6- and 10-mm thickness). Within each size group, half of the samples underwent pulse lavage (n = 6) with saline solution and half were left untreated (no lavage; control group, n = 6). For each treatment and size group, 3 samples were analyzed for DNA content as an indicator of the number of residual nucleated cells; the other 3 samples were histologically analyzed to assess the presence and distribution of cells within subchondral bone pores in 3 specific locations within the plug: peripheral, intermediate, and core. Results: Osteochondral plugs treated with pulse lavage did not show a significant decrease in DNA content in comparison with untreated plugs. Overall, histological analysis did not show a significant difference between the treated and untreated groups ( P = .23). Subgroup analysis by size demonstrated decreased marrow content in treated versus untreated groups in the thinner plug sizes (14 × 6 mm and 24 × 6 mm). Histological evaluation by zone demonstrated a significant difference between groups only in the peripheral zone ( P = .04). Conclusion: Pulse lavage has limited effectiveness in removing marrow elements, in particular in plugs that are larger in diameter and, more importantly, in thickness. Better techniques for subchondral bone treatment are required for more thorough removal of potentially immunogenic marrow elements. Clinical Relevance: OCA transplantation has become an established treatment modality. Unfortunately, OCA is not without limitations, chiefly its mode of failure through inadequate integration of the allograft subchondral bone with subsequent collapse. In an effort to improve integration, current clinical practice calls for pulse lavage to remove allogenic bone marrow from the subchondral bone in hopes of decreasing the immunogenicity of the graft and facilitating revascularization.
Impact of Mergers and Acquisitions on Accounting-based Performance of Acquiring Firms in India
Authors: Aggarwal Puja , Garg Sonia 
Published: August 2019

Purpose: Merger is a corporate restructuring strategy that affects the performance of the company on many parameters. This study aims to examine the growth of M&A transactions in India in last two decades and the impact of merger on the accounting-based performance of the acquiring company. Methodology: The data of 68 mergers during the year 2007-08 - 2011-12 is analysed to capture the said impact. The accounting-based performance is measured on seven variables divided into three categories- profitability, liquidity and solvency. The accounting-based performance five years’ pre-merger is compared with five years’ post-merger. The similar comparison is done for 3 years pre and post-merger. Average of all the 7 parameters pre and post-merger are compared arithmetically and then using paired sample ‘t’test. The firms were also divided into manufacturing and service sector firms to see the impact of merger on different categories of firms. Findings: We found that merger has significantly impacted profitability and liquidity of the acquiring firm positively in five years but had no significant impact on solvency position of the company. Service sector firms have outperformed manufacturing firms and started showing significant improvement in accounting variables in medium term. Originality: We assure the originality of the work done in this article.
Effects of Different Timing of Alveolar Bone Graft on Craniofacial Morphology in Unilateral Cleft Lip and Palate
Authors: Brudnicki Andrzej , Sawicka Ewa , Brudnicka Renata , Fudalej Piotr Stanisław 
Published: August 2019

Objective: To evaluate the effect of the timing of secondary alveolar bone graft (SABG) on craniofacial morphology in patients with complete unilateral cleft lip and palate (UCLP). Design: Single-center retrospective assessment of consecutively treated nonsyndromic patients with complete UCLP. Participants: One hundred sixty-seven patients (108 males, 59 females) with complete UCLP in whom the cleft was repaired with 1-stage method at approximately 8 months of age. The age of 128 patients at SABG varied from 1.4 to 11.5 years (SABG group), while 39 patients still awaited SABG at the moment of cephalometric evaluation (no-SABG group). Methods: Craniofacial morphology was assessed on lateral cephalograms taken at 10 years of age (standard deviation = 0.8; range: 7.5-12.3) using linear and angular measurements. T tests and regression models were made to analyze data. Results: Regression models demonstrated that the effect of SABG on the craniofacial morphology was limited—cephalometric variables which were statistically significantly different between SABG and no-SABG groups showed no association with the timing of SABG when (1) age of primary repair of the cleft, (2) age of cephalometric evaluation, (3) cleft side, (4) gender, and (5) operator were controlled for. Only the length of the maxilla (Condylion-point A) was affected—1-year delay of SABG corresponded with an increase in Co-point A distance by 0.52 mm. However, adjusted R 2 of the model was 0.11. Conclusions: Our findings cautiously indicate that SABG performed before 8 years of age can have limited negative effect on craniofacial morphology. Nevertheless, our results should be confirmed by cleft centers practicing alternative surgical repairs of the cleft.