bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Study to Assess the Proarrhythmic Potential of Mirtazapine Using Concentration‐QTc (C‐QTc) Analysis
Authors: Gurkan Sevgi , Liu Fang , Chain Anne , Gutstein David E. 
Published: July 2018

AbstractMost new chemical entities with systemic availability are required to be tested in a study specifically designed to exclude drug‐induced corrected QT interval (QTc) effects, the so‐called thorough QT/QTc study. Mirtazapine (Remeron™) is an antidepressant indicated for the treatment of episodes of major depression, which was originally approved in 1994 without a thorough QT study. To evaluate the proarrhythmic potential of mirtazapine, we performed a QT/QTc study with a novel design including implementation of an analysis of the relationship between drug concentration and the QTc interval as the primary assessment of proarrhythmic potential of mirtazapine. The least squares mean differences of the corrected QT interval between mirtazapine and placebo at the geometric mean maximum concentration of drug in blood plasma (90% confidence interval) were 2.39 milliseconds (0.70, 4.07) at the 45‐mg dose and 4.00 milliseconds (1.18, 6.83) at the 75‐mg dose level of mirtazapine. Modeling of the concentration/QTc relationship for moxifloxacin confirmed that the assay method was adequately sensitive. This trial showed a positive relationship between mirtazapine concentrations and prolongation of the QTc interval. However, the degree of QT prolongation observed with both 45‐mg and 75‐mg doses of mirtazapine was not at a level generally considered to be clinically meaningful. This study further demonstrates that analysis of the relationship between drug concentration and the QTc interval may be a reasonable alternative to traditional TQT studies to assess risk of QT prolongation.
Platelets regulate leucocyte responses to Toll‐like receptor stimulation
Authors: Hally Kathryn E , La Flamme Anne C , Harding Scott A , Larsen Peter D 
Published: July 2018

AbstractObjectivesPlatelets are important regulators of vascular thrombosis and inflammation and are known to express Toll‐like receptors (TLRs). Through TLRs, platelets mediate a number of responses by interacting with leucocytes. Here, we report the extent to which platelets modulate in vitro peripheral blood mononuclear cells (PBMCs) and granulocyte responses to TLR4, TLR2/1 and TLR2/6 stimulation in healthy subjects.MethodsPeripheral blood mononuclear cells and granulocytes from 10 healthy volunteers were cultured alone or cocultured with platelets. Cultures were left unstimulated or stimulated with 1 or 100 ng mL−1 of either LPS (TLR4 agonist), Pam3CSK4 (TLR2/1 agonist) or fibroblast‐stimulating lipopeptide (FSL)‐1 (TLR2/6 agonist). Neutrophil activation (CD66b expression), monocyte activation (HLA‐DR), granulocyte elastase production and PBMC cytokine and chemokine production were examined.ResultsPlatelet coculture decreased neutrophil CD66b expression in response to LPS, Pam3CSK4 and FSL‐1, and modestly decreased monocyte HLA‐DR expression in response to low‐dose LPS. Platelets reduced granulocyte elastase secretion in response to low doses of all TLR agonists tested. In response to LPS, platelet coculture reduced IL‐6, tumor necrosis factor (TNF)‐α and MIP‐1β production, and increased IL‐10 production by PBMCs. In response to FSL‐1, platelets increased IL‐6, IL‐10 and MIP‐1β production, but reduced TNF‐α production. Platelet coculture did not alter PBMC cytokine/chemokine production in response to Pam3CSK4.ConclusionThis study challenges the notion that platelets act solely in a pro‐inflammatory manner. Rather, platelets are complex immunomodulators that regulate leucocyte responses to TLR stimulation in a TLR agonist‐specific manner. Platelets may modulate leucocyte responses to dampen inflammation, and this platelet effect may play an important role in reducing inflammation‐mediated host damage.
Association between maternal body mass index in early pregnancy and anorexia nervosa in daughters
Authors: Razaz Neda , Cnattingius Sven 
Published: July 2018

AbstractBackgroundThe etiology of anorexia nervosa is poorly understood. Although genetic factors play a major role, maternal factors, and obstetric complications are possible environmental causes. We investigated the association between maternal overweight and obesity in early pregnancy and risk of anorexia nervosa in daughters.MethodsA retrospective cohort study including all live singleton females born in Sweden from 1992 through 2002. Anorexia nervosa diagnosis was identified by using the nation‐wide Swedish Patient and Cause of Death Registers. Multivariable Cox hazards regression was used to estimate adjusted hazard ratios (aHRs) and 95% CIs, adjusting for confounders. Stratified Cox regressions were applied to data on siblings to adjust for unmeasured familial confounding.ResultsAmong 486,688 live singleton females, 2,414 (0.50%) were diagnosed with anorexia nervosa through 2012. The aHR of anorexia nervosa decreased linearly by maternal BMI (p‐value for trend < .001). When compared with daughters of normal weight mothers (body mass index [BMI] 18.5–24.9), aHRs (95%CI) of anorexia nervosa were 0.74 (0.65–0.84) in daughters of overweight mothers (BMI 25–29.9) and 0.61 (0.47–0.78) in daughters of mothers with obesity Grade I (BMI 30–34.9). In sibling control analysis, no associations were observed between maternal BMI and aHRs of anorexia nervosa in offspring.ConclusionsThe rate of anorexia nervosa decreased with maternal overweight and obesity in a dose–response manner. However, the sibling control analysis suggests that these findings are not consistent with causals effects of maternal BMI on anorexia nervosa in offspring.
Software implementation of UI interface for realizing communication robot in community‐centric system
Authors: Yamashita Yoshihiro , Nishitani Takao , Tamura Eichi , Shimokawara Eri , Yamaguchi Toru 
Published: July 2018

AbstractIn this paper, we describe the implementation and evaluation of a noncontact type of propagation system, which is an essential element of the communication function of people and robots, which is indispensable for the reality of our proposed community‐centric systems. We implemented this algorithm on JavaVM, which is the most portable, realized real‐time performance and got the possibility of deploying the algorithm on robot system. In addition, in preparation for future expansion, we got the guideline of the improvement to the communication UI by bottleneck analysis.
Theoretical studies on energy degradation estimation and minimization in laminar convective flow towards the microscale
Authors: Rastogi Pallavi , Mahulikar Shripad P. 
Published: July 2018

AbstractThe energy degraded into heat (qdeg) in laminar microconvective flow is of fundamental interest for minimizing the irreversibilities. The change in qdeg for N—number of microtubes each of diameter (DN) is studied relative to the reference tube (N = 1) of 1 mm diameter, towards the microscale. The total mass flow rate and total heat flow rate to be removed are kept fixed through all N tubes. Results show that for given l, there exists an optimum DN ( = DN,opt) and a corresponding optimum N at which, the change in sum‐total qdeg is minimum. As l decreases, DN,opt shifts towards the microscale. General criterion for DN,opt is analytically obtained in terms of Peclet number, Brinkman number, and dimensionless microtube length. The reported study and findings are of significance for the optimum design of microchannel heat sinks.
Triple diffusive flow of nanofluid with buoyancy forces and nonlinear thermal radiation over a horizontal plate
Authors: Archana M. , Reddy M. G. , Gireesha B. J. , Prasannakumara B. C. , Shehzad S. A. 
Published: July 2018

AbstractThe present attempt is made to elaborate the features of triple diffusive convective flow of an incompressible nanoliquid induced by horizontal surface under buoyancy forces. The effect of nonlinear thermal radiation is taken into account. Heat flux model of radiation is formulated through Rosseland's approximation. The radiation phenomenon plays a key role in modern solar energy equipment's. The nondimensional variables are introduced to convert the dimensional mathematical expressions into dimensionless single independent variable. Numerical scheme is developed to obtain the solution of mathematical model. The importance of controlling constraints on flow quantities are characterized through plots. The quantities of engineering importance are computed and elaborated graphically. It is noticed that the presence of salts and nanoparticles enhance the thermal performance of base liquid. The liquid temperature and its relevant thickness of thermal layer improved significantly with an increment in the values of radiative parameter. The larger values of parameters of Brownian motion and thermophoretic correspond to higher temperature profiles.
Postsynthetic Covalent Modification in Covalent Organic Frameworks
Authors: Yusran Yusran , Fang Qianrong , Qiu Shilun 
Published: July 2018

AbstractThe modification of covalent organic frameworks (COFs) based on postsynthetic covalent linkages is discussed in this review. In this strategy, the COF is preparedas scaffold and then assembled with functional groups with preservation of structural skeleton. Recent studies indicate that a number of COFs, such as COF‐5 and 3D‐OH‐COOF, are controllable to postsynthetic modification. Furthermore, covalentmodifications including triazole, ester, amide, sulfide, o‐carbamate, ether, and oxime are suitable for postsynthetic functionalization. The rapid development of postsynthetic modification demonstrates that this approach will provide a general platform to create COFs as robust functional porous materials for wide applications.
Pharmacometabolomics Reveals Irinotecan Mechanism of Action in Cancer Patients
Authors: Bao Xun , Wu Jianmei , Kim Seongho , LoRusso Patricia , Li Jing 
Published: July 2018

AbstractThe purpose of this study was to identify early circulating metabolite changes implicated in the mechanism of action of irinotecan, a DNA topoisomerase I inhibitor, in cancer patients. A liquid chromatography–tandem mass spectrometry–based targeted metabolomic platform capable of measuring 254 endogenous metabolites was applied to profile circulating metabolites in plasma samples collected pre‐ and post‐irinotecan treatment from 13 cancer patients. To gain further mechanistic insights, metabolic profiling was also performed for the culture medium of human primary hepatocytes (HepatoCells) and 2 cancer cell lines on exposure to SN‐38 (an active metabolite of irinotecan). Intracellular reactive oxygen species (ROS) was detected by dihydroethidium assay. Irinotecan induced a global metabolic change in patient plasma, as represented by elevations of circulating purine/pyrimidine nucleobases, acylcarnitines, and specific amino acid metabolites. The plasma metabolic signature was well replicated in HepatoCells medium on SN‐38 exposure, whereas in cancer cell medium SN‐38 induced accumulation of pyrimidine/purine nucleosides and nucleobases while having no impact on acylcarnitines and amino acid metabolites. SN‐38 induced ROS in HepatoCells, but not in cancer cells. Distinct metabolite signatures of SN‐38 exposure in HepatoCells medium and cancer cell medium revealed different mechanisms of drug action on hepatocytes and cancer cells. Elevations in circulating purine/pyrimidine nucleobases may stem from nucleotide degradation following irinotecan‐induced DNA double‐strand breaks. Accumulations of circulating acylcarnitines and specific amino acid metabolites may reflect, at least in part, irinotecan‐induced mitochondrial dysfunction and oxidative stress in the liver. The plasma metabolic signature of irinotecan exposure provides early insights into irinotecan mechanism of action in patients.
Polymorphisms in TRAIL predict long‐term survival and extrahepatic recurrence following initial hepatectomy for hepatocellular carcinoma
Authors: Imaoka Yuki , Ohira Masahiro , Yano Takuya , Nakano Ryosuke , Tanimine Naoki , Shimizu Seiichi , Kuroda Shintaro , Tahara Hiroyuki , Kobayashi Tsuyoshi , Ohdan Hideki 
Published: July 2018

AbstractBackgroundLiver natural killer (NK) cells are the first cells to respond to infections and malignancies, such as intraoperative tumor spill. Liver NK cells express tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL), a marker for hepatocellular carcinoma (HCC). However, the influence of TRAIL single‐nucleotide polymorphisms (SNPs) on hepatectomy patients with HCC remains unclear.MethodsHere, we investigated TRAIL SNPs (rs1131568, rs1131579, and rs1131580) located at positions 1525, 1588, and 1595 of exon 5 of the TNFSF10 gene. A total of 104 HCC patients who underwent initial hepatectomy were analyzed. Kaplan–Meier survival analysis and Cox proportional hazard regression were conducted to evaluate the associations between TRAIL genotypes and clinical HCC outcomes.ResultsPatients harboring the homozygous AA genotype of TRAIL SNPs rs1131568 and rs1131579 and the TT genotype of the TRAIL SNP rs1131580 had lower overall survival and higher rates of extrahepatic recurrence (EHR) than patients harboring the wild type or heterozygous genotypes. Moreover, univariate and multivariate Cox regression analysis revealed that the homozygous genotypes of the target TRAIL SNPs were independent predictive factors for EHR after initial hepatectomy for HCC.ConclusionOur findings revealed that the homozygous genotypes of TRAIL SNPs are independent predictors of EHR in initial hepatectomy patients with HCC.
Frontline Science: RIP2 promotes house dust mite–induced allergic airway inflammation
Authors: Miller Madelyn H , Shehat Michael G , Alcedo Karel P , Spinel Lina P , Soulakova Julia , Tigno-Aranjuez Justine T 
Published: July 2018

Abstract
House dust mites (HDMs) are one of the most significant environmental allergens in the establishment of the so-called “Atopic March.” It is known that the immune response to HDM is Th2 dominant, but the innate mechanisms leading to HDM-induced type 2 responses are still not completely understood. A number of innate immune receptors have been implicated in the response to HDM including toll-like receptors, C-type lectin receptors, and protease activated receptors. NOD2 is a member of the NOD-like receptor family, which has been reported to be involved in the establishment of type 2 immunity and in blocking respiratory tolerance. NOD2 mediates its effects through its downstream effector kinase, receptor interacting protein (RIP2). It has not been shown if RIP2 is involved in the innate response to HDM and in the resulting generation of type 2 immunity. Furthermore, the role of RIP2 in modulating allergic airway inflammation has been controversial. In this study, we show that RIP2 is activated in airway epithelial cells in response to HDM and is important for the production of CCL2. Using a murine HDM asthma model, we demonstrate that lung pathology, local airway inflammation, inflammatory cytokines, HDM-specific IgG1 antibody production, and HDM-specific Th2 responses are all reduced in RIP2 knockout mice compared to WT animals. These data illustrate that RIP2 can be activated by a relevant allergic stimulus and that such activation can contribute to allergic airway inflammation. These findings also suggest that RIP2 inhibitors might have some efficacy in down-regulating the inflammatory response in type 2 dominated diseases.
Tidal shifts in the vertical distribution of bivalve larvae: Vertical advection vs. active behavior
Authors: Weinstock Jane B. , Morello Scott L. , Conlon LeAnn M. , Xue Huijie , Yund Philip O. 
Published: July 2018

AbstractSome previous studies, though not all, have reported that vertical distributions of bivalve larvae shift upward in the water column on flood tides and downward on ebb tides. When observed, such shifts have been interpreted as reflecting the vertical migration of larvae (i.e., an active behavioral process). This interpretation assumes that tidally driven vertical advection is insignificant compared to larval swimming speeds, but that assumption may not be valid in all regions. We demonstrated that the vertical distribution of mussel (Mytilus edulis) larvae shifted upward on flood tides on all surveyed dates at sites in the eastern Gulf of Maine. We then used a high‐resolution coastal circulation model to predict the vertical distribution of passive particles at one site on four sample dates. The modeled distribution shifts explained 99% of the variance in the larval vertical distribution. Finally, we conducted a multipart meta‐analysis of published papers on tidal shifts to assess whether variation in the results among studies could be explained by tidal vertical advection via two proxies—tidal range and shelf slope. For well‐replicated studies that could be analyzed with a paired t‐test, tidal range explained 78% of the variance in the test statistic. A multiple regression approach applied to distributional shifts from a broader set of studies indicated significant effects of tidal range and interactions between tidal range, slope, and slope heterogeneity. Our results demonstrate the importance of considering passive processes when evaluating how the vertical distribution of weakly swimming meroplankton varies between tidal phases.
Excellent outcome of acute lymphoblastic leukaemia with TCF3‐PBX1 rearrangement in Hong Kong
Authors: Lin Anna , Cheng Frankie W.T. , Chiang Alan K.S. , Luk Chung‐wing , Li Rever C.H. , Ling Alvin S.C. , Cheuk Daniel K.L. , Chang Kai‐on , Ku Dennis , Lee Vincent , Ha Shau‐Yin , Li Chi‐Kong 
Published: July 2018

AbstractObjectiveThe aim of this study was to review clinical outcomes and prognosis of paediatric patients with acute lymphoblastic leukaemia (ALL) with TCF3‐PBX1 rearrangement.PatientsAll children in Hong Kong diagnosed with ALL with TCF3‐PBX1 rearrangement over the past two decades were included.MethodsSix hundred and twenty‐four newly diagnosed patients with ALL from four consecutive studies were enrolled from 1997 to 2016. Patients carrying TCF3‐PBX1 rearrangement and patients at intermediate risk without the gene expression were compared for clinical characteristics, overall survival and event‐free survival (EFS).ResultsThe TCF3‐PBX1 rearrangement was detected in 30 of 624 patients (4.8%). Results were consistent across the consecutive clinical trials employed in the past two decades. Compared with 239 intermediate risk patients without TCF3‐PBX1 rearrangement, the 5‐year overall survival and EFS for patients with TCF3‐PBX1 rearrangement was superior, with both at 100% (P = 0.12 and P = 0.029).ConclusionThis population‐based study over the past 20 years demonstrated that patients with TCF3‐PBX1 rearrangement had favourable EFS compared with other intermediate risk patients treated with a similar chemotherapy backbone.
Token economy to improve adherence to activities of daily living
Authors: Hickey Victoria , Flesch Laura , Lane Adam , Pai Ahna L.H. , Huber John , Badia Priscila , Davies Stella M. , Dandoy Christopher E. 
Published: July 2018

AbstractBackgroundParticipation in key activities of daily living (ADL), including daily bathing, physical activity, and oral hygiene, can decrease the risk of bloodstream infections, oral complications, and deconditioning in pediatric patients undergoing hematopoietic stem cell transplant (HSCT). However, many patients fail to perform ADL during their inpatient stay. To improve inpatient adherence to ADL, we tested a token economy to engage patients, families, and the clinical team in improving adherence to these important health behaviors during this critical time.MethodsWe used a controlled before‐after study design to test our hypothesis. All patients were prescribed three ADL. We used an “all or none” measurement for each component of the ADL 1‐2‐3 initiative to measure adherence. HSCT patients with poor ADL adherence (<20%) were eligible to receive the intervention, which consisted of rewarding patients through an ADL via a token economy.ResultsTwenty‐one patients participated in the study. ADL adherence for the 14 days prior to intervention in study subjects (n = 294 inpatient days) averaged 0.51 ADL per day (95% CI 0.45–0.57). In the 14 days postinitiation of the token economy intervention (n = 294 inpatient days), the average adherence was 2.5 ADL per day (95% CI 2.4–2.5; P = <0.001).DiscussionPositive reinforcement through a token economy system is associated with improved adherence to ADL in hospitalized pediatric patients who demonstrated poor ADL adherence at baseline. We believe this intervention can positively impact adherence to targeted health behaviors with the ability to correlate with improved health outcomes.
Gain of function conferred by selenocysteine: catalytic enhancement of one‐electron transfer reactions by thioredoxin reductase
Authors: Barber Drew R. , Hondal Robert J. 
Published: July 2018

AbstractSelenocysteine (Sec) is the 21st amino acid in the genetic code and it is present in a small number of proteins where it replaces the much more commonly used amino acid cysteine (Cys). It is both more complicated and bioenergetically costly to insert Sec into a protein in comparison to Cys, and this cost is most likely compensated by a gain of function to the enzyme/protein in which it is incorporated. Here we investigate one such gain of function, the enhancement of one‐electron transfer catalysis. We compared the ability of Sec‐containing mouse mitochondrial thioredoxin reductase (mTrxR2) to catalyze the reduction of bovine cytochrome c, ascorbyl radical, and dehydroascorbate in comparison to Cys‐containing thioredoxin reductases from D. melanogaster (DmTrxR) and P. falciparum (PfTrxR). The Sec‐containing mTrxR2 was able to reduce all three substrates, while the Cys‐containing enzymes had little or no activity. In addition, we constructed Cys➔Sec mutants of DmTrxR and PfTrxR and found that this substitution resulted in a gain of function, as these mutant enzymes were now able to catalyze the reduction of these substrates. We also found that in the case of PfTrxR, reduction of cytochrome c was enhanced five‐fold in a truncated PfTrxR in which the C‐terminal redox center was removed. This shows that some of the ability of thioredoxin reductase to reduce this substrate comes from the flavin coenzyme. We also discuss a possible mechanism by which Sec‐containing thioredoxin reductase reduces dehydroascorbate to ascorbate by two sequential, one‐electron reductions, in part catalyzed by Sec.