bluuebunny/crossref_metadata_2025 huggingface dataset:
A real‐time experimental investigation of building integrated thermal energy storage with air‐conditioning system for indoor temperature regulation
Authors: Chinnasamy Veerakumar , Appukuttan Sreekumar
Published: March 2019

In this article, a novel concept of the latent heat thermal energy storage system combined with the conventional cooling system is proposed for the application of indoor thermal comfort. Lauryl alcohol with a melting point of 22‐25°C is selected as phase change materials (PCM) for the study. From the results of experiment conducted with different mass of PCM, there is no change in temperature drop achieved while increasing PCM mass but there is increase in discharge time. The average air temperature in bottom chamber is maintained at 26°C which is in thermal comfort range throughout the experiment. For the experiments with different inlet air temperatures, higher drop in top chamber outlet air temperature is achieved for higher inlet temperatures. The temperature of the room can bring down to human thermal comfort range with a minimum duration of time with the proposed system irrespective of initial room temperature. The proposed system helps to maintain the buildings in human thermal comfort range with less‐energy consumption when the conventional air‐conditioning system is not in operation which in turn decreases the major energy consumption by the building sector through other auxiliary energy source.
Preparation and thermal properties of shape‐stabilized polyethylene glycol/mesoporous silica composite phase change materials for thermal energy storage
Authors: Wang Chaoming , Cai Zhengyu , Chen Ke , Huang Jun , Wang Tingjun
Published: March 2019

Mesoporous silica (MS) was prepared through a simple self‐assembly procedure under alkaline condition with tetraethyl orthosilicate (TEOS) as SiO2 precursor and cetyltrimethyl ammonium bromide (CTAB) as the template. A series of shape‐stabilized composite phase change materials (ss‐CPCMs), using polyethylene glycol 6000 (PEG6000) as the PCM and MS as the matrix with different mass percentage of PEG6000 loadings, was prepared through a vacuum impregnation method. N2 adsorption‐desorption analyzer measurement showed the specific surface area and average pore size of the as‐prepared porous silica were determined to be 760 m2/g and about 3 nm, respectively. Differential scanning calorimetry (DSC) measurements indicated that the melting peak temperatures and latent heats of melting of the composites are varied from 52.3°C to 62.6°C and 32.9 to 186.4 J/g (PEG6000 mass fractions: 0%‐80%), which was proportional to PEG6000 content. Fourier‐transform infrared (FT‐IR) spectroscopy results implied that only the physical interaction existed between the PEG6000 and SiO2 matrix. The shape‐stability measurements suggested the composite with the 70% mass loading of PEG6000 can still maintained the original shape and no leakage were observed above the much higher melting temperature of PEG6000 (105°C). Thermal cycling test showed that the ss‐CPCM had good thermal reliability and chemical stability although it was experienced 500 melting and cooling cycles. Moreover, the thermal decomposition temperature of the composites (393.2°C) was much larger than the melting temperature of pure PEG6000 (62.6°C), which indicated that composite presented excellent thermal stabilities and was suitable for thermal energy storage applications.
Response of a Small Mammal Population Postremediation for an Accidental Bitumen and Steam Release from a Wellhead in the Athabasca Oil Sands
Authors: Smits Judit E.G. , Sanders Greg , Charlebois Michael
Published: March 2019

Two releases from steam assisted gravity drainage (SAGD) wellheads occurred 3 yr apart. To track recovery of the affected areas, red-backed voles were studied 1 and 4 yr later, using population estimates, hepatic detoxification effort, body condition, and tissue metal levels as bioindicators of site recovery. From years 1 to 4, higher ethoxyresorufin-O-deethylase induction was no longer evident, capture rate was lower, and body lead residues were no longer (inversely) correlated with body condition. Environ Toxicol Chem 2019;38:1542–1548. © 2019 SETAC

Abstract
A stabilized extremum‐preserving scheme for nonlinear parabolic equation on polygonal meshes
Authors: Peng Gang , Gao Zhiming , Feng Xinlong
Published: March 2019

In this paper, a stabilized extremum‐preserving scheme is introduced for the nonlinear parabolic equation on polygonal meshes. The so‐called harmonic averaging points located at the interface of heterogeneity are employed to define the auxiliary unknowns and can be interpolated by the cell‐centered unknowns. This scheme has only cell‐centered unknowns and possesses a small stencil. A stabilized term is constructed to improve the stability of this scheme. The stability analysis of this scheme is obtained under standard assumptions. Numerical results illustrate that the scheme satisfies the extremum principle with anisotropic full tensor coefficient problems and has optimal convergence rate in space on distorted meshes.
Using accounting‐based information on young firms to predict bankruptcy
Authors: Lohmann Christian , Ohliger Thorsten
Published: March 2019

This study analyzes the nonlinear relationships between accounting‐based key performance indicators and the probability that the firm in question will become bankrupt or not. The analysis focuses particularly on young firms and examines whether these nonlinear relationships are affected by a firm's age. The analysis of nonlinear relationships between various predictors of bankruptcy and their interaction effects is based on a structured additive regression model and on a comprehensive data set on German firms. The results of this analysis provide empirical evidence that a firm's age has a considerable effect on how accounting‐based key performance indicators can be used to predict the likelihood that a firm will go bankrupt. More specifically, the results show that there are differences between older firms and young firms with respect to the nonlinear effects of the equity ratio, the return on assets, and the sales growth on their probability of bankruptcy.
New drugs creating new challenges in acute myeloid leukemia
Authors: Tiong Ing S. , Wei Andrew H.
Published: March 2019

The therapeutic landscape is rapidly changing, with eight new drugs approved by the Food and Drug Administration within the last 2 years, including midostaurin and gilteritinib for FLT3 mutant newly diagnosed and relapsed/refractory (R/R) acute myeloid leukemia (AML), respectively; CPX‐351 (liposomal cytarabine and daunorubicin) for therapy‐related AML and AML with myelodysplasia‐related changes; gemtuzumab ozogamicin (anti‐CD33 monoclonal antibody conjugated with calicheamicin) for newly diagnosed and R/R CD33‐positive AML; enasidenib and ivosidenib for IDH2 and IDH1 mutant R/R AML, respectively. Novel therapies have also emerged for newly diagnosed AML in adults who are age 75 years or older, or who have comorbidities that preclude the use of intensive induction chemotherapy. These include venetoclax (BCL‐2 inhibitor) in combination with hypomethylating agents (azacitidine or decitabine) or low‐dose cytarabine (LDAC), and glasdegib (sonic hedgehog pathway inhibitor) in combination with LDAC. This flurry of new drug approvals has markedly altered the treatment landscape in AML and provided new opportunities, as well as new challenges for treating clinicians. This review will focus on how these drugs might shape clinical practice and the hurdles likely to be faced by new therapies seeking entry into this dynamic and rapidly changing therapeutic landscape.
Establishing a high‐resolution stratigraphy in the Holocene marine sequence of the ancient Theodosian harbor of Istanbul with the help of dendrochronology
Authors: Yalçın M. Namık , Sezerer‐Bulut Meltem , Pearson Charlotte , Kuniholm Peter , Algan Oya , Wazny Tomasz
Published: March 2019

Salvage excavations in the Theodosian harbor (Yenikapı‐Istanbul) have uncovered diverse archaeological objects including 36 shipwrecks and various Byzantine period wooden docks. The sequence of these docks provided a unique opportunity to obtain a high‐resolution stratigraphy. The new approach is based on stratigraphic interpretation of deformation patterns created by the posts in soft sediments, combined with dendrochronological dating of the posts. Dendrochronology offers the potential to date the posts to within one calendar year of felling, a level of precision and accuracy rare in sedimentological analysis. The posts, most of them Quercus, were rammed during six different time periods. The first period is associated with posts cut in 528 AD. The second and third periods are dated by posts cut in 583 and 594 AD, respectively. The fourth‐period dates within 8–10 years of 639 AD. The fifth period could be dated only roughly to between 690 and 770 AD. The last period produced a possible placement of after 778 AD. This new approach helps to establish a high‐resolution stratigraphy. Furthermore, it provides information about sedimentation history and specific anthropogenic events.
Grey matter myelination
Authors: Timmler Sebastian , Simons Mikael
Published: March 2019

There is now increasing evidence that myelin is not only generated early in development, but also during adulthood possibly contributing to lifelong plasticity of the brain. In particular, human cortical areas responsible for the highest cognitive functions seem to require decades until they have reached their maximal amount of myelination. Currently, we know very little about the mechanisms and the functions of grey matter myelination. In this emerging field key questions await to be addressed: How long does myelination last in humans? How is grey matter myelination regulated? What is the function of myelin in the grey matter? Does grey matter myelination limit and/or promote neuronal plasticity? Finding answers to these questions will be important for our understanding of normal, but also abnormal cortex function in a number of neurological and psychiatric diseases.
Firm–government relationships: A social exchange view of corporate tax compliance
Authors: Lee Seung‐Hyun , Gokalp Omer N. , Kim Jinsil
Published: March 2019

Research Summary

The economic exchange view of corporate tax compliance holds that when governments fail to provide adequate public services, firms comply less with taxes as quid pro quo. However, firms differ widely in the degree to which they respond to government inefficiencies in the form of tax noncompliance. We argue that such heterogeneity is largely because firm–government economic exchanges do not happen in a vacuum, but rather within the context of social exchange. Factors such as bribery, tax compliance burden, and consistency of tax enforcement affect firms' perceptions of fairness and trust in the social contract and moderate the quid pro quo in the economic exchange. We find broad support for our hypotheses in a sample from transition economies in Eastern Europe and Central Asia.

Managerial Summary

Firms' propensity to pay their fair share of taxes is a function of the level of service provided by the government. Such an eye‐for‐an‐eye mentality would manifest more strongly when firms face higher levels of corruption or when they must shoulder a heavier tax burden; however, this mentality would be less apparent when tax enforcement is consistent and efficient. The degree of firms' effort to balance the economic relationship with the government is therefore influenced by how well they believe the social contract is upheld by their government within a broader social exchange relationship. While the prevalence of bribery and heavy compliance burden damages firms' perception of fairness and trust toward the government, consistent tax enforcement improves it.
Enantioselective Total Synthesis of (−)‐Doliculide Using Catalytic Asymmetric Hydrogenations
Authors: Che Wen , Wen Danyang C. , Zhu Shou‐Fei , Zhou Qi‐Lin
Published: March 2019

A concise and efficient strategy has been developed to construct a polyketide chain by employing relay asymmetric hydrogenations catalyzed by two chiral spiro iridium catalysts. By using this strategy, an enantioselective total synthesis of (−)‐doliculide has been achieved in 19 steps with 6.9 % overall yield. The route features high enantioselectivity and diastereoselectivity. The catalyst loading can be as low as 0.005 mol‐%. It is convenient to obtain natural polyketides and their analogues by this strategy.
Interaction between turbulence and thermal radiation in combined heat transfer channel flows
Authors: Moghaddam Saied , Bazdidi‐Tehrani Farzad , Aghaamini Masoud
Published: March 2019

The aim of the present work is to examine the effects of interaction between turbulence and thermal radiation on the fully developed turbulent channel flow with variable properties in the presence of combined mixed convection‐radiation heat transfer. The vertical and horizontal channels under study are formed by differentially heated flat parallel plates. Large eddy simulation and the low Mach number approach are used to solve the governing equations. Also, the radiative transfer equation is solved using the method. The results are achieved by developing a solver in an open‐source computational fluid dynamics toolbox. The main focus is to find out whether neglecting turbulence‐radiation interaction (TRI) is a valid assumption for such flows under consideration. The present results show that, in both configurations, the maximum values of emission TRI and incident TRI are 2% and 3%, respectively. These results are consistent with the previous findings suggesting that in the nonreactive flows, these two terms are negligible.
Investigating the role of expectancy in caffeine withdrawal using the balanced placebo design
Authors: Juliano Laura M. , Kardel Peter G. , Harrell Paul T. , Muench Christine , Edwards Kathryn C.
Published: March 2019

Objective

This study investigated psychological influences on drug withdrawal symptomatology using a caffeine‐based model.

Methods

Using the 2 × 2 balanced placebo design caffeine dose (given caffeinated vs decaffeinated coffee) was crossed with dose expectancy (told caffeine vs. decaf) among 87 (16‐hr abstinent) regular coffee consumers in a 2‐day study.

Results

There were effects of expectancy and pharmacology that differed depending on the measure. Those told decaf reported greater caffeine cravings than those told caffeine 45 min and 8 hr postmanipulation. There were no expectancy effects on withdrawal symptoms or cognitive performance. There were pharmacological effects on all measures. Those given decaf reported greater withdrawal symptoms and showed poorer cognitive performance 45 min and 8 hr postmanipulation, with effects for headache and flu‐like symptoms first emerging 8 hr postmanipulation (i.e., 24 hr abstinence in given decaf conditions). Caffeine readministration alleviated all withdrawal symptoms and cognitive decrements within 45 min. No drug by expectancy interactions were observed.

Conclusions

These findings confirm a strong pharmacological basis for caffeine withdrawal and an important role of cognition in drug craving. Future research should investigate the role of expectancy in drug withdrawal and craving and the potential use of expectancy manipulations in symptom prevention and management.
Trajectories of class–switching‐related egg and cow's milk allergen‐specific immunoglobulin isotype formation and its modification by eczema with low‐ and high‐affinity immunoglobulin E during early infancy
Authors: Irahara Makoto , Shinahara Wakako , Sugimoto Mayumi , Ogawa Yukiko , Shitsukawa Keiji , Kubota Kenji , Yang Limin , Ohya Yukihiro , Saito Hirohisa , Kagami Shoji , Arisawa Kokichi , Kido Hiroshi
Published: March 2019

Introduction

Allergen‐specific immunoglobulin isotype formation associated with immunoglobulin class‐switching during the lactation period is the immunological background for food allergy in infants. We analyzed the serial changes in the production of feeding type‐related egg‐ and milk‐specific immunoglobulin isotypes from birth to 6 months of age with or without eczema in 84 infants.

Methods

Allergen‐specific immunoglobulin G1 (IgG1), IgG2, IgG3, IgG4, IgA, and IgE levels of hen's egg and bovine milk were measured in cord blood and blood samples from infants at 2, 4, and 6 months of age by the densely carboxylated protein microarray.

Results

Formula and mixed feeding were associated with a rapid increase in cow's milk allergen‐specific immunoglobulins and feeding type‐related significant differences in casein‐specific immunoglobulin levels were detected. Breast and mixed feeding were associated with slow but significant increase in ovalbumin‐specific IgG1 and IgE levels, but not other immunoglobulins. We found two different immunoglobulin isotype formation at 6 months of age with low‐ or high‐affinity IgE against ovalbumin. One isotype formation pattern had relatively high ovalbumin‐specific IgG1 levels, detectable IgG2, and low‐affinity IgE, while the other had low ovalbumin‐specific IgG1 levels, undetectable IgG2, and high levels of high‐affinity IgE. The incidence of eczema was significantly higher in the latter pattern (84.6%), compared with the remaining infants (42.2%).

Conclusions

Feeding practice‐related allergen sensitization and immunoglobulin isotype formation were identified during the lactation period. The development of eczema during the lactation period could potentially modify the immunoglobulin isotype formation with high levels of high‐affinity IgE.
A pilot precision medicine trial for children with diffuse intrinsic pontine glioma—PNOC003: A report from the Pacific Pediatric Neuro‐Oncology Consortium
Authors: Mueller Sabine , Jain Payal , Liang Winnie S. , Kilburn Lindsay , Kline Cassie , Gupta Nalin , Panditharatna Eshini , Magge Suresh N. , Zhang Bo , Zhu Yuankun , Crawford John R. , Banerjee Anu , Nazemi Kellie , Packer Roger J. , Petritsch Claudia K. , Truffaux Nathalene , Roos Alison , Nasser Sara , Phillips Joanna J. , Solomon David , Molinaro Annette , Waanders Angela J. , Byron Sara A. , Berens Michael E. , Kuhn John , Nazarian Javad , Prados Michael , Resnick Adam C.
Published: March 2019

This clinical trial evaluated whether whole exome sequencing (WES) and RNA sequencing (RNAseq) of paired normal and tumor tissues could be incorporated into a personalized treatment plan for newly diagnosed patients (<25 years of age) with diffuse intrinsic pontine glioma (DIPG). Additionally, whole genome sequencing (WGS) was compared to WES to determine if WGS would further inform treatment decisions, and whether circulating tumor DNA (ctDNA) could detect the H3K27M mutation to allow assessment of therapy response. Patients were selected across three Pacific Pediatric Neuro‐Oncology Consortium member institutions between September 2014 and January 2016. WES and RNAseq were performed at diagnosis and recurrence when possible in a CLIA‐certified laboratory. Patient‐derived cell line development was attempted for each subject. Collection of blood for ctDNA was done prior to treatment and with each MRI. A specialized tumor board generated a treatment recommendation including up to four FDA‐approved agents based upon the genomic alterations detected. A treatment plan was successfully issued within 21 business days from tissue collection for all 15 subjects, with 14 of the 15 subjects fulfilling the feasibility criteria. WGS results did not significantly deviate from WES‐based therapy recommendations; however, WGS data provided further insight into tumor evolution and fidelity of patient‐derived cell models. Detection of the H3F3A or HIST1H3B K27M (H3K27M) mutation using ctDNA was successful in 92% of H3K27M mutant cases. A personalized treatment recommendation for DIPG can be rendered within a multicenter setting using comprehensive next‐generation sequencing technology in a clinically relevant timeframe.
Incidence of second primary malignancy after breast cancer and related risk factors—Is breast‐conserving surgery safe? A nested case–control study
Authors: Li Zhuyue , Wang Kang , Shi Yang , Zhang Xuemei , Wen Jin
Published: March 2019

Risk of second primary malignancy (SPM) is increasing. We aimed to assess the incidence and related risk factors of SPM among breast cancer (BC) patients from this nested case–control study using the SEER database. BC patients with SPM were identified as the case group and SPM‐free patients were defined as the control group. Propensity score matching of cases with controls by the year of the first primary BC diagnosis was conducted at the ratio of 1:5, and 97,242 BC patients were enrolled from 1998 to 2013 after the matching. The incidence of SPM in BC patients stratified by age groups and cancer sites was compared to the general population using the adjusted standardized incidence ratio (SIR) and the risk factors for SPM were examined using Cox proportional hazard regressions. Our study showed BC patients had excess risk for SPM than the general population (adjusted SIR for all cancer sites = 12.94, p < 0.001) and the incidence of SPM among them decreased with age. The risk of SPM was significantly related to the following demographical and clinical variables: age (40–59 vs. 18–39, HR = 1.33; 60–79 vs. 18–39, HR = 2.39; ≥80 vs. 18–39, HR = 2.84), race (black vs. white, HR = 1.12), histological type (lobular BC vs. ductal BC, HR = 1.15), radiotherapy (HR = 1.33), marital status (married vs. single, HR = 0.88) and estrogen receptor status (positive vs. negative, HR = 0.85). Consistent results were found in subgroup analysis stratified by contralateral‐breast SPMs and nonbreast SPMs.
Somatic genome alterations in relation to age in lung adenocarcinoma
Authors: Meucci Stefano , Keilholz Ulrich , Heim Daniel , Klauschen Frederick , Cacciatore Stefano
Published: March 2019

Lung adenocarcinoma (LUAD) is the most common cause of global cancer‐related mortality and the major risk factor is smoking consumption. By analyzing 486 LUAD samples from The Cancer Genome Atlas, we detected a higher mutational burden among younger patients in the global cohort as well as in the TP53‐mutated subcohort. The interaction effect of patient age and TP53 mutations significantly affected the mutational rate of younger TP53‐mutated patients. Furthermore, we detected a significant enrichment of the smoking‐related signature SI4 (SI4) among younger TP53‐mutated patients, meanwhile the age‐related Signature 1 (SI1) significantly increased in proportion to patient age. Although present and past smoking is reported in the TP53 wild‐type patients, we observed a lower average number of somatic mutations, with no correlation with patient age. Overall, TP53 mutations were significantly higher in younger patients and mainly characterized by SI4 and Signature 24 (SI24). Therefore, TP53 seemed to acquire a particular sensitivity to smoking related C>A mutations in younger patients. We hypothesize that TP53 mutations at a younger age might be a crucial factor enhancing the sensitivity to smoking‐related mutations leading to a burst of somatic alterations. The mutational profile of cancer cell might reflect the mutational processes operative in aging in a given tissue. Therefore, TP53‐mutated and TP53 wild‐type patient groups might represent phenotypes which endure aging‐related mutational processes with different strength. Our study provides indications of age‐dependent differences in mutational backgrounds that might be relevant for cancer prevention and age‐adjusted treatment approaches.
A large collection of integrated genomically characterized patient‐derived xenografts highlighting the heterogeneity of triple‐negative breast cancer
Authors: Coussy Florence , de Koning Leanne , Lavigne Marion , Bernard Virginie , Ouine Berengere , Boulai Anais , El Botty Rania , Dahmani Ahmed , Montaudon Elodie , Assayag Franck , Morisset Ludivine , Huguet Lea , Sourd Laura , Painsec Pierre , Callens Celine , Chateau‐Joubert Sophie , Servely Jean‐Luc , Larcher Thibaut , Reyes Cecile , Girard Elodie , Pierron Gaelle , Laurent Cecile , Vacher Sophie , Baulande Sylvain , Melaabi Samia , Vincent‐Salomon Anne , Gentien David , Dieras Veronique , Bieche Ivan , Marangoni Elisabetta
Published: March 2019

Triple‐negative breast cancer (TNBC) represents 10% of all breast cancers and is a very heterogeneous disease. Globally, women with TNBC have a poor prognosis, and the development of effective targeted therapies remains a real challenge. Patient‐derived xenografts (PDX) are clinically relevant models that have emerged as important tools for the analysis of drug activity and predictive biomarker discovery. The purpose of this work was to analyze the molecular heterogeneity of a large panel of TNBC PDX (n = 61) in order to test targeted therapies and identify biomarkers of response. At the gene expression level, TNBC PDX represent all of the various TNBC subtypes identified by the Lehmann classification except for immunomodulatory subtype, which is underrepresented in PDX. NGS and copy number data showed a similar diversity of significantly mutated gene and somatic copy number alteration in PDX and the Cancer Genome Atlas TNBC patients. The genes most commonly altered were TP53 and oncogenes and tumor suppressors of the PI3K/AKT/mTOR and MAPK pathways. PDX showed similar morphology and immunohistochemistry markers to those of the original tumors. Efficacy experiments with PI3K and MAPK inhibitor monotherapy or combination therapy showed an antitumor activity in PDX carrying genomic mutations of PIK3CA and NRAS genes. TNBC PDX reproduce the molecular heterogeneity of TNBC patients. This large collection of PDX is a clinically relevant platform for drug testing, biomarker discovery and translational research.
Combinations of single nucleotide polymorphisms identified in genome‐wide association studies determine risk for colorectal cancer
Authors: Xin Junyi , Du Mulong , Gu Dongying , Ge Yuqiu , Li Shuwei , Chu Haiyan , Meng Yixuan , Shen Hongbing , Zhang Zhengdong , Wang Meilin
Published: March 2019

Genome‐wide association studies (GWASs) have identified single nucleotide polymorphisms (SNPs) associated with colorectal cancer (CRC) risk, but whether these SNPs have additive effects on the risk of CRC remains unclear. We performed a systematic analysis of GWAS‐identified SNPs using GWAS datasets from China (2,248 patients and 3,173 controls) and Europe (4,461 patients and 4,140 controls). We analyzed 58 independent variants from DNA samples from Chinese populations and found 19 SNPs that were significantly associated with CRC risk. We identified two genetic risk scores (GRSs) based on 58 and 19 SNPs, which were significantly associated with an increased risk of CRC. A decision curve analysis showed higher predictive power for the 58 SNPs. Using all the 58 SNPs to assess 5‐year absolute risk (AR), we found that, at a cutoff of 0.4% (two times the median AR) and 0.6% (three times the median AR), approximately 32.76 and 16.45% of Chinese individuals were grouped as high risk for developing CRC, respectively. Risk stratification analysis further indicated that the population in the top 30% risk group accounted for 46.71% of the CRC cases. In addition, the 58 SNPs could explain approximately 1.13% of the phenotypic variance in Chinese populations. Similar findings were found in European populations. Combinations of SNPs identified in GWASs may therefore be useful for identifying individuals at high risk for CRC.
Genetically engineered CAR NK cells display selective cytotoxicity against FLT3‐positive B‐ALL and inhibit in vivo leukemia growth
Authors: Oelsner Sarah , Waldmann Anja , Billmeier Arne , Röder Jasmin , Lindner Aline , Ullrich Evelyn , Marschalek Rolf , Dotti Gianpietro , Jung Gundram , Große‐Hovest Ludger , Oberoi Pranav , Bader Peter , Wels Winfried S.
Published: March 2019

Chimeric antigen receptor (CAR)‐engineered natural killer (NK) cells represent a promising effector cell type for adoptive cancer immunotherapy. Both, genetically modified donor‐derived NK cells as well as continuously expanding NK‐92 cells are currently under clinical development. To enhance their therapeutic utility for the treatment of pre‐B‐cell acute lymphoblastic leukemia (B‐ALL), we engineered NK‐92 cells by lentiviral gene transfer to express a FMS‐like tyrosine kinase 3 (FLT3)‐specific CAR that contains a composite CD28‐CD3ζ signaling domain. FLT3 has primarily been described as a therapeutic target for acute myeloid leukemia, but overexpression of FLT3 has also been reported in B‐ALL. Exposure of FLT3‐positive targets to CAR NK‐92 cells resulted in conjugate formation between NK and leukemia cells, NK‐cell degranulation and selective cytotoxicity toward established B‐ALL cell lines and primary blasts that were resistant to parental NK‐92. In a SEM B‐ALL xenograft model in NOD‐SCID IL2R γnull mice, treatment with CAR NK‐92 but not parental NK‐92 cells markedly inhibited disease progression, demonstrating high antileukemic activity in vivo. As FLT3 is known to be also expressed on precursor cells, we assessed the feasibility of incorporating an inducible caspase‐9 (iCasp9) suicide switch to enhance safety of our approach. Upon addition of the chemical dimerizer AP20187 to NK‐92 cells coexpressing the FLT3‐specific CAR and iCasp9, rapid iCasp9 activation was observed, precluding further CAR‐mediated cytotoxicity. Our data demonstrate that B‐ALL can be effectively targeted by FLT3‐specific CAR NK cells which may complement CD19‐directed immunotherapies, particularly in cases of inherent or acquired resistance to the latter.
Chlorinated Natural Products and Related Halogenases
Authors: Zeng Jia , Zhan Jixun
Published: March 2019

Halogenated compounds are well‐known for their diverse bioactivities and wide applications in pharmaceutical industry, chemical engineering and other fields. Novel halometabolites isolated from nature inspire scientists to synthesize these “chance compounds”, which were, however, usually hampered by the extreme catalytic conditions and severe selectivity challenges. In the past several decades, enzymatic reactions have been brought into attention for their efficiency, selectivity, and mild reaction conditions. Synthetic biology which is in compliance with the laws of nature to a large extent shed light on the rational biosynthesis of halogenated compounds. This article summarizes several representative categories of halogenated natural products and halogenases to seek clues to the relationship between the structures and halogenase mechanisms. Some types of halogenase convert the basic building blocks to diverse early intermediates during natural product biosynthetic processes, while others are involved in the late tailoring steps to afford the final structures of halogenated molecules. The broad substrate specificity and strong regioselectivity exhibited in some halogenases are irreplaceable advantages for biosynthesis. In addition, tremendous efforts and encouraging results enable us to engineer the enzymes or techniques to synthesize “unnatural” halogenated natural products. More reaction mechanisms and structural data are expected to be revealed exponentially in this rapid growing realm.
A comparison of song‐lyric and prose self‐instruction procedures for increasing novel skills in children
Authors: Bloom Lorraine B. , Kettering Tracy L. , Walker Diana
Published: March 2019

We compared the effects of the effects of self‐instructions in the form of prose or song lyrics in the acquisition of gross motor tasks in 4 third‐grade children. We taught participants 4 pairs of gross motor tasks, with one task in each pair taught with prose self‐instructions and the other taught with song lyric self‐instructions. Both self‐instruction procedures were effective for teaching tasks; however, acquisition was quicker with song lyric self‐instruction for 4 task pairs, acquisition was quicker with prose self‐instruction for 3 task pairs; and similar for 1 task pair. Participants were then able to select their preferred method of self‐instruction for a novel, applied skill. Two participants selected song‐lyric self‐instructions and 2 participants selected prose self‐instructions.
Rational and irrational use of nonsterile compounded medications
Authors: McBane Sarah E. , Coon Scott A. , Anderson Keri C. , Bertch Karen E. , Cox Mara , Kain Courtney , LaRochelle Joseph , Neumann Deeter R. , Philbrick Ann M.
Published: March 2019

Nonsterile compounding is a fundamental component of pharmacy practice, and compounded medications are sometimes essential to optimize a patient's medication therapy. However, controversies surround the rational use of nonsterile compounded medications. Factors including drug cost and availability and the need for a precise dosage or unique formulation may provide a legitimate reason to prepare a compounded medication. Nonetheless, clinical pharmacists should ensure a rational basis for the use of such preparations. The relative paucity of data surrounding the regulation of these formulations, as well as that surrounding their promotion and production, complicates the evaluation of their safety and efficacy. This is especially true when compounded medications are used in special cases that already lack data for the use of commercially available products. Ethical issues also surround the rational use of these nonsterile compounded medications, including the absence of their proven safety and efficacy, the lack of regulation of promotional practices regarding their use, the pricing associated with them, the strategies needed to obtain third‐party coverage for them, and the limited standards in place for the actual production of compounded medications. Indeed, more evidence documenting the safety and efficacy of compounded medications is needed, together with standardization of formulations and better regulation of promotional practices and qualifications of compounding personnel. ACCP supports increased regulation of compounding to promote the appropriate use of these preparations.
Inhibition of cortical neural networks using infrared laser
Authors: Xia Qingling , Nyberg Tobias
Published: March 2019

The aim of the present study is to optimize parameters for inhibiting neuronal activity safely and investigating thermal inhibition of rat cortex neural networks in vitro by continuous infrared (IR) laser. Rat cortex neurons were cultured on multi‐electrode arrays until neural networks were formed with spontaneous neural activity. Neurons were then irradiated to inhibit the activity of the networks using different powers of 1550 nm IR laser light. A finite element heating model, calibrated by the open glass pipette method, was used to calculate temperature increases at different laser irradiation intensities. A damage signal ratio (DSR) was evaluated to avoid excessive heating that may damage cells. The DSR predicted that cortex neurons should be safe at temperatures up to 49.6°C for 30 seconds, but experiments suggested that cortex neurons should not be exposed to temperatures over 46°C for 30 seconds. Neural response experiments showed that the inhibition of neural activity is temperature dependent. The normal neural activity could be inhibited safely with an inhibition degree up to 80% and induced epileptiform activity could be suppressed. These results show that continuous IR laser radiations provide a possible way to safely inhibit the neural network activity.
Impact of trivalent ions on the stability and cohesion of calcium polyphosphate coacervates for embolization applications
Authors: Valliant Esther Mae , Filiaggi Mark Joseph
Published: March 2019

Polyphosphates (PPs) are of interest as temporary in situ setting embolic agents for which cohesive characteristics are vital. Trivalent ions Al3+ and Ga3+ were substituted into calcium PP up to 10 mol % for two PP chain lengths (degree of polymerization, Dp 200 and 9000) and the effect on the dissolution rate of the resulting coacervate was examined. High levels of trivalent ions were found to increase the dissolution rate, especially with aluminum (Al) where the coacervate with the greatest Al content (10 mol %) and larger Dp completely dissolved within the first few hours in tris(hydroxymethyl)aminomethane buffered saline. Conversely, small amounts of trivalent ions slowed the dissolution rate of the coacervates compared to those containing calcium only. The coacervate compositions determined to have the fastest and slowest ion release were evaluated for cohesion upon injection into a simulated blood vessel using a dual lumen needle. PPs with lower trivalent content had a higher coacervate yield overall, with 5% Ga and Dp 200 yielding the smallest proportion of coacervate particulates that could be implicated in unwanted distal embolization. However, further studies are required to evaluate the formation and duration of occlusions in vivo so that the PP composition can best be tailored to meet clinical requirements. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B:2638–2648, 2019.
Methylation analysis highlights novel prognostic criteria in human‐metastasized melanoma
Authors: Cai Weiyang , Ding Xiaoxia , Li Jingjing , Li Zhiming
Published: March 2019

Melanoma accounts for 90% of the deaths associated with cutaneous neoplasms, and the 5‐year survival rate of patients with the advanced stage is about 20%. Many mechanisms are involved in melanoma progression, but dynamic epigenetic changes are likely to be critical contributors, especially for DNA methylation. However, we know little about the methylation events involved in melanoma lymph node metastasis (LNM), a deficit that is of particular concern because it has a growing incidence and mortality. To identify DNA methylated‐associated changes involved in the formation of metastatic melanoma, we explored the different methylated genes (DMGs) between primary and LNM melanoma by Illumina Human Methylation 450 K BeadArray GSE44661. By integrating DNA methylation and messenger RNA expression data from The Cancer Genome Atlas database, we identified these DNA methylation biomarkers. Pathway analysis highlighted these DMGs, which were closely related to the carcinogenesis of melanoma, such as cell cycle regulation and RNA transcription process. Furthermore, according to the univariate and multivariate Cox regression analysis, we constructed a four‐DMG prognostic signature model, which could precisely predict the outcome of melanoma in a more exact way. In summary, this four‐DMG based risk score model successfully predicts the survival of melanoma. It is independent of other clinical characteristics and is good for prognosis prediction.
Inhibition of tyrosine kinases protects against lipopolysaccharide‐induced acute lung injury by preventing nuclear export of Nrf2
Authors: Duan Jiaxiang , Yang Zhen , Huang Jian , Zhu Yuan , Zhao Hailin , Unwith Sandeep , Gao Xian , Lu Kaizhi , Ning Jiaolin
Published: March 2019

Acute Lung Injury is a common severe pathological condition that is usually caused by lipopolysaccharide (LPS) infection from bacteria. Enhanced activity of nuclear factor erythroid 2–related factor 2 (Nrf2) could attenuate LPS induced lung injury, However, it still remains unknown whether the enhanced activity of Nrf2 via suppression of Nrf2 nucleus export attenuates the LPS induced lung injury. The aim of this study is to investigate the effects of inhibitors of Fyn on the LPS‐induced acute lung injury and to explore its underlying molecular mechanisms. Nrf2 localization in the cells was observed by using confocal microscopy and its transcriptional activation was measured by Electrophoretic Mobility Shift Assay and controlled genes expression levels. The lung injury severity was examined by histopathological scoring and oxidative stress level. In this study, we showed that PP2, LMB, and Nrf2 Y568A abrogated Nrf2 nuclear export and thus enhance the Nrf2 transcriptional activity. PP2 attenuated lung injury and the reduction of cells viability induced by LPS. The current study demonstrated, for the first time, that increase of expression of Nrf2 controlled protective genes via suppression of Nrf2 nucleus export could attenuate lung injury.
Mitigative effects of the bioactive flavonol fisetin on high‐fat/high‐sucrose induced nonalcoholic fatty liver disease in rats
Authors: Gaballah Hanaa H. , El‐Horany Hemat E. , Helal Duaa S.
Published: March 2019

Background

Worldwide growing rates of obesity are correlated with the rising prevalence of nonalcoholic fatty liver disease (NAFLD) with limited available therapeutics.

Aim

The present study was undertaken to investigate the modulatory effects of dietary supplementation fisetin on hepatocyte nuclear factor 4 α (HNF4α) gene expression, hepatic lipin‐1 signaling, thioredoxin‐interacting protein (TXNIP) levels, poly‐(ADP‐ribose)‐polymerase‐1 (PARP‐1) activity, as well as some oxidative stress parameters in a rat model of high‐fat/high‐sucrose (HFHS) induced NAFLD.

Methods

Sixty male albino rats were allocated into four equal groups: normal control group, fisetin‐treated control group, NAFLD group, and fisetin‐treated NAFLD group. Gene expression levels of HNF4‐α were estimated using quantitative real‐time reverse transcription polymerase chain reaction (RT‐PCR), while Lipin‐1, TXNIP levels, and PARP‐1 activity were estimated by enzyme‐linked immunosorbent assay (ELISA); lipid profile, hepatic lipid contents, hepatic lipoperoxides, fatty acid synthase activity, and total antioxidant capacity were also assessed colorimetrically.

Results

Fisetin ameliorated HFHS‐induced NAFLD; where it suppressed hepatic lipid accumulation, upregulated HNF4‐α /lipin‐1 signaling, mitigated oxidative stress, inhibited reactive oxygen species (ROS)‐mediated TXNIP induction, and PARP‐1 activation
. In conclusion, fisetin could confer protection against NAFLD and impede its progression. However,additional experimental scrutiny is needed to verify these findings.
Transcription factor FOXP3: A repressor of the TFPI gene?
Authors: Skretting Grethe , Andersen Elisabeth , Myklebust Christiane F. , Sandset Per Morten , Tinholt Mari , Iversen Nina , Stavik Benedicte
Published: March 2019

Single nucleotide polymorphisms (SNPs) may play an important role in the risk of certain diseases. We have previously shown that the ‐287T/C SNP of the tissue factor pathway inhibitor (TFPI) gene promoter region exerts differential impact on TFPI mRNA expression; the C allele being associated with higher TFPI expression, which in turn is associated with reduced risk of thrombosis. In the present study, we aimed to reveal the underlying molecular mechanisms using human embryonic kidney 293 (HEK293) and Michigan Cancer Foundation‐7 (MCF7) cells that both express TFPI. Transfecting the cells with luciferase reporter gene constructs containing the TFPI promoter with either the T or the C allele of ‐287T/C resulted in increased luciferase activity with the C allele relative to the T allele. Three potential candidate transcription factors for binding to the two ‐287 alleles were predicted using the ALGGEN PROMO software, and results from electrophoretic mobility shift assays indicated that forkhead box protein 3 (FOXP3), initially identified as a functional marker of T regulator cells, bound more specifically to the T allele compared with the C allele. By chromatin immunoprecipitation assays analysis it was confirmed that FOXP3 was able to bind to the DNA region that contains the SNP. Knockdown or overexpression of FOXP3 resulted in increased or decreased TFPI levels, respectively, in both cell types. In conclusion, this study indicates that FOXP3 most likely is involved in the increased levels of TFPI observed with the ‐287C allele and also that FOXP3 might be a repressor for TFPI expression.
Evaluation of global laboratory methods and establishing on‐therapy ranges for monitoring apixaban and rivaroxaban: Experience at a single institution
Authors: Park Soon Ho , Seo Yiel‐Hea , Park Pil‐Whan , Kim Kyung‐Hee , Seo Ja Young , Lee Hwan Tae , Kwoun Woo‐Jae , Ahn Jeong‐Yeal
Published: March 2019

Background

Apixaban and rivaroxaban are approved for the prevention and treatment of deep vein thrombosis (DVT), pulmonary embolism (PE), and embolic stroke in atrial fibrillation (AF) patients. The aim of this study was to find appropriate methods of monitoring the anticoagulant effects of are direct oral anticoagulants (DOACs) and establish on‐therapy ranges using conventional tests.

Methods

A total of 184 samples were collected from 91 patients receiving DOACs. Concentrations of apixaban and rivaroxaban in plasma were accessed by an anti‐factor Xa chromogenic assay. PT, APTT, antithrombin, D‐dimer, dRVVT screen/confirm, FDP, and fibrinogen levels were measured. On‐therapy ranges were calculated by substituting previously reported trough plasma concentrations of DOACs.

Results

Anti‐factor Xa chromogenic assay‐based DOACs levels were 26.0‐279.5 (115.9 ± 56.5) ng/mL for apixaban at 2.5 mg BID, 19.9‐565.1 (205.3 ± 162.4) ng/mL for apixaban at 5 mg BID, 2.3‐395.3 (205.3 ± 162.4) ng/mL for rivaroxaban at 15 mg OD, 3.6‐494.8 (119.6 ± 95.1) ng/mL for rivaroxaban at 20 mg OD, and 9.6‐431.4 (140.8 ± 113.6) ng/mL for rivaroxaban at 15 mg BID. PT (%), antithrombin, and dRVVT confirm tests showed good correlation with plasma apixaban levels. Plasma rivaroxaban concentrations were correlated well with PT (sec), PT (%),and dRVVT confirm results. On‐therapy ranges established for dRVVT confirm test by linear regression were as follows: 1.32‐1.52 for apixaban 2.5 mg BID, 1.12‐1.75 for apixaban 5 mg BID, 1.11‐1.78 for rivaroxaban 15 mg OD, 1.09‐1.64 for rivaroxaban 20 mg OD, and 1.22‐1.81 for rivaroxaban 20 mg BID.

Conclusions

Apixaban concentrations were well correlated with PT (%), antithrombin, and dRVVT confirm test. Rivaroxaban concentrations showed good correlation with PT (sec), PT (%), and dRVVT confirm test.
Comparison of the Pharmacokinetic Properties of Naloxone Following the Use of FDA‐Approved Intranasal and Intramuscular Devices Versus a Common Improvised Nasal Naloxone Device
Authors: Krieter Philip A. , Chiang C. Nora , Gyaw Shwe , McCann David J.
Published: March 2019

For more than a decade, first responders and the general public have been able to treat suspected opioid overdoses using an improvised nasal naloxone device (INND) constructed from a prefilled syringe containing 2 mg of naloxone (1 mg/mL) attached to a mucosal atomization device. In recent years, the U.S. Food and Drug Administration (FDA)–approved Ezvio, an autoinjector that delivers 2 mg by intramuscular injection and Narcan nasal spray (2‐ and 4‐mg strengths; 0.1 mL/dose) for the emergency treatment of a known or suspected opioid overdose. The present study was conducted to compare the pharmacokinetics of naloxone using the FDA‐approved devices (each administered once) and either 1 or 2 administrations using the INND. When naloxone was administered twice using the improvised device, the doses were separated by 2 minutes. The highest maximum plasma concentration was achieved using the 4‐mg FDA‐approved spray. The highest exposures at 5 minutes postdose, based on AUC values, were after administration with the autoinjector and the 4‐mg FDA‐approved spray; at 10, 15, and 20 minutes postdose, the latter yielded the greatest exposure. Even after 2 administrations, the INND failed to achieve naloxone plasma levels comparable to the FDA‐approved devices at any time. The ease of use and higher plasma concentrations achieved using the 4‐mg FDA‐approved spray, compared with the INND, should be considered when deciding which naloxone device to use.