bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intermittent dosing of the transforming growth factor beta receptor 1 inhibitor, BMS‐986260, mitigates class‐based cardiovascular toxicity in dogs but not rats
Authors: Rak Gregory D. , White Melvin R. , Augustine‐Rauch Karen , Newsome Courtni , Graziano Michael J. , Schulze Gene E. 
Published: February 2020

AbstractSmall‐molecule inhibitors of transforming growth factor beta receptor 1 (TGFβRI) have a history of significant class‐based toxicities (eg, cardiac valvulopathy) in preclinical species that have limited their development as new medicines. Nevertheless, some TGFβRI inhibitors have entered into clinical trials using intermittent‐dosing schedules and exposure limits in an attempt to avoid these toxicities. This report describes the toxicity profile of the small‐molecule TGFβRI inhibitor, BMS‐986260, in rats and dogs. Daily oral dosing for 10 days resulted in valvulopathy and/or aortic pathology at systemic exposures that would have been targeted clinically, preventing further development with this dosing schedule. These toxicities were not observed in either species in 1‐month studies using the same doses on an intermittent‐dosing schedule of 3 days on and 4 days off (QDx3 once weekly). Subsequently, 3‐month studies were conducted (QDx3 once weekly), and while there were no cardiovascular findings in dogs, valvulopathy and mortality occurred early in rats. The only difference compared to the 1‐month study was that the rats in the 3‐month study were 2 weeks younger at the start of dosing. Therefore, a follow‐up 1‐month study was conducted to evaluate whether the age of rats influences sensitivity to target‐mediated toxicity. Using the same dosing schedule and similar doses as in the 3‐month study, there was no difference in the toxicity of BMS‐986260 in young (8 weeks) or adult (8 months) rats. In summary, an intermittent‐dosing schedule mitigated target‐based cardiovascular toxicity in dogs but did not prevent valvulopathy in rats, and thus the development of BMS‐986260 was terminated.
Positive role of calcium phosphate ceramics regulated inflammation in the osteogenic differentiation of mesenchymal stem cells
Authors: Wang Jing , Chen Xuening , Yang Xiao , Guo Bo , Li Danyang , Zhu Xiangdong , Zhang Xingdong 
Published: February 2020

AbstractRecently, researches have confirmed the crucial role of inflammatory response in Ca‐P ceramic‐induced osteogenesis, however, the underlying mechanism has not yet been fully understood. In this study, BCP and β‐TCP ceramics were used as material models to investigate the effect of physicochemical properties on inflammatory response in vitro. The results showed that BCP and β‐TCP could support macrophages attachment, proliferation, and spreading favorably, as well as promote gene expressions of inflammatory related cytokines (IL‐1, IL‐6, MCP‐1, and TNF‐α) and growth factors (TGF‐β, FGF, PDGF, VEGF, IGF, and EGF). BCP showed a facilitating function on the gene expressions earlier than β‐TCP. Further coculture experiments performed in vitro demonstrated that the CMs containing various increased cytokines for macrophages pre‐culture could significantly promote MSCs osteogenic differentiation, which was confirmed by the gene expressions of osteogenic specific markers and the intracellular OCN product accumulation under the stimulation of BCP and β‐TCP ceramics. Further evidence was found from the formation of mineralized nodules in BCM and TCM. In addition, this study showed a concise relationship between Ca‐P ceramic induced inflammation and its osteoinductivity that the increased cytokines and growth factors from macrophages could promote MSCs osteogenic differentiation.
Dimethyl fumarate protects thioacetamide‐induced liver damage in rats: Studies on Nrf2, NLRP3, and NF‐κB
Authors: Dwivedi Durgesh K. , Jena Gopabandhu , Kumar Vinod 
Published: February 2020

AbstractThe present study was designed to investigate the hepatoprotective potential of dimethyl fumarate (DMF) against thioacetamide (TAA)‐induced liver damage. Wistar rats were treated with DMF (12.5, 25, and 50 mg/kg/day, orally) and TAA (200 mg/kg intraperitoneally, every third day) for 6 consecutive weeks. TAA exposure significantly reduced body weight, increased liver weight and index, and intervention with DMF did not ameliorate these parameters. DMF treatment significantly restored TAA‐induced increase in the levels of aspartate aminotransferase, alanine aminotransferase, γ‐glutamyl transferase, total bilirubin, uric acid, malondialdehyde, reduced glutathione, and histopathological findings such as inflammatory cell infiltration, deposition of collagen, necrosis, and bridging fibrosis. DMF treatment significantly ameliorated TAA‐induced hepatic stellate cell activation, increase in inflammatory cascade markers (NACHT, LRR, and PYD domains‐containing protein 3; NLRP3, apoptosis‐associated speck like protein containing a caspase recruitment domain; ASC, caspase‐1, nuclear factor‐kappa B; NF‐κB, interleukin‐6), fibrogenic makers (α‐smooth muscle actin; ɑ‐SMA, transforming growth factor; TGF‐β1, fibronectin, collagen 1) and antioxidant markers (nuclear factor (erythroid‐derived 2)‐like factor 2; Nrf2, superoxide dismutase‐1; SOD‐1, catalase). The present findings concluded that DMF protects against TAA‐induced hepatic damage mediated through the downregulation of inflammatory cascades and upregulation of antioxidant status.
Serum exosomal miR‐378 upregulation is associated with poor prognosis in non–small‐cell lung cancer patients
Authors: Zhang Yan , Xu Hongjie 
Published: February 2020

AbstractBackgroundDeregulated circulating microRNAs (miRNAs) are potential biomarkers for the early detection and prognosis prediction of non–small‐cell lung cancer (NSCLC). The aim of the present study was to investigate the expression pattern of serum exosomal miR‐378 in NSCLC and its correlation with clinical variables.MethodsQuantitative reverse transcription‐polymerase chain reaction (qRT‐PCR) was performed to detect serum exosomal miR‐378 levels in 103 patients with NSCLC and 60 control subjects.ResultsOur results showed that serum exosomal miR‐378 was significantly overexpressed in NSCLC patients, and serum exosomal miR‐378 upregulation was clearly associated with positive lymph node metastasis and advanced TNM stage. In addition, receiver operating characteristic (ROC) analysis demonstrated that combination of serum exosomal miR‐378 expression and carcinoembryonic antigen (CEA) had a high discriminating power to differentiate NSCLC subjects from controls. Moreover, serum exosomal miR‐378 levels in 73 NSCLC cases were significantly decreased after radiotherapy and could be used as an indicator of radiotherapeutic response in NSCLC. Furthermore, survival analyses revealed that patients with higher serum exosomal miR‐378 expression had poor overall survival. Multivariate analysis showed that serum exosomal miR‐378 expression was independently associated with overall survival.ConclusionsCollectively, serum exosomal miR‐378 has strong potential as a promising non‐invasive biomarker for screening and monitoring NSCLC.
Brain abnormalities on neuroimaging in Children with Congenital Zika Syndrome in Salvador, Brazil, and its possible implications on neuropsychological development
Authors: Sanders Pereira Pinto Paula , de Almeida Thalita Madeira , Monteiro Lucas , Souza Mirela Maisa da Silva , Alves dos Santos George Anderson , Cardoso Cristiane Wanderley , dos Santos Letícia Marques , Ribeiro Guilherme Sousa , dos Santos Darci Neves 
Published: February 2020

AbstractObjectiveTo characterize the spectrum of brain damages presented in children affected by Congenital Zika Syndrome (CZS), verify the existence of a co‐occurrence pattern of these damages and discuss possible implications for the neuropsychological development.MethodsDescriptive, quantitative, individualized, and cross‐sectional study using secondary sources. We selected 136 children with CZS from the database of the Center of Strategic Information on Health Vigilance of the Municipal Office of Salvador, Brazil. We conducted descriptive and multiple correspondence analyses.ResultsAmong the set of analyzed variables, microcephaly (51.5%), ventriculomegaly (57.4%), and brain calcifications (77.2%) were identified as the most frequent. The multiple correspondence analysis showed that the combination of these three variables (32.4%) was what better represented the spectrum of brain damages in the Central Nervous System.InterpretationDamage in the sensory‐motor, cognitive and language development, as well as neurodevelopmental disorders, are described in the literature as impairments associated, either isolated or combined, with these damages, and it is worth highlighting that, in combined brain damages, impairments tend to be more severe. The findings of this study may contribute to understanding the repercussions of CZS on the neuropsychological development of children affected by the epidemic.
Structure‐guided screening of chemical database to identify NS3‐NS2B inhibitors for effective therapeutic application in dengue infection
Authors: Bhowmick Shovonlal , Alissa Siham A. , Wabaidur Saikh Mohammad , Chikhale Rupesh V. , Islam Md Ataul 
Published: February 2020

AbstractDengue infection is the most common arthropod‐borne disease caused by dengue viruses, predominantly affecting millions of human beings annually. To find out promising chemical entities for therapeutic application in Dengue, in the current research, a multi‐step virtual screening effort was conceived to screen out the entire “screening library” of the Asinex database. Initially, through “Lipinski rule of five” filtration criterion almost 0.6 million compounds were collected and docked with NS3‐NS2B protein. Thereby, the chemical space was reduced to about 3500 compounds through the analysis of binding affinity obtained from molecular docking study in AutoDock Vina. Further, the “Virtual Screening Workflow” (VSW) utility of Schrödinger suite was used, which follows a stepwise multiple docking programs such as ‐ high‐throughput virtual screening (HTVS), standard precision (SP), and extra precision (XP) docking, and in postprocessing analysis the MM‐GBSA based free binding energy calculation. Finally, five potent molecules were proposed as potential inhibitors for the dengue NS3‐NS2B protein based on the investigation of molecular interactions map and protein‐ligand fingerprint analyses. Different pharmacokinetics and drug‐likeness parameters were also checked, which favour the potentiality of selected molecules for being drug‐like candidates. The molecular dynamics (MD) simulation analyses of protein‐ligand complexes were explained that NS3‐NS2B bound with proposed molecules quite stable in dynamic states as observed from the root means square deviation (RMSD) and root means square fluctuation (RMSF) parameters. The binding free energy was calculated using MM‐GBSA method from the MD simulation trajectories revealed that all proposed molecules possess such a strong binding affinity towards the dengue NS3‐NS2B protein. Therefore, proposed molecules may be potential chemical components for effective inhibition of dengue NS3‐NS2B protein subjected to experimental validation.
Hypoxic‐ischemic‐related cerebrovascular changes and potential therapeutic strategies in the neonatal brain
Authors: Disdier Clémence , Stonestreet Barbara S. 
Published: February 2020

AbstractPerinatal hypoxic‐ischemic (HI)‐related brain injury is an important cause of morbidity and long‐standing disability in newborns. The only currently approved therapeutic strategy available to reduce brain injury in the newborn is hypothermia. Therapeutic hypothermia can only be used to treat HI encephalopathy in full‐term infants and survivors remain at high risk for a wide spectrum of neurodevelopmental abnormalities as a result of residual brain injury. Therefore, there is an urgent need for adjunctive therapeutic strategies. Inflammation and neurovascular damage are important factors that contribute to the pathophysiology of HI‐related brain injury and represent exciting potential targets for therapeutic intervention. In this review, we address the role of each component of the neurovascular unit (NVU) in the pathophysiology of HI‐related injury in the neonatal brain. Disruption of the blood–brain barrier (BBB) observed in the early hours after an HI‐related event is associated with a response at the basal lamina level, which comprises astrocytes, pericytes, and immune cells, all of which could affect BBB function to further exacerbate parenchymal injury. Future research is required to determine potential drugs that could prevent or attenuate neurovascular damage and/or augment repair. However, some studies have reported beneficial effects of hypothermia, erythropoietin, stem cell therapy, anti‐cytokine therapy and metformin in ameliorating several different facets of damage to the NVU after HI‐related brain injury in the perinatal period.
A Long‐Living Bioengineered Neural Tissue Platform to Study Neurodegeneration
Authors: Rouleau Nicolas , Cantley William L. , Liaudanskaya Volha , Berk Alexander , Du Chuang , Rusk William , Peirent Emily , Koester Cole , Nieland Thomas J. F. , Kaplan David L. 
Published: February 2020

AbstractThe prevalence of dementia and other neurodegenerative diseases continues to rise as age demographics in the population shift, inspiring the development of long‐term tissue culture systems with which to study chronic brain disease. Here, it is investigated whether a 3D bioengineered neural tissue model derived from human induced pluripotent stem cells (hiPSCs) can remain stable and functional for multiple years in culture. Silk‐based scaffolds are seeded with neurons and glial cells derived from hiPSCs supplied by human donors who are either healthy or have been diagnosed with Alzheimer's disease. Cell retention and markers of stress remain stable for over 2 years. Diseased samples display decreased spontaneous electrical activity and a subset displays sporadic‐like indicators of increased pathological β‐amyloid and tau markers characteristic of Alzheimer's disease with concomitant increases in oxidative stress. It can be concluded that the long‐term stability of the platform is suited to study chronic brain disease including neurodegeneration.
Medicinal chemistry strategies toward host targeting antiviral agents
Authors: Ji Xingyue , Li Zhuorong 
Published: February 2020

AbstractDirect‐acting antiviral agents (DAAs) represent a class of drugs targeting viral proteins and have been demonstrated to be very successful in combating viral infections in clinic. However, DAAs suffer from several inherent limitations, including narrow‐spectrum antiviral profiles and liability to drug resistance, and hence there are still unmet needs in the treatment of viral infections. In comparison, host targeting antivirals (HTAs) target host factors for antiviral treatment. Since host proteins are probably broadly required for various viral infections, HTAs are not only perceived, but also demonstrated to exhibit broad‐spectrum antiviral activities. In addition, host proteins are not under the genetic control of viral genome, and hence HTAs possess much higher genetic barrier to drug resistance as compared with DAAs. In recent years, much progress has been made to the development of HTAs with the approval of chemokine receptor type 5 antagonist maraviroc for human immunodeficiency virus treatment and more in the pipeline for other viral infections. In this review, we summarize various host proteins as antiviral targets from a medicinal chemistry prospective. Challenges and issues associated with HTAs are also discussed.
LncRNA XIST modulates HIF‐1A/AXL signaling pathway by inhibiting miR‐93‐5p in colorectal cancer
Authors: Yang Li‐guang , Cao Ming‐zheng , Zhang Jie , Li Xiao‐yan , Sun Qin‐li 
Published: February 2020

AbstractBackgroundLong noncoding RNA (LncRNA) XIST is one of the genes that exists in different types of cancers. Earlier researches showed that XIST can advance the progression of colorectal cancer. Nevertheless, the potential molecular mechanism of XIST in combination with miR‐93‐5p has not been explored in colorectal cancer.MethodsWe performed qRT‐PCR to explore the level of XIST. And a serious experiments in vitro and in vivo were performed to explore the function of XIST. The relationship between XIST/HIF‐1A and miR‐93‐5p was confirmed by RIP and dual‐luciferase assays.ResultsIn the present research, our team demonstrated the upregulation of XIST expression, which was related to tumor progression, and the downregulation of miR‐93‐5p in cells and tissues of colorectal cancer. XIST is the competitive endogenous RNA of miR‐93‐5p to promote HIF‐1A, and then the upregulated AXL level facilitates the EMT process, migration, and proliferation of colorectal cancer. At last, we proved that XIST enhanced the in vivo and in vitro activities of colorectal cancer by regulating AXL signaling.ConclusionIn summary, the above results indicate that XIST promotes colorectal cancer tumorigenesis by regulating miR‐93‐5p/HIF‐1A/AXL signaling pathway, which will supply a novel perspective to diagnose and treat colorectal cancer disease.
A T‐junction power divider with tunable operating frequency and dividing ratio
Authors: Li Wentao , Chai Xuejing , Ye Xiutiao , Shi Xiaowei 
Published: February 2020

AbstractThis letter presents a T‐junction power divider (PD) with both tunable operating frequency and dividing ratio, simultaneously. The proposed design consists of two adjustable 90° phase shifters and a pair of shunt stubs loaded with two varactor diodes. The operating frequency can be tuned by controlling the varactor diodes loaded onto the 90° phase shifters. In addition, the tunable shunt stubs comprised of a short circuited and an open circuited stubs loaded with varactor diodes are employed to realize impedance matching and different dividing ratios at accurate operating frequencies. For verification, a prototype of the proposed PD with dimensions of 25.9 mm × 50 mm is designed, fabricated, and measured. The measured results show that the operating frequency can be tuned from 1 to 1.55 GHz, while the power dividing ratio can be tuned from 2:1 to 20:1. Good agreement between the simulation and measurement results is observed.
Qualitative and quantitative 1H NMR spectroscopy for determination of divalent metal cation concentration in model salt solutions, food supplements, and pharmaceutical products by using EDTA as chelating agent
Authors: Hafer Elina , Holzgrabe Ulrike , Kraus Katharina , Adams Kristie , Hook James M. , Diehl Bernd 
Published: February 2020

AbstractThis paper introduces an 1H NMR method to identify individual divalent metal cations Be2+, Mg2+, Ca2+, Sr2+, Zn2+, Cd2+, Hg2+, Sn2+, and Pb2+ in aqueous salt solutions through their unique signal shift and coupling after complexation with the salt of ethylenediaminetetraacetic acid (EDTA). Furthermore, quantitative determination applied for the divalent metal cations Ca2+, Mg2+, Hg2+, Sn2+, Pb2+, and Zn2+ (limit of quantification: 5–22 μg/ml) can be achieved using an excess of EDTA with aqueous model salt solutions. An internal standard is not required because a known excess of EDTA is added and the remaining free EDTA can be used to recalculate the quantity of chelated metal cations. The utility of the method is demonstrated for the analysis of divalent cations in some food supplements and in pharmaceutical products.
MR spectroscopy using static higher order shimming with dynamic linear terms (HOS‐DLT) for improved water suppression, interleaved MRS‐fMRI, and navigator‐based motion correction at 7T
Authors: Boer Vincent O. , Andersen Mads , Lind Anna , Lee Nam Gyun , Marsman Anouk , Petersen Esben T. 
Published: February 2020

PurposeTo interleave global and local higher order shimming for single voxel MRS. Single voxel MR spectroscopy requires optimization of the B0 field homogeneity in the region of the voxel to obtain a narrow linewidth and provide high data quality. However, the optimization of local higher order fields on a localized MRS voxel typically leads to large field offsets outside that volume. This compromises interleaved MR sequence elements that benefit from global field homogeneity such as water suppression, interleaved MRS‐fMRI, and MR motion correction.MethodsA shimming algorithm was developed to optimize the MRS voxel homogeneity and the whole brain homogeneity for interleaved sequence elements, using static higher order shims and dynamic linear terms (HOS‐DLT). Shimming performance was evaluated using 6 brain regions and 10 subjects. Furthermore, the benefits of HOS‐DLT was demonstrated for water suppression, MRS‐fMRI, and motion corrected MRS using fat‐navigators.ResultsThe HOS‐DLT algorithm was shown to improve the whole brain homogeneity compared to an MRS voxel‐based shim, without compromising the MRS voxel homogeneity. Improved water suppression over the brain, reduced image distortions in MRS‐fMRI, and improved quality of motion navigators were demonstrated using the HOS‐DLT method.ConclusionHOS‐DLT shimming allowed for both local and global field homogeneity, providing excellent MR spectroscopy data quality, as well as good field homogeneity for interleaved sequence elements, even without the need for dynamic higher order shimming capabilities.
Improved autoregressive model for correction of noise serial correlation in fast fMRI
Authors: Luo Qingfei , Misaki Masaya , Mulyana Ben , Wong Chung‐Ki , Bodurka Jerzy 
Published: February 2020

PurposeIn rapidly acquired functional MRI (fast fMRI) data, the noise serial correlations (SC) can produce problematically overestimated T‐statistics which lead to invalid statistical inferences. This study aims to evaluate and improve the accuracy of high‐order autoregressive model (AR(p), where p is the model order) based prewhitening method in the SC correction.MethodsFast fMRI images were acquired at rest (null data) using a multiband simultaneous multi‐slice echo planar imaging pulse sequence with repetition time (TR) = 300 and 500 ms. The SC effect in the fast fMRI data was corrected using the prewhitening method based on two AR(p) models: (1) the conventional model (fixed AR(p)) which preselects a constant p for all the image voxels; (2) an improved model (ARAICc) that employs the corrected Akaike information criterion voxel‐wise to automatically select the model orders for each voxel. To evaluate accuracy of SC correction, false positive characteristics were measured by assuming the presence of block and event‐related tasks in the null data without image smoothing. The performance of prewhitening was also examined in smoothed images by adding pseudo task fMRI signals into the null data and comparing the detected to simulated activations (ground truth).ResultsThe measured false positive characteristics agreed well with the theoretical curve when using the ARAICc, and the activation maps in the smoothed data matched the ground truth. The ARAICc showed improved performance than the fixed AR(p) method.ConclusionThe ARAICc can effectively remove noise SC, and accurate statistical analysis results can be obtained with the ARAICc correction in fast fMRI.