bluuebunny/crossref_metadata_2025_split huggingface dataset:
Binding and uptake of single and dual‐opsonized targets by macrophages
Authors: Naik Urja , Nguyen Quynh Phuong Hai , Harrison Rene E. 
Published: June 2019

AbstractOur current understanding of phagocytosis is largely derived from studies of individual receptor‐ligand interactions and their downstream signaling pathways. Because phagocytes are exposed to a variety of ligands on heterogeneous target particles in vivo, it is important to observe the engagement of multiple receptors simultaneously and the triggered involvement of downstream signaling pathways. Potential crosstalk between the two well‐characterized opsonic receptors, FcγR and CR3, was briefly explored in the early 1970s, where macrophages were challenged with dual‐opsonized targets. However, subsequent studies on receptor crosstalk were primarily restricted to using single opsonins on different targets, typically at saturating opsonin conditions. Beyond validating these initial explorations on receptor crosstalk, we identify the early signaling mechanisms that underlie the binding and phagocytosis during the simultaneous activation of both opsonic receptors, through the presence of a dual‐opsonized target (immunoglobulin G [IgG] and C3bi), compared with single receptor activation. For this purpose, we used signaling protein inhibitor studies as well as live cell brightfield and fluorescent imaging to fully understand the role of tyrosine kinases, F‐actin dynamics and internalization kinetics for FcγR and CR3. Importantly, opsonic receptors were studied together and in isolation, in the context of sparsely opsonized targets. We observed enhanced particle binding and a synergistic effect on particle internalization during the simultaneous activation of FcγR and CR3 engaged with sparsely opsonized targets. Inhibition of early signaling and cytoskeletal molecules revealed a differential involvement of Src kinase for FcγR‐ vs CR3‐ and dual receptor‐mediated phagocytosis. Src activity recruits Syk kinase and we observed intermediate levels of Syk phosphorylation in dual‐opsonized particles compared with those opsonized with IgG or C3bi alone. These results likely explain the intermediate levels of F‐actin that is recruited to sites of dual‐opsonized particle uptake and the notoriously delayed internalization of C3bi‐opsonized targets by macrophages.
Brain‐derived neurotrophic factor downregulation in gastric cancer
Authors: Esfandi Farbod , Bouraghi Hamid , Glassy Mark C , Taheri Mohammad , Kahaei Mir Salar , Kholghi Oskooei Vahid , Ghafouri‐Fard Soudeh 
Published: June 2019

AbstractThe brain‐derived neurotrophic factor (BDNF) is a certain type of growth factor that participates in the correct construction of the brain. Moreover, some reports have shown its participation in the tumorigenesis process. A long noncoding RNA known as BDNF‐antisense (BDNF‐AS) is shown to be transcribed from the antisense direction of the BDNF gene and control its expression. In the current study, we compared expression levels of BDNF and its antisense in gastric cancer tissues and adjacent noncancerous tissues (ANCTs) using quantitative real‐time polymerase chain reaction. Expression of both genes tended to decrease in gastric cancer tissues in comparison with ANCTs (expression ratio = 0.4 and P = .06 for BDNF; expression ratio = 0.35 and P = .05 for BDNF‐AS, respectively). Relative transcript levels of both genes were remarkably associated with the site of primary tumor in a way that all cardia tumors had low levels of both BDNF and BDNF‐AS in comparison with their paired ANCTs (P = .002 and P = <.001). We also found higher amounts of both genes in malignant samples obtained from older patients (P = .01 and P = .03 for BDNF and BDNF‐AS, respectively). Besides, BDNF expression was higher in tumors with lymphatic/vascular invasion (P = .01). There was also a trend toward upregulation of BDNF‐AS in tumors with lymphatic/vascular invasion (P = .05). The current study underscores the role of BDNF and BDNF‐AS in the pathogenic process leading to gastric cancer.
Cell‐penetrable nanobodies (transbodies) that inhibit the tyrosine kinase activity of EGFR leading to the impediment of human lung adenocarcinoma cell motility and survival
Authors: Tabtimmai Lueacha , Suphakun Praphasri , Srisook Pimonwan , Kiriwan Duangnapa , Phanthong Siratcha , Kiatwuthinon Pichamon , Chaicumpa Wanpen , Choowongkomon Kiattawee 
Published: June 2019

AbstractMost patients suffering from non–small cell lung cancer (NSCLC) have epidermal growth factor receptor (EGFR) overexpression. Currently, EGFR tyrosine kinase inhibitors (TKIs) that act as the ATP‐analogs and monoclonal antibodies (MAbs) to EGFR‐ectodomain that block intracellular signaling are used for the treatment of advanced NSCLC. Unfortunately, adverse effects due to the TKI off‐target and drug resistance occur in a significant number of the treated patients while some NSCLC genotypes do not respond to the therapeutic MAbs. Thus, a more effective remedy for the treatment of EGFR‐overexpressed cancers is deemed necessary. In this study, VH/VHH displayed‐phage clones that are bound to recombinant EGFR‐TK were fished‐out from a humanized‐camel VH/VHH phage display library. VH/VHH of three phage‐infected Escherichia coli clones (VH18, VHH35, and VH36) were linked molecularly to nonaarginine (R9) for making them cell penetrable. R9‐VH18, R9‐VHH35, and R9‐VH36 were cytotoxic to human adenocarcinomic alveolar basal epithelial cells (A549) at the fifty percent inhibitory concentration (IC50) 0.181 ± 0.132, 0.00961 ± 0.00516, and 0.00996 ± 0.00752 μM, respectively, which were approximately 1000‐fold more effective than small molecular TKIs. R9‐VH18 and R9‐VH36 also delayed cancer cell migration in a scratch‐wound assay. Computerized homology modeling and intermolecular docking revealed that VH18 and VHH35 used CDR3 to interact with EGFR‐TK residues close to the catalytic site, which might sterically hinder the ATP‐binding of the TK; VH36 used CDR2 to bind at the asymmetric dimerization surface, which might disrupt EGFR dimerization leading to inhibition of intracellular signaling. The humanized‐cell penetrable nanobodies have a high potential for developing further towards a clinical application.
Stimulating DDX3 expression by serotonin 5‐HT receptor 7 through phosphorylation of p53 via the AC‐PKA‐ERK signaling pathway
Authors: Kang Li‐Jung , Nguyen Khoa V.A. , Eom Sanung , Choi Yeo‐Jin , Nguyen Cam Ngoc , Lee Jaeeun , Kim Chaelin , Lee Shinhui , Lee Seong‐Gene , Lee Jun‐Ho 
Published: June 2019

AbstractDDX3 is a host viral factor that can inhibit the hepatitis B virus‐induced innate immune responses. In this study, the 20 bioactive compounds have screened the effects on DDX3 and we found that 5‐HT upregulated DDX3 promoter activity via the 5‐HT7 receptor on liver hepatocellular cells (HepG2 cells) by using a luciferase assay, reverse transcription‐polymerase chain reaction analysis, and Western blot analysis. Furthermore, we are trying to elucidate the pathways involved in the stimulating effect of 5‐HT on DDX3 expression to induce innate immune responses against hepatitis B virus infection. A knockdown of the 5‐HT7 receptor by transfection si‐5‐HT7 receptors or si‐control into HepG2 cells treated by 5‐HT (or 5‐HT plus agonist) confirmed the role of the 5‐HT7 receptor in DDX3 expression. The IFN‐β‐Luc expression and level of hepatitis B virus surface Antigen (HBsAg) showed that DDX3 mediated by the 5‐HT7 agonist (AS‐19) increased IFN‐β expression and inhibited HBV replication. Luciferase assays showed the involvement of 5‐HT7 receptors in DDX3 expression via cAMP/AC/PKA pathways by using protein kinase A (PKA) and adenylyl cyclase inhibitor (MDL 12330A). AS‐19 mediated DDX3 promoter activated PKA extracellular signal‐regulated kinase ERK signaling the p53 phosphorylation (‐1080/‐1070) resulted in upregulation of DDX3 promoter transactivation via the 5‐HT7 receptors agonist. Overall, 5‐HT7 was found to be a new potential target to inhibit hepatitis B infection by activating AC/PKA/ERK pathways by phosphorylating p53 via the 5‐HT7 agonist response by mediating DDX3 expression.
Vitamin D receptor gene polymorphism is associated with multiple myeloma
Authors: Rui Hongbing , Liu Ying , Lin Meiying , Zheng Xiaoqiang 
Published: June 2019

AbstractObjectivesThe aim of this study was to explore the Vitamin D receptor (VDR) gene polymorphism and its association with multiple myeloma (MM) development.MethodsThe peripheral blood of 40 MM cases and 84 healthy controls were collected. Polymerase chain reaction (PCR) and DNA sequencing were applied to detect VDR gene polymorphism (including: FokI, BsmI, ApaI, and TaqI). SHESIS biological information software was used to analyze genotypes, alleles, linkage disequilibrium (LD), haplotype distribution, and their association with MM.ResultsCompared with controls, the MM group had a significantly higher frequency of the A allele in BsmI site (8.7% vs 2.4%) and C allele in the TaqI site (10.5% vs 3.6%). These two alleles were closely associated with an increased risk of MM (P = .025; P = .030). The highly rare genotypes (BsmI‐AA and TaqI‐CC) were found in one patient with MM.ConclusionVDR gene polymorphisms may be a molecular marker of MM risk.
NEAT1 promotes colon cancer progression through sponging miR‐495‐3p and activating CDK6 in vitro and in vivo
Authors: He Zhiyun , Dang Jie , Song Ailin , Cui Xiang , Ma Zhijun , Zhang Zhongtao 
Published: June 2019

AbstractRecently, increasing evidence has indicated lncRNAs are powerful regulators in the progression of multiple tumors. Dysregulation of lncRNA NEAT1 has been recognized in many cancer types. Meanwhile, the studies on NEAT1 function have suggested that NEAT1 can serve as a crucial oncogene. Nevertheless, the investigation of NEAT1 in colon cancer is still few. In our study, the function of NEAT1 was studied in colon cancer. As we observed, NEAT1 level was obviously elevated in colon cancer cells. Then, HCT‐116 and SW620 cells were stably infected with shRNA‐NEAT1 for 48 hr. As exhibited, silence of NEAT1 could greatly repress colon cancer cell progression. Apoptosis of colon cancer cells was triggered and the cell cycle progression was remarkably inhibited by downregulation of NEAT1. Interestingly, as exhibited, miR‐495‐3p was obviously decreased in colon cancer cells and it significantly suppressed colon cancer progression. Subsequently, miR‐495‐3p was predicted as a target of NEAT1. CDK6 was speculated as the target of miR‐495‐3p and miR‐495‐3p modulated its expression negatively. Finally, it was indicated that NEAT1 promoted colon cancer development through modulating miR‐495‐3p and CDK6 in vivo. Taken these together, we reported that NEAT1 could sponge miR‐495‐3p to contribute to colon cancer progression through activating CDK6.
Zinc ions increase GH signaling ability through regulation of available plasma membrane‐localized GHR
Authors: Li Ruonan , Hui Junnan , Luo Gan , Hong Pan , Li Lingqian , Yang Yu , Zheng Xin , Lan Hainan 
Published: June 2019

AbstractIt is well known that zinc ion (Zn2+) can regulate the biological activity of growth hormone (GH). However, until now, the mechanism by which Zn2+ regulates GH biological activity remains unclear. In the current study, we first performed molecular docking between Zn2+ and porcine GH (pGH) using computational biology. We then explored the effect of Zn2+ on the GH signaling ability in the cell model expressing porcine growth hormone receptor (GHR). It was found that the phosphorylation levels of Janus kinase 2, signal transducers and activators of transcription 5/3/1, and GHR increased significantly under Zn2+ treatment, indicating that Zn2+ can enhance the signaling ability of GH/GHR. On this basis, we further explored how Zn2+ regulates the biological activity of GH/GHR. The results showed that downregulation and turnover of GHR changed under Zn2+/pGH treatment. Zn2+ enhanced the membrane residence time of pGH/GHR and delayed GHR downregulation. Further investigation showed that the internalization dynamic of pGH/GHR was changed by Zn2+, which prolonged the residence time of pGH/GHR in the cell membrane. These factors acted together to upregulate the signaling of GH/GHR. This study lays a foundation for further exploration of the biological effects of Zn2+ on GH.
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Retracted: Long noncoding RNA BCAR4 promotes glioma cell proliferation via EGFR/PI3K/AKT signaling pathway
Authors: Wei Lian , Yi Zhao , Guo Kongyan , Long Xu 
Published: June 2019

AbstractLong noncoding RNA Breast Cancer Antiestrogen Resistance 4 (BCAR4) has been identified to be oncogenic in several cancers. In our study, we demonstrated that BCAR4 expression was significantly upregulated in glioma tissues compared with paired nontumor tissues. In addition, higher BCAR4 level was associated with poor overall survival in patients with glioma. Besides, we also discovered that knockdown of BCAR4 inhibited cell proliferation, whereas BCAR4 overexpression promoted this process. Intriguingly, we proved a cellular transformation of normal human astrocyte cells (NHAs) in response to enforced expression of BCAR4. In addition, we revealed that BCAR4 affected cell proliferation in glioma cells by promoting cell cycle progression and inhibiting cell apoptosis. Mechanistically, we uncovered that BCAR4 activated PI3K/AKT signaling pathway in glioma through upregulating EGFR and interacting with it. Moreover, activating PI3K/AKT pathway could reverse the repressive effects caused by BCAR4 silence on the biological behaviors of glioma cells, whereas inhibition of this pathway rescued the impact of BACR4 upregulation in NHAs. These findings disclosed that BCAR4 contributes to glioma progression by enhancing cell growth via activating EGFR/PI3K/AKT pathway, providing potent evidence that BCAR4 could be an effective new target for treatment and prognosis of glioma patients.
Drug‐Drug Interaction Study to Assess the Effect of Cytochrome P450 Inhibition and Induction on the Pharmacokinetics of the Novel Cereblon Modulator Avadomide (CC‐122) in Healthy Adult Subjects
Authors: Ogasawara Ken , MacGorman Kimberly , Liu Liangang , Chen Jian , Carayannopoulos Leonidas N. , Zhou Simon , Palmisano Maria , Li Yan 
Published: June 2019

AbstractAvadomide (CC‐122) is a novel immunomodulatory drug that binds to cereblon, a member of the Cullin 4‐RING E3 ubiquitin ligase complex. Avadomide has multiple pharmacologic activities including potent immune modulation, antiangiogenic, antitumor, and antiproliferative activity and is being evaluated as an oncology treatment for hematologic malignancies and advanced solid tumors. In vitro study has indicated that cytochrome P450 (CYP) 3A and CYP1A2 appear to be the major enzymes involved in the oxidative metabolism of avadomide. The effects of CYP3A inhibition/induction and CYP1A2 inhibition on the pharmacokinetics of avadomide in healthy adult subjects were assessed in 3 parts of an open‐label, nonrandomized, 2‐period, single‐sequence crossover study. Following a single oral dose of 3 mg, avadomide exposure when coadministered with the CYP1A2 inhibitor fluvoxamine was 154.81% and 107.59% of that when administered alone, for area under the plasma concentration‐time curve from time 0 to infinity (AUC0‐inf) and maximum observed plasma concentration (Cmax), respectively. Avadomide exposures, when coadministered with the CYP3A inhibitor itraconazole, were 100.0% and 93.64% of that when administered alone, for AUC0‐inf and Cmax, respectively. Avadomide exposures when coadministered with the CYP3A inducer rifampin were 62.83% and 88.17% of that when administered alone, for AUC0‐inf and Cmax, respectively. Avadomide was well tolerated when administered as a single oral dose of 3 mg alone or coadministered with fluvoxamine, itraconazole, or rifampin. These results should serve as the basis for avadomide dose recommendations when it is coadministered with strong CYP3A and CYP1A2 inhibitors and with rifampin.
Soluble adenylyl cyclase‐mediated cAMP signaling and the putative role of PKA and EPAC in cerebral mitochondrial function
Authors: Jakobsen Emil , Lange Sofie C. , Bak Lasse K. 
Published: June 2019

AbstractMitochondria produce the bulk of the ATP in most cells, including brain cells. Regulating this complex machinery to match the energetic needs of the cell is a complicated process that we have yet to understand in its entirety. In this context, 3′,5′‐cyclic AMP (cAMP) has been suggested to play a seminal role in signaling‐metabolism coupling and regulation of mitochondrial ATP production. In cells, cAMP signals may affect mitochondria from the cytosolic side but more recently, a cAMP signal produced within the matrix of mitochondria by soluble adenylyl cyclase (sAC) has been suggested to regulate respiration and thus ATP production. However, little is known about these processes in brain mitochondria, and the effectors of the cAMP signal generated within the matrix are not completely clear since both protein kinase A (PKA) and exchange protein activated by cAMP 1 (EPAC1) have been suggested to be involved. Here, we review the current knowledge and relate it to brain mitochondria. Further, based on measurements of respiration, membrane potential, and ATP production in isolated mouse brain cortical mitochondria we show that inhibitors of sAC, PKA, or EPAC affect mitochondrial function in distinct ways. In conclusion, we suggest that brain mitochondria do regulate their function via sAC‐mediated cAMP signals and that both PKA and EPAC could be involved downstream of sAC. Finally, due to the role of faulty mitochondrial function in a range of neurological diseases, we expect that the function of sAC‐cAMP‐PKA/EPAC signaling in brain mitochondria will likely attract further attention.
Association of PROtein and CAloric Intake and Clinical Outcomes in Adult SEPTic and Non‐Septic ICU Patients on Prolonged Mechanical Ventilation: The PROCASEPT Retrospective Study
Authors: de Koning Marie‐Sophie Louise Yvonne , Koekkoek Wilhelmina Aria Christina (Kristine) , Kars Johannes Cornelis Nicolaas (Hans) , van Zanten Arthur Raymond Hubert 
Published: June 2019

AbstractBackgroundThe optimal nutritional support for critically ill septic patients remains unknown. This study evaluates the associations of macronutrient intake during the first week of intensive care unit (ICU) admission and long‐term clinical outcomes in septic and non‐septic patients.MethodsProlonged mechanically ventilated patients were retrospectively studied. The association of protein (low: <0.8 g/kg/d, medium: 0.8–1.2 g/kg/d, high >1.2 g/kg/d) and energy intake (<80%, 80%–110%, 110% of target) during days 1–3 and 4–7 after ICU admission and 6‐month mortality was analyzed for septic and non‐septic patients separately.ResultsA total of 423 patients were investigated. Of these, 297 had sepsis. In the sepsis group, medium protein
intake at days 4–7 was associated with lower 6‐month mortality (hazard ratio [HR]: 0.646, 95% confidence interval [CI]: 0.418‐0.996, P=0.048) compared with high intake. In the non‐sepsis group, early high and late low protein intake were associated with higher 6‐month mortality (HR: 3.902, 95% CI: 1.505‐10.115, P=0.005; HR: 2.642, 95% CI: 1.128‐6.189, P=0.025) compared with low and high protein intake, respectively. For energy intake, late energy intake of >110% was associated with decreased mortality in septic patients (HR: 0.400, 95% CI: 0.222‐0.721, P=0.002), whereas in non‐septic patients, late medium energy intake (80%–110%) was associated with better survival (HR: 0.379, 95% CI: 0.175‐0.820, P=0.014), both compared with low energy intake.ConclusionDivergent associations of macronutrient intake were found; early high protein intake in non‐septic patients, but not in septic patients, was found to be associated with higher 6‐month mortality.
The role of radiation therapy and margin width in localized soft‐tissue sarcoma: Analysis from the US Sarcoma Collaborative
Authors: Gannon Nicholas P. , King David M. , Ethun Cecilia G. , Charlson John , Tran Thuy B. , Poultsides George , Grignol Valerie , Howard J. Harrison , Tseng Jennifer , Roggin Kevin K. , Votanopoulos Konstantinos , Krasnick Bradley , Fields Ryan C. , Cardona Kenneth , Bedi Meena 
Published: June 2019

AbstractBackground and ObjectivesSoft‐tissue sarcomas (STSs) are often treated with resection and radiation (RT)±chemotherapy. The role of RT in decreasing resection width to achieve local control is unclear. We evaluated RT on margin width to achieve local control and local recurrence (LR).MethodsFrom 2000 to 2016, 514 patients with localized STS were identified from the US Sarcoma Collaborative database. Patients were stratified by a margin and local control was compared amongst treatment groups.ResultsLR was 9% with positive, 4.2% with ≤1 mm, and 9.3% with >1 mm margins (P = .315). In the ≤1 mm group, LR was 5.7% without RT, 0% with preoperative RT, and 0% with postoperative RT (P < .0001). In the >1 mm group, LR was 10.2%, 0%, and 3.7% in the no preoperative and postoperative RT groups, respectively (P = .005). RT did not influence LR in patients with positive margins. In stage I‐III and II‐III patients, local recurrence‐free survival was higher following RT (P = .008 and P = .05, respectively).ConclusionsRT may play a larger role in minimizing LR than margin status. In patients with positive margins, RT may decrease LR to similar rates as a negative margin without RT and may be considered to decrease the risk of LR with anticipated close/positive margins.
Commentary on the Special Issue on Moral Injury: Unpacking Two Models for Understanding Moral Injury
Authors: Nash William P. 
Published: June 2019

AbstractThe most robust finding of moral injury (MI) research thus far—that past exposure to potentially morally injurious events predicts current symptoms of posttraumatic stress disorder (PTSD)—challenges conceptions that trauma is exclusively the result of fear‐evoking brushes with death or sexual assault. It also calls into question the applicability to MI of treatments for PTSD grounded in the fear model of trauma. In the current article, two divergent theoretical models that have been applied to the understanding and treatment of moral injury are compared: the stress–appraisal–coping model and the stress injury model. Attention is drawn to the differences between how these models conceptualize stress and distress, including psychological trauma, and to their potential implications for the sustainment of mental health stigma, especially in military and veteran populations.
Optical Information Multiplexing with Nonlinear Coding Metasurfaces
Authors: Ma Menglin , Li Zhi , Liu Wenwei , Tang Chengchun , Li Zhancheng , Cheng Hua , Li Junjie , Chen Shuqi , Tian Jianguo 
Published: June 2019

AbstractCoding metasurfaces, as a new type of design concept, have provided many attractive functionalities for manipulating the wave fronts of light. Previous research only focused on linear coding metasurfaces; however, with the increasing demand for highly integrated and compact multifunctional chips, the drawbacks of linear coding metasurfaces, the constraints on information capacity and operating frequency are becoming more and more obvious. Here, Pancharatnam–Berry‐phase‐based nonlinear coding metasurfaces are proposed, in which convenient digital signal processing is employed to design multidimensional information channels in nonlinear optical processes to achieve optical information multiplexing. In order to confirm the feasibility of this methodology, by encoding various focusing functionalities and image information into nonlinear metasurfaces, a multifocal metalens and a multifunctional metasurface are theoretically designed, and their excellent performances are experimentally demonstrated. The proposed nonlinear coding metasurfaces may provide a promising platform for information encryption, multi‐channel optical data storage, and real space encoding imaging.