bluuebunny/crossref_metadata_2025 huggingface dataset:
A Compact CPW-Fed Low-Profile Wideband Circularly Polarized Slot Antenna with a Planar Ring Reflector for GNSS Applications
Authors: Yuan Jiade , Li Yujie , Xu Zhimeng , Zheng Jiamin
Published: October 2019

A compact low-profile wideband circularly polarized slot antenna for global navigation satellite system (GNSS) is presented. The antenna comprises a planar slot radiator with a coplanar waveguide (CPW) feed and a modified ring-shaped reflector to achieve unidirectional radiation. The modified reflector is an inner square patch with four slantly cut corners, a center ring, and an outer ring with a notch; they significantly reduce the separation between the antenna radiator and reflector and therefore the overall antenna height. The overall dimensions are λ0/3 × λ0/3 × λ0/30 (λ0 denotes the free space wavelength at lower frequency). The measured −10 dB bandwidth of |S11|, 3-dB axial ratio (AR) bandwidth, and maximum gain are of 1.53–2.28 GHz, 1.558–1.672 GHz, and 5.87 dBi, respectively. The proposed antenna is simple without any additional feeding networks or shorting probes.
Stochastic Bifurcations of a Fractional‐Order Vibro‐Impact System Driven by Additive and Multiplicative Gaussian White Noises
Authors: Yang Yong-Ge , Sun Ya-Hui , Xu Wei
Published: October 2019

Stochastic fractional‐order systems or stochastic vibro‐impact systems can present rich dynamical behaviors, and lots of studies dealing with stochastic fractional‐order systems or stochastic vibro‐impact systems are available now, while the discussion on the stochastic systems with both vibro‐impact factors and fractional derivative element is rare. This paper is concerned with the stochastic bifurcation of a fractional‐order vibro‐impact system driven by additive and multiplicative Gaussian white noises. Firstly, we can remove the discontinuity of the original system with the help of nonsmooth transformation and obtain the equivalent stochastic system. Then, we adopt the stochastic averaging method to get the approximately analytical solutions. At last, an example is discussed in detail to assess the reliability of the developed approach. We also find that the coefficient of restitution factor, fractional derivative coefficient, and fractional derivative order can induce the stochastic bifurcation.
Assessment of the Effectiveness of Vitamin Supplement in Treating Eczema: A Systematic Review and Meta-Analysis
Authors: Zhu Ziyu , Yang Ziyi , Wang Chunyi , Liu Handeng
Published: October 2019

Background. The morbidity of eczema has increased in the recent years, and the methods to prevent or ameliorate its effects are becoming more important. To this end, this research was conducted to determine the effectiveness of vitamin supplements in eczema therapy. Method. Embase, PubMed, and Cochrane Central Register of Clinical Trials were searched. Only randomized controlled trials were included, and we included all quantified eligible data where the SCORing Atopic Dermatitis (SCORAD) Index or Eczema Area and Severity Index (EASI) scores were applied to assess the severity of eczema. Results. Ten studies fulfilled the inclusion criteria, and eight of them were included for quantitative analysis (total: 456 patients). Compared to the controls, the SCORAD index or EASI decreased in the vitamin supplement group (mean difference −5.96, 95% CI: −7.69 to −4.23 for vitamin D3; mean difference −5.72, 95% CI: −11.41 to −0.03 for vitamin E; and mean difference −3.19, 95% CI: −4.27 to −2.10 for vitamin B12). Conclusion. This study suggests that vitamin supplements could be important therapeutics to help manage eczema patients.
The DNMT1/miR-34a Axis Is Involved in the Stemness of Human Osteosarcoma Cells and Derived Stem-Like Cells
Authors: Liang Xiao , Xu Chang , Wang Wanchun , Li Xiang
Published: October 2019

The DNA methyltransferase 1 (DNMT1)/miR-34a axis promoted carcinogenesis of various types of cancers. However, no literature reported its contribution to the stemness of osteosarcoma cancer stem-like cells (OSLCs). We sought to determine whether the DNMT1/miR-34a axis facilitates the stemness of OSLCs. We here revealed the higher DNMT1 activity and expression, lower miR-34a expression with high methylation of its promoter, and stronger stemness of OSLCs, as manifested by elevated sphere and colony formation capacities; CD133, CD44, ABCG2, Bmi1, Sox2, and Oct4 protein amounts in vitro; and carcinogenicity in a nude mouse xenograft model, when compared to the parental U2OS cells. 5-Azacytidine (Aza-dC) repressed DNMT1 activation and upregulated miR-34a expression by promoter demethylation and suppressed the stemness of OSLCs in a dose-dependent manner. DNMT1 knockdown increased miR-34a and reduced the stemness of OSLCs. Transfection with a miR-34a mimic repressed the stemness of OSLCs but did not alter DNMT1 activity and expression. Conversely, DNMT1 overexpression declined miR-34a levels, promoting the stemness of U2OS cells. Transfection with a miR-34a inhibitor enhanced the stemness of U2OS cells, without affecting the DNMT1 activity and expression. Importantly, reexpression of miR-34a could rescue the effects of DNMT1 overexpression on miR-34a inhibition as well as the stemness promotion without affecting the activity and expression of DNMT1. Our results revealed that aberrant activation of DNMT1 caused promoter methylation of miR-34a, leading to miR-34a underexpression, and the role of the DNMT1/miR-34a axis in promoting and sustaining the stemness of OSLCs.
Robust Control of Disturbed Fractional‐Order Economical Chaotic Systems with Uncertain Parameters
Authors: Xu Song , Lv Hui , Liu Heng , Liu Aijing
Published: October 2019

This paper focuses on the robust control of fractional‐order economical chaotic system (FOECS) with parametric uncertainties and external disturbances. The dynamical behavior of FOECS is studied by numerical simulation, and circuit implementations of FOECS are also given. Based on fractional‐order Lyapunov stability theorems, a robust adaptive controller, which can guarantee that all signals remain bounded and the tracking error tends to a small region, is designed. The proposed method can be used to control a large range of fractional‐order systems with system uncertainties. Fractional‐order adaptation laws are constructed to update the estimation of adaptive parameters. Finally, the robustness and effectiveness of our control method are indicated by simulation results.
Molecular Dynamics Simulation of the Cu/Au Nanoparticle Alloying Process
Authors: Zhang Linxing , Li Qibin , Tian Sen , Hong Guang
Published: October 2019

Sintering is an important approach for the alloying of different metals, which is affected by factors such as temperature, grain size, and material properties. And it represents a complex thermodynamic process. This paper had adopted the molecular dynamics methods to investigate the evolution process of nanostructure during the sintering of Cu and Au nanoparticles. The changes in crystalline during the nanosintering process were observed, and the radial distribution function of atoms, the shrinkage ratio, and the sintering neck of the systems were discussed. The initial sintering temperature and melting temperature of the system were obtained; at the same time, the characteristics of the sintering neck with changes in temperature during the nanosintering process were revealed.
Multicenter Assessment of Radiation Exposure during Pediatric Cardiac Catheterizations Using a Novel Imaging System
Authors: Lamers Luke J. , Morray Brian H. , Nugent Alan , Speidel Michael , Suntharos Petch , Prieto Lourdes
Published: October 2019

Objectives. To quantify radiation exposure during pediatric cardiac catheterizations performed by multiple operators on a new imaging platform, the Artis Q.zen (Siemens Healthcare, Forchheim, Germany), and to compare these data to contemporary benchmark values. Background. The Artis Q.zen has been shown to achieve significant radiation reduction during select types of pediatric cardiac catheterizations in small single-center studies. No large multicenter study exists quantifying patient dose exposure for a broad spectrum of procedures. Methods. Retrospective collection of Air Kerma (AK) and dose area product (DAP) for all pediatric cardiac catheterizations performed on this new imaging platform at four institutions over a two-year time period. Results. A total of 1,127 pediatric cardiac catheterizations were analyzed. Compared to dose data from earlier generation Artis Zee imaging systems, this study demonstrates 70–80% dose reduction (AK and DAP) for similar patient and procedure types. Compared to contemporary benchmark data for common interventional procedures, this study demonstrates an average percent reduction in AK and DAP from the lowest dose saving per intervention of 39% for AK and 27% for DAP for transcatheter pulmonary valve implantation up to 77% reduction in AK and 70% reduction in DAP for atrial septal defect closure. Conclusion. Use of next-generation imaging platforms for pediatric cardiac catheterizations can substantially decrease patient radiation exposure. This multicenter study defines new low-dose radiation measures achievable on a novel imaging system.
Network Growth Modeling to Capture Individual Lexical Learning
Authors: Beckage Nicole M. , Colunga Eliana
Published: October 2019

Network models of language provide a systematic way of linking cognitive processes to the structure and connectivity of language. Using network growth models to capture learning, we focus on the study of the emergence of complexity in early language learners. Specifically, we capture the emergent structure of young toddler’s vocabularies through network growth models assuming underlying knowledge representations of semantic and phonological networks. In construction and analyses of these network growth models, we explore whether phonological or semantic relationships between words play a larger role in predicting network growth as these young learners add new words to their lexicon. We also examine how the importance of these semantic and phonological representations changes during the course of development. We propose a novel and significant theoretical framework for network growth models of acquisition and test the ability of these models to predict what words a specific child is likely to learn approximately one month in the future. We find that which acquisition model best fits is influenced by the underlying network representation, the assumed process of growth, and the network centrality measure used to relate the cognitive underpinnings of acquisition to network growth. The joint importance of representation, process, and the contribution of individual words to the predictive accuracy of the network model highlights the complex and multifaceted nature of early acquisition, provides new tools, and suggests experimental hypotheses for studying lexical acquisition.
Curcumin Inhibits ERK/c-Jun Expressions and Phosphorylation against Endometrial Carcinoma
Authors: Zhang Zhenxue , Yi Pengfei , Tu Changchun , Zhan Jiejie , Jiang Liping , Zhang Fanglin
Published: October 2019

Curcumin has been shown to have anticancer effects in a variety of tumors. However, there are fewer studies on the role of curcumin in endometrial carcinoma (EC). The purpose of this experiment was to examine the inhibitory effect of curcumin on endometrial carcinoma cells and ERK/c-Jun signaling pathway. We first predicted the mechanism of action of curcumin on endometrial carcinoma by network pharmacology. Then, we found that curcumin can decrease the cell viability of Ishikawa cells, inhibit the migration of cancer cells, induce apoptosis, and cause cell cycle arrest in the S phase. For molecular mechanism, curcumin reduced the mRNA expression levels of ERK2 and JUN genes and inhibited the phosphorylation of ERK and c-Jun. This suggests that curcumin inhibits the proliferation of endometrial carcinoma cells by downregulating ERK/c-Jun signaling pathway activity.
A Bibliometric Analysis of Publications on Oxycodone from 1998 to 2017
Authors: Lei Fan , Ye Jishi , Wang Juan , Xia Zhongyuan
Published: October 2019

Background. Oxycodone is a widely used opioid analgesic, which is involved in cancer pain and non-cancer pain. This study is intended to understand the publication characteristics of oxycodone research field and assess the quality of pertinent articles from 1998 to 2017. Methods. Oxycodone-related publications from 1998 to 2017 were retrieved from the Web of Science (WOS) and PubMed database. These papers were coded across several categories, such as total number, journals, countries, institutions, authors and citations reports. And the analysis of co-occurrence keywords was handled by VOSviewer software. Results. According to search strategies, a total of 2659 articles on oxycodone were published in world from 1998 to 2017 in WOS. Among the top 10 most productive organizations, six of them were American institutes, two of them were pharmaceutical enterprises and the other three were Finnish, Australian and Canadian institutes, which is similar with the distribution by country/region. Drewes AM from Denmark published most articles and PAIN MEDICINE is the most productive journal in oxycodone area. Meanwhile, clinical studies occupy a dominant position during the past 20 years. The 10 most cited papers were listed. Among these articles, 8 of them are reviews and 2 of those are meta-analysis. And the last decade (2008–2017) displayed that the newest keywords focus on “double-blind”, “randomized controlled trial” and “neuropathic pain”. Conclusions. The findings provided a comprehensive overview of oxycodone research. In view of the adverse effects of oxycodone, high-quality oxycodone studies both in basic studies and clinical trials need to be completed.
Angioedema Activity Score (AAS): A Valid and Reliable Tool to Use in Asian Patients
Authors: Kulthanan Kanokvalai , Chularojanamontri Leena , Rujitharanawong Chuda , Weerasubpong Puncharas , Weller Karsten , Maurer Marcus
Published: October 2019

The Angioedema Activity Score (AAS) is recommended by the EAACI/GA2LEN/EDF/WAO guidelines for urticaria as the standard measure for assessing disease activity in patients with recurrent angioedema (RAE). To date, it has been translated into 80 languages for use in 52 countries, but it has not been formally validated in Asian patient populations. As RAE may be different in Asian and non-Asian patients, it is important to validate and characterize the reliability of tools to assess RAE disease activity in Asian patients. This study proposed to demonstrate the validity and reliability of the AAS in Asian patients. Accordingly, this study aimed to generate and validate the Thai version of the AAS and to characterize its reliability in Asian patients, specifically in Thailand. A structured translation was conducted with approval from the original authors. The Patient Global Assessment of Disease Activity (PGA-DA) was used as an instrument to compare with the Thai version of the AAS. In total, 86 patients with RAE participated in the study. Seventy-six (88%) patients had RAE with chronic spontaneous urticaria. The Thai AAS was found to be a valid and reliable instrument, with high convergent and known-groups validities, excellent internal consistency, and good test-retest reliability. The validity and reliability of the AAS for assessing RAE disease activity in Asian patients have been demonstrated by our study, making it the first to do so. This will help promote the use of the AAS, in clinical trials and practice, in Asia. It will also facilitate the comparison of disease activity in patients with RAE inside and outside Asia in future studies. However, a limitation of this study was its small number of patients.
Parallel Signaling through IRE1α and PERK Regulates Pancreatic Neuroendocrine Tumor Growth and Survival
Authors: Moore Paul C. , Qi Jenny Y. , Thamsen Maike , Ghosh Rajarshi , Peng Justin , Gliedt Micah J. , Meza-Acevedo Rosa , Warren Rachel E. , Hiniker Annie , Kim Grace E. , Maly Dustin J. , Backes Bradley J. , Papa Feroz R. , Oakes Scott A.
Published: October 2019

Master regulators of the unfolded protein response (UPR), IRE1α and PERK, promote adaptation or apoptosis depending on the level of endoplasmic reticulum (ER) stress. Although the UPR is activated in many cancers, its effects on tumor growth remain unclear. Derived from endocrine cells, pancreatic neuroendocrine tumors (PanNET) universally hypersecrete one or more peptide hormones, likely sensitizing these cells to high ER protein-folding stress. To assess whether targeting the UPR is a viable therapeutic strategy, we analyzed human PanNET samples and found evidence of elevated ER stress and UPR activation. Genetic and pharmacologic modulation of IRE1α and PERK in cultured cells, xenograft, and spontaneous genetic (RIP-Tag2) mouse models of PanNETs revealed that UPR signaling was optimized for adaptation and that inhibiting either IRE1α or PERK led to hyperactivation and apoptotic signaling through the reciprocal arm, thereby halting tumor growth and survival. These results provide a strong rationale for therapeutically targeting the UPR in PanNETs and other cancers with elevated ER stress.

Significance:

The UPR is upregulated in pancreatic neuroendocrine tumors and its inhibition significantly reduces tumor growth in preclinical models, providing strong rationale for targeting the UPR in these cancers.
Targeting Novel Sodium Iodide Symporter Interactors ADP-Ribosylation Factor 4 and Valosin-Containing Protein Enhances Radioiodine Uptake
Authors: Fletcher Alice , Read Martin L. , Thornton Caitlin E.M. , Larner Dean P. , Poole Vikki L. , Brookes Katie , Nieto Hannah R. , Alshahrani Mohammed , Thompson Rebecca J. , Lavery Gareth G. , Landa Iñigo , Fagin James A. , Campbell Moray J. , Boelaert Kristien , Turnell Andrew S. , Smith Vicki E. , McCabe Christopher J.
Published: October 2019

The sodium iodide symporter (NIS) is required for iodide uptake, which facilitates thyroid hormone biosynthesis. NIS has been exploited for over 75 years in ablative radioiodine (RAI) treatment of thyroid cancer, where its ability to transport radioisotopes depends on its localization to the plasma membrane. The advent of NIS-based in vivo imaging and theranostic strategies in other malignancies and disease modalities has recently increased the clinical importance of NIS. However, NIS trafficking remains ill-defined. Here, we used tandem mass spectrometry followed by coimmunoprecipitation and proximity ligation assays to identify and validate two key nodes—ADP-ribosylation factor 4 (ARF4) and valosin-containing protein (VCP)—controlling NIS trafficking. Using cell-surface biotinylation assays and highly inclined and laminated optical sheet microscopy, we demonstrated that ARF4 enhanced NIS vesicular trafficking from the Golgi to the plasma membrane, whereas VCP—a principal component of endoplasmic reticulum (ER)–associated degradation—governed NIS proteolysis. Gene expression analysis indicated VCP expression was particularly induced in aggressive thyroid cancers and in patients who had poorer outcomes following RAI treatment. Two repurposed FDA-approved VCP inhibitors abrogated VCP-mediated repression of NIS function, resulting in significantly increased NIS at the cell-surface and markedly increased RAI uptake in mouse and human thyroid models. Collectively, these discoveries delineate NIS trafficking and highlight the new possibility of systemically enhancing RAI therapy in patients using FDA-approved drugs.

Significance:

These findings show that ARF4 and VCP are involved in NIS trafficking to the plasma membrane and highlight the possible therapeutic role of VCP inhibitors in enhancing radioiodine effectiveness in radioiodine-refractory thyroid cancer.
A Phase Ib/II Trial of the First-in-Class Anti-CXCR4 Antibody Ulocuplumab in Combination with Lenalidomide or Bortezomib Plus Dexamethasone in Relapsed Multiple Myeloma
Authors: Ghobrial Irene M. , Liu Chia-Jen , Redd Robert A. , Perez Raymond P. , Baz Rachid , Zavidij Oksana , Sklavenitis-Pistofidis Romanos , Richardson Paul G. , Anderson Kenneth C. , Laubach Jacob , Henrick Patrick , Savell Alexandra , Reyes Kaitlen , Hornburg Kalvis , Chuma Stacey , Sabbatini Peter , Robbins Michael D. , Becker Pamela S.
Published: October 2019

Purpose:

Ulocuplumab (BMS-936564) is a first-in-class fully human IgG4 monoclonal anti-CXCR4 antibody that inhibits the binding of CXCR4 to CXCL12.

Patients and Methods:

This phase Ib/II study aimed to determine the safety and tolerability of ulocuplumab alone and in combination with lenalidomide and dexamethasone (Arm A), or bortezomib and dexamethasone (Arm B), in patients with relapsed/refractory multiple myeloma.

Results:

Forty-six patients were evaluated (median age, 60 years; range, 53–67). The median number of prior therapies was 3 (range, 1–11), with 70% of subjects having received ≥3. This trial had a dose-escalation and a dose-expansion part. Using a 3+3 design on both arms of the trial, ulocuplumab's dose was escalated to a maximum of 10 mg/kg without reaching MTD. The most common treatment-related adverse events (AE) were neutropenia (13 patients, 43.3%) in Arm A and thrombocytopenia (6 patients, 37.5%) in Arm B. No deaths related to study drugs occurred. The combination of ulocuplumab with lenalidomide and dexamethasone showed a high response rate (PR or better) of 55.2% and a clinical benefit rate of 72.4%, even in patients who had been previously treated with immunomodulatory agents (IMiD).

Conclusions:

This study showed that blockade of the CXCR4–CXCL12 axis by ulocuplumab is safe with acceptable AEs and leads to a high response rate in combination with lenalidomide and dexamethasone in patients with relapsed/refractory myeloma, making CXCR4 inhibitors a promising class of antimyeloma drugs that should be further explored in clinical trials.
How to Train Your T Cells: Overcoming Immune Dysfunction in Multiple Myeloma
Authors: Cohen Adam D. , Raje Noopur , Fowler Jessica A. , Mezzi Khalid , Scott Emma C. , Dhodapkar Madhav V.
Published: October 2019

The progression of multiple myeloma, a hematologic malignancy characterized by unregulated plasma cell growth, is associated with increasing innate and adaptive immune system dysfunction, notably in the T-cell repertoire. Although treatment advances in multiple myeloma have led to deeper and more durable clinical responses, the disease remains incurable for most patients. Therapeutic strategies aimed at overcoming the immunosuppressive tumor microenvironment and activating the host immune system have recently shown promise in multiple myeloma, particularly in the relapsed and/or refractory disease setting. As the efficacy of T-cell–dependent immuno-oncology therapy is likely affected by the health of the endogenous T-cell repertoire, these therapies may also provide benefit in alternate treatment settings (e.g., precursor disease; after stem cell transplantation). This review describes T-cell–associated changes during the evolution of multiple myeloma and provides an overview of T-cell–dependent immuno-oncology approaches under investigation. Vaccine and checkpoint inhibitor interventions are being explored across the multiple myeloma disease continuum; treatment modalities that redirect patient T cells to elicit an anti–multiple myeloma response, namely, chimeric antigen receptor (CAR) T cells and bispecific antibodies [including BiTE (bispecific T-cell engager) molecules], have been primarily evaluated to date in the relapsed and/or refractory disease setting. CAR T cells and bispecific antibodies/antibody constructs directed against B-cell maturation antigen have generated excitement, with clinical data demonstrating deep responses. An increased understanding of the complex interplay between the immune system and multiple myeloma throughout the disease course will aid in maximizing the potential for T-cell–dependent immuno-oncology strategies in multiple myeloma.
A Solution to the Dilution: The Role for Biomarkers in Advanced Ovarian Cancer
Authors: Handley Katelyn F. , Sood Anil K.
Published: October 2019

Reliable approaches to predict residual disease prior to primary debulking surgery have been sought to further personalize surgical approaches. Reliance on molecular biomarkers alone in a complex clinical environment is challenging and algorithms that incorporate both molecular and clinical features may need to be considered.

See related article by Heitz et al., p. 213
Radiation Responses of 2D and 3D Glioblastoma Cells: A Novel, 3D-specific Radioprotective Role of VEGF/Akt Signaling through Functional Activation of NHEJ
Authors: Gomez-Roman Natividad , Chong Ming Y , Chahal Sandeep K. , Caragher Seamus P. , Jackson Mark R. , Stevenson Katrina H. , Dongre Sidhartha A. , Chalmers Anthony J.
Published: October 2019

Glioblastoma is resistant to conventional treatments and has dismal prognosis. Despite promising in vitro data, molecular targeted agents have failed to improve outcomes in patients, indicating that conventional two-dimensional (2D) in vitro models of GBM do not recapitulate the clinical scenario. Responses of primary glioblastoma stem-like cells (GSC) to radiation in combination with EGFR, VEGF, and Akt inhibition were investigated in conventional 2D cultures and a three-dimensional (3D) in vitro model of GBM that recapitulates key GBM clinical features. VEGF deprivation had no effect on radiation responses of 2D GSCs, but enhanced radiosensitivity of GSC cultures in 3D. The opposite effects were observed for EGFR inhibition. Detailed analysis of VEGF and EGF signaling demonstrated a radioprotective role of Akt that correlates with VEGF in 3D and with EGFR in 2D. In all cases, positive correlations were observed between increased radiosensitivity, markers of unrepaired DNA damage and persistent phospho-DNA-PK nuclear foci. Conversely, increased numbers of Rad51 foci were observed in radioresistant populations, indicating a novel role for VEGF/Akt signaling in influencing radiosensitivity by regulating the balance between nonhomologous end-joining and homologous recombination–mediated DNA repair. Differential activation of tyrosine kinase receptors in 2D and 3D models of GBM explains the well documented discrepancy between preclinical and clinical effects of EGFR inhibitors. Data obtained from our 3D model identify novel determinants and mechanisms of DNA repair and radiosensitivity in GBM, and confirm Akt as a promising therapeutic target in this cancer of unmet need.
Glutamine Deprivation Induces PD-L1 Expression via Activation of EGFR/ERK/c-Jun Signaling in Renal Cancer
Authors: Ma Guofeng , Liang Ye , Chen Yuanbin , Wang Liping , Li Dan , Liang Zhijuan , Wang Xiao , Tian Dongxu , Yang Xuecheng , Niu Haitao
Published: October 2019

The programmed death-ligand 1/programmed death-1 (PD-L1/PD-1) pathway plays a pivotal role in the immune escape of tumors. Many tumor cells show “glutamine dependence.” However, the relationship between glutamine metabolism and PD-L1 expression has not been reported. In this study, changes in PD-L1 expression in renal carcinoma cells were evaluated during glutamine deprivation and recovery. Although PD-L1 expression differed in two renal cancer cell lines, both cell lines upregulated PD-L1 during glutamine deprivation, and the upregulated PD-L1 was restored to normal after glutamine recovery. Mechanistically, glutamine deprivation resulted in activation of EGFR signaling via ERKs 1 and 2 (ERK1/2) and c-Jun. In addition, treatment of renal cancer cells with EGF also induced PD-L1 expression and ERK1/2 phosphorylation. Finally, inhibitors of EGFR, ERK, and c-Jun all inhibited phosphorylation of c-Jun and downregulated PD-L1 expression induced by glutamine deprivation. Taken together, the data suggest that glutamine regulates the expression of PD-L1 through the EGFR/ERK/c-Jun pathway in renal cancer.

Implications:

This study reveals glutamine deprivation induces PD-L1 expression via activation of EGFR/ERK/c-Jun signaling in renal cancer and provides novel markers for the treatment of renal cancer.
A Polymorphism in Interleukin-1β Gene Is Associated with the Development of Pouchitis in Japanese Patients with Ulcerative Colitis
Authors: Okada Satoshi , Hata Keisuke , Shinagawa Takahide , Noguchi Tatsuki , Tanaka Toshiaki , Kawai Kazushige , Nozawa Hiroaki , Ishihara Soichiro
Published: October 2019

Background: Major complications in patients with ulcerative colitis (UC) include UC-associated cancer (UCAC) and postoperative pouchitis. We aimed to identify SNPs associated with UCAC/high-grade dysplasia (HGD) and pouchitis. Methods: Patients with UC who underwent ileal pouch-anal anastomosis (IPAA) with >2 years of follow-up after functioning pouches were included. Pouchoscopies were performed at least once to diagnose pouchitis according to the modified pouchitis disease activity index. SNP genotyping was performed for 8 SNPs reportedly associated with UCAC and pouchitis, namely: ELF1 (rs7329174), FCGR2A, (rs1801274), interleukin-1β (IL-1B; rs1143627), ITLN1 (rs2274910), MHC (rs7765379), TNFα (rs1799964), TNFSF15 (rs3810936), and UHMK1 (rs768910), using TaqMan genotyping technologies. We investigated the association of these SNPs with UCAC/HGD and pouchitis. Patients’ background data were retrospectively collected, including the presence of preoperative extraintestinal manifestation (EIM). Results: A total of 91 Japanese patients with UC were included. None of the 8 SNPs were associated with UCAC/HGD in our cohort. Multivariable analyses proved that the presence of preoperative EIM (hazard ratio [HR] 3.313, 95% CI 1.325–8.289) and IL-1B (rs1143627) TT genotype (HR 2.425, 95% CI 1.049–5.61) were independent predictive factors for the development of overall pouchitis. The presence of preoperative EIM (HR 3.977, 95% CI 1.292–12.24) and IL-1B (rs1143627 TT genotype; HR 3.382, 95% CI 1.101–10.39) were also independent predictive factors for the development of chronic pouchitis. Conclusions: The IL-1B (rs1143627) TT genotype and preoperative EIM were statistically significant predictors of pouchitis development after IPAA in patients with UC.
Assessment for Assisted Peritoneal Dialysis by Peritoneal Dialysis Nurses: Results of a Cohort Study
Authors: Guillouët Sonia , Boyer Annabel , Lanot Antoine , Ficheux Maxence , Lobbedez Thierry , Béchade Clémence
Published: October 2019

Background: Selection of patients for assisted peritoneal dialysis (PD) is based on the nurse’s assessment of the patient. There is no data available about the nurse’s assessment of the PD patient at the initiation of PD to estimate the need for assisted PD at the national level. This study was carried out to evaluate the association between the nurse’s subjective assessment of the patient’s inability to be treated by self-care PD, the nurse evaluation of the patient disabilities and the utilization of nurse or family assisted PD. Methods: This was a retrospective study of patients starting PD between July 1, 2010 and 2015 and registered in the nurse section of the French Language PD Registry (RDPLF). Poisson regression and a linear regression model with a robust variance estimator were used for the statistical analysis to determine relative risks (RRs) and risk differences (RDs). Results: Of 4,101 PD patients, 403 were treated by family assisted PD, and 1,695 were treated by nurse-assisted PD. In the multivariate analysis, the nurse’s subjective assessment of the patient’s inability to be treated by self-care PD was associated with nurse-assisted PD (5.40 [4.58–6.35], 67% [64–70%]) and family assisted PD (11.11 [8.49–14.56], RD 62% [57–67%]). Nurse-assisted PD and family assisted PD were associated with functional impairment (RR 1.25 [95% CI 1.16–1.36], RD 14% [95% CI 10–19%] and RR 2.02 [95% CI 1.69–2.41], RD 27% [95% CI 20–34%] respectively), cognitive dysfunction (RR 1.23 [95% CI 1.15–1.32], RD 15% [95% CI 11–18%] and RR 1.73 [95% CI 1.39–2.16], RD 12% [95% CI 7–18%] respectively) and deafness (RR 1.10 [95% CI 1.04–1.16], RD 8% [95% CI 5–11%] and RR 1.46 [95% CI 1.22–1.74], RD 10% [95% CI 6–14%] respectively). Conclusion: Our results showed that the nurse’s subjective assessment of the patient’s inability to be treated by self-care PD and the patient’s disabilities were strongly associated with the utilization of nurse- and family assisted PD.
Extracellular Vesicles From Adipose Stem Cells Prevent Muscle Damage and Inflammation in a Mouse Model of Hind Limb Ischemia
Authors: Figliolini Federico , Ranghino Andrea , Grange Cristina , Cedrino Massimo , Tapparo Marta , Cavallari Claudia , Rossi Andrea , Togliatto Gabriele , Femminò Saveria , Gugliuzza Maria Vittoria , Camussi Giovanni , Brizzi Maria Felice
Published: October 2019

Objectives:

Critical hindlimb ischemia is a severe consequence of peripheral artery disease. Surgical treatment does not prevent skeletal muscle impairment or improve long-term patient outcomes. The present study investigates the protective/regenerative potential and the mechanism of action of adipose stem cell-derived extracellular vesicles (ASC-EVs) in a mouse model of hindlimb ischemia.

Approach and Results:

We demonstrated that ASC-EVs exert a protective effect on muscle damage by acting both on tissue microvessels and muscle cells. The genes involved in muscle regeneration were up-regulated in the ischemic muscles of ASC-EV-treated animals. MyoD expression has also been confirmed in satellite cells. This was followed by a reduction in muscle function impairment in vivo. ASC-EVs drive myoblast proliferation and differentiation in the in vitro ischemia/reoxygenation model. Moreover, ASC-EVs have shown an anti-apoptotic effect both in vitro and in vivo. Transcriptomic analyses have revealed that ASC-EVs carry a variety of pro-angiogenic mRNAs, while proteomic analyses have demonstrated an enrichment of NRG1 (neuregulin 1). A NRG1 blocking antibody used in vivo demonstrated that NRG1 is relevant to ASC-EV-induced muscle protection, vascular growth, and recruitment of inflammatory cells. Finally, bioinformatic analyses on 18 molecules that were commonly detected in ASC-EVs, including mRNAs and proteins, confirmed the enrichment of pathways involved in vascular growth and muscle regeneration/protection.

Conclusions:

This study demonstrates that ASC-EVs display pro-angiogenic and skeletal muscle protective properties that are associated with their NRG1/mRNA cargo. We, therefore, propose that ASC-EVs are a useful tool for therapeutic angiogenesis and muscle protection.
Medical Therapy Utilization and Long-Term Outcomes Following Percutaneous Coronary Intervention
Authors: Xie Joe X. , Gunzburger Elise C. , Kaun Lindsay , Plomondon Mary E. , Barón Anna E. , Waldo Stephen W. , Virani Salim S. , Maddox Thomas M. , Mavromatis Kreton
Published: October 2019

Background:

Optimal medical therapy is endorsed by national guidelines in the management of ischemic heart disease; however, few studies have examined its long-term utilization following percutaneous coronary intervention (PCI) and association with clinical outcomes. We sought to assess longitudinal trends in medical therapy use after PCI and its prognostic significance.

Methods and Results:

From the Veteran Affairs Clinical Assessment, Reporting, and Tracking System Program, we retrospectively identified 57 900 Veteran’s Affairs patients undergoing PCI from January 2005 to May 2014. Using prescription fill dates, the utilization of 4 classes of medical therapy including statins, β-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, P2Y12 inhibitors, and their composites were assessed at discharge, 6 months, 1, 3, and 5 years post-PCI. Multivariable Cox regression models were developed to assess the association between medical therapy status and major adverse cardiovascular events, defined as all-cause mortality, rehospitalization for myocardial infarction, rehospitalization for stroke, or repeat revascularization. At discharge following PCI, 58.3% of patients received all 4 classes of medical therapy. Utilization of statins, β-blockers, and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers decreased from 89%, 84.9%, and 72.2% on discharge, respectively, to 72.7%, 67.9%, and 57.9% at 5 years. Prescription refills of P2Y12 inhibitors declined from 96.5% on discharge to 28.3% at 5 years, driven by a large decline in P2Y12 inhibitor use after 1 year. Use of each class of medical therapy, and its composite use, was associated with a significant reduction in major adverse cardiovascular events at 5 years, with the largest effect size seen by the use of statins (HR, 0.77; 95% CI, 0.75–0.79;
P
<0.0001) and P2Y12 inhibitors (HR, 0.82; 95% CI, 0.79–0.85;
P
<0.0001).

Conclusions:

Consistent declines in medical therapy use following PCI were observed over time, which is associated with worse outcomes. Further efforts are needed to promote long-term adherence to secondary prevention therapies after revascularization.
Blood Pressure Normalization–Independent Cardioprotective Effects of Endogenous, Physical Activity–Induced αCGRP (α Calcitonin Gene-Related Peptide) in Chronically Hypertensive Mice
Authors: Skaria Tom , Mitchell Katharyn Jean , Vogel Olga , Wälchli Thomas , Gassmann Max , Vogel Johannes
Published: October 2019

Rationale:

αCGRP (α calcitonin gene-related peptide), one of the strongest vasodilators, is cardioprotective in hypertension by reducing the elevated blood pressure.

Objective:

However, we hypothesize that endogenous, physical activity–induced αCGRP has blood pressure–independent cardioprotective effects in chronic hypertension.

Methods and Results:

Chronically hypertensive (one-kidney-one-clip surgery) wild-type and αCGRP
−/−
sedentary or voluntary wheel running mice were treated with vehicle, αCGRP, or the αCGRP receptor antagonist CGRP8-37. Cardiac function and myocardial phenotype were evaluated echocardiographically and by molecular, cellular, and histological analysis, respectively. Blood pressure was similar among all hypertensive experimental groups. Endogenous αCGRP limited pathological remodeling and heart failure in sedentary, chronically hypertensive wild-type mice. In these mice, voluntary wheel running significantly improved myocardial phenotype and function, which was abolished by CGRP8-37 treatment. In αCGRP
−/−
mice, αCGRP treatment, in contrast to voluntary wheel running, improved myocardial phenotype and function. Specific inhibition of proliferation and myofibroblast differentiation of primary, murine cardiac fibroblasts by αCGRP suggests involvement of these cells in αCGRP-dependent blunting of pathological cardiac remodeling.

Conclusions:

Endogenous, physical activity–induced αCGRP has blood pressure–independent cardioprotective effects and is crucial for maintaining cardiac function in chronic hypertension. Consequently, inhibiting endogenous αCGRP signaling, as currently approved for migraine prophylaxis, could endanger patients with hypertension.
Deficiency of Cardiac Natriuretic Peptide Signaling Promotes Peripartum Cardiomyopathy-Like Remodeling in the Mouse Heart
Authors: Otani Kentaro , Tokudome Takeshi , Kamiya Chizuko A. , Mao Yuanjie , Nishimura Hirohito , Hasegawa Takeshi , Arai Yuji , Kaneko Mari , Shioi Go , Ishida Junji , Fukamizu Akiyoshi , Osaki Tsukasa , Nagai-Okatani Chiaki , Minamino Naoto , Ensho Takuya , Hino Jun , Murata Shunsuke , Takegami Misa , Nishimura Kunihiro , Kishimoto Ichiro , Miyazato Mikiya , Harada-Shiba Mariko , Yoshimatsu Jun , Nakao Kazuwa , Ikeda Tomoaki , Kangawa Kenji
Published: October 2019

Background:

The maternal circulatory system and hormone balance both change dynamically during pregnancy, delivery, and the postpartum period. Although atrial natriuretic peptides and brain natriuretic peptides produced in the heart control circulatory homeostasis through their common receptor, NPR1, the physiologic and pathophysiologic roles of endogenous atrial natriuretic peptide/brain natriuretic peptide in the perinatal period are not fully understood.

Methods:

To clarify the physiologic and pathophysiologic roles of the endogenous atrial natriuretic peptide/brain natriuretic peptide–NPR1 system during the perinatal period, the phenotype of female wild-type and conventional or tissue-specific Npr1-knockout mice during the perinatal period was examined, especially focusing on maternal heart weight, blood pressure, and cardiac function.

Results:

In wild-type mice, lactation but not pregnancy induced reversible cardiac hypertrophy accompanied by increases in fetal cardiac gene mRNAs and ERK1/2 (extracellular signaling-regulated kinase) phosphorylation. Npr1-knockout mice exhibited significantly higher plasma aldosterone level than did wild-type mice, severe cardiac hypertrophy accompanied by fibrosis, and left ventricular dysfunction in the lactation period. Npr1-knockout mice showed a high mortality rate over consecutive pregnancy–lactation cycles. In the hearts of Npr1-knockout mice during or after the lactation period, an increase in interleukin-6 mRNA expression, phosphorylation of signal transducer and activator of transcription 3, and activation of the calcineurin–nuclear factor of the activated T cells pathway were observed. Pharmacologic inhibition of the mineralocorticoid receptor or neuron-specific deletion of the mineralocorticoid receptor gene significantly ameliorated cardiac hypertrophy in lactating Npr1-knockout mice. Anti–interleukin-6 receptor antibody administration tended to reduce cardiac hypertrophy in lactating Npr1-knockout mice.

Conclusions:

These results suggest that the characteristics of lactation-induced cardiac hypertrophy in wild-type mice are different from exercise-induced cardiac hypertrophy, and that the endogenous atrial natriuretic peptide/brain natriuretic peptide–NPR1 system plays an important role in protecting the maternal heart from interleukin-6–induced inflammation and remodeling in the lactation period, a condition mimicking peripartum cardiomyopathy.
Temporal Trends and Clinical Outcomes of Transcatheter Aortic Valve Replacement in Nonagenarians
Authors: Mentias Amgad , Saad Marwan , Desai Milind Y. , Horwitz Phillip A. , Rossen James D. , Panaich Sidakpal , Elbadawi Ayman , Qazi Abdul , Sorajja Paul , Jneid Hani , Kapadia Samir , London Barry , Vaughan Sarrazin Mary S.
Published: October 2019

Background

Contemporary outcomes of transcatheter aortic valve replacement (
TAVR
) in nonagenarians are unknown.

Methods and Results

We identified 13 544 nonagenarians (aged 90–100 years) who underwent
TAVR
between 2012 and 2016 using Medicare claims. Generalized estimating equations were used to study the change in short‐term outcomes among nonagenarians over time. We compared outcomes between nonagenarians and non‐nonagenarians undergoing
TAVR
in 2016. A mixed‐effect multivariable logistic regression was performed to determine predictors of 30‐day mortality in nonagenarians in 2016. A center was defined as a
high‐volume center
if it performed ≥100
TAVR
procedures per year. After adjusting for changes in patients’ characteristics, risk‐adjusted 30‐day mortality declined in nonagenarians from 9.8% in 2012 to 4.4% in 2016 (
P
<0.001), whereas mortality for patients <90 years decreased from 6.4% to 3.5%. In 2016, 35 712
TAVR
procedures were performed, of which 12.7% were in nonagenarians. Overall, in‐hospital mortality in 2016 was higher in nonagenarians compared with younger patients (2.4% versus 1.7%,
P
<0.05) but did not differ in analysis limited to high‐volume centers (2.2% versus 1.7%; odds ratio: 1.33; 95%
CI
, 0.97–1.81;
P
=0.07). Important predictors of 30‐day mortality in nonagenarians included in‐hospital stroke (adjusted odds ratio [aOR]: 8.67; 95%
CI
, 5.03–15.00), acute kidney injury (
aOR
: 4.11; 95%
CI
, 2.90–5.83), blood transfusion (
aOR
: 2.66; 95%
CI
, 1.81–3.90), respiratory complications (
aOR
: 2.96; 95%
CI
, 1.52–5.76), heart failure (
aOR
: 1.86; 95%
CI
, 1.04–3.34), coagulopathy (
aOR
: 1.59; 95%
CI
, 1.12–2.26;
P
<0.05 for all).

Conclusions

Short‐term outcomes after
TAVR
have improved in nonagenarians. Several procedural complications were associated with increased 30‐day mortality among nonagenarians.
Lower Blood Pressure After Transcatheter or Surgical Aortic Valve Replacement is Associated with Increased Mortality
Authors: Lindman Brian R. , Goel Kashish , Bermejo Javier , Beckman Joshua , O'Leary Jared , Barker Colin M. , Kaiser Clayton , Cavalcante João L. , Elmariah Sammy , Huang Jian , Hickey Graeme L. , Adams David H. , Popma Jeffrey J. , Reardon Michael J.
Published: October 2019

Background

Blood pressure (
BP
) guidelines for patients with aortic stenosis or a history of aortic stenosis treated with aortic valve replacement (
AVR
) match those in the general population, but this extrapolation may not be warranted.

Methods and Results

Among patients enrolled in the Medtronic intermediate, high, and extreme risk trials, we included those with a transcatheter
AVR
(n=1794) or surgical
AVR
(n=1103) who were alive at 30 days. The associations between early (average of discharge and 30 day post‐
AVR
) systolic
BP
(
SBP
) and diastolic
BP
(
DBP
) measurements and clinical outcomes between 30 days and 1 year were evaluated. Among 2897 patients, after adjustment, spline curves demonstrated an association between lower
SBP
(<120 mm Hg, representing 21% of patients) and
DBP
(<60 mm Hg, representing 30% of patients) and increased all‐cause and cardiovascular mortality and repeat hospitalization. These relationships were unchanged when patients with moderate‐to‐severe aortic regurgitation post‐
AVR
were excluded. After adjustment, compared with
DBP
60 to <80 mm Hg,
DBP
30 to <60 mm Hg was associated with increased all‐cause (adjusted hazard ratio 1.62, 95%
CI
1.23–2.14) and cardiovascular mortality (adjusted hazard ratio 2.13, 95%
CI
1.52–3.00), but
DBP
80 to <100 mm Hg was not. Similarly, after adjustment, compared with
SBP
120 to <150 mm Hg,
SBP
90 to <120 mm Hg was associated with increased all‐cause (adjusted hazard ratio 1.63, 95%
CI
1.21–2.21) and cardiovascular mortality (adjusted hazard ratio 1.81, 95%
CI
1.25–2.61), but
SBP
150 to <180 mm Hg was not.

Conclusions

Lower
BP
in the first month after transcatheter AVR or surgical AVR is common and associated with increased mortality and repeat hospitalization. Clarifying optimal
BP
targets in these patients ought to be a priority and may improve patient outcomes.

Clinical Trial Registration Information

URL:
http://www.clinicaltrials.gov
. Unique identifiers:
NCT
01586910,
NCT
01240902.
The Origins of Plurilateralism in International Trade Law
Authors: Lewis Meredith Kolsky
Published: October 2019

This article examines the historical experience with and understanding of plurilateral trade agreements throughout the General Agreement on Tariffs and Trade (GATT) and World Trade Organization (WTO) to better contextualise assessments of the continued viability of the single undertaking and the recent resurgence of plurilateralism in international trade law. Plurilateral agreements have been playing a significant role in international trade relations for the past fifty years. As such, the current wave of plurilateral agreements does not represent a sea change in approach to trade liberalisation, but rather a continuation of a process that originated many decades ago. Further, while the WTO agreements are multilateral in that they apply to all members, they can also be seen as plurilateral in that not all WTO members have identical responsibilities under such agreements. The article concludes that plurilateralism and multilateralism have much in common, and hence may be mutually supportive rather than binary choices.