T-cell agonists in cancer immunotherapy

Cancer cells can evade immune surveillance in the body. However, immune checkpoint inhibitors can interrupt this evasion and enhance the antitumor activity of T cells. Other mechanisms for promoting antitumor T-cell function are the targeting of costimulatory molecules expressed on the surface of T cells, such as 4-1BB, OX40, inducible T-cell costimulator and glucocorticoid-induced tumor necrosis factor receptor. In addition, CD40 targets the modulation of the activation of antigen-presenting cells, which ultimately leads to T-cell activation. Agonists of these costimulatory molecules have demonstrated promising results in preclinical and early-phase trials and are now being tested in ongoing clinical trials. In addition, researchers are conducting trials of combinations of such immune modulators with checkpoint blockade, radiotherapy and cytotoxic chemotherapeutic drugs in patients with advanced tumors. This review gives a comprehensive picture of the current knowledge of T-cell agonists based on their use in recent and ongoing clinical trials

Fabrication of Nanostructures on a Large-Area Substrate with a Minimized Stitch Error Using the Step-and-Repeat Nanoimprint Process

Nanoimprint lithography (NIL) is suitable for achieving high uniformity and mass production. However, in conventional NIL, a stamp suitable for the substrate size is required to increase the substrate size. To address this issue, we fabricated nanostructures on a large-area substrate using step-and-repeat NIL after making a small stamp. A stamp was produced using glass, and a nano-pillar pattern with a diameter of 600 nm, an interval of 400 nm, and a height of 270 nm was used during the experiment. The area of the pattern on the stamp was 10 mm × 10 mm, and the step-and-repeat process was performed 25 times to transfer the nanostructures to a 4-inch substrate. In addition, stitch gaps were created between the patterns, which could decrease the performance upon future application. To minimize this stitch gap, a high-precision glass scale was attached to the stamp feeder to precisely control the position and to minimize the step difference. Moreover, an experiment was conducted to minimize the stitch gap by adjusting the movement interval of the stamp, and the stitch spacing was minimized by moving the stamp position by 9.97 mm. This approach will facilitate the manufacturing of large-area substrates and other structures in the future

Robust Priority for Strategic Environmental Assessment with Incomplete Information Using Multi-Criteria Decision Making Analysis

This study investigates how the priority rankings for dam construction sites vary with multi-criteria decision making (MCDM) techniques and generation approaches for incomplete information. Strategic environmental assessment (SEA) seeks to recommend sustainable dam construction sites based on their environmental and ecological impacts in a long-term plan for dam construction (LPDC) in South Korea. However, if specific information is missing, the SEA is less useful for choosing a dam construction site. In this study, we applied AHP, ELECTRE III, PROMETHEE II and Compromise Programming as MCDM techniques, and used binomial and uniform distributions to generate missing information. We considered five dam site selection situations and compared the results as they depended on both MCDM techniques and information generation methods. The binomial generation method showed the most obvious priorities. All MCDM techniques showed similar priorities in the dam site selection results except for ELECTREE III. The results demonstrate that selecting an appropriate MCDM technique is more important than the data generation method. However, using binomial distribution to generate missing information is more effective in providing a robust priority than uniform distribution, which is a commonly used technique

High-performance bifunctional electrocatalyst for iron-chromium redox flow batteries

Despite a variety of advantages over the presently dominant vanadium redox flow batteries, the commercialization of iron-chromium redox flow batteries (ICRFBs) is hindered by sluggish Cr2+/Cr3+ redox reactions and vulnerability to the hydrogen evolution reaction (HER). To address these issues, here, we report a promising electrocatalyst comprising Ketjenblack (KB) carbon with embedded bismuth nanoparticles (Bi-C). The uniform incorporation of Bi nanoparticles into KB carbon via a simple reduction process excellently promotes the electrochemical activity of Cr2+/Cr3+ redox reactions while retarding the HER. A combination of experimental analysis and density functional theory (DFT) calculations indicates that these phenomena are attributable to the synergistic effect of Bi and KB, which inhibits hydrogen evolution and provides active sites to enhance the Cr2+/ Cr3+ redox reaction, respectively. An ICRFB cell containing the Bi-C catalyst as the negative electrode exhibits a high energy efficiency of 86.54% with excellent capacity retention during charge-discharge cycling at room temperature. This study offers an intelligent hybrid material as a useful design principle for electrocatalysts capable of addressing the critical problems in ICRFBs.

The experience of device failure after cochlear implantation

Abstract Background The present study describes the treatment of patients at a tertiary institution who experienced device failure after Cochlear Implantation (CI), as well as identifying prodromic symptoms that could assist in the timely identification and management of device failure. Study design Retrospective database review (January 2000–May 2017). Setting Single tertiary hospital. Methods Factors recorded included the etiology of hearing loss; age at first and revision CI surgeries; surgical information, including operation time and approach; electrical outcomes after implantation; device implanted; symptoms of device failure; history of head trauma; and audiologic outcomes as determined by categories of auditory performance (CAP). Results From January 2000 to May 2017, 1431 CIs were performed, with 27 (1.9%) undergoing revision surgeries due to device failure. The most common etiology of hearing loss was idiopathic (12/27), followed by cochlear hypoplasia (5/27). Mean age at initial CI was 11.8 (1–72) years, with 21 being pre-lingual and 6 being post-lingual. Of the total devices initially implanted, 80.5% were from Cochlear, 15.9% from MED-EL, and 3.5% from Advanced Bionics. The failure rates of these devices were 1.3%, 3.1%, and 10.0%, respectively. The most suggestive symptom of device failure was intermittent loss of signal. Mean CAP scores were 5.17 before reimplantation and 5.54 and 5.81 at 1- and 3-years, respectively, after reimplantation. Conclusion The most suggestive symptom preceding device failure was intermittent loss of signal. Patients who present with this symptom should undergo electrical examination for suspected device failure. Audiologic outcomes showed continuous development despite revision surgeries

Identification of tumor suppressor miRNAs by integrative miRNA and mRNA sequencing of matched tumor–normal samples in lung adenocarcinoma

© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.The roles of miRNAs in lung cancer have not yet been explored systematically at the genome scale despite their important regulatory functions. Here, we report an integrative analysis of miRNA and mRNA sequencing data for matched tumor–normal samples from 109 Korean female patients with non-small-cell lung adenocarcinoma (LUAD). We produced miRNA sequencing (miRNA-Seq) and RNA-Seq data for 48 patients and RNA-Seq data for 61 additional patients. Subsequent differential expression analysis with stringent criteria yielded 44 miRNAs and 2322 genes. Integrative gene set analysis of the differentially expressed miRNAs and genes using miRNA–target information revealed several regulatory processes related to the cell cycle that were targeted by tumor suppressor miRNAs (TSmiR). We performed colony formation assays in A549 and NCI-H460 cell lines to test the tumor-suppressive activity of downregulated miRNAs in cancer and identified 7 novel TSmiRs (miR-144-5p, miR-218-1-3p, miR-223-3p, miR-27a-5p, miR-30a-3p, miR-30c-2-3p, miR-338-5p). Two miRNAs, miR-30a-3p and miR-30c-2-3p, showed differential survival characteristics in the Tumor Cancer Genome Atlas (TCGA) LUAD patient cohort indicating their prognostic value. Finally, we identified a network cluster of miRNAs and target genes that could be responsible for cell cycle regulation. Our study not only provides a dataset of miRNA as well as mRNA sequencing from the matched tumor–normal samples, but also reports several novel TSmiRs that could potentially be developed into prognostic biomarkers or therapeutic RNA drug

Association between cotinine-verified smoking status and moderately increased albuminuria in the middle-aged and older population in Korea: A nationwide population-based study.

ObjectivesAlthough several self-reported questionnaire-based studies have found an association between smoking and moderately increased albuminuria, this result remains controversial. We investigated whether moderately increased albuminuria was associated with smoking status, verified by urinary cotinine (an objective biomarker of tobacco exposure), using population-based, nationally representative data.MethodsThis study included 2059 participants aged ≥ 50 years from the 2014 Korean National Health and Nutrition Examination Survey. Individuals with a urinary cotinine level ≥ 50 ng/mL were identified as cotinine-verified smokers. Moderately increased albuminuria was defined as a urine albumin-to-creatinine ratio ranging between ≥ 30 mg/g and ResultsAmong the study participants, 16.9% were cotinine-verified smokers, 84.8% of whom were men. After adjustment for multiple covariates, cotinine-verified smokers showed a significant positive association with moderately increased albuminuria (adjusted odds ratio: 4.37, 95% confidence interval: 1.63-11.71) compared with cotinine-verified non-smokers. The association between urinary cotinine and moderately increased albuminuria did not differ with age, sex, obesity, or comorbidities (P-value for interaction > 0.05 in all cases).ConclusionThis large-scale observational study showed that cotinine-verified smoking is associated with moderately increased albuminuria in the Korean middle-aged and older general population, suggesting that smoking must be strictly controlled to reduce the risk of moderately increased albuminuria

Zinc-fingers and homeoboxes 1 (ZHX1) binds DNA methyltransferase (DNMT) 3B to enhance DNMT3B-mediated transcriptional repression

DNA methyltransferases (DNMT) 313 is a de novo DNMT that represses transcription independent of DNMT activity. In order to gain a better insight into DNMTB3-mediated transcriptional repression, we performed a yeast two-hybrid analysis using DNMT3B as a bait. Of the various binding candidates, ZHX1, a member of zinc-finger and homeobox protein, was found to interact with DNMT3B in vivo and in vitro. N-terminal PWWP domain of DNMT3B was required for its interaction with homeobox motifs of ZHX1. ZHX1 contains nuclear localization signal at C-terminal homeobox motif, and both ZHX1 and DNMT3B were co-localized in nucleus. Furthermore, we found that ZHX1 enhanced the transcriptional repression mediated by DNMT3B when DNMT3B is directly targeted to DNA. These results showed for the first the direct linkage between DNMT and zinc-fingers homeoboxes protein, leading to enhanced gene silencing by DNMT3B. (c) 2007 Elsevier Inc. All rights reserved