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Background Pharmacist plays an integral role in promoting antimicrobial stewardship (AS) strategies by committing to the evidence-based activities in this field. The present study aims to document trends in actual achievements through bibliometric analysis and identify the future direction of pharmacists with expertise in AS by describing the characteristics of articles on AS written by Japanese pharmacists. Methods The study searched for articles written in Japanese and English on Ichushi-Web and MEDLINE, respectively, until December 2020 for published articles relevant to AS. The articles were classified into the seven groups according to content. Interrupted time series analysis (ITSA) was performed to identify the effect of the certification system for infection control pharmacy specialists (ICPSs) on the number of articles in Japanese. Results The study retrieved 476 and 145 titles from Ichushi-Web and MEDLINE, respectively, out of which 383 and 123 articles written in Japanese and English, respectively, were considered relevant to AS. A continued publication was found for Japanese articles written by pharmacists assigned to large-sized hospitals since 1998, whereas few articles in English were published until 2017. The most frequent content of articles in both languages was intervention (56.7 and 59.0%, respectively). ITSA indicated that the number of publication slightly increased before [ β 1 = 1.33, 95% confidence interval (CI): − 0.62–3.28; P  = 0.169] the implementation of the system. Moreover, the level ( β 2 = 11.41, 95%CI: − 0.23–23.05; P  = 0.054) increased after the implementation of the system, whereas the slope decreased ( β 3 = − 2.07, 95%CI: − 4.16–0.03; P  = 0.053). However, the changes were not statistically significant. Conclusion The study identified the contribution of pharmacists by documenting trends in AS practice and by conducting bibliometric analysis. The implementation of the ICPS certification system positively influenced the trend of publications. Therefore, the study recommends that policymakers and stakeholders should promote and support the evidence-based activities for AS for pharmacists in small- to medium-sized hospitals.

Under India’s DRIP program over 5,000 large dams are to be rehabilitated in accordance with modern dam safety standards. In order to prioritize the rehabilitation works for such a large number of dams, India’s Central Water Commission, needed a risk screening tool to allow for a portfolio risk screening. The tool was developed by simplifying sound principles of risk analysis followed by a comprehensive validation process. The application of the tool is relatively easy and the process of generating risk index for a single dam may take as little as few hours to 1-2 days, depending on the availability of data and personnel familiar with the dam making the tool ideal for helping to prioritize dam safety remedial projects for India’s dam safety program and for other large portfolio’s around the world. Dans le cadre du programme DRIP de l’Inde, plus de 5 000 grands barrages doivent être réhabilités conformément aux normes modernes de sécurité des barrages. Afin d’établir un ordre de priorité pour les travaux de réhabilitation d’un si grand nombre de barrages, la Commission centrale de l’eau de l’Inde avait besoin d’un outil d’évaluation des risques pour permettre un contrôle des risques en portefeuille. L’outil a été développé en simplifiant des principes solides de l’analyse des risques suivis d’un processus complet d’action valide. L’application de l’outil est relativement facile et le processus de génération d'un indice de risque pour un seul barrage peut prendre de quelques heures à 1 ou 2 jours selon la disponibilité des données et du personnel connaissant bien le barrage rendant l’outil idéal pour aider à prioriser les projets de réparation de la sécurité des barrages pour le programme de sécurité des barrages de l’Inde et pour d’autres grands portefeuilles à travers le monde.

We study the lattice cutoff (\\(a\\)) and quark mass dependences of pion masses and decay constants in the \\(N_f = 2\\) twisted mass QCD, using the Wilson chiral perturbation theory to the next leading order (NLO). In order to investigate the region near zero quark mass, we introduce the power counting scheme where \\(O(a^2, am)\\) terms are included in the tree level effective Lagrangian. At the NLO of this power counting scheme, we calculate the charged pion mass and decay constant as a function of the lattice cutoff as well as the twisted quark mass at the maximal twist. In this paper, we adopt two different definitions for the maximal twist. We confirm that the difference between the two appears as the \\(O(a^2)\\) effects so that the automatic \\(O(a)\\) improvement is realized for both definitions.

Background: To assess the prognostic role and the antitumor immunological relevance of ecotropic viral integration site 2B (EVI2B) in metastatic melanoma. Methods: In this study, we integrated clinical data, mRNA expression data, and the distribution and fraction of tumor infiltrating lymphocytes (TILs) using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets (GSE65904 and GSE19234). Results: The univariate and multivariate analyses showed that higher gene expression of EVI2B was significantly associated with longer prognoses. The EVI2B-high melanoma tissue had favorable histological parameters such as a brisk global distribution pattern and clustering structure of TILs (i.e., Banfield and Raftery index) with enriched CD8+ T cells over regulatory T cells and increased cytotoxicity scores. In addition, EVI2B expression positively correlated with IFN-γ signature genes (CXCL10, CXCL9, HLA-DRA, IDO1, IFNG, and STAT1) and other various immunomodulatory genes. Conclusion: EVI2B is a novel prognostic biomarker with IFN-γ associated immune infiltration in metastatic melanoma.

FXYD3 is a protein-coding gene, belonging to the FXYD protein family associated with Na+/K+-ATPase enzymes and chloride ion channels. Accumulating evidence suggests the biological role of FXYD3 in multiple cancers. However, the prognostic value of FXYD3 expression in clear renal cell carcinoma (KIRC) is unclear. Therefore, we evaluated the clinical data with tumor-infiltrating lymphocytes (TILs) and immunoinhibitory gene expression data using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) dataset (GSE29609). First, the FXYD3 high KIRC patients had distinct clinical characteristics, including age, sex, disease stage, histological grade, and hypoxia-related gene expressions. Next, FXYD3 gene expression was correlated with poor overall survival in both TCGA and GSE29609 cohorts. The ESTIMATE algorithm revealed that higher FXYD3 mRNA levels were associated with increased infiltration of immune cells and tumor purity. Moreover, the FXYD3 high KIRC tissue harbored increased TILs such as B cells, CD8+ T cells, and M1 macrophage, whereas NK cells and neutrophils were decreased. In addition, we showed FXYD3 was co-expressed with several immunoinhibitory genes related to T cell exhaustion such as LGALS9, CTLA4, BTLA, PDCD1, and LAG3. In conclusion, FXYD3 is an unfavorable prognostic biomarker associated with hypoxia, pro-tumor TILs, and T cell exhaustion.

Irreversible inhibition of disease-associated proteins with small molecules is a powerful approach for achieving increased and sustained pharmacological potency. Here, we introduce α-chlorofluoroacetamide (CFA) as a novel warhead of targeted covalent inhibitor (TCI). Despite weak intrinsic reactivity, CFA-appended quinazoline showed high reactivity toward Cys797 of epidermal growth factor receptor (EGFR). In cells, CFA-quinazoline showed higher target specificity for EGFR than the corresponding Michael acceptors in a wide concentration range (0.1–10 μM). The cysteine adduct of the CFA derivative was susceptible to hydrolysis and reversibly yielded intact thiol but was stable in solvent-sequestered ATP-binding pocket of EGFR. This environment-dependent hydrolysis can potentially reduce off-target protein modification by CFA-based drugs. Oral administration of CFA quinazoline NS-062 significantly suppressed tumor growth in a mouse xenograft model. Further, CFA-appended pyrazolopyrimidine irreversibly inhibited Bruton’s tyrosine kinase with higher target specificity. These results demonstrate the utility of CFA as a new class warheads for TCI. Discovery and exploitation of inherent reaction features of chlorofluoroacetamide (CFA) as a warhead such as low off-target activity and reversible reactivity with cysteine enable specific covalent inhibition of targeted kinases.

Immunotherapy with immune‐checkpoint therapy has recently been used to treat oral squamous cell carcinomas (OSCCs). However, improvements in current immunotherapy are expected because response rates are limited. Transforming growth factor‐β (TGF‐β) creates an immunosuppressive tumor microenvironment (TME) by inducing the production of regulatory T‐cells (Tregs) and cancer‐associated fibroblasts and inhibiting the function of cytotoxic T‐lymphocytes (CTLs) and natural killer cells. TGF‐β may be an important target in the development of novel cancer immunotherapies. In this study, we investigated the suppressive effect of TGF‐β on CTL function in vitro using OSCC cell lines and their specific CTLs. Moreover, TGFB1 mRNA expression and T‐cell infiltration in 25 OSCC tissues were examined by in situ hybridization and multifluorescence immunohistochemistry. We found that TGF‐β suppressed the function of antigen‐specific CTLs in the priming and effector phases in vitro. Additionally, TGF‐β inhibitor effectively restored the CTL function, and TGFB1 mRNA was primarily expressed in the tumor invasive front. Interestingly, we found a significant negative correlation between TGFB1 mRNA expression and the CD8+ T‐cell/Treg ratio and between TGFB1 mRNA expression and the Ki‐67 expression in CD8+ T‐cells, indicating that TGF‐β also suppressed the function of CTLs in situ. Our findings suggest that the regulation of TGF‐β function restores the immunosuppressive TME to active status and is important for developing new immunotherapeutic strategies, such as a combination of immune‐checkpoint inhibitors and TGF‐β inhibitors, for OSCCs. We found that, TGF‐β suppressed the function of antigen‐specific CTLs in the priming and effector phases in vitro. And, we found a significant negative correlation between TGFB1 mRNA expression and the CD8+ T‐cell/Treg ratio. Inhibition of TGF‐β restores the immunosuppressive TME to active status by a mechanism different from that of immune‐checkpoint inhibitors, suggesting that the combination of both may lead to a new therapeutic strategy for OSCCs.

NY‐ESO‐1 is a cancer/testis antigen expressed in various cancer types. However, the induction of NY‐ESO‐1‐specific CTLs through vaccines is somewhat difficult. Thus, we developed a new type of artificial adjuvant vector cell (aAVC‐NY‐ESO‐1) expressing a CD1d‐NKT cell ligand complex and a tumor‐associated antigen, NY‐ESO‐1. First, we determined the activation of invariant natural killer T (iNKT) and natural killer (NK) cell responses by aAVC‐NY‐ESO‐1. We then showed that the NY‐ESO‐1‐specific CTL response was successfully elicited through aAVC‐NY‐ESO‐1 therapy. After injection of aAVC‐NY‐ESO‐1, we found that dendritic cells (DCs) in situ expressed high levels of costimulatory molecules and produced interleukn‐12 (IL‐12), indicating that DCs undergo maturation in vivo. Furthermore, the NY‐ESO‐1 antigen from aAVC‐NY‐ESO‐1 was delivered to the DCs in vivo, and it was presented on MHC class I molecules. The cross‐presentation of the NY‐ESO‐1 antigen was absent in conventional DC‐deficient mice, suggesting a host DC‐mediated CTL response. Thus, this strategy helps generate sufficient CD8+ NY‐ESO‐1‐specific CTLs along with iNKT and NK cell activation, resulting in a strong antitumor effect. Furthermore, we established a human DC‐transferred NOD/Shi‐scid/IL‐2γcnull immunodeficient mouse model and showed that the NY‐ESO‐1 antigen from aAVC‐NY‐ESO‐1 was cross‐presented to antigen‐specific CTLs through human DCs. Taken together, these data suggest that aAVC‐NY‐ESO‐1 has potential for harnessing innate and adaptive immunity against NY‐ESO‐1‐expressing malignancies. In this study, we developed a new type of artificial adjuvant vector cell (aAVC‐NY‐ESO‐1) expressing a CD1d‐NKT cell ligand complex and a tumor‐associated antigen, NY‐ESO‐1. Although the induction of CTLs by vaccines for NY‐ESO‐1 is believed to be difficult, we successfully showed the NY‐ESO‐1‐specific CTLs by aAVC‐NY‐ESO‐1 therapy. As a key mechanism, we also determined that the NY‐ESO‐1 antigen from aAVC‐NY‐ESO‐1 was delivered to the DCs in situ.

Arabidopsis thaliana zygotes form a circumferential cortical microtubule (CMT) band that moves upward along the longitudinal axis of the cylindrical cell; however, how and why this CMT band moves remain unknown. Based on several recently proposed feedback mechanisms of CMT reorientation, we hypothesized that a directional cue (DC) changes CMT orientation. We constructed an agent-based simulation model with a DC to observe what happens during CMT formation using different parameters. We determined that the output CMT band can become larger than the input DC zone and identified two types of self-organization processes depending on the parameters used. Furthermore, using well-defined parameters that form a static CMT band, we artificially changed the position of the input DC zone, revealing that CMT band movement requires a DC to move at an appropriate speed.