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The physiological practice course at Saitama Medical University provides students with the opportunity to learn physiological principles through wet labs and discussions. To develop a more effective method for maximizing learning outcomes, we extended the course's schedule from one day (1d) to two days (2d) per theme, evaluated self-administered questionnaires between two different years (pre and post-change), and examined whether the increased course length affected learning outcomes. Within the 2018 curriculum year, every theme of the course was completed in a day, including experiments in the wet lab and discussions. In 2019, each theme was assessed for two days. The second-year undergraduate medical students anonymously submitted the self-assessment questionnaire that addressed several aspects, such as understanding of the theme, through a 5-point Likert scale. The average Likert scores varied from 4 to 4.5 point for all questions, and significant differences were not found between the 1d and 2d courses. However, the ratio of students with the highest points increased for one question of the 2d course: 43.6% (1d) to 53.4% (2d) for understanding. Further, the standard deviation (SD) values decreased in the 2d course for every question: 0.29 (1d) to 0.15 (2d) for interest, 0.33 (1d) to 0.19 (2d) for understanding, 0.30 (d) to 0.17 (d) for communication, 0.34 (1d) to 0.19 (2d) for general evaluation. This reduction in the SD values indicated that the educational content was imparted more efficiently to students in the 2d course. Thus, we concluded that extending the course time facilitated dissemination of educational content for every theme.The online version contains supplementary material available at 10.1007/s40670-022-01563-4.

Background The association between the development of checkpoint inhibitor pneumonitis (CIP) with tumor response and survival has remained unclear so far. The aim of the present study was to evaluate the association between CIP and the clinical efficacy of anti‐programmed cell death‐1 antibody in patients with advanced non‐small cell lung cancer (NSCLC). Methods Between January 2016 and August 2019, 203 advanced NSCLC patients were administered with nivolumab or pembrolizumab. Comparisons were made between patients with and without CIP. We evaluated the time‐to‐treatment failure (TTF), progression‐free survival (PFS), and overall survival (OS). Results CIP was observed in 28 (14%) patients. CIP was associated with a longer PFS (18.9 months [95% confidence interval, CI: 8.7 months–not reached] vs. 3.9 months [95% CI: 3.4–5.1 months, p, This study aimed to evaluate the association between checkpoint inhibitor pneumonitis (CIP) and the clinical efficacy of anti‐programmed cell death‐1 monotherapy in patients with advanced non‐small cell lung cancer (NSCLC). CIP was associated with a longer PFS (18.9 months vs. 3.9 months, p

Brain-derived neurotrophic factor (BDNF) plays a crucial role in numerous brain functions, including memory consolidation. Previously, we generated a Bdnf-Luciferase transgenic (Bdnf-Luc) mouse strain to visualize changes in Bdnf expression using in vivo bioluminescence imaging. We successfully visualized activity-dependent Bdnf induction in living mouse brains using a d-luciferin analog, TokeOni, which distributes to the brain and produces near-infrared bioluminescence. In this study, we compared the patterns of bioluminescence signals within the whole body of the Bdnf-Luc mice produced by d-luciferin, TokeOni and seMpai, another d-luciferin analog that produces a near-infrared light. As recently reported, hepatic background signals were observed in wild-type mice when using TokeOni. Bioluminescence signals were strongly observed from the region containing the liver when using d-luciferin and TokeOni. Additionally, we detected signals from the brain when using TokeOni. Compared with d-luciferin and TokeOni, signals were widely detected in the whole body of Bdnf-Luc mice by seMpai. The signals produced by seMpai were strong in the regions containing skeletal muscles in particular. Taken together, the patterns of bioluminescence signals in Bdnf-Luc mice vary when using different luciferase substrates. Therefore, the expression of Bdnf in tissues and organs of interest could be visualized by selecting an appropriate substrate.

Purpose Subendometrial myometrium exerts wave‐like activity throughout the menstrual cycle, and uterine peristalsis is markedly reduced during the implantation phase. We hypothesized that abnormal uterine peristalsis has an adverse effect on the endometrial decidualization process. We conducted an in vitro culture experiment to investigate the effect of cyclic stretch on the morphological and biological endometrial decidual process. Methods Primary human endometrial stromal cells (HESCs) were isolated from hysterectomy specimens and incubated with or without 8‐bromo‐cyclic adenosine monophosphate (8‐br‐cAMP) and medroxyprogesterone acetate (MPA) for 3 days. After decidualization, cultures were continued for 24 hours with or without cyclic stretch using a computer‐operated cell tension system. Results Cyclic stretch significantly repressed expression of decidual markers including insulin‐like growth factor‐binding protein 1 (IGFBP1), prolactin (PRL), forkhead box O1 (FOXO1), and WNT4 on decidualized HESCs. In addition, cyclic stretch of decidualized HESCs affected the decidual morphological phenotype to an elongated shape. The alternation of F‐actin localization in decidualized HESCs was not observed in response to cyclic stretch. Conclusions These data suggest that cyclic stretch inhibits the morphological and biological decidual process of HESCs. Our findings imply that uterine abnormal contractions during the implantation period impair endometrial decidualization and contribute to infertility., Alterations to F‐actin localization in non‐decidualized HESCs and decidualized HESCs with or without cyclic stretch.

Interestingly, only the D‐form of firefly luciferin produces light by luciferin–luciferase (L–L) reaction. Certain firefly luciferin analogues with modified structures maintain bioluminescence (BL) activity; however, all L‐form luciferin analogues show no BL activity. To this date, our group has developed luciferin analogues with moderate BL activity that produce light of various wavelengths. For in vivo bioluminescence imaging, one of the important factors for detection sensitivity is tissue permeability of the number of photons emitted by L–L reaction, and the wavelengths of light in the near‐infrared (NIR) range (700–900 nm) are most appropriate for the purpose. Some NIR luciferin analogues by us had performance for in vivo experiments to make it possible to detect photons from deep target tissues in mice with high sensitivity, whereas only a few of them can produce NIR light by the L–L reactions with wild‐type luciferase and/or mutant luciferase. Based on the structure–activity relationships, we designed and synthesized here a luciferin analogue with the 5‐allyl‐6‐dimethylamino‐2‐naphthylethenyl moiety. This analogue exhibited NIR BL emissions with wild‐type luciferase (λ max = 705 nm) and mutant luciferase AlaLuc (λ max = 655 nm).

Background A hepatitis A epidemic occurred among men who have sex with men (MSM) in Japan in 2017–2018. In this study, we employ a parsimonious mathematical model to epidemiologically investigate the dynamics of infection, aiming to evaluate the effectiveness of campaign-based interventions among MSM to raise awareness of the situation. Methods A mathematical model describing a mixture of human-to-human transmission and environmental transmission was fitted to surveillance data. Taking seasonally varying environmental transmission into account, we estimated the reproduction number of hepatitis A virus during the course of epidemic, and, especially, the abrupt decline in this reproduction number following campaign-based interventions. Results The reproduction number prior to the countermeasures ranged from 2.6 to 3.1 and then began to decrease following campaign-based interventions. After the first countermeasure, the reproduction number decreased, but the epidemic remained supercritical (i.e., Rt > 1). The value of Rt dropped well below one following the second countermeasure, which used web articles to widely disseminate information about the epidemic risk. Conclusions Although the effective reproduction number, Rt, changes because of both intrinsic and extrinsic factors, the timing of the examined countermeasures against hepatitis A in the MSM population was consistent with the abrupt declines observed in Rt. Even without vaccination, the epidemic was brought under control, and risky behaviors may have been changed by the increase in situation awareness reached through web articles.

Implantation is a highly organized process that involves an interaction between a competent blastocyst and a receptive uterus. Despite significant research efforts, the molecular mechanisms governing this complex process remain elusive. Here, we investigated the effect of dicalcin, an S100-like Ca2+-binding protein, on the attachment of choriocarcinoma cells (BeWo cells) onto a monolayer of endometrial carcinoma cells (Ishikawa cells). Extracellularly administered dicalcin bound to both BeWo and Ishikawa cells. Pretreatment of BeWo spheroids with dicalcin reduced the attachment ratio of the spheroids onto the monolayer, whereas that of Ishikawa cells showed no apparent change. We identified the partial amino acid sequence of human dicalcin that exhibited maximum suppression for BeWo spheroid attachment. Transmission electron microscopy analysis revealed that the dicalcin-derived peptide caused a dilation of the intercellular junction between BeWo and ISK cells. Peptide treatment of BeWo spheroids downregulated the expression of integrinαvβ3 in BeWo cells, and induced alterations in their phalloidin-staining pattern, as measured by the length of each F-actin fiber and the thickness of the cortical stress fiber. Thus, dicalcin affects reorganization of the intracellular actin meshwork and subsequently the intensity of attachment, functioning as a novel suppressor of implantation.

Background Anti-programmed cell death 1 antibody is a standard therapy for advanced non-small cell lung cancer (NSCLC). However, immune-related adverse events (irAEs), such as skin reactions, are frequently observed. Although skin reactions are associated with clinical efficacy in melanoma, this association in advanced NSCLC and predictors of irAEs remain unclear. Accordingly, this study identified potential correlations of skin reactions with clinical efficacy and clinical predictors of development of skin reactions. Subjects, Materials, and Methods We retrospectively surveyed patients with advanced NSCLC who received nivolumab or pembrolizumab monotherapy at Sendai Kousei Hospital (n = 155) during January 2016 to April 2018. Treatment efficacy was evaluated in patients with and without skin reactions, and associated predictive markers were determined. A 6-week landmark analysis was conducted to assess the clinical benefit of early skin reactions. Results Skin reactions were observed in 51 patients with a median time to onset of 6.4 weeks. The overall response rate (ORR) was significantly higher in patients with skin reactions (57% vs. 19%, p < .001). Median progression-free survival (PFS) durations of 12.9 and 3.5 months and overall survival durations of not reached and 11.4 months were observed in patients with and without skin reactions, respectively. In the 6-week landmark analysis, the ORR was significantly higher in patients with skin reactions, and skin reactions were significantly associated with increased PFS. A multivariate analysis identified pre-existing rheumatoid factor (RF) as an independent predictor of skin reactions. Conclusion Skin reactions appeared beneficial in patients treated with nivolumab/pembrolizumab for advanced NSCLC and could be predicted by pre-existing RF. Further large-scale validations studies are warranted.

As a means of achieving highly sensitive bioluminescence imaging of deep tissues utilizing the firefly luciferin-luciferase (L-L) reaction, we previously reported a luciferin analogue, AkaLumine, which exhibits high cell-permeability and emits near-infrared (NIR) light with high tissue-penetration by the L-L reaction. However, while AkaLumine enables us to observe targets in deep tissues, its poor solubility in aqueous media limits its utility for in vivo imaging. Herein, to address this issue, we have synthesized three AkaLumine derivatives with N-heterocyclic aromatic rings as new red luciferin analogues that have substantially higher solubility than that of AkaLumine in phosphate buffered saline solution. One of the derivatives (herein termed seMpai) exhibits an emission maximum at 675 nm upon L-L reaction with Photinus pyralis luciferase and presents an activity in mouse-tissue imaging similar to that of AkaLumine. It is hoped that seMpai will extend the application of high-sensitivity NIR bioluminescence imaging in a wide range of biomedical research fields.

Firefly bioluminescence, which produces high-efficiency light, is widely used in life science applications. For in vivo bioluminescence imaging, the near-infrared range (650–900 nm) is suitable bec...

The firefly bioluminescence reaction has been exploited for in vivo optical imaging in life sciences. To develop highly sensitive bioluminescence imaging technology, many researchers have synthesized luciferin analogs and luciferase mutants. This chapter first discusses synthetic luciferin analogs and their structure–activity relationships at the luminescence wavelength of the firefly bioluminescence reaction. We then discuss the development of luciferin analogs that produce near-infrared (NIR) light. Since NIR light is highly permeable for biological tissues, NIR luciferin analogs might sensitively detect signals from deep biological tissues such as the brain and lungs. Finally, we introduce two NIR luciferin analogs (TokeOni and seMpai) and a newly developed bioluminescence imaging system (AkaBLI). TokeOni can detect single-cell signals in mouse tissue and luminescence signals from marmoset brain, whereas seMpai can detect breast cancer micro-metastasis. Both reagents are valid for in vivo bioluminescence imaging with high sensitivity.

Bioluminescence reactions are widely applied in optical in vivo imaging in the life science and medical fields. Such reactions produce light upon the oxidation of a luciferin (substrate) catalyzed by a luciferase (enzyme), and this bioluminescence enables the quantification of tumor cells and gene expression in animal models. Many researchers have developed single-color or multicolor bioluminescence systems based on artificial luciferin analogues and/or luciferase mutants, for application in vivo bioluminescence imaging (BLI). In the current review, we focus on the characteristics of firefly BLI technology and discuss the development of luciferin analogues for high-resolution in vivo BLI. In addition, we discuss the novel luciferin analogues TokeOni and seMpai, which show potential as high-sensitivity in vivo BLI reagents.

T-cell acute lymphoblastic leukemia (T-ALL) is a hardly curable disease with a high relapse rate. 20 analogs were synthesized based on the structures of two kinds of fungi-derived polyenylpyrrole products (rumbrin (1) and auxarconjugatin-B (2)) to suppress the growth of T-ALL-derived cell line CCRF-CEM and tested for growth-inhibiting activity. The octatetraenylpyrrole analog gave an IC50 of 0.27 μM in CCRF-CEM cells, while it did not affect Burkitt lymphoma-derived cell line Raji and the cervical cancer cell line HeLa, or the oral cancer cell line HSC-3 (IC50 > 10 μM). This compound will be a promising compound for developing T-ALL-specific drugs.

Altered levels of brain-derived neurotrophic factor (BDNF) have been reported in neurologically diseased human brains. Therefore, it is important to understand how the expression of BDNF is controlled under pathophysiological as well as physiological conditions. Here, we report a method to visualize changes in BDNF expression in the living mouse brain using bioluminescence imaging (BLI). We previously generated a novel transgenic mouse strain, Bdnf-Luciferase (Luc), to monitor changes in Bdnf expression; however, it was difficult to detect brain-derived signals in the strain using BLI with d-luciferin, probably because of incomplete substrate distribution and light penetration. We demonstrate that TokeOni, which uniformly distributes throughout the whole mouse body after systematic injection and produces a near-infrared bioluminescence light, was suitable for detecting signals from the brain of the Bdnf-Luc mouse. We clearly detected brain-derived bioluminescence signals that crossed the skin and skull after intraperitoneal injection of TokeOni. However, repeated BLI using TokeOni should be limited, because repeated injection of TokeOni on the same day reduced the bioluminescence signal, presumably by product inhibition. We successfully visualized kainic acid-induced Bdnf expression in the hippocampus and sensory stimulation-induced Bdnf expression in the visual cortex. Taken together, non-invasive near-infrared BLI using Bdnf-Luc mice with TokeOni allowed us to evaluate alterations in BDNF levels in the living mouse brain. This will enable better understanding of the involvement of BDNF expression in the pathogenesis and pathophysiology of neurological diseases.

Although anti-PD-1/PD-L1 monotherapy has achieved clinical success in non-small cell lung cancer (NSCLC), definitive predictive biomarkers remain to be elucidated. In this study, we performed whole-transcriptome sequencing of pretreatment tumor tissue samples and pretreatment and on-treatment whole blood samples (WB) samples obtained from a clinically annotated cohort of NSCLC patients (n = 40) treated with nivolumab (anti-PD-1) monotherapy. Using a single-sample gene set enrichment scoring method, we found that the tumors of responders with lung adenocarcinoma (LUAD, n = 20) are inherently immunogenic to promote antitumor immunity, whereas those with lung squamous cell carcinoma (LUSC, n = 18) have a less immunosuppressive tumor microenvironment. These findings suggested that nivolumab may function as a molecular targeted agent in LUAD and as an immunomodulating agent in LUSC. In addition, our study explains why the reliability of PD-L1 expression on tumor cells as a predictive biomarker for the response to nivolumab monotherapy is quite different between LUAD and LUSC.

Introduction: Immune checkpoint inhibitors (ICIs) can lead to immune-related adverse events (irAEs). A correlation between the development of irAEs and efficacy has been suggested; however, it is unclear whether there is a relationship between programmed death ligand 1 (PD-L1) expression and the development of these events. Methods: We performed a retrospective study of advanced or metastatic non-small cell lung cancer (NSCLC) patients who were treated with pembrolizumab monotherapy at our institution between May 2015 and April 2018 (n = 44). Patients were categorized into two groups, specifically those with irAEs (irAE group) or without (non-irAE group), and we evaluated the objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Predictors of irAEs were examined by multivariate analysis. Results: irAEs of any grade occurred in 31 (70.5%) patients. The median PFS was 10.9 months in the irAE group versus 3.7 months in the non-irAE group (P < 0.001). ORR and DCR were also higher in the irAE group than in the non-irAE group. Furthermore, high PD-L1 expression (≥50%) was a predictive factor of irAE based on logistic regression (P = 0.004). Conclusions: In patients with advanced NSCLC treated with pembrolizumab monotherapy, ORR, DCR, and PFS were significantly better in the irAE group than in the non-irAE group. High PD-L1 expression, at the time of pretreatment, was identified as an independent predictor of irAE development. We believe that more careful management of irAEs for individuals with high PD-L1 expression is needed to improve clinical benefits. Further, PD-L1 expression might be useful for ICI risk management.

e21097 Background: Although anti-PD-1/PD-L1 monotherapy has achieved clinical success in non-small cell lung cancer (NSCLC), definitive predictive biomarkers remain to be elucidated. We assumed that by combining gene expression signatures with patient clinical data, we could identify a novel promising biomarker to predict response to anti-PD-1/PD-L1 monotherapy in NSCLC patients. Moreover, the characterization of these signatures will help us to decipher the complexity of tumor-immune interactions and better understand the tumor microenvironment (TME) that favors clinical response to nivolumab monotherapy. Methods: From clinically annotated NSCLC patients (n = 40) with nivolumab monotherapy in the second- or later-line settings, we prospectively collected tumor tissues and peripheral blood mononuclear cells (PBMCs) before first dose of nivolumab and PBMCs after first 4 or 5 doses of nivolumab. All tumor tissue and PBMC samples obtained were applied to whole-transcriptome sequencing (RNA-seq). We extracted transcriptomic datasets of lung adenocarcinoma (LUAD) (n = 20) and lung squamous cell carcinoma (LUSC) (n = 18) from the results, separately analyzed each histological subtype. To elucidate biological processes associated with clinical outcomes, we performed a supervised gene set enrichment analysis (GSEA) approach and an unsupervised single sample scoring approach. Results: In LUAD, we observed that gene sets related to interferon (type I and II) signaling (‘IFN signatures’) and antigen processing and presentation (‘APP signatures’) were significantly enriched in pre-treatment PBMCs of responders. IFN and APP signatures, which are closely related to each other, functionally cooperate to activate anti-tumor immune response. The enrichment of IFN and APP signatures provides the possibility that responders have a pre-existing anti-tumor immunity prior to nivolumab monotherapy. In LUSC, neither IFN nor APP signatures were enriched in pre-treatment tumor tissues and PBMCs of responders. Instead, gene sets related to the regulation of the TME (‘TME signatures’) are significantly enriched in pre-treatment tumor tissues of non-responders. The enrichment of TME signatures suggested that non-responders have an extremely immunosuppressive TME. These findings highlighted that responsive LUAD inherently have a high immunogenicity to elicit effective anti-tumor responses, whereas responsive LUSC have a similar level of immunogenicity as non-responsive LUSC but are free from an extremely immunosuppressive TME. Conclusions: We found that nivolumab enhanced anti-tumor immunity in patients with LUAD in a quite different way from patients with LUSC. Our study provides a blueprint for innovating combinational immunotherapy and supporting patient selection and treatment strategies on long-term clinical outcomes.

Bioluminescence imaging (BLI) is useful to monitor cell movement and gene expression in live animals. However, D-luciferin has a short wavelength (560 nm) which is absorbed by tissues and the use of near-infrared (NIR) luciferin analogues enable high sensitivity in vivo BLI. The AkaLumine-AkaLuc BLI system (Aka-BLI) can detect resolution at the single-cell level; however, it has a clear hepatic background signal. Here, to enable the highly sensitive detection of bioluminescence from the surrounding liver tissues, we focused on seMpai (C15H16N3O2S) which has been synthesized as a luciferin analogue and has high luminescent abilities as same as AkaLumine. We demonstrated that seMpai BLI could detect micro-signals near the liver without any background signal. The solution of seMpai was neutral; therefore, seMpai imaging did not cause any adverse effect in mice. seMpai enabled a highly sensitive in vivo BLI as compared to previous techniques. Our findings suggest that the development of a novel mutated luciferase against seMpai may enable a highly sensitive BLI at the single-cell level without any background signal. Novel seMpai BLI system can be used for in vivo imaging in the fields of life sciences and medicine.

IMPORTANCE: Administration of anti–programmed cell death protein 1 (anti–PD-1) is now standard therapy in advanced non–small cell lung cancer (NSCLC). However, immune checkpoint inhibitors, including anti–PD-1, have not been assessed in patients with subclinical disease with advanced NSCLC, and no useful clinical biomarkers have been associated with immune-related adverse events (irAEs) among these patients treated with anti–PD-1. OBJECTIVE: To assess the safety and efficacy of anti–PD-1 treatment in patients with subclinical disease with advanced NSCLC and with or without preexisting autoimmune markers, including rheumatoid factor, antinuclear antibody, antithyroglobulin, and antithyroid peroxidase; and to assess potential clinical biomarkers that may be meaningfully and conveniently associated with clinical benefit or with irAEs following anti–PD-1 treatment. DESIGN, SETTING, AND PARTICIPANTS: This medical records analysis retrospectively evaluated 137 patients who received nivolumab or pembrolizumab monotherapy at Sendai Kousei Hospital in Japan between January 2016 and January 2018. Treatment efficacy and irAEs were evaluated along with candidate factors that may be associated with irAEs. EXPOSURES: Absence or presence of specific autoimmune markers and antibodies before treatment. MAIN OUTCOMES AND MEASURES: Preexisting antibodies and autoimmune markers, progression-free survival (PFS), and irAEs. RESULTS: Of 137 patients with advanced NSCLC, 105 were men, the median age was 68 (range, 36-88) years, 99 underwent nivolumab monotherapy, 38 underwent pembrolizumab monotherapy, and 134 had an Eastern Cooperative Oncology Group performance status of 0 or 1. The median PFS was 6.5 (95% CI, 4.4-12.9) months among patients with examined preexisting antibodies and 3.5 (95% CI, 2.4-4.1) months among patients without, suggesting significantly better prognosis in the former. The hazard ratio for disease progression or death in the presence of the examined preexisting antibodies was 0.53 (95% CI, 0.36-0.79; P = .002). The PFS was significantly longer among patients with any preexisting antibodies than among those without. The examined preexisting antibodies (48 patients [73%]) and rheumatoid factor (26 patients [39%]) were more common among patients who developed irAEs. Multivariate analysis indicated that the presence of the examined preexisting antibodies was independently associated with irAEs (odds ratio, 3.25; 95% CI, 1.59-6.65; P = .001). Skin reactions were more frequent among patients with preexisting rheumatoid factor (47% vs 24%, P = .02), whereas thyroid dysfunction was more frequent among patients with preexisting antithyroid antibodies (20% vs 1%, P

Background Immune-related adverse events (irAEs) are frequently observed with nivolumab monotherapy. This study aimed to evaluate whether the development of irAEs correlates with treatment response in advanced non-small-cell lung cancer (NSCLC). Patients and Methods We conducted a retrospective study of patients who received nivolumab monotherapy at Sendai Kousei Hospital (n = 70). The patients were categorized into two groups based on the incidence of irAEs: those with irAEs (irAE group) or those without (non-irAE group). Treatment efficacy was evaluated in each group. The patients were further categorized into responders and nonresponders, and predictive factors of treatment response were determined. Results The objective response rate was 57% in the irAE group versus 12% in the non-irAE group. Median progression-free survival was 12.0 months in the irAE versus 3.6 months in the non-irAE group. The incidence of both irAEs and pre-existing antithyroid antibody was significantly higher in responders than in nonresponders. Multivariate analysis identified incidence of irAEs and pre-existing antithyroid antibody as an independent predictor of treatment response. Conclusion Objective response rate and progression-free survival were significantly better in the irAE than in the non-irAE group in patients with advanced NSCLC treated with nivolumab monotherapy. The development of irAEs was associated with clinical efficacy, and the presence of pre-existing antithyroid antibody might be correlated with treatment response to nivolumab monotherapy. Implications for Practice Immune-related adverse events (irAEs) are frequently observed with nivolumab monotherapy. This study evaluted whether the development of irAEs correlates with treatment response in advanced non-small-cell lung cancer. Results showed that the objective response rate and progression-free survival were significantly better in the patients who developed irAEs than in the patients who did not develop irAEs, and the incidence of irAEs and positivity for antithyroid antibody at pretreatment were independent predictors of treatment response of nivolumab monotherapy. Therefore, the development of irAEs predicts clinical benefit and suggests that cautious management of irAEs can lead to achieving maximum clinical benefit from nivolumab monotherapy.

7 pages; International audience; Reversibility and number-conservation are widely studied physics-like constraints for cellular automata (CA). Although both seem to be 'natural' constraints for a CA, it was conjectured that one-dimensional reversible and number-conserving CA (RNCCA) only has a limited computing ability. Particularly in the case of radius 1/2 (2-neighbor), it was shown that the class of RNCCA is equal to a trivial class of CA, so called shift-identity product cellular automata (SIPCA). But recently it was also shown that a RNCCA of neighborhood size four is computation-universal. In this paper, we list radius 1 (3-neighbor) RNCCAs up to 4-state by exhaustive search. In contrast to the radius 1/2 case, there are three new types of nontrivial RNCCA rules in the case of 4-state. We also show that it is possible to compose new nontrivial RNCCAs by modifying a SIPCA even when the state number is larger than four.

In this paper, we formulate an age-structured epidemic model for the demographic transition in which we assume that the cultural norms leading to lower fertility are transmitted amongst individuals in the same way as infectious diseases. First, we formulate the basic model as an abstract homogeneous Cauchy problem on a Banach space to prove the existence, uniqueness, and well-posedness of solutions. Next based on the normalization arguments, we investigate the existence of nontrivial exponential solutions and then study the linearized stability at the exponential solutions using the idea of asynchronous exponential growth. The relative stability defined in the normalized system and the absolute (orbital) stability in the original system are examined. For the boundary exponential solutions corresponding to infection-free or totally infected status, we formulate the stability condition using reproduction numbers. We show that bi-unstability of boundary exponential solutions is one of conditions which guarantee the existence of coexistent exponential solutions.

The electrical resistance and magnetoresistance of Fe70Ni30 Invar alloy have been measured at high pressure up to 15GPa. It is found that the coefficients of T2 term in the electrical resistance increases with increasing pressure but tends to saturate above 12GPa suggesting a peak above 15GPa, which implies a pressure-induced quantum phase transition. We found for the first time that the magnetoresistance at 4.2K is negative below 11GPa but becomes positive above 12GPa. This corresponds to a crossover in the electronic state from localized moment regime to a paramagnetic or new magnetic state. The origins will be discussed briefly in connection with the recent experimental results and theoretical calculation.

Firefly bioluminescence is widely used in life science research as a useful analysis tool. For example, the adenosine-5`-triphosphate (ATP)-dependent enzymatic firefly bioluminescence reaction has long been utilized as a microbial monitoring tool. Rapid and sensitive firefly luciferin-luciferase combinations are used not only to measure cell viability but also for reporter-gene assays. Recently, bioluminescence was utilized as a noninvasive, real-time imaging tool for living subjects to monitor cells and biological events. However, the number of commercialized luciferase genes is limited and tissue-permeable near-infrared (NIR) region emitting light is required for in vivo imaging. In this review, recent studies describing synthetic luciferin analogues predicted to have red-shifted bioluminescence are summarized. Luciferase substrates emitting red, green, and blue light that were designed and developed in our laboratory are presented. The longest emission wavelength of the synthesized luciferin analogues was recorded at 675 nm, which is within the NIR region. This compound is now commercially available as "Aka Lumine®".