The globalization of drug development has resulted in an increasing implementation of multiregional clinical trials (MCTs) in Japan. However, ethnic variations and low Japanese patient population in MCTs may impact post-marketing drug safety. This study compared the frequency of safety-related package insert revisions between drugs developed through MCTs and those developed otherwise (non-MCTs) in Japan and the United States. The analysis also investigated factors contributing to racial differences and the prevalence of MCTs. We retrospectively analyzed 227 new active-ingredient drugs approved in Japan between 2012 and 2021. Data on package insert revisions within 5 years of approval were collected from the Pharmaceuticals and Medical Devices Agency and the U.S. Food and Drug Administration databases. Comparisons were made by development method (MCT vs. non-MCT), metabolic enzyme polymorphisms, drug classification, approval process, and manufacturer. In Japan, the mean number of package insert revisions within 5 years was significantly higher for MCT drugs than for non-MCT drugs (0.28 vs. 0.17, p = 0.040). In the United States, no significant difference between MCT and non-MCT drugs was observed. Antineoplastic drugs and immunosuppressants demonstrated higher revision frequencies in both countries, with overall revisions greater in the United States than in Japan. MCT-developed drugs and antineoplastic/immunosuppressant drugs require careful post-marketing safety evaluation in Japanese patients. Differences in regulatory systems and post-marketing surveillance likely contribute to the observed variation in revision frequency between Japan and the United States.

Malnutrition, a global health problem, impairs immune function and increases susceptibility to infection. The thymus, a primary lymphoid organ, is highly sensitive to nutritional status and is known to undergo atrophy under malnutrition. However, the temporal progression of thymic changes during malnutrition remains unclear. In this study, we used a mouse model of short-term starvation, in which dietary intake was completely withheld for 24 or 48 h to model acute fasting. The thymus of 48-h-starved mice, but not that of 24-h-starved mice, exhibited marked atrophy with a significant reduction in absolute weight. Expression levels of Th2-associated cytokines, including Il5, Il6, and Il10, were increased following 48 h of starvation, indicating polarization of Th0 cells toward a Th2-like phenotype. These phenotypic changes were not observed after 24 h of starvation. In addition, the protein level of type IV collagen was elevated in the thymus of 48-h-starved mice, proposing that dietary-restriction-induced remodeling of thymic extracellular matrix represents a novel mechanism underlying acute fasting-induced immunodeficiency.

This retrospective study examined patients with advanced or recurrent gastric cancer who received nivolumab monotherapy as a third-line or later treatment at Saitama Cancer Center (Saitama, Japan) between January 2018 and June 2022. The aim was to assess the incidence of immune-related adverse events (irAEs) and explore their association with patient prognosis. Patients who experienced Grade 1 or higher irAEs, as defined by the Common Terminology Criteria for Adverse Events version 5.0, were categorized into the irAE group, whereas those without irAEs comprised the non-irAE group. Among the 134 patients analyzed, 38 (28.4%) developed irAEs, with skin disorders and hypothyroidism being the most common. Overall survival (OS) was significantly longer in the irAE group (median OS: 13.23 months; 95% confidence interval [CI]: 6.94–24.83) than in the non-irAE group (median OS: 4.83 months; 95% CI: 3.76–5.63) (p < 0.001). Significant differences were also observed between the two groups in terms of primary tumor resection and disease stage (p < 0.05). Multivariate analysis identified the presence of irAEs (hazard ratio [HR]: 0.23) and subsequent treatments after nivolumab (HR: 0.29) as favorable prognostic factors. Conversely, elevated alkaline phosphatase levels were associated with poorer outcomes (HR: 1.64) (p < 0.001). These findings suggest that the development of irAEs during nivolumab monotherapy may be linked to improved survival outcomes in patients with advanced or recurrent gastric cancer.

Neuroinflammation induced by microglial activation has recently attracted attention as a cause of neurodegenerative diseases, such as Alzheimer’s disease (AD). Candida albicans is a prevalent fungal species in human microbiota, and suspected of causing AD through neuroinflammation, as C. albicans has been detected in the brain tissue of AD patients, and the intravenous injection of C. albicans induced mild memory impairment, accompanied by C. albicans invasion of the brain and neuroinflammation in mice. However, the detailed mechanism by which C. albicans induces neuroinflammation remains unclear. In this study, we showed that candidalysin, a cytolytic peptide toxin secreted by C. albicans, induces the production of the inflammatory cytokine IL-6 accompanied by nuclear translocation of nuclear factor-kappaB (NF-κB) through the degradation of inhibitor of κBα (IκBα) in the human microglial cell line HMC3. We also found that candidalysin induced autophagy, and that an autophagy inhibitor suppressed candidalysin-induced IκBα degradation, nuclear translocation of NF-κB, and IL-6 mRNA expression. These findings suggest that candidalysin triggers autophagy, which induces inflammatory responses via NF-κB in human microglia. Thus, the present study may have uncovered an important pathway for neuroinflammation via microglia when C. albicans invades the brain.

In Western countries, magnesium sulfate (MgSO₄) for threatened preterm labor is recommended as short-term tocolysis (₄ tocolysis on maternal renal function. This retrospective observational study included pregnant women hospitalized for threatened preterm labor who received MgSO₄ therapy at Fukuoka University Hospital between January and December 2021. Eligible patients were ≥18 years old, ≥22 weeks of gestation, and treated with MgSO₄ for ≥24 h. A total of 66 patients were classified into short-term (n = 26) and long-term (≥48 h) group (n = 40). The primary outcome was the incidence of acute kidney injury (AKI). Secondary outcomes included changes in serum creatinine level (ΔCr; peak – baseline) and correlations between ΔCr and Mg exposure (duration, daily dose, serum Mg concentration). Neonatal laboratory values at birth were also assessed. AKI occurred in 0% and 2.5% (1/40) of the short- and long-term groups, respectively; the affected case met creatinine-based AKI criteria but impairment was not clinically significant. ΔCr showed a weak positive correlation with treatment duration (ρ = 0.321, P = 0.009), while daily Mg dose and serum Mg levels were not correlated. Long-term group neonates showed higher serum Mg (P = 0.038) and lower Ca (P = 0.045). Long-term MgSO₄ tocolysis may cause mild renal burden but appears unlikely to induce clinically significant maternal renal dysfunction under careful monitoring. Maternal and neonatal electrolyte monitoring is advisable during prolonged MgSO₄ therapy.

Plexin (Plxn) family molecules are the receptor for semaphorins and their involvement in tumor malignancy is also demonstrated. However, the regulatory roles of Plxns in cancer-stemness have not been completely understood. Previously we found that Sema3a and its receptor PlxnA1 confer the high proliferative capacity and the resistance against epidermal growth factor receptor (EGFR) inhibitors to mouse-derived lewis lung cancer (LLC) cells constitutively expressing green fluorescent protein (GFP) (LLC-GFP). Here we show that PlxnA1 is essential for maintaining cancer stem-like property of LLC-GFP-derived cancer stem cells (LLC-GFPstem). Plxna1 knockdown downregulated stem cell markers, Sox2 and Cd44, in LLC-GFPstem cells. Importantly, the sphere-forming and tumorigenic capacity of LLC-GFPstem cells was lost by Plxna1 knockdown. These results demonstrate that PlxnA1 is essential for LLC-GFPstem cells to maintain their cancer stem-like properties.

Thymic involution is a hallmark of aging characterized by reduced thymic size and function, leading to impaired T lymphocyte development and increased susceptibility to infection and cancer. While previous studies have described histological and cellular changes during thymic aging, the impact on vasculature and extracellular matrix (ECM) organization remains incompletely understood. In this study, we analyzed thymic tissue from young (8–10 weeks) and aged (18–27 weeks) mice to investigate age-associated changes in blood vessels and ECM components. Immunohistochemical analysis revealed that CD34-positive blood vessels in the cortex were abundant, elongated, and oriented toward the medulla in young thymus, but were significantly reduced and structurally disorganized in aged thymus. In contrast, CD31-positive vessels were localized mainly in the medulla and remained largely unaffected. ECM proteins laminin and tenascin-C displayed well-aligned vascular structures in young mice, but became more dispersed and mesh-like in aged thymus. Collagen type I, prominently detected in large blood vessels and some microvessels in young thymus, was nearly absent in aged samples. These structural changes were accompanied by a specific upregulation of Mmp3 mRNA, encoding matrix metalloproteinase-3, which is known to degrade ECM proteins and disrupt vascular integrity. The remodeling of blood vessels and ECM in the aged thymus may weaken the blood-thymus barrier, impair T lymphocyte development, and contribute to inflammaging. Our findings provide new insights into the microenvironmental deterioration of the thymus with age and identify vascular and ECM remodeling as potential therapeutic targets to mitigate age-related immune decline.

Background: Migraine impairs daily functioning, and concerns persist about underdiagnosis, inappropriate pharmacotherapy, and medication-overuse headache (MOH). Triptan access has widened in Japan, with stepped-care guidance, yet avoiding overuse remains difficult. Methods: Using NDB Open Data Releases 1–9 (FY2014–FY2022), we quantified annual outpatient and community-pharmacy triptan prescriptions. Volumes were stratified by sex, drug, and 5-year age bands, and absolute/percentage changes were calculated versus FY2014. To contextualize age-structure shifts, we referenced total patient counts for ICD-10 G43 from the e-Stat Patient Survey (2014, 2017, 2020, 2023). Associations between sex and drug were tested by chi-square on contingency tables aggregated across releases. Results: Total prescriptions approximately doubled by FY2022 (31,095,293 tablets), comprising 6,219,190 for males and 24,876,103 for females (~4-fold female predominance). All five triptans increased, with the largest gains for rizatriptan (~2.3×) and eletriptan (~2.2×). The greatest increases occurred in males aged 15–19 years (~2.78×) and 60–64 years (~2.73×) and in females aged 55–59 years (~2.58×) and 15–19 years (~2.56×). The modal age band shifted from 40–44 years in FY2014 to 45–49 years in FY2022. Sex-by-drug distribution differed significantly (χ², p<0.0001); in FY2022, rizatriptan predominated in males (followed by sumatriptan) and eletriptan in females (followed by rizatriptan). Conclusions: From 2014 to 2022, triptan use in Japan rose with persistent female predominance, growth among adolescents (particularly males) and middle-to-older adults, and an older peak age. Findings suggest contributions from expanded care-seeking, rising social burden, chronification, and MOH. Multilevel actions—early diagnosis, rational use with MOH prevention, school/workplace support, timely specialist referral, and proactive pharmacist engagement—are warranted.

In Japan, wiping with distilled water and disinfectant ethanol is the most common method of cleaning biological safety cabinets (BSCs). In 2020, an electrolyzed water generator WOX-30WA-M2 was approved for hand disinfection. This medical device generates hypochlorite water (0.0035% hypochlorous acid and 0.015% hydrochloric acid: HClO water) and alkaline electrolyzed water (0.03% sodium hydroxide: AEW) from salt water. We investigated whether a new cleaning method for BSCs using HClO water and AEW is superior to the conventional cleaning method in removing anticancer drug residues. A model using stainless steel plates contaminated with cyclophosphamide (CPA) was prepared, and the level of CPA residue remaining after wiping was compared with the conventional method. The new cleaning method was more effective than the conventional method with respect to the level of CPA residue remaining. High-performance liquid chromatography was employed to confirm the effect of various solvents on CPA removal. The peak area of CPA decreased with increasing chlorine concentration, accompanied by the appearance of 3-chloro-CPA.Although the sum of CPA and 3-chloro-CPA areas could provide a more comprehensive evaluation of total compound recovery, accurate quantification was not feasible in this study because 3-chloro-CPA is unstable and no certified standard was available. As an alternative, we confirmed the qualitative restoration of CPA after solid-phase extraction (SPE) treatment, suggesting that the apparent loss was mainly due to reversible formation of chlorinated derivatives rather than irreversible degradation. Use of an electrolyzed water for cleaning BSCs should reduce inhalation exposure due to evaporation of residual anticancer agents and also reduce alcohol use. Sequential wipe-off of HClO water and AEW is non-corrosive to stainless steel and maintains the effectiveness of sanitization and antifouling, suggesting this is a safe method for cleaning BSCs.

Organotin compounds are synthetic organometallic compounds with high lipophilicity, persistence, and slow degradation rates in the environment, which promote bioaccumulation and biomagnification through the food chain. Tributyltin (TBT) is widely used in antifouling paints, wood preservatives, and pesticides. It persists in sediments and enters the human diet via seafood. Exposure has been detected in breast milk and umbilical cord blood. In mammals, organotin compounds demonstrate efficient gastrointestinal absorption, are distributed in lipid-rich organs, that is, the liver, adipose tissue, adrenal glands, and brain, and are primarily excreted via bile and feces. Regarding its mechanism of action, TBT disrupts endocrine and cellular homeostasis through multiple pathways. It disturbs steroid production, acting as an agonist for RXR/PPARγ to promote lipogenesis, impairs mitochondrial function, increases reactive oxygen species, disrupts Ca²⁺ balance, and induces intrinsic apoptosis. Immunotoxicity and developmental toxicity are issues of concern. The neurotoxic effects include increased blood–brain barrier permeability, localized brain accumulation, glutamate-mediated excitotoxicity, and sustained downregulation of the AMPA subunit GluA2 via NRF-1. This renders neurons Ca²⁺ permeable and vulnerable to stress. Although TBT is the most studied species, comparative findings for its metabolites, dibutyltin and monobutyltin, remain fragmentary, and chronic and life-stage-specific risks have not been fully elucidated. In this review, I have synthesized the current knowledge on environmental sources, fate, and mammalian toxicity and outlined priority areas for risk assessment.

The use of nanoparticles in various industrial fields is increasing. Aluminum oxide nanoparticles (nAlO) exhibit excellent functionality and are thus widely used for industrial purposes. However, the potential biological hazards of nAlO have not been addressed. Therefore, we investigated the in vivo effects and drug interactions of nAlO. Administration of nAlO to mice via the tail vein induced acute kidney injury but not liver injury. nAlO induced kidney injury when co-administered with cisplatin or 5-aminosalicylic acid. Thus, our results indicate that nAlO exhibits potential nephrotoxicity either alone or through drug interactions.

The developing brain establishes mature neural circuits through processes such as neuronal differentiation and synapse formation. However, these processes are susceptible to disruption by external factors, including exposure to environmental chemicals. These disruptions have been associated with neurodevelopmental disorders, such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). This underscores the increasing significance of developmental neurotoxicity (DNT) assessment. However, conventional DNT testing methods are extremely costly and time-consuming, making broad in vivo coverage of the large number of chemicals in use impractical. Therefore, there is an increasing international demand for more efficient, quantitative screening approaches. Bioluminescence imaging (BLI) using reporter transgenic (Tg) mice enables the noninvasive visualization of gene expression and signal transduction in living animals and has been widely applied in fields such as oncology and regenerative medicine. This review highlights recent advances in the application of reporter Tg mice to assess DNT and explores their potential applications in DNT screening, chemical risk assessment, and future research on developmental neurotoxicity.

Hinoki cypress (Chamaecyparis obtusa) is an evergreen conifer endemic to Japan. The benefits of hinoki fragrance for the central nervous system have garnered increasing attention, and its inhalation is gaining popularity. While hinoki essential oils are available from various manufacturers, the growing regions of the trees and plant parts used for extraction differ among products, and the characteristic benefits of each product are not clearly defined. In this study, we performed gas chromatography with flame ionization detection (GC-FID) and GC-MS analysis on ten commercial hinoki essential oils, one from leaf and nine derived from wood, to examine differences in volatile components between plant parts and among wood-derived samples. The results showed that sabinene, bornyl acetate and α-terpinyl acetate were the major components in leaf-derived oils, while α-pinene and δ-cadinene predominated in wood-derived oils. Among the wood-derived samples, the ratio of α-pinene to δ-cadinene was categorized into three distinct patterns: samples with higher α-pinene content, samples with higher δ-cadinene content, and samples in which both components were present in nearly equal amounts. Differences in chemical composition and the relative proportion of components may influence the physiological effects of hinoki essential oil. Evaluating how these variations affect health benefits could contribute to product quality assessment and help establish tailored applications for each specific chemical profile.

Objective: Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with early onset. Sleep disturbances in children with ADHD may impair attention and learning and exacerbate symptoms. Maintaining good sleep is crucial in ADHD treatment. This study investigated the effects of ADHD medications on subjective and objective sleep in children under 18, employing actigraphy and a questionnaire. Methods: This single-centre prospective observational study enrolled patients under 18 receiving methylphenidate (MPH), lisdexamfetamine (LDX), atomoxetine (ATX), or guanfacine (GXR) between June 1 and August 31, 2022. Patients using other drugs were excluded. Subjective sleep was assessed using the Athens Insomnia Scale (AIS), and objective sleep variables were analysed using an actigraph worn on the waist. Results: A total of 21 patients were enrolled. AIS total scores of 4 or more were significantly more common in GXR-treated patients (P = 0.009) than in ATX-treated patients. However, other variables were not statistically significant. Among patients receiving non-psychostimulant monotherapy, sleep time was longer (P = 0.045), and postural changes were more frequent (P < 0.001) than in those receiving combined psychostimulant and non-psychostimulant therapy. Conclusions: Findings suggest ATX may improve subjective sleep more effectively than GXR. A trend toward shorter sleep period time was observed in the combined group, likely due to the arousal effects of psychostimulants. Reduced postural changes in the combined group may indicate altered sleep structure.

Patients undergoing hemodialysis face a significantly elevated risk of cardiovascular disease (CVD) mortality. Uremic toxins, particularly indoxyl sulfate (IS) and p-cresyl sulfate (PCS), accumulate in patients undergoing dialysis and contribute to cardiovascular complications. Although IS and PCS concentrations are often assessed individually, this pilot study developed and validated an integrated scoring system combining these values to improve CVD mortality prediction. This prospective study included 66 patients undergoing hemodialysis at the Hitoyoshi Medical Center between 2008–2018. The IS + PCS score was calculated using Cox proportional hazards analysis. The primary endpoint was CVD death. The IS + PCS score was strongly associated with CVD mortality. IS alone exhibited high sensitivity (91.67%) but low specificity (44.44%), whereas PCS alone showed high specificity (92.59%) but low sensitivity (25.00%). The IS + PCS score achieved balanced sensitivity (83.33%) and specificity (57.41%), with a higher F1 score (0.44) than that of IS alone (0.41) and PCS alone (0.32). Leave-one-out cross-validation confirmed internal validity (mean C-index: 0.645). The IS + PCS score demonstrated potential as a prognostic predictor of CVD mortality in patients undergoing hemodialysis. While the score achieved balanced sensitivity and specificity, with an F1 score exceeding that of the individual markers, time-dependent receiver operating characteristic analysis showed no superiority over IS alone at any time point. These findings suggest that the integrated score combines the complementary strengths of both toxins, but requires validation in larger cohorts to establish clinical superiority.

5-Hydroxymethylcytosine (5hmC) is beginning to be expected to play a role as a diagnostic and prognostic marker of diseases. On the other hand, we developed the methylated-site display-amplified fragment length polymorphism (MSD-AFLP), an affordable, large-scale (approximately 40,000-50,000 CpG sites), highly sensitive methylation profiling method, and applied it to environmental health and disease biomarker discovery research. Herein, we attempted to modify the MSD-AFLP method to detect 5hmC. To validate this method, we compared hydroxymethylation levels among tissues using mouse samples to determine whether this method could detect tissue-specific differential 5hmC. We also considered combining this method with next generation sequencing (NGS). Comparisons using AFLP revealed that in some sites, the variation in hydroxymethylated DNA was greater than that in methylated DNA between tissues. Therefore, we determined the hydroxymethylation levels at these sites using Glucosylation-mediated restriction enzyme sensitive qPCR (gRES-qPCR) to confirm the accuracy of the AFLP analysis. The differences in hydroxymethylation levels between tissues were similar between the two methods. The protocol for combination with NGS was evaluated by comparing the AFLP data with 11 DNA fragments. The differences in hydroxymethylation levels between tissues were similar between the two methods. Cluster analysis demonstrated that NGS data were comparable to AFLP data in detecting differential and contrasting hydroxymethylation patterns across tissues. This method, based on the MSD-AFLP technique, will contribute to various epigenetics-based research, including the discovery of biomarkers and therapeutic drug targets.