Tohoku J. Exp. Med. [JOURNAL]
Sun
200 papers
KLF16-induced Increase of GARS Promotes Glycolysis in Hepatocellular Carcinoma by Stabilizing FOXK1.
Wang J, Fan R, Li J … +2 more , Qi H, Lin L
Tohoku J Exp Med · 2025 Dec · PMID 40603105 · Publisher ↗
Reprogramming of glucose metabolism is a hallmark of hepatocellular carcinoma (HCC); however, the intrinsic mechanisms underlying this phenomenon remain unclear. The present study aimed to investigate the role and potent...
Reprogramming of glucose metabolism is a hallmark of hepatocellular carcinoma (HCC); however, the intrinsic mechanisms underlying this phenomenon remain unclear. The present study aimed to investigate the role and potential mechanism of glycyl-tRNA synthetase (GARS) in HCC glycolysis. Our results revealed an increase in the expression of Kruppel-like factor 16 (KLF16) and forkhead box K1 (FOXK1) in HCC tissues and correlated with an unfavorable prognosis. Mechanistically, we demonstrated that KLF16 binds to the promoter region of GARS, thereby enhancing its transcription. Subsequently, the GARS protein then binds to FOXK1, resulting in reduced ubiquitination and increased stability of FOXK1. FOXK1 then promotes glycolysis by directly stimulating the transcription of lactate dehydrogenase A, pyruvate kinase M2 and glucose transporter 1 in HCC cells. Additionally, KLF16 knockdown inhibited glycolysis in HCCLM3 cells both in vitro and in vivo. Collectively, these findings indicate that the KLF16-GARS-FOXK1 axis plays a critical role in regulating HCC growth and glycolysis. Targeting this pathway may hold a promising therapeutic strategy for HCC treatment.
Blue Light-Blocking Glasses Attenuate Light-Induced Melatonin Suppression in Healthy Japanese Adults.
Onodera Y, Kubota N, Miyagi N … +4 more , Matsuura N, Muramatsu S, Kato Y, Yamanaka Y
Tohoku J Exp Med · 2026 May · PMID 40603104 · Publisher ↗
The human circadian pacemaker entrains to the environmental light-dark cycle and regulates daily sleep-wake patterns and various physiological functions. The circadian pacemaker receives light input from the retina via t...
The human circadian pacemaker entrains to the environmental light-dark cycle and regulates daily sleep-wake patterns and various physiological functions. The circadian pacemaker receives light input from the retina via the retinohypothalamic tract, which contains intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing melanopsin. These ipRGCs are most sensitive to blue light (460-480 nm). Exposure to blue light before bedtime disrupts sleep and circadian rhythms, whereas blue light-blocking glasses have been shown to attenuate light-induced melatonin suppression. This study evaluated the effectiveness of commercially available blue light-blocking glasses (BG) in protecting nocturnal melatonin secretion under bright light conditions (~2,000 lux at eye level, 5,800K) in healthy Japanese adults. Seven participants (3 males, 4 females; age 22 ± 4 years) were exposed to 3 light conditions: dim light (< 5 lux, DL), bright light (~2,000 lux, BL), and bright light with blue light-blocking glasses (BL+BG). The BG block wavelengths shorter than 500 nm and reduce light intensity by 51%. Saliva samples were collected hourly from 20.0 h to 23.0 h and every 30 minutes from 23.5 h to 1.0 h in a controlled laboratory setting. Melatonin levels significantly decreased in the BL condition compared to the DL condition throughout the experiment. In contrast, melatonin levels in the BL+BG condition were not significantly different from those in the DL condition. These findings imply that blue light-blocking glasses attenuate light-induced melatonin suppression and help prevent phase-delay shifts of circadian rhythms. Further research is necessary to assess the broader effects of these glasses on sleep and circadian rhythms.
The Association of High Mobility Group Box-1 with Sepsis Susceptibility and Mortality Risk: A Meta-Analysis.
Yang S, Song X, Jin X … +1 more , Huang X
Tohoku J Exp Med · 2026 Jun · PMID 40603103 · Publisher ↗
High mobility group box-1 (HMGB1) regulates inflammation, immune response, DNA repair, and cell death, which is crucial in the pathogenesis of sepsis; while its role in sepsis susceptibility and mortality risk remains in...
High mobility group box-1 (HMGB1) regulates inflammation, immune response, DNA repair, and cell death, which is crucial in the pathogenesis of sepsis; while its role in sepsis susceptibility and mortality risk remains inconsistent. Hence, this meta-analysis systemically investigated the dysregulation level of HMGB1 and its association with mortality risk. PubMed, Web of Science, Embase, and Cochrane Library databases were searched until May 2024. Studies written in English and comparing HMGB1 level in serum or plasma detected by enzyme-linked immunosorbent assay between adult sepsis patients and controls, or non-survivors and survivors of sepsis, were eligible. Twenty-eight studies containing 3,110 subjects were included. The quality of studies was satisfactory evaluated by the Newcastle-Ottawa scale. Pooled analyses showed that HMGB1 was increased in sepsis patients versus controls (P < 0.001). Subgroup analysis revealed that HMGB1 was increased in sepsis patients versus healthy controls (P < 0.001), but less varied between sepsis patients and non-sepsis controls (P = 0.081). Additionally, HMGB1 was elevated in non-survivors versus survivors of sepsis (P = 0.030). Publication bias existed in HMGB1 differences between sepsis patients and controls; but it was adjusted using the trim-and-fill method, and the statistical significance did not change after that. Sensitivity analysis indicated acceptable robustness. In conclusion, this study suggests the potential of HMGB1 to serve as a possible biomarker for sepsis diagnosis and mortality risk stratification.
miR-324-3p Drives Malignant Behaviors of Tumor Cells by Promoting M2 Macrophage Polarization in Laryngeal Squamous Cell Carcinoma.
Huang J, Chen X, Chen X
Tohoku J Exp Med · 2026 Mar · PMID 40571644 · Publisher ↗
Laryngeal squamous cell carcinoma (LSCC) ranks first in mortality among head and neck tumors. MicroRNA (miR)-324-3p has a dual role depending on the tumor type. Currently, biological significance of miR-324-3p in LSCC ne...
Laryngeal squamous cell carcinoma (LSCC) ranks first in mortality among head and neck tumors. MicroRNA (miR)-324-3p has a dual role depending on the tumor type. Currently, biological significance of miR-324-3p in LSCC needs to be validated. The study attempts to make clear whether miR-324-3p modulates cell malignancy by interacting with tumor-associated macrophages in LSCC. THP-1-differentiated macrophages were co-cultured with LSCC cells to mimic tumor microenvironment in vitro. The viability, migration, and invasion of LSCC cells were assessed by cell counting, wound-healing, and transwell invasion assays. Evaluation of the expression of CD163, CD206, and miR-324-3p was undertaken by quantitative polymerase chain reaction. Determination of CD163 and CD206 protein levels was done by western blot. The release of Transforming growth factor-beta (TGF-β) and interleukin-10 were detected by enzyme-linked immunosorbent assay. Higher expression of miR-324-3p was observed in LSCC cells. The polarization of Macrophage type 2 (M2-type) macrophages was promoted and the viability, migration, and invasion of TU177 cells were strengthened in the co-culture system. Furthermore, miR-324-3p silencing decreased the polarization of M2-type macrophages, along with reduced viability, migration, and invasion of TU177 cells. Conversely, miR-324-3p overexpression drove the polarization of M2-type macrophages, accompanied by elevated malignant behaviors of TU686 cells. Interestingly, dysregulation of miR-324-3p did not affect the viability, migration and invasion of LSCC cells in the absence of co-incubation with macrophages. The miR-324-3p facilitates malignant behaviors of tumor cells by promoting M2 macrophage polarization in LSCC, suggesting that miR-324-3p may be a promising target for LSCC treatment by mediating the tumor microenvironment.
Ligustilide Promotes Gastric Cancer Cell Apoptosis via Endoplasmic Reticulum Stress-Induced Mitochondrial Dysfunction and Autophagy.
Liu H, Xiang Q, Mei S … +5 more , Yang J, Ma D, Wang B, Song E, Zhu H
Tohoku J Exp Med · 2026 Apr · PMID 40571643 · Publisher ↗
Ligustilide is a natural benzoquinone derivative with many pharmacological properties, including anticancer and anti-inflammatory activities. Here, we investigated the antitumor efficacy of ligustilide in gastric cancer....
Ligustilide is a natural benzoquinone derivative with many pharmacological properties, including anticancer and anti-inflammatory activities. Here, we investigated the antitumor efficacy of ligustilide in gastric cancer. MKN74 and AGS cells were treated with 20, 60, and 100 µM ligustilide. The antitumor efficacy of ligustilide was studied with MTT assays, colony formation assays, and flow cytometry. Apoptosis-, endoplasmic reticulum stress-, and autophagy-associated proteins were examined by immunoblotting and immunofluorescence. JC-1 staining was used to detect mitochondrial membrane potential in cancer cells. Tumor-bearing mice were intraperitoneally injected with 5 mg/kg ligustilide. Tumor weight and tumor volume were measured after 20 days of administration. We demonstrated that ligustilide suppressed gastric cancer cell proliferation by inducing cell cycle arrest and apoptosis. Mechanistically, ligustilide disrupted mitochondrial function by increasing the Bax/Bcl-2 ratio, triggering cytochrome c release into the cytoplasm, and activating caspase-3 and PARP cleavage, ultimately leading to mitochondrial membrane potential loss. Furthermore, ligustilide enhanced autophagy, as evidenced by elevated LC3-II/LC3-I ratio and ATG5 expression, accompanied by reduced p62 levels. This autophagic response was mediated through endoplasmic reticulum stress via the PERK-eIF2α-CHOP pathway. Notably, the proapoptotic effects of ligustilide were attenuated by 4-phenylbutyric acid (an ER stress inhibitor) or 3-methyladenine (an autophagy inhibitor). Consistent with in vitro findings, 4-phenylbutyric acid also abrogated the antitumor efficacy of ligustilidein vivo by concurrently suppressing apoptosis and autophagy.Overall, ligustilide triggers mitochondrial dysfunction, autophagy, and endoplasmic reticulum stress, collectively promoting gastric cancer cell death and suppressing survival.
Modulation of Th17/Treg Balance by Total Flavonoids from Semen Cuscutae through PGRMC2 in a Diminished Ovarian Reserve Rat Model.
Zhou T, Xu S, Tang J … +3 more , Han X, Jiang Y, Chen H
Tohoku J Exp Med · 2026 Mar · PMID 40571642 · Publisher ↗
Diminished ovarian reserve (DOR) is a critical challenge in reproductive health, leading to reduced fertility and hormonal imbalances. Current treatments such as assisted reproductive technologies and hormone replacement...
Diminished ovarian reserve (DOR) is a critical challenge in reproductive health, leading to reduced fertility and hormonal imbalances. Current treatments such as assisted reproductive technologies and hormone replacement therapy often have limited success and adverse effects. Progesterone receptor membrane component 2 (PGRMC2) is a protein essential for various reproductive processes and is involved in ovarian folliculogenesis, with its increased expression associated with DOR. This study investigates the protective mechanisms of total flavonoids from Semen Cuscutae (TFSC) on ovarian reserve through PGRMC2 modulation and T helper 17 cell (Th17)/regulatory T cell (Treg) immune balance in a DOR rat model. DOR was induced in rats by administering 50 mg/kg tripterygium glycosides (TG) via intragastric administration once daily for 15 days. Various analytical techniques were used to assess the effects of TFSC, including immunohistochemistry for ovarian tissue analysis, Western blotting to measure PGRMC2 protein expression, flow cytometry for evaluating Th17/Treg ratio, and Enzyme-linked immunosorbent assay (ELISA) to quantify serum cytokine levels. Results demonstrate that TFSC enhances ovarian function, up-regulates PGRMC2 expression, and restores immune homeostasis, highlighting its potential as an alternative therapeutic strategy. By elucidating TFSC's role in immune modulation and ovarian function, this study paves the way for developing targeted therapies to improve outcomes for women with DOR.
Comparative Analysis of Perinatal Outcomes in Type 1 and Type 2 Diabetes Pregnancies: A Retrospective Study.
Sue-Nagumo M, Morita A, Higeta D … +8 more , Inoue M, Osaki A, Yoshino S, Matsumoto S, Horiguchi K, Okada S, Iwase A, Yamada E
Tohoku J Exp Med · 2025 Nov · PMID 40571641 · Publisher ↗
The prevalence of type 1 (T1D) and type 2 (T2D) diabetes in reproductive women is rising. Subclinical hyperglycemia's impact on adverse pregnancy outcomes is evident. Nevertheless, the variance in outcomes between T1D an...
The prevalence of type 1 (T1D) and type 2 (T2D) diabetes in reproductive women is rising. Subclinical hyperglycemia's impact on adverse pregnancy outcomes is evident. Nevertheless, the variance in outcomes between T1D and T2D pregnancies is not well-defined. We retrospectively analyzed 68 pregnancies (28 T1D, 40 T2D) at the Gunma University Hospital (Dec 2017-Mar 2022), examining maternal characteristics, insulin therapy, prepregnancy body mass index (BMI), glycated hemoglobin (HbA1c) levels, daily insulin dose, gestational weight gain, and perinatal outcomes. In T1D pregnancies, those with large-for-gestational age (LGA) infants had less improvement in HbA1c early in pregnancy and greater weight gain overall. Notably, even non-obese women with T1D often gained excessive weight, which was closely tied to LGA risk. The risk increased sharply when third-trimester HbA1c exceeded 48 mmol/mol (6.5%). These findings suggest that, despite significant gestational weight gain, insulin doses may not have been sufficiently escalated to match increased insulin resistance, contributing to both poor glycemic control and a higher risk of LGA in T1D pregnancies. Our study underscores the importance of tailoring insulin therapy and weight management to reduce LGA risk in T1D. As the use of advanced technologies such as continuous glucose monitoring (CGM), continuous subcutaneous insulin infusion (CSII), and sensor-augmented pump (SAP) therapy continues to expand in pregnancy care, ongoing data updates will be essential to refine clinical strategies and improve maternal and neonatal outcomes.
Dysregulated Long Non-Coding RNA DANCR in Polycystic Ovary Syndrome Drives Granulosa Cell Apoptosis and Contributes to Ovarian Dysfunction via miR-185-5p.
An J, Zhou Q, Liu X … +4 more , Ren J, Cheng Y, Liu Y, Cao Z
Tohoku J Exp Med · 2026 Mar · PMID 40571640 · Publisher ↗
This study investigates the expression patterns of lncRNA differentiation antagonizing non-protein coding RNA (DANCR) and microRNA (miR)-185-5p, and their potential roles in the pathogenesis of polycystic ovary syndrome...
This study investigates the expression patterns of lncRNA differentiation antagonizing non-protein coding RNA (DANCR) and microRNA (miR)-185-5p, and their potential roles in the pathogenesis of polycystic ovary syndrome (PCOS). Involved 100 patients with PCOS as the case group and 80 non-PCOS patients with fallopian tube diseases as the control group. The relative levels of serum DANCR and miR-185-5p were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Pearson's method was performed to estimate the correlation between DANCR and abnormal indicators in the PCOS group. The effects of DANCR and miR-185-5p on cell viability and apoptosis were evaluated by Cell Count Kit (CCK)-8 assay and flow cytometry. The target relationship between DANCR and miR-185-5p was verified via a luciferase reporter assay. Compared with the control group, DANCR expression was elevated, while miR-185-5p levels were reduced in the serum of patients with PCOS. When further grouped, patients with PCOS and insulin resistance (IR) showed higher DANCR levels and lower miR-185-5p levels than those without IR. Receiver operator characteristic (ROC) curve analysis displayed that the sensitivity and specificity of DANCR to distinguish PCOS from control groups were 74.0% and 88.7%, respectively. In KGN cells, down-regulation of DANCR expression enhanced cell viability and suppressed cell apoptosis by elevating miR-185-5p levels. Luciferase reporter gene assays confirmed that miR-185-5p directly targeted DANCR and was negatively regulated by DANCR. Our findings suggest that dysregulated upregulation of DANCR might promote granulosa cell apoptosis and impair cell viability by repressing miR-185-5p, thereby exacerbating POCS progression.
Immunolocalization of CD28, CTLA-4 and CD80 in Non-Small Cell Lung Carcinoma: Combined CD28/CTLA-4/CD80 Status is a Potent Prognostic Factor of These Patients.
Sato T, Takagi K, Inoue C … +8 more , Higuchi M, Sakuma N, Kojimahara M, Sagawa M, Tanaki M, Hojo H, Suzuki T, Suzuki O
Tohoku J Exp Med · 2026 May · PMID 40533179 · Publisher ↗
The cellular immune response to tumors is regulated by the competition between the CD28 and CTLA-4 molecules on T cells for CD80 on the surface of antigen-presenting cells (APCs). It has been reported that CD80 expressio...
The cellular immune response to tumors is regulated by the competition between the CD28 and CTLA-4 molecules on T cells for CD80 on the surface of antigen-presenting cells (APCs). It has been reported that CD80 expression plays a critical role in tumor immune responses in malignant tumors, and the clinical pathological significance of CD80 and CTLA-4 expression in lung carcinoma has also been discussed. We previously demonstrated that the immunolocalization of CD80 is an adverse prognostic factor in patients with non-small cell lung carcinoma (NSCLC). However, no studies have reported the expression of CD28, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and CD80 in lung carcinoma simultaneously, and the significance of these molecules in T cells function remains unclear. Therefore, in this study, we immunolocalized CD28, CTLA-4 and CD80 in 119 NSCLC tissues and examined the significance of their cooperative interactions. The death rate of the patients who detected 2 or 3 factors among the CD28-low, CTLA-4-high, and CD80-high status groups was much higher (18-46%) than those who showed 0 and 1 factor (0% and 13%, respectively). When we classified CD28/CTLA-4/CD80 status according to their expression, it was significantly associated with stage, pT, lymph node metastasis, histological type, and programmed cell death-ligand 1 (PD-L1). Moreover, multivariate analysis demonstrated that CD28/CTLA-4/CD80 combined status was an independent, poor prognostic factor. Therefore, CD28/CTLA-4/CD80 combined status is suggested a potent prognostic factor in the NSCLC. This is possibly because their cooperative interactions potently regulate T cells function in NSCLC, leading to a worse prognosis.
HSPA1B Regulates the Expression of Blood Pressure Related Genes in Human Umbilical Vein Endothelial Cells (HUVECs) and Its Mechanism.
Zhong L, Zhang B, Nafeisha K … +2 more , Xilinguli W, Kurexi Y
Tohoku J Exp Med · 2025 Dec · PMID 40533178 · Publisher ↗
This study explores the regulatory effects of Heat Shock Protein A1B (HSPA1B) on gene expression related to blood pressure in Human Umbilical Vein Endothelial Cells (HUVECs) and delineates its underlying mechanisms. Give...
This study explores the regulatory effects of Heat Shock Protein A1B (HSPA1B) on gene expression related to blood pressure in Human Umbilical Vein Endothelial Cells (HUVECs) and delineates its underlying mechanisms. Given the global prevalence of hypertension as a major risk factor for cardiovascular and cerebrovascular diseases, understanding its molecular underpinnings is crucial. We utilized cloning, cell culture, RNA isolation, cDNA synthesis, PCR amplification, high-throughput sequencing, and alternative splicing analysis to evaluate the impact of HSPA1B overexpression on HUVECs. The findings revealed that HSPA1B overexpression leads to significant changes in gene expression and alternative splicing patterns, implicating various molecular pathways. Notably, genes associated with inflammation, immune response, apoptosis, and endothelial function were upregulated, while others were downregulated. These alterations suggest that HSPA1B may influence endothelial cell responses under stress conditions. This study provides insights into the molecular mechanisms that could contribute to hypertension development and identifies HSPA1B as a potential area for further research in therapeutic strategies to manage this condition.
Evaluation and Comparison of Intervertebral Disc Degeneration Models Induced by Cervical Instability in Rats.
Wang Y, Chen J, Zhang D … +9 more , Lin H, Fan X, Lu S, Huang Y, Guo W, Liang J, Huang Z, Hu H, Liu Q
Tohoku J Exp Med · 2026 Jun · PMID 40533177 · Publisher ↗
Creating intervertebral disc degeneration (IDD) models is paramount for basic research. The investigation was to identify the commonalities and distinctions between two strategies for provoking IDD: the cervical dorsal m...
Creating intervertebral disc degeneration (IDD) models is paramount for basic research. The investigation was to identify the commonalities and distinctions between two strategies for provoking IDD: the cervical dorsal muscles resection (CMS) and the facet joints resection (FR). Thirty-two 3-month-old male Sprague Dawley rats were randomly split into four groups: FR, CMS and two shams. For the CMS group, the cervical dorsal muscles was excised, whereas, the FR cohort sawed the bilateral facet joints of C5/6. Twelve weeks postprocedure, C5/6 intervertebral discs were collected, and the bone microstructure of C5 vertebrae were analyzed by Micro-CT, as well as the defect rates of C5/6 vertebral endplates and the intervertebral disc height (IDH) of C5/6. Finally, histological staining was employed to evaluate the disc degeneration scores (DDS). Twelve weeks post operatively, both CMS and FR groups demonstrated significant IDD, with the pronounced deterioration of vertebral endplates, a diminished intervertebral height, and a notably elevated disc degeneration score within the model rats. Yet, the two models also exhibited distinct features. Primarily, the FR rats showed a significant boost in vertebral bone volume fraction, a trend not visible in the CMS rats. Additionally, the CMS rats presented more advanced endplate deterioration. Lastly, the CMS rats revealed a reduced IDH and an elevated DDS in comparison to the FR rats. Both CMS and FR prove successful in causing IDD. Nonetheless, a comparison of the two models revealed a more profound degeneration of the intervertebral disc in CMS rats relative to FR counterparts.
Bacillus Licheniformis Capsules (Live) Modulates Gut Microbiota and Enhances Immune Function in Chemotherapy Patients with Non-Small Cell Lung Cancer.
Yu J, Shi H, Wang X … +4 more , Lu S, Sun C, Jin W, Shu Y
Tohoku J Exp Med · 2026 May · PMID 40533176 · Publisher ↗
This study investigates the impact of Bacillus Licheniformis Capsules (live) on patients with non-small cell lung cancer (NSCLC) undergoing chemotherapy. Clinical data from 79 NSCLC patients who developed grade 2-3 diarr...
This study investigates the impact of Bacillus Licheniformis Capsules (live) on patients with non-small cell lung cancer (NSCLC) undergoing chemotherapy. Clinical data from 79 NSCLC patients who developed grade 2-3 diarrhea during the first cycle of chemotherapy and admitted to our hospital between March 2020 and February 2023 were retrospectively analyzed and assigned to a control group (n = 42, treated from March 2020 to June 2022 with Pemetrexed + Cisplatin regimen) and a study group (n = 37, treated from July 2022 to February 2023 with Pemetrexed + Cisplatin regimen + Bacillus Licheniformis Capsules) based on their treatment regimens. The study group exhibited significantly higher overall response rate compared to the control group (P < 0.05). Post-treatment, both groups exhibited decreased levels of Enterococcus, Enterobacteriaceae, interleukin (IL)-4, IL-17, high-sensitivity C-reactive protein, and improved Functional Assessment of Cancer Therapy-Lung scores, with more pronounced improvements in the study group. Levels of Lactobacillus, Bifidobacterium, and interferon gamma increased significantly, with greater increases in the study group (P < 0.05). Both groups showed reductions in CD3, CD4, CD4/CD8 ratio, waist-to-hip ratio, and body mass index post-treatment, but these markers remained higher in the study group. CD8+ levels increased in both groups post-treatment but were much lower in the study group (P < 0.05). No significant difference was noted in the complication rates between the 2 groups. Bacillus Licheniformis Capsules (live) enhances the efficacy of chemotherapy in NSCLC patients by modulating gut microbiota, reducing inflammatory responses, and improving immune function and quality of life, without compromising safety.
Cimetidine for Pediatric Use in Japan: Rising Prescriptions for a New Indication.
Oshima K, Inage E, Toriumi S … +9 more , Oishi K, Yamada H, Baba Y, Kudo T, Ohtsuka Y, Nishikomori R, Nakamura H, Michihata N, Shoji H
Tohoku J Exp Med · 2026 Jan · PMID 40533175 · Publisher ↗
Cimetidine is effective for treating periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome, primarily in children, and is covered by public insurance in Japan. However, as demand for ga...
Cimetidine is effective for treating periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome, primarily in children, and is covered by public insurance in Japan. However, as demand for gastric ulcer treatment declines, cimetidine production has been restricted, raising concerns about supply for pediatric patients. We analyzed Japanese prescription trends in adults and children using publicly available data. Specifically, national reimbursement data were used to assess annual cimetidine prescription volumes by age group and pediatric share. Chronological changes were examined based on original formulation supply. In the database, 11 and 6 cimetidine products (including discontinued stock) were available for outpatient and in-hospital dispensing, respectively. Annually, 1.01 million and 80,000 cimetidine tablets (200-mg equivalents) were dispensed for patients under 15 years in outpatient and in-hospital settings, respectively. No inpatient prescriptions were recorded. Pediatric prescriptions peaked at ages 5-9 years, differing from adult trends, and accounted for 2.5% of total prescriptions. Although overall dispensing volumes are declining, pediatric prescriptions are increasing. Despite overall demand decreasing, approximately 1 million 200-mg cimetidine tablets are needed annually for use in children, and pediatric demand is increasing. Therefore, securing production of this new indication is essential.
Gaze Patterns of Children with Communication Difficulties Associated with Core Symptoms of Autism Spectrum Disorder.
Kobayashi M, Kobayashi T, Obara T … +16 more , Narita A, Miyake A, Suzuki T, Ishikuro M, Orui M, Kodama EN, Shimizu R, Hamanaka Y, Izumi Y, Hozawa A, Fuse N, Kikuchi A, Tamiya G, Kure S, Kuriyama S, Yamamoto M
Tohoku J Exp Med · 2026 Apr · PMID 40500226 · Publisher ↗
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interactions. There is an urgent need to establish objective, simple, and accurate screening and diagnostic methods for ASD...
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interactions. There is an urgent need to establish objective, simple, and accurate screening and diagnostic methods for ASD in childhood. Recently, the ability to visualize and quantify eye movements has emerged, suggesting that ASD may exhibit characteristic gaze patterns. To examine the potential of gaze patterns as an early marker of ASD, we analyzed the relationship between gaze patterns at ages 4-6 and individual ASD characteristics, as determined by the Autism Spectrum Quotient Japanese version for children (AQ-J-child) at age 6, using data from 4- to 6-year-old children recruited into the BirThree Cohort Study of the Tohoku Medical Megabank Project. The median gaze rate, which represents the percentage of time the subjects spent looking at the screen during the test, was 92%, reflecting the highly versatile nature and proper execution of this test in our study. We found that children with social impairment tend to prefer looking at geometric patterns. In addition, children with communication difficulties tend to spend less time looking at the eyes in still images of human faces. Our analyses of the relationships between various gaze results and ASD characteristics defined by AQ-J-child revealed that specific gaze preferences are significantly associated with communication difficulties, social impairment, and impaired imagination. These findings indicate that the gaze measurement results show strong correlations with specific aspects of ASD. Therefore, gaze patterns demonstrate the potential to reflect one aspect of ASD.
Age-Specific Trends and Health Status of Children Aged 12-19 Years with Specified Chronic Pediatric Diseases in Japan - Insights from a National Database Study.
Kuwahara E, Moriichi A, Kato H
Tohoku J Exp Med · 2026 Apr · PMID 40500225 · Publisher ↗
Japan has a national financial assistance program called the "Specified Chronic Pediatric Diseases of Japan" (SCPDJ; also called "Shouman" in Japanese) for children with chronic diseases designated by the Japanese Minist...
Japan has a national financial assistance program called the "Specified Chronic Pediatric Diseases of Japan" (SCPDJ; also called "Shouman" in Japanese) for children with chronic diseases designated by the Japanese Ministry of Health, Labour and Welfare. The information of registrants in the system is digitized for research. We utilized the database to clarify the characteristics of children with diseases designated by the SCPDJ program. Analysis was performed with a particular focus on patients aged 12-19 years, which are considered the important ages for transition support from pediatric to adult medical care. The data included 69,061 cases aged 0 to 19 years from April 2016 to March 2017. The number of registrants showed a cumulative increase from 2 years toward adulthood. There were four distribution patterns for registered age and age at onset by disease category: 1) both age and age of onset peaked at age 0; 2) age distribution was mostly flat, while the most common age of onset was age 0; 3) age distribution peaked in older age groups, while age of onset of 0 was most common; and 4) both age and age of onset peaked at older ages. Approximately half of the patients aged 12-19 years were diagnosed after reaching school age. Although the disease condition of most patients remained good, some aged 12-19 years experienced exacerbation. The database was analyzed to provide an overview of children with diseases designated by the SCPDJ program and issues related to transition to adult care systems.
The Utility of a Modified Data-Driven Motion Correction Method Incorporating Computed Tomography Positional Data for Positron Emission Tomography.
Odagiri H, Watabe H, Takanami K … +9 more , Yamaguchi N, Kawakami H, Katsuki A, Tanaka Y, Takeuchi T, Kodama H, Usui A, Takase K, Kaneta T
Tohoku J Exp Med · 2026 Apr · PMID 40500224 · Publisher ↗
In positron emission tomography/computed tomography (PET/CT), long image acquisition time often causes patient motion and misalignment between the PET and CT images. This misalignment can compromise the accuracy of atten...
In positron emission tomography/computed tomography (PET/CT), long image acquisition time often causes patient motion and misalignment between the PET and CT images. This misalignment can compromise the accuracy of attenuation correction and quantitative values, thus affecting diagnostic reliability. Recently, data-driven motion correction (DDMC) methods have been developed to detect motion using brief static PET images, and our previous study also demonstrated the effectiveness of the DDMC method. However, DDMC assumes alignment between PET reference images and CT scans used for attenuation correction. When patients move after CT scan, the PET and CT images misalign, necessitating rescanning or manual realignment. The present study introduces a modified approach, namely DDMC+CT, that integrates CT positional data into the DDMC process to address PET/CT misalignment. We evaluated the DDMC+CT approach using a phantom study and clinical images. The phantom study simulated PET/CT misalignment by moving a Hoffman phantom post-CT scan, with contrast and standardized uptake values (SUV) compared with and without DDMC+CT. The clinical images included whole-body PET/CT scans with head and neck motion, where quantitative and visual assessments were performed. The DDMC+CT method successfully corrected PET/CT misalignment in phantom and clinical images, yielding SUV and contrast values consistent with reference images, resulting in improved diagnostic accuracy. The DDMC+CT method demonstrates a potential for clinical application, where it may minimize rescans and reduce patient and operator burden by allowing automatic misalignment correction.
Assessment of the Physical Properties, Drug Loadability and Release Profile, and Biocompatibility of UniPearls® Microspheres.
Guo F, Xu M, Ren B … +1 more , Han F
Tohoku J Exp Med · 2026 Mar · PMID 40500223 · Publisher ↗
Microspheres based transarterial chemoembolization is important for liver cancer treatment. UniPearls is a novel product of microspheres featuring a uniform particle size and independently developed in China. This study...
Microspheres based transarterial chemoembolization is important for liver cancer treatment. UniPearls is a novel product of microspheres featuring a uniform particle size and independently developed in China. This study aimed to investigate the physical properties, drug loading and releasing ability, and biocompatibility of UniPearls. Various experiments were performed including: compression rupture, suspendability, simulated use, drug loading, drug releasing, cytotoxicity, mouse lymphoma assay (MLA), muscle implant, intradermal reaction, guinea pig maximization test (GPMT), and systemic toxicity. UniPearls or UniPearls extraction liquid was set as experimental group(s), while HepaSphere or related extraction liquid was set as control group(s). UniPearls showed no microsphere rupture after compression to 1 μm for 10 or 20 min, but some ruptures for 30 min, and microspheres were successfully suspended in a short time. In a 3-dimensional (3D) hepatic artery model, UniPearls exhibited no microsphere break, delivery block, shape change or unexpected catheter outflow during simulated experiment. The maximum loading rates of 40-100 mg doxorubicin and irinotecan were 100% and 97.4% by UniPearls, respectively; then the releasing rates at plateaus with different-dose doxorubicin and irinotecan ranged 34.0%-46.5% and 85.6%-91.8%, respectively. In vitro experiments revealed no cytotoxicity or impact on inducing gene mutation by UniPearls. In vivo experiments disclosed no local reaction, skin sensitization, obvious acute/subchronic systemic toxicity symptoms by UniPearls. Besides, the above indexes were not different between UniPearls and controls (HepaSphere or related extraction liquids). UniPearls serves as a good product of microspheres, benefiting from its satisfied physical properties, drug loadability, releasing ability and biocompatibility.
Analysis of the Correlation between SLC6A4 rs1042173 Gene Polymorphisms and the Effect of Sufentanil Epidural Labor Analgesia in Pregnant Women.
Ma X, Tang J, Shen Y … +3 more , Wang B, Liu J, Wu X
Tohoku J Exp Med · 2026 Mar · PMID 40500222 · Publisher ↗
Sufentanil exhibits potent analgesic efficacy with a prolonged duration of action, making it a frequently utilized agent for labor analgesia. This study aimed to investigate the association between SLC6A4 rs1042173 polym...
Sufentanil exhibits potent analgesic efficacy with a prolonged duration of action, making it a frequently utilized agent for labor analgesia. This study aimed to investigate the association between SLC6A4 rs1042173 polymorphisms and the efficacy of sufentanil epidural analgesia during labor in primiparous women. This study enrolled 288 full-term primiparas eligible for vaginal delivery. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was utilized to detect the SLC6A4 rs1042173 polymorphism. The Hardy-Weinberg equilibrium test was conducted to assess the representativeness of the samples relative to the population. Logistic regression analysis was performed to examine the association between the SLC6A4 rs1042173 polymorphism and labor analgesia, as well as to identify independent influencing factors. The pharmacokinetics of sufentanil in pregnant women were significantly influenced by the SLC6A4 rs1042173 polymorphism. The Visual Analogue Scale (VAS) indicated that the SLC6A4 rs1042173 genotype significantly influenced the analgesic response patterns in pregnant women. In the early stages of drug action, the TT and TG genotypes exhibited higher sensitivity (P < 0.001). Regarding specific adverse reactions, significant differences were noted in the incidences of nausea, urinary retention, and abnormal fetal heart rate monitoring among pregnant women with different genotypes (P < 0.05). Logistic regression analysis revealed significant correlations between the rs1042173 polymorphism and both the VAS score at 2 hours (P = 0.014) post-administration and the Activity, Pulse, Grimace, Appearance, Respiration (Apgar) scores at 1 minute (P < 0.001) of newborns. SLC6A4 rs1042173 gene polymorphisms were significantly associated with the analgesic efficacy of sufentanil epidural anesthesia in primiparas.
Sex-Difference in Olfactory Interhemispheric Malformation Caused by Pax6 Haploinsufficiency.
Joko N, Kikkawa T, Inoue T … +1 more , Osumi N
Tohoku J Exp Med · 2025 Aug · PMID 40467486 · Publisher ↗
Sex differences are increasingly recognized as critical factors influencing the onset and manifestation of various neurodevelopmental disorders, including autism spectrum disorder (ASD). Among ASD-associated genes, Pax6,...
Sex differences are increasingly recognized as critical factors influencing the onset and manifestation of various neurodevelopmental disorders, including autism spectrum disorder (ASD). Among ASD-associated genes, Pax6, which encodes a transcription factor, has been implicated in sex-dependent phenotypes when mutated. The anterior commissure (AC), a major commissural pathway involved in higher cognitive and social functions, exhibits structural abnormalities both in individuals with ASD and in those carrying Pax6 mutations. Anatomically, the AC consists of two principal fiber bundles: the anterior limb (aAC), connecting the olfactory bulbs and anterior olfactory nucleus, and the posterior limb (pAC), connecting the piriform cortex and amygdaloid regions, both converging at the midline. In this study, we investigated sex-specific structural abnormalities of the AC in Pax6 mutant mice. Analysis of horizontal and sagittal AC sections revealed that Pax6 haploinsufficiency in mice induces abnormal de-fasciculation in the aAC and aberrant intermingling of aAC and pAC fibers at the midline. Notably, Pax6 mutant females exhibited more diverse phenotypes. These females showed a pronounced reduction in overall AC size and disruptions in pAC shape regularity, likely due to a more severe disruption of the boundary between the aAC and pAC axon bundles. These sex-dependent alterations in AC morphology may contribute to the sexually dimorphic phenotypes observed in various neurodevelopmental disorders, including autism spectrum disorder.
Cyanoacrylate is still an Effective Surgical Strategy for Homeostasis: A Rodent Model of Liver Trauma and Evaluation of Early Wound Healing.
Orhan A, Demiryas S, Hatipoğlu E … +3 more , Yanar K, Kepil N, Pekmezci S
Tohoku J Exp Med · 2026 Jan · PMID 40467485 · Publisher ↗
The potential hemostatic effects of cyanoacrylate are well-known, but the histopathological effects on application sites are not clearly established. This study aims to understand the histopathological and biochemical pa...
The potential hemostatic effects of cyanoacrylate are well-known, but the histopathological effects on application sites are not clearly established. This study aims to understand the histopathological and biochemical parameters of cyanoacrylate application during the early periods of liver traumas. For this purpose, Wistar albino rats weighing 250-300 g were divided into five groups, and liver lacerations on liver lobes were created in study groups. During the study, hematocrit levels during the pre-operative phase and before sacrification, duration of bleeding, post-operative adhesions of intraabdominal compartments, levels of biochemical markers such as hydroxyproline, collagen, matrix metalloproteinase, and histopathological evaluation of liver regeneration were taken into consideration. Results revealed fibrin sealant and cyanoacrylate managed to achieve better hemostasis compared to mechanical compression and regenerated cellulose. Peritoneal Adhesion Scores of regenerated cellulose and cyanoacrylate were higher compared to mechanical compression and fibrin sealant. Histopathologically, all groups had similar levels of fibrosis, only slightly lesser in the mechanical compression group. Biochemical evaluations showed regenerated cellulose and cyanoacrylate had elevated levels of hydroxyproline, collagen I and III. In conclusion, our study demonstrated that cyanoacrylate was as effective as other tissue sealants in achieving hemostasis, and did not increase fibrosis in the early stages of liver regeneration.
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