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Background/Objectives: Mesothelioma is a highly aggressive tumor with a poor prognosis that typically develops after a long latency period following asbestos exposure. Although immunotherapy combined with chemotherapy is increasingly used, the efficacy of standard treatments remains limited. This study aimed to explore ferroptosis induction as a potential therapeutic strategy for mesothelioma. Methods: We first screened microbial culture extracts collected from soil and marine environments to identify compounds with selective cytotoxicity against mesothelioma cells. Gene expression profiling was performed to investigate the mechanism of cell death induced by the identified compound. To assess intrinsic ferroptosis susceptibility, patient-derived mesothelioma cell lines and immortalized mesothelial cell lines were treated with RSL3, a GPX4 inhibitor. Results: Screening identified brefeldin A as a compound that selectively induces cell death in mesothelioma cells. Gene expression profiling revealed transcriptional changes consistent with ferroptosis induction. Treatment with RSL3 demonstrated marked variability in ferroptosis sensitivity across cell lines; the subgroup showing high sensitivity to RSL3 did not exhibit significant genetic alterations in NF2 or BAP1, but contained a significantly higher proportion of epithelioid tumors in histological classification. Conclusions: Our findings highlight ferroptosis induction as a promising antitumor mechanism in mesothelioma, particularly in the epithelioid subtype. While GPX4 inhibitors such as RSL3 are effective in vitro, further studies are needed to overcome pharmacological limitations and define molecular determinants of ferroptosis susceptibility, which may inform future personalized therapeutic strategies.

Shugoshin 1 (SGO1) is required for accurate chromosome segregation during mitosis and meiosis; however, its other functions, especially at interphase, are not clearly understood. Here, we found that downregulation of SGO1 caused a synergistic phenotype in cells overexpressing MYCN. Downregulation of SGO1 impaired proliferation and induced DNA damage followed by a senescence-like phenotype only in MYCN-overexpressing neuroblastoma cells. In these cells, SGO1 knockdown induced DNA damage, even during interphase and this effect was independent of cohesin. Furthermore, MYCN-promoted SGO1 transcription and SGO1 expression tended to be higher in MYCN- or MYC-overexpressing cancers. Together, these findings indicate that SGO1 plays a role in the DNA damage response in interphase. Therefore, we propose that SGO1 represents a potential molecular target for treatment of MYCN -amplified neuroblastoma.

BackgroundA phase 3, multinational, randomized, non-inferiority trial (REFLECT) compared the efficacy and safety of lenvatinib (LEN) and sorafenib (SOR) in patients with unresectable hepatocellular carcinoma (uHCC). LEN had an effect on overall survival (OS) compared to SOR, statistically confirmed by non-inferiority [OS: median = 13.6 months vs. 12.3 months; hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.79–1.06], and demonstrated statistically significant improvements in progression-free survival (PFS) and the objective response rate (ORR) in the overall population. The results of a subset analysis that evaluated the efficacy and safety of LEN and SOR in the Japanese population are reported.MethodsThe intent-to-treat population enrolled in Japan was analyzed.ResultsOf 954 patients in the overall population, 168 Japanese patients were assigned to the LEN arm (N = 81) or the SOR arm (N = 87). Median OS was 17.6 months for LEN vs. 17.8 months for SOR (HR 0.90; 95% CI 0.62–1.29). LEN showed statistically significant improvements over SOR in PFS (7.2 months vs. 4.6 months) and ORR (29.6% vs. 6.9%). The relative dose intensity of LEN and SOR in the Japanese population was lower than in the overall population. Frequently observed, related adverse events included palmar-plantar erythrodysaesthesia syndrome (PPES), hypertension, decreased appetite, and proteinuria in the LEN arm, and PPES, hypertension, diarrhea, and alopecia in the SOR arm.ConclusionsThe efficacy and safety of LEN in the Japanese population were similar to those in the overall population of REFLECT. With manageable adverse events, LEN is a new treatment option for Japanese patients with uHCC.Trial registration IDClinicalTrials.gov. No. NCT01761266.

Microbiota-derived short-chain fatty acids (SCFAs) and organic acids produced by the fermentation of non-digestible fibre can communicate from the microbiome to host tissues and modulate homeostasis in mammals. The microbiome has circadian rhythmicity and helps the host circadian clock function. We investigated the effect of SCFA or fibre-containing diets on circadian clock phase adjustment in mouse peripheral tissues (liver, kidney, and submandibular gland). Initially, caecal SCFA concentrations, particularly acetate and butyrate, induced significant day-night differences at high concentrations during the active period, which were correlated with lower caecal pH. By monitoring luciferase activity correlated with the clock gene Period2 in vivo , we found that oral administration of mixed SCFA (acetate, butyrate, and propionate) and an organic acid (lactate), or single administration of each SCFA or lactate for three days, caused phase changes in the peripheral clocks with stimulation timing dependency. However, this effect was not detected in cultured fibroblasts or cultured liver slices with SCFA applied to the culture medium, suggesting SCFA-induced indirect modulation of circadian clocks in vivo . Finally, cellobiose-containing diets facilitated SCFA production and refeeding-induced peripheral clock entrainment. SCFA oral gavage and prebiotic supplementation can facilitate peripheral clock adjustment, suggesting prebiotics as novel therapeutic candidates for misalignment.

A mutual relationship between nocturia and sleep disturbances is assumed; however, evidence for these associations in the general population remains limited, particularly regarding sleep-promoting lifestyle habits. This cross-sectional internet study examined associations between nocturia, sleep issues, and lifestyle habits perceived as promoting sleep in 3,317 participants in July 2019. The prevalence of nocturia increased with age, while overall sleep satisfaction tended to improve with age. However, individuals with more frequent nocturnal voids reported lower sleep satisfaction. Sleep dissatisfaction was significantly correlated with nocturnal urinary frequency in both men ( r  = 0.16) and women ( r  = 0.18, p  < 0.001), emphasizing the impact of nocturia on sleep quality. Furthermore, it revealed that nocturia was associated with various sleep issues. In men, mid-wakefulness (OR = 3.32, p  < 0.001) and difficulty falling asleep (OR = 1.37, p  < 0.050) were key factors, whereas in women, mid-wakefulness (OR = 11.2, p  < 0.001) and shallow sleep (OR = 1.77, p  = 0.010) were significant. Notably, it was found that lifestyle habits, such as drinking tea or alcohol, which can exacerbate nocturia and reduce sleep quality, are undertaken with intention of promoting good sleep. Conversely, good bedding (OR = 0.75, p  = 0.010) was associated with fewer nocturnal voids. These findings highlight the complex interplay between nocturia, sleep issues, and lifestyle behaviors, providing valuable insights for addressing these interconnected issues.

Aims/Introduction We evaluated the effect of the MiniMed™ 770G, an insulin pump using hybrid closed‐loop technology, on blood glucose management and quality of life in Japanese people with type 1 diabetes. Materials and Methods This was a 52‐week, prospective, observational study. Fifty Japanese people with type 1 diabetes switched from the MiniMed™ 640G to 770G, and we analyzed the continuous glucose monitoring data of 24 subjects who used auto mode throughout the study. We also analyzed the scores of the Diabetes Therapy‐Related Quality of Life questionnaire completed by 26 auto‐mode users before and after the treatment change. Results The baseline time in range 70–180 mg/dL was 67.3 (54.8–78.4)%, with a significant improvement beginning 8 weeks after the switch and lasting until 52 weeks. The baseline time below range <70 mg/dL was 1.9 (0.6–3.6)%, with a significant increase at week 8; however, the mean value was less than 4% throughout the study period. On the other hand, the number of blood glucose measurements significantly increased. While there was no significant difference in the overall change in the total Diabetes Therapy‐Related Quality of Life score, there was a significant decrease in the treatment satisfaction score. Conclusions Use of the MiniMed™ 770G improved continuous glucose monitoring metrics. However, treatment satisfaction decreased, probably due to the increased frequency of blood glucose monitoring necessary to maintain auto mode. Use of the MiniMed™ 770G improved continuous glucose monitoring metrics. However, treatment satisfaction decreased, probably due to the increased frequency of blood glucose monitoring necessary to maintain auto mode.

Dehydroeffusol, a phenanthrene isolated from Juncus effusus , is a Chinese medicine. To explore an efficacy of dehydroeffusol administration for prevention and cure of Alzheimer’s disease, here we examined the effect of dehydroeffusol on amyloid β 1-42 (Aβ 1-42 )-mediated hippocampal neurodegeneration . Dehydroeffusol (15 mg/kg body weight) was orally administered to mice once a day for 6 days and then human Aβ 1-42 was injected intracerebroventricularly followed by oral administration for 12 days. Neurodegeneration in the dentate granule cell layer, which was determined 2 weeks after Aβ 1-42 injection, was rescued by dehydroeffusol administration. Aβ staining (uptake) was not reduced in the dentate granule cell layer by pre-administration of dehydroeffusol for 6 days, while increase in intracellular Zn 2+ induced with Aβ 1-42 was reduced, suggesting that pre-administration of dehydroeffusol prior to Aβ 1-42 injection is effective for Aβ 1-42 -mediated neurodegeneration that was linked with intracellular Zn 2+ toxicity. As a matter of fact, pre-administration of dehydroeffusol rescued Aβ 1-42 -mediated neurodegeneration. Interestingly, pre-administration of dehydroeffusol increased synthesis of metallothioneins, intracellular Zn 2+ -binding proteins, in the dentate granule cell layer, which can capture Zn 2+ from Zn-Aβ 1-42 complexes. The present study indicates that pre-administration of dehydroeffusol protects Aβ 1-42 -mediated neurodegeneration in the hippocampus by reducing intracellular Zn 2+ toxicity, which is linked with induced synthesis of metallothioneins. Dehydroeffusol, a novel inducer of metallothioneins, may protect Aβ 1-42 -induced pathogenesis in Alzheimer’s disease.

To elucidate the origin and migration history of the “Mansen elements,” a group of temperate grassland plants mainly distributed in northeastern Asia, phylogeographic analyses based on chloroplast DNA markers and double-digest restriction site-associated DNA sequencing (ddRAD-seq) data were performed on Viola orientalis, one of the representative species of the group. Phylogenetic analyses using ddRAD-seq data revealed that the populations of V. orientalis were clustered into five clades, among which the continental clades made of populations from Russia and Korea diverged more than 100,000 years earlier than the Japanese clades. The Japanese clade likely diverged during the last glacial period, followed by a further post-glacial divergence into the Kyushu and the Honshu subclades. Our study demonstrated that V. orientalis originated in the continental area of northeastern Asia and, during the last glacial period, has spread southward through the Korean Peninsula across the Japanese Islands. This finding supports the previously proposed evolutionary hypothesis regarding the origin and migration routes of the Mansen elements.

Background/AimsTo investigate the time-dependent change of corneal endothelial cell (CEC) morphology and density (CECD) in patients with glaucoma post instillation of rho-associated protein kinase inhibitor ripasudil (Rip) 0.4% eye drops.MethodsThis observational study involved 163 eyes of 163 patients with glaucoma in whom CEC morphological change was evaluated by CECD calculated via non-contact specular microscopy (NCSM) before and at 1 or 3 months post-Rip instillation. The change of CECD was plotted along with elapsed time from last instillation of Rip. The patients were divided into the following three groups based on the elapsed time post-Rip instillation: Early Group (<2 hours), Middle Group (≥2 hours, yet <6 hours) and Late Group (≥6 hours). The rate of CECD change was then analysed and compared among the three groups. An additional eight eyes of four patients with glaucoma were enrolled for a time-dependent study, with NCSM images evaluated before and at 1, 2, 3, 4 and 6 hours post-Rip instillation.ResultsMorphological changes in the CECs appeared within 1 hour and recovered to normal within 6 hours post instillation. In the Early, Middle and Late Group, the median rate of CECD change as calculated by the NCSM automated software was −5.68%, −4.95% and −0.07%, respectively. The CEC images showed the same morphological changes with observational study in all four cases.ConclusionDue to transient morphological changes, the NCSM software produced misleading data for determining CECD within 1 hour post-Rip instillation, yet revealed that CEC morphology gradually recovered to normal within 6 hours.

Purpose Microstate analysis involves examining the temporal dynamics of electroencephalogram (EEG) signals and serves as a crucial method for exploring the neural basis of psychiatric disorders. This study investigates the effects of transcranial direct current stimulation (tDCS) on specific microstate parameter maps‐D and C in patients with depression, specifically targeting the dorsomedial prefrontal cortex (DMPFC) and left dorsolateral prefrontal cortex (DLPFC). Methods We conducted an open‐label, between‐subject, crossover trial involving 19 patients clinically diagnosed with depression. A 1 mA electrical current was administered, with anodal stimulation specifically targeting the DMPFC or the left DLPFC. Microstate maps were derived from resting‐state EEG recordings obtained prior to and following the application of tDCS. The EEG data were categorized into five distinct microstate classes for subsequent analysis. Findings The findings revealed a significant increase in the duration of microstate class D following stimulation in both groups, while microstate class C exhibited no notable changes. Additionally, a significant association was identified between the transition from microstate D to C and alterations in the State‐Trait Anxiety Inventory‐State (STAI‐S) scores after left DLPFC stimulation. Conclusion Microstate map D appears to be associated with psychiatric disorders and executive functions, whereas map C may relate to the salience network and mind‐wandering. Our findings suggest that microstate maps D and C are responsive to tDCS stimuli, indicating their potential as objective tools for anxiety assessment. Employing transition‐focused parameters in EEG microstate analysis may enhance the tracking of rapidly fluctuating emotional states, rather than relying solely on duration metrics. Furthermore, the integration of non‐invasive brain stimulation techniques, such as tDCS, with EEG microstate analysis holds significant promise for elucidating the neural mechanisms involved in depression. Trial Registration UMIN‐CTR Clinical Trial: UMIN000015046 The findings demonstrated a significant increase in the duration of microstate class D following stimulation, while no changes were observed in class C. Moreover, transitions from microstate class C to D exhibited a correlation with the state‐trait anxiety inventory‐state anxiety (STAI‐SA) scores following dorsomedial prefrontal cortex (DMPFC) stimulation. In contrast, transitions from class D to C were linked to left dorsolateral prefrontal cortex (DLPFC) stimulation, albeit without a significant correlation. These results underscore the distinct and site‐specific effects of neural stimulation on anxiety‐related brain states.