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Peritoneal fibrosis (PF) is a severe complication of peritoneal dialysis, but there are few effective therapies for it. Recent studies have revealed a new biological function of trehalose as an autophagy inducer. Thus far, there are few reports regarding the therapeutic effects of trehalose on fibrotic diseases. Therefore, we examined whether trehalose has anti-fibrotic effects on PF. PF was induced by intraperitoneal injection of chlorhexidine gluconate (CG). CG challenges induced the increase of peritoneal thickness, ColIα 1 mRNA expression and hydroxyproline content, all of which were significantly attenuated by trehalose. In addition, CG challenges induced a marked peritoneal accumulation of α-SMA + myofibroblasts that was reduced by trehalose. The number of Wt1 + α-SMA + cells in the peritoneum increased following CG challenges, suggesting that a part of α-SMA + myofibroblasts were derived from peritoneal mesothelial cells (PMCs). The number of Wt1 + α-SMA + cells was also suppressed by trehalose. Additionally, trehalose attenuated the increase of α-SMA and ColIα 1 mRNA expression induced by TGF-β 1 through Snail protein degradation, which was dependent on autophagy in PMCs. These results suggest that trehalose might be a novel therapeutic agent for PF through the induction of autophagy and the suppression of mesothelial-to-mesenchymal transition in PMCs.

d-serine administration prevents kidney damage in murine models of acute kidney injury, and risperidone inhibits the activity of d-amino acid oxidase, which regulate plasma d-amino acid levels. This pilot randomized controlled trial investigated the effects of risperidone on glucose, amino acid metabolism, and kidney function in healthy adults. Healthy adults with a homeostasis model assessment of insulin resistance (HOMA-IR) of ≥ 1.6 and estimated glomerular filtration rate (eGFR) of ≥ 60 mL/min/1.73m2 were randomly assigned to the risperidone and control groups. The risperidone group received 0.5 mg/day risperidone for 4 days. The primary outcome was mean change in HOMA-IR on day 5, and the secondary outcomes were changes in d-amino acid levels, eGFR, and urinary albumin. Seven participants were randomized to the risperidone and control groups. The changes in HOMA-IR, eGFR, and urinary albumin on day 5 were not significantly different between the two groups (all p > 0.05). Mean changes in plasma d-serine level and urinary d-serine/creatinine ratio were significantly higher in the risperidone group than in the control group (0.2 vs. -0.3 nmol/mL, p = 0.03 and 38.2 vs. -25.8 nmol/mL, p = 0.01, respectively). Short-term risperidone affects d-serine metabolism without instigating acute adverse effects on kidney or glucose homeostasis in healthy individuals. Clinical Trial Registry number: This study was registered with the Japan Registry for Clinical Trials (jRCTs041210165).

Background This study assessed the association of pathological kidney lesions with cardiovascular events in biopsy-proven diabetic kidney disease (DKD) with type 2 diabetes. Methods This multicenter, retrospective study involved 244 patients with no previous cardiovascular events before biopsy, estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m 2 at biopsy (baseline), and ≥ 1 year of observation after biopsy. The outcomes were the first occurrence of cardiovascular events (cardiovascular death, non-fatal myocardial infarction, coronary intervention, or non-fatal stroke), and non-cardiovascular deaths before cardiovascular events were considered competing events. The association between the severity of each pathological lesion and cardiovascular events was investigated. Results During follow-up (median: 6.4 years), 43 patients experienced cardiovascular events. The baseline clinical characteristics did not differ according to cardiovascular events. The cumulative incidence of cardiovascular events was higher in patients with mesangiolysis, global glomerulosclerosis ≥ 50%, moderate/severe interstitial inflammation, and moderate/severe arteriolar hyalinosis than in those having less advanced each lesion. Fine–Gray regression models revealed that global glomerulosclerosis ≥ 50% (subdistribution hazard ratio [SHR]: 3.85; 95% confidence interval [95% CI] 1.28–11.52), moderate/severe interstitial inflammation (SHR: 2.49; 95% CI 1.18–5.29), and moderate/severe arteriolar hyalinosis (SHR: 3.51; 95% CI 1.15–10.69) were linked to increased risk of cardiovascular events, after adjusting for clinical variables including RAAS inhibitors use at baseline. Adding the severity of these lesions to clinical variables improved the predictive value for cardiovascular events. Conclusions In DKD with type 2 diabetes, advanced glomerulosclerosis, interstitial inflammation, and arteriolar hyalinosis were associated with cardiovascular events, adding predictive value to clinical features.

Homologous recombination deficiency (HRD) tests, including MyChoice CDx, are companion diagnostics for poly (ADP‐ribose) polymerase (PARP) inhibitors. BRCA1 promoter hypermethylation, a major HRD cause, may correlate with poorer prognosis. This study aimed to develop a simple, accurate method for detecting BRCA1 promoter hypermethylation and elucidate the characteristics of such cases. BRCA1 promoter methylation was analyzed using bisulfite sequencing (BIS‐seq) in high‐grade serous ovarian carcinoma specimens. We developed a newly developed BRCA1 methylation assay, BRCA1‐Fragment Analysis of Methylation (BRCA1‐FAM), which combines restriction enzyme digestion with fragment analysis. The accuracy of this assay was compared to the results of BIS‐seq. We evaluated the relationship between BRCA1 promoter hypermethylation and prognosis and examined its association with BRCA1 expression and loss of heterozygosity. BRCA1 mutations and promoter methylation were mutually exclusive in the analyzed cases, with methylation observed in 28.9% (22/76) of primary debulking surgery cases. The BRCA1‐FAM showed high sensitivity (91.3%) and specificity (100%) for detecting BRCA1 promoter hypermethylation, comparable to BIS‐seq. Cases with BRCA1 promoter hypermethylation had significantly poorer progression‐free survival (log‐rank test, p = 0.048). Among these cases, 86.4% displayed abnormal BRCA1 immunostaining, with lower frequencies of BRCA1 loss of heterozygosity compared to those of other groups. BRCA1 promoter hypermethylation is associated with poor prognosis, underscoring the importance of its identification for HRD stratification. BRCA1‐FAM is a simple and highly accurate method for evaluating BRCA1 promoter methylation. This approach may potentially enhance the precision of personalized therapies for ovarian cancer. With the aim of clinical applications, we established a simplified evaluation method for BRCA1 methylation using fragment analysis, called BRCA1‐FAM. We confirmed that high‐grade serous ovarian cancer patients with BRCA1 methylation had poor prognosis. The introduction of BRCA1 methylation testing is expected to contribute to the stratification of prognosis and drug selection for HRD tumors.

RNAs, such as noncoding RNA, microRNA, and recently mRNA, have been recognized as signal transduction molecules. CD271, also known as nerve growth factor receptor, has a critical role in cancer, although the precise mechanism is still unclear. Here, we show that CD271 mRNA, but not CD271 protein, facilitates spheroid cell proliferation. We established CD271−/− cells lacking both mRNA and protein of CD271, as well as CD271 protein knockout cells lacking only CD271 protein, from hypopharyngeal and oral squamous cell carcinoma lines. Sphere formation was reduced in CD271−/− cells but not in CD271 protein knockout cells. Mutated CD271 mRNA, which is not translated to a protein, promoted sphere formation. CD271 mRNA bound to hnRNPA2B1 protein at the 3′‐UTR region, and the inhibition of this interaction reduced sphere formation. In surgical specimens, the CD271 mRNA/protein expression ratio was higher in the cancerous area than in the noncancerous area. These data suggest CD271 mRNA has dual functions, encompassing protein‐coding and noncoding roles, with its noncoding RNA function being predominant in oral and head and neck squamous cell carcinoma. We found that CD271 mRNA, but not CD271 protein, plays a role in the sphere proliferation of cancer cells. The CD271 mRNA bound to the hnRNPA2B1 protein, an RNA‐binding protein that promotes tumor malignancy.

Percutaneous transhepatic gallbladder drainage (PTGBD) is an alternative to percutaneous transhepatic biliary drainage (PTBD) for cases with obstructive jaundice in which the bile duct obstruction is below the confluence of the cystic ducts. This retrospective study aimed to evaluate the usefulness of PTGBD and PTBD in patients with obstructive jaundice. We recruited patients who had undergone percutaneous biliary drainage for acute cholangitis and obstructive jaundice at two institutions between January 2017 and March 2024. In principle, PTBD was the first choice. PTGBD was selected for cases where the intrahepatic bile duct diameter was ≤ 5 mm or ≥ 6 mm with significant respiratory-related variability of the positioning of the bile ducts. In other cases, PTBD was chosen. Fifty-five patients were included in this analysis. However, patients with intrahepatic or hilar bile duct stenosis, post choledocholithiasis, complex cholecystitis, total bilirubin levels of < 2.0 mg/dL, and uncorrectable bleeding tendency and those who had undergone the procedure and later discontinued without puncture were excluded. The technical success rates, clinical success rates, and complication rates of the procedure were evaluated. The technical success rates were 96.3% (26/27) and 82.1% (23/28) in the PTGBD and PTBD groups, respectively. The clinical success rates were 85.2% (23/27) and 67.9% (19/28) in the PTGBD and PTBD groups, respectively. The complication rates were 18.5% (5/27) and 25.0% (7/28) in the PTGBD and PTBD groups, respectively. No serious complications were observed in either group. Hence, the two groups did not significantly differ in any of the endpoints. The outcomes of PTGBD were comparable to those of PTBD in patients with obstructive jaundice. Hence, PTGBD is a reasonable treatment option for cases of obstructive jaundice in which PTBD is not feasible.

Background Endoscopic submucosal dissection (ESD) is technically difficult and requires considerable training. The authors have developed a multi-loop traction device (MLTD), a new traction device that offers easy attachment and detachment. We aimed to evaluate the utility of MLTD in ESD. Methods This ex vivo pilot study was a prospective, block-randomized, comparative study of a porcine stomach model. Twenty-four lesions were assigned to a group that undertook ESD using the MLTD (M-ESD group) and a group that undertook conventional ESD (C-ESD group) to compare the speed of submucosal dissection. In addition, the data of consecutive 10 patients with eleven gastric lesions was collected using electronic medical records to clarify the inaugural clinical outcomes of gastric ESD using MLTD. Results The median (interquartile range) speed of submucosal dissection in the M-ESD and C-ESD groups were 141.5 (60.9–177.6) mm2/min and 35.5 (20.8–52.3) mm2/min, respectively; submucosal dissection was significantly faster in the M-ESD group (p < 0.05). The rate of en bloc resection and R0 resection was 100% in both groups, and there were no perforation in either group. The MLTD attachment time was 2.5 ± 0.9 min and the MLTD extraction time was 1.0 ± 1.1 min. Clinical outcomes of MLTD in gastric ESD were almost the same as those of ex vivo pilot study. Conclusions MLTD increased the speed of submucosal dissection in ESD and was similarly effective when used by expert and trainee endoscopists without perforation. MLTD can potentially ensure a safer and faster ESD.

Cancer stem cells (CSCs) define a subpopulation of cancer cells that are resistant to therapy. However, little is known of how CSC characteristics are regulated. We previously showed that dormant cancer stem cells are enriched with a CD274 low fraction of cholangiocarcinoma cells. Here we found that BEX2 was highly expressed in CD274 low cells, and that BEX2 knockdown decreased the tumorigenicity and G 0 phase of cholangiocarcinoma cells. BEX2 was found to be expressed predominantly in G 0 phase and starvation induced the USF2 transcriptional factor, which induced BEX2 transcription. Comprehensive screening of BEX2 binding proteins identified E3 ubiquitin ligase complex proteins, FEM1B and CUL2, and a mitochondrial protein TUFM, and further demonstrated that knockdown of BEX2 or TUFM increased mitochondria-related oxygen consumption and decreased tumorigenicity in cholangiocarcinoma cells. These results suggest that BEX2 is essential for maintaining dormant cancer stem cells through the suppression of mitochondrial activity in cholangiocarcinoma.

Hymenoscyphus fraxineus is the causal agent of ash dieback, a devastating disease of European ash (Fraxinus excelsior). Although the pathogen is believed to have originated in East Asia and has been confirmed in Japan, European ash trees cultivated in the Sapporo Experimental Forest of Hokkaido University remain asymptomatic despite the presence of H. fraxineus. In this study, we investigated the early infection behavior of H. fraxineus and associated host defense responses by comparing asymptomatic F. excelsior with the susceptible control species F. angustifolia. Leaflets were inoculated with ascospores, and fungal development as well as host responses were examined microscopically during early infection stages. In addition, we analyzed the accumulation of selected coumarins, which have been proposed as candidate compounds associated with ash dieback tolerance, and assessed their effects on ascospore germination. We found that fungal growth was consistently restricted on F. excelsior at 7 days post inoculation, particularly at the stage of invasion into adjacent epidermal cells. Fraxetin was detected in F. excelsior leaflets but not in F. angustifolia, and fraxetin treatment significantly reduced ascospore germination in vitro. While typical markers of induced resistance were not clearly detected at the examined time points, these results indicate that constitutive chemical traits, including fraxetin accumulation, may contribute to early-stage suppression of H. fraxineus growth in F. excelsior. Together, our findings provide insight into early host–pathogen interactions associated with ash dieback tolerance and highlight the potential role of constitutive defenses during initial infection.