Endoscopic hand suturing has the potential to reduce bleeding after gastric endoscopic submucosal dissection in patients on antithrombotic agents: Multicenter phase II study.

OBJECTIVES: The risk of postoperative bleeding is high after gastric endoscopic submucosal dissection (ESD) in patients continuously treated with antithrombotic agents (ATAs). The effectiveness of endoscopic hand suturing (EHS) on bleeding after gastric ESD was investigated in patients at high risk of delayed bleeding. METHODS: Patients with neoplasms ≤2 cm who underwent gastric ESD and continued to receive perioperative ATAs were enrolled in this multicenter phase II study. The mucosal defect was closed with EHS after removing the lesion. Postoperative bleeding rate was assessed for 3-4 postoperative weeks as a primary outcome measure. The technical success of EHS and adverse events were also assessed. Based on expected and threshold postoperative bleeding rates of 10% and 25%, respectively, we aimed to include 48 patients in the study. RESULTS: A total of 49 patients were enrolled in the study, and 43 patients were finally registered as the per-protocol set. The postoperative bleeding rate was 7.0% (3/43 patients; the upper limit of one-sided 95% confidence interval [CI], 17.1% and 97.5% CI, 19.1%). The upper limits of the CI were below the threshold value (25%), and the postoperative bleeding rate was below the expected value (10%). The technical EHS success rate, closure maintenance rate on postoperative day 3, and postoperative subclinical bleeding rate were 100%, 83%, and 2%, respectively. No severe adverse events related to EHS were observed. CONCLUSIONS: Endoscopic hand suturing may prevent postoperative bleeding in patients undergoing gastric ESD while being treated continuously with ATAs (UMIN000038140).

The Rubicon-WIPI axis regulates exosome biogenesis during ageing.

Cells release intraluminal vesicles in multivesicular bodies as exosomes to communicate with other cells. Although recent studies suggest an intimate link between exosome biogenesis and autophagy, the detailed mechanism is not fully understood. Here we employed comprehensive RNA interference screening for autophagy-related factors and discovered that Rubicon, a negative regulator of autophagy, is essential for exosome release. Rubicon recruits WIPI2d to endosomes to promote exosome biogenesis. Interactome analysis of WIPI2d identified the ESCRT components that are required for intraluminal vesicle formation. Notably, we found that Rubicon is required for an age-dependent increase of exosome release in mice. In addition, small RNA sequencing of serum exosomes revealed that Rubicon determines the fate of exosomal microRNAs associated with cellular senescence and longevity pathways. Taken together, our current results suggest that the Rubicon-WIPI axis functions as a key regulator of exosome biogenesis and is responsible for age-dependent changes in exosome quantity and quality.

Dipeptidylpeptidase-4-targeted activatable fluorescent probes visualize senescent cells.

Senescent cells promote cancer development and progression through chronic inflammation caused by a senescence-associated secretory phenotype (SASP). Although various senotherapeutic strategies targeting senescent cells have been developed for the prevention and treatment of cancers, technology for the in vivo detection and evaluation of senescent cell accumulation has not yet been established. Here, we identified activatable fluorescent probes targeting dipeptidylpeptidase-4 (DPP4) as an effective probe for detecting senescent cells through an enzymatic activity-based screening of fluorescent probes. We also determined that these probes were highly, selectively, and rapidly activated in senescent cells during live cell imaging. Furthermore, we successfully visualized senescent cells in the organs of mice using DPP4-targeted probes. These results are expected to lead to the development of a diagnostic technology for noninvasively detecting senescent cells in vivo and could play a role in the application of DPP4 prodrugs for senotherapy.

Exploring simple ways to avoid collecting highly 137Cs-contaminated Aralia elata buds for the revival of local wild vegetable cultures.

Collection and cooking of wild vegetables have provided seasonal enjoyments for Japanese local people as provisioning and cultural ecosystem services. However, the Fukushima Daiichi Nuclear Power Plant accident in March 2011 caused extensive radiocesium contamination of wild vegetables. Restrictions on commercial shipments of wild vegetables have been in place for the last 10 years. Some species, including buds of Aralia elata, are currently showing radiocesium concentrations both above and below the Japanese reference level for food (100 Bq/kg), implying that there are factors decreasing and increasing the 137Cs concentration. Here, we evaluated easy-to-measure environmental variables (dose rate at the soil surface, organic soil layer thickness, slope steepness, and presence/absence of decontamination practices) and the 137Cs concentrations of 40 A. elata buds at 38 locations in Fukushima Prefecture to provide helpful information on avoiding collecting highly contaminated buds. The 137Cs concentrations in A. elata buds ranged from 1 to 6,280 Bq/kg fresh weight and increased significantly with increases in the dose rate at the soil surface (0.10-6.50 µSv/h). Meanwhile, the 137Cs concentration in A. elata buds were not reduced by decontamination practices. These findings suggest that measuring the latest dose rate at the soil surface at the base of A. elata plants is a helpful way to avoid collecting buds with higher 137Cs concentrations and aid in the management of species in polluted regions.

The Association between Menstrual Symptoms and Presenteeism: A Cross-Sectional Study for Women Working in Central Tokyo.

Menstrual symptoms lower women's work performance, but to what extent one's performance declines during the perimenstrual periods is unclear. This cross-sectional study evaluated relative presenteeism by the severity of menstrual symptoms in working women. Participants included women who joined a health promotion event in Tokyo. The severity of PMS and symptoms during menstruation were categorized based on their frequency, and the outcome variable was relative presenteeism as the ratio of work performance during the perimenstrual periods to that during the inter-menstrual period. An analysis of variance (ANOVA) was performed. Of the 312 participants, 238 were eligible, 50% of whom claimed severe symptoms in either PMS or during menstruation. Participants were divided into four groups (1) without severe menstrual symptoms, (2) severe PMS alone, (3) severe symptoms during menstruation alone, and (4) both severe PMS and symptoms during menstruation-and the mean relative presenteeism was 91% (standard deviation (SD) 23), 69% (SD 21), 76% (SD 16), and 69% (SD 27), respectively (p < 0.01). A between-group comparison revealed statistically significant differences in relative presenteeism, when group (1) served as the criterion for comparisons (p < 0.01). This study demonstrates that severe PMS alone, as well as both severe PMS and symptoms during menstruation, particularly decreased work performance.

Network of extracellular vesicles surrounding senescent cells.

Extracellular vesicles (EVs) are small lipid bilayers released from cells that contain cellular components such as proteins, nucleic acids, lipids, and metabolites. Biological information is transmitted between cells via the EV content. Cancer and senescent cells secrete more EVs than normal cells, delivering more information to the surrounding recipient cells. Cellular senescence is a state of irreversible cell cycle arrest caused by the accumulation of DNA damage. Senescent cells secrete various inflammatory proteins known as the senescence-associated secretory phenotype (SASP). Inflammatory SASP factors, including small EVs, induce chronic inflammation and lead to various age-related pathologies. Recently, senolytic drugs that selectively induce cell death in senescent cells have been developed to suppress the pathogenesis of age-related diseases. This review describes the characteristics of senescent cells, the functions of EVs released from senescent cells, and the therapeutic effects of EVs on age-related diseases. Understanding the biology of EVs secreted from senescent cells will provide valuable insights for achieving healthy longevity in an aging society.

Effectiveness of a Lifestyle Improvement Support App in Combination with a Wearable Device in Japanese People with Type 2 Diabetes Mellitus: STEP-DM Study.

INTRODUCTION: Although the use of application (app)s and wearable devices supporting diabetes treatment has spread rapidly in recent years, evidence of their impact, especially in combination of them, is limited. TOMOCO™ is a lifestyle improvement support app that features interactive virtual conversations according to the programmed algorithm guiding users toward their goals of lifestyle improvement. We hypothesized that TOMOCO™ in combination with Fitbit, which accurately tracks users' activity level, would encourage people with type 2 diabetes mellitus (T2DM) to change their lifestyles and improve their glycated hemoglobin (HbA1c) levels without changes in conventional therapy. Thus, we performed the present study to explore the effectiveness of this combination in Japanese participants with T2DM who had not achieved their glycemic targets. METHODS: In this single-arm exploratory study, participants with T2DM used the TOMOCO™ and Fitbit in addition to the conventional diet/exercise therapy and anti-diabetic drug for 12 weeks. They were provided with feedback/advice by health care providers based on the TOMOCO™ and Fitbit records. The primary endpoint was the change in HbA1c from baseline to the end of the observation period. Data were expressed as mean ± standard deviation. RESULTS: Fifty-nine (96.7%) of the 61 participants (male, 42 [71.2%]; age, 60.1 ± 8.7 years; HbA1c level, 7.48 ± 0.37% at screening) completed the study. At the end of the observation period, the HbA1c was significantly reduced (- 0.41 ± 0.41%, p < 0.001). This trend was consistent across the preselected patient characteristics, including sex, age, and body mass index. However, it was more pronounced in the participants with earlier stages of behavioral changes defined by the transtheoretical model at baseline. CONCLUSIONS: The unique features of TOMOCO™ in combination with Fitbit, together with conventional therapy, may promote a healthy lifestyle and thus contribute to improving HbA1c in people with T2DM. CLINICAL TRIAL REGISTRATION: jRCT1070220007.

Renal outcomes with sodium-glucose cotransporter 2 inhibitors in Japanese people with grade 3 chronic kidney disease and type 2 diabetes: Analysis of medical administrative databases.

AIM: To evaluate whether sodium-glucose cotransporter 2 inhibitor (SGLT2i) therapy is associated with a reduction of renal events compared with other glucose-lowering drugs (oGLDs) among Japanese people with type 2 diabetes (T2D) and grade 3 (G3) chronic kidney disease (CKD) in a real-world clinical practice setting. MATERIALS AND METHODS: People with T2D who were newly prescribed an SGLT2i or an oGLD from April 2014 to November 2021 (without prior use of index drugs for ≥ 1 year prior to index date) and G3 CKD (estimated glomerular filtration rate [eGFR] ≥ 30 to < 60 mL/min/1.73 m2) were selected from the Medical Data Vision database (MDV-DB) and the Real-World Data database (RWD-DB). SGLT2i and oGLD users were matched (1:1) using propensity score on patient background characteristics. The primary endpoint was a composite of the development of end-stage kidney disease or a sustained decline in eGFR of 50% or more. Hazard ratios (HRs) were estimated using the Cox proportional hazards model. RESULTS: Overall, 3190 (1595 per group) patients in the MDV-DB and 2572 (1286 per group) patients in the RWD-DB were included in the analyses. The composite outcome was significantly lower in the SGLT2i group than in the oGLD group in the MDV-DB (HR 0.49, 95% confidence interval [CI] 0.33 to 0.74, P < 0.001) and in the RWD-DB (HR 0.57, 95% CI 0.37 to 0.88, P = 0.011). CONCLUSIONS: Japanese people with T2D and G3 CKD initiating an SGLT2i had a lower risk of renal events than people initiating an oGLD.

Nanoparticles Based on Natural Lipids Reveal Extent of Impacts of Designed Physical Characteristics on Biological Functions.

Nanoparticles based on lipids (LNPs) are essential in pharmaceuticals and intercellular communication, and their design parameters span a diverse range of molecules and assemblies. In bridging the gap in insight between extracellular vesicles (EVs) and synthetic LNPs, one challenge is understanding their in-cell/in-body behavior when simultaneously assessing more than one physical characteristic. Herein, we demonstrate comprehensive evaluation of LNP behavior by using LNPs based on natural lipids (N-LNPs) with designed physical characteristics: size tuned using microfluidic methods, surface fluidity designed based on EV components, and stiffness tuned using biomolecules. We produce 12 types of N-LNPs having different physical characteristics─two sizes, three membrane fluidities, and two stiffnesses for in vitro evaluation─and evaluate cellular uptake vitality and endocytic pathways of N-LNPs based on the physical characteristics of N-LNPs. To reveal the extent of the impact of the predesigned physical characteristics of N-LNPs on cellular uptakes in vivo, we also carried out animal experiments with four types of N-LNPs having different sizes and fluidities. The use of N-LNPs has helped to clarify the extent of the impact of inextricably related, designed physical characteristics on transportation and provided a bidirectional guidepost for the streamlined design and understanding of the biological functions of LNPs.

Late-onset Myoclonic Seizure in a 78-year-old Woman with Gaucher Disease.

We herein report a 78-year-old woman with Gaucher disease (GD) who was initially diagnosed with GD type 1, had been receiving long-term enzyme replacement therapy since 58 years old, and developed neurological manifestations in her 70s. The neurological manifestations included myoclonic seizures and progressive cognitive decline. Although it is rare for GD patients to first develop neurologic manifestations at such an advanced age, physicians engaged in long-term care for GD patients should be alert for this possibility.

A simpler diagnostic algorithm of the Japan Esophageal Society classification for Barrett's esophagus-related superficial neoplasia.

BACKGROUND: We previously developed a Japan Esophageal Society Barrett's Esophagus (JES-BE) magnifying endoscopic classification for superficial BE-related neoplasms (BERN) and validated it in a nationwide multicenter study that followed a diagnostic flow chart based on mucosal and vascular patterns (MP, VP) with nine diagnostic criteria. Our present post hoc analysis aims to further simplify the diagnostic criteria for superficial BERN. METHODS: We used data from our previous study, including 10 reviewers' assessments for 156 images of high-magnifying narrow-band imaging (HM-NBI) (67 dysplastic and 89 non-dysplastic histology). We statistically analyzed the diagnostic performance of each diagnostic criterion of MP (form, size, arrangement, density, and white zone), VP (form, caliber change, location, and greenish thick vessels [GTV]), and all their combinations to achieve a simpler diagnostic algorithm to detect superficial BERN. RESULTS: Diagnostic accuracy values based on the MP of each single criterion or combined criteria showed a marked trend of being higher than those based on VP. In reviewers' assessments of visible MPs, the combination of irregularity for form, size, or white zone had the highest diagnostic performance, with a sensitivity of 87% and a specificity of 91% for dysplastic histology; in the assessments of invisible MPs, GTV had the highest diagnostic performance among the VP of each single criterion and all combinations of two or more criteria (sensitivity, 93%; specificity, 92%). CONCLUSION: The present post hoc analysis suggests the feasibility of further simplifying the diagnostic algorithm of the JES-BE classification. Further studies in a practical setting are required to validate these results.

Case Report: Intraventricular Cerliponase Alfa Treatment in a Patient with Advanced Neuronal Ceroid Lipofuscinosis Type 2.

Neuronal ceroid lipofuscinosis type 2 (CLN2) is an autosomal recessive lysosomal disease caused by decreased activity of the enzyme tripeptidyl peptidase 1 (TPP1) due to pathogenic variants in the TPP1 gene. Cerliponase alfa, a recombinant proenzyme form of TPP1, has shown efficacy in preventing motor and language function decline in early-stage CLN2. However, the safety and effects of this therapy in advanced-stage CLN2 are unclear. We herein report a case of intraventricular cerliponase alfa treatment for over a year in a patient with advanced-stage CLN2. The results suggest the safety and potential efficacy of treatment at an advanced stage of CLN2.

YBX1 Regulates Satellite II RNA Loading into Small Extracellular Vesicles and Promotes the Senescent Phenotype.

Senescent cells secrete inflammatory proteins and small extracellular vesicles (sEVs), collectively termed senescence-associated secretory phenotype (SASP), and promote age-related diseases. Epigenetic alteration in senescent cells induces the expression of satellite II (SATII) RNA, non-coding RNA transcribed from pericentromeric repetitive sequences in the genome, leading to the expression of inflammatory SASP genes. SATII RNA is contained in sEVs and functions as an SASP factor in recipient cells. However, the molecular mechanism of SATII RNA loading into sEVs is unclear. In this study, we identified Y-box binding protein 1 (YBX1) as a carrier of SATII RNA via mass spectrometry analysis after RNA pull-down. sEVs containing SATII RNA induced cellular senescence and promoted the expression of inflammatory SASP genes in recipient cells. YBX1 knockdown significantly reduced SATII RNA levels in sEVs and inhibited the propagation of SASP in recipient cells. The analysis of the clinical dataset revealed that YBX1 expression is higher in cancer stroma than in normal stroma of breast and ovarian cancer tissues. Furthermore, high YBX1 expression was correlated with poor prognosis in breast and ovarian cancers. This study demonstrated that SATII RNA loading into sEVs is regulated via YBX1 and that YBX1 is a promising target in novel cancer therapy.

The Association between the Severity of Dysmenorrhea and Psychological Distress of Women Working in Central Tokyo-A Preliminary Study.

This study aims to clarify the association between the severity of dysmenorrhea and psychological distress among working women in central Tokyo and examine the effect modification of job stressors. The participants in this cross-sectional study were 312 women who had undergone health check-ups in the "Marunouchi Hokenshitsu" project. The severity of dysmenorrhea was defined as the degree of daily life disturbance with menstrual pain, and the outcome variable was the K6 scores. To assess the association of psychological distress with the severity of dysmenorrhea, multiple regression analyses were performed. The results revealed that 18.3% of the 289 working women were in the moderate/severe group of dysmenorrhea. In multiple regression analysis, moderate/severe dysmenorrhea was significantly associated with higher levels of psychological distress, but the significance disappeared after adjusting for gynecology such as premenstrual syndrome (PMS) and workplace-related factors. The degree of job control was significantly associated with lower levels of psychological distress and may modify psychological distress caused by dysmenorrhea. Moderate/severe dysmenorrhea may be associated with higher levels of psychological distress in working women, and psychological symptoms of PMS) and the degree of job control were possible effect factors, and there may be effect modification by the degree of job control.

Alteration in the chromatin landscape during the DNA damage response: Continuous rotation of the gear driving cellular senescence and aging.

The DNA damage response (DDR) is a crucial biological mechanism for maintaining cellular homeostasis in living organisms. This complex process involves a cascade of signaling pathways that orchestrate the sensing and processing of DNA lesions. Perturbations in this process may cause DNA repair failure, genomic instability, and irreversible cell cycle arrest, known as cellular senescence, potentially culminating in tumorigenesis. Persistent DDR exerts continuous and cumulative pressure on global chromatin dynamics, resulting in altered chromatin structure and perturbed epigenetic regulations, which are highly associated with cellular senescence and aging. Sustained DDR activation and heterochromatin changes further promote senescence-associated secretory phenotype (SASP), which is responsible for aging-related diseases and cancer development. In this review, we discuss the diverse mechanisms by which DDR leads to cellular senescence and triggers SASP, together with the evidence for DDR-induced chromatin remodeling and epigenetic regulation in relation to aging.

Chromatin conformational changes at human satellite II contribute to the senescence phenotype in the tumor microenvironment.

Cellular senescence and senescence-associated secretory phenotype (SASP) in stromal cells within the tumor microenvironment promote cancer progression. Although cellular senescence has been shown to induce changes in the higher-order chromatin structure and abnormal transcription of repetitive elements in the genome, the functional significance of these changes is unclear. In this study, we examined the human satellite II (hSATII) loci in the pericentromere to understand these changes and their functional significance. Our results indicated that the hSATII loci decompact during senescence induction, resulting in new DNA-DNA interactions in distinct genomic regions, which we refer to as DRISR (Distinctive Regions Interacted with Satellite II in Replicative senescent Fibroblasts). Interestingly, decompaction occurs before the expression of hSATII RNA. The DRISR with altered chromatin accessibility was enriched for motifs associated with cellular senescence and inflammatory SASP genes. Moreover, DNA-fluorescence in situ hybridization analysis of the breast cancer tissues revealed hSATII decompaction in cancer and stromal cells. Furthermore, we reanalyzed the single-cell assay for transposase-accessible chromatin with sequencing data and found increased SASP-related gene expression in fibroblasts exhibiting hSATII decompaction in breast cancer tissues. These findings suggest that changes in the higher-order chromatin structure of the pericentromeric repetitive sequences during cellular senescence might directly contribute to the cellular senescence phenotype and cancer progression via inflammatory gene expression.

Type B2 vessels and infiltrative growth patterns b and c are associated with lymphatic invasion in pT1a-lamina propria mucosa esophageal squamous cell carcinoma.

BACKGROUND: Tumor growth pattern correlates with outcomes in patients with esophageal squamous cell carcinoma (ESCC), however, the clinical significance of the tumor growth pattern in pT1a-lamina propria mucosa (LPM) type of ESCC was unclear. This study was conducted to clarify clinicopathological features of tumor growth patterns in pT1a-LPM type ESCC and the relationship between tumor growth patterns and magnifying endoscopic findings. METHODS: Eighty-seven lesions diagnosed as pT1a-LPM ESCC were included. Clinicopathological findings including tumor growth pattern and narrow band imaging with magnifying endoscopy (NBI-ME) in the LPM area were investigated. RESULTS: Eighty-seven lesions were classified as infiltrative growth pattern-a (INF-a): expansive growth (n = 81), INF-b: intermediate growth (n = 4) and INF-c: infiltrative growth pattern (n = 2). Lymphatic invasion was shown in one INF-b and one INF-c lesion. NBI-ME and histopathological images were matched for 30 lesions. The microvascular pattern was classified into types B1 (n = 23) and B2 (n = 7) using the JES classification. All 23 type B1 lesions were classified as INF-a without lymphatic invasion. Type B2 lesions were classified as INF-a (n = 2), INF-b (n = 4) and INF-c (n = 1), and lymphatic invasion was present in two lesions (INF-b and INF-c). The rate of lymphatic invasion was significantly higher in type B2 than type B1 (p = 0.048). CONCLUSIONS: The tumor growth pattern of pT1a-LPM ESCC was mostly INF-a in type B1 patterns. Type B2 patterns are rarely present in pT1a-LPM ESCC, however lymphatic invasion with INF-b or INF-c was frequently observed. Careful observation before endoscopic resection with NBI-ME is important to identify B2 patterns to predict histopathology.

Identification of Novel Senescent Markers in Small Extracellular Vesicles.

Senescent cells exhibit several typical features, including the senescence-associated secretory phenotype (SASP), promoting the secretion of various inflammatory proteins and small extracellular vesicles (EVs). SASP factors cause chronic inflammation, leading to age-related diseases. Recently, therapeutic strategies targeting senescent cells, known as senolytics, have gained attention; however, noninvasive methods to detect senescent cells in living organisms have not been established. Therefore, the goal of this study was to identify novel senescent markers using small EVs (sEVs). sEVs were isolated from young and senescent fibroblasts using three different methods, including size-exclusion chromatography, affinity column for phosphatidylserine, and immunoprecipitation using antibodies against tetraspanin proteins, followed by mass spectrometry. Principal component analysis revealed that the protein composition of sEVs released from senescent cells was significantly different from that of young cells. Importantly, we identified ATP6V0D1 and RTN4 as novel markers that are frequently upregulated in sEVs from senescent and progeria cells derived from patients with Werner syndrome. Furthermore, these two proteins were significantly enriched in sEVs from the serum of aged mice. This study supports the potential use of senescent markers from sEVs to detect the presence of senescent cells in vivo.