A detailed intake-status profiling of seafoods in adult food-protein-induced enterocolitis syndrome patients.

BACKGROUND: Adults with food-protein-induced enterocolitis syndrome (FPIES) often develop severe abdominal symptoms after eating seafood. However, no investigation of a food elimination strategy for adult FPIES patients has been performed to date. METHODS: We conducted a retrospective cohort study of seafood-avoidant adults by telephone interview, based on the diagnostic criteria for adult FPIES reported by González et al. We compared the clinical profiles, abdominal symptoms, and causative seafoods between FPIES and immediate-type food allergy (IgE-mediated FA) patients. We also profiled the detailed intake-status of seafoods in adult FPIES patients. RESULTS: Twenty-two (18.8 %) of 117 adults with seafood-allergy were diagnosed with FPIES. Compared with the IgE-mediated FA patients, FPIES patients had an older age of onset, more pre-existing gastrointestinal and atopic diseases, more episodes, longer latency and duration of symptoms, more nausea, abdominal distention, and severe abdominal pain, and more frequent vomiting and diarrhea. In particular, abdominal distention-reflecting intestinal edema and luminal fluid retention-may be the most distinctive characteristic symptom in adult FPIES (p < 0.001). Bivalves, especially oysters, were the most common cause of FPIES. Strikingly, intake-status profiling revealed that many FPIES patients can safely ingest an average of 92.6 % of seafood species other than the causative species. CONCLUSIONS: There are many differentiators between FPIES and IgE-mediated FA, which may reflect differences in the underlying immunological mechanisms. Although seafood FPIES is unlikely to induce tolerance, many patients can ingest a wide variety of seafood species after a long period from onset.

Prognostic significance of C-reactive protein in unresectable hepatocellular carcinoma treated with atezolizumab and bevacizumab.

AIM: C-reactive protein (CRP) is both an inflammatory and prognostic marker in various cancers. This study aimed to elucidate the characteristics of CRP and the prognostic factors in patients who were administered with atezolizumab plus bevacizumab (ATZ + BEV) for unresectable hepatocellular carcinoma (HCC). METHODS: A total of 213 patients who received ATZ + BEV for HCC from November 2020 to March 2023 at 15 hospitals were enrolled in this retrospective study. The prognosis was analyzed by subdividing the patients based on baseline characteristics, radiologic response, and treatment lines. Accuracy of survival prediction was assessed using CRP, alpha fetoprotein (AFP), C-reactive protein and alpha fetoprotein in immunotherapy (CRAFITY), and Glasgow Prognostic Score. RESULTS: Compared with patients with baseline CRP <1 mg/dL, those with baseline CRP ≥1 mg/dL (n = 45) had a significantly higher baseline albumin-bilirubin score and AFP levels, significantly lower disease control rate (62.2%), and significantly shorter median overall survival (hazards ratios 2.292; 95% confidence interval 1.313-5.107; log-rank test, p < 0.001). Multivariate analysis identified CRP ≥1 mg/dL, AFP ≥100 ng/mL, and modified albumin-bilirubin grade as the significant prognostic factors. The baseline CRP, AFP, CRAFITY, and Glasgow Prognostic Score demonstrated higher discrimination for 1-year survival prediction after first-line ATZ + BEV administration, compared with beyond second line, with area under the receiver operating characteristic curves of 0.759, 0.761, 0.805, and 0.717, respectively. CONCLUSIONS: CRP was a significant biomarker in patients treated with ATZ + BEV for HCC. Elevated CRP levels may indicate aggressive cancer progression and potential resistance to ATZ + BEV therapy.

Segmental arterial mediolysis with a ruptured visceral artery on two consecutive days.

Background: We describe a case of segmental arterial mediolysis in which a vessel ruptured on two consecutive days. Case Presentation: A 69-year-old man presented with sudden-onset abdominal pain. Computed tomography showed a hematoma in the gastric wall. The patient was discharged after the pain was relieved but returned 8 h later with abdominal pain and shock. Repeated computed tomography revealed a massive intra-abdominal hemorrhage without previous aneurysm formation. Emergency angiography and coil embolization were successfully carried out. Segmental arterial mediolysis was diagnosed after irregular vasodilated lesions were observed in multiple arteries. Conclusion: This case suggests that accurately predicting the next vessel rupture is difficult. For patients experiencing intra-abdominal bleeding with segmental arterial mediolysis, we suggest treating only ruptured aneurysms and closely following-up unruptured aneurysms.

Anticoagulation against portal vein thrombosis reduces mortality and liver cirrhosis-related complications: A propensity score-matched study.

AIM: Portal vein thrombosis (PVT) is one of the common complications of liver cirrhosis. Although anticoagulation contributes to thrombus resolution and is considered the first-choice treatment, its impact on patients' prognosis is still controversial. This study aimed to clarify the benefit of anticoagulation on mortality, liver function, and the incidence of liver cirrhosis-related complications in cirrhotic PVT patients. METHODS: We conducted a multicenter retrospective review in which we included 78 eligible patients with PVT out of 439. After propensity score matching, 21 cirrhotic PVT patients were included in each one of the untreated control and anticoagulation groups. RESULTS: Overall survival was significantly improved in the anticoagulation group compared with the control group (p = 0.041), along with PVT size reduction (53.3% vs. 108.2%, p = 0.009). At the time of CT follow-up, the anticoagulation group showed a lower ALBI score (p = 0.037) and its prevalence of massive ascites was significantly lower (p = 0.043) compared with the control group. The incidence of overt encephalopathy was also lower in the anticoagulation group (p = 0.041). The cumulative incidence of bleeding events did not differ significantly between the two groups. CONCLUSIONS: Anticoagulation improves the survival of patients with cirrhotic PVT. Preserved liver function and reduced risks of cirrhosis-related complications under the treatment may have contributed to a better prognosis. Given its efficacy and safety, anticoagulation is worth initiating in patients with PVT.

Lymphocyte-to-monocyte ratio as a prognostic and potential tumor microenvironment indicator in advanced soft tissue sarcoma treated with first-line doxorubicin therapy.

Prognostic value of hematologic indices and their association with the tumor microenvironment (TME) remain unclear in advanced soft tissue sarcoma (STS). We aimed to evaluate their prognostic value and correlation with the TME status in advanced STS treated with first-line doxorubicin (DXR) therapy. Clinical data and three hematological indices, including lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio, and neutrophil-to-lymphocyte ratio, were collected from 149 patients with advanced STS. The TME status was pathologically examined by CD3, CD68, and CD20 staining of resected tumor slides. In a multivariate Cox analysis, low LMR and absence of primary tumor resection were independently associated with worse overall survival (OS) (HR 3.93, p = 0.001; HR 1.71, p = 0.03). A prognostic model using these variables predicted OS with greater area under curves than those obtained using Systemic Inflammatory Score and Glasgow Prognostic Score. The LMR significantly correlated with the tumoral CD3/CD68-positive cell ratio in surgical specimens (R = 0.959, p = 0.04). In conclusion, LMR was a prognostic factor in advanced STS treated with first-line DXR therapy. LMR could partially reflect anti-tumor immunity in the TME and have the prognostic value. The potential role of LMR as an indicator of TME status warrants further investigation.

Obesity-induced metabolic imbalance allosterically modulates CtBP2 to inhibit PPAR-alpha transcriptional activity.

Maintenance of metabolic homeostasis is secured by metabolite-sensing systems, which can be overwhelmed by constant macronutrient surplus in obesity. Not only the uptake processes but also the consumption of energy substrates determine the cellular metabolic burden. We herein describe a novel transcriptional system in this context comprised of peroxisome proliferator-activated receptor alpha (PPARα), a master regulator for fatty acid oxidation, and C-terminal binding protein 2 (CtBP2), a metabolite-sensing transcriptional corepressor. CtBP2 interacts with PPARα to repress its activity, and the interaction is enhanced upon binding to malonyl-CoA, a metabolic intermediate increased in tissues in obesity and reported to suppress fatty acid oxidation through inhibition of carnitine palmitoyltransferase 1. In line with our preceding observations that CtBP2 adopts a monomeric configuration upon binding to acyl-CoAs, we determined that mutations in CtBP2 that shift the conformational equilibrium toward monomers increase the interaction between CtBP2 and PPARα. In contrast, metabolic manipulations that reduce malonyl-CoA decreased the formation of the CtBP2-PPARα complex. Consistent with these in vitro findings, we found that the CtBP2-PPARα interaction is accelerated in obese livers while genetic deletion of CtBP2 in the liver causes derepression of PPARα target genes. These findings support our model where CtBP2 exists primarily as a monomer in the metabolic milieu of obesity to repress PPARα, representing a liability in metabolic diseases that can be exploited to develop therapeutic approaches.

Comparison of adult food protein-induced enterocolitis syndrome to crustaceans and immediate-type food allergy.

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is increasingly found in adults. FPIES requires different treatment from immediate-type food allergy (FA) in emergency medicine. However, no comparison of the clinical presentations of these diseases has been reported. OBJECTIVE: To compare the clinical presentations and causative crustaceans of adult FPIES and FA using a standardized questionnaire and to thereby lay the groundwork for establishing an algorithm that distinguishes those diseases. METHODS: We conducted a retrospective cohort study of crustacean-avoidant adults by telephone interview based on the previously reported diagnostic criteria for adult FPIES to compare the clinical features and crustacean intake status between FPIES and FA. RESULTS: Of 73 adult patients with crustacean allergy, 8 (11%) were diagnosed with having FPIES and 53 (73%) FA. Compared with the patients with FA, those with FPIES had a longer latency period (P < .01), more episodes (P = .02), longer duration of symptoms (P = .04), more frequent abdominal distention (P = .02), and severe colic pain (P = .02). Half of the patients with FPIES experienced fear of death during an episode. Panulirus japonicus (Japanese spiny lobster) and Homarus weber (lobster) were significantly common FPIES-causing foods. A statistically significant 62.5% of patients with FPIES were able to ingest some type of crustacean. CONCLUSION: FPIES and FA can be clearly differentiated by the abdominal symptoms, latency period, and duration of episodes. Furthermore, some patients with FPIES do not necessarily need to avoid all crustaceans. Our findings lay the groundwork for establishing an algorithm that distinguishes FPIES from FA in adults.

Periodic and Aperiodic NiFe Nanomagnet/Ferrimagnet Hybrid Structures for 2D Magnon Steering and Interferometry with High Extinction Ratio.

Magnons, quanta of spin waves, are known to enable information processing with low power consumption at the nanoscale. So far, however, experimentally realized half-adders, wave-logic, and binary output operations are based on few µm-long spin waves and restricted to one spatial direction. Here, magnons with wavelengths λ down to 50 nm in ferrimagnetic Y3 Fe5 O12 below 2D lattices of periodic and aperiodic ferromagnetic nanopillars are explored. Due to their high rotational symmetries and engineered magnetic resonances, the lattices allow short-wave magnons to propagate in arbitrarily chosen on-chip directions when excited by conventional coplanar waveguides. Performing interferometry with magnons over macroscopic distances of 350 × λ without loss of coherency, unprecedentedly high extinction ratios of up to 26 (±8) dB [31 (±2) dB] for a binary 1/0 output operation at λ = 69 nm (λ = 154 nm) are achieved in this work. The reported findings and design criteria for 2D magnon interferometry are particularly important in view of the realization of complex neuronal networks recently proposed for interfering spin waves underneath nanomagnets.

The efficacy of dupilumab in induction and maintenance of remission in an adult patient with steroid-dependent eosinophilic enteritis (EoN).

Eosinophilic enteritis (EoN) is associated with an eosinophilic infiltrate confined to the small intestine, but treatment options other than diet and corticosteroid therapy are scarce. There is only one report of the use of dupilumab for eosinophilic gastrointestinal disease, involving three pediatric patients. We report a case of successful induction of remission with dupilumab in a 53 year-old female patient with steroid-dependent EoN. The patient presented to the emergency room with uncontrollable abdominal pain and CT revealed a thickened ileal wall and small amount of ascites. Despite no abnormalities on endoscopy, histological examination revealed numerous eosinophilic infiltrates (> 100/HPF) and degranulation in the ileal lamina propria, diagnosing the patient with EoN. The patient achieved clinical remission with prednisolone, but EoN relapsed during tapering. Long-term steroid therapy was inappropriate due to mandibular osteomyelitis and osteoporosis, and she was switched to 9 mg budesonide, an intestine-soluble topical steroid without effect. Dupilumab administration resulted in resolution of abdominal pain, and remission was maintained after discontinuation of budesonide. Histological remission was confirmed 2 months after dupilumab administration. This is the first report of remission induced and maintained with dupilumab in an adult patient with EoN.

Development of risk scores for early and late recurrence of colonic diverticular hemorrhage.

OBJECTIVES: Colonic diverticular hemorrhage (CDH) often recurs. Although several studies have suggested that early rebleeding (ER) and late rebleeding (LR) should be treated independently, and several ER/LR risk factors have been identified, an integrated system for risk evaluation is still lacking. This study aimed to develop risk scores for early and late rebleeding of CDH. METHODS: This two-center, retrospective cohort study included 218 patients between 2008 and 2021. ER and LR risk factors were identified using multivariate analysis, and risk scores were developed using the odds ratios of each risk factor. RESULTS: The ER and LR rates were 32.6 and 25.7%, respectively. High heart rate on admission, early endoscopy from the visit, no bowel preparation and no endoscopic treatment were identified as risk factors for ER. On the other hand, LR risk factors included a history of hypertension and diabetes, early endoscopy from the visit, and the use of endoscopic clips. The ER risk score [area under the curve (AUC) = 0.71] was highly sensitive (90.3%) at a cutoff point of 6 and highly specific (98.0%) at a cutoff point of 15. The LR risk score (AUC = 0.70) was highly sensitive (91.1%) at a cutoff point of 2.6 and highly specific (88.3%) at a cutoff point of 7.1. CONCLUSIONS: The ER and LR risk scores were established for the first time, and they can divide CDH patients based on their risk of rebleeding as well as provide clinicians with practical information about the CDH management.

Colonoscopic observation time as a predictor of stigmata of recent hemorrhage identification in colonic diverticular hemorrhage.

OBJECTIVES: The strategy of identifying stigmata of recent hemorrhage (SRH) and treating the bleeding source is important for the prevention of rebleeding in colonic diverticular hemorrhage (CDH). However, there are few known reports on SRH identification thus far. This large multicenter study evaluated factors correlated with SRH identification, including observation time during colonoscopy. METHODS: A total of 392 CDH cases were classified into presumptive CDH (n = 276) or definitive CDH with SRH (n = 116) on the basis of colonoscopy results. Multivariate Cox proportional hazards regression was employed to identify factors correlated with SRH identification. For the endoscopic treatment, endoscopic clips (EC), endoscopic band ligation (EBL) or endoscopic detachable snare ligation (EDSL) was performed. RESULTS: Longer observation time was significantly correlated with SRH identification in multivariate analysis (OR, 10.3 [95% CI: 3.84-27.9], p<.001). Receiver operating characteristic curve (ROC) analysis of the SRH identification rate by observation time indicated a high area under the curve (AUC) (0.79), and the threshold of the observation time was calculated at 19 min using Youden's index. Moreover, the patients taken endoscopic hemostasis showed significantly lower early rebleeding rate than patients without endoscopic hemostasis (16.4% vs. 31.9%, p=.001), suggesting the importance of identifying SRH and treating the bleeding source for reducing the risk of recurrent bleeding. CONCLUSIONS: Long-observation time correlated with SRH identification in this study, in which bowel preparation and water-jet scope and cap attachment are commonly used. This is the first known study to highlight the significance of observation time in the SRH identification rates.

Spin dynamics, loop formation and cooperative reversal in artificial quasicrystals with tailored exchange coupling.

Aperiodicity and un-conventional rotational symmetries allow quasicrystalline structures to exhibit unusual physical and functional properties. In magnetism, artificial ferromagnetic quasicrystals exhibited knee anomalies suggesting reprogrammable magnetic properties via non-stochastic switching. However, the decisive roles of short-range exchange and long-range dipolar interactions have not yet been clarified for optimized reconfigurable functionality. We report broadband spin-wave spectroscopy and X-ray photoemission electron microscopy on different quasicrystal lattices consisting of ferromagnetic Ni81Fe19 nanobars arranged on aperiodic Penrose and Ammann tilings with different exchange and dipolar interactions. We imaged the magnetic states of partially reversed quasicrystals and analyzed their configurations in terms of the charge model, geometrical frustration and the formation of flux-closure loops. Only the exchange-coupled lattices are found to show aperiodicity-specific collective phenomena and non-stochastic switching. Both, exchange and dipolarly coupled quasicrystals show magnonic excitations with narrow linewidths in minor loop measurements. Thereby reconfigurable functionalities in spintronics and magnonics become realistic.

Palliative Radiation Therapy for Intramedullary Spinal Cord Metastasis.

BACKGROUND/AIM: The purpose of this study was to retrospectively review the outcomes of intramedullary spinal cord metastasis (ISCM) and identify predictors for ambulation after radiotherapy (RT). PATIENTS AND METHODS: We analyzed 16 lesions in 15 patients treated with RT for ISCM at our clinic from October 2009 to April 2020 to evaluate predictors for improved ambulation following RT. RESULTS: The primary diseases included nine cases of lung cancer, two cases of breast cancer, and several others. The RT schedule was primarily 30 Gy/10 fractions in seven cases, while others were applied to nine cases. The median overall survival time was 99 days. After RT, all seven patients who could walk prior to RT were still able to walk (100%), whereas only two of nine patients who could not walk prior to RT were able to walk (22%, p=0.004). CONCLUSION: Ambulation prior to RT was a significant predictor of ambulation ability after RT.

BATF epigenetically and transcriptionally controls the activation program of regulatory T cells in human tumors.

Regulatory T (Treg) cells suppress effective antitumor immunity in tumor-bearing hosts, thereby becoming promising targets in cancer immunotherapy. Despite the importance of Treg cells in tumor immunity, little is known about their differentiation process and epigenetic profiles in the tumor microenvironment (TME). Here, we showed that Treg cells in the TME of human lung cancers harbored a completely different open chromatin profile compared with CD8+ T cells, conventional CD4+ T cells in the TME, and peripheral Treg cells. The integrative sequencing analyses including ATAC, single-cell RNA, and single-cell ATAC sequencing revealed that BATF, IRF4, NF-κB, and NR4A were important transcription factors for Treg cell differentiation in the TME. In particular, BATF was identified as a key regulator, which leveraged Treg cell differentiation through epigenetically controlling activation-associated gene expression, resulting in the robustness of Treg cells in the TME. The single-cell sequencing approaches also revealed that tissue-resident and tumor-infiltrating Treg cells followed a common pathway for differentiation and activation in a BATF-dependent manner heading toward Treg cells with the most differentiated and activated phenotypes in tissues and tumors. BATF deficiency in Treg cells remarkably inhibited tumor growth, and high BATF expression was associated with poor prognosis in lung cancer, kidney cancer, and melanoma. These findings indicate one of the specific chromatin remodeling and differentiation programs of Treg cells in the TME, which can be applied in the development of Treg cell-targeted therapies.

＜Editors' Choice＞ Elective nodal irradiation versus involved field radiotherapy for limited disease small cell lung cancer: a single-institution experience.

Elective nodal irradiation (ENI) and involved field radiotherapy (IFRT) are definitive radiotherapeutic approaches used to treat patients with limited-disease small cell lung cancer (LD-SCLC). However, no solid consensus exists on their optimal target volume. The current study aimed to assess the clinical outcomes of patients with LD-SCLC who received definitive ENI or IFRT. A retrospective single-institution study of patients who received definitive radiotherapy between 2008 and 2020 was performed. All patients underwent whole-body positron emission tomography/computed tomography before three-dimensional conformal radiotherapy. Among the 37 patients analyzed, 22 and 15 received ENI and IFRT, respectively. The thoracic radiotherapy dose was mostly either 60 Gy in 30 fractions delivered in 2-Gy fractions once daily or 45 Gy in 30 fractions delivered in 1.5-Gy fractions twice daily. The median follow-up period was 21.4 months. A total of 12 patients (32%) experienced locoregional relapse: 10 within and 2 outside the irradiation fields. One patient in the IFRT group experienced isolated nodal failure. Differences in locoregional relapse-free, progression-free, and overall survival rates between ENI and IFRT were not significant. Overall, IFRT did not promote a significant increase in locoregional recurrence compared to ENI. Our findings suggested the utility of IFRT in standard clinical practice and support its use for patients with LD-SCLC.

A case of localized colorectal wild-type ATTR amyloidosis complicated by early stage colorectal cancer and a CMV-associated ulcer during the long-term follow-up.

Gastrointestinal involvement is a rare manifestation of systemic amyloidosis, and few reports have been published on localized amyloidosis of the colon. Only one case report has been published on the long-term prognosis of localized colorectal amyloidosis, and there are no previous reports on localized colorectal ATTR amyloidosis. Here, we report an 80-year-old male with localized colorectal wild-type ATTR amyloidosis who presented with edematous mucosa with vascular changes throughout the colon. He did not exhibit any symptoms or endoscopic exacerbation for 8 years after diagnosis. However, after 8 years, he developed early stage colorectal cancer and cytomegalovirus-associated ulcer. He was treated with endoscopic submucosal dissection, which was relatively challenging due to his hemorrhagic condition and poor elevation of the submucosa caused by amyloid deposits. Since the tumor was completely resected, he will undergo regular follow-up. Our review of 20 previous cases of localized colorectal amyloidosis revealed its clinical features and long-term prognosis. Specifically, ours is the second case of a diffuse pan-colon type of colorectal localized amyloidosis, which may lead to various complications, such as colorectal cancer, over a long period of time, and thus, regular follow-up is necessary.

Case report of recurrent spontaneous tumor lysis syndrome in a patient with esophageal cancer recovered via chemotherapy.

Tumor lysis syndrome (TLS) is a life-threatening oncological emergency. Only one TLS case has been reported in patients with esophageal cancer. We report the case of a 61-year-old man with recurrent spontaneous TLS caused by esophageal cancer. He was admitted to our hospital to investigate low back pain and dysphagia. Endoscopy and computed tomography revealed esophageal cancer with multiple liver and bone metastases. He was diagnosed with laboratory TLS based on high serum uric acid and phosphorus. After intravenous fluids and allopurinol were administrated, chemotherapy with 5-fluorouracil and cisplatin was started the next day. Although he transiently developed clinical TLS, it was resolved with conservative treatment. However, mild renal dysfunction was prolonged and cisplatin was reduced in the second course. As a consequence, recurrence of spontaous TLS (sTLS) was induced at the end of the course. In the third course, docetaxel was added to the regimen, and since then the patient have not develop sTLS. To the best of our knowledge, this is the first report regarding recurrent sTLS developed on the basis of solid tumors and was successfully controlled by chemotherapy. Although TLS complications are rare in esophageal cancer, early diagnosis and the adjustment of regimen resulted in stable chemotherapy.

Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments.

The balance of programmed death-1 (PD-1)-expressing CD8+ T cells and regulatory T (Treg) cells in the tumor microenvironment (TME) determines the clinical efficacy of PD-1 blockade therapy through the competition of their reactivation. However, factors that determine this balance remain unknown. Here, we show that Treg cells gain higher PD-1 expression than effector T cells in highly glycolytic tumors, including MYC-amplified tumors and liver tumors. Under low-glucose environments via glucose consumption by tumor cells, Treg cells actively absorbed lactic acid (LA) through monocarboxylate transporter 1 (MCT1), promoting NFAT1 translocation into the nucleus, thereby enhancing the expression of PD-1, whereas PD-1 expression by effector T cells was dampened. PD-1 blockade invigorated the PD-1-expressing Treg cells, resulting in treatment failure. We propose that LA in the highly glycolytic TME is an active checkpoint for the function of Treg cells in the TME via upregulation of PD-1 expression.

Importance of Telomere Shortening in the Pathogenesis of Ulcerative Colitis: A New Treatment From the Aspect of Telomeres in Intestinal Epithelial Cells.

BACKGROUND AND AIMS: Ulcerative colitis [UC] is a chronic inflammatory disease of the colon with frequent relapses. Telomere shortening in intestinal epithelial cells has been reported in severe or longstanding cases. However, its influence on UC pathogenesis remains unelucidated. To this end, we evaluated telomere shortening using a long-term organoid inflammation model that we had originally established. METHODS: A UC model using human colon organoids was established to assess telomere changes chronologically. MST-312 was used for the telomerase inhibition assay. The potential of telomerase activators as a novel UC treatment was evaluated with an in vitro model, including microarray analysis, and histological changes were assessed using xenotransplantation into mouse colonic mucosa. RESULTS: Our UC model reproduced telomere shortening in vitro, which was induced by the continuous suppression of telomerase activity via P53. MST-312-based analysis revealed that telomere shortening was involved in the pathogenesis of UC. Madecassoside [MD] improved the telomere length of the UC model and UC patient-derived organoids, which further promoted cell proliferation in vitro and improved the graft take-rate of xenotransplantation. Moreover, histological analysis revealed that MD induced normal crypt structure with abundant goblet cells. CONCLUSIONS: This study is the first to reveal the mechanism and importance of telomere shortening in the pathogenesis of UC. MD could be a novel candidate for UC treatment beyond endoscopic mucosal healing.

Skeletal muscle releases extracellular vesicles with distinct protein and microRNA signatures that function in the muscle microenvironment.

Extracellular vesicles (EVs) contain various regulatory molecules and mediate intercellular communications. Although EVs are secreted from various cell types, including skeletal muscle cells, and are present in the blood, their identity is poorly characterized in vivo, limiting the identification of their origin in the blood. Since skeletal muscle is the largest organ in the body, it could substantially contribute to circulating EVs as their source. However, due to the lack of defined markers that distinguish skeletal muscle-derived EVs (SkM-EVs) from others, whether skeletal muscle releases EVs in vivo and how much SkM-EVs account for plasma EVs remain poorly understood. In this work, we perform quantitative proteomic analyses on EVs released from C2C12 cells and human iPS cell-derived myocytes and identify potential marker proteins that mark SkM-EVs. These markers we identified apply to in vivo tracking of SkM-EVs. The results show that skeletal muscle makes only a subtle contribution to plasma EVs as their source in both control and exercise conditions in mice. On the other hand, we demonstrate that SkM-EVs are concentrated in the skeletal muscle interstitium. Furthermore, we show that interstitium EVs are highly enriched with the muscle-specific miRNAs and repress the expression of the paired box transcription factor Pax7, a master regulator for myogenesis. Taken together, our findings confirm previous studies showing that skeletal muscle cells release exosome-like EVs with specific protein and miRNA profiles in vivo and suggest that SkM-EVs mainly play a role within the muscle microenvironment where they accumulate.