Integrated Bioinformatics and Experimental Validation to Identify a Disulfidptosis-Related lncRNA Model for Prognostic Prediction in Papillary Renal Cell Carcinoma.

AIMS: This study aimed to construct a prognostic model for papillary renal cell carcinoma (pRCC) utilizing disulfidptosis-associated long non-coding RNAs (lncRNAs). Additionally, it investigated the potential of these lncRNAs in predicting immune responses and drug sensitivity in pRCC. BACKGROUND: LncRNAs have been implicated in the progression and prognosis of pRCC. Recently, disulfidptosis, an emerging form of regulated cell death, has shown potential as a therapeutic approach for cancer. However, the potential association between disulfidptosis-related lncRNAs and pRCC remains unclear. METHODS: We analyzed transcriptome profiling and clinical data of pRCC patients from The Cancer Genome Atlas database. Using Pearson correlation analysis, we identified lncRNAs associated with disulfidptosis. Based on the identified disulfidptosis-related lncRNAs that were correlated with overall survival (OS), we constructed a novel prediction model using the least absolute shrinkage and selection operator, univariable Cox regression, and multivariable Cox regression analyses. The model's utility was assessed through Kaplan-Meier survival, receiver operating characteristics, and principal component analyses. Moreover, functional analysis helped identify potential prognostic mechanisms, and the prediction of chemical drugs for pRCC was also performed. Finally, qRT-PCR validated the expression of prognostic lncRNAs in pRCC cells and patient samples. RESULTS: Our prediction model was based on nine disulfidptosis-related lncRNAs. Evaluation and validation analyses demonstrated that the model had excellent, consistent, and independent prognostic value for pRCC patients, with area under the curve (AUC) values of 0.954, 0.910, and 0.830 for 1-, 3-, and 5-year OS, respectively. Through functional analysis, we discovered a significant correlation between the identified prognostic signature and immunity. Additionally, in terms of chemotherapy sensitivity, our analysis indicated that the low-risk group exhibited higher sensitivity to sunitinib and pazopanib. Furthermore, the expression patterns of the identified lncRNAs were validated in samples obtained from pRCC cells and patients. CONCLUSION: This study successfully established and validated a novel disulfidptosis-related prediction model. The findings suggest the potential involvement of immune-related pathways in lncRNA signature-associated survival. This model holds promise for differentiating prognosis and improving personalized therapeutic strategies for pRCC in clinical practice.

Interactive training with a novel simulation model for upper gastrointestinal endoscopic hemostasis improves trainee technique and confidence.

Background and study aims Endoscopic hemostasis is a life-saving procedure for gastrointestinal bleeding; however, training for it is often performed on real patients and during urgent situations that put patients at risk. Reports of simulation-based training models for endoscopic hemostasis are scarce. Herein, we developed a novel simulator called "Medical Rising STAR-Ulcer type" to practice endoscopic hemostasis with hemoclips and coagulation graspers. This study aimed to evaluate the reproducibility of the clinical difficulty of this model and the effectiveness of simulation-based training for clipping hemostasis. Patients and methods This was a prospective educational study. Fifty gastroenterology residents from Japan and Canada were recruited to participate in a simulation-based training program. The primary outcome was the success rate for clipping hemostasis. We measured differences in trainee subjective assessment scores and evaluated the co-occurrence network based on comments after training. Results The hemostasis success rate of the trainees significantly increased after instruction (64% vs. 86%, P < 0.05). The success rate for ulcers in the upper body of the stomach (59%), a high-difficulty site, was significantly lower than that for ulcers in the antrum, even after feedback and instruction. Trainee self-perceived proficiency and confidence significantly improved after simulation-based training ( P < 0.05). Co-occurrence network analysis showed that trainees valued a structured learning approach, acknowledged simulator limitations, and recognized the need for continuous skill refinement. Conclusions Our study demonstrates the potential of our simulation-based training model as a valuable tool for improving technical skills and confidence in trainees learning to perform endoscopic hemostasis.

A Novel Dry Simulator Model for Learning Comprehensive Endoscopic Retrograde Cholangiopancreatography/Endoscopic Sphincterotomy Procedures while Minimizing Adverse Bleeding Events (with Video).

INTRODUCTION: Endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic sphincterotomy (EST) are essential skills for performing endoscopic cholangiopancreatic procedures. However, these procedures have a high incidence of adverse events, and current training predominantly relies on patient-based approaches. Herein, we aimed to develop an ERCP/EST simulator model to address the need for safer training alternatives, especially for learners with limited ERCP experience. METHODS: The model was designed to facilitate the use of actual endoscopic devices, supporting learning objectives that align with the components of the validated Bethesda ERCP Skill Assessment Tool (BESAT). BESAT focuses on skills, such as papillary alignment, maintenance of duodenoscope position, gentle and efficient cannulation, controlled sphincterotomy in the correct trajectory, and guidewire manipulation. Thirty gastroenterology trainees used the simulator between May 2022 and March 2023, and their satisfaction was assessed using a visual analog scale (VAS) and pre- and post-training questionnaires. RESULTS: The novel simulator model comprised a disposable duodenal papillary section, suitable for incision with an electrosurgical knife, alongside washable upper gastrointestinal tract and bile duct sections for repeated use. The duodenal papillary section enabled reproduction of a realistic endoscope position and the adverse bleeding events due to improper incisions. The bile duct section allowed for the reproduction of fluoroscopic-like images, enabling learners to practice guidewire guidance and insertion of other devices. Following training, the median VAS score reflecting the expectation for model learning significantly increased from 69.5 (interquartile range [IQR]: 55.5-76.5) to 85.5 (IQR: 78.0-92.0) (p < 0.01). All participants expressed a desire for repeated simulator training sessions. CONCLUSIONS: This innovative simulator could serve as a practical educational tool, particularly beneficial for novices in ERCP. It could facilitate hands-on practice with actual devices, enhancing procedural fluency and understanding of precise incisions to minimize the risk of bleeding complications during EST.

Similar Effect of Vonoprazan and Oral Proton Pump Inhibitors for Preventing Rebleeding in Cases of Upper Gastrointestinal Bleeding.

Objective The use of a proton pump inhibitor (PPI) reduces rebleeding and mortality in patients with upper gastrointestinal bleeding (UGIB). Vonoprazan is a novel oral agent with strong and sustained acid-inhibitory activity. We clarified the effect of vonoprazan compared with oral PPIs in such patients. Methods We analyzed the Diagnosis Procedure Combination database. The primary outcome was rebleeding, and secondary outcomes were in-hospital mortality and in-hospital mortality after rebleeding. Propensity score matching was performed to balance the comparison groups, and logistic regression analyses were used to compare the outcomes between vonoprazan and oral PPIs. Patients Patients on vonoprazan or oral PPIs who underwent endoscopic hemostasis for UGIB between 2014 and 2019 were included. Results We enrolled 78,964 patients, of whom 27,101 and 51,863 were prescribed vonoprazan and a PPI, respectively. After propensity score matching, the rebleeding rate of vonoprazan did not significantly differ from that of oral PPIs [6.4% vs. 6.1%; odds ratio (OR), 1.05; 95% confidence interval (CI), 0.98-1.13]; similarly, the in-hospital mortality rate (1.4% vs. 1.5%; OR, 0.91; 95% CI, 0.79-1.05) and in-hospital mortality after rebleeding (0.3% vs. 0.2%; OR, 1.09; 95% CI, 0.78-1.54) also did not significantly differ between the groups. The acquired findings were robust across dose-restricted analyses and several sensitivity analyses. Conclusion Rebleeding and in-hospital mortality risks in patients on vonoprazan were similar to those in patients on oral PPIs. Considering the higher cost of vonoprazan, oral PPIs might be an optimal oral agent as an acid-suppressive therapy in such patients.

Role of T-box transcription factor 3 in gastric cancers.

The expression of T-box transcription factor 3 (TBX3) has been identified in various cancers, including gastric cancers. Its role in breast cancers and melanomas has been intensively studied, and its contribution to the progression of cancers through suppressing senescence and promoting epithelial-mesenchymal transition has been reported. Recent reports on the role of TBX3 in gastric cancers have implied its involvement in gastric carcinogenesis. Considering its pivotal role in the initiation and progression of cancers, TBX3 could be a promising therapeutic target for gastric cancers.

Discrepancy between Abdominal Symptoms and Endoscopic Findings in Patients with Gastro-duodenal Eosinophilia: A Case Series.

Some patients present gastro-duodenal eosinophilia without abdominal symptoms. Nine cases with gastro-duodenal eosinophilia were seen at the Tohoku University Hospital between January 2011 and June 2022. Seven (78%) patients had a background of allergic or hyper-eosinophilic disease. Esophagogastroduodenoscopy showed erosions (n=6), discoloration (n=4), ulcers (n=3), erythema (n=3), muskmelon-like appearance (n=2), and cracks (n=1). Two cases were asymptomatic with eosinophilic gastroenteritis (EGE)-like endoscopic findings, and two were symptomatic with normal endoscopic findings. The discrepancy between the abdominal symptoms and esophagogastroduodenoscopy findings suggests that clinicians should assess patients for background allergic disease, regardless of abdominal symptoms.

How Family Living Arrangements and Migration Distances Shape the Settlement Intentions of Rural Migrant Workers in China.

Rural migrant workers and their families will decide the future of China's urbanization. Using data from the "China Migrants Dynamic Survey and Hundreds of Villages Investigation" carried out in 2018, we examine whether and how family living arrangements and migration distances shape rural migrant workers' settlement intentions in urban areas. In general, rural migrant workers' settlement intention is shown to be weak. However, individuals with children are more likely to have a stronger intention to settle permanently in urban areas. Among geographical factors, geospatial distance exerts a negative influence on migrant parents' settlement intention when the interaction effect of family living arrangements and migration distances is considered. Migrant families are increasingly concentrated in cities near their hometowns with a low entry barrier that allows them to gain access to better amenities. Socio-economic factors, especially disposable income, human resources, and housing conditions, play significant roles in migrant parents' settlement intention. The age and hometown region of migrant parents are also closely related to their intentions to settle in urban areas. Potential channels for the management of urbanization policy are also explored.

Wnt Signaling and Aging of the Gastrointestinal Tract.

Aging is considered a risk factor for various diseases including cancers. In this aging society, there is an urgent need to clarify the molecular mechanisms involved in aging. Wnt signaling has been shown to play a crucial role in the maintenance and differentiation of tissue stem cells, and intensive studies have elucidated its pivotal role in the aging of neural and muscle stem cells. However, until recently, such studies on the gastrointestinal tract have been limited. In this review, we discuss recent advances in the study of the role of Wnt signaling in the aging of the gastrointestinal tract and aging-related carcinogenesis.

Decreased Expression of NRF2 Target Genes after Alcohol Exposure in the Background Esophageal Mucosa of Patients with Esophageal Squamous Cell Carcinoma.

Patients with esophageal squamous cell carcinoma (ESCC) might have a specific mechanism for the carcinogenesis by alcohol consumption in the background esophageal mucosa, and nuclear factor erythroid 2-related factor 2 (NRF2), which plays a protective role against esophageal carcinogenesis, and barrier dysfunction might be associated with this phenomenon. This study aimed to confirm this hypothesis. Twenty patients with superficial ESCCs (ESCC patients) and 20 age- and sex-matched patients without ESCC (non-ESCC patients) were enrolled. Biopsy samples were obtained from non-neoplastic esophageal mucosa: one for histological evaluation, one for quantitative real-time polymerase chain reaction (PCR), and two for the mini-Ussing chamber system to measure transepithelial electrical resistance (TEER) and, thereafter, for PCR. The TEER after acetaldehyde or both acetaldehyde and ethanol exposure did not differ significantly between ESCC and non-ESCC patients. Unlike non-ESCC patients, mRNA levels of NRF2 target genes and claudin4 in ESCC patients tended to decrease after the exposure, with a significant difference between no exposure and both acetaldehyde and ethanol exposure in NRF2 target genes (p < 0.05). Furthermore, in ESCC patients, the decreased tendency of mRNA levels of NRF2 target genes after the exposure was more pronounced in high-risk states, such as aldehyde dehydrogenase 2 (ALDH2) Lys alleles (Glu/Lys + Lys/Lys), Lugol-voiding lesion grade C, and drinking history. In conclusion, the protective role of NRF2 against carcinogenesis from alcohol exposure might be disrupted in the background esophageal mucosa of ESCC patients, which might lead to a high incidence of metachronous ESCC.

Prolonged Diarrhea Following COVID-19 Vaccination: A Case Report and Literature Review.

Vaccination against coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently underway across countries worldwide. However, the prevalence and characteristics of prolonged adverse events lasting for several months after receiving the vaccine remain largely unknown. We herein report a 46-year-old woman with prolonged diarrhea and vomiting after receiving the BNT162b2 mRNA vaccine for COVID-19. She had no notable medical history, including that of gastrointestinal diseases. She developed vomiting several hours after receiving the first vaccine dose and further developed severe diarrhea after 7 days. Several days after the second vaccine dose, her condition deteriorated, unrelieved by symptomatic therapies, including anti-diarrheal drugs. Abdominal computed tomography (CT) revealed inflammatory changes in the entire segment of the small intestine with wall thickening. The upper and lower gastrointestinal and capsule endoscopies were unremarkable. The patient's symptoms persisted for more than 6 months after the second vaccine dose. A Vaccine Adverse Event Reporting System (VAERS) database search suggested that diarrhea is observed in approximately 3% of all vaccine recipients, but a literature review indicated that prolonged gastrointestinal symptoms lasting for several months is very rare. In summary, a case of prolonged unexplained gastrointestinal symptoms, possibly based on inflammatory changes in the small intestine, is described. A literature search revealed that this type of manifestation is very rare, and further evidence is needed to determine the causality between vaccination and gastrointestinal symptoms.

Effectiveness of second-look endoscopy after gastric endoscopic submucosal dissection in patients taking antithrombotic agents: a multicenter propensity score matching analysis.

BACKGROUND: The risk of bleeding after gastric endoscopic submucosal dissection (ESD) in antithrombotic agent users has increased, and its management remains a problem. Second-look endoscopy (SLE) following gastric ESD in antithrombotic agent users may be effective in preventing delayed bleeding, but this requires elucidation. Therefore, this study aimed to investigate the efficacy of SLE in reducing bleeding after gastric ESD in patients receiving antithrombotic agents. METHODS: This retrospective cohort study was conducted at 19 referral hospitals in Japan. A total of 1,245 patients who were receiving antithrombotic agents underwent gastric ESD between January 2013 and July 2018. The incidence of delayed bleeding was compared between SLE and non-SLE groups using propensity score matching analysis. RESULTS: Overall, 858 patients (SLE group, 657 patients; non-SLE group, 201 patients) were analyzed. After matching, 198 pairs were created. Delayed bleeding occurred in 10 patients (5.1%) in the SLE group and 16 patients (8.1%) in the non-SLE group [odds ratio (OR) 0.605, 95% confidence interval (CI) 0.23-1.46, p = 0.310]. In the subgroup analysis, SLE reduced the incidence of delayed bleeding in patients receiving heparin bridging therapy (6.3% and 40.0%, respectively; p = 0.004). In the SLE group, prophylactic coagulation did not significantly reduce delayed bleeding compared to the no treatment group (14.6% and 8.6%, respectively; p = 0.140). CONCLUSIONS: SLE was ineffective in reducing bleeding after gastric ESD in antithrombotic agent users, overall. A prospective comparative study is warranted to definitively evaluate the effectiveness of SLE in reducing bleeding in high-risk patients.

Recent approach for preventing complications in upper gastrointestinal endoscopic submucosal dissection.

Although endoscopic submucosal dissection (ESD) is a minimally invasive treatment method for upper gastrointestinal (GI) tumors, patients undergoing upper GI ESD sometimes fall into a serious condition from complications. Thus, it is important to fully understand how to prevent complications when performing upper GI ESD. One of the major complications in esophageal and gastric ESD is intraoperative perforation. To prevent this complication, blind dissection should be avoided. Traction-assisted ESD is a useful technique for maintaining good endoscopic view. This method was proven to reduce the incidence of intraoperative perforation, which would become a standard technique in esophageal and gastric ESD. In gastric ESD, delayed bleeding is the most common complication. Recently, a novel prediction model (BEST-J score) consisting of 10 factors with four risk categories for delayed bleeding in gastric ESD was established, and a free mobile application is now available. For reducing delayed bleeding in gastric ESD, vonoprazan ≥20 mg/day is the sole reliable method in the current status. Duodenal ESD is still challenging with a much higher frequency of complications, such as perforation and delayed bleeding, than ESD in other organs. However, with the development of improved devices and techniques, the frequency of complications in duodenal ESD has been decreasing. To prevent intraoperative perforation, some ESD techniques, such as using the distal tips of the Clutch Cutter, were developed. An endoscopic mucosal defect closure technique would be mandatory for preventing delayed complications. However, several unresolved issues, including standardization of duodenal ESD, remain and further studies are demanded.

Parietal Cell Dysfunction: A Rare Cause of Gastric Neuroendocrine Neoplasm with Achlorhydria and Extreme Hypergastrinemia.

A 69-year-old woman with multiple neuroendocrine neoplasms (NENs) was referred to our hospital. Although she had extreme hypergastrinemia (11,675 pg/mL), no findings that indicated types I to III gastric NENs were found. Although gastric corpus atrophy was suspected on conventional white-light imaging, findings on magnifying endoscopy with narrow-band imaging indicated no severe atrophy. A biopsy from the background fundic gland mucosa revealed no atrophic changes, parietal cells with vacuolated cytoplasm and negative findings for H+K+-ATPase. Thus, this case was diagnosed as multiple NENs with parietal cell dysfunction. Neither progression nor metastasis has been confirmed during two-year follow-up.

Suppressed Cellular Senescence Mediated by T-box3 in Aged Gastric Epithelial Cells may Contribute to Aging-related Carcinogenesis.

Aging is a risk factor for cancers in various organs. Recent advances in the organoid culturing system have made it viable to investigate the influence of aging utilizing these mini organs. In this study, we aimed to examine the implications of aging for gastric carcinogenesis. Gastric organoids established from aged mice grew larger, proliferated vigorously, and survived longer than that from young mice. Because Wnt/ß-catenin signaling was intensified in the aged organoids and because removal of Wnt-related factors diminished their proliferation, we investigated for Wnt target gene that contributed to enhanced proliferation and discovered that the aged organoids expressed the transcription factor T-box3 (Tbx3), which has been reported to suppress cellular senescence. Indeed, cellular senescence was suppressed in the aged organoids, and this resulted from enhanced G2-M transition. As for the mechanism involved in the intensified Wnt/ß-catenin signaling, we identified that Dickkopf3 (Dkk3) expression was reduced in the aged organoids due to methylation of the Dkk3 gene. Finally, the expression of TBX3 was enhanced in human atrophic gastritis and even more enhanced in human gastric cancers. In addition, its expression correlated positively with patients' age. These results indicated that the emergence of antisenescent property in aged gastric organoids due to enhanced Tbx3 expression led to accelerated cellular proliferation and organoid formation. Because the enhanced Tbx3 expression seen in aged gastric organoids was also observed in human gastric cancer tissues, this Dkk3-Wnt-Tbx3 pathway may be involved in aging-related gastric carcinogenesis. Significance: This work provides an insight into the mechanism involved in aging-related gastric carcinogenesis through studies utilizing organoids established from young and aged murine stomachs.

Predictors of early and late mortality after the treatment for early gastric cancers.

OBJECTIVES: Although many patients with early gastric cancers (EGCs) die of non-gastric cancer-related causes, the association of the risk categories of lymph node metastasis (LNM) with all-cause mortality remains unclear. We aimed to clarify the predictors of early and late mortality, separately. METHODS: Patients with endoscopic resection or gastrectomy for EGCs between 2003 and 2017 were retrospectively enrolled. We analyzed predictors for early and late mortality, including risk categories of LNM, treatment method, and nine non-cancer-related indices, separately, with a cut-off value of 3 years. RESULTS: We enrolled 1439 patients with a median follow-up period of 79 months. The 5-year overall survival rate was 86.8%. In the multivariate Cox analysis, the most important predictors for early and late mortality were age ≥85 years (hazard ratio [HR] 2.88 and 4.54, respectively) and Eastern Cooperative Oncology Group Performance Status ≥2 (HR 3.00 and 4.19, respectively). Charlson comorbidity index ≥2 (HR 2.76 and 1.99, respectively), American Society of Anesthesiologists Physical Status ≥3 (HR 2.35 and 1.79, respectively), and C-reactive protein/albumin ratio ≥0.028 (HR 2.30 and 1.58, respectively) were also predictors for both early and late mortality. Male (HR 2.26), intermediate- (HR 2.12)/high-risk (HR 1.85) of LNM in eCura system, and sarcopenia evaluated by the psoas muscle mass index (HR 1.70) were predictors for early mortality. CONCLUSION: The combined assessment of multiple predictors might help to predict early and/or late mortality in patients with EGCs. The eCura system was associated with early mortality.

Linked-color Imaging May Help Improve the Visibility of Superficial Barrett's Esophageal Adenocarcinoma by Increasing the Color Difference.

Objective Linked-color imaging (LCI), a new technology for image-enhanced endoscopy, emphasizes the color of the mucosa, and its practicality in the detection of early gastric and colon cancers has been reported. However, whether or not LCI is useful for the diagnosis of Barrett's adenocarcinoma (BA) has been unclear. In this study, we explored whether or not LCI enhances the color difference between a BA lesion and the surrounding mucosa. Methods Twenty-one lesions from 20 consecutive patients with superficial BA who underwent endoscopic submucosal dissection between November 2014 and September 2017 were retrospectively examined. The color differences (ΔE*) between the inside and outside of the lesion were evaluated retrospectively using white-light imaging (WLI), blue-light imaging (BLI), and LCI objectively, based on a Commission Internationale de l'Eclairage (CIE) lab color system. Furthermore, we compared the morphology, color, and circumferential location of the lesion. Results The median values of the color difference (ΔE*) in WLI and BLI were 9.1 and 5.8, respectively, and no difference was observed. In LCI, the median color difference was 17.6, which was higher than that of WLI and BLI. Regardless of the morphology, color, and circumferential location of BA lesions, the color difference was larger in LCI than in WLI. Conclusion LCI increases the color difference between the BA and the surrounding Barrett's mucosa.

Photodynamic Therapy with Tumor Cell Discrimination through RNA-Targeting Ability of Photosensitizer.

Photodynamic therapy (PDT) represents an effective treatment to cure cancer. The targeting ability of the photosensitizer is of utmost importance. Photosensitizers that discriminate cancer cells can avoid the killing of normal cells and improve PDT efficacy. However, the design and synthesis of photosensitizers conjugated with a recognition unit of cancer cell markers is complex and may not effectively target cancer. Considering that the total RNA content in cancer cells is commonly higher than in normal cells, this study has developed the photosensitizer QICY with RNA-targeting abilities for the discrimination of cancer cells. QICY was specifically located in cancer cells rather than normal cells due to their stronger electrostatic interactions with RNA, thereby further improving the PDT effects on the cancer cells. After intravenous injection into mice bearing a xenograft tumor, QICY accumulated into the tumor location through the enhanced permeability and retention effect, automatically targeted cancer cells under the control of RNA, and inhibited tumor growth under 630 nm laser irradiation without obvious side effects. This intelligent photosensitizer with RNA-targeting ability not only simplifies the design and synthesis of cancer-cell-targeting photosensitizers but also paves the way for the further development of highly efficient PDTs.

Vulnerable Older Adults' Identification, Geographic Distribution, and Policy Implications in China.

With the population aging and urbanization in China, vulnerable older adults tend to show more complex characteristics, bringing great challenges to public health policies. Using China Longitudinal Aging Social Survey data 2014, this paper builds a comprehensive index system for the identification of vulnerable older adults from three dimensions, including health, economy, and social support, then divides older adults into four support levels and six small classes by using the typological method. The results show that older adults in urgent need of assistance or priority are those poor in health and economic conditions, 1.46% of them are highly vulnerable because of the lack of social support; 12.76% of them obtain a certain social support are moderately vulnerable; and 34.72% of them are slightly vulnerable with disadvantage in only one dimension. The geographic distribution of different types of vulnerable older adults varies significantly. The paper provides evidence to design more feasible and specific policies with comprehensive considerations for different types of vulnerable older adults residing in different regions.