Ultra-Processed Food Consumption and Long-Term Risk of Irritable Bowel Syndrome: A Large-Scale Prospective Cohort Study.

BACKGROUND & AIMS: The considerable disease burden of irritable bowel syndrome (IBS) has coincided with the increase of ultraprocessed food (UPF) consumption over the past few decades. However, epidemiologic evidence for an association is lacking. We aimed to examine the long-term risk of IBS associated with UPF consumption in a large-scale prospective cohort. METHODS: Participants who completed 24-hour dietary recalls during 2009 to 2012 from the UK Biobank, and free of IBS, celiac disease, inflammatory bowel disease, and any cancer at baseline, were included (N = 178,711; 53.1% female). UPF consumption was defined according to the NOVA food classification system, expressed as a percentage of UPF content in the total diet intake (as grams per day). The primary outcome was incident IBS. A Cox proportional hazard model was performed to estimate associated risk. RESULTS: The mean UPF consumption was 21.0% (SD, 11.0%) of the total diet. During a median of 11.3 years of follow-up, 2690 incident IBS cases were identified. An 8% higher risk of IBS (hazard ratio, 1.08; 95% CI, 1.04-1.12) was associated with every 10% increment of UPF consumption. Compared with the lowest quartile of UPF consumption, the highest quartile was associated with a significantly increased risk of incident IBS (hazard ratio, 1.19; 95% CI, 1.07-1.33; Ptrend < .001). Subgroup analyses by age, sex, body mass index, smoking, and alcohol drinking status also showed similar results, except for the never/previous drinking subgroup. Further sensitivity analyses confirmed the positive association with a higher UPF consumption. CONCLUSIONS: Our findings provide evidence that a higher UPF consumption is associated with an increased risk of incident IBS, with a significant dose-response relationship.

RIOK3 sustains colorectal cancer cell survival under glucose deprivation via an HSP90α-dependent pathway.

Glucose oxidation via the pentose phosphate pathway serves as the primary cellular mechanism for generating nicotinamide adenine dinucleotide phosphate (NADPH). The central regions of solid tumors typically experience glucose deficiency, emphasizing the need for sustained NADPH production crucial to tumor cell survival. This study highlights the crucial role of RIOK3 in maintaining NADPH production and colorectal cancer (CRC) cell survival during glucose deficiency. Our findings revealed upregulated RIOK3 expression upon glucose deprivation, with RIOK3 knockout significantly reducing cancer cell survival. Mechanistically, RIOK3 interacts with heat shock protein 90α (HSP90α), a chaperone integral to various cellular processes, thereby facilitating HSP90α binding to isocitrate dehydrogenase 1 (IDH1). This interaction further upregulates IDH1 expression, enhancing NADPH production and preserving redox balance. Furthermore, RIOK3 inhibition had no discernible effect on intracellular NADPH levels and cell death rates in HSP90α-knockdown cells. Collectively, our findings suggest that RIOK3 sustains colon cancer cell survival in low-glucose environments through an HSP90α-dependent pathway. This highlights the significance of the RIOK3-HSP90α-IDH1 cascade, providing insights into potential targeted therapeutic strategies for CRC in metabolic stress conditions.

TRIM28 suppresses cancer stem-like characteristics in gastric cancer cells through Wnt/ß-catenin signaling pathways.

The influences of TRIM28 on the gastric tumorigenesis together with potential molecular mechanisms remain to be studied. We aimed at exploring the important effects of TRIM28 on gastric cancer (GC) and uncovering underling molecular mechanisms. Through immunohistochemistry analysis of 20 pairs of GC and the peritumoral tissues, the expression level of TRIM28 was determined. A variety of assays were applied to explore the important roles of TRIM28 in GC. Western blotting and qRT-PCR analyses were used to analyze the association between TRIM28 and the Wnt/ß-catenin signaling pathway. TRIM28 was highly expressed in GC tissues than peritumoral tissues. And high expression level of TRIM28 in GC was associated with good prognostic effects. In vitro functional assays suggested TRIM28 knockdown enhanced the proliferation and clone formation of GC cell. Moreover, TRIM28 knockdown enhanced the expression level of stemness markers, strengthened sphere-forming and drug-resistance properties of GC cells, suggesting important effect on GC cell stemness. Besides, our analysis showed that the Wnt/ß-catenin signaling was involved in the effect of TRIM28 on GC cell stemness property, and blocking Wnt/ß-catenin signaling pathway obviously rescued the promotion influence of TRIM28 knockdown. Overall, TRIM28 has an important influence on regulating the stem-like property of GC cell via Wnt/ß-catenin signaling, suggesting TRIM28 a promising drug target and a potential predictor of prognosis.

Non-alcoholic fatty liver degree and long-term risk of incident inflammatory bowel disease: A large-scale prospective cohort study.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and inflammatory bowel disease (IBD) have shown similar worsening epidemic patterns globally and shared various overlapping pathophysiological mechanisms. However, evidence on the relationship between NAFLD and IBD risk is lacking. We aimed to investigate the associations between long-term risk of incident IBD and NAFLD in a large prospective cohort. METHODS: Participants from the United Kingdom Biobank cohort (https://biobank.ndph.ox.ac.uk/) who were free of IBD and alcoholic liver disease at baseline were enrolled. Baseline non-alcoholic fatty liver degree was measured by the well-established fatty liver index (FLI). The outcome of interest included incident IBD, ulcerative colitis (UC), and Crohn's disease (CD). Multivariable Cox proportional hazard regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Among 418,721 participants (mean FLI: 48.11 ± 30.11), 160,807 (38.40%) participants were diagnosed as NAFLD at baseline. During a median of 12.4 years' follow-up, 2346 incident IBD cases (1545 UC, 653 CD, and 148 IBD-unclassified) were identified. Due to limited events, those IBD-unclassified were combined in UC or CD when examining the associated risk of UC or CD, separately. Compared with the lowest quartile of FLI, the highest quartile showed a separately 36.00%, 25.00%, and 58.00% higher risk of incident IBD (HRQ4vs.Q1 = 1.36, 95% CI: 1.19-1.55, Ptrend <0.001), UC (HRQ4vs.Q1 = 1.25, 95% CI: 1.07-1.46, Ptrend = 0.047), and CD (HRQ4vs.Q1 = 1.58, 95% CI: 1.26-1.97, Ptrend <0.001) after multivariable adjustment. Compared with non-NAFLD, NAFLD participants had a significantly higher risk of incident IBD (HR = 1.13, 95% CI: 1.04-1.24) and CD (HR = 1.36, 95% CI: 1.17-1.58). CONCLUSIONS: Higher degree of non-alcoholic fatty liver is associated with increased risk of incident IBD. Interventions aimed at improving NAFLD may be a potential targeted strategy for the detection and treatment of IBD.

ID1 expressing macrophages support cancer cell stemness and limit CD8+ T cell infiltration in colorectal cancer.

Elimination of cancer stem cells (CSCs) and reinvigoration of antitumor immunity remain unmet challenges for cancer therapy. Tumor-associated macrophages (TAMs) constitute the prominant population of immune cells in tumor tissues, contributing to the formation of CSC niches and a suppressive immune microenvironment. Here, we report that high expression of inhibitor of differentiation 1 (ID1) in TAMs correlates with poor outcome in patients with colorectal cancer (CRC). ID1 expressing macrophages maintain cancer stemness and impede CD8+ T cell infiltration. Mechanistically, ID1 interacts with STAT1 to induce its cytoplasmic distribution and inhibits STAT1-mediated SerpinB2 and CCL4 transcription, two secretory factors responsible for cancer stemness inhibition and CD8+ T cell recruitment. Reducing ID1 expression ameliorates CRC progression and enhances tumor sensitivity to immunotherapy and chemotherapy. Collectively, our study highlights the pivotal role of ID1 in controlling the protumor phenotype of TAMs and paves the way for therapeutic targeting of ID1 in CRC.

Frailty and pre-frailty with long-term risk of elderly-onset inflammatory bowel disease: A large-scale prospective cohort study.

PURPOSE: To investigate the prospective association of frailty status with the long-term risk of elderly-onset IBD in a large prospective cohort. METHODS: Participants free of IBD and cancer at enrollment from the UK Biobank cohort were included. Baseline pre-frail and frail status was measured by Fried phenotype including weight loss, exhaustion, low grip strength, low physical activity and slow walking pace, defined as meeting one or two criteria and meeting three or more criteria. Primary outcome was elderly-onset IBD, including elderly-onset ulcerative colitis (UC) and Crohn's disease (CD). Multivariable Cox regression was conducted to examine the related associations. RESULTS: Overall, 417,253 participants (aged 56.18 ± 8.09 years) were included. Of whom, 19,243 (4.6 %) and 188,219 (45.1 %) were considered frail and pre-frail, respectively. During a median of 12.4 years follow-up, 1503 elderly-onset IBD cases (1001 UC, 413 CD, and 89 IBD-Unclassified) were identified. Compared with non-frail, individuals with frail (HR=1.40, 95 %CI: 1.13-1.73) and pre-frail (HR=1.15, 1.03-1.28) showed significantly higher risk of elderly-onset IBD after multivariable adjustment (Ptrend<0.001). The positive association was more evident regarding risk of elderly-onset CD (HR=2.16, 1.49-3.13 for frail; HR=1.49,1.20-1.85 for pre-frail; Ptrend<0.001). Sensitivity analyses and subgroup analyses according to age, gender and body mass index (BMI) demonstrated similar results. CONCLUSIONS: Frailty and pre-frailty are associated with increased risk of elderly-onset IBD, particularly elderly-onset CD.

Machine-Learning-Assisted Procoagulant Extracellular Vesicle Barcode Assay toward High-Performance Evaluation of Thrombosis-Induced Death Risk in Cancer Patients.

Venous thromboembolism (VTE) is the most fatal complication in cancer patients. Unfortunately, the frequent misdiagnosis of VTE owing to the lack of accurate and efficient evaluation approaches may cause belated medical intervention and even sudden death. Herein, we present a rapid, easily operable, highly specific, and highly sensitive procoagulant extracellular vesicle barcode (PEVB) assay composed of TiO2 nanoflower (TiNFs) for visually evaluating VTE risk in cancer patients. TiNFs demonstrate rapid label-free EV capture capability by the synergetic effect of TiO2-phospholipids molecular interactions and topological interactions between TiNFs and EVs. From ordinary plasma samples, the PEVB assay can evaluate potential VTE risk by integrating TiNFs-based EV capture and in situ EV procoagulant ability test with machine-learning-assisted clinical data analysis. We demonstrate the feasibility of this PEVB assay in VTE risk evaluation by screening 167 cancer patients, as well as the high specificity (97.1%) and high sensitivity (96.8%), fully exceeding the nonspecific and posterior traditional VTE test. Together, we proposed a TiNFs platform allowing for highly accurate and timely diagnosis of VTE in cancer patients.

IL-8-mediated overexpression of ZNF274 promotes the proliferation and migration of colorectal cancer cells through the transactivation of MRPL40.

Background: Colorectal cancer (CRC) is one of the most prevalent malignant tumors with high morbidity and mortality rates worldwide. ZNF274, a member of the zinc-finger-protein family of transcription factors, is critical in chromosomal remodelling and tumorigenesis. However, the role of ZNF274 in CRC and the underlying molecular mechanisms remain unclear. Methods: Immunohistochemical analysis was performed to quantify the expression of ZNF274 in human CRC tissues. The Kaplan‒Meier method was used to analyse the relationship between ZNF274 expression and CRC prognosis. The correlation between ZNF274 expression and clinical features was analyzed using Cox regression analysis. Cell proliferation and migration were evaluated by CCK-8, colony formation, and Transwell assays. The limma R package was used to analyse IL-8-related differentially expressed genes in the GSE30364 dataset. The DAVID method was used to screen significantly enriched pathways. Chromatin immunoprecipitation (ChIP)-qPCR and luciferase reporter assays were performed to determine the transcriptional regulation of MRPL40 by ZNF274. Results: ZNF274 was overexpressed in CRC tissues and indicated poor prognosis. High ZNF274 expression was linked to larger tumor size, invasion, lymph node metastasis, and AJCC stage. Ectopic expression promoted CRC cell proliferation and migration. Mechanistically, MRPL40 was identified as the direct target gene that transactivates the expression of ZNF274. Moreover, IL-8 upregulated ZNF274 expression in a dose-dependent manner. Downregulation of either ZNF274 or MRPL40 expression abrogated the effect of IL-8 on promoting the proliferation and migration of CRC. Conclusion: This study revealed an oncogenic role of ZNF274 and the mechanism by which ZNF274 participated in IL-8-induced promotion of CRC progression. These findings demonstrate that ZNF274 could be used as a prognostic factor and potential therapeutic target for CRC treatment.

Glucocorticoid receptor-mediated Nr1d1 chromatin circadian misalignment in stress-induced irritable bowel syndrome.

Stress-elevated glucocorticoids cause circadian disturbances and gut-brain axis (GBA) disorders, including irritable bowel syndrome (IBS). We hypothesized that the glucocorticoid receptor (GR/NR3C1) might cause chromatin circadian misalignment in the colon epithelium. We observed significantly decreased core circadian gene Nr1d1 in water avoidance stressed (WAS) BALB/c colon epithelium, like in IBS patients. WAS decreased GR binding at the Nr1d1 promoter E-box (enhancer box), and GR could suppress Nr1d1 via this site. Stress also altered GR binding at the E-box sites along the Ikzf3-Nr1d1 chromatin and remodeled circadian chromatin 3D structures, including Ikzf3-Nr1d1 super-enhancer, Dbp, and Npas2. Intestinal deletion of Nr3c1 specifically abolished these stress-induced transcriptional alternations relevant to IBS phenotypes in BALB/c mice. GR mediated Ikzf3-Nr1d1 chromatin disease related circadian misalignment in stress-induced IBS animal model. This animal model dataset suggests that regulatory SNPs of human IKZF3-NR1D1 transcription through conserved chromatin looping have translational potential based on the GR-mediated circadian-stress crosstalk.

Effect of 3-Dimensional Imaging Device on Polyp and Adenoma Detection During Colonoscopy: A Randomized Controlled Trial.

INTRODUCTION: To evaluate the effect of 3-dimensional (3D) imaging device on polyp and adenoma detection during colonoscopy. METHODS: In a single-blind, randomized controlled trial, participants aged 18-70 years who underwent diagnostic or screening colonoscopy were consecutively enrolled between August 2019 and May 2022. Each participant was randomized in a 1:1 ratio to undergo either 2-dimensional (2D-3D) colonoscopy or 3D-2D colonoscopy through computer-generated random numbers. Primary outcome included polyp detection rate (PDR) and adenoma detection rate (ADR), defined as the proportion of individuals with at least 1 polyp or adenoma detected during colonoscopy. The primary analysis was intention-to-treat. RESULTS: Of 1,196 participants recruited, 571 in 2D-3D group and 583 in 3D-2D group were finally included after excluding those who met the exclusion criteria. The PDR between 2D and 3D groups was separately 39.6% and 40.5% during phase 1 (odds ratio [OR] = 0.96, 95% confidence interval [CI]: 0.76-1.22, P = 0.801), whereas PDR was significantly higher in 3D group (27.7%) than that of 2D group (19.9%) during phase 2, with a 1.54-fold increase (1.17-2.02, P = 0.002). Similarly, the ADR during phase 1 between 2D (24.7%) and 3D (23.8%) groups was not significant (OR = 1.05, 0.80-1.37, P = 0.788), while ADR was significantly higher in 3D group (13.8%) than that of 2D group (9.9%) during phase 2, with a 1.45-fold increase (1.01-2.08, P = 0.041). Further subgroup analysis confirmed significantly higher PDR and ADR of 3D group during phase 2, particularly in midlevel and junior endoscopists. DISCUSSION: The 3D imaging device could improve overall PDR and ADR during colonoscopy, particularly in midlevel and junior endoscopists. Trial number: ChiCTR1900025000.

Identification of novel serum autoantibody biomarkers for early esophageal squamous cell carcinoma and high-grade intraepithelial neoplasia detection.

Background: Early diagnosis of esophageal squamous cell carcinoma (ESCC) is critical for effective treatment and optimal prognosis; however, less study on serum biomarkers for the early ESCC detection has been reported. The aim of this study was to identify and evaluate several serum autoantibody biomarkers in early ESCC. Methods: We initially screened candidate tumor-associated autoantibodies (TAAbs) associated with ESCC by serological proteome analysis (SERPA) combined with nanoliter-liquid chromatography combined with quadrupole time of flight tandem mass spectrometry (nano-LC-Q-TOF-MS/MS), and the TAAbs were further subjected to analysis by Enzyme-linked immunosorbent assay (ELISA) in a clinical cohort (386 participants, including 161 patients with ESCC, 49 patients with high-grade intraepithelial neoplasia [HGIN] and 176 healthy controls [HC]). Receiver operating characteristic (ROC) curve was plotted to evaluate the diagnostic performance. Results: The serum levels of CETN2 and POFUT1 autoantibodies which were identified by SERPA were statistically different between ESCC or HGIN patients and HC in ELISA analysis with the area under the curve (AUC) values of 0.709 (95%CI: 0.654-0.764) and 0.741 (95%CI: 0.689-0.793), 0.717 (95%CI: 0.634-0.800) and 0.703 (95%CI: 0.627-0.779) for detection of ESCC and HGIN, respectively. Combining these two markers, the AUCs were 0.781 (95%CI: 0.733-0.829), 0.754 (95%CI: 0.694-0.814) and 0.756 (95%CI: 0.686-0.827) when distinguishing ESCC, early ESCC and HGIN from HC, respectively. Meanwhile, the expression of CETN2 and POFUT1 was found to be correlated with ESCC progression. Conclusions: Our data suggest that CETN2 and POFUT1 autoantibodies have potential diagnostic value for ESCC and HGIN, which may provide novel insights for early ESCC and precancerous lesions detection.

Identification and evaluation of novel serum autoantibody biomarkers for early diagnosis of gastric cancer and precancerous lesion.

PURPOSE: Early diagnosis is crucial for optimal prognosis of gastric cancer (GC). Hereby, we aimed to identify novel serum autoantibody-based biomarkers for precancerous lesion (PL) and early GC. METHODS: We performed serological proteome analysis (SERPA) combined with nanoliter-liquid chromatography combined with quadrupole time of flight tandem mass spectrometry (Nano-LC-Q-TOF-MS/MS) to screen for GC-associated autoantibodies. The identified autoantibodies were analyzed for potential detection value for PL and GC by enzyme-linked immunosorbent assay (ELISA). Receiver operating characteristic (ROC) curves analysis was conducted to evaluate the accuracy of the biomarkers. RESULTS: We identified seven candidates, such as mRNA export factor (RAE1), Nucleophosmin 1 (NPM1), phosphoglycerate kinase 1 (PGK1), and ADP-ribosylation factor 4 (ARF4). Antibodies against all seven proteins were present at higher levels in sera from 242 patients (51 PL, 78 early GC, 113 advanced GC) compared with sera from 122 healthy individuals. RAE1-specific autoantibody discriminated best between patients at different GC stages, with area under the curve (AUC) values of 0.710, 0.745, and 0.804 for PL, early GC, and advanced GC, respectively. Two predictive models composed of gender, RAE1, PGK1, NPM1, and ARF4 autoantibodies (Model 2 for PL) and of age, gender, RAE1, PGK1, and NPM1 autoantibodies (Model 3 for early GC) had improved diagnostic efficiencies, with AUCs of 0.803 and 0.857, sensitivities of 66.7% and 75.6%, and specificities of 78.7% and 87.7%, respectively. CONCLUSION: The identified serum tumor-associated autoantibodies (TAAbs) may have good potential for early detection of GC and PL.

Coffee and tea intake with long-term risk of irritable bowel syndrome: a large-scale prospective cohort study.

BACKGROUND: To investigate prospective association of coffee and tea intake with incident irritable bowel syndrome (IBS) in a long-term cohort. METHODS: Participants free of IBS, coeliac disease, inflammatory bowel disease and any cancer at baseline from UK Biobank were included. Coffee and tea intake was measured separately via baseline touchscreen questionnaire, with four categories for each intake (0, 0.5-1, 2-3 and ≥4 cups/day). Primary outcome was incident IBS. Cox proportional hazard model was used to estimate associated risk. RESULTS: Among 425 387 participants, 83 955(19.7%) and 186 887(43.9%) consumed ≥4 cups/day of coffee and tea at baseline, respectively. During median 12.4-year follow-up, incident IBS was identified in 7736 participants. Compared with no coffee intake, consumption of 0.5-1, 2-3 and ≥4 cups/day was associated with lower IBS risk [hazard ratio (HR)=0.93, 95% CI: 0.87-0.99; 0.91, 0.85-0.97; 0.81, 0.76-0.88; Ptrend < 0.001]. Specifically, decreased risk was evident in individuals who consumed instant (HR = 0.83, 0.78-0.88) or ground coffee (HR = 0.82, 0.76-0.88) compared with no coffee drink. Regarding tea intake, protective association was only found in individuals who consumed 0.5-1 cup/day (HR = 0.87, 0.80-0.95), whereas no significant association was detected in those who consumed 2-3 (HR = 0.94, 0.88-1.01) or ≥4 cups/day (HR = 0.95, 0.89-1.02) compared with no-tea intake (Ptrend = 0.848). CONCLUSIONS: Higher intake of coffee, particularly instant and ground coffee, is associated with lower risk of incident IBS, with significant dose-response relationship. Moderate-tea intake (0.5-1 cup/day) is associated with lower IBS risk.

Pseudotyped Viruses for Orthohantavirus.

Orthohantaviruses, members of the Orthohantavirus genus of Hantaviridae family of the Bunyavirales order, are enveloped, negative-sense, single-stranded, tripartite RNA viruses. They are emerging zoonotic pathogens carried by small mammals including rodents, moles, shrews, and bats and are the etiologic agents of hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS) among humans. With the characteristics of low biological risk but strong operability, a variety of pseudotyped viruses have been constructed as alternatives to authentic orthohantaviruses to help delineate the roles of host factors in viral entry and other virus-host interactions, to assist in deciphering mechanisms of immune response and correlates of protection, to enhance our understanding of viral antigenic property, to characterize viral entry inhibitors, and to be developed as vaccines. In this chapter, we will discuss the general property of orthohantavirus, construction of pseudotyped orthohantaviruses based on different packaging systems, and their current applications.

Frailty status and risk of irritable bowel syndrome in middle-aged and older adults: A large-scale prospective cohort study.

Background: Frailty is a public health problem for ageing society, however, evidence is lacking regarding its impact on intestinal functions. We aimed to examine prospective relationships of frailty and pre-frailty in middle-aged and older adults with incident irritable bowel syndrome (IBS) in a large-scale population-based cohort. Methods: Participants (aged 37-73 years) free of IBS, coeliac disease, inflammatory bowel disease and any cancer at baseline were included, using data from the UK Biobank (collected 2006-2010, 22 assessment centres). Participants without available primary care data were excluded. Frailty status was assessed using Fried phenotype including five criteria (weight loss, exhaustion, low grip strength, low physical activity, slow walking pace). Participants who met at least three criteria were defined as frail, and those who fulfilled one or two criteria were defined as pre-frail. Primary outcome was incident IBS. Cox proportional hazard model was conducted to examine the associated risk of incident IBS. Findings: Among 176,423 participants (mean age 56.19 years), 7994 (4.5%) and 78,957 (44.8%) were frail and pre-frail at baseline. During a median of 13.2-year follow-up, 4155 cases of incident IBS were identified. Compared with non-frail individuals, those with frail (HR = 1.80, 95% CI: 1.59-2.04) and pre-frail (HR = 1.21, 1.14-1.30) showed significantly higher risk of developing IBS after multivariable adjustment (Ptrend < 0.001). Specifically, the positive association was not only observed in older adults (HR = 1.69, 1.37-2.08 for frail; 1.24, 1.12-1.39 for pre-frail), but also in middle-aged adults (HR = 1.90, 1.62-2.22 for frail; 1.19, 1.10-1.30 for pre-frail), both with Ptrend < 0.001. Further sensitivity analysis and subgroup analysis indicated similar results. Interpretation: Frailty and pre-frailty in middle-aged and older adults are associated with increased risk of incident clinical diagnosis of IBS. Funding: National Natural Science Foundation of China (No. 82070550) & National Key Research and Development Program of China (2022YFC2504002, 2022YFC2504003).

Endoscopic ultrasound-guided gallbladder endoscopic mucosal resection: a pilot porcine study.

INTRODUCTION: Endoscopic ultrasound (EUS)-guided natural orifice transluminal gallbladder polypectomy provides a minimally invasive alternative to cholecystectomy. The study aimed to investigate the feasibility and safety of protocol for gallbladder endoscopic mucosal resection (gEMR) under EUS guidance using a porcine model. MATERIAL AND METHODS: Fifteen Bama mini pigs were randomly divided into the control (CG, n = 3) and experimental (EG, n = 12) groups. EUS-guided fine needle aspiration was performed in the CG and used to establish a gallbladder pathway for polyp resection under EUS guidance in the EG. Procedural safety was evaluated using routine blood and biochemical tests, microbial bile cultures, histopathological tests, and enzyme-linked immunosorbent assays for inflammatory adhesion factors. RESULTS: EUS-guided metal stents were successfully deployed in all 12 pigs. Two cases of stent displacement occurred postoperatively, and one pig died of infectious peritonitis on the first day after stent implantation. In 11 surviving experimental animals, mature gallbladder paths were formed at 7-14 days after gastro-cholecystostomy, through which gEMR of gallbladder polyps was successfully performed. There were no significant changes in levels of inflammatory and adhesion factors during the postoperative process. CONCLUSIONS: EUS-gEMR may be a safe and effective minimally invasive treatment approach for gallbladder polyps.

Inflammatory Bowel Disease and Long-term Risk of Cancer: A Prospective Cohort Study Among Half a Million Adults in UK Biobank.

BACKGROUND: This study aims to examine the prospective association of inflammatory bowel disease (IBD) with long-term risk of overall, site-specific cancer and cancer-specific mortality in middle-aged and older people. METHODS: The study included participants free of any cancer at baseline from the UK Biobank, with IBD patients as an exposure group and non-IBD patients as a reference group. Primary outcome was the incidence of overall cancer and cancer-specific mortality. Secondary outcomes included site-specific cancers and types of digestive cancers. Cox proportional hazard model was used to investigate the associated risk of incident malignancies and related mortality. RESULTS: Among 455 927 participants, 5142 were diagnosed with IBD (3258 ulcerative colitis [UC]; 1449 Crohn's disease [CD]; others unspecified). During a median of 12.2-year follow-up, 890 cases of incident cancer were identified in IBD patients (15.74 per 1000 person years) compared with 63 675 cases in reference individuals (12.46 per 1000 person years). Of these cases, 220 and 12 838 cancer-specific deaths occurred in IBD and non-IBD groups. Compared with non-IBD participants, the adjusted hazard ratio (AHR) for overall cancer and cancer-specific mortality was 1.17 (95% CI, 1.09-1.25) and 1.26 (95% CI, 1.18-1.35) among IBD patients, with an AHR of 1.15 (95% CI, 1.02-1.31) and 1.38 (95% CI, 1.08-1.75) in UC and 1.15 (95% CI, 1.06-1.25) and 1.25 (95% CI, 1.06-1.49) in CD, respectively. Specifically, increased risk of digestive (1.33; 95% CI, 1.12-1.57), nonmelanoma (1.25; 95% CI, 1.11-1.41), and male genital (1.29; 95% CI, 1.09-1.52) cancers was observed in IBD patients. CONCLUSIONS: Compared with non-IBD, IBD may be associated with an increased risk of overall cancer and cancer-specific mortality, particularly digestive cancers, nonmelanoma and male genital cancers.

Regardless of IBD subtype, IBD may be associated with a 17% excess risk of incident overall cancer and a 26% higher risk of death due to cancer compared with non-IBD participants­and the risk seemed even higher in UC patients.

Distinct tumor microenvironment landscapes of rectal cancer for prognosis and prediction of immunotherapy response.

PURPOSE: Tumor microenvironment (TME) affects the progression of rectal cancer (RC), and the clinical relevance of its immune elements was widely reported. Here we aim to delineate the complete TME landscape, including non-immune features, to improve our understanding of RC heterogeneity and provide a better strategy for precision medicine. METHODS: Single-cell analysis of GSE161277 using Seurat and Cellcall was performed to identify cell-cell interactions. The ssGSEA was employed to quantify the TME elements in TCGA patients, which were further clustered into subtypes by hclust. WGCNA and LASSO were combined to construct a degenerated signature for prognosis, and its performance was validated in two GEO datasets. RESULTS: We proposed a subtyping strategy based on the abundance of both immune and non-immune components, which divided all RC patients into 4 subtypes (Immune-, Canonical-, Dormant- and Stem-like). Different subtypes exhibited distinct mutation landscapes, biological features, immune characteristics, immunotherapy responses and prognoses. Next, WGCNA and LASSO regression were combined to construct a 10-gene signature based on differentially expressed genes among different subtypes. Subgroups divided by this signature also exhibited different clinical parameters and responses to immune checkpoint blockades. Diverse machine learning algorithms were applied to achieve higher accuracy for survival prediction and a nomogram was further established in combination with M stage and age to provide an accurate and visual prediction of prognosis. CONCLUSIONS: We identified four TME-based RC subtypes with distinct biological and clinical features. Based on those subtypes, we also proposed a degenerated 10-gene signature to predict the prognosis and immunotherapy response.