Gallstone disease is associated with an increased risk of inflammatory bowel disease: results from three prospective cohort studies.

INTRODUCTION: Gallstone diseases impact intestinal inflammation, bile flow, and gut microbiota, which in turn may increase the risk of inflammatory bowel disease (IBD). However, epidemiological studies exploring the associations between gallstone diseases and subsequent IBD risk have been limited. METHODS: This is a combined analysis of three prospective cohort studies (Nurses' Health Study (NHS), NHS II, and UK Biobank), and replicated in a case-control study (Chinese IBD Etiology Study, CIES). We evaluated the hazard ratios (HRs) / odds ratios (ORs) between gallstone diseases with IBD risk by Cox- or conditional logistic-regression, adjusting for demographic characteristics, lifestyles, comorbidities, and medication usage. FINDINGS: We identified 3480 cases of IBD over 2,127,471 person-years of follow-up in the 3 cohort studies. The participants with gallstone disease had a 38% increase in risk of IBD (HR 1.38, 95% confidence intervals [CI] 1.21-1.59), 68% increase in Crohn's disease (CD) (HR 1.68, 95% CI 1.38-2.06) and 24% increase in ulcerative colitis (UC) (HR 1.24, 95% CI 1.03-1.49). In CIES, we found even larger magnitude of effects between gallstone diseases and IBD risk (IBD: OR 3.03, 95% CI 2.32-3.97; CD: OR 5.31; 95% CI 3.71-7.60; UC: OR 1.49; 95% CI 1.07-2.06). There were no major differences in the estimated associations between presence of unremoved gallstones and prior cholecystectomy with IBD risk. DISCUSSION: Gallstone disease was linked to an increased risk of IBD and its subtypes, independent of traditional risk factors. Further research is needed to confirm these associations and clarify the underlying biological mechanisms.

N-acetyltransferase 10 affects the proliferation of intrahepatic cholangiocarcinoma and M2-type polarization of macrophages by regulating C-C motif chemokine ligand 2.

BACKGROUND: N-acetyltransferase 10 (NAT10) plays a crucial role in the occurrence and development of various tumors. However, the current regulatory mechanism of NAT10 in tumors is limited to its presence in tumor cells. Here, we aimed to reveal the role of NAT10 in intrahepatic cholangiocarcinoma (ICC) and investigate its effect on macrophage polarization in the tumor microenvironment (TME). METHODS: The correlation between NAT10 and ICC clinicopathology was analyzed using tissue microarray (TMA), while the effect of NAT10 on ICC proliferation was verified in vitro and in vivo. Additionally, the downstream target of NAT10, C-C motif chemokine ligand 2 (CCL2), was identified by Oxford Nanopore Technologies full-length transcriptome sequencing, RNA immunoprecipitation-quantitative polymerase chain reaction, and coimmunoprecipitation experiments. It was confirmed by co-culture that ICC cells could polarize macrophages towards M2 type through the influence of NAT10 on CCL2 protein expression level. Through RNA-sequencing, molecular docking, and surface plasmon resonance (SPR) assays, it was confirmed that berberine (BBR) can specifically bind CCL2 to inhibit ICC development. RESULTS: High expression level of NAT10 was associated with poor clinicopathological manifestations of ICC. In vitro, the knockdown of NAT10 inhibited the proliferative activity of ICC cells and tumor growth in vivo, while its overexpression promoted ICC proliferation. Mechanically, by binding to CCL2 messenger RNA, NAT10 increased CCL2 protein expression level in ICC and their extracellular matrix, thereby promoting the proliferation of ICC cells and M2-type polarization of macrophages. BBR can target CCL2, inhibit ICC proliferation, and reduce M2-type polarization of macrophages. CONCLUSIONS: NAT10 promotes ICC proliferation and M2-type polarization of macrophages by up-regulating CCL2, whereas BBR inhibits ICC proliferation and M2-type polarization of macrophages by inhibiting CCL2.

Dietary patterns, genetic predisposition, and risk of cholelithiasis: a large-scale prospective cohort study.

Background: Limited epidemiological evidence exists concerning the impact of healthy dietary patterns on reducing the risk of cholelithiasis. We aimed to examine the association of seven established dietary patterns with subsequent cholelithiasis risk and whether this association was modified by genetic risk. Methods: We conducted a prospective cohort study from the UK Biobank, including 155,323 participants initially free of cholelithiasis and cholecystectomy. Dietary patterns were assessed using a validated food frequency questionnaire (Oxford WebQ), covering Mediterranean Diet Score (MED), alternate Mediterranean Diet Score(aMED), overall Plant-based Diet Index (PDI), healthy Plant-based Diet Index (hPDI), unhealthy Plant-based Diet Index (uPDI), Healthy Eating Index 2015 (HEI-2015) and EAT-lancet Score. Genetic risk was quantified and stratified by a polygenic risk score (PRS) incorporating 13 known cholelithiasis-associated loci. Cox proportional hazards regression was employed to estimate the association between dietary patterns, PRS, and cholelithiasis incidence, adjusting for potential confounders. Results: During a median follow-up of 13.3 years, 5,056 cases of cholelithiasis were identified. After adjusting for potential confounders, adherence to aMED and HEI-2015 dietary patterns reduced cholelithiasis risk by 10% (HR: 0.90; 95%CI: 0.83-0.98) and 11% (HR: 0.89; 95%CI: 0.82-0.96), respectively. A significant decrease in cholelithiasis risk was observed across PRS quintiles, low PRS was associated with a 16% reduced risk (HR: 0.84; 95%CI: 0.77-0.92). Participants with both high dietary scores and low genetic risk had the lowest cholelithiasis risk, with an HR of 0.76 (95%CI: 0.64-0.91) for aMED and 0.73 (95%CI: 0.61-0.88) for HEI-2015. Conclusion: Higher adherence to aMED and HEI-2015 might significantly decrease the risk of cholelithiasis, irrespective of genetic risk. Our results highlighted the potential of diet intervention for cholelithiasis prevention in the general population.

Beyond ribosomal function: RPS6 deficiency suppresses cholangiocarcinoma cell growth by disrupting alternative splicing.

Cholangiocarcinoma (CCA) is a bile duct malignancy with a dismal prognosis. This study systematically investigated the role of the ribosomal protein S6 (RPS6) gene, which is dependent in CCA. We found that RPS6 upregulation in CCA tissues was correlated with a poor prognosis. Functional investigations have shown that alterations in RPS6 expression, both gain- and loss-of function could affect the proliferation of CCA cells. In xenograft tumor models, RPS6 overexpression enhances tumorigenicity, whereas RPS6 silencing reduces it. Integration analysis using RNA-seq and proteomics elucidated downstream signaling pathways of RPS6 depletion by affecting the cell cycle, especially DNA replication. Immunoprecipitation followed by mass spectrometry has identified numerous spliceosome complex proteins associated with RPS6. Transcriptomic profiling revealed that RPS6 affects numerous alternative splicing (AS) events, and combined with RNA immunoprecipitation sequencing, revealed that minichromosome maintenance complex component 7 (MCM7) binds to RPS6, which regulates its AS and increases oncogenic activity in CCA. Targeting RPS6 with vivo phosphorodiamidate morpholino oligomer (V-PMO) significantly inhibited the growth of CCA cells, patient-derived organoids, and subcutaneous xenograft tumor. Taken together, the data demonstrate that RPS6 is an oncogenic regulator in CCA and that RPS6-V-PMO could be repositioned as a promising strategy for treating CCA.

Development and Preclinical Evaluation of 18F-Labeled PEGylated Sansalvamide A Decapeptide for Noninvasive Evaluation of Hsp90 Status in Pancreas Cancer.

Heat shock protein 90 (Hsp90) is a promising target for cancer therapy and imaging. Accurate detection of Hsp90 levels in tumors via noninvasive PET imaging might be beneficial for management. To achieve this, the precursor compound Dimer-Sansalvamide A (Dimer-San A) was PEGylated and modified by conjugating it with the bifunctional chelator 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). The 18F-labeled PEGylated Dimer-SanA decapeptide (18F-PEGylated San A) was completed within 30 min using a two-step process. In vitro stability and specificity were assessed, including competition studies with the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). MicroPET imaging was performed on PL45 tumor-bearing mice to evaluate probe accumulation and tumor-to-muscle ratios. Biodistribution studies determined the route of excretion. The probe resulted in a radiochemical yield of 23.11% with a purity exceeding 95%. In vitro, 18F-PEGylated San A exhibited high stability and selectively accumulated in Hsp90-positive PL45 cells, with binding effectively blocked by the Hsp90 inhibitor 17AAG, confirming its specificity. MicroPET imaging of PL45 tumor-bearing mice showed significant probe accumulation in tumor tissues at 1 and 2 h postinjection (4.06 ± 0.30 and 3.72 ± 0.61%ID/g, respectively), with optimal tumor-to-muscle ratios observed at 2 h postinjection (6.09 ± 1.92). While 18F-PEGylated San A demonstrates enhanced water solubility, as indicated by increased kidney uptake relative to liver accumulation. The study successfully incorporated PEG units to create the novel probe 18F-PEGylated San A targeting to Hsp90 without affecting its targeting capability, aimed at improving the pharmacokinetics and PET imaging of Hsp90 expression noninvasively.

Biliary fibrosis is an important but neglected pathological feature in hepatobiliary disorders: from molecular mechanisms to clinical implications.

Fibrosis resulting from pathological repair secondary to recurrent or persistent tissue damage often leads to organ failure and mortality. Biliary fibrosis is a crucial but easily neglected pathological feature in hepatobiliary disorders, which may promote the development and progression of benign and malignant biliary diseases through pathological healing mechanisms secondary to biliary tract injuries. Elucidating the etiology and pathogenesis of biliary fibrosis is beneficial to the prevention and treatment of biliary diseases. In this review, we emphasized the importance of biliary fibrosis in cholangiopathies and summarized the clinical manifestations, epidemiology, and aberrant cellular composition involving the biliary ductules, cholangiocytes, immune system, fibroblasts, and the microbiome. We also focused on pivotal signaling pathways and offered insights into ongoing clinical trials and proposing a strategic approach for managing biliary fibrosis-related cholangiopathies. This review will offer a comprehensive perspective on biliary fibrosis and provide an important reference for future mechanism research and innovative therapy to prevent or reverse fibrosis.

Design of the distribution of iron oxide (Fe3O4) nano-particle drug in realistic cholangiocarcinoma model and the simulation of temperature increase during magnetic induction hyperthermia.

The prognosis for Cholangiocarcinoma (CCA) is unfavorable, necessitating the development of new therapeutic approach such as magnetic hyperthermia therapy (MHT) which is induced by magnetic nano-particle (MNPs) drug to bridge the treatment gap. Given the deep location of CCA within the abdominal cavity and proximity to vital organs, accurately predict the individualized treatment effects and safety brought by the distribution of MNPs in tumor will be crucial for the advancement of MHT in CCA. The Mimics software was used in this study to conduct three-dimensional reconstruction of abdominal computed tomography (CT) and magnetic reso-nance imaging images from clinical patients, resulting in the generation of a realistic digital geometric model representing the human biliary tract and its adjacent structures. Subsequently, The COMSOL Multiphysics software was utilized for modeling CCA and calculating the heat transfer law resulting from the multi-regional distribution of MNPs in CCA. The temperature within the central region of irregular CCA measured approximately 46°C, and most areas within the tumor displayed temperatures surpassing 41°C. The temperature of the inner edge of CCA is only 39 ∼ 41℃, however, it can be ameliorated by adjusting the local drug concentration through simulation system. For CCA with diverse morphologies and anatomical locations, the multi-regional distribution patterns of intratumoral MNPs and a slight overlap of drug distribution areas synergistically enhance intratumoral temperature while ensuring treatment safety. The present study highlights the practicality and imperative of incorporating personalized intratumoral MNPs distribution strategy into clinical practice for MHT, which can be achieved through the development of an integrated simulation system which incorporates medical image data and numerical calculations.

A Review of Research on the Mechanism of Tumor Regulation by N-Acetyltransferase 10.

N-acetyltransferase 10 (NAT10) is an important acetyltransferase that regulates telomerase activity and participates in DNA damage reactions, ribosomal RNA (rRNA) transcriptional activation, cell division, microtubule acetylation, and other important cellular processes. Abnormalities in the expression or distribution of NAT10 result in diseases such as Hutchinson-Gilford progeria syndrome (HGPS) and various tumors, with serious consequences. Remodelin, an inhibitor of NAT10, delays HGPS progression; many studies have been conducted on its role in tumor therapy. A major breakthrough in the study of NAT10 was the discovery of mRNA N4-acetylcytidine (ac4C) modification, which can increase mRNA stability and translation efficiency significantly. In addition, NAT10 modifies the mRNA of ac4C, which is associated with tumor development. Here, we present a review of pertinent studies focusing on NAT10, particularly its role in cancer, to provide researchers with a concise and informative summary of the current state of knowledge about this topic. The conclusions drawn from this review could provide a new direction for tumor treatment.

Early prediction of acute gallstone pancreatitis severity: a novel machine learning model based on CT features and open access online prediction platform.

BACKGROUND: Early diagnosis of acute gallstone pancreatitis severity (GSP) is challenging in clinical practice. We aimed to investigate the efficacy of CT features and radiomics for the early prediction of acute GSP severity. METHODS: We retrospectively recruited GSP patients who underwent CT imaging within 48 h of admission from tertiary referral centre. Radiomics and CT features were extracted from CT scans. The clinical and CT features were selected by the random forest algorithm to develop the ML GSP model for the identification of severity of GSP (mild or severe), and its predictive efficacy was compared with radiomics model. The predictive performance was assessed by the area under operating characteristic curve. Calibration curve and decision curve analysis were performed to demonstrate the classification performance and clinical efficacy. Furthermore, we built a web-based open access GSP severity calculator. The study was registered with ClinicalTrials.gov (NCT05498961). RESULTS: A total of 301 patients were enrolled. They were randomly assigned into the training (n = 210) and validation (n = 91) cohorts at a ratio of 7:3. The random forest algorithm identified the level of calcium ions, WBC count, urea level, combined cholecystitis, gallbladder wall thickening, gallstones, and hydrothorax as the seven predictive factors for severity of GSP. In the validation cohort, the areas under the curve for the radiomics model and ML GSP model were 0.841 (0.757-0.926) and 0.914 (0.851-0.978), respectively. The calibration plot shows that the ML GSP model has good consistency between the prediction probability and the observation probability. Decision curve analysis showed that the ML GSP model had high clinical utility. CONCLUSIONS: We built the ML GSP model based on clinical and CT image features and distributed it as a free web-based calculator. Our results indicated that the ML GSP model is useful for predicting the severity of GSP.

ML GSP model based on machine learning has good severity discrimination in both training and validation cohorts (0.916 (0.872­0.958), 0.914 (0.851­0.978), respectively).We built an online user-friendly platform for the ML GSP model to help clinicians better identify the severity of GSP.

Individualized prevention of proton pump inhibitor related adverse events by risk stratification.

Proton pump inhibitors (PPIs) are commonly used for gastric acid-related disorders, but their safety profile and risk stratification for high-burden diseases need further investigation. Analyzing over 2 million participants from five prospective cohorts from the US, the UK, and China, we found that PPI use correlated with increased risk of 15 leading global diseases, such as ischemic heart disease, diabetes, respiratory infections, and chronic kidney disease. These associations showed dose-response relationships and consistency across different PPI types. PPI-related absolute risks increased with baseline risks, with approximately 82% of cases occurring in those at the upper 40% of the baseline predicted risk, and only 11.5% of cases occurring in individuals at the lower 50% of the baseline risk. While statistical association does not necessarily imply causation, its potential safety concerns suggest that personalized use of PPIs through risk stratification might guide appropriate decision-making for patients, clinicians, and the public.

Genetic risk, adherence to healthy lifestyle behaviors, and risk of cholelithiasis: A population-based cohort study.

OBJECTIVE: Genetic and lifestyles contribute to cholelithiasis, but the impact of adhering to healthy lifestyle on cholelithiasis risk remains uncertain. We aimed to assess combined lifestyle factors and a polygenic risk score on incident cholelithiasis. METHODS: We utilized cholelithiasis genome-wide association study (GWAS) data from FinnGen study, constructing varied polygenic risk score (PRS), and applied them to 317,640 UK Biobank participants. The relative and absolute risk of incident cholelithiasis associated with six well-established lifestyle risk factors, was evaluated and stratified by PRS (low risk [quintile 1], intermediate risk [quintiles 2-4] and high risk [quintile 5]). Lifestyle score was also categorized into favorable, intermediate, and unfavorable groups. RESULTS: The PRS derived from 13 single nucleotide polymorphisms (p ≤ 5 × 10-6, r2 < 0.001) showed the best performance. A significant gradient of increase in risk of cholelithiasis was observed across the quintiles of the polygenic risk score (p < 0.001). Compared to participants with low genetic risk, those with intermediate or high genetic risk had a 10% (95% confidence interval [CI] = 1.05-1.17) and 24% (95% CI = 1.16-1.32) higher risk of cholelithiasis. An unfavorable lifestyle was associated with an approximately 50% higher risk of cholelithiasis than a favorable lifestyle. Participants with high genetic risk and an unfavorable lifestyle had 98% (Hazard ratio [HR]: 1.98; 95% CI: 1.67-2.35) higher risk of cholelithiasis than those with low genetic risk and a favorable lifestyle. CONCLUSIONS: Our study highlights the importance of lifestyle behaviors intervention on cholelithiasis risk regardless of the genetic risk in White European population.

Purification, identification and Cryo-EM structure of prostatic acid phosphatase in human semen.

Prostatic acid phosphatase (PAP) is a glycoprotein that plays a crucial role in the hydrolysis of phosphate ester present in prostatic exudates. It is a well-established indicator for prostate cancer due to its elevated serum levels in disease progression. Despite its abundance in semen, PAP's influence on male fertility has not been extensively studied. In our study, we report a significantly optimized method for purifying human endogenous PAP, achieving remarkably high efficiency and active protein recovery rate. This achievement allowed us to better analyze and understand the PAP protein. We determined the cryo-electron microscopic (Cryo-EM) structure of prostatic acid phosphatase in its physiological state for the first time. Our structural and gel filtration analysis confirmed the formation of a tight homodimer structure of human PAP. This functional homodimer displayed an elongated conformation in the cryo-EM structure compared to the previously reported crystal structure. Additionally, there was a notable 5-degree rotation in the angle between the α domain and α/ß domain of each monomer. Through structural analysis, we revealed three potential glycosylation sites: Asn94, Asn220, and Asn333. These sites contained varying numbers and forms of glycosyl units, suggesting sugar moieties influence PAP function. Furthermore, we found that the active sites of PAP, His44 and Asp290, are located between the two protein domains. Overall, our study not only provide an optimized approach for PAP purification, but also offer crucial insights into its structural characteristics. These findings lay the groundwork for further investigations into the physiological function and potential therapeutic applications of this important protein.

High incidence of gallstones after Roux-en-Y reconstruction gastrectomy in gastric cancer: a multicenter, long-term cohort study.

BACKGROUND: Roux-en-Y reconstruction is a common anastomosis technique during gastrectomy in gastric cancer. There is a lack of studies on gallstones after Roux-en-Y reconstruction gastrectomy. This study investigated the incidence and potential risk factors associated with gallstones after Roux-en-Y reconstructive gastrectomy in gastric cancer. METHODS: The study analyzed data from gastric cancer who underwent radical gastrectomy and Roux-en-Y reconstruction at two hospitals between January 2014 and December 2020. The patients fall into distal and total gastrectomy groups based on the extent of gastrectomy. The cumulative event probability curve was plotted using the Kaplan-Meier, and differences in gallstone between groups were evaluated using the Log-Rank. Propensity score matching was applied to construct a balanced total versus distal gastrectomies cohort. A Cox regression was employed to analyze the risk factors for gallstones after Roux-en-Y reconstructive gastrectomy in gastric cancer. Further subgroup analysis was performed. RESULTS: Five hundred thirty-one patients were included in this study, 201 in the distal gastrectomy group and 330 in the total gastrectomy. During the follow-up, gallstones occurred in 170 cases after gastrectomy, of which 145 cases accounted for 85.29% of all stones in the first two years after surgery. Then, to reduce the impact of bias, a 1:1 propensity score matching analysis was performed on the two groups of patients. A total of 344 patients were evaluated, with each subgroup comprising 172 patients. In the matched population, the Cox regression analysis revealed that females, BMI ≥23 kg/m 2 , total gastrectomy, No.12 lymph node dissection, and adjuvant chemotherapy were risk factors for gallstones after Roux-en-Y reconstructive gastrectomy. Subgroup analysis showed that open surgery further increased the risk of gallstones after total gastrectomy. CONCLUSION: The incidence of gallstones increased significantly within 2years after Roux-en-Y reconstructive gastrectomy for gastric cancer. Patients with these risk factors should be followed closely after gastrectomy to avoid symptomatic gallstones.

Regular use of paracetamol and risk of liver cancer: a prospective cohort study.

BACKGROUND: Paracetamol induces hepatotoxicity and subsequent liver injury, which may increase the risk of liver cancer, but epidemiological evidence remains unclear. We conducted this study to evaluate the association between paracetamol use and the risk of liver cancer. METHODS: This prospective study included 464,244 participants free of cancer diagnosis from the UK Biobank. Incident liver cancer was identified through linkage to cancer and death registries and the National Health Service Central Register using the International Classification of Diseases (ICD)-10 codes (C22). An overlap-weighted Cox proportional hazards model was utilized to calculate the hazard ratio (HR) and 95% confidence interval (CI) for the risk of liver cancer associated with paracetamol use. The number needed to harm (NNH) was calculated at 10 years of follow-up. RESULTS: During a median of 12.6 years of follow-up, 627 cases of liver cancer were identified. Paracetamol users had a 28% higher risk of liver cancer than nonusers (HR 1.28, 95% CI 1.06-1.54). This association was robust in several sensitivity analyses and subgroup analyses, and the quantitative bias analysis indicated that the result remains sturdy to unmeasured confounding factors (E-value 1.88, lower 95% CI 1.31). The NNH was 1106.4 at the 10 years of follow-up. CONCLUSION: The regular use of paracetamol was associated with a higher risk of liver cancer. Physicians should be cautious when prescribing paracetamol, and it is recommended to assess the potential risk of liver cancer to personalize the use of paracetamol.

Establishment and characterization of a novel hilar cholangiocarcinoma cell line, CBC3T-1.

Cholangiocarcinoma (CCA) is a group of malignant heterogeneous cancer arising from the biliary tree. The tumor is characterized by insidious onset, high degree of malignancy, poor prognosis, and high recurrence rate. Immortalized cancer cell lines are the best and easiest models for in vitro cancer research. Here, we established a naturally immortalized highly tumorigenic hilar cholangiocarcinoma (hCCA) cell line, CBC3T-1. The CBC3T-1 cell line was cultured for over 60 passages. Thorough analysis showed that CBC3T-1 cells share characteristics similar to original tumor cells from patients with cholangiocarcinoma and display a stable phenotype, including features of epithelial origin, stem cell-like properties, as well as a high invasive and migratory capability and tumorigenicity in mice. Furthermore, this cell line showed the best sensitivity to paclitaxel, followed by gemcitabine. RNA sequencing and whole­exome sequencing showed that cancer-associated pathways and somatic mutations played a dominant role in the development of CCA. We established and characterized a new hCCA cell line, CBC3T-1, which contributes to a better understanding of bile duct cancer, and can be used to study tumorigenesis and progression and the role of anticancer drugs.

First report on establishment and characterization of the extrahepatic cholangiocarcinoma sarcoma cell line CBC2T-2.

BACKGROUND: Extrahepatic cholangiocarcinoma sarcoma is extremely rare in clinical practice. These cells consist of both epithelial and mesenchymal cells. Patient-derived cell lines that maintain tumor characteristics are valuable tools for studying the molecular mechanisms associated with carcinosarcoma. However, cholangiocarcinoma sarcoma cell lines are not available in cell banks. AIM: To establish and characterize a new extrahepatic cholangiocarcinoma sarcoma cell line, namely CBC2T-2. METHODS: We conducted a short tandem repeat (STR) test to confirm the identity of the CBC2T-2 cell line. Furthermore, we assessed the migratory and invasive properties of the cells and performed clonogenicity assay to evaluate the ability of individual cells to form colonies. The tumorigenic potential of CBC2T-2 cells was tested in vivo using non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice. The cells were injected subcutaneously and tumor formation was observed. In addition, immunohistochemical analysis was carried out to examine the expression of epithelial marker CK19 and mesenchymal marker vimentin in both CBC2T-2 cells and xenografts. The CBC2T-2 cell line was used to screen the potential therapeutic effects of various clinical agents in patients with cholangiocarcinoma sarcoma. Lastly, whole-exome sequencing was performed to identify genetic alterations and screen for somatic mutations in the CBC2T-2 cell line. RESULTS: The STR test showed that there was no cross-contamination and the results were identical to those of the original tissue. The cells showed round or oval-shaped epithelioid cells and mesenchymal cells with spindle-shaped or elongated morphology. The cells exhibited a high proliferation ratio with a doubling time of 47.11 h. This cell line has migratory, invasive, and clonogenic abilities. The chromosomes in the CBC2T-2 cells were polyploidy, with numbers ranging from 69 to 79. The subcutaneous tumorigenic assay confirmed the in vivo tumorigenic ability of CBC2T-2 cells in NOD/SCID mice. CBC2T-2 cells and xenografts were positive for both the epithelial marker, CK19, and the mesenchymal marker, vimentin. These results suggest that CBC2T-2 cells may have both epithelial and mesenchymal characteristics. The cells were also used to screen clinical agents in patients with cholangiocarcinoma sarcoma, and a combination of paclitaxel and gemcitabine was found to be the most effective treatment option. CONCLUSION: We established the first human cholangiocarcinoma sarcoma cell line, CBC2T-2, with stable biogenetic traits. This cell line, as a research model, has a high clinical value and would facilitate the understanding of the pathogenesis of cholangiocarcinoma sarcoma.

Cholecystectomy is associated with a higher risk of irritable bowel syndrome in the UK Biobank: a prospective cohort study.

Background: Recent studies have shown that bile acids are essential in irritable bowel syndrome (IBS) pathology, and cholecystectomy has direct effects on bile acid metabolism. However, whether cholecystectomy increases the risk of IBS remains unclear. We aimed to investigate the association between cholecystectomy and IBS risk in the UK Biobank (UKB). Methods: This study is a prospective analysis of 413,472 participants who were free of IBS, inflammatory bowel disease, cancer, or common benign digestive tract diseases. We identified incidents of IBS through self-reporting or links to primary healthcare and hospitalization data. We evaluated hazard ratios (HRs) adjusted for sociodemographic characteristics, health behaviours, comorbidities, and medications. Results: During a median follow-up period of 12.7 years, we observed 15,503 new cases of IBS. Participants with a history of cholecystectomy had a 46% higher risk of IBS than those without (HR = 1.46, 95% CI: 1.32-1.60), and further subtype analysis showed that the risk of IBS with diarrhoea was significantly higher than the risk of IBS without diarrhoea (HR = 1.71, 95% CI: 1.30-2.25 vs. HR = 1.42, 95% CI: 1.28-1.58). The overall covariate-adjusted HRs for IBS were similar between the group with both cholecystectomy and gallstones (HR = 1.45, 95% CI: 1.32-1.58) and the group with cholecystectomy without gallstones (HR = 1.50, 95% CI: 1.36-1.67) when the group without both cholecystectomy and gallstones was used as a reference. The overall covariate-adjusted HR was not significantly different in the group without cholecystectomy with gallstones (HR = 1.18, 95% CI: 0.95-1.47). The positive association of cholecystectomy with IBS risk did not change when stratifying the data based on age, sex, BMI, smoking, alcohol consumption, healthy diet, quality sleep, physical activity, type 2 diabetes, hypertension, hyperlipidaemia, mental illness, NSAID intake, or acid inhibitor intake. Sensitivity analyses, including propensity score matching analysis and lagging the exposure for two or four years, indicated that the effects were robust. Conclusion: Cholecystectomy was associated with a higher risk of IBS, especially IBS with diarrhoea. Additional prospective randomized controlled and experimental studies are warranted to further validate the association and to explore the relevant biological mechanisms.

The gut microbiome dysbiosis and regulation by fecal microbiota transplantation: umbrella review.

Background: Gut microbiome dysbiosis has been implicated in various gastrointestinal and extra-gastrointestinal diseases, but evidence on the efficacy and safety of fecal microbiota transplantation (FMT) for therapeutic indications remains unclear. Methods: The gutMDisorder database was used to summarize the associations between gut microbiome dysbiosis and diseases. We performed an umbrella review of published meta-analyses to determine the evidence synthesis on the efficacy and safety of FMT in treating various diseases. Our study was registered in PROSPERO (CRD42022301226). Results: Gut microbiome dysbiosis was associated with 117 gastrointestinal and extra-gastrointestinal. Colorectal cancer was associated with 92 dysbiosis. Dysbiosis involving Firmicutes (phylum) was associated with 34 diseases. We identified 62 published meta-analyses of FMT. FMT was found to be effective for 13 diseases, with a 95.56% cure rate (95% CI: 93.88-97.05%) for recurrent Chloridoids difficile infection (rCDI). Evidence was high quality for rCDI and moderate to high quality for ulcerative colitis and Crohn's disease but low to very low quality for other diseases. Conclusion: Gut microbiome dysbiosis may be implicated in numerous diseases. Substantial evidence suggests FMT improves clinical outcomes for certain indications, but evidence quality varies greatly depending on the specific indication, route of administration, frequency of instillation, fecal preparation, and donor type. This variability should inform clinical, policy, and implementation decisions regarding FMT.

A protocol of Chinese expert consensuses for the management of health risk in the general public.

Introduction: Non-communicable diseases (NCDs) represent the leading cause of mortality and disability worldwide. Robust evidence has demonstrated that modifiable lifestyle factors such as unhealthy diet, smoking, alcohol consumption and physical inactivity are the primary causes of NCDs. Although a series of guidelines for the management of NCDs have been published in China, these guidelines mainly focus on clinical practice targeting clinicians rather than the general population, and the evidence for NCD prevention based on modifiable lifestyle factors has been disorganized. Therefore, comprehensive and evidence-based guidance for the risk management of major NCDs for the general Chinese population is urgently needed. To achieve this overarching aim, we plan to develop a series of expert consensuses covering 15 major NCDs on health risk management for the general Chinese population. The objectives of these consensuses are (1) to identify and recommend suitable risk assessment methods for the Chinese population; and (2) to make recommendations for the prevention of major NCDs by integrating the current best evidence and experts' opinions. Methods and analysis: For each expert consensus, we will establish a consensus working group comprising 40-50 members. Consensus questions will be formulated by integrating literature reviews, expert opinions, and an online survey. Systematic reviews will be considered as the primary evidence sources. We will conduct new systematic reviews if there are no eligible systematic reviews, the methodological quality is low, or the existing systematic reviews have been published for more than 3 years. We will evaluate the quality of evidence and make recommendations according to the GRADE approach. The consensuses will be reported according to the Reporting Items for Practice Guidelines in Healthcare (RIGHT).