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.

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.

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.

Multiscale unsupervised network for deformable image registration.

BACKGROUND: Deformable image registration (DIR) plays an important part in many clinical tasks, and deep learning has made significant progress in DIR over the past few years. OBJECTIVE: To propose a fast multiscale unsupervised deformable image registration (referred to as FMIRNet) method for monomodal image registration. METHODS: We designed a multiscale fusion module to estimate the large displacement field by combining and refining the deformation fields of three scales. The spatial attention mechanism was employed in our fusion module to weight the displacement field pixel by pixel. Except mean square error (MSE), we additionally added structural similarity (ssim) measure during the training phase to enhance the structural consistency between the deformed images and the fixed images. RESULTS: Our registration method was evaluated on EchoNet, CHAOS and SLIVER, and had indeed performance improvement in terms of SSIM, NCC and NMI scores. Furthermore, we integrated the FMIRNet into the segmentation network (FCN, UNet) to boost the segmentation task on a dataset with few manual annotations in our joint leaning frameworks. The experimental results indicated that the joint segmentation methods had performance improvement in terms of Dice, HD and ASSD scores. CONCLUSIONS: Our proposed FMIRNet is effective for large deformation estimation, and its registration capability is generalizable and robust in joint registration and segmentation frameworks to generate reliable labels for training segmentation tasks.

Confounded association between proton pump inhibitor use and risk of biliary tract cancer: Result from three cohorts.

Recent epidemiological studies suggested that proton pump inhibitor (PPI) use was associated with an increased risk of biliary tract cancer (BTC), however, confounders were not adequately controlled. Our study aimed to evaluate PPI use and subsequent risk of BTC and its subtypes in three well-established cohorts. We conducted a pooled analysis of the subjects free of cancers in UK Biobank (n = 463 643), Nurses' Health Study (NHS, n = 80 235) and NHS II (n = 95 869). Propensity score weighted Cox models were used to estimate marginal HRs of PPIs use on BTC risk, accounting for potential confounders. We documented 284 BTC cases in UK Biobank (median follow-up: 7.6 years), and 91 cases in NHS and NHS II cohorts (median follow-up: 15.8 years). In UK biobank, PPI users had a 96% higher risk of BTC compared to nonusers in crude model (HR 1.96, 95% CI 1.44-2.66), but the effect was attenuated to null after adjusting for potential confounders (HR 0.95, 95% CI 0.60-1.49). PPI use was not associated with risk of BTC in the pooled analysis of three cohorts (HR 0.93, 95% CI 0.60-1.43). We also observed no associations between PPI use with risk of intrahepatic (HR 1.00, 95% CI 0.49-2.04), extrahepatic bile duct (HR 1.09, 95% CI 0.52-2.27) and gallbladder cancers (HR 0.66, 95% CI 0.26-1.66) in UK Biobank. In summary, regular use of PPIs was not associated with the risk of BTC and its subtypes.

High serum uric acid may associate with the increased risk of colorectal cancer in females: A prospective cohort study.

Elevated serum uric acid (SUA) levels have been previously reported to play a role in multiple types of cancers. However, epidemiological studies evaluating SUA levels and colorectal cancer risk remain sparse. This cohort study included 444 462 participants between the ages of 40 and 69 years from the UK Biobank, followed up from 2006 to 2010. Multivariable adjusted Cox regression models were used to estimate hazard ratios (HRs). During a mean follow-up of 6.6 years, 2033 and 855 cases of colon and rectal cancers, respectively, were diagnosed. The multivariable-adjusted HRs for risks of colon cancer in the lowest uric acid categories (≤3.5 mg/dL) compared with the reference groups were 1.31 (95% confidence interval [CI] = 0.75-2.29) in males and 1.26 (95% CI = 1.03-1.55) in females. The HRs in the highest uric acid groups (>8.4 mg/dL) were 1.16 (95% CI = 0.83-1.63) in males and 2.00 (95% CI = 1.02-3.92) in females. The corresponding HRs of rectal cancer in the lowest uric acid groups compared with the reference group were 2.21 (95% CI = 1.15-4.23) in males and 0.98 (95% CI = 0.66-1.45) in females. The HRs in the highest uric acid groups were 1.35 (95% CI = 0.82-2.23) in males and 3.81 (95% CI = 1.38-10.56) in females. In conclusion, SUA showed a U-shaped association with colon cancer risk in both male and female populations. The same pattern was observed in male patients with rectal cancer. However, SUA levels were positively associated with occurrence of rectal cancer in female subjects.

UDRSNet: An unsupervised deformable registration module based on image structure similarity.

BACKGROUND: Image registration is a challenging problem in many clinical tasks, but deep learning has made significant progress in this area over the past few years. Real-time and robust registration has been made possible by supervised transformation estimation. However, the quality of registrations using this framework depends on the quality of ground truth labels such as displacement field. PURPOSE: To propose a simple and reliable method for registering medical images based on image structure similarity in a completely unsupervised manner. METHODS: We proposed a deep cascade unsupervised deformable registration approach to align images without reliable clinical data labels. Our basic network was composed of a displacement estimation module (ResUnet) and a deformation module (spatial transformer layers). We adopted l 2 $l_2$ -norm to regularize the deformation field instead of the traditional l 1 $l_1$ -norm regularization. Additionally, we utilized structural similarity (ssim) estimation during the training stage to enhance the structural consistency between the deformed images and the reference images. RESULTS: Experiments results indicated that by incorporating ssim loss, our cascaded methods not only achieved higher dice score of 0.9873, ssim score of 0.9559, normalized cross-correlation (NCC) score of 0.9950, and lower relative sum of squared difference (SSD) error of 0.0313 on CT images, but also outperformed the comparative methods on ultrasound dataset. The statistical t $t$ -test results also proved that these improvements of our method have statistical significance. CONCLUSIONS: In this study, the promising results based on diverse evaluation metrics have demonstrated that our model is simple and effective in deformable image registration (DIR). The generalization ability of the model was also verified through experiments on liver CT images and cardiac ultrasound images.

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.

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.

Three-Dimensional Voxel-Wise Quantitative Assessment of Imaging Features in Hepatocellular Carcinoma.

Voxel-wise quantitative assessment of typical characteristics in three-dimensional (3D) multiphase computed tomography (CT) imaging, especially arterial phase hyperenhancement (APHE) and subsequent washout (WO), is crucial for the diagnosis and therapy of hepatocellular carcinoma (HCC). However, this process is still missing in practice. Radiologists often visually estimate these features, which limit the diagnostic accuracy due to subjective interpretation and qualitative assessment. Quantitative assessment is one of the solutions to this problem. However, performing voxel-wise assessment in 3D is difficult due to the misalignments between images caused by respiratory and other physiological motions. In this paper, based on the Liver Imaging Reporting and Data System (v2018), we propose a registration-based quantitative model for the 3D voxel-wise assessment of image characteristics through multiple CT imaging phases. Specifically, we selected three phases from sequential CT imaging phases, i.e., pre-contrast phase (Pre), arterial phase (AP), delayed phase (DP), and then registered Pre and DP images to the AP image to extract and assess the major imaging characteristics. An iterative reweighted local cross-correlation was applied in the proposed registration model to construct the fidelity term for comparison of intensity features across different imaging phases, which is challenging due to their distinct intensity appearance. Experiments on clinical dataset showed that the means of dice similarity coefficient of liver were 98.6% and 98.1%, those of surface distance were 0.38 and 0.54 mm, and those of Hausdorff distance were 4.34 and 6.16 mm, indicating that quantitative estimation can be accomplished with high accuracy. For the classification of APHE, the result obtained by our method was consistent with those acquired by experts. For the WO, the effectiveness of the model was verified in terms of WO volume ratio.

Proton pump inhibitors may enhance the risk of digestive diseases by regulating intestinal microbiota.

Proton pump inhibitors (PPIs) are the most used acid-inhibitory drugs, with a wide range of applications in the treatment of various digestive diseases. However, recently, there has been a growing number of digestive complications linked to PPIs, and several studies have indicated that the intestinal flora play an important role in these complications. Therefore, developing a greater understanding of the role of the gut microbiota in PPI-related digestive diseases is essential. Here, we summarize the current research on the correlation between PPI-related digestive disorders and intestinal flora and establish the altered strains and possible pathogenic mechanisms of the different diseases. We aimed to provide a theoretical basis and reference for the future treatment and prevention of PPI-related digestive complications based on the regulation of the intestinal microbiota.

Lanatoside C decelerates proliferation and induces apoptosis through inhibition of STAT3 and ROS-mediated mitochondrial membrane potential transformation in cholangiocarcinoma.

Introduction: The incidence of cholangiocarcinoma (CCA) has increased worldwide in recent years. Given the poor prognosis associated with the current management approach of CCA, new therapeutic agents are warranted to improve the prognosis of this patient population. Methods: In this study, we extracted five cardiac glycosides (CGs) from natural plants: digoxin, lanatoside A, lanatoside C, lanatoside B, and gitoxin. Follow-up experiments were performed to assess the effect of these five extracts on cholangiocarcinoma cells and compounds with the best efficacy were selected. Lanatoside C (Lan C) was selected as the most potent natural extract for subsequent experiments. We explored the potential mechanism underlying the anticancer activity of Lan C on cholangiocarcinoma cells by flow cytometry, western blot, immunofluorescence, transcriptomics sequencing, network pharmacology and in vivo experiments. Results: We found that Lan C time-dependently inhibited the growth and induced apoptosis of HuCCT-1 and TFK-1 cholangiocarcinoma cells. Besides Lan C increased the reactive oxygen species (ROS) content in cholangiocarcinoma cells, decreased the mitochondrial membrane potential (MMP) and resulted in apoptosis. Besides, Lan C downregulated the protein expression of STAT3, leading to decreased expression of Bcl-2 and Bcl-xl, increased expression of Bax, activation of caspase-3, and initiation of apoptosis. N-acetyl-L-cysteine (NAC) pretreatment reversed the effect of Lan C. In vivo, we found that Lan C inhibited the growth of cholangiocarcinoma xenografts without toxic effects on normal cells. Tumor immunohistochemistry showed that nude mice transplanted with human cholangiocarcinoma cells treated with Lan C exhibited decreased STAT3 expression and increased caspase-9 and caspase-3 expression in tumors, consistent with the in vitro results. Conclusion: In summary, our results substantiates that cardiac glycosides have strong anti-CCA effects. Interestingly the biological activity of Lan C provides a new anticancer candidate for the treatment of cholangiocarcinoma.

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.

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.

The N6-Methyladenosine Modification and Its Role in mRNA Metabolism and Gastrointestinal Tract Disease.

The N6-methyladenosine (m6A) modification is the most abundant internal modification of messenger RNA (mRNA) in higher eukaryotes. Under the actions of methyltransferase, demethylase and methyl-binding protein, m6A resulting from RNA methylation becomes dynamic and reversible, similar to that from DNA methylation, and this effect allows the generated mRNA to participate in metabolism processes, such as splicing, transport, translation, and degradation. The most common tumors are those found in the gastrointestinal tract, and research on these tumors has flourished since the discovery of m6A. Overall, further analysis of the mechanism of m6A and its role in tumors may contribute to new ideas for the treatment of tumors. m6A also plays an important role in non-tumor diseases of the gastrointestinal tract. This manuscript reviews the current knowledge of m6A-related proteins, mRNA metabolism and their application in gastrointestinal tract disease.

Dynamic changes in liver volume calculated using a three-dimensional visualisation system after microwave ablation of hepatocellular carcinomas.

OBJECTIVES: To investigate the changes in liver volume and function after microwave ablation (MWA) of hepatocellular carcinomas (HCCs). MATERIALS AND METHODS: We retrospectively analysed 76 patients with 106 nodules who underwent MWA for HCCs ≤5 cm between January 2015 and September 2017. Liver and ablation volumes were calculated using a three-dimensional visualisation system on MRI. Multiple regression analysis was used to estimate the association between the ablation volume and liver volume changes. Deformable image registration (DIR) was performed to confirm the influence of liver volume changes on curative effect evaluation after ablation. RESULTS: The initial liver and tumour volumes were 1262.1 ± 259.91 cm3 (range: 864.9-1966.8) and 2.5 cm3 (interquartile range [IQR]: 1.3-8.8), respectively. Compared to the initial liver volumes, the entire live volume (ELV) increased by 10.1% ± 8.93% (range: -4.9% to 46.68%) on the 3rd day after ablation. Subsequently, it recovered to initial level at the 3rd month and maintained its level during the 1-year follow-up. The median total ablation volume was 34.9 cm3 (IQR: 20.4-65.4) on the 3rd day after ablation, which decreased by 71.2% (IQR: 57.4%-78.1%) 1 year after ablation. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (T-Bil) peaked within 3 days after MWA and recovered to normal within 1 month. The ablation volume proportion of the ELV was an independent risk factor for the increase in the ELV and AST, ALT and T-Bil levels within 3 days after ablation. When DIR was conducted to fuse ablation zone and tumour, the reshaped tumour volumes were enlarged by 40% because of the increase in ELV. CONCLUSIONS: MWA of HCCs based on the Milan criteria could induce temporary increases in ELV and RLV within 3 days after ablation, but both parameters recovered to initial levels 3 months after ablation. This indicates that MWA of early-stage HCCs would not lead to liver volume loss and could potentially protect liver function. The liver cannot be treated as an incompressible organ after ablation, and the appropriate deformation constraint should be designed for DIR to evaluate ablation margin accurately.

Phosphoproteomics reveals that cinobufotalin promotes intrahepatic cholangiocarcinoma cell apoptosis by activating the ATM/CHK2/p53 signaling pathway.

Intrahepatic cholangiocarcinoma (ICC) is a malignant tumor that originates from bile duct's epithelial cells and is usually characterized by insidious symptoms and poor prognosis. Cinobufotalin (CB), an active ingredient obtained from the Traditional Chinese Medicine ChanSu, is purported to exhibit a wide range of antitumorigenic activities. However, the mechanism by which it achieves such pharmacological effects remains elusive. Here, we disclosed the mechanism of action by which CB inhibits ICC cells. Initial experiments revealed that the proliferation of RBE and HCCC-9810 cells was significantly inhibited by CB with IC50 values of 0.342 µM and 0.421 µM respectively. CB induced the expression of caspase-3 subsequently leading to the apoptosis of ICC cells. Phosphoproteomics revealed that the phosphorylation of many proteins associated with DNA damage response increased. Kinase-substrate enrichment analysis revealed that ATM was activated after CB treatment, while CDK1 was inactivated. Activated ATM increased p-CHK2-T68 and p-p53-S15, which promoted the expression of FAS, DR4 and DR5 and triggered cell apoptosis. In summary, this work reveals the role of CB in inducing DNA damage and cell apoptosis involved in the activation of the ATM/CHK2/p53 signaling pathway, and indicates that CB may serve as a chemotherapeutic drug candidate for ICC treatment.

Alterperylenol as a Novel Thioredoxin Reductase Inhibitor Induces Liver Cancer Cell Apoptosis and Ferroptosis.

Natural products are a rich resource for discovering innovational drugs. Herein, we isolated and characterized two compounds dihydroalterperylenol (DAP) and alterperylenol (AP) from Alternaria sp. MG1, an endophytic fungus isolated from Vitis quinquangularis, and investigated the underlying antitumor mechanism of AP. Mechanistically, AP inhibits the growth of HepG2 cells by targeting the selenoprotein thioredoxin reductase (TrxR) and ultimately induces cell apoptosis and ferroptosis. Compared to DAP, the α,ß-unsaturated carbonyl structure of AP is an indispensable moiety for its antitumor activity and TrxR inhibition. Specifically, inhibition of TrxR causes the extensive reactive oxygen species and consequently results in DNA damage, G2/M cell cycle arrest, and mitochondrial fission. Furthermore, ferroptosis is driven via excess toxic lipid peroxidation and elevation of intracellular iron levels via regulating iron-related proteins. In vivo validation also shows that AP owns anticancer activity in xenograft mice. Collectively, our results disclose a novel natural TrxR inhibitor AP exerting the antitumor effect via inducing cell apoptosis and ferroptosis and evidence that AP is a promising candidate agent for liver carcinoma therapy. The link of TrxR inhibition to ferroptosis further highlights the physiological importance of TrxR in regulating ferroptosis.

A Semiautomated Deep Learning Approach for Pancreas Segmentation.

Accurate pancreas segmentation from 3D CT volumes is important for pancreas diseases therapy. It is challenging to accurately delineate the pancreas due to the poor intensity contrast and intrinsic large variations in volume, shape, and location. In this paper, we propose a semiautomated deformable U-Net, i.e., DUNet for the pancreas segmentation. The key innovation of our proposed method is a deformable convolution module, which adaptively adds learned offsets to each sampling position of 2D convolutional kernel to enhance feature representation. Combining deformable convolution module with U-Net enables our DUNet to flexibly capture pancreatic features and improve the geometric modeling capability of U-Net. Moreover, a nonlinear Dice-based loss function is designed to tackle the class-imbalanced problem in the pancreas segmentation. Experimental results show that our proposed method outperforms all comparison methods on the same NIH dataset.

Identification of hub genes involved in the occurrence and development of hepatocellular carcinoma via bioinformatics analysis.

Hepatocellular carcinoma (HCC) is a heterogeneous malignancy, which is a major cause of cancer morbidity and mortality worldwide. Thus, the aim of the present study was to identify the hub genes and underlying pathways of HCC via bioinformatics analyses. The present study screened three datasets, including GSE112790, GSE84402 and GSE74656 from the Gene Expression Omnibus (GEO) database, and downloaded the RNA-sequencing of HCC from The Cancer Genome Atlas (TCGA) database. The differentially expressed genes (DEGs) in both the GEO and TCGA datasets were filtered, and the screened DEGs were subsequently analyzed for functional enrichment pathways. A protein-protein interaction (PPI) network was constructed, and hub genes were further screened to create the Kaplan-Meier curve using cBioPortal. The expression levels of hub genes were then validated in different datasets using the Oncomine database. In addition, associations between expression and tumor grade, hepatitis virus infection status, satellites and vascular invasion were assessed. A total of 126 DEGs were identified, containing 70 upregulated genes and 56 downregulated genes from the GEO and TCGA databases. By constructing the PPI network, the present study identified hub genes, including cyclin B1 (CCNB1), cell-division cycle protein 20 (CDC20), cyclin-dependent kinase 1, BUB1 mitotic checkpoint serine/threonine kinase ß (BUB1B), cyclin A2, nucleolar and spindle associated protein 1, ubiquitin-conjugating enzyme E2 C (UBE2C) and ZW10 interactor. Furthermore, upregulated CCNB1, CDC20, BUB1B and UBE2C expression levels indicated worse disease-free and overall survival. Moreover, a meta-analysis of tumor and healthy tissues in the Oncomine database demonstrated that BUB1B and UBE2C were highly expressed in HCC. The present study also analyzed the data of HCC in TCGA database using univariate and multivariate Cox analyses, and demonstrated that BUB1B and UBE2C may be used as independent prognostic factors. In conclusion, the present study identified several genes and the signaling pathways that were associated with tumorigenesis using bioinformatics analyses, which could be potential targets for the diagnosis and treatment of HCC.