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.

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.

Lipiodol emulsion as a dual chemoradiation-sensitizer for pancreatic cancer treatment.

Pancreatic ductal adenocarcinoma (PDAC) has a low survival rate and limited treatment options. Concurrent chemoradiotherapy is considered beneficial to improve tumor control, but the low drug bioavailability at tumor site and the low radiation tolerance of surrounding healthy organs greatly limits its effectiveness. Lipiodol, a natural drug carrier used in clinical transarterial chemoembolization, has shown potential as a radiosensitizer due to its high Z element iodine composition. Thus, this study aims to repurpose lipiodol as a sensitizer to simultaneously enhance chemo- and radiotherapy for PDAC. To this end, a stable lipiodol emulsion (IOE) loaded with gemcitabine is designed using clinically approved surfactants. At in vivo level, IOE demonstrates better radiotherapeutic effect than existing nanoradiosensitizers and enhanced drug bioavailability over free drug, leading to significant tumor inhibition and improved survival rates under concurrent chemo-radiotherapy. This may due to the sustained drug release, homogenous spatial distribution, and long-term retention ability of IOE in solid PDAC tumor. Furthermore, to better understand the functioning mechanism of drug-loaded IOE, in vitro study is conducted to reveal the ROS- and DNA damage-related therapeutic pathways. Lastly, a comprehensive toxicity assessment also proves the good biocompatibility and safety of as-prepared IOE. This study offers a clinically feasible sensitizer for simultaneous chemoradiotherapy and holds potential for other types of cancer treatment in clinics.

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.

Spleen volume is associated with overt hepatic encephalopathy after transjugular intrahepatic portosystemic shunt in patients with portal hypertension.

BACKGROUND: Portal shunt and immune status related to the spleen are related to the occurrence of hepatic encephalopathy (HE). It is unknown whether spleen volume before transjugular intrahepatic portosystemic shunt (TIPS) is related to postoperative HE. AIM: To investigate the relationship between spleen volume and the occurrence of HE. METHODS: This study included 135 patients with liver cirrhosis who underwent TIPS, and liver and spleen volumes were elevated upon computed tomography imaging. The Kaplan-Meier curve was used to compare the difference in the incidence rate of HE among patients with different spleen volumes. Univariate and multivariate Cox regression analyses were performed to identify the factors affecting overt HE (OHE). Restricted cubic spline was used to examine the shapes of the dose-response association between spleen volumes and OHE risk. RESULTS: The results showed that 37 (27.2%) of 135 patients experienced OHE during a 1-year follow-up period. Compared with preoperative spleen volume (901.30 ± 471.90 cm3), there was a significant decrease in spleen volume after TIPS (697.60 ± 281.0 cm3) in OHE patients. As the severity of OHE increased, the spleen volume significantly decreased (P < 0.05). Compared with patients with a spleen volume ≥ 782.4 cm3, those with a spleen volume < 782.4 cm3 had a higher incidence of HE (P < 0.05). Cox regression analysis showed that spleen volume was an independent risk factor for post-TIPS OHE (hazard ratio = 0.494, P < 0.05). Restricted cubic spline model showed that with an increasing spleen volume, OHE risk showed an initial increase and then decrease (P < 0.05). CONCLUSION: Spleen volume is related to the occurrence of OHE after TIPS. Preoperative spleen volume is an independent risk factor for post-TIPS OHE.

A radiomics approach for predicting gait freezing in Parkinson's disease based on resting-state functional magnetic resonance imaging indices: a cross-sectional study.

Freezing of gait is a significant and debilitating motor symptom often observed in individuals with Parkinson's disease. Resting-state functional magnetic resonance imaging, along with its multi-level feature indices, has provided a fresh perspective and valuable insight into the study of freezing of gait in Parkinson's disease. It has been revealed that Parkinson's disease is accompanied by widespread irregularities in inherent brain network activity. However, the effective integration of the multi-level indices of resting-state functional magnetic resonance imaging into clinical settings for the diagnosis of freezing of gait in Parkinson's disease remains a challenge. Although previous studies have demonstrated that radiomics can extract optimal features as biomarkers to identify or predict diseases, a knowledge gap still exists in the field of freezing of gait in Parkinson's disease. This cross-sectional study aimed to evaluate the ability of radiomics features based on multi-level indices of resting-state functional magnetic resonance imaging, along with clinical features, to distinguish between Parkinson's disease patients with and without freezing of gait. We recruited 28 patients with Parkinson's disease who had freezing of gait (15 men and 13 women, average age 63 years) and 30 patients with Parkinson's disease who had no freezing of gait (16 men and 14 women, average age 64 years). Magnetic resonance imaging scans were obtained using a 3.0T scanner to extract the mean amplitude of low-frequency fluctuations, mean regional homogeneity, and degree centrality. Neurological and clinical characteristics were also evaluated. We used the least absolute shrinkage and selection operator algorithm to extract features and established feedforward neural network models based solely on resting-state functional magnetic resonance imaging indicators. We then performed predictive analysis of three distinct groups based on resting-state functional magnetic resonance imaging indicators indicators combined with clinical features. Subsequently, we conducted 100 additional five-fold cross-validations to determine the most effective model for each classification task and evaluated the performance of the model using the area under the receiver operating characteristic curve. The results showed that when differentiating patients with Parkinson's disease who had freezing of gait from those who did not have freezing of gait, or from healthy controls, the models using only the mean regional homogeneity values achieved the highest area under the receiver operating characteristic curve values of 0.750 (with an accuracy of 70.9%) and 0.759 (with an accuracy of 65.3%), respectively. When classifying patients with Parkinson's disease who had freezing of gait from those who had no freezing of gait, the model using the mean amplitude of low-frequency fluctuation values combined with two clinical features achieved the highest area under the receiver operating characteristic curve of 0.847 (with an accuracy of 74.3%). The most significant features for patients with Parkinson's disease who had freezing of gait were amplitude of low-frequency fluctuation alterations in the left parahippocampal gyrus and two clinical characteristics: Montreal Cognitive Assessment and Hamilton Depression Scale scores. Our findings suggest that radiomics features derived from resting-state functional magnetic resonance imaging indices and clinical information can serve as valuable indices for the identification of freezing of gait in Parkinson's disease.

Impact of deep brain stimulation on urogenital function in Parkinson's disease: a systematic review and meta-analysis.

Objectives: Deep Brain Stimulation (DBS) effectively treats Parkinson's motor symptoms, but its effects on the urogenital system are debated. Methods: A research was conducted in PubMed, Embase, Cochrane Library, Web of Science, and Scopus until February 27, 2024. We primarily focused on DBS's impact on Parkinson's patients' Urine storage function, voiding function, sexual function, and quality of life. Results: Our meta-analysis included 14 studies. The main results showed that DBS resulted in fewer instances of urinary urgency (OR = 1.85, 95% CI: 1.26 to 2.70, p = 0.002) and increased maximum bladder capacity (MD = -66.10, 95% CI: -119.37 to -12.82, p = 0.02) in terms of urinary storage function. However, there were no significant differences in first desire to void and strong desire to void. In terms of voiding function, DBS showed significant improvements in maximum flow rate (MD = -0.64, 95% CI: -1.23 to -0.05, p = 0.03), post-void residual (MD = -6.79, 95% CI: 4.54 to 9.05, P < 0.00001) and detrusor pressure during maximum flow (MD = -1.37, 95% CI: -2.73 to -0.02, p = 0.05). Additionally, there was no significant difference in sexual function between the two groups (MD = -1.41, 95% CI: -12.40 to 9.57, p = 0.80). Conclusion: DBS has demonstrated a certain degree of efficacy in ameliorating urinary storage and voiding function in patients with Parkinson's disease. However, certain urodynamic parameters or scores do not demonstrate any statistically significant disparities. Furthermore, DBS has no significant impact on erectile function in male Parkinson's patients. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023476661, identifier CRD42023476661.

First-passage properties of bundled networks.

Bundled networks, obtained by attaching a copy of a fiber structure to each node on the base structure, serve as important realistic models for the geometry and dynamics of nontranslationally invariant systems in condensed matter physics. Here, we analyze the first-passage properties, including the mean first-passage time, the mean-trapping time, the global-mean first-passage time (GFPT), and the stationary distribution, of a biased random walk within such networks, in which a random walker moves to a neighbor on base with probability γ and to a neighbor on fiber with probability 1-γ when the walker at a node on base. We reveal the primary properties of both the base and fiber structure, which govern the first-passage characteristics of the bundled network. Explicit expressions between these quantities in the bundled networks and the related quantities in the component structures are presented. GFPT serves as a crucial indicator for evaluating network transport efficiency. Unexpectedly, bases and fibers with similar scaling of GFPT can construct bundled networks exhibiting different scaling behaviors of GFPT. Therefore, bundled networks can be tailored to accommodate specific dynamic property requirements by choosing a suitable base and fiber structure. These findings contribute to advancing the design and optimization of network structures.

Comparison of efficacies of different treatments for nontuberculous mycobacterial pulmonary disease in Anhui Province, China.

INTRODUCTION: Although nontuberculous mycobacterial (NTM) infection is a common cause of pulmonary disease worldwide, few studies have focused on epidemiological and therapeutic factors related to NTM cases in Anhui Province, China. This retrospective study aimed to identify aetiological and clinical factors, and treatment outcomes of patients with NTM pulmonary disease (NTMPD) in Anhui. METHODOLOGY: Retrospective clinical data obtained from medical records of NTMPD patients seeking care at Anhui Chest Hospital from July 2019 to June 2022 were analyzed. Treatment outcomes were compared between two patient groups: one receiving a standardised NTM treatment regimen and the other receiving precision treatment regimens. RESULTS: Genotypic analysis of 672 clinical NTMPD-associated isolates revealed that most were Mycobacterium intracellulare, while drug-susceptibility test results demonstrated diverse antibiotic resistance profiles for these isolates. Cough was the most common symptom for 101 NTMPD patients. After patients of both groups received treatment, symptoms improved, sputum culture conversion was observed for some patients, imaging findings stabilised; however, no statistically significant intergroup differences in treatment outcomes were found. CONCLUSIONS: In this study, M. intracellulare was the predominant NTM species identified in isolates obtained from NTMPD patients. Drug resistance profiles of our patient isolates were complex, highlighting the need for administration of timely, more effective, standardised treatments for patients with NTMPD in Anhui Province, China.

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In infants with severe bronchopulmonary dysplasia (sBPD), severe pulmonary lobar emphysema may occur as a complication, contributing to significant impairment in ventilation. Clinical management of these infants is extremely challenging and some may require lobectomy to improve ventilation. However, prior to the lobectomy, it is very difficult to assess whether the remaining lung parenchyma would be able to sustain adequate ventilation postoperatively. In addition, preoperative planning and perioperative management are also quite challenging in these patients. This paper reports the utility of selective bronchial occlusion in assessing the safety and efficacy of lobectomy in a case of sBPD complicated by severe right upper lobar emphysema. Since infants with sBPD already have poor lung development and significant lung injury, lobectomy should be viewed as a non-traditional therapy and be carried out with extreme caution. Selective bronchial occlusion test can be an effective tool in assessing the risks and benefits of lobectomy in cases with sBPD and lobar emphysema. However, given the technical difficulty, successful application of this technique requires close collaboration of an experienced interdisciplinary team.

High-frame-rate contrast-enhanced ultrasound to differentiate between clear cell renal cell carcinoma and angiomyolipoma.

BACKGROUND: To investigate the diagnostic efficacy of high-frame-rate contrast-enhanced ultrasound (H-CEUS) in differentiating between clear cell renal cell carcinoma (CCRCC) and angiomyolipoma (AML). METHODS: A retrospective study was performed on the clinical data of 79 patients diagnosed with CCRCC and 31 patients diagnosed with AML at the First Affiliated Hospital of Nanchang University between October 2022 and December 2023. Conventional ultrasound (US) and H-CEUS examinations were conducted on all patients prior to surgery, dynamic images were recorded from the US, and the qualitative and quantitative parameters of H-CEUS were collected. The t-test, χ² test and non-parametric Mann-Whitney test were employed to assess differences in clinical data, US characteristics, and qualitative and quantitative parameters of H-CEUS between the CCRCC and AML groups. The independent risk factors of CCRCC were identified using binary logistic regression. The receiver operator characteristic (ROC) curve was constructed to evaluate the diagnostic effectiveness of clinical + US and H-CEUS in differentiating between CCRCC and AML. RESULTS: The CCRCC group and the AML group exhibited significant differences in patient gender, operation mode, nodular echo, and nodule blood flow (χ²=11.698, -, -,=10.582; P<0.001, <0.001, <0.001, and = 0.014, respectively). In addition, the H-CEUS qualitative analysis demonstrated significant differences between the AML group and the CCRCC group with respect to enhancement mode, regression mode, peak intensity, enhancement uniformity, no enhancement, and presence or absence of pseudocapsule (χ²=41.614, -, -, = 2.758, = 42.099, -; P<0.001, <0.001, <0.001, 0.097, <0.001, and <0.001, respectively). The Arrival time (AT) in the CCRCC group was significantly shorter than that in the AML group, as determined by quantitative analysis of H-CEUS (Z=-3.266, P = 0.001). Furthermore, the Peak intensity (PI), Ascent slope (AS), and The area under the curve (AUC) exhibited significantly higher values in the CCRCC group compared to the AML group (Z=-2.043,=-2.545,=-3.565; P = 0.041, = 0.011, and <0.001, respectively). Logistic regression analysis indicated that only gender, nodule echo, the pseudocapsule, AS, and AUC of H-CEUS were independent risk factors of CCRCC. The ROC curve revealed that combining gender and nodule echo yielded a sensitivity of 92.4%, specificity of 64.5%, and an AUC of 0.847 in distinguishing between CCRCC and AML. When combining the H-CEUS parameters of pseudocapsule, AS, and AUC, the sensitivity, specificity, and AUC for distinguishing between CCRCC and AML were 84.8%, 96.8%, and 0.918, respectively. No statistically significant difference was observed in the diagnostic effectiveness of the two methods (Z=-1.286, P = 0.198). However, H-CEUS demonstrated better AUC and specificity. CONCLUSIONS: H-CEUS enhances the sensitivity and specificity of differentiating between CCRCC and AML by improving the temporal resolution, offering a more precise diagnostic foundation for identifying the most appropriate therapy for patients.

A functional study reveals CsNAC086 regulated the biosynthesis of flavonols in Camellia sinensis.

MAIN CONCLUSION: CsNAC086 was found to promote the expression of CsFLS, thus promoting the accumulation of flavonols in Camellia sinensis. Flavonols, the main flavonoids in tea plants, play an important role in the taste and quality of tea. In this study, a NAC TF gene CsNAC086 was isolated from tea plants and confirmed its regulatory role in the expression of flavonol synthase which is a key gene involved in the biosynthesis of flavonols in tea plant. Yeast transcription-activity assays showed that CsNAC086 has self-activation activity. The transcriptional activator domain of CsNAC086 is located in the non-conserved C-terminal region (positions 171-550), while the conserved NAC domain (positions 1-170) does not have self-activation activity. Silencing the CsNAC086 gene using antisense oligonucleotides significantly decreased the expression of CsFLS. As a result, the concentration of flavonols decreased significantly. In overexpressing CsNAC086 tobacco leaves, the expression of NtFLS was significantly increased. Compared with wild-type tobacco, the flavonols concentration increased. Yeast one-hybrid assays showed CsNAC086 did not directly regulate the gene expression of CsFLS. These findings indicate that CsNAC086 plays a role in regulating flavonols biosynthesis in tea plants, which has important implications for selecting and breeding of high-flavonols-concentration containing tea-plant cultivars.

Proton pump inhibitors stabilize the expression of PD-L1 on cell membrane depending on the phosphorylation of GSK3ß.

BACKGROUND: Preclinical and clinical evidence indicates that proton pump inhibitors (PPIs) may indirectly diminish the microbiome diversity, thereby reducing the effectiveness of immune checkpoint inhibitors (ICIs). Conversely, recent publications have shown that PPIs could potentially enhance the response to ICIs. The precise mechanism through which PPIs modulate the ICIs remains unclear. In this study, we discovered a novel molecular function of PPIs in regulating immune invasion, specifically through inducing PD-L1 translocation in various tumor cells. METHODS: C57BL/6 mice subcutaneous transplantation model is used to verify the potential efficacy of PPIs and PD-L1 antibody. Western blotting analysis and phosphorylated chip are used to verify the alteration of PD-L1-related pathways after being treated with PPIs. The related gene expression is performed by qRT-PCR and luciferase reporter analysis. We also collected 60 clinical patients diagnosed with esophageal cancer or reflux esophagitis and then detected the expression of PD-L1 in the tissue samples by immunohistochemistry. RESULTS: We observed that the IC50 of tumor cells in response to PPIs was significantly higher than that of normal epithelial cells. PPIs significantly increased the expression of PD-L1 on cell membrane at clinically relevant concentrations. Furthermore, pre-treatment with PPIs appeared to synergize the efficiency of anti-PD-L1 antibodies in mouse models. However, PPI administration did not alter the transcription or total protein level of PD-L1 in multiple tumor cells. Using a phosphorylated protein chip, we identified that PPIs enhanced the phosphorylation of GSK3ß, then leading to PD-L1 protein translocation to the cell membranes. The capacity of PPIs to upregulate PD-L1 was negated following GSK3ß knockout. Furthermore, our clinical data showed that the PPIs use resulted in increased PD-L1 expression in esophageal cancer patients. CONCLUSION: We mainly address a significant and novel mechanism that the usage of PPIs could directly induce the expression of PD-L1 by inducing GSK3ß phosphorylation and facilitate primary tumor progression and metastasis.

Integrated analysis of scRNA-seq and bulk RNA-seq reveals that GPRC5A is an important prognostic gene in pancreatic cancer and is associated with B-cell Infiltration in pancreatic cancer.

Introduction: Pancreatic cancer (PC) is a malignancy with poor prognosis. This investigation aimed to determine the relevant genes that affect the prognosis of PC and investigate their relationship with immune infiltration. Methods: : First, we acquired PC single-cell chip data from the GEO database to scrutinize dissimilarities in immune cell infiltration and differential genes between cancerous and adjacent tissues. Subsequently, we combined clinical data from TCGA to identify genes relevant to PC prognosis. Employing Cox and Lasso regression analyses, we constructed a multifactorial Cox prognostic model, which we subsequently confirmed. The prognostic gene expression in PC was authenticated using RT-PCR. Moreover, we employed the TIMER online database to examine the relationship between the expression of prognostic genes and T and B cell infiltration. Additionally, the expression of GPRC5A and its correlation with B cells infiltration and patient prognosis were ascertained in tissue chips using multiple immune fluorescence staining. Results: The single-cell analysis unveiled dissimilarities in B-cell infiltration between cancerous and neighboring tissues. We developed a prognostic model utilizing three genes, indicating that patients with high-risk scores experienced a more unfavorable prognosis. Immune infiltration analysis revealed a significant correlation among YWHAZ, GPRC5A, and B cell immune infiltration. In tissue samples, GPRC5A exhibited substantial overexpression and a robust association with an adverse prognosis, demonstrating a positive correlation with B cell infiltration. Conclusion: GPRC5A is an independent risk factor in PC and correlated with B cell immune infiltration in PC. These outcomes indicated that GPRC5A is a viable target for treating PC.

Fractal and first-passage properties of a class of self-similar networks.

A class of self-similar networks, obtained by recursively replacing each edge of the current network with a well-designed structure (generator) and known as edge-iteration networks, has garnered considerable attention owing to its role in presenting rich network models to mimic real objects with self-similar structures. The generator dominates the structural and dynamic properties of edge-iteration networks. However, the general relationships between these networks' structural and dynamic properties and their generators remain unclear. We study the fractal and first-passage properties, such as the fractal dimension, walk dimension, resistance exponent, spectral dimension, and global mean first-passage time, which is the mean time for a walker, starting from a randomly selected node and reaching the fixed target node for the first time. We disclose the properties of the generators that dominate the fractal and first-passage properties of general edge-iteration networks. A clear relationship between the fractal and first-passage properties of the edge-iteration networks and the related properties of the generators are presented. The upper and lower bounds of these quantities are also discussed. Thus, networks can be customized to meet the requirements of fractal and dynamic properties by selecting an appropriate generator and tuning their structural parameters. The results obtained here shed light on the design and optimization of network structures.

Analysis of the association between urinary glyphosate exposure and fatty liver index: a study for US adults.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a prevalent condition that often goes unrecognized in the population, and many risk factors for this disease are not well understood. Glyphosate (GLY) is one of the most commonly used herbicides worldwide, and exposure to this chemical in the environment is significant. However, studies exploring the association between GLY exposure and NAFLD remain limited. Therefore, the aim of this study was to assess the association between urinary glyphosate (uGLY) level and fatty liver index (FLI) using data from the National Health and Nutrition Examination Survey (NHANES), which includes uGLY measurements. METHODS: The log function of uGLY was converted and expressed as Loge(uGLY) with the constant "e" as the base and used for subsequent analysis. The association between Loge(uGLY) (the independent variable) level and FLI (the dependent variable) was assessed by multiple linear regression analysis. Smoothing curve fitting and a generalized additive model were used to assess if there was a nonlinear association between the independent and the dependent variables. A subgroup analysis was used to find susceptible individuals of the association between the independent variable and the dependent variable. RESULTS: A final total of 2238 participants were included in this study. Participants were categorized into two groups (< -1.011 and ≥ -1.011 ng/ml) based on the median value of Loge(uGLY). A total of 1125 participants had Loge(uGLY) levels ≥ -1.011 ng/ml and higher FLI. The result of multiple linear regression analysis showed a positive association between Loge(uGLY) and FLI (Beta coefficient = 2.16, 95% CI: 0.71, 3.61). Smoothing curve fitting and threshold effect analysis indicated a linear association between Loge(uGLY) and FLI [likelihood ratio(LLR) = 0.364]. Subgroup analyses showed that the positive association between Loge(uGLY) and FLI was more pronounced in participants who were female, aged between 40 and 60 years, had borderline diabetes history, and without hypertension history. In addition, participants of races/ethnicities other than (Mexican American, White and Black) were particularly sensitive to the positive association between Loge(uGLY) and FLI. CONCLUSIONS: A positive linear association was found between Loge(uGLY) level and FLI. Participants who were female, 40 to 60 years old, and of ethnic backgrounds other than Mexican American, White, and Black, deserve more attention.

Azide-modified corrole phosphorus complexes for endoplasmic reticulum-targeted fluorescence bioimaging and effective cancer photodynamic therapy.

Study on corrole photosensitizers (PSs) for photodynamic therapy (PDT) has made remarkable progress. Targeted delivery of PSs is of great significance for enhancing therapeutic efficiency, decreasing the dosage, and reducing systemic toxicity during PDT. The development of PSs that can be specifically delivered to the subcellular organelle is still an attractive and challenging work. Herein, we synthesize a series of azide-modified corrole phosphorus and gallium complex PSs, in which phosphorus corrole 2-P could not only precisely target the endoplasmic reticulum (ER) with a Pearson correlation coefficient (PCC) up to 0.92 but also possesses the highest singlet oxygen quantum yields (ΦΔ = 0.75). This renders it remarkable PDT activity at a very low dosage (IC50 = 23 nM) towards HepG2 tumor cell line while ablating solid tumors in vivo with excellent biosecurity. Furthermore, 2-P exhibits intense red fluorescence (ΦF = 0.25), outstanding photostability, and a large Stokes shift (190 nm), making it a promising fluorescent probe for ER. This study provides a clinically potential photosensitizer for cancer photodynamic therapy and a promising ER fluorescent probe for bioimaging.

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.