Fe-doped Cu-based bimetallic metal-organic frameworks as nanoscale microwave sensitizers for enhancing microwave thermal and dynamic therapy for hepatocellular carcinoma.

Microwave ablation (MWA) is recognized as a novel treatment modality that can kill tumor cells by heating the ions and polar molecules in these cells through high-speed rotation and friction. However, the size and location of the tumor affect the effective ablation range of microwave hyperthermia, resulting in residual tumor tissue and a high recurrence rate. Due to their tunable porous structure and high specific surface area, metal-organic frameworks (MOFs) can serve as microwave sensitizers, promoting microwave energy conversion owing to ion collisions in the porous structure of the MOFs. Moreover, iron-based compounds are known to possess peroxidase-like catalytic activity. Therefore, Fe-doped Cu bimetallic MOFs (FCMs) were prepared through a hydrothermal process. These FCM nanoparticles not only increased the efficiency of microwave-thermal energy conversion as microwave sensitizers but also promoted the generation of reactive oxygen species (ROS) by consuming glutathione (GSH) and promoted the Fenton reaction to enhance microwave dynamic therapy (MDT). The in vitro and in vivo results showed that the combination of MWA and MDT treatment effectively destroyed tumor tissues via microwave irradiation without inducing significant side effects on normal tissues. This study provides a new approach for the combined application of MOFs and microwave ablation, demonstrating excellent potential for future applications.

CRIP1 suppresses BBOX1-mediated carnitine metabolism to promote stemness in hepatocellular carcinoma.

Carnitine metabolism is thought to be negatively correlated with the progression of hepatocellular carcinoma (HCC) and the specific molecular mechanism is yet to be fully elucidated. Here, we report that little characterized cysteine-rich protein 1 (CRIP1) is upregulated in HCC and associated with poor prognosis. Moreover, CRIP1 promoted HCC cancer stem-like properties by downregulating carnitine energy metabolism. Mechanistically, CRIP1 interacted with BBOX1 and the E3 ligase STUB1, promoting BBOX1 ubiquitination and proteasomal degradation, and leading to the downregulation of carnitine. BBOX1 ubiquitination at lysine 240 is required for CRIP1-mediated control of carnitine metabolism and cancer stem-like properties. Further, our data showed that acetylcarnitine downregulation in CRIP1-overexpressing cells decreased beta-catenin acetylation and promoted nuclear accumulation of beta-catenin, thus facilitating cancer stem-like properties. Clinically, patients with higher CRIP1 protein levels had lower BBOX1 levels but higher nuclear beta-catenin levels in HCC tissues. Together, our findings identify CRIP1 as novel upstream control factor for carnitine metabolism and cancer stem-like properties, suggesting targeting of the CRIP1/BBOX1/ß-catenin axis as a promising strategy for HCC treatment.

ABCC5 facilitates the acquired resistance of sorafenib through the inhibition of SLC7A11-induced ferroptosis in hepatocellular carcinoma.

Sorafenib is a first-line molecular-target drug for advanced hepatocellular carcinoma (HCC), and reducing sorafenib resistance is an important issue to be resolved for the clinical treatment of HCC. In the current study, we identified that ABCC5 is a critical regulator and a promising therapeutic target of acquired sorafenib resistance in human hepatocellular carcinoma cells. The expression of ABCC5 was dramatically induced in sorafenib-resistant HCC cells and was remarkably associated with poor clinical prognoses. The down-regulation of ABCC5 expression could significantly reduce the resistance of sorafenib to HCC cells. Importantly, activation of PI3K/AKT/NRF2 axis was essential for sorafenib to induce ABCC5 expression. ABCC5 increased intracellular glutathione (GSH) and attenuated lipid peroxidation accumulation by stabilizing SLC7A11 protein, which inhibited ferroptosis. Additionally, the inhibition of ABCC5 enhanced the anti-cancer activity of sorafenib in vitro and in vivo. These findings demonstrate a novel molecular mechanism of acquired sorafenib resistance and also suggest that ABCC5 is a new regulator of ferroptosis in HCC cells.

MYEOV increases HES1 expression and promotes pancreatic cancer progression by enhancing SOX9 transactivity.

Emerging evidence indicates that myeloma overexpressed (MYEOV) is an oncogene and plays crucial roles in multiple human cancers. However, its roles in the development of pancreatic ductal adenocarcinoma (PDAC) remain elusive. Here, we provide evidence of essential roles of MYEOV in the development and progression of PDAC. In tumor specimens derived from pancreatic cancer patients, MYEOV was overexpressed and associated with poor prognosis. In addition, MYEOV expression in PDAC was upregulated through promoter hypomethylation. MYEOV depletion impaired metastatic ability and proliferation of PDAC cells both in vitro and in vivo, whereas its overexpression had the opposite effect. Mechanistic investigations revealed that MYEOV interacted with SRY-Box Transcription Factor 9 (SOX9), a well-known oncogenic transcription factor in PDAC. This interaction occurred mainly in the nuclei of PDAC cells and increased transcriptional activity of SOX9. Furthermore, MYEOV promoted the expression of Hairy and enhancer of split homolog-1 (HES1), a SOX9 target gene, by enhancing SOX9 DNA-binding ability to the HES1 enhancer without affecting the protein level and subcellular localization of SOX9. HES1 knockdown partly abrogated the oncogenic effect of MYEOV. Our findings suggest that MYEOV could be a potential prognostic biomarker and therapeutic target for PDAC.

Correction to: Pre-metastatic niche triggers SDF-1/CXCR4 axis and promotes organ colonisation by hepatocellular circulating tumour cells via downregulation of Prrx1.

An amendment to this paper has been published and can be accessed via the original article.

Pre-metastatic niche triggers SDF-1/CXCR4 axis and promotes organ colonisation by hepatocellular circulating tumour cells via downregulation of Prrx1.

BACKGROUND: Circulating tumour cells (CTCs), especially mesenchymal CTCs, are important determinants of metastasis, which leads to most recurrence and mortality in hepatocellular carcinoma (HCC). However, little is known about the underlying mechanisms of CTC colonisation in pre-metastatic niches. METHODS: Detection and classification of CTCs in patients were performed using the CanPatrol™ system. A lentiviral vector expressing Prrx1-targeting shRNA was constructed to generate a stable HCC cell line with low expression of Prrx1. The effect of Prrx1 knockdown on stemness, migration, and drug resistance of the cell line was assessed, including involvement of SDF-1/CXCR4 signalling. Promising clinical applications of an inhibitor of STAT3 tyrosine phosphorylation, C188-9, and specific blockade with CXCR4 antibody were explored. RESULTS: The number of mesenchymal CTCs in blood was closely associated with tumour recurrence or metastasis. Pre-metastatic niche-derived SDF-1 could downregulate Prrx1, which induced the stemness, drug resistance, and increased expression of CXCR4 in HCC cells through the STAT3 pathway in vitro. In vivo, mice bearing tumours of Prrx1 low-expressing cells had significantly shorter survival. In xenograft tumours and clinical samples, loss of Prrx1 was negatively correlated with increased expression of CXCR4 in lung metastatic sites compared with that in the primary foci. CONCLUSIONS: These findings demonstrate that decreased expression of Prrx1 stimulates SDF-1/CXCR4 signalling and contributes to organ colonisation with blood CTCs in HCC. STAT3 inhibition and specific blockade of CXCR4 have clinical potential as therapeutics for eliminating organ metastasis in advanced HCC.

Multi-sensor Fusion Road Friction Coefficient Estimation During Steering with Lyapunov Method.

The road friction coefficient is a key parameter for autonomous vehicles and vehicle dynamic control. With the development of autonomous vehicles, increasingly, more environmental perception sensors are being installed on vehicles, which means that more information can be used to estimate the road friction coefficient. In this paper, a nonlinear observer aided by vehicle lateral displacement information for estimating the road friction coefficient is proposed. First, the tire brush model is modified to describe the tire characteristics more precisely in high friction conditions using tire test data. Then, on the basis of vehicle dynamics and a kinematic model, a nonlinear observer is designed, and the self-aligning torque of the wheel, lateral acceleration, and vehicle lateral displacement are used to estimate the road friction coefficient during steering. Finally, slalom tests and DLC (Double Line Change) tests in high friction conditions are conducted to verify the proposed estimation algorithm. Test results showed that the proposed method performs well during steering and the estimated road friction coefficient converges to the reference value rapidly.

IMU-Based Automated Vehicle Slip Angle and Attitude Estimation Aided by Vehicle Dynamics.

The slip angle and attitude are vital for automated driving. In this paper, a systematic inertial measurement unit (IMU)-based vehicle slip angle and attitude estimation method aided by vehicle dynamics is proposed. This method can estimate the slip angle and attitude simultaneously and autonomously. With accurate attitude, the slip angle can be estimated precisely even though the vehicle dynamic model (VDM)-based velocity estimator diverges for a short time. First, the longitudinal velocity, pitch angle, lateral velocity, and roll angle were estimated by two estimators based on VDM considering the lever arm between the IMU and rotation center. When this information was in high fidelity, it was applied to aid the IMU-based slip angle and attitude estimators to eliminate the accumulated error correctly. Since there is a time delay in detecting the abnormal estimation results from VDM-based estimators during critical steering, a novel delay estimation and prediction structure was proposed to avoid the outlier feedback from vehicle dynamics estimators for the IMU-based slip angle and attitude estimators. Finally, the proposed estimation method was validated under large lateral excitation experimental tests including double lane change (DLC) and slalom maneuvers.

Diagnostic Value of Different Phenotype Circulating Tumor Cells in Hepatocellular Carcinoma.

BACKGROUND: A growing body of research indicates that the monitoring of circulating tumor cells (CTCs) may have great significance to the diagnosis of malignant tumors, assessment of condition, selection of treatment methods, and evaluation of prognosis and has a broad range of potential applications. However, the value of CTCs with different phenotypes in the diagnosis of hepatocellular carcinoma (HCC) and assessment of patient condition remains unclear. METHODS: We collected 5 ml of peripheral blood from 176 patients who were found to have space-occupying lesions in the liver via B-ultrasound diagnosis at Zhujiang Hospital affiliated with Southern Medical University between August 2015 and October 2017 and used CanPatrol™ CTCs assay technology to isolate and count CTCs with different phenotypes in the patients' peripheral blood. This allowed analysis of the value of CTCs with different phenotypes in the diagnosis of HCC and assessment of BCLC stage. RESULTS: We used CanPatrol™ CTCs assay technology to isolate different types of CTCs: epithelial CTCs (only stained for epithelial markers), mesenchymal CTCs (only stained for mesenchymal markers), mixed CTCs (stained for epithelial markers and mesenchymal markers), and total CTCs (all of the foregoing CTC phenotypes). Of 176 observed patients, 6 patients were finally diagnosed as other malignant tumor liver metastasis, 113 were diagnosed as having hepatocellular carcinoma, and 57 were diagnosed as having nonmalignant liver diseases. Furthermore, we intend to evaluate the diagnostic value of different phenotype CTCs count in discrimination between hepatocellular carcinoma and nonmalignant liver diseases. We found that CTCs of all types were significantly more numerous in the peripheral blood of the HCC group patients than in the NLD group patients (P < 0.05). Furthermore, of the different types of CTCs, total CTCs had the greatest diagnostic value (AUC 0.774; 95% CI, 0.704-0.834). A further discovery was that the AUC values for total CTCs, AFP, and a combined model (combined use of total CTCs and AFP) were 0.774 (95%CI, 0.704-0.834), 0.669 (95%CI, 0.587-0.750), and 0.821 (95%CI, 0.756-0.886). Late-stage HCC patients (BCLC stage B-C) had a higher peripheral blood mesenchymal CTC count than early-stage patients (BCLC stage 0-A) (median:1 vs 0), and mesenchymal CTCs ≥ 1 was the cut-off value for the diagnosis of BCLC stage in HCC patients (sensitivity: 66.67%, specificity: 59.46%, Youden index: 0.26). CONCLUSIONS: Total CTCs are more effective than AFP in the diagnosis of HCC; combined use of total CTCs and AFP can enhance the sensitivity of HCC diagnosis.