HDAC2 promotes autophagy-associated HCC malignant progression by transcriptionally activating LAPTM4B.

Hepatocellular carcinoma (HCC) is a significant global health challenge. The activation of autophagy plays an essential role in promoting the proliferation and survival of cancer cells. However, the upstream regulatory network and mechanisms governing autophagy in HCC remain unclear. This study demonstrated that histone deacetylase 2 (HDAC2) regulates autophagy in HCC. Its expression was elevated in HCC tissues, and high HDAC2 expression was strongly associated with poor prognosis in individuals with HCC. Integrated in vitro and in vivo investigations confirmed that HDAC2 promotes autophagy and autophagy-related malignant progression in HCC. Mechanistically, HDAC2 bound specifically to the lysosome-associated protein transmembrane 4-ß (LAPTM4B) promoter at four distinct binding sites, enhancing its transcriptional activation and driving autophagy-related malignant progression in HCC. These findings establish LAPTM4B as a direct target gene of HDAC2. Furthermore, the selective inhibitor of HDAC2 effectively alleviated the malignant development of HCC. In addition, multivariate Cox regression analysis of 105 human HCC samples revealed that HDAC2 expression is an independent predictor of HCC prognosis. This study underscores the crucial role of the HDAC2-LAPTM4B axis in regulating autophagy in the malignant evolution of HCC and highlights the potential of targeting HDAC2 to prevent and halt the malignant progression of HCC.

Optimization of Mg-Al Layered Double Hydroxide Film Preparation and Corrosion Resistance Study on AZ91D Mg Alloy by Multivariate Polynomial Regression Fitting.

Layered double hydroxide (LDH) films have received extensive attention for their unique physical barrier function and ion exchange properties, which make them promising candidates for corrosion protection of magnesium alloys. In this paper, we used the multiple polynomial regression fitting method to establish a regression equation for the electrochemical corrosion resistance with the reaction temperature (T), pH, and reaction time (t) of the Mg-Al LDH film on the AZ91D magnesium alloy. The goodness of fit, confidence, and residual analyses confirmed the high accuracy of the model equation. According to the calculation using the fmincon function, the best corrosion resistance of the prepared samples could be achieved when the parameters are T = 135 °C, pH = 12.0, and t = 15 h. Then, the experimental results showed that the corrosion current density (Icorr) of the obtained LDH film under the above conditions could be 1.07 × 10-7 A/cm2, approximately 3 orders of magnitude lower than the magnesium alloy substrate, after immersion in a 3.5 wt % NaCl solution for 180 h, the surface structure of the LDH film did not change significantly, and the Icorr was still 2 orders of magnitude higher than that of the magnesium alloy substrate. Hence, a synergistic effect equation for the reaction temperature, pH, and reaction time on the corrosion resistance of the LDH film on a magnesium alloy surface prepared by the hydrothermal method was obtained. Moreover, using this equation, we obtained an LDH film with good corrosion resistance and durability, providing theoretical guidance for optimizing the process of preparing the LDH film by the hydrothermal method in practical applications.

Nanomaterials Boost CAR-T Therapy for Solid Tumors.

T cell engineering, particularly via chimeric antigen receptor (CAR) modifications for enhancing tumor specificity, has shown efficacy in treating hematologic malignancies. The extension of CAR-T cell therapy to solid tumors, however, is impeded by several challenges: The absence of tumor-specific antigens, antigen heterogeneity, a complex immunosuppressive tumor microenvironment, and physical barriers to cell infiltration. Additionally, limitations in CAR-T cell manufacturing capacity and the high costs associated with these therapies restrict their widespread application. The integration of nanomaterials into CAR-T cell production and application offers a promising avenue to mitigate these challenges. Utilizing nanomaterials in the production of CAR-T cells can decrease product variability and lower production expenses, positively impacting the targeting and persistence of CAR-T cells in treatment and minimizing adverse effects. This review comprehensively evaluates the use of various nanomaterials in the production of CAR-T cells, genetic modification, and in vivo delivery. It discusses their underlying mechanisms and potential for clinical application, with a focus on improving specificity and safety in CAR-T cell therapy.

Unleashing the power of immune checkpoints: Post-translational modification of novel molecules and clinical applications.

Immune checkpoint molecules play a pivotal role in the initiation, regulation, and termination of immune responses. Tumor cells exploit these checkpoints to dampen immune cell function, facilitating immune evasion. Clinical interventions target this mechanism by obstructing the binding of immune checkpoints to their ligands, thereby restoring the anti-tumor capabilities of immune cells. Notably, therapies centered on immune checkpoint inhibitors, particularly PD-1/PD-L1 and CTLA-4 blocking antibodies, have demonstrated significant clinical promise. However, a considerable portion of patients still encounter suboptimal efficacy and develop resistance. Recent years have witnessed an exponential surge in preclinical and clinical trials investigating novel immune checkpoint molecules such as TIM3, LAG3, TIGIT, NKG2D, and CD47, along with their respective ligands. The processes governing immune checkpoint molecules, from their synthesis to transmembrane deployment, interaction with ligands, and eventual degradation, are intricately tied to post-translational modifications. These modifications encompass glycosylation, phosphorylation, ubiquitination, neddylation, SUMOylation, palmitoylation, and ectodomain shedding. This discussion proceeds to provide a concise overview of the structural characteristics of several novel immune checkpoints and their ligands. Additionally, it outlines the regulatory mechanisms governed by post-translational modifications, offering insights into their potential clinical applications in immune checkpoint blockade.

Renal cell carcinoma and venous tumor thrombus: predicting sarcomatoid dedifferentiation through preoperative IVIM-based MR imaging.

PURPOSE: To evaluate the value of preoperative intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) and conventional MRI indicators in identifying sarcomatoid dedifferentiation in renal cell carcinoma (RCC) and tumor thrombus. METHODS: From September 2016 to April 2023, consecutive patients with RCC and tumor thrombus who received routine MRI examination and IVIM-DWI before radical resection were enrolled prospectively. Kaplan-Meier method with log-rank test was used to calculate and compare the survival probability. The preoperative imaging features were analyzed. Univariate and multivariable logistic regression analyses were employed to identify independent predictors of sarcomatoid dedifferentiation. The predictive ability was evaluated by receiver operating characteristic (ROC) curves. RESULTS: Twenty-two patients (15.3%) of the 144 patients in the training set (median age, 58.0 years [IQR, 52.0-65.0 years]; 108 men) and 11 patients (22.4%) of the 49 patients in the test set (median age, 58.0 years [IQR, 53.0-63.0 years]; 38 men) had sarcomatoid dedifferentiated tumors. Patients with sarcomatoid-differentiated tumors had poor progress-free survival in the training set and test set (P < 0.001 and P = 0.007). f value (P = 0.011), mN stage (P = 0.007), and necrosis (P = 0.041) were independent predictors for predicting sarcomatoid dedifferentiation in the training set. The model combining conventional MRI features and f value had AUCs of 0.832 (95% CI 0.755-0.909) and 0.825 (95% CI 0.702-0.948) in predicting sarcomatoid dedifferentiation in the training set and test set. CONCLUSION: It is feasible to preoperatively identify sarcomatoid dedifferentiation based on IVIM-DWI and conventional MR imaging indicators.

Intravoxel Incoherent Motion Diffusion-Weighted MR Imaging and Venous Tumor Thrombus Consistency in Renal Cell Carcinoma.

BACKGROUND: Venous tumor thrombus (VTT) consistency of renal cell carcinoma (RCC) is an important consideration in nephrectomy plus thrombectomy. However, evaluation of VTT consistency through preoperative MR imaging is lacking. PURPOSE: To evaluate VTT consistency of RCC through intravoxel incoherent motion-diffusion weighted imaging (IVIM-DWI) derived parameters (Dt , Dp , f, and ADC) and the apparent diffusion coefficient (ADC) value. STUDY TYPE: Retrospective. POPULATION: One hundred and nineteen patients (aged 55.8 ± 11.5 years, 85 male) with histologically-proven RCC and VTT who underwent radical resection. FIELD STRENGTH/SEQUENCES: 3.0-T; two-dimensional single-shot diffusion-weighted echo planar imaging sequence at 9 b-values (0-800 s/mm2 ). ASSESSMENT: IVIM parameters and ADC values of the primary tumor and the VTT were calculated. The VTT consistency (friable vs. solid) was determined through intraoperative findings of two urologists. The accuracy of VTT consistency classification based on the individual IVIM parameters of primary tumors and of VTT, and based on models combining parameters, was assessed. Type of operation, intra-operative blood loss, and operation length were recorded. STATISTICAL TESTS: Shapiro-Wilk test; Mann-Whitney U test; Student's t-test; Chi-square test; Receiver operating characteristic (ROC) analysis. Statistical significance level was P < 0.05. RESULTS: Of the enrolled 119 patients, 33 patients (27.7%) had friable VTT. Patients with friable VTT were significantly more likely to experience open surgery, have significantly more intraoperative blood loss, and significantly longer operative duration. The area under the ROC curve (AUC) values of Dt of the primary tumor and VTT in classifying VTT consistency were 0.758 (95% CI 0.671-0.832) and 0.712 (95% CI 0.622-0.792), respectively. The AUC value of the model combining Dp and Dt of VTT was 0.800 (95% CI 0.717-0.868). Furthermore, the AUC of the model combining Dp and Dt of VTT and Dt of the primary tumor was 0.886 (95% CI 0.814-0.937). CONCLUSION: IVIM-derived parameters had the potential to predict VTT consistency of RCC. EVIDENCE LEVEL: 3 Technical Efficacy: Stage 2.

The Overlap Subgroup of Functional Dyspepsia Exhibits More Severely Impaired Gastric and Autonomic Functions.

GOALS: A combination of multiple tests was introduced to noninvasively investigate the differences in pathophysiologies among functional dyspepsia (FD) subgroups, including postprandial distress syndrome (PDS), epigastric pain syndrome (EPS), and overlap. BACKGROUND: It has not been extensively evaluated whether different pathophysiologies are involved in FD subgroups. STUDY: This multicenter study included 364 FD patients fulfilling Rome IV criteria and 47 healthy controls. A combined noninvasive gastric and autonomic function test was performed: The electrogastrogram and electrocardiogram were recorded simultaneously in the fasting state and after a drink test. Symptoms after drinking were recorded using visual analog scale. RESULTS: (1) Compared with HC, FD patients showed a decreased maximum tolerable volume (MTV) ( P <0.01) and percentage of normal gastric slow waves [normal gastric slow waves (%NSW)] ( P <0.01), and increased postdrinking symptoms, anxiety ( P <0.01), and depression ( P <0.01). The drink reduced %NSW in both FD patients and HC; however, the effect was more potent in patients. (2) The PDS and overlap groups displayed a reduced MTV ( P <0.05). The overlap group exhibited a higher symptom score at 30 minutes after drinking, and higher anxiety and depression scores, and a higher sympathovagal ratio than the EPS ( P <0.05 for all) and PDS ( P <0.01 for all). (3) In the PDS subgroup, the MTV, postprandial sympathovagal ratio, and depression were associated with the overall dyspepsia symptom scale (DSS, P =0.034, 0.021, 0.043, respectively). No significant associations were found in the other 2 subgroups. CONCLUSIONS: The combination of multiple tests can detect pathophysiological abnormities in FD patients. Overall, patients with overlap symptoms display more severe pathophysiologies.