Postoperative lenvatinib + PD-1 blockade reduces early tumor recurrence in hepatocellular carcinoma with microvascular invasion (Barcelona Clinic Liver Cancer stage 0 or A): a propensity score matching analysis.

BACKGROUND: This study aimed to determine the effectiveness of postoperative adjuvant lenvatinib + PD-1 blockade for patients with early-stage hepatocellular carcinoma (HCC) with microvascular invasion (MVI). METHODS: A total of 393 patients with HCC (Barcelona Clinic Liver Cancer stage 0 or A) who underwent curative hepatectomy with histopathologically proven MVI were enrolled according to the inclusion and exclusion criteria and assigned to 2 groups: surgery alone (surgery-alone group) and surgery with lenvatinib and PD-1 blockade (surgery + lenvatinib + PD-1 group) to compare recurrence-free survival (RFS), overall survival (OS), recurrence type, and annual recurrence rate after the application of propensity score matching (PSM). The Cox proportional hazards model was used for univariate and multivariate analyses. RESULTS: Overall, 99 matched pairs were selected using PSM. Patients in the surgery + lenvatinib + PD-1 group had significantly higher 3-year RFS rates (76.8%, 65.7%, and 53.5%) than patients in the surgery-alone group (60.6%, 45.5%, and 37.4%) (P = .012). The 2 groups showed no significant difference in recurrence types and OS. Surgery alone, MVI-M2, and alpha-fetoprotein of ≥200 ng/mL were independent risk factors for RFS (P < .05), and history of alcohol use disorder was an independent risk factor for OS (P = .022). CONCLUSION: Postoperative lenvatinib + PD-1 blockade improved the RFS in patients with HCC with MVI and was particularly beneficial for specific individuals.

Revisiting the chaperonin T-complex protein-1 ring complex in human health and disease: A proteostasis modulator and beyond.

BACKGROUND: Disrupted protein homeostasis (proteostasis) has been demonstrated to facilitate the progression of various diseases. The cytosolic T-complex protein-1 ring complex (TRiC/CCT) was discovered to be a critical player in orchestrating proteostasis by folding eukaryotic proteins, guiding intracellular localisation and suppressing protein aggregation. Intensive investigations of TRiC/CCT in different fields have improved the understanding of its role and molecular mechanism in multiple physiological and pathological processes. MAIN BODY: In this review, we embark on a journey through the dynamic protein folding cycle of TRiC/CCT, unraveling the intricate mechanisms of its substrate selection, recognition, and intriguing folding and assembly processes. In addition to discussing the critical role of TRiC/CCT in maintaining proteostasis, we detail its involvement in cell cycle regulation, apoptosis, autophagy, metabolic control, adaptive immunity and signal transduction processes. Furthermore, we meticulously catalogue a compendium of TRiC-associated diseases, such as neuropathies, cardiovascular diseases and various malignancies. Specifically, we report the roles and molecular mechanisms of TRiC/CCT in regulating cancer formation and progression. Finally, we discuss unresolved issues in TRiC/CCT research, highlighting the efforts required for translation to clinical applications, such as diagnosis and treatment. CONCLUSION: This review aims to provide a comprehensive view of TRiC/CCT for researchers to inspire further investigations and explorations of potential translational possibilities.

The Role of Nuclear Receptors in the Pathogenesis and Treatment of Non-alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is a global health burden closely linked to insulin resistance, obesity, and type 2 diabetes. The complex pathophysiology of NAFLD involves multiple cellular pathways and molecular factors. Nuclear receptors (NRs) have emerged as crucial regulators of lipid metabolism and inflammation in NAFLD, offering potential therapeutic targets for NAFLD. Targeting PPARs and FXRs has shown promise in ameliorating NAFLD symptoms and halting disease progression. However, further investigation is needed to address side effects and personalize therapy approaches. This review summarizes the current understanding of the involvement of NRs in the pathogenesis of NAFLD and explores their therapeutic potential. We discuss the role of several NRs in modulating lipid homeostasis in the liver, including peroxisome proliferator-activated receptors (PPARs), liver X receptors (LXRs), farnesoid X receptors (FXRs), REV-ERB, hepatocyte nuclear factor 4α (HNF4α), constitutive androstane receptor (CAR) and pregnane X receptor (PXR).The expanding knowledge of NRs in NAFLD offers new avenues for targeted therapies, necessitating exploration of novel treatment strategies and optimization of existing approaches to combat this increasingly prevalent disease.

Anatomical Resection Improved the Outcome of Intrahepatic Cholangiocarcinoma: A Propensity Score Matching Analysis of a Retrospective Cohort.

Background: Intrahepatic cholangiocarcinoma (ICC) is the second most common liver malignancy after hepatocellular carcinoma (HCC), with a dismal prognosis and high heterogeneity. The oncological advantages of anatomical resection (AR) and nonanatomical resection (NAR) in HCC have been studied, but surgical strategies for ICC remain controversial with insufficient investigations. Materials and Methods: From Jan 2013 to Dec 2016, 3880 consecutive patients were retrospectively reviewed from a single center. Patients with ICC undergoing AR or NAR have been enrolled according to inclusion and exclusion criteria. Propensity score matching (PSM) analysis was performed between two groups with a 1 : 1 ratio. The primary endpoint was overall survival (OS), and the secondary endpoints included disease-free survival (DFS), intraoperative patterns, postoperative morbidity, mortality, complications and recurrence. A prognostic nomogram was developed by a multivariate Cox proportion hazard model. Results: After PSM, 99 paired cases were selected from 276 patients enrolled in this study. Patients in the AR group achieved better 1-, 3-, and 5-year OS (70%, 46%, and 34%, respectively) and DFS (61%, 21%, and 10%, respectively) than patients in the NAR group with statistical significance after PSM analysis. The postoperative complications and recurrence patterns were comparable between the two groups. Multivariate analysis identified NAR, tumor size >5 cm, multiple tumors, and poor differentiation as independent risk factors for OS (p < 0.05). Selected patients can benefit most from AR, according to subgroup analysis. A prognostic nomogram based on six independent risk factors for OS and factors with clinical significance was constructed to predict OS in ICC patients. Conclusion: AR improved the long-term survival of ICC with comparable postoperative complications and similar recurrence patterns. AR is suggested in ICC patients with sufficient remnant liver volume. In addition to surgery strategy, malignant characteristics of tumors are risk factors for ICC prognosis.

Discoidin domain receptor 1 promotes hepatocellular carcinoma progression through modulation of SLC1A5 and the mTORC1 signaling pathway.

PURPOSE: Hepatocellular carcinoma (HCC) is one of the most common cancers in the world with a high mortality rate. Receptor tyrosine kinases play important roles in the occurrence and development of various cancers. Discoid protein domain receptor 1 (DDR1) is a special type of transmembrane receptor tyrosine kinase. Here, we show that the expression of DDR1 is significantly increased in HCC and is related to a poor clinical prognosis. METHODS: The expression of DDR1 in HCC cell lines and primary HCC specimens was evaluated using Western blotting and immunohistochemistry. A correlation between DDR1 and SLC1A5 expression was also investigated in primary HCC specimens. Cell proliferation was evaluated using in vitro CCK8 and colony formation assays. Gene knock-down and overexpression assays, CHX, NH4CL and Mg132 interference tests and immunoprecipitation, as well as nude mouse xenograft models were used to assess the mechanism by which DDR1 promotes tumorigenesis in vitro and in vivo. RESULTS: We found that DDR1 promotes the proliferation of HCC cells and accelerates the growth of HCC tumor xenografts, while DDR1 downregulation had the opposite effect. We also found that loss or gain of DDR1 expression affected HCC cell cycle progression. Mechanistically, we found that DDR1 interacts with SLC1A5, which belongs to the solute carrier (SLC) family of transporters, and regulates its stability, thereby affecting the mTORC1 signaling pathway. In addition, we found that SLC1A5 regulation by DDR1 can be restored by lysosome inhibitors. We also found that DDR1 is highly expressed in HCC tissues and that increased DDR1 expression predicts a shorter overall survival (OS) time. We additionally found that the expression of SLC1A5 was positively correlated with that of DDR1. Together, our data indicate that DDR1 acts as a tumor-promoting factor that can control HCC cell proliferation and cell cycle progression by stabilizing SLC1A5 in a lysosome-dependent way. CONCLUSIONS: Our study reveals a new mechanism by which DDR1 plays a liver cancer-promoting role. We also found that DDR1 expression serves as an independent prognostic marker, and that DDR1 and SLC1A5 expression levels are positively correlated in clinical samples. Our findings provide a new perspective for understanding HCC development and offers new targets for the treatment and management of HCC.

Machine learning-based multiparametric traditional multislice computed tomography radiomics for improving the discrimination of parotid neoplasms.

Characterization of parotid tumors is important for treatment planning and prognosis, and parotid tumor discrimination has recently been developed at the molecular level. The aim of the present study was to establish a machine learning (ML) predictive model based on multiparametric traditional multislice CT (MSCT) radiomic and clinical data analysis to improve the accuracy of differentiation among pleomorphic adenoma (PA), Warthin tumor (WT) and parotid carcinoma (PCa). A total of 345 patients (200 with WT, 91 with PA and 54 with PCa) with pathologically confirmed parotid tumors were retrospectively enrolled from five independent institutions between January 2010 and May 2019. A total of 273 patients recruited from institutions 1, 2 and 3 were randomly assigned to the training model; the independent validation set consisted of 72 patients treated at institutions 1, 4 and 5. Data were investigated using a linear discriminant analysis-based ML classifier. Feature selection and dimension reduction were conducted using reproducibility testing and a wrapper method. The diagnostic accuracy of the predictive model was compared with histopathological findings as reference results. This classifier achieved a satisfactory performance for the discrimination of PA, WT and PCa, with a total accuracy of 82.1% in the training cohort and 80.5% in the validation cohort. In conclusion, ML-based multiparametric traditional MSCT radiomics can improve the accuracy of differentiation among PA, WT and PCa. The findings of the present study should be validated by multicenter prospective studies using completely independent external data.

GSK3ß mediates the carcinogenic effect of HPV16 in cervical cancer.

Cervical cancer is one of the most prevalent and fatal cancers among women and infection of the human papillomavirus (HPV) is the most important risk factor. This study investigated how HPV16 regulated GSK3ß expression and function to promote cervical cancers. The expression of GSK3ß was analyzed by quantitative PCR and western blot. The proliferation, invasion, and clonogenic survival of cells with different E6/E7 levels were measured by MTT, transwell invasion assays, and soft agar colony-forming assays, respectively. The levels of GSK3ß were correlated with the copy numbers and expression levels of HPV16 E6/E7 genes. HPV16 E6/E7 genes regulated GSK3ß transcription through an element located in the promoter 85 and 250 base pairs upstream of the transcription start site. The abilities of cell proliferation, invasion, and clonogenic survival were increased in C33A cells by ectopic HPV16 E6/E7 and decreased in CaSki cells by knocking down HPV16 E6/E7 levels. Meanwhile, LiCl increased GSK3ß transcript levels and the proliferation of CaSki cells in a HPV16-dependent manner. These data indicated that GSK3ß may participated in HPV16 mediated deregulation of wnt/ß-catenin and other signaling pathways promoting the progression and invasion of cervical cancers.