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Abstract Background The escalating prevalence of metabolic diseases has led to a rapid increase in non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (NASH-HCC). While oxaliplatin (OXA)-based hepatic arterial infusion chemotherapy (HAIC) has shown promise in advanced-stage HCC patients, its efficacy in NASH-HCC remains uncertain. This study aims to assess the effectiveness of OXA-based HAIC and elucidate the mechanisms underlying OXA resistance in NASH-HCC. Methods The key lncRNAs were screened through RNA-seq analysis of NASH/non-NASH and OXA-sensitive/OXA-resistant (OXA-S/R) HCC tissues. The biological functions of the lnc-OXAR (OXA resistance–related lncRNA in NASH-HCC) in NASH-HCC were verified through a series of in vitro and in vivo experiments. The molecular mechanism of lnc-OXAR was elucidated by fluorescence in situ hybridization, immunoprecipitation-mass spectrometry (FISH), Immunoprecipitation-Mass Spectrometry (IP-MS), RNA pulldown, RNA immunoprecipitation (RIP), methylated RNA immunoprecipitation sequencing (MeRIP-Seq) and a dual-luciferase reporter assay. Results NASH-HCC exhibited reduced responsiveness to OXA-based HAIC compared to non-NASH HCC. We identified and validated a novel transcript namedlnc-OXAR, which played a crucial role in conferring OXA resistance to NASH-HCC. Inhibition of lnc-OXAR suppressed HCC cell growth and restored OXA sensitivity both in NASH-HCC mouse models and in vitro. Mechanistically, lnc-OXAR recruited Ku70 and cystatin A (CSTA), preventing Ku70 degradation and facilitating DNA double-strand break (DSB) repair, thereby promoting OXA resistance in NASH-HCC. Additionally, WTAP-mediated m6A modification enhanced the stability of lnc-OXAR in an IGF2BP2-dependent manner. Notably, silencing lnc-OXAR significantly enhanced the response to OXA in patient-derived xenograft (PDX) models derived from NASH-HCC. Conclusions The reduced responsiveness of NASH-HCC to OXA treatment can be attributed to the upregulation of lnc-OXAR. Our findings provide a rationale for stratifying HCC patients undergoing OXA-based HAIC based on etiology. Lnc-OXAR holds promise as a novel target for overcoming OXA resistance in NASH-HCC and improving prognosis.

Abstract The constrained effectiveness of photodynamic therapy (PDT) has impeded its widespread use in clinical practice. Urgent efforts are needed to address the shortcomings faced in photodynamic therapy, such as photosensitizer toxicity, short half‐life, and limited action range of reactive oxygen species (ROS). In this study, a biodegradable copolymer nanoamplifier is reported that contains ruthenium complex (Ru‐complex) as photosensitizer (PS) and rhenium complex (Re‐complex) as carbon monoxide (CO)‐release molecule (CORM). The well‐designed nanoamplifier brings PS and CORM into close spatial proximity, significantly promotes the utilization of light‐stimulated reactive oxygen species (ROS), and cascaded amplifying CO release, thus enabling an enhanced synergistic effect of PDT and gas therapy for cancer treatment. Moreover, owing to its intrinsic photodegradable nature, the nanoamplifier exhibits good tumor accumulation and penetration ability, and excellent biocompatibility in vivo. These findings suggest that the biodegradable cascaded nanoamplifiers pave the way for a synergistic and clinically viable integration of photodynamic and gas therapy.

Abstract Introduction Regorafenib remains the standard and widely used second‐line strategy for advanced hepatocellular carcinoma (HCC). There is still a lack of large‐scale multicenter real‐world evidence concerning the concurrent use of regorafenib with immune checkpoint inhibitors (ICI). This study aims to evaluate whether combining regorafenib with ICI provides greater clinical benefit than regorafenib monotherapy as second‐line therapy for advanced HCC under real‐world circumstances. Patients and Methods The study included 208 patients from five medical facilities. One hundred forty‐three patients received regorafenib plus ICI combination therapy, while 65 patients received regorafenib monotherapy. Propensity score matching (PSM) analysis was employed. Results The regorafenib plus ICI group demonstrated significantly higher objective response rate (24.3% vs. 10.3%, after PSM, p = 0.030) and disease control rate (79.4% vs. 50.0%, after PSM, p

Abstract Methytransferase-like proteins 9 (METTL9) has been characterized as an oncogene in several cancers, however, its role in hepatocellular carcinoma (HCC) remains unknown. Here, we investigated the function and molecular mechanism of METTL9 in HCC. We showed that METTL9 expression was elevated in HCC, and its high expression was associated with poor survival outcomes. Knockdown of METTL9 observed a significant inhibition of HCC cell viability, migration, and invasion both in vitro and in vivo. By contrast, METTL9 overexpression HCC cells obtained stronger abilities in cell proliferation and migration. Mechanistically, we discovered that METTL9 knockdown led to a reduction in the expression level of SLC7A11, a key suppressor of ferroptosis, in turn, promoted ferroptosis in HCC cells, impeding the progression of HCC. Moreover, we have proved that targeting METTL9 could significantly restrain the growth of HCC patient-derived xenograft (PDX). Our study established METTL9 as a critical role in promoting HCC development and provides a foundation for further investigation and potential therapeutic interventions targeting ferroptosis in HCC.

Abstract Background Non-homologous DNA end joining (NHEJ) is the predominant DNA double-strand break (DSB) repair pathway in human. However, the relationship between NHEJ pathway and hepatocellular carcinoma (HCC) is unclear. We aimed to explore the potential prognostic role of NHEJ genes and to develop an NHEJ-based prognosis signature for HCC. Methods Two cohorts from public database were incorporated into this study. The Kaplan–Meier curve, the Least absolute shrinkage and selection operator (LASSO) regression analysis, and Cox analyses were implemented to determine the prognostic genes. A NHEJ-related risk model was created and verified by independent cohorts. We derived enriched pathways between the high- and low-risk groups using Gene Set Enrichment Analysis (GSEA). CIBERSORT and microenvironment cell populations-counter algorithm were used to perform immune infiltration analysis. XRCC6 is a core NHEJ gene and immunohistochemistry (IHC) was further performed to elucidate the prognostic impact. In vitro proliferation assays were conducted to investigate the specific effect of XRCC6. Results A novel NHEJ-related risk model was developed based on 6 NHEJ genes and patients were divided into distinct risk groups according to the risk score. The high-risk group had a poorer survival than those in the low-risk group (P < 0.001). Meanwhile, an obvious discrepancy in the landscape of the immune microenvironment also indicated that distinct immune status might be a potential determinant affecting prognosis as well as immunotherapy reactiveness. High XRCC6 expression level associates with poor outcome in HCC. Moreover, XRCC6 could promote HCC cell proliferation in vitro. Conclusions In brief, this work reveals a novel NHEJ-related risk signature for prognostic evaluation of HCC patients, which may be a potential biomarker of HCC immunotherapy.

Abstract Background Hepatocellular carcinoma (HCC) cells undergo reprogramming of glucose metabolism to support uncontrolled proliferation, of which the intrinsic mechanism still merits further investigation. Although regulatory factor X6 (RFX6) is aberrantly expressed in different cancers, its precise role in cancer development remains ambiguous. Methods Microarrays of HCC tissues were employed to investigate the expression of RFX6 in tumour and adjacent non‐neoplastic tissues. Functional assays were employed to explore the role of RFX6 in HCC development. Chromatin immunoprecipitation, untargeted metabolome profiling and sequencing were performed to identify potential downstream genes and pathways regulated by RFX6. Metabolic assays were employed to investigate the effect of RFX6 on glycolysis in HCC cells. Bioinformatics databases were used to validate the above findings. Results HCC tissues exhibited elevated expression of RFX6. High RFX6 expression represented as an independent hazard factor correlated to poor prognosis in patients with HCC. RFX6 deficiency inhibited HCC development in vitro and in vivo, while its overexpression exerted opposite functions. Mechanistically, RFX6 bound to the promoter area of phosphoglycerate mutase 1 (PGAM1) and upregulated its expression. The increased PGAM1 protein levels enhanced glycolysis and further promoted the development of HCC. Conclusions RFX6 acted as a novel driver for HCC development by promoting aerobic glycolysis, disclosing the potential of the RFX6–PGAM1 axis for therapeutic targeting.

An innovative cascade predictor is presented in this study to forecast the state of recurrent neural networks (RNNs) with delayed output. This cascade predictor is a chain-structured observer, as opposed to the conventional single observer, and is made up of several sub-observers that individually estimate the state of the neurons at various periods. This new cascade predictor is more useful than the conventional single observer in predicting neural network states when the output delay is arbitrarily large but known. In contrast to examining the stability of error systems solely employing the Lyapunov–Krasovskii functional (LKF), several new global asymptotic stability standards are obtained by combining the application of the Linear Parameter Varying (LPV) approach, LKF and convex principle. Finally, a series of numerical simulations verify the efficacy of the obtained results.

This paper presents synchronization of mixed continuous-discrete complex network via impulse-quantizing approach. A delay-partitioning group strategy is proposed and impulse-quantizing control is designed to derive theoretical criteria ensuring scale-type synchronization of complex networks. Our results show that synchronization of mixed continuous-discrete complex networks can be realized by controlling delay-partitioning subgroup nodes with impulsive quantization. The theoretical results give scale-limited sufficient conditions for quantized synchronization relying on control gains, impulsive intervals, and delays. A numerical simulation is given to demonstrate the effectiveness of the theoretical results.

Abstract Transarterial chemoembolization (TACE) is the major treatment for advanced hepatocellular carcinoma (HCC), but it may cause hypoxic environment, leading to rapid progression after treatment. Here, using high‐throughput sequencing on different models, S100 calcium binding protein A9 (S100A9) is identified as a key oncogene involved in post‐TACE progression. Depletion or pharmacologic inhibition of S100A9 significantly dampens the growth and metastatic ability of HCC. Mechanistically, TACE induces S100A9 via hypoxia‐inducible factor 1α (HIF1A)‐mediated pathway. S100A9 acts as a scaffold recruiting ubiquitin specific peptidase 10 and phosphoglycerate mutase family member 5 (PGAM5) to form a tripolymer, causing the deubiquitination and stabilization of PGAM5, leading to mitochondrial fission and reactive oxygen species production, thereby promoting the growth and metastasis of HCC. Higher S100A9 level in HCC tissue or in serum predicts a worse outcome for HCC patients. Collectively, this study identifies S100A9 as a key driver for post‐TACE HCC progression. Targeting S100A9 may be a promising therapeutic strategy for HCC patients.

In this paper, we mainly investigate global exponential synchronization for master-slave complex-valued neural networks (CVNNs) under a time-scale impulsive strategy. CVNNs are separated into real and imaginary parts, which lead to two real-valued neural networks (RVNNs). Firstly, impulsive Halanay differential inequality on time scales as well as the comparison between general exponential function and exponential function in timescale sense is given based on the calculus of time scales. Then by constructing the appropriate Lyapunov functional and using the established lemma and proposition, the concepts of average impulsive interval (AII) and average impulsive gain (AIG), some novel synchronization criteria for the given master-slave CVNNs in impulsive form are obtained. Additionally, the convergence rate is estimated explicitly. Finally, one numerical example is given to show the effectiveness of the proposed results.

Abstract Zirconium nitride (ZrN) ceramics were prepared via hot pressed sintering (HP) at 1750 °C in N2 atmosphere with ZrO2–Y2O3 as sintering additive. X-ray diffraction was applied to analyze the phase composition of the as-prepared ceramics to study the high temperature phase relation in ZrN–ZrO2–Y2O3 ternary system and establish ZrN–ZrO2–Y2O3 ternary phase diagrams. The results show that ZrN and tetragonal ZrO2 (t-ZrO2) solid solution, face-centered cubic ZrO2 (c-ZrO2) solid solution, body-centered cubic Y2O3 (c-Y2O3) solid solution coexist in the system of ZrN–ZrO2–Y2O3.

We investigate a class of fuzzy neural networks with Hebbian-type unsupervised learning on time scales. By using Lyapunov functional method, some new sufficient conditions are derived to ensure learning dynamics and exponential stability of fuzzy networks on time scales. Our results are general and can include continuous-time learning-based fuzzy networks and corresponding discrete-time analogues. Moreover, our results reveal some new learning behavior of fuzzy synapses on time scales which are seldom discussed in the literature.

Wilson-Cowan model of neuronal population with time-varying delays is considered in this paper. Some sufficient conditions for the existence and delay-based exponential stability of a unique almost periodic solution are established. The approaches are based on constructing Lyapunov functionals and the well-known Banach contraction mapping principle. The results are new, easily checkable, and complement existing periodic ones.

We investigate the number of periodic solutions of second-order asymptotically linear difference system. The main tools are Morse theory and twist number, and the discussion in this paper is divided into three cases. As the system is resonant at infinity, we use perturbation method to study the compactness condition of functional. We obtain some new results concerning the lower bounds of the nonconstant periodic solutions for discrete system.

We present dynamical analysis of discrete-time delayed neural networks with impulsive effect. Under impulsive effect, we derive some new criteria for the invariance and attractivity of discrete-time neural networks by using decomposition approach and delay difference inequalities. Our results improve or extend the existing ones.

Background: The long-term survival of patients with hepatocellular carcinoma (HCC) with portal vein tumour thrombus (PVTT) is poor. Systemic therapy, transcatheter arterial chemoembolization (TACE), and hepatic artery infusion chemotherapy are widely used in HCC patients with PVTT. This study aims to explore the efficacy of combining systemic therapy with transarterial-based therapy in HCC patients with PVTT. Materials and methods: The authors retrospectively reviewed data of HCC patients with PVTT treated with combination therapy (TACE-hepatic artery infusion chemotherapy with tyrosine kinase inhibitors and PD-1 inhibitors) or TACE alone in SYSUCC from 2011 to 2020. The overall survival (OS), progression-free survival, and overall response rate were compared. Propensity score matching was used to minimize confounding bias. Results: A total of 743 HCC patients with PVTT received combination therapy (n = 139) or TACE alone (n = 604). After propensity score matching, the overall response rate was significantly higher in the combination group than in the TACE group [42.1% vs. 5.0%, P < 0.001 (response evaluation criteria in solid tumours); 53.7% vs. 7.8%, P < 0.001 (modified response evaluation criteria in solid tumours)]. The combination group showed significantly better OS than the TACE group (median OS not reached vs. 10.4 months, P < 0.001). The median progression-free survival of the combination and TACE groups was 14.8 and 2.3 months (P < 0.001), respectively. Tumour downstaging followed by salvage liver resection was significantly more common for the combination therapy group than for TACE group (46.3% vs. 4.5%, P < 0.001). After salvage liver resection, 31.6% (30/95) and 1.7% (3/179) of the patients achieved a pathological complete response in the combination and TACE groups, respectively (P < 0.001). The grade 3/4 adverse events rates were similar between the two groups (28.1% vs. 35.9%, P = 0.092). Conclusion: Compared with TACE alone, combination therapy was safe enough and resulted in survival benefits. This is a promising treatment option for HCC patients with PVTT. [ABSTRACT FROM AUTHOR]