ANXA5: A Key Regulator of Immune Cell Infiltration in Hepatocellular Carcinoma.

BACKGROUND Hepatocellular carcinoma (HCC) poses a significant threat to human life and is the most prevalent form of liver cancer. The intricate interplay between apoptosis, a common form of programmed cell death, and its role in immune regulation stands as a crucial mechanism influencing tumor metastasis. MATERIAL AND METHODS Utilizing HCC samples from the TCGA database and 61 anoikis-related genes (ARGs) sourced from GeneCards, we analyzed the relationship between ARGs and immune cell infiltration in HCC. Subsequently, we identified long non-coding RNAs (lncRNAs) associated with ARGs, using the least absolute shrinkage and selection operator (LASSO) regression analysis to construct a robust prognostic model. The predictive capabilities of the model were then validated through examination in a single-cell dataset. RESULTS Our constructed prognostic model, derived from lncRNAs linked to ARGs, comprised 11 significant lncRNAs: NRAV, MCM3AP-AS1, OTUD6B-AS1, AC026356.1, AC009133.1, DDX11-AS1, AC108463.2, MIR4435-2HG, WARS2-AS1, LINC01094, and HCG18. The risk score assigned to HCC samples demonstrated associations with immune indicators and the infiltration of immune cells. Further, we identified Annexin A5 (ANXA5) as the pivotal gene among ARGs, with it exerting a prominent role in regulating the lncRNA gene signature. Our validation in a single-cell database elucidated the involvement of ANXA5 in immune cell infiltration, specifically in the regulation of mononuclear cells. CONCLUSIONS This study delves into the intricate correlation between ARGs and immune cell infiltration in HCC, culminating in the development of a novel prognostic model reliant on 11 ARGs-associated lncRNAs. Furthermore, our findings highlight ANXA5 as a promising target for immune regulation in HCC, offering new perspectives for immune therapy in the context of HCC.

Minimally Invasive Delivery of Percutaneous Ablation Agent via Magnetic Colloidal Hydrogel Injection for Treatment of Hepatocellular Carcinoma.

Percutaneous thermotherapy, a minimally invasive operational procedure, is employed in the ablation of deep tumor lesions by means of target-delivering heat. Conventional thermal ablation methods, such as radiofrequency or microwave ablation, to a certain extent, are subjected to extended ablation time as well as biosafety risks of unwanted overheating. Given its effectiveness and safety, percutaneous thermotherapy gains a fresh perspective, thanks to magnetic hyperthermia. In this respect, an injectable- and magnetic-hydrogel-construct-based thermal ablation agent is likely to be a candidate for the aforementioned clinical translation. Adopting a simple and environment-friendly strategy, a magnetic colloidal hydrogel injection is introduced by a binary system comprising super-paramagnetic Fe3O4 nanoparticles and gelatin nanoparticles. The colloidal hydrogel constructs, unlike conventional bulk hydrogel, can be easily extruded through a percutaneous needle and then self-heal in a reversible manner owing to the unique electrostatic cross-linking. The introduction of magnetic building blocks is exhibited with a rapid magnetothermal response to an alternating magnetic field. Such hydrogel injection is capable of generating heat without limitation of deep penetration. The materials achieve outstanding therapeutic results in mouse and rabbit models. These findings constitute a new class of locoregional interventional thermal therapies with minimal collateral damages.

Injectable Hydrogels Including Magnetic Nanosheets for Multidisciplinary Treatment of Hepatocellular Carcinoma via Magnetic Hyperthermia.

Relapse and unresectability have become the main obstacle for further improving hepatocellular carcinoma (HCC) treatment effect. Currently, single therapy for HCC in clinical practice is limited by postoperative recurrence, intraoperative blood loss and poor patient outcomes. Multidisciplinary therapy has been recognized as the key to improving the long-term survival rate for HCC. However, the clinical application of HCC synthetic therapy is restricted by single functional biomaterials. In this study, a magnetic nanocomposite hydrogel (CG-IM) with iron oxide nanoparticle-loaded mica nanosheets (Iron oxide nanoparticles@Mica, IM) is reported. This biocompatible magnetic hydrogel integrated high injectability, magnetocaloric property, mechanical robustness, wet adhesion, and hemostasis, leading to efficient HCC multidisciplinary therapies including postoperative tumor margin treatment and percutaneous locoregional ablation. After minimally invasive hepatectomy of HCC, the CG-IM hydrogel can facilely seal the bleeding hepatic margin, followed by magnetic hyperthermia ablation to effectively prevent recurrence. In addition, CG-IM hydrogel can inhibit unresectable HCC by magnetic hyperthermia through the percutaneous intervention under ultrasound guidance.

Injectable magnetic montmorillonite colloidal gel for the postoperative treatment of hepatocellular carcinoma.

Bioactive materials have been extensively developed for the adjuvant therapy of cancer. However, few materials can meet the requirements for the postoperative resection of hepatocellular carcinoma (HCC) due to massive bleeding and high recurrence. In particular, combination therapy for HCC has been highly recommended in clinical practice, including surgical resection, interventional therapy, ablation therapy and chemotherapy. Herein, an injectable magnetic colloidal gel (MCG) was developed by controllable electrostatic attraction between clinically available magnetic montmorillonites and amphoteric gelatin nanoparticles. The optimized MCG exhibited an effective magnetic heating effect, remarkable rheological properties, and high gel network stability, realizing the synergistic treatment of postoperative HCC by stimuli-responsive drug delivery, hemostasis and magnetic hyperthermia. Furthermore, a minimal invasive MCG-induced interventional magnetic hyperthermia therapy (MHT) under ultrasound guidance was realized on hepatic tumor rabbits, providing an alternative therapeutics to treat the postoperative recurrence. Overall, MCG is a clinically available injectable formulation for adjuvant therapy after HCC surgical resection.

In situ Thermal-Responsive Magnetic Hydrogel for Multidisciplinary Therapy of Hepatocellular Carcinoma.

Current surgical single modality treatments for hepatocellular carcinoma (HCC) were restricted by recurrence, blood loss, significant trauma, and poor prognostic. Although multidisciplinary strategies for HCC treatment have been highly recommended by the clinical guidelines, there was limited choice of materials and treatments. Herein, we reported an in situ formed magnetic hydrogel with promising bioapplicable thermal-responsiveness, strong adhesion in wet conditions, high magnetic hyperthermia, and biocompatibility, leading to efficient HCC multidisciplinary treatment including postoperative treatment and transarterial embolization therapy. In vivo results indicated that this hydrogel could reduce the postoperative recurrence rate. The hemostatic ability of the thermal-responsive hydrogel was further demonstrated in both the liver scratch model and liver tumor resection. Computed tomography imaging suggested that the hydrogel could completely embolize the arterial vessels of rabbit liver tumor by vascular intervention operation, which could serve as multidisciplinary responsive materials to external magnetic field and body temperature for HCC treatment.

STING agonist enhances the efficacy of programmed death-ligand 1 monoclonal antibody in breast cancer immunotherapy by activating the interferon-ß signalling pathway.

This study aimed to explore the role of a stimulator of interferon (IFN) gene (STING) agonist in breast cancer (BCa) immunotherapy. Clinical samples were collected from 37 patients with BCa. A tumor-bearing mouse model was established by injecting 4T1 cells into the mammary fat pad of mice. STING agonist and atezolizumab were injected in the mice twice a week for 2 weeks. Peripheral blood, tumor mass, lung, liver, brain cortex and kidney samples of the tumor-bearing mice were collected. Anti-IFN alpha receptor subunit 1 (IFNAR1) was used to treat 4T1 cells. Tumor tissues of patients with BCa exhibited lower STING and high programmed cell death protein 1 and programmed death-ligand 1 protein expressions. The STING agonist inhibited 4T1 cell growth in mice (P < 0.001) and increased the IFN-ß level and phosphorylation of STING, TBK1, IRF3 and STAT1 in tumor mass of tumor-bearing mice (P < 0.001). It synergized with atezolizumab to inhibit 4T1 cell growth in mice and increased tumor necrosis factor-α, IFN-ß, interleukin-10 and IFN-γ levels in the peripheral blood and tumor mass (P < 0.01). It synergized with atezolizumab to increase CD8+ cytotoxic T cells and decrease FOXP3+ Treg cells in the tumor-bearing mouse model. The STING agonist was nontoxic to the lung, liver, brain cortex and kidney. Anti-IFNAR1 reversed the STING agonist promotion on TBK1, IRF3 and STAT1 phosphorylation in 4T1 cells (P < 0.01). STING agonists enhance the efficacy of atezolizumab in BCa immunotherapy by activating the IFN-ß signaling pathway.

Simultaneous single-cell phenotype analysis of hepatocellular carcinoma CTCs using a SERS-aptamer based microfluidic chip.

Hepatocellular carcinoma (HCC) is a harmful malady that truly debilitates human health, and hence it is of significance to isolate and on-line profile the phenotype of HCC cells for further diagnosis and therapy. We developed a novel strategy for efficient capture and in situ heterogeneous phenotype analysis of circulating tumor cells (CTCs) at the single-cell level based on surface-enhanced Raman scattering (SERS) fingerprint characteristics. Herein, a new microfluidic chip with lantern-like bypass structure was designed to capture CTCs by their large size from whole blood. Furthermore, two types of SERS-aptamer nanotags were fabricated, realizing spectral recognition of single CTCs in accordance with the surface membrane protein expression. Up to 84% of CTCs with a purity of 95% were captured from whole blood samples using the present SERS-aptamer based microfluidic chip at 20 µL min-1. The results showed that the proposed strategy can successfully identify HCC cell subtypes by SERS measurements, which was related to the clinical surface biomarkers. This may open a new avenue for serving as a powerful tool of cancer diagnosis and prognosis evaluation.

Injectable ferrimagnetic silk fibroin hydrogel for magnetic hyperthermia ablation of deep tumor.

Due to the well-recognized biocompatibility, silk fibroin hydrogels have been developed for biomedical applications including bone regeneration, drug delivery and cancer therapy. For the treatment of cancer, silk-based photothermal agents exhibit the high photothermal conversion efficiency, but the limited light penetration depth of photothermal therapy restricts the treatment of some tumors in deep positions, such as liver tumor and glioma. To provide an alternative strategy, here we developed an injectable magnetic hydrogel based on silk fibroin and iron oxide nanocubes (IONCs). The as-prepared ferrimagnetic silk fibroin hydrogel could be easily injected through a syringe into tumor, especially rabbit hepatocellular carcinoma in deeper positions using ultrasound-guided interventional treatment. Compared with photothermal agents, the embedded IONCs endowed the ferrimagnetic silk fibroin hydrogel with remote hyperthermia performance under an alternating magnetic field, resulting in the effective magnetic hyperthermia of deep tumors including subcutaneously implanted tumor model in Balb/c mouse after the coverage of a fresh pork tissue and orthotopic transplantation liver tumor in rabbit. Furthermore, due to the confinement of IONCs in silk fibroin hydrogel, the undesired thermal damage toward normal tissue could be avoided compared with directly administrating monodispersed magnetic nanoparticles.

Activatable Cell-Penetrating Peptide Conjugated Polymeric Nanoparticles with Gd-Chelation and Aggregation-Induced Emission for Bimodal MR and Fluorescence Imaging of Tumors.

Activatable cell-penetrating peptide (ACPP) conjugated polymeric nanoparticles containing gadolinium (Gd)-chelates and aggregation-induced emission fluorogens (AIEgens) have been synthesized and applied as a magnetic resonance imaging (MRI) and fluorescence imaging (FI) bimodal imaging probe with active tumor targeting. The polymeric nanoparticles have been generated by dissolving presynthesized linear block copolymers into water directly. With AIEgens, N-BP5-Gd-ACPPs showed tumor cell penetration, which can be characterized by in vitro FI. Preliminary in vivo experiments of Gd-chelated nanoparticles have demonstrated promising characteristics as a tumor-targeting MRI contrast agent with good biocompatibility. This study impacts the synthesis of functional copolymers and polymeric nanoparticles for their applications in bioimaging.

Randomized trial of umbilical incisional hernia in high-risk patients: extraction of gallbladder through subxiphoid port vs. umbilical port after laparoscopic cholecystectomy.

INTRODUCTION: Trocar site incisional hernia (TSIH) is one of the most common complications of laparoscopic surgery. Using the umbilical port as a common hole for removing the gallbladder in laparoscopic cholecystectomy is more likely to lead to TSIH than other ports. Thus, extracting the gallbladder through other ports may reduce the incidence of TSIH. AIM: To ascertain whether extraction of the gallbladder through the subxiphoid port is more beneficial for reducing umbilical incisional hernia than the umbilical port. MATERIAL AND METHODS: From April 2014 to March 2017, a randomized clinical trial was conducted among patients with high risk of incisional hernia and accepted for three-port laparoscopic cholecystectomy (TLC) in our department. 182 patients with indications of cholecystectomy were allocated randomly to group A (subxiphoid port) and group B (umbilical port). Data collection was carried out on operative time, postoperative pain, hospital stay, wound infection and TSIH in the early postoperative course, and at 1, 10, and 24 months after surgery. RESULTS: The incidence of TSIH in group A was lower than that in group B (4.9% vs. 14.6%; odds ratio = 8.02; 95% CI: 2.15-47.6; p < 0.001). The mean operative time of group A was significantly shorter than that of group B (35 ±15.16 min vs. 42 ±14.58 min, p < 0.01). There was no significant difference in wound infection rate between group A and group B (p = 0.068). The data of hospital stay (p = 0.428) and postoperative pain (p = 0.349) of all analyzed patients were similar in the two groups. CONCLUSIONS: Extraction of the gallbladder through the subxiphoid port can reduce umbilical incisional hernia in high-risk patients effectively.

Contribution of mononuclear bone marrow cells to carbon tetrachloride-induced liver fibrosis in rats.

AIM: To study the inhibitory effect of mononuclear bone marrow cell (BMC) transplantation on carbon tetrachloride (CCl(4)) -induced liver fibrosis in rats. METHODS: Rat liver fibrosis models were induced by CCl(4) and alcohol administration. After 8 wk, twenty rats were randomly allocated into treatment group (n = 10) and control group (n = 10). BMC were infused into the rats in treatment group via the portal vein, while heparinized saline was infused in control group. CCl(4) was hypodermically injected into the rats twice a week for 4 wk. At the end of wk 12, all rats were humanely sacrificed. Liver samples were taken and stained with HE or Masson trichrome. The general conditions, liver fibrosis (hydroxyproline and collagen fibre) and liver pathological grades in rats were evaluated. RESULTS: The general conditions of the rats in treatment group improved markedly, but not in control group. Hydroxyproline was 504.6 +/- 128.8 microg/g in treatment group, and 596.0 +/- 341.8 microg/g in control group. The percentage of collagen fibre was 3.75% +/- 0.98% in treatment group and 5.02% +/- 0.44% in control group. There was a significant difference between the two groups (P < 0.05). Liver pathological grade decreased from grade IV to grade III partially in treatment group (P < 0.05) with no obvious improvement in control group (P > 0.05). There was a significant difference between treatment group and control group (P < 0.05). CONCLUSION: Transplantation of BMC can improve liver fibrosis due to chronic liver injury in rats.