Anti-CTLA-4 antibody self-presented dendritic cell nanovesicles boost the immunotherapy of hepatocellular carcinoma after microwave ablation.

Microwave ablation (MWA) is a frequently adopted regional therapy for treating hepatocellular carcinoma (HCC) in clinic. However, incomplete microwave ablation (IMWA) is often inevitable due to the restraint of ablating large tumors or tumors in special locations, resulting in a high recurrence rate of HCC. Moreover, the most promising immune checkpoint blockade (ICB)-based immunotherapy is raising hindered by the toxicity and insufficient immune response.

Liver transplantation following two conversions in a patient with huge hepatocellular carcinoma and portal vein invasion: A case report.

Background: Surgical resection and liver transplantation (LT) are the most effective curative options for hepatocellular carcinoma (HCC). However, few patients with huge HCC (> 10 cm in diameter), especially those with portal vein tumor thrombus (PVTT), can receive these treatments. Selective internal radiation therapy (SIRT) can be used as a conversion therapy for them because it has the dual benefit of shrinking tumors and increasing residual hepatic volume.

Microbial-derived Urolithin A Targets GLS1 to Inhibit Glutaminolysis and Attenuate Cirrhotic Portal Hypertension.

Background & Aims: Cirrhotic portal hypertension (CPH) is the leading cause of mortality in patients with cirrhosis. Over 50% of patients with CPH treated with current clinical pharmacotherapy still present variceal bleeding or sometimes death owing to insufficient reduction in portal pressure. Elevated intrahepatic vascular resistance (IHVR) plays a fundamental role in increasing portal pressure.

Manganese oxide-constructed multifunctional biomimetic nanovaccine for robust tumor-specific T cell priming and chemodynamic therapy.

The development of manganese oxide-based chemodynamic immunotherapy is emerging as a key strategy against solid tumors. However, the limited efficacy of nanoplatform in inducing efficient tumor therapeutic effects and creating the prominent antitumor immune responses remains a crucial issue. In this study, we construct a novel multifunctional biomimetic nanovaccine comprising manganese oxide-loaded poly(2-diisopropylaminoethyl methacrylate) (MP) nanoparticles and a coating layer of hybrid cell membrane (RHM) derived from manganese oxide-remodeled 4T1 cells and dendritic cells (DCs) (collectively called MP@RHM) for combination chemodynamic immunotherapy.

The Effect of Servant Leadership on Work Engagement: The Role of Employee Resilience and Organizational Support.

Employees suffer from low resources in the workplace because of multiple work roles in project-based organization (PBO). Based on the conservation of resources theory (COR), this study identifies both employee resilience and organizational support as critical personal and job resources. It then examines how servant leadership enhances employee work engagement in PBO through the mediating roles of employee resilience and organizational support.

FuncPhos-STR: An integrated deep neural network for functional phosphosite prediction based on AlphaFold protein structure and dynamics.

Phosphorylation modifications play important regulatory roles in most biological processes. However, the functional assignment for the vast majority of the identified phosphosites remains a major challenge. Here, we provide a deep learning framework named FuncPhos-STR as an online resource, for functional prediction and structural visualization of human proteome-level phosphosites.

Lenvatinib, sintilimab plus transarterial chemoembolization for advanced stage hepatocellular carcinoma: A phase II study.

Background & Aims: Our retrospective study has suggested encouraging outcomes of lenvatinib combined with PD-1 inhibitor and transarterial chemoembolization (TACE) on advanced hepatocellular carcinoma (HCC). This phase II trial was conducted to prospectively investigate the efficacy and safety of lenvatinib, sintilimab (a PD-1 inhibitor) plus TACE (Len-Sin-TACE) in patients with advanced stage HCC.

Methods: This was a single-arm phase II trial.

Anchoring Microbubbles on Cerebrovascular Endothelium as a New Strategy Enabling Low-Energy Ultrasound-Assisted Delivery of Varisized Agents Across Blood-Brain Barrier.

The protective blood-brain barrier (BBB) prevents most therapeutic agents from entering the brain. Currently, focused ultrasound (FUS) is mostly employed to create microbubbles that induce a cavitation effect to open the BBB. However, microbubbles pass quickly through brain microvessels, substantially limiting the cavitation effect.

Intratumoral Lactate Depletion Based on Injectable Nanoparticles-Hydrogel Composite System Synergizes with Immunotherapy against Postablative Hepatocellular Carcinoma Recurrence.

Thermal ablation is a crucial therapeutic modality for hepatocellular carcinoma (HCC), but its efficacy is often hindered by the high recurrence rate attributed to insufficient ablation. Furthermore, the residual tumors following insufficient ablation exhibit a more pronounced immunosuppressive state, which accelerates the disease progression and leads to immune checkpoint blockade (ICB) resistance. Herein, evidence is presented that heightened intratumoral lactate accumulation, stemming from the augmented glycolytic activity of postablative residual HCC cells, may serve as a crucial driving force in exacerbating the immunosuppressive state of the tumor microenvironment (TME).

HBV suppresses macrophage immune responses by impairing the TCA cycle through the induction of CS/PDHC hyperacetylation.

Background: It is now understood that HBV can induce innate and adaptive immune response disorders by affecting immunosuppressive macrophages, resulting in chronic HBV infection. However, the underlying mechanism is not fully understood. Dysregulated protein acetylation can reportedly influence the differentiation and functions of innate immune cells by coordinating metabolic signaling.

Tyrosine-kinase inhibitor combined with iodine-125 seed brachytherapy for hepatocellular carcinoma refractory to transarterial chemoembolization: a propensity-matched study.

Purpose: To investigate the efficacy and safety of tyrosine-kinase inhibitor (TKI) combined with iodine-125 seed brachytherapy (TKI-I) versus TKI alone for patients with hepatocellular carcinoma (HCC) refractory to transarterial chemoembolization (TACE).

Methods: Data of patients with TACE-refractory HCC who received TKI (sorafenib or lenvatinib) or TKI-I from September 2018 to December 2020 were retrospectively analyzed. A propensity score matching (PSM) was performed to diminish potential bias.

T cell-mediated targeted delivery of tadalafil regulates immunosuppression and polyamine metabolism to overcome immune checkpoint blockade resistance in hepatocellular carcinoma.

Background: Immune checkpoint blockade (ICB) monotherapy provides poor survival benefit in hepatocellular carcinoma (HCC) due to ICB resistance caused by immunosuppressive tumor microenvironment (TME) and drug discontinuation resulting from immune-related side effects. Thus, novel strategies that can simultaneously reshape immunosuppressive TME and ameliorate side effects are urgently needed.

Methods: Both in vitro and orthotopic HCC models were used to explore and demonstrate the new role of a conventional, clinically used drug, tadalafil (TA), in conquering immunosuppressive TME.

Regorafenib enhances anti-tumor efficacy of immune checkpoint inhibitor by regulating IFN-γ/NSDHL/SREBP1/TGF-β1 axis in hepatocellular carcinoma.

Immune checkpoint inhibitor (ICI) shows low response rate in hepatocellular carcinoma (HCC) but the mechanisms underlying ICI resistance remains unclear. Interferon-γ (IFN-γ) has been widely determined as a prototypical antitumor cytokine. However, growing studies suggest that IFN-γ also mediates immunosuppression to promote tumor progression.

Inhibition of CEMIP potentiates the effect of sorafenib on metastatic hepatocellular carcinoma by reducing the stiffness of lung metastases.

Hepatocellular carcinoma (HCC) with lung metastasis is associated with poor prognosis and poor therapeutic outcomes. Studies have demonstrated that stiffened stroma can promote metastasis in various tumors. However, how the lung mechanical microenvironment favors circulating tumor cells remains unclear in metastatic HCC.

Remodelling of tumour microenvironment by microwave ablation potentiates immunotherapy of AXL-specific CAR T cells against non-small cell lung cancer.

The complex immunosuppressive tumour microenvironment (TME) and lack of tumour-specific targets hinder the application of chimeric antigen receptor (CAR) T cells in the treatment of solid tumours. Combining local treatment with CAR T cell immunotherapy may regulate the TME and enhance the killing potency of CAR T cells in solid tumours. Here, we show that AXL, which is highly expressed in non-small cell lung cancer (NSCLC) but not in normal tissues, might be a target for CAR T cell therapy.

Transarterial Chemoembolization Combined With Lenvatinib Plus PD-1 Inhibitor for Advanced Hepatocellular Carcinoma: A Retrospective Cohort Study.

Purpose: To investigate the efficacy and safety of transarterial chemoembolization (TACE) combined with lenvatinib plus PD-1 inhibitor (TACE-L-P) versus TACE combined with lenvatinib (TACE-L) for patients with advanced hepatocellular carcinoma (HCC).

Materials And Methods: Data of advanced HCC patients treated with TACE-L-P (TACE-L-P group) or TACE-L (TACE-L group) from January 2019 to December 2020 were prospectively collected and retrospectively analyzed. The differences in overall survival (OS), progression-free survival (PFS), tumor responses (based on modified Response Evaluation Criteria in Solid Tumors) and adverse events (AEs) were compared between the two groups.

Regorafenib Combined with PD-1 Blockade Immunotherapy versus Regorafenib as Second-Line Treatment for Advanced Hepatocellular Carcinoma: A Multicenter Retrospective Study.

Purpose: To evaluate the safety and efficacy of regorafenib combined with anti-PD-1 antibody sintilimab (rego-sintilimab) as a second-line treatment for advanced hepatocellular carcinoma (HCC).

Methods: This multicenter retrospective study evaluated consecutive patients with advanced HCC who received rego-sintilimab (rego-sintilimab group) or regorafenib alone (regorafenib group) as a second-line treatment from January 2019 to December 2020. Adverse events, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared between the two groups.

The Roles of IRF-8 in Regulating IL-9-Mediated Immunologic Mechanisms in the Development of DLBCL: A State-of-the-Art Literature Review.

Interferon regulatory factor 8 (IRF-8) is a transcription suppressor that functions through associations with other transcription factors, contributing to the growth and differentiation of bone marrow cells and the activation of macrophages. IRF-8 expression profoundly affects pathogenic processes ranging from infections to blood diseases. Interleukin-9 (IL-9) is a multipotent cytokine that acts on a variety of immune cells by binding to the IL-9 receptor (IL-9R) and is involved in a variety of diseases such as cancer, autoimmune diseases, and other pathogen-mediated immune regulatory diseases.

CAR NK-92 cells targeting DLL3 kill effectively small cell lung cancer cells in vitro and in vivo.

Small cell lung cancer (SCLC) is characterized by a high relapse rate, drug tolerance, and limited treatment choices. Chimeric antigen receptor (CAR)-modified NK cells represent a promising immunotherapeutic modality for cancer treatment. However, their potential applications have not been explored in SCLC.

Drug-Eluting Bead Transarterial Chemoembolization Combined with FOLFOX-Based Hepatic Arterial Infusion Chemotherapy for Large or Huge Hepatocellular Carcinoma.

Purpose: To evaluate the safety and efficacy of drug-eluting bead transarterial chemoembolization (DEB-TACE) combined with oxaliplatin plus fluorouracil and leucovorin (FOLFOX)-based hepatic arterial infusion chemotherapy (D-TACE-HAIC) for unresectable large (5.1-10 cm) or huge (>10 cm) hepatocellular carcinoma (HCC).

Methods: This retrospective study evaluated consecutive patients with unresectable large or huge HCC who underwent D-TACE-HAIC (D-TACE-HAIC group) or DEB-TACE (DEB-TACE group) from January 2017 to December 2020.

Development of mesothelin-specific CAR NK-92 cells for the treatment of gastric cancer.

The application of chimeric antigen receptor (CAR) NK cells in solid tumors is hindered by lack of tumor-specific targets and inefficient CAR NK cell efficacy. It has been reported that mesothelin (MSLN) may be an ideal immunotherapy target for gastric cancer. However, the feasibility of using anti-MSLN CAR NK cells to treat gastric cancer remains to be studied.

The Combination Immunotherapy of TLR9 Agonist and OX40 Agonist via Intratumoural Injection for Hepatocellular Carcinoma.

Background: The response rate of immunotherapy via immune checkpoint blockade in hepatocellular carcinoma (HCC) is limited due to multiple immune evasion mechanisms. OX40 is a T cell co-stimulating molecule which suppresses the cancer immune evasion by activating effector T cells (Teffs) and counteracting regulatory T cells (Tregs). TLR9 belongs to the toll-like receptor superfamily which promotes tumour antigen presentation by stimulating the maturation of dendritic cells.

Sublethal heat stress-induced O-GlcNAcylation coordinates the Warburg effect to promote hepatocellular carcinoma recurrence and metastasis after thermal ablation.

The malignant transformation of residual hepatocellular carcinoma (HCC) cells after thermal ablation is considered as the main factor promoting postoperative HCC progression, which greatly limits the improvement of long-term survival, and at present there is no effective targeted therapeutic strategies. The Warburg effect is a metabolic feature correlated highly with malignant transformation (e.g.