Avapritinib efficacy in primary hepatic neuroendocrine carcinoma with elevated PDGFRA expression: Insights from a PDX model study.

BACKGROUND & AIMS: Primary Hepatic Neuroendocrine Carcinoma (PHNEC) is a rare and aggressive tumor with high recurrence rates. Surgical resection remains the only therapeutic strategy. The effectiveness of tyrosine kinase inhibitors (TKIs) for PHNEC remains unclear due to limited research. METHODS: We employed immunohistochemical staining to diagnose PHNEC and assess the expression of eight tyrosine kinase receptors in tumor tissues, including VEGFRs, PDGFRA, EGFR, FGFRs et al. A patient-derived xenograft (PDX) model was established using PHNEC tumor tissues to test the efficacy of TKIs. PDX mice bearing tumors were treated with Avapritinib, an FDA-approved PDGFRA-targeting drug, at a daily oral dose of 10 mg/kg for 2 weeks. RESULTS: Pathological analysis confirmed the diagnosis of PHNEC with positive expression of Neural cell adhesion molecule (NCAM/CD56), Synaptophysin (Syn), and Somatostatin receptor 2 (SSTR-2), and negative expression of Hep (Hepatocyte Paraffin 1), a biomarker for Hepatocellular carcinoma. Notably, PDGFRA was significantly overexpressed in PHNEC tumor tissues compared to other tyrosine kinases. Avapritinib treatment significantly reduced tumor growth in PDX mice by 73.9 % (p = 0.008). Additionally, Avapritinib treatment led to a marked decrease in PDGFRA and Ki-67 expression, suggesting that it inhibits tumor cell proliferation by suppressing PDGFRA. CONCLUSION: Our findings suggest that PDGFRA is a potential therapeutic target for PHNEC, and its inhibition with Avapritinib may offer clinical benefits to patients with this rare malignancy.

ARHGEF39 targeted by E2F1 fosters hepatocellular carcinoma metastasis by mediating fatty acid metabolism.

BACKGROUND: Hepatocellular carcinoma (HCC) stands as the prevailing manifestation of primary liver cancer. Previous studies have implicated ARHGEF39 in various cancer progression processes, but its impact on HCC metastasis remains unclear. METHODS: Bioinformatics analysis and qRT-PCR were employed to test ARHGEF39 expression in HCC tissues and cells, identified enriched pathways associated with ARHGEF39, and investigated its regulatory relationship with E2F1. The impact of ARHGEF39 overexpression or knockdown on cellular phenotypes in HCC was assessed through the implementation of CCK-8 and Transwell assays. Accumulation of neutral lipids was determined by BODIPY 493/503 staining, while levels of triglycerides and phospholipids were measured using specific assay kits. Expression of E-cadherin, Vimentin, MMP-2, MMP-9, and FASN were analyzed by Western blot. The interaction between ARHGEF39 and E2F1 was validated through ChIP and dual-luciferase reporter assays. RESULTS: Our study demonstrated upregulated expression of both ARHGEF39 and E2F1 in HCC, with ARHGEF39 being associated with fatty acid metabolism (FAM) pathways. Additionally, ARHGEF39 was identified as a downstream target gene of E2F1. Cell-based experiments unmasked that high expression of ARHGEF39 mediated the promotion of HCC cell viability, migration, and invasion via enhanced FAM. Moreover, rescue assays demonstrated that the promotion of HCC cell metastasis by high ARHGEF39 expression was attenuated upon treatment with Orlistat. Conversely, the knockdown of E2F1 suppressed HCC cell metastasis and FAM, while the upregulation of ARHGEF39 counteracted the repressive effects of E2F1 downregulation on the metastatic potential of HCC cells. CONCLUSION: Our findings confirmed the critical role of ARHGEF39 in HCC metastasis and unmasked potential molecular mechanisms through which ARHGEF39 fostered HCC metastasis via FAM, providing a theoretical basis for exploring novel molecular markers and preventive strategies for HCC metastasis.

Effect of Scanning Strategy on the Microstructure and Triboperformance of FeNiCrMo Coating Manufactured by Plasma Transferred Arc.

To increase the coating thickness and service life of the FeNiCrMo coating, a plasma transferred arc (PTA) double-track alloying technique was employed to enhance the surface triboperformance of the ductile iron. Optical microscopy (OM), X-ray diffraction (XRD), electron probe X-ray microanalyzer (EPMA), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Vickers hardness tester, and tribological tester were subsequently used to evaluate the effect of the double alloying treatment tracks on the microstructure and triboperformance of the coating. The results indicate that the content of the cementite in the sample with a double-track treatment increases 3.90 wt.% and the content of the martensite decreases 13.04 wt.% compared with the sample with a single-track treatment, which results in the maximum microhardness of the sample fabricated by double track increasing from 837 ± 10 HV0.2 for the sample fabricated by single track to 871 ± 7 HV0.2. Thus, the wear rate is lower than that of the sample with a single-track treatment. In addition, the distribution of alloying elements is more uniform and coating thickness is higher in the double track than those of the single-track-treated one. Therefore, the double-track PTA alloying treatment is favored for hardfacing ductile iron with a FeNiCrMo alloy coating due to its enhanced triboperformance and longer service life.

Deubiquitinating enzyme JOSD2 promotes hepatocellular carcinoma progression through interacting with and inhibiting CTNNB1 degradation.

Although a variety of molecular targets have been identified, hepatocellular carcinoma (HCC) remains among the leading causes of death. As functions of they deubiquitinating enzyme Josephin domain containing 2 (JOSD2) in cancers are still poorly understood, we investigated its function and molecular mechanism in the regulation of HCC progression. Here, we indicated that JOSD2 expression is elevated in patient samples with HCC and positively associated with poor prognosis. Moreover, the promoting roles of JOSD2 in HCC cell survival, migration, and invasion were determined using in vitro models. Importantly, a mechanistic study revealed that JOSD2 binds to and decreases the ubiquitination level of catenin beta 1 (CTNNB1), a key component of Wnt signaling, thereby augmenting Wnt pathway transduction. Furthermore, a series of rescue experiments confirmed the significance of CTNNB1 in the modulation of HCC progression by JOSD2. Our study uncovered JOSD2 as a novel prognostic marker for patients with HCC and identified CTNNB1 as a pivotal partner and downstream target protein of JOSD2, which may aid in the development of JOSD2 as a promising molecular target for HCC treatment.

DNAM1 and 2B4 Costimulatory Domains Enhance the Cytotoxicity of Anti-GPC3 Chimeric Antigen Receptor-Modified Natural Killer Cells Against Hepatocellular Cancer Cells in vitro.

PURPOSE: Hepatocellular cancer (HCC) is the sixth most prevalent cancer and the third leading cause of cancer-related death worldwide. Cellular immunotherapy against glypican 3 (GPC3) has recently been used in the treatment of HCC, following the success of chimeric antigen receptor (CAR)-T therapy in treatment of B cell malignancy. However, CAR-T cells are not "off-the-shelf" and always cause cytokine release syndrome, which can be eliminated by using natural killer (NK) cells as effector cells. Since a costimulatory signal is necessary for the activation, persistence, or cytotoxicity of CAR-T cells, we speculated that the costimulatory signal is also required for CAR-NK cells in HCC treatment. METHODS: Five anti-GPC3 CAR plasmids containing different costimulatory domains were constructed. They included Z (only the CD3ζ domain, no costimulatory domain), CD28.Z (T-cell costimulatory domain CD28), DNAM1/2B4.Z (NK-cell-associated costimulatory domain DNAM1 or 2B4), and DNAM1.2B4.Z (both NK-cell-associated costimulatory domains). Respective CAR-NK-92 cells were generated. The MTT viability assay was performed to evaluate the effect of the different costimulatory domains on CAR-NK-cell proliferation. The effect on persistence was analyzed using an apoptosis assay and flow cytometry. Special cytotoxicity against normal hepatocellular cells and GPC3+ malignant cells was investigated in vitro. The concentration of cytokines (TNF-α and IFN-γ) released by CAR-NK-92 cells was also measured by ELISA. RESULTS: NK-cell-associated costimulatory signal was necessary for CAR-NK-92 cells. CAR-NK-92 cells with DNAM1 and/or 2B4 expanded more quickly and persisted with a lower apoptotic ratio, compared to the presence of CD28 or no costimulatory signal. All CAR-NK-92 cells showed special cellular cytotoxicity in vitro. CAR-NK-92 cells with NK-cell-associated costimulatory domains exhibited higher cytotoxic ability compared with those without any costimulatory domain or with T-cell costimulatory domain. CAR-NK-92 cells with both DNAM1 and 2B4 displayed the highest cytotoxicity. The cytokine release assay results were consistent with those of the cytotoxicity assay. CONCLUSION: We provided the first evidence supporting a strategy using DNAM1 and 2B4 costimulatory domains to generate anti-GPC3 CAR-NK-92 cells, which exhibits enhanced cytotoxicity against hepatocellular cancer cells in vitro.

Localization Based on MAP and PSO for Drifting-Restricted Underwater Acoustic Sensor Networks.

Localization is a critical issue for Underwater Acoustic Sensor Networks (UASNs). Existing localization algorithms mainly focus on localizing unknown nodes (location-unaware) by measuring their distances to beacon nodes (location-aware), whereas ignoring additional challenges posed by harsh underwater environments. Especially, underwater nodes move constantly with ocean currents and measurement noises vary with distances. In this paper, we consider a special drifting-restricted UASN and propose a novel beacon-free algorithm, called MAP-PSO. It consists of two steps: MAP estimation and PSO localization. In MAP estimation, we analyze nodes' mobility patterns, which provide the priori knowledge for localization, and characterize distance measurements under the assumption of additive and multiplicative noises, which serve as the likelihood information for localization. Then the priori and likelihood information are fused to derive the localization objective function. In PSO localization, a swarm of particles are used to search the best location solution from local and global views simultaneously. Moreover, we eliminate the localization ambiguity using a novel reference selection mechanism and improve the convergence speed using a bound constraint mechanism. In the simulations, we evaluate the performance of the proposed algorithm under different settings and determine the optimal values for tunable parameters. The results show that our algorithm outperforms the benchmark method with high localization accuracy and low energy consumption.