alterations on liver hemodynamics on IR injury following administration of medication.

Objective To investigate the role of alprostadil on hepatic perfusion after transarterial chemoembolization(TACE) for hepatocellular carcinoma. Methods Sixty-four consecutive patients with HCC were randomized to either treatment with PGE_1 after TACE (treatment group, 32 cases) or no additional treatment after TACE (control group, 32 cases). In PGE_1 group, Lipo-PGE_1 was administered intravenously once a day for total of seven days, once after completion of TACE. The dosage of Lipo-PGE_1 was 0.4μg/kg and rote 0.05 μg·kg~(-1)·min~(-1). In control group, regular TACE was used. All patients underwent hepatic CT perfusion within 1 week before TACE and 4 weeks after TACE. The parameters of hepatic perfusion, including hepatic arterial perfusion value (HAP), portal vein perfusion value (PVP), total liver perfusion value (TLP) , and hepatic arterial perfusion index (HPI) were measured and compared. Chi-Square test was used for comparison of CT perfusion parameters in different stage, and t test was used for comparison of each CT porfusion parameter between two groups. Results In control group, HAP of pre-TACE, 4 weeks after first TACE, and 4 weeks after second TACE was (0.18±0.08), (0.22±0.09), (0.32±0.10) ml·min~(-1)·ml~(-1), respectively. Likewise, PVP was (1.11±0.31)、(0.82±0.27)、(0.59±0.25) ml·min~(-1)·ml~(-1), respectively, and TLP was (1.29±0.33), (1.04±0.28), (0.91±0.24) ml·min~(-1)·ml~(-1), respectively, and HPI was (14.31±6.36)%, (21.37±9.07)%, (36.67±13.42)%, respectively. The perfusion parameters at different stages of TACE were statistically different (F=19.71,27.47,14.75,41.41, P<0.05). In PGE1 group, HAP before TACE, after first TACE, and after second TACE was (0.17±0.08), (0.20±0.08), (0.26±0.08) ml·min~(-1)·mi~(-1) respectively, and PVP was (1.09±0.36), (1.03±0.40), (0.91±0.41) ml·min~(-1)·ml~(-1), respectively, and TLP was (1.26±0.38), (1.23±0.40), (1.17±0.44) ml·min~(-1)·ml~(-1) respectively, and HPI was (14.04±6.71)%, (17.26±7.86)%, (23.93±8.96)%, respectively. The difference of HAP and HPI at different stage of TACE was significant (F = 10.78, 13.05, P < 0.05), but there was no significant difference both PVP and TLP (F = 1.73,0.39, P > 0.05). The difference of PVP and TLP between the control and PGE1 group was significant after first TACE(t = -2.37, -2.14, P <0.05)and second TACE (t = 2.55, - 4.49, P < 0.05) In addition, after the second TACE, the HAP and HPI were also significantly different (t = - 3.41,5.09, P < 0.05). Conclusions PVP and TLP decrease while HAP and HPI increase after TACE. Lipo-PGE1 improves hepatic peffusion after TACE, exerting its greatest effect by increasing portal vein perfusion. Consequently, treatment with Lipo-PGE1 appears to increase liver tissue perfusion and thereby alleviate injury induced by TACE.

Objective: To investigate the effects of mono-carbonyl analogues of curcumin (L6H21) on paraquat (PQ) -induced injury in HK-2 cell line and explore its underlying mechanisms. Methods: Cultured HK-2 cells were challenged by PQ with or without L6H21 treatment. Cell viability and apoptosis were determined by CCK-8 assay and flow cytometry, respectively. Gene expressions and protein levels of apoptotic and inflammatory factors were assessed by RT-PCR, ELISA, and western blot. Intracellular ROS production was detected by DCFH-DA staining. Superoxide dismutase (SOD) and malondialdehyde (MDA) were examined by chemical colorimetry. Results: 1) PQ challenge significantly inhibited HK-2 cells proliferation, which was prevented by L6H21 administration. PQ dramatically induced HK-2 apoptosis evidenced by increasing expressions of caspase-9, caspase-3 and Bax, while decreasing Bcl-2 level. However, PQ induced these apoptotic effects in HK-2 cells were reversed by L6H21. Similarly, PQ exposure obviously enhanced activity of NF-κB and levels of cytokines (TNF-α、IL-6) in HK-2 cells, which was inhibited by L6H21. Furthermore, administration of L6H21 inhibited PQ induced ROS and MDA production, and promoted SOD level in HK-2 cells. Conclusion L6H21 administration inhibits PQ-induced apoptosis in HK-2 cells possibly by reducing inflammation and oxidative damage.

Purpose: This study aimed to investigate the clinicopathologic features and mutational landscape of patients with hepatitis B virus (HBV)–related advanced hepatocellular carcinomas (HCC) undergoing transcatheter arterial chemoembolization (TACE). Materials and Methods: From January 2017 to December 2018, 38 patients newly diagnosed with HBV-related advanced HCC were enrolled in the final analysis. Their pathological tissues and corresponding blood samples before TACE treatment were collected for whole-exome sequencing. Response to TACE was evaluated at 1-3 months after two consecutive use of TACE. Predictive factors were analyzed by univariate and multivariate analyses in a bivariate Logistic regression model. Enrichment of related pathways of all driver genes were acquired using the gene set enrichment analysis (GSEA). Results: Among 38 patients, 23 (60.5%) exhibited TACE failure/refractoriness. Patients with TACE failure/refractoriness showed higher frequency of TP53 mutation than their counterparts (p=0.020). Univariate and multivariate analyses showed that only vascular invasion and TP53 mutation were significantly correlated with TACE failure/refractoriness in HBV-related advanced HCC. Of the 16 patients without vascular invasion, eight (50.0%) had TP53 mutations, and TP53 mutation was associated with TACE failure/refractoriness (p=0.041). Moreover, GSEA showed that mitogen-activated protein kinase and apoptosis pathways induced by TP53 mutation were possibly associated with TACE failure/refractoriness. Conclusion Our study suggested that TP53 mutation was independently related with TACE efficacy, which may work via mitogen-activated protein kinase and apoptosis pathways. These findings may provide evidence to help distinguish patients who will particularly benefit from TACE from those who require more personalized therapeutic regimens and rigorous surveillance in HBV-related advanced HCC.

OBJECTIVETo investigate the protective effect of ulinastatin (UTI) on HK-2 cells during paraquat (PQ)-induced injury and its underlying mechanisms.

METHODSRoutinely cultured HK-2 cells were divided into blank control group, PQ group, UTI+PQ group and UTI group. Cell viability was determined by CCK-8 assay. The concentration of PQ in HK-2 cells were measured by high performance liquid chromatography (HPLC). The production of total reactive oxygen species (ROS) were detected by fluorescence microscopy. The activities of superoxide dismutase activity (SOD) and the content of malondialdehyde (MDA) in HK-2 cells were observed by chemical colorimetry. The levels of tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA).

RESULTSPQ, even at a dose of 200 µM, could significant suppress the viability of HK-2 cells in a dose-dependent and time-dependent. UTI showed no significant inhibitory effect on the viability of HK-2 cells when given at a dose below 8 000 U/ml (P > 0.05). Compared with the PQ group, the UTI+PQ group had significantly increased the viability of HK-2 cells in a dose-dependent of UTI (P < 0.05). Compared with the PQ group on the same hour, the UTI+PQ group showed decreased in PQ concentration in HK-2 cells (P < 0.05 for all except 6 h). Compared with the blank control group, the PQ group had significantly decreased SOD activity and significantly increased ROS level and MDA content (P < 0.05). Compared with the PQ group, the UTI+PQ group had significantly increased SOD activity and significantly decreased ROS level and MDA content (P < 0.05). Compared with the blank control group, the PQ group had significantly increased IL-6 and TNF-α level (P < 0.05); Compared with the PQ group, the UTI+PQ group had significantly decreased IL-6 and TNF-α level (P < 0.05).

CONCLUSIONUTI significantly reduces the PQ-induced oxidative damage and inflammatory injury and its mechanism may be by reducing the accumulation of PQ in HK-2 cells.

Cell Line ; Cell Survival ; drug effects ; Glycoproteins ; pharmacology ; Humans ; Interleukin-6 ; metabolism ; Malondialdehyde ; metabolism ; Oxidative Stress ; Paraquat ; toxicity ; Reactive Oxygen Species ; metabolism ; Superoxide Dismutase ; metabolism ; Tumor Necrosis Factor-alpha ; metabolism

Cryoablation (CRA) and microwave ablation (MWA) are two main local treatments for hepatocellular carcinoma (HCC). However, which one is more curative and suitable for combining with immunotherapy is still controversial. Herein, CRA induced higher tumoral PD-L1 expression and more T cells infiltration, but less PD-L1^highCD11b⁺ myeloid cells infiltration than MWA in HCC. Furthermore, CRA had better curative effect than MWA for anti-PD-L1 combination therapy in mouse models. Mechanistically, anti-PD-L1 antibody facilitated infiltration of CD8⁺ T cells by enhancing the secretion of CXCL9 from cDC1 cells after CRA therapy. On the other hand, anti-PD-L1 antibody promoted the infiltration of NK cells to eliminate PD-L1^highCD11b⁺ myeloid cells by antibody-dependent cell-mediated cytotoxicity (ADCC) effect after CRA therapy. Both aspects relieved the immunosuppressive microenvironment after CRA therapy. Notably, the wild-type PD-L1 Avelumab (Bavencio), compared to the mutant PD-L1 atezolizumab (Tecentriq), was better at inducing the ADCC effect to target PD-L1^highCD11b⁺ myeloid cells. Collectively, our study uncovered the novel insights that CRA showed superior curative effect than MWA in combining with anti-PD-L1 antibody by strengthening CTL/NK cell immune responses, which provided a strong rationale for combining CRA and PD-L1 blockade in the clinical treatment for HCC.