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Kun-Ming Chan,1 Yin Lai,1 Hao-Chien Hung,1 Jin-Chiao Lee,1 Chih-Hsien Cheng,1 Yu-Chao Wang,1 Tsung-Han Wu,1 Chen-Fang Lee,1 Ting-Jung Wu,1 Hong-Shiue Chou,1 Ching-Ting Wang,2 Pei-Mei Chai,2 Hsin-Yi Lien,3 Wei-Chen Lee1 1Department of General Surgery and Chang Gung Transplantation Institute, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan; 2Department of Nursing, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan; 3Graduate School of Education, Ming Chuan University, Taoyuan, TaiwanCorrespondence: Kun-Ming Chan, Department of General Surgery and Chang Gung Transplantation Institute, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, No. 5 Fu-Hsing Street, Gui-Shan District, Taoyuan City, 33305, Taiwan, Tel +886-3-3281200 Ext 3366, Fax +886-3-3285818, Email chankunming@cgmh.org.twBackground: Tyrosine kinase inhibitors (TKIs) remain the primary therapeutic option for patients with advanced-stage hepatocellular carcinoma (HCC). However, the selection of a suitable TKI is an issue in real-world clinical practice. Thus, this study aimed to identify patients most likely to benefit from lenvatinib treatment.Methods: A retrospective review of 143 patients with unresectable advanced-stage HCC treated with lenvatinib between January 2020 and December 2021 was performed. Outcomes related to lenvatinib treatment were measured, and the clinical parameters affecting prognosis were analyzed.Results: Overall, the median time of progression-free survival (PFS) and overall survival (OS) were 7.1 months and 17.7 months, respectively. Prognostic analyses found that Child-Pugh score > 5 (hazard ratio [HR] = 2.43, 95% confidence interval [CI] = 1.55– 3.80, p = 0.001) was a significant factor affecting the PFS of HCC after lenvatinib treatment. Child-Pugh score > 5 (HR = 2.12, 95% CI = 1.20– 3.74, p = 0.009), body weight ≥ 60 kg (HR = 0.54, 95% CI = 0.32– 0.90, p = 0.020), and additional trans-arterial chemoembolization (TACE) treatment (HR = 0.38, 95% CI = 0.21– 0.70, p = 0.003) were significant prognostic factors for OS. However, early α-fetoprotein reduction was not significantly correlated with patient outcomes. Additionally, patients with pre-treatment neutrophil-lymphocyte ratio > 4.07 showed a significant worse PFS and OS than other patients.Conclusion: The outcome of patients with advanced-stage HCC remains poor. However, the host condition, including good physical status and better functional liver preservation, largely affected the outcome of patients receiving lenvatinib treatment. Moreover, additional locoregional therapy for intrahepatic HCC, other than TKI treatment, can be considered in certain patients to achieve a favorable outcome.Keywords: hepatocellular carcinoma, advanced-stage, tyrosine kinase inhibitor, lenvatinib, outcome

Lenvatinib and atezolizumab plus bevacizumab(A + B) have been used for unresectable hepatocellular carcinoma (HCC) as first-line therapy. Real-world studies comparison of efficacy and safety in these two regimens are limited, we therefore conduct this study to investigate these issues.We retrospectively reviewed patients received lenvatinib (n = 46) and A + B (n = 46) as first-line systemic therapy for unresectable HCC in a tertiary medical center. Objective response rate (ORR), progression free survival (PFS), and overall survival (OS) were evaluated according to modified Response Evaluation Criteria in Solid Tumors (mRECIST). Inverse probability weighting (IPW) was performed for baseline clinical features balance.A total of 92 patients with median age of 63.8 year-old, 78.3% male, 85.9% viral hepatitis infected, 67.4% BCLC stage C were enrolled. The median treatment and follow-up duration were 4.7 months and 9.4 months, respectively. There was no significant difference in ORR (26.1% vs. 41.3%, p = 0.1226), PFS (5.9 vs. 5.3 months, p = 0.4066), and OS (not reached vs. not reached, p = 0.7128) between the lenvatinib and A + B groups. After IPW, the results of survival and response rate were also compared. Subgroup analysis suggested that using lenvatinib was not inferior to A + B in regards of PFS, including those with elder, Child-Pugh class B, beyond up-to-seven, or portal vein invasion VP4 patients. Among the lenvatinib treated patients, multivariate analysis showed patients elder than 65-year-old was an independent predictor associated with shorter PFS (adjust HR: 2.085[0.914-4.753], p = 0.0213). The incidence rates of adverse events were similar between two groups (76 vs. 63%, p = 0.1740). Both of two regimens had similarly few impact on liver function by comparison of baseline, third month, and sixth month albumin-bilirubin index and Child-Pugh score.The efficacy and safety of lenvatinib are similar to A + B as a first-line systemic therapy for unresectable HCC.

Introduction: Hepatitis often occurs after the initiation of immune checkpoint inhibitor (ICI) treatment. The time and grade of hepatitis after ICI initiates and the prognostic role of immune-related hepatitis in patients with advanced hepatocellular carcinoma (aHCC) remains unclear. Methods: In this real-world analysis, we enrolled aHCC patients receiving ICIs, documented the highest level of liver enzymes during/after ICIs, and analyzed the survival impact of different hepatitis patterns. Results: One hundred and ninety-three aHCC patients receiving ICIs were recruited. During ICIs, 88.6% of all patients experienced aspartate transaminase (AST) elevations (Grade III/IV: 7.8%). For alanine transaminase (ALT), 81.3% had elevated levels (Grade III/IV: 3.6%), and 41.5% of patients had elevated bilirubin levels (Grade 3/4: 6.7%). The median AST, ALT, and total bilirubin values significantly increased after ICI treatment initiated (all p < 0.001) and similarly, after excluding progressive disease ( p = 0.014, p = 0.002, p < 0.001). The median time of hepatitis occurrence is from the 4.0 th –15.9 th weeks. Multivariate analysis showed that patterns of liver enzyme change of AST and total bilirubin in patients receiving ICIs significantly correlate to overall survival (OS, p = 0.009 and 0.001, respectively). After ICI termination, patients with late elevated bilirubin ( p = 0.003) and AST ( p = 0.005) would indicate poor survival. Discussion/ Conclusion: Hepatitis patterns in patients with aHCC under ICI therapy can predict OS. Close monitoring of hepatitis could help to promptly predict the outcomes of patients receiving ICIs.

Background Cardiac glycosides, which inhibit Na+ /K+ -ATPase, display inotropic effects for the treatment of congestive heart failure and cardiac arrhythmia. Recent studies have suggested signaling downstream of Na+ /K+ -ATPase action in the regulation of cell proliferation and apoptosis and have revealed the anticancer activity of cardiac glycosides. The study aims to characterize the anticancer potential of ascleposide, a natural cardenolide, and to uncover its primary target and underlying mechanism against human castration-resistant prostate cancer (CRPC). Methods Cell proliferation was examined in CRPC PC-3 and DU-145 cells using sulforhodamine B assay, carboxyfluorescein succinimidyl ester staining assay and clonogenic examination. Flow cytometric analysis was used to detect the distribution of cell cycle phase, mitochondrial membrane potential, intracellular Na+ and Ca2+ levels, and reactive oxygen species production. Protein expression was examined using Western blot analysis. Endocytosis of Na+ /K+ -ATPase was determined using confocal immunofluorescence microscopic examination. Results Ascleposide induced an increase of intracellular Na+ and a potent antiproliferative effect. It also induced a decrease of G1 phase distribution while an increase in both G2/M and apoptotic sub-G1 phases, and downregulated several cell cycle regulator proteins, including cyclins, Cdk, p21, and p27 Cip/Kip proteins, Rb and c-Myc. Ascleposide decreased the expression of antiapoptotic Bcl-2 members (eg, Bcl-2 and Mcl-1) but upregulated proapoptotic member (eg, Bak), leading to a significant loss of mitochondrial membrane potential and activation of both caspase-9 and caspase-3. Ascleposide also dramatically induced tubulin acetylation, leading to inhibition of the catalytic activity of Na+ /K+ -ATPase. Notably, extracellular high K+ (16 mM) significantly blunted ascleposide-mediated effects. Furthermore, ascleposide induced a p38 MAPK-dependent endocytosis of Na+ /K+ -ATPase and downregulated the protein expression of Na+ /K+ -ATPase α1 subunit. Conclusion Ascleposide displays antiproliferative and apoptotic activities dependent on the inhibition of Na+ /K+ -ATPase pumping activity through p38 MAPK-mediated endocytosis of Na+ /K+ -ATPase and downregulation of α1 subunit, which in turn cause tubulin acetylation and cell cycle arrest. Cell apoptosis is ultimately triggered by the activation of caspase cascade attributed to mitochondrial damage through the downregulation of Bcl-2 and Mcl-1 protein expressions while upregulation of Bak protein levels. The data also suggest the potential of ascleposide in anti-CRPC development.

The claim that quality of membrane fabrication is based on surface smoothness of substrate has been known since the 1960s. In this study, we propose a concept based on the interfacial interaction between the carbon molecular sieving (CMS) selective layer and the Al2O3 substrate to understand the development of the CMS membrane's micro-structure at the molecular level, especially for natural gas purification. We further compare the results with those of our previous work to determine the dominant influence on the structural development of CMS membranes, and discover a remarkable enhancement in H2/CH4 and CO2/CH4 gas pair separation performances that surpass the upper limit for polymer membranes proposed by Robeson. Permselectivity performance was found to be strongly related to substrate properties, and especially to the surface roughness. When TiO2 intermediately layer and polishing technology was used to modify the roughness of the substrate, the supported CMS membrane displayed an improvement of 364% and 144% (or 720.1 ± 16.0 and 86.3 ± 5.1) in H2/CH4 and CO2/CH4 selectivities, respectively, when compared to bare alumina-supported membranes prepared under the same conditions; the H2 permeability also increased from 537.5 to 566.1 Barrer. These results indicated an important connection between the substrate structure and the performance of the CMS membranes, providing a new understanding of the influence of each preparation parameter and a route to tailoring the structure of CMS membranes that benefit gas separation applications.

Summary: The sterile inflammation caused by damage-associated molecular patterns (DAMPs) worsens the prognosis following primary injury such as ischemic stroke. However, there are no effective treatments to regulate DAMPs. Here, we report that AIM (or CD5L) protein reduces sterile inflammation by attenuating DAMPs and that AIM administration ameliorates the deleterious effects of ischemic stroke. AIM binds to DAMPs via charge-based interactions and disulfide bond formation. This AIM association promotes the phagocytic removal of DAMPs and neutralizes DAMPs by impeding their binding to inflammatory receptors. In experimental stroke, AIM-deficient mice exhibit severe neurological damage and higher mortality with greater levels of DAMPs and associated inflammation in the brain than wild-type mice, in which brain AIM levels increase following stroke onset. Recombinant AIM administration reduces sterile inflammation in the infarcted region, leading to a profound reduction of animal mortality. Our findings provide a basis for the therapies targeting DAMPs to improve ischemic stroke.

Cardiac glycosides, which inhibit NaCell proliferation was examined in CRPC PC-3 and DU-145 cells using sulforhodamine B assay, carboxyfluorescein succinimidyl ester staining assay and clonogenic examination. Flow cytometric analysis was used to detect the distribution of cell cycle phase, mitochondrial membrane potential, intracellular NaAscleposide induced an increase of intracellular NaAscleposide displays antiproliferative and apoptotic activities dependent on the inhibition of Na

This work is a continuation of our previous study investigating the role of the intermediate layer in carbon molecular sieve membrane (CMSM) formation and its impact on the gas separation performance. Herein, the effect of key preparation variables of CMS/TiO2 membrane prepared from the polyetherimide (PEI) precursor on the membrane’s structure and CO2/CH4 separation quality was studied. A set of CMS/TiO2/Al2O3 membranes produced under different conditions (pH of the sol-gel for the intermediate TiO2 layer preparation, the TiO2 interlayer thickness and the carbon separation layer thickness) was prepared, characterized by the AFM, FE-SEM and EDXS methods and tested for CO2/CH4 separation efficiency. In addition, a molecular simulation was applied to investigate the effect of intermediate TiO2 layer.All prepared membranes had good separation quality (the separation factor between 37 and 65). The best results for membranes with the thickest TiO2 interlayer prepared at pH = 5 were identified; notably, membrane samples with the thin defect free carbon separation layer achieved the best balance of permeance vs. selectivity and exceeded the Robeson upper bound. The molecular simulation results support the finding of the intermediate layer plays a vital role for the synthesis of gas separation membranes.

A new CMS membrane with smaller gas pair H2/CO2 and H2/CH4 separation factor of approximately 8.3 and 726, with an H2 permeability of 600.7 Barrer, was synthesized by coating it on titanium gel-modified alumina supports. After calcination, the titanium gel provided an interconnected nano-network intermediate layer for casting dope to penetrate the support and form an interlocking matrix. By adjusting the hydrolysis-condensation rate using acid catalysts, the intermediate layer structure can be modified, which is beneficial for supporting CMS membrane with high adhesion, but not with an interlocking depth too high to increase mass-transfer resistance. Three adhesion mechanisms are proposed in this study to investigate intrinsic adhesion of the selective layer on the TiO2/Al2O3 composite support. These mechanism are mechanical interlocking, chemical bonding, and adsorption. The relationship between permselectivity and adhesion was also evaluated. An adequate/slight pore penetration with strong mechanical interlocking can enhance adhesion without sacrificing high permeance. The new CMS membrane is a promising candidate for electricity generation/hydrogen production with CO2-capture and oxygen-fuel applications.

Background: Incidence and mortality rates for cancer have increased dramatically in the recent 30 years in Taiwan. However, not all patients receive treatment. Treatment refusal might impair patient survival and life quality. In order to improve this situation, we proposed this study to evaluate factors that are related to refusal of treatment in cancer patients via a cancer case manager system. Materials and Methods: This study analysed data from a case management system during the period from 2010 to 2012 at a medical center in Northern Taiwan. We enrolled a total of 14,974 patients who were diagnosed with cancer. Using the PRECEDE Model as a framework, we conducted logistic regression analysis to identify independent variables that are significantly associated with refusal of therapy in cancer patients. A multivariate logistic regression model was also applied to estimate adjusted the odds ratios (ORs) with 95% confidence intervals (95%CI). Results: A total of 253 patients (1.69%) refused treatment. The multivariate logistic regression result showed that the high risk factors for refusal of treatment in cancer patient included: concerns about adverse effects (p