Syngeneic mesenchymal stem cells loaded with telomerase-dependent oncolytic adenoviruses enhance anti-metastatic efficacy.

Oncolytic adenoviruses have emerged as a promising therapeutic approach for cancer therapy. However, systemic delivery of the viruses to metastatic tumors remains a major challenge. Mesenchymal stem cells (MSCs) possess tumor tropism property and can be used as cellular vehicles for delivering oncolytic adenoviruses to tumor sites. Since telomerase activity is found in ~90% of human carcinomas, but undetected in normal adult cells, the human telomerase reverse transcriptase gene (TERT) promoter can be exploited for regulating the replication of oncolytic adenoviruses. Here, we evaluated the antitumor effects of syngeneic murine MSCs loaded with the luciferase-expressing, telomerase-dependent oncolytic adenovirus Ad.GS2 (MSC-Ad.GS2) and Ad.GS2 alone on metastatic MBT-2 bladder tumors. MSCs supported a low degree of Ad.GS2 replication, which could be augmented by coculture with MBT-2 cells or tumor-conditioned medium (TCM), suggesting that viral replication is increased when MSC-Ad.GS2 migrates to tumor sites. MBT-2 cells and TCM enhanced viral replication in Ad.GS2-infected MSCs. SDF-1 is a stem cell homing factor. Our results suggest that the SDF-1/STAT3/TERT signaling axis in MSCs in response to the tumor microenvironment may contribute to the enhanced replication of Ad.GS2 carried by MSCs. Notably, we demonstrate the potent therapeutic efficacy of systemically delivered MSC-Ad.GS2 in pleural disseminated tumor and experimental metastasis models using intrapleural and tail vein injection of MBT-2 cells, respectively. Treatment with MSC-Ad.GS2 significantly reduced tumor growth and prolonged the survival of mice bearing metastatic bladder tumors. Since telomerase is expressed in a broad spectrum of cancers, this therapeutic strategy may be broadly applicable.

Preventing viral relapse with prophylactic tenofovir in hepatitis B carriers receiving chemotherapy: a phase IV randomized study in Taiwan.

BACKGROUND AND AIMS: This study aimed to compare the efficacy of shorter vs. longer tenofovir disoproxil fumarate (TDF) prophylaxis in preventing hepatitis B virus (HBV) relapse in cancer patients with chronic hepatitis B (CHB) undergoing chemotherapy. METHODS: This phase IV, prospective randomized trial enrolled cancer patients with CHB from 2014 to 2019 in Taiwan. Included patients were randomized to receive either 24- (Arm A) or 48-week (Arm B) post-chemotherapy TDF and compared for cumulative incidence of virological and clinical relapse. Logistic regressions were conducted to determine the factors associated with HBV relapse. RESULTS: One hundred patients were randomized, and 41 patients in Arm A and 46 in Arm B completed the TDF treatment. No significant difference was found in cumulative incidence of virological relapse (Arm A: 94.4%, Arm B: 93.1%, p = 0.110) or clinical relapse among patients with baseline HBV DNA > 2000 IU/mL (Arm A: 38.9%, Arm B: 26.7%, p = 0.420) between the two arms. High baseline HBV DNA ≥ 10,000 IU/mL (OR = 51.22) and HBsAg ≥ 1000 IU/mL (OR = 8.64) were independently associated with an increased virological relapse. Alanine aminotransferase (ALT), serum phosphorus, vitamin D, and estimated glomerular filtration rate (eGFR) remained stable throughout the study. CONCLUSIONS: The 24-week preventative TDF has comparable efficacy to the 48-week treatment in virologic and clinical relapse. High baseline HBsAg or HBV DNA is associated with a higher risk of HBV relapse. These findings imply a 24-week duration of TDF treatment with a close monitor for patients with a high baseline viral load. Hepatitis B virus infection is a prominent cause of liver cancer and chronic liver disease and affected millions of people worldwide. When HBV-infected people are exposed to immunosuppressive medication or chemotherapy for cancer, the chance of HBV reactivation rises considerably. This trial showed 24-week tenofovir disoproxil fumarate (TDF) may be sufficient for preventing HBV relapse in cancer patients receiving chemotherapy. CLINICAL TRIAL REGISTRATION NUMBER: NCT02081469.

Hepatocellular carcinoma reduced, HBsAg loss increased, and survival improved after finite therapy in hepatitis B patients with cirrhosis.

BACKGROUND AND AIMS: Long-term nucleos(t)ide analog (Nuc) treatment can reduce HCC in patients with HBV-related liver cirrhosis (HBV-LC). Earlier small cohort studies showed a comparable 5-year incidence of HCC in HBeAg-negative patients with HBV-LC who stopped and those continued Nuc therapy. This study aimed to validate these findings using a large cohort with 10-year follow-up. APPROACH AND RESULTS: From 2 centers, 494 HBeAg-negative patients with HBV-LC who stopped (finite group) and 593 who continued (continuous group) Nuc therapy were recruited. HCC, HBsAg loss, liver-related mortality/transplantation, and overall survival rates were compared between 2 groups with 1:1 propensity score matching of sex, treatment history, types of Nuc, age, transaminases, platelet count, and HBsAg levels at end of therapy in finite group or 3-year on-therapy in continuous groups. During a median follow-up of 6.2 (3.4-8.9) years, the annual and 10-year HCC incidence were lower in finite group (1.6 vs. 3.3%/y and 10-y 15.7% vs. 26.8%, respectively; log-rank test, p <0.0001). The finite group showed greater HBsAg decline/year (-0.116 vs. -0.095 log 10 IU/mL, p =0.0026) and 7.6 times higher 10-year incidence of HBsAg loss (22.7% vs. 3%, p <0.0001). Multivariate Cox regression showed finite therapy an independent factor for HBsAg loss (adjusted HR: 11.79) but protective against HCC (adjusted HR: 0.593), liver-related mortality/transplantation (adjusted HR: 0.312), and overall mortality (adjusted HR: 0.382). CONCLUSIONS: Finite Nuc therapy in HBeAg-negative HBV-LC may reduce HCC incidence, increase HBsAg loss, and improve survival. Greater HBsAg decline/loss may reflect enhanced immunity and contribute to the reduction of hepatic carcinogenesis.

Thiamet G as a Potential Treatment for Polycystic Kidney Disease.

BACKGROUND/AIM: Autosomal dominant polycystic kidney disease (ADPKD) is a prevalent genetic disorder primarily caused by mutations in Pkd1 (PC1), which account for the majority of ADPKD cases. These mutations contribute to the formation of cysts in the kidneys and other organs, ultimately leading to renal failure. Unfortunately, there are currently no available preventive treatments for this disease. MATERIALS AND METHODS: In this study, we utilized Pkd1-knockdown mice and cells to investigate the potential involvement of O-GlcNAcylation in the progression of PKD. Additionally, we examined the effects of thiamet G, an inhibitor of O-GlcNAcase (OGA), on PKD mice. RESULTS: Our findings indicate that both O-GlcNAcylation and OGT (O-GlcNAc transferase) were downregulated in the renal tissues of Pkd1-silenced mice. Furthermore, O-GlcNAcylation was shown to regulate the stability and function of the C-terminal cytoplasmic tail (CTT) of PC1. Treatment of PKD mice with thiamet G resulted in a reduction of renal cytogenesis in these animals. CONCLUSION: These results highlight the unique role of O-GlcNAcylation in the development of cyst formation in PKD and propose it as a potential therapeutic target for the treatment of PKD.

Optimization of Continuous Casting for Preventing Surface Peeling Defects on Titanium-Containing Ferrite Stainless Steel.

The surfaces of cold-rolled titanium-containing ferrite stainless steel (TCFSS) strips produced from scrap are prone to severe peeling owing to cracking near slab inclusions during hot rolling. In this study, the Taguchi method was used to prevent peeling defects and clogging of the submerged entrance nozzle, and the optimal casting parameters, such as the degree of casting overheating, casting speed, stirring time, and inclination, were determined. The results showed that increasing the degree of casting overheating and decreasing the casting speed prevented clogging and effectively mitigated peeling defects. Sample A3B1C3D2 had the optimal parameters to reduce the clog thickness to less than 1.5 mm, i.e., a degree of overheating of 60 °C, a casting speed of 0.80 m/min, a stirring time of 12.0 s, and an inclination angle of 6.0°. Sample A3B1C1D3 had the optimal parameters to prevent peeling defects, i.e., a degree of overheating of 60 °C, a casting speed of 0.80 m/min, a stirring time of 10.0 s, and an inclination angle of 6.2°. When casting using these optimal parameters, no peeling defects were observed on the surfaces of the TCFSS strips. The TCFSS strips produced using the optimized parameters exhibited the required mechanical properties and satisfied the design criteria. The parameters included a tensile strength of ≥415 MPa, a yield strength of ≥205 MPa, an elongation of ≥22%, and a hardness of ≤89 HRB.

Comparing Predictability of Non-invasive Tools for Hepatocellular Carcinoma in Treated Chronic Hepatitis C Patients.

BACKGROUND: Non-invasive tools including liver stiffness measurement (LSM) or FIB-4, assessed before or after direct acting antivirals (DAA), have been suggested to predict hepatocellular carcinoma (HCC). AIMS: This study aims to compare predictability of HCC by these methods at different time points, to validate the HCC surveillance suggestion by guidelines, and to propose personalized strategy. METHODS: Chronic hepatitis C whose LSM and FIB-4 were available at pretherapy and after sustained virological response (SVR) were enrolled. Advanced chronic liver disease (ACLD) was defined as pretherapy LSM ≥ 10 kPa or FIB-4 index ≥ 3.25 or ultrasound signs of cirrhosis plus platelet count < 150,000/µL. The predictabilities were compared by area under ROC. The cumulative HCC incidences were calculated by Kaplan-Meier analysis. RESULTS: Among 466 ACLD patients, 40 patients developed HCC during a follow-up duration of 26.8 months. Comparable predictive performances for HCC between LSM and FIB-4 at pretherapy and SVR were noted. By guidelines suggestion using pretherapy LSM = 10 kPa (advanced fibrosis) and 13 kPa (cirrhosis) for risk stratification, the annual HCC incidences of those with LSM of < 10, 10-12.9 and ≥ 13 kPa were 1.1, 3.6, and 5.0%, respectively. Combination of baseline LSM < 12 kPa and SVR FIB-4 < 3.7 could further stratify relatively low risk of HCC in ACLD patients of annal incidence of 1.2%. CONCLUSIONS: ACLD patients who met advanced fibrosis but not cirrhosis by guidelines' cut-offs still posed high risk of HCC. Baseline LSM with SVR FIB-4 can be applied to stratify low, intermediate, and high risk of HCC for personalizing surveillance strategies after SVR.

Polypeptide Bilayer Assembly-Mediated Gene Delivery Enhances Chemotherapy in Cancer Cells.

Developing gene vectors with high transfection efficiency and low cytotoxicity to humans is crucial to improve gene therapy outcomes. This study set out to investigate the use of cationic polypeptide bilayer assemblies formed by coil-sheet poly(l-lysine)-block-poly(l-benzyl-cysteine) (PLL-b-PBLC) as gene vectors that present improved transfection efficiency, endosomal escape, and biocompatibility compared to PLL. The formation of the polyplexes was triggered by hydrogen bonding, hydrophobic interactions, and electrostatic association between the cationic PLL segments and the negatively charged plasmid encoding p53, resulting in self-assembled polypeptide chains. Transfection efficiency of these polyplexes increased with increments of PLL-to-PBLC block ratios, with PLL15-b-PBLC5 bilayers exhibiting the best in vitro transfection efficiency among all, suggesting that PLL-b-PBLC bilayer assemblies are efficient in the protection and stabilization of genes. The polypeptide bilayer gene vector reversed the cisplatin sensitivity of p53-null cancer cells by increasing apoptotic signaling. Consistent with in vitro results, mouse xenograft studies revealed that PLL15-b-PBLC5/plasmid encoding p53 therapy significantly suppressed tumor growth and enhanced low-dose cisplatin treatment, while extending survival of tumor-bearing mice and avoiding significant body weight loss. This study presents a feasible gene therapy that, combined with low-dose chemotherapeutic drugs, may treat genetically resistant cancers while reducing side effects in clinical patients.

Association of Common Variants in OLA1 Gene with Preclinical Atherosclerosis.

Reactive oxygen species impair the blood vessels, leading to the initiation of atherosclerosis, and migration and proliferation of vascular smooth muscle cells and neovascularization by endothelial cells of vasa vasorum are essential for atherosclerosis development. Obg-like ATPase 1 (OLA1), a negative regulator in cellular responses to oxidative stress, binds to breast cancer susceptibility gene 1 (BRCA1), which protects vascular endothelial and smooth muscle cells against reactive oxygen species. However, it is not known whether OLA1 is genetically correlated with atherosclerosis. Here, we conducted two independent population-based case-control studies to explore the effects of variants in OLA1 genes on preclinical atherosclerosis. A total of 564 and 746 subjects who had thicker and normal carotid intima-media thickness (cIMT), respectively, were enrolled. Among 55 screened SNPs, rs35145102, rs201641962, rs12466587, rs4131583, and rs16862482 in OLA1 showed significant associations with cIMT. SNP rs35145102 is a 3'-utr variant and correlates with the differential expression of OLA1 in immune cells. These five genetic markers form a single closely linked block and H1-ATTGT and H2-GCCTC were the top two most prevalent 5-locus haplotypes. The H1 + H1 genotype negatively and H1 + H2 genotype positively correlated with thicker cIMT. The five identified SNPs in the OLA1 gene showed significant correlations with cIMT. Furthermore, we found that OLA1 was required for migration and proliferation of human aortic endothelial and smooth muscle cells and regulated vascular tube formation by human aortic endothelial cells. Therefore, these genetic variants in the OLA1 gene may serve as markers for risk prediction of atherosclerotic diseases.

Optimization of Hot Rolling Scheduling of Steel Strip with High Bending Performance.

Poor formability in hot-rolled strips may be attributed to the many pearlite-banded structures (PBSs) that develop in steel during the hot-rolling process. The challenge of manufacturing strips with minimum PBSs is that multiple factors influence the amount and distribution of the PBSs. This study used the Taguchi method to find the optimum hot-rolling parameters to obtain strips with a reduced number of PBSs. The strips were then subjected to bending tests to evaluate their ductility. The first part analyzes the contribution of selected parameters to the hot-rolling process: (1) finishing rolling temperature, (2) finishing rolling speed, (3) coiling temperature, and (4) coiling speed. The second part confirms, using bending tests, the influence of the finishing rolling temperatures 780, 800, 820, 840, 860, 870, and 880 °C on the formability of an A36 hot-rolled strip. Based on the experimental protocol for the study, the optimal process parameters were determined to be the finishing rolling speed (0.80 m/s), finishing rolling temperature (870 °C), coiling speed (2.80 m/s), and coiling temperature (650 °C). When the A36 strip was prepared at the optimum parameters, the average length and thickness of the PBS were 108.61 ± 0.11 µm and 10.18 ± 0.12 µm, respectively. According to the Taguchi analysis, the finishing rolling temperature had the most significant influence on the dimensions of the PBS. In tests where the hot-rolled A36 strip was bent to 90° and 180°, at the finishing rolling temperatures of 870 °C and 880 °C, no cracking was observed at the R angle.

Innate-like bystander-activated CD38+ HLA-DR+ CD8+ T cells play a pathogenic role in patients with chronic hepatitis C.

BACKGROUND AND AIMS: HCV-specific T cells are few and exhausted in patients with chronic hepatitis C (CHC). Whether these T cells are responsible for the liver damage and fibrosis is still debated. However, cluster of differentiation 38-positive (CD38+ ) human leukocyte antigen DR-positive (HLA-DR+ ) CD8+ T cells are regarded as bystander CD8+ T cells that cause liver injury in acute hepatitis. We propose that these innate CD8+ T cells play a pathogenic role in CHC. METHODS: Lymphocytes from peripheral blood were obtained from 108 patients with CHC and 43 healthy subjects. Immunophenotyping, functional assays, T-cell receptor (TCR) repertoire, and cytotoxic assay of CD38+ HLA-DR+ CD8+ T cells were studied. RESULTS: The percentage of CD38+ HLA-DR+ CD8+ T cells increased significantly in patients with CHC. These cells expressed higher levels of effector memory and proinflammatory chemokine molecules and showed higher interferon-γ production than CD38- HLA-DR- CD8 T cells. They were largely composed of non-HCV-specific CD8+ T cells as assessed by HLA-A2-restricted pentamers and next-generation sequencing analysis of the TCR repertoire. In addition, these CD38+ HLA-DR+ CD8+ T cells had strong cytotoxicity, which could be inhibited by anti-DNAX accessory molecule 1, anti-NKG2 family member D, and anti-natural killer NKp30 antibodies. Lastly, the percentage of CD38+ HLA-DR+ CD8+ T cells was significantly associated with liver injury and fibrosis and decreased significantly along with serum alanine aminotransferase normalization after successful direct-acting antiviral treatment. CONCLUSIONS: The TCR-independent, cytokine-responsive bystander CD38+ HLA-DR+ CD8+ T cells are strongly cytotoxic and play a pathogenic role in patients with CHC.

Multi-Omics Analyses Identify Signatures in Patients with Liver Cirrhosis and Hepatocellular Carcinoma.

Gut bacterial/viral dysbiosis, changes in circulating metabolites, and plasma cytokines/chemokines have been previously associated with various liver diseases. Here, we analyzed the associations between fecal microbial composition, circulating metabolites, and plasma cytokines/chemokines in patients with liver cirrhosis (LC) and hepatocellular carcinoma (HCC). We recruited 10 HCC patients, 18 LC patients, and 17 healthy individuals. Their stool samples were used for gene sequencing of bacterial 16S rRNA and viral genomes, while plasma samples were utilized for the determination of endotoxin, zonulin, metabolite, and cytokine/chemokine levels. Dysbiosis was observed among gut bacteria and viruses, with significant changes in abundance at the genus and species levels, respectively. However, no differences were found between cohorts in the alpha and beta diversity. Plasma lipopolysaccharides and zonulin, but not trimethylamine N-oxide, were progressively increased in LC and HCC subjects. Profiling plasma metabolites and selected cytokines/chemokines revealed differential changes in the LC and HCC cohorts. Following joint correlation and correlation network analyses, regardless of etiology, common network signatures shared by LC and HCC patients were characterized by the gut virus Stenotrophomonas virus DLP5 and the uncultured Caudovirales phage, plasma metabolites pyruvic acid and acetic acid, and plasma cytokines/chemokines eotaxin and PDGF-AB/BB, respectively. Additionally, LC- and HCC-specific correlation networks were also identified. This study provides novel insights into altered gut microbial/viral composition that may contribute to pre-HCC disorders, metabolic reprogramming, or inflammatory microenvironments for hepatocarcinogenesis.

The Pro-Survival Oct4/Stat1/Mcl-1 Axis Is Associated with Poor Prognosis in Lung Adenocarcinoma Patients.

The embryonic stem cell marker Oct4 is expressed in several human cancers and is positively correlated with a poor outcome in cancer patients. However, its physiological role in cancer progression remains poorly understood. Tumor cells block apoptosis to escape cell death so that they can proliferate indefinitely, leading to ineffective therapy for cancer patients. In this study, we investigated whether Oct4 regulates the apoptosis pathway and contributes to poor prognosis in patients with lung adenocarcinoma. Our results revealed that Oct4 expression is correlated with Stat1 expression in lung adenocarcinoma patients and Oct4 is directly bound to the Stat1 promoter to transactivate Stat1 in lung adenocarcinoma cells. Expression of the Stat1 downstream gene Mcl-1 increased in Oct4-overexpressing cancer cells, while Stat1 knockdown in Oct4-overexpressing cancer cells sensitized them to cisplatin-induced apoptosis. Furthermore, Oct4 promoted Stat1 expression and tumor growth, whereas silencing of Stat1 reduced Oct4-induced tumor growth in human lung tumor xenograft models. Taken together, we demonstrate that Oct4 is a pro-survival factor by inducing Stat1 expression and that the Oct4/Stat1/Mcl-1 axis may be a potential therapeutic target for lung adenocarcinoma.

Targeting Intra-Pulmonary P53-Dependent Long Non-Coding RNA Expression as a Therapeutic Intervention for Systemic Lupus Erythematosus-Associated Diffuse Alveolar Hemorrhage.

Diffuse alveolar hemorrhage (DAH) in systemic lupus erythematosus (SLE) is associated with significant mortality, requiring a thorough understanding of its complex mechanisms to develop novel therapeutics for disease control. Activated p53-dependent apoptosis with dysregulated long non-coding RNA (lncRNA) expression is involved in the SLE pathogenesis and correlated with clinical activity. We examined the expression of apoptosis-related p53-dependent lncRNA, including H19, HOTAIR and lincRNA-p21 in SLE-associated DAH patients. Increased lincRNA-p21 levels were detected in circulating mononuclear cells, mainly in CD4+ and CD14+ cells. Higher expression of p53, lincRNA-p21 and cell apoptosis was identified in lung tissues. Lentivirus-based short hairpin RNA (shRNA)-transduced stable transfectants were created for examining the targeting efficacy in lncRNA. Under pristane stimulation, alveolar epithelial cells had increased p53, lincRNA-p21 and downstream Bax levels with elevated apoptotic ratios. After pristane injection, C57/BL6 mice developed DAH with increased pulmonary expression of p53, lincRNA-p21 and cell apoptosis. Intra-pulmonary delivery of shRNA targeting lincRNA-p21 reduced hemorrhage frequencies and improved anemia status through decreasing Bax expression and cell apoptosis. Our findings demonstrate increased p53-dependent lncRNA expression with accelerated cell apoptosis in the lungs of SLE-associated DAH patients, and show the therapeutic potential of targeting intra-pulmonary lncRNA expression in a pristane-induced model of DAH.

Molecular Mechanism of Vitamin K2 Protection against Amyloid-ß-Induced Cytotoxicity.

The pathological role of vitamin K2 in Alzheimer's disease (AD) involves a definite link between impaired cognitive functions and decreased serum vitamin K levels. Vitamin K2 supplementation may have a protective effect on AD. However, the mechanism underlying vitamin K2 protection has not been elucidated. With the amyloid-ß (Aß) cascade hypothesis, we constructed a clone containing the C-terminal fragment of amyloid precursor protein (ß-CTF/APP), transfected in astroglioma C6 cells and used this cell model (ß-CTF/C6) to study the protective effect of vitamin K2 against Aß cytotoxicity. Both cellular and biochemical assays, including cell viability and reactive oxygen species (ROS), assays assay, and Western blot and caspase activity analyses, were used to characterize and unveil the protective role and mechanism of vitamin K2 protecting against Aß-induced cytotoxicity. Vitamin K2 treatment dose-dependently decreased the death of neural cells. The protective effect of vitamin K2 could be abolished by adding warfarin, a vitamin K2 antagonist. The addition of vitamin K2 reduced the ROS formation and inhibited the caspase-3 mediated apoptosis induced by Aß peptides, indicating that the mechanism underlying the vitamin K2 protection is likely against Aß-mediated apoptosis. Inhibitor assay and Western blot analyses revealed that the possible mechanism of vitamin K2 protection against Aß-mediated apoptosis might be via regulating phosphatidylinositol 3-kinase (PI3K) associated-signaling pathway and inhibiting caspase-3-mediated apoptosis. Our study demonstrates that vitamin K2 can protect neural cells against Aß toxicity.

Hybrid ZnO/chitosan antimicrobial coatings with enhanced mechanical and bioactive properties for titanium implants.

A biocomposite coating comprising chitosan and ZnO deposited on a porous Ti oxide is developed to avoid orthopedic and dental implant-related infections. The coating comprised of an inner layer of nanoporous TiO2 and the outer layer of the chitosan matrix with ZnO nanoparticles. Microbiological tests show that chitosan coating is effective against Escherichia coli (E. coli), however, its ability to inhibit bacterial adhesion is very limited. A 1.2-fold increase in the antibacterial activity of chitosan/ZnO coating against E. coli was detected as compared to the chitosan coating alone, and the chitosan/ZnO efficiently inhibited biofilm formation. In addition, the chitosan/ZnO coating exhibited improved bioactivity compared to the chitosan coating. The improvement in antibacterial properties and bioactivity of the chitosan/ZnO coating is attributed to the release of Zn2+ ions. The critical force of scratching the chitosan/ZnO coating was approximately twice that of the chitosan coating. The potentiodynamic polarization results confirmed that the corrosion resistance of the implant with ZnO/chitosan/Ti structure was improved. In addition, cytocompatibility evaluation indicated that the chitosan/ZnO coating has good cytocompatibility in MG-63 cells as compared to pure Ti.

Advanced Liver Fibrosis Is Associated with Necroinflammatory Grade but Not Hepatic Steatosis in Chronic Hepatitis B Patients.

BACKGROUND AND AIMS: Patients with chronic hepatitis B (CHB) are at an increased risk of disease progression. The influence of hepatic steatosis (HS) to liver fibrosis was controversial. We aim to investigate the association between HS and liver fibrosis and explore the predicting factors for advanced fibrosis. METHODS: CHB patients undergoing liver biopsy with complete assessments of HS, necroinflammation grade [histological activity index (HAI) score], and fibrosis stage were retrospectively recruited. Logistic regression analysis was performed to determine the factors associated with advanced liver fibrosis. RESULTS: In this cohort of 672 patients, 342 (50.9%) had HS and 267 (39.4%) were of advanced liver fibrosis. Age [odds ratio (OR) 1.026, 95% confidence interval (CI) 1.007-1.046, p = 0.008], body mass index (BMI, OR 1.091, 95% CI 1.026-1.159, p = 0.005), genotype (C vs. B) (OR 2.790, 95% CI 1.847-4.214, p < 0.001), platelet (OR 0.986, 95% CI 0.982-0.991, p < 0.001), and HAI score (OR 1.197, 95% CI 1.114-1.285, p < 0.001) were independent factors for advanced liver fibrosis in multivariate logistic regression analysis. HAI score was also a significantly associated factor for significant liver fibrosis in non-cirrhotic subpopulation (OR 1.578, 95% CI 1.375-1.810, p < 0.001). HS was not related to advanced/significant liver fibrosis in overall/non-cirrhotic population (p > 0.05). CONCLUSIONS: Significant or advanced liver fibrosis is associated with grade of necroinflammation but not with HS in CHB patients.

Effects of Reinforcement Ratios and Sintering Temperatures on the Mechanical Properties of Titanium Nitride/Nickel Composites.

In this study, powder metallurgy was used to fabricate titanium nitride/nickel metal-matrix composites. First, titanium and nickel powders with weight ratios of 20:80, 50:50 and 80:20 were dry mixed for 24 h. After cold isostatic pressing, the green compacts were soaked in a water-based hot forging lubricant and sintered at 850, 950 and 1050 °C for 1.5 h in an air atmosphere. The effects of the amounts of titanium powder and the sintering temperatures on the mechanical properties (hardness, wear resistance and compressive strength) of the composites were investigated. The results indicated that titanium gradually transformed into titanium nitride near the surface after sintering due to the carbothermal reduction reaction; this transformation was observed to significantly increase the hardness. In addition, an oxygen-rich film was observed to form between the titanium nitride particles and the nickel matrix. An optimum sintering temperature of 950 °C provides the composites (titanium-nickel weight ratios of 20:80) the best mechanical properties (wear resistance and compressive strength) among other groups. Furthermore, increasing the titanium content to 80% in the composite increased the hardness; however, the wear resistance and compressive strength decreased.

Peptide Fibrillar Assemblies Exhibit Membranolytic Effects and Antimetastatic Activity on Lung Cancer Cells.

Cancer metastasis is a central oncology concern that worsens patient conditions and increases mortality in a short period of time. During metastatic events, mitochondria undergo specific physiological alterations that have emerged as notable therapeutic targets to counter cancer progression. In this study, we use drug-free, cationic peptide fibrillar assemblies (PFAs) formed by poly(L-Lysine)-block-poly(L-Threonine) (Lys-b-Thr) to target mitochondria. These PFAs interact with cellular and mitochondrial membranes via electrostatic interactions, resulting in membranolysis. Charge repulsion and hydrogen-bonding interactions exerted by Lys and Thr segments dictate the packing of the peptides and enable the PFAs to display enhanced membranolytic activity toward cancer cells. Cytochrome c (cyt c), endonuclease G, and apoptosis-inducing factor were released from mitochondria after treatment of lung cancer cells, subsequently inducing caspase-dependent and caspase-independent apoptotic pathways. A metastatic xenograft mouse model was used to show how the PFAs significantly suppressed lung metastasis and inhibited tumor growth, while avoiding significant body weight loss and mortality. Antimetastatic activities of PFAs are also demonstrated by in vitro inhibition of lung cancer cell migration and clonogenesis. Our results imply that the cationic PFAs achieved the intended and targeted mitochondrial damage, providing an efficient antimetastatic therapy.

Impact of hepatic steatosis on treatment response in nuclesos(t)ide analogue-treated HBeAg-positive chronic hepatitis B: a retrospective study.

BACKGROUND: The impact of hepatic steatosis (HS) on treatment response following nucleos(t)ide analogue (NA) treatment for chronic hepatitis B (CHB) patients has not been clearly elucidated. We aimed to investigate the difference in HBeAg seroclearance between NA-treated HBeAg-positive CHB patients with and without HS. METHODS: We retrospectively recruited HBeAg-positive CHB patients receiving liver biopsy and NA monotherapy. The baseline clinical characteristics and cumulative incidence of HBeAg seroclearance were compared between patients with and without HS and age/gender-matched subgroup analysis was performed. RESULTS: A total of 196 patients were enrolled from 2003 April to 2016 October. The mean age was 39.6 ± 11.2 years, 142 (72.4%) were males and 94 (48%) had histological evidence of HS. Median treatment duration and follow-up period were 24.3 months and 54.9 months, respectively. HBeAg seroclearance was achieved in 56/102 (54.9%) and 54/94 (57.4%) patients with and without HS, respectively (p = 0.830). The 5-year cumulative incidence of HBeAg seroclearance in patients with and without HS was 62.8 and 67.7% in overall population (p = 0.398) and 62.4 and 66.9% in age/gender-matched subgroups (p = 0.395), respectively. The rate of HBeAg seroclearance was comparable between patients with or without HS in different NA monotherapy (all p > 0.05). CONCLUSIONS: HS had no significant impact on HBeAg seroclearance in HBeAg-positive CHB patients with NA monotherapy during long-term follow-up.