Proposal of a Network System to Solve the Problem of Small Volume in Liver Transplantation; Catholic Medical Center Network.

INTRODUCTION: Liver transplantation (LT) is a complex and demanding procedure associated with significant perioperative challenges and risks. Concerns have arisen regarding LT outcomes in low-volume centers. We implemented an integrated training and surgical team network to address these concerns within the Catholic Medical Center (CMC) network. This study presents a comprehensive review of our 9-year LT experience within the CMC medical network. METHOD: A retrospective study of LT procedures conducted between January 2013 and August 2021 in 6 CMC-affiliated hospitals was performed. One center was categorized as a high-volume center, conducting over 60 cases annually, and the remaining 5 were considered small-volume centers. The primary endpoints assessed were 1-year and 5-year survival rates. RESULTS: A total of 793 LTs were performed during the study period. The high-volume center performed 411 living donor LT (LDLT) cases and 127 deceased donor LT (DDLT) cases. Also, 146 LDLT cases and 109 DDLT cases were performed in 5 small-volume centers. One-year and 5-year patient survival for LDLT recipients was 88.3% and 78.8% in the high-volume center and 85.6% and 80.6% in the low-volume center. Five-year survival was not significantly different in small-volume centers (P = .903). For DDLT recipients, 1-year and 5-year patient survival was 80.3% and 70.6% in the high-volume center and 76.1% and 67.6% in the low-volume center. In DDLT cases, 5-year survival was not significantly different in small-volume centers (P = .445). CONCLUSION: In conclusion, comparable outcomes for liver transplantation can be obtained in a small-volume center with a high level of integrated training systems and networks.

Resonant cavity phosphor.

While phosphors play an immensely important role in solid-state lighting and full-colour displays, it has been noted lately that their performance can be largely improved via structural engineering. Here, phosphor material is synergistically merged with yet another structurally engineered platform, resonant cavity (RC). When a 40-nm-thick colloidal quantum dot (CQD) film is embedded in a tailored RC with a moderate cavity quality factor (Q ≈ 90), it gains the ability to absorb the majority (~87%) of excitation photons, resulting in significantly enhanced CQD fluorescence (~29×) across a reasonably broad linewidth (~13 nm). The colour gamut covered by red and green pixels implemented using the RC phosphor-along with a broad bandwidth (~20 nm) blue excitation source-exceeds that of the sRGB standard (~121%). The simple planar geometry facilitates design and implementation of the RC phosphor, making it promising for use in real applications.

Percutaneous cholecystoduodenal stent as a definite treatment for acute cholecystitis in elderly or comorbid patients: a bicentric retrospective study

PURPOSE: To investigate the safety and efficacy of percutaneous cholecystoduodenal stent (CDS) placement to prevent recurrence of acute cholecystitis in patients who were unfit for cholecystectomy. METHODS: Between April 2016 and January 2022, 46 patients [median age (range) = 81 (37-99) years; men = 15] with acute cholecystitis who were unfit for surgery underwent percutaneous cholecystostomy followed by a CDS placement in two institutions. Plastic stents of three different materials were used [polyethylene, polyurethane (PU), and polycarbonate (PCB)-based PU]. Clinical outcomes, including technical and clinical success rates and early (<30 days) and delayed adverse events, were retrospectively assessed by stent type. RESULTS: CDS placement was technically successful in 39 patients. Clinical success, defined as cholecystostomy catheter removal, was achieved in 35 of 39 patients. Immediate complications, such as acute pancreatitis and peritonitis, occurred in two patients. Two patients experienced recurrent cholecystitis during a 113-day follow-up (range, 3-1,723). Three-stent groups had significantly different delayed complications on Fisher's exact test (P = 0.021). The Bonferroni post-hoc analysis showed the PCB-PU group tended to have fewer complications than the PU group (P = 0.060). CONCLUSION: CDS placement is applicable in treating acute cholecystitis patients who were initially unfit for surgery, but further investigation is needed. Although it was not statistically significant, a PCB-PU stent can be suitable for this use because it tends to have fewer delayed complications and is equipped with a drawstring and side holes.

Engineering Silk Protein to Modulate Polymorphic Transitions for Green Lithography Resists.

Silk protein is being increasingly introduced as a prospective material for biomedical devices. However, a limited locus to intervene in nature-oriented silk protein makes it challenging to implement on-demand functions to silk. Here, we report how polymorphic transitions are related with molecular structures of artificially synthesized silk protein and design principles to construct a green-lithographic and high-performative protein resist. The repetition number and ratio of two major building blocks in synthesized silk protein are essential to determine the size and content of ß-sheet crystallites, and radicals resulting from tyrosine cleavages by the 193 nm laser irradiation induce the ß-sheet to α-helix transition. Synthesized silk is designed to exclusively comprise homogeneous building blocks and exhibit high crystallization and tyrosine-richness, thus constituting an excellent basis for developing a high-performance deep-UV photoresist. Additionally, our findings can be conjugated to design an electron-beam resist governed by the different irradiation-protein interaction mechanisms. All synthesis and lithography processes are fully water-based, promising green lithography. Using the engineered silk, a nanopatterned planar color filter showing the reduced angle dependence can be obtained. Our study provides insights into the industrial scale production of silk protein with on-demand functions.

Structurally engineered colloidal quantum dot phosphor using TiO2 photonic crystal backbone.

Photonic crystal (PhC) phosphor, in which the phosphor material is periodically modulated for an enhancement in color-conversion efficiency via resonant absorption of excitation photons, is a paradigm-shifting structural phosphor platform. Two-dimensional (2D) square-lattice PhC phosphor is currently considered the most advanced platform because of not only its high efficiency, but also its immunity to excitation polarization. In the present study, two major modifications are made to further improve the performance of the 2D PhC phosphor: increasing the refractive index contrast and planarizing the surface. The index contrast is improved by replacing the PhC backbone material with TiO2 whereas the surface planarization is achieved by removing excessive colloidal quantum dots from the surface. In comparison with the reference phosphor, the upgraded PhC phosphor exhibits ~59 times enhanced absorption (in simulations) and ~7 times enhanced emission (in experiments), both of which are unprecedentedly high. Our results not only brighten the viability and applicability of the PhC phosphor but also spur the phosphor development through structural engineering of phosphor materials.

Steroid-Resistant Rejection in Liver Transplant: A Single-Center Study for Risk Factor and Second-Line Treatment.

BACKGROUND: Steroid-resistant rejection (SRR) in liver transplant occurs in about 10% of T cell-mediated rejection; prognosis of SRR is known to be worse than steroid-sensitive rejection (SSR). Only a few studies describe treatment methods or features for SRR, and there is no clear consensus yet. Therefore, the purpose of this study is to describe the difference between SSR and SRR and to compare the effect of the SRR treatment method performed our institution. METHODS: This study is a 10-year, retrospective cohort study at Seoul St Mary's Hospital; clinical data were collected from January 2008 to December 2017. Of 663 cases, 154 patients (23.3%) underwent steroid pulse therapy for rejection; we excluded 30 patients who did not undergo liver biopsy. A total of 124 patients (18.7%) with biopsy-proven rejection were analyzed for this study. RESULTS: Child-Turcotte-Pugh score, cold ischemia time, and cytomegalovirus (CMV) infection showed a statistically significant difference in 2 groups. Multivariate analysis was performed on risk factors of SRR at first rejection. CMV infection and total bilirubin at first rejection and numbers of rejection were significant results. Both overall survival and allograft survival rate of SSR are higher than SRR (P < .001). Of second-line treatment patients, 13 patients (54.2%) recovered, and 11 patients (45.8%) failed to recover. Survival was the highest in patients using antithymocyte globulin and in patients with liver retransplant. CONCLUSIONS: When the first rejection in liver transplant occurs, patients with high bilirubin level ​​and previous CMV infections are more likely to have SRR, so if they do not respond to steroid pulse therapy for the first time, either using antithymocyte globulin or liver retransplant preparation should be considered.

Efficacy of Tumor Markers After Liver Transplantation In Patients With Hepatocellular Carcinoma.

OBJECTIVE: The most reliable treatment for hepatocellular carcinoma (HCC) is liver transplantation (LT). Recurrence of HCC after LT is the most serious problem; therefore, early diagnosis of recurrent HCC is very important. This study investigated the efficacy of tumor markers in patients with LT for HCC. METHODS AND MATERIALS: From January 2008 to December 2016, 242 patients underwent LT for HCC. The operation of LT and immunosuppressive methods were the same as those of general LT patients. All patients were followed up with alpha-fetoprotein (AFP) and protein induced by vitamin K absence (PIVKA)-II. The 41 patients (16.9%) recurred during follow-up period. RESULTS: The factors associated with recurrence were tumor markers (AFP, PIVKA-II), maximum tumor diameter, number, microvascular invasion, Milan criteria, and Edmondson-Steiner grade. In 41 patients with recurrent HCC, 14 patients (34.15%) were both elevated in 2 markers and 18 patients (43.9%) were elevated in 1 tumor marker. There was no relationship between tumor marker and recurrent site. The survival rate of patients with recurrence in 1, 3, and 5 years were 78.6%, 34.7%, and 23.7%, respectively. Curability of treatment and elevation of tumor marker before treatment were correlated with patient survival after recurrence. When the receiver operating characteristic curve was used, the area under the curve value using the sum of AFP and PIVKA-II before LT was 0.827. CONCLUSIONS: In this study, tumor markers (AFP, PIVKA-II) for HCC were correlated with post-transplant recurrence factors and may be a useful tool for early diagnosis and to predict the prognosis after recurrence.

PGC-1α is downregulated in a mouse model of obstructive cholestasis but not in a model of liver fibrosis.

Several studies have indicated that cholestatic liver damage involves mitochondria dysfunction. However, the precise mechanism by which hydrophobic bile salts cause mitochondrial dysfunction is not clear. In this study, we intended to determine the pathogenesis of cholestatic liver injury associated with peroxisome proliferator-activated receptor-γ co-activator 1α (PGC-1α). A mouse model of cholestatic liver disease was generated by surgical ligation of the bile duct (BDL), and a mouse model of fibrosis was developed through serial administration of thioacetamide. After obtaining liver specimens on scheduled days, we compared the expression of the antioxidant enzymes (superoxide dismutase 2 [SOD2], catalase, and glutathione peroxidase-1[GPx-1]) and PGC-1α in livers from mice with fibrosis and cholestasis using western blotting, immunohistochemistry, and immunofluorescence. We found that cholestatic livers exhibit lower expression of antioxidant enzymes, such as SOD2, catalase, and PGC-1α. In contrast, fibrotic livers exhibit higher expression of antioxidant enzymes and PGC-1α. In addition, cholestatic livers exhibited significantly lower expression of pro-apoptotic markers (Bax) as compared to fibrotic livers. It is well known that overexpression of PGC-1α increases mitochondrial antioxidant enzyme expression, and vice versa. Thus, we concluded that obstructive cholestasis decreases expression of PGC-1α, which may lead to decreased expression of mitochondrial antioxidant enzymes, thereby rendering mice with cholestatic livers vulnerable to ROS-induced cell death.

A novel antifibrotic strategy utilizing conditioned media obtained from miR-150-transfected adipose-derived stem cells: validation of an animal model of liver fibrosis.

The limitations of stem cells have led researchers to investigate the secretome, which is the secretory materials in stem cells, since the principal mechanism of action of stem cells is mediated by the secretome. In this study, we determined the antifibrotic potential of the secretome released from miR-150-transfected adipose-derived stromal cells (ASCs). The secretome released from ASCs that were transfected with antifibrotic miR-150 was obtained (referred to as the miR-150 secretome). To validate the antifibrotic effects of the miR-150 secretome, we generated in vitro and in vivo models of liver fibrosis by treating human hepatic stellate cells (LX2 cells) with thioacetamide (TAA) and subcutaneous injection of TAA into mice, respectively. In the in vitro model, more significant reductions in the expression of fibrosis-related markers, such as TGFß, Col1A1, and α-SMA, were observed by using the miR-150 secretome than the control secretome, specifically in TAA-treated LX2 cells. In the in vivo model, infusion of the miR-150 secretome into mice with liver fibrosis abrogated the increase in serum levels of systemic inflammatory cytokines, such as IL-6 and TNF-α, and induced increased expression of antifibrotic, proliferation, and antioxidant activity markers in the liver. Our in vitro and in vivo experiments indicate that the miR-150 secretome is superior to the naive secretome in terms of ameliorating liver fibrosis, minimizing systemic inflammatory responses, and promoting antioxidant enzyme expression. Therefore, we conclude that miR-150 transfection into ASCs has the potential to induce the release of secretory materials with enhanced antifibrotic, proliferative, and antioxidant properties.

Ameliorating liver fibrosis in an animal model using the secretome released from miR-122-transfected adipose-derived stem cells.

BACKGROUND: Recently, the exclusive use of mesenchymal stem cell (MSC)-secreted molecules, called secretome, rather than cells, has been evaluated for overcoming the limitations of cell-based therapy, while maintaining its advantages. However, the use of naïve secretome may not fully satisfy the specificity of each disease. Therefore, it appears to be more advantageous to use the functionally reinforced secretome through a series of processes involving physico-chemical adjustments or genetic manipulation rather than to the use naïve secretome. AIM: To determine the therapeutic potential of the secretome released from miR-122-transfected adipose-derived stromal cells (ASCs). METHODS: We collected secretory materials released from ASCs that had been transfected with antifibrotic miR-122 (MCM) and compared their antifibrotic effects with those of the naïve secretome (CM). MCM and CM were intravenously administered to the mouse model of thioacetamide-induced liver fibrosis, and their therapeutic potentials were compared. RESULTS: MCM infusion provided higher therapeutic potential in terms of: (A) Reducing collagen content in the liver; (B) Inhibiting proinflammatory cytokines; and (C) Reducing abnormally elevated liver enzymes than the infusion of the naïve secretome. The proteomic analysis of MCM also indicated that the contents of antifibrotic proteins were significantly elevated compared to those in the naïve secretome. CONCLUSION: We could, thus, conclude that the secretome released from miR-122-transfected ASCs has higher antifibrotic and anti-inflammatory properties than the naïve secretome. Because miR-122 transfection into ASCs provides a specific way of potentiating the antifibrotic properties of ASC secretome, it could be considered as an enhanced method for reinforcing secretome effectiveness.

Isolation of Secretome with Enhanced Antifibrotic Properties from miR-214-Transfected Adipose-Derived Stem Cells.

BACKGROUND: Secretome refers to the total set of molecules secreted or surface-shed by stem cells. The limitations of stem cell research have led numerous investigators to turn their attention to the use of secretome instead of stem cells. In this study, we intended to reinforce antifibrotic properties of the secretome released from adipose-derived stem cells (ASCs) transfected with miR-214. METHODS: We generated miR-214-transfected ASCs, and extracted the secretome (miR214-secretome) from conditioned media of the transfected ASCs through a series of ultrafiltrations. Subsequently, we intravenously injected the miR-214-secretome into mice with liver fibrosis, and determined the effects of miR-214-secretome on liver fibrosis. RESULTS: Compared with that by naïve secretome, liver fibrosis was ameliorated by intravenous infusion of miR-214-secretome into mice with liver fibrosis, which was demonstrated by significantly lower expression of fibrosis-related markers (alpha-smooth muscle actin, transforming growth factor-ß, and metalloproteinases-2) in the livers as well as lower fibrotic scores in the special stained livers compared with naïve secretome. The infusion of miR-214-secretome also led to lesser local and systemic inflammation, higher expression of an antioxidant enzyme (superoxide dismutase), and higher liver proliferative and synthetic function. CONCLUSION: MicroRNA-214 transfection stimulates ASCs to release the secretome with higher antifibrotic and anti-inflammatory properties. miR-214-secretome is thus expected to be one of the prominent ways of overcoming liver fibrosis, if further studies consistently validate its safety and efficiency.

Efficacy and safety of a novel topical agent for gallstone dissolution: 2-methoxy-6-methylpyridine.

BACKGROUND: Although methyl-tertiary butyl ether (MTBE) is the only clinical topical agent for gallstone dissolution, its use is limited by its side effects mostly arising from a relatively low boiling point (55 °C). In this study, we developed the gallstone-dissolving compound containing an aromatic moiety, named 2-methoxy-6-methylpyridine (MMP) with higher boiling point (156 °C), and compared its effectiveness and toxicities with MTBE. METHODS: The dissolubility of MTBE and MMP in vitro was determined by placing human gallstones in glass containers with either solvent and, then, measuring their dry weights. Their dissolubility in vivo was determined by comparing the weights of solvent-treated gallstones and control (dimethyl sulfoxide)-treated gallstones, after directly injecting each solvent into the gallbladder in hamster models with cholesterol and pigmented gallstones. RESULTS: In the in vitro dissolution test, MMP demonstrated statistically higher dissolubility than did MTBE for cholesterol and pigmented gallstones (88.2% vs. 65.7%, 50.8% vs. 29.0%, respectively; P < 0.05). In the in vivo experiments, MMP exhibited 59.0% and 54.3% dissolubility for cholesterol and pigmented gallstones, respectively, which were significantly higher than those of MTBE (50.0% and 32.0%, respectively; P < 0.05). The immunohistochemical stains of gallbladder specimens obtained from the MMP-treated hamsters demonstrated that MMP did not significantly increase the expression of cleaved caspase 9 or significantly decrease the expression of proliferation cell nuclear antigen. CONCLUSIONS: This study demonstrated that MMP has better potential than does MTBE in dissolving gallstones, especially pigmented gallstones, while resulting in lesser toxicities.

LY3009120, a pan-Raf kinase inhibitor, inhibits adipogenesis of 3T3-L1 cells by controlling the expression and phosphorylation of C/EBP-α, PPAR-γ, STAT­3, FAS, ACC, perilipin A, and AMPK.

Excessive preadipocyte differentiation/adipogenesis is closely linked to the development of obesity. LY3009120 is a pan­Raf kinase inhibitor and is known for its anticancer activities. In the present study, the effect of LY3009120 on 3T3­L1 cell adipogenesis was investigated. The differentiation of 3T3­L1 preadipocytes into adipocytes was measured by Oil Red O staining and AdipoRed assay. Changes of cellular protein expression and phosphorylation levels in differentiating 3T3­L1 preadipocytes in the absence or presence of LY3009120 were determined by western blotting analysis. Cell count assay was used to assess the cytotoxicity of LY3009120 on 3T3­L1 cells. At 0.3 µM, LY3009120 markedly inhibited lipid accumulation and decreased triglyceride content in differentiating 3T3­L1 cells. However, it had minimal effect on the elevated expression and phosphorylation of three Raf kinase isoforms (C­Raf, A­Raf, and B­Raf) observed in the cells. LY3009120 reduced not only the expression of CCAAT/enhancer­binding protein­α (C/EBP­α), peroxisome proliferator­activated receptor­Î³ (PPAR­Î³), fatty acid synthase (FAS), acetyl CoA carboxylase (ACC), and perilipin A, but also reduced the phosphorylation of signal transducer and activator of transcription­3 (STAT­3) in differentiating 3T3­L1 cells. LY3009120 also increased the phosphorylation of adenosine 3',5'­cyclic monophosphate (cAMP)­activated protein kinase (AMPK), but did not affect the phosphorylation or expression of liver kinase B1 in these cells. In summary, this is the first report, to the best of our knowledge, demonstrating that LY3009120 has an anti­adipogenic effect on 3T3­L1 cells, which may be mediated through control of the expression and phosphorylation of C/EBP­α, PPAR­Î³, STAT­3, FAS, ACC, perilipin A, and AMPK.

Anti-Adipogenic Effects on 3T3-L1 Cells and Zebrafish by Tanshinone IIA.

Tanshinone IIA is a diterpene quinone isolated from the roots of Salviamiltiorrhiza bunge that has traditionally been used in China for the treatment of cardiovascular and cerebrovascular disorders. Although there is recent evidence showing that tanshinone IIA has an anti-obesity effect, its underlying mechanism of anti-obesity effect is poorly understood. Here, we investigated the effect of tanshinone IIA on lipid accumulation in 3T3-L1 preadipocytes and zebrafish. Notably, tanshinone IIA at 10 µM concentration greatly reduced lipid accumulation and triglyceride (TG) contents during 3T3-L1 preadipocyte differentiation, suggesting its anti-adipogenic effect. On mechanistic levels, tanshinone IIA reduced the expression levels of CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), fatty acid synthase (FAS), and perilipin A but also the phosphorylation levels of signal transducer and activator of transcription-3/5 (STAT-3/5) in differentiating 3T3-L1 cells. In addition, tanshinone IIA strongly inhibited leptin and resistin mRNA expression in differentiating 3T3-L1 cells. Importantly, the tanshinone IIA's lipid-reducing effect was also seen in zebrafish. In sum, these findings demonstrate that tanshinone IIA has anti-adipogenic effects on 3T3-L1 cells and zebrafish, and its anti-adipogenic effect on 3T3-L1 cells is largely attributable to the reduced expression and/or phosphorylation levels of C/EBP-α, PPAR-γ, FAS, perilipin A, and STAT-3/5.

Sanguinarine induces apoptosis in A549 human lung cancer cells primarily via cellular glutathione depletion.

Sanguinarine is a plant-derived benzophenanthridine alkaloid and has been shown to possess anti-tumor activities against various cancer cells. In this study, we investigated whether sanguinarine induces apoptosis in A549 human lung cancer cells. Treatment of A549 cells with sanguinarine induced apoptosis in a dose- and time-dependent manner. Treatment with sanguinarine led to activation of caspases and MAPKs as well as increased MKP-1 expression. Importantly, pretreatment with z-VAD-fmk, a pan caspase inhibitor suppressed the sanguinarine-induced apoptosis in A549 cells. Moreover, pretreatment with NAC, a sulfhydryl group-containing reducing agent strongly suppressed the apoptotic response and caspase activation to sanguinarine. However, the sanguinarine-mediated cytotoxicity in A549 cells was not protected by pharmacological inhibition of MAPKs or MKP-1 siRNA-mediated knockdown of MKP-1. These results collectively suggest that sanguinarine induces apoptosis in A549 cells through cellular glutathione depletion and the subsequent caspase activation.