Role of autophagy-related genes in liver cancer prognosis.

Autophagy, a highly conserved process of protein and organelle degradation, has emerged as a critical regulator in various diseases, including cancer progression. In the context of liver cancer, the predictive value of autophagy-related genes remains ambiguous. Leveraging chip datasets from the TCGA and GTEx databases, we identified 23 differentially expressed autophagy-related genes in liver cancer. Notably, five key autophagy genes, PRKAA2, BIRC5, MAPT, IGF1, and SPNS1, were highlighted as potential prognostic markers, with MAPT showing significant overexpression in clinical samples. In vitro cellular assays further demonstrated that MAPT promotes liver cancer cell proliferation, migration, and invasion by inhibiting autophagy and suppressing apoptosis. Subsequent in vivo studies further corroborated the pro-tumorigenic role of MAPT by suppressing autophagy. Collectively, our model based on the five key genes provides a promising tool for predicting liver cancer prognosis, with MAPT emerging as a pivotal factor in tumor progression through autophagy modulation.

Endothelial ß-catenin upregulation and Y142 phosphorylation drive diabetic angiogenesis via upregulating KDR/HDAC9.

BACKGROUND: Diabetic angiogenesis is closely associated with disabilities and death caused by diabetic microvascular complications. Advanced glycation end products (AGEs) are abnormally accumulated in diabetic patients and are a key pathogenic factor for diabetic angiogenesis. The present study focuses on understanding the mechanisms underlying diabetic angiogenesis and identifying therapeutic targets based on these mechanisms. METHODS: In this study, AGE-induced angiogenesis serves as a model to investigate the mechanisms underlying diabetic angiogensis. Mouse aortic rings, matrigel plugs, and HUVECs or 293T cells were employed as research objects to explore this pathological process by using transcriptomics, gene promoter reporter assays, virtual screening and so on. RESULTS: Here, we found that AGEs activated Wnt/ß-catenin signaling pathway and enhanced the ß-catenin protein level by affecting the expression of ß-catenin degradation-related genes, such as FZDs (Frizzled receptors), LRPs (LDL Receptor Related Proteins), and AXIN1. AGEs could also mediate ß-catenin Y142 phosphorylation through VEGFR1 isoform5. These dual effects of AGEs elevated the nuclear translocation of ß-catenin and sequentially induced the expression of KDR (Kinase Insert Domain Receptor) and HDAC9 (Histone Deacetylase 9) by POU5F1 and NANOG, respectively, thus mediating angiogenesis. Finally, through virtual screening, Bioymifi, an inhibitor that blocks VEGFR1 isoform5-ß-catenin complex interaction and alleviates AGE-induced angiogenesis, was identified. CONCLUSION: Collectively, this study offers insight into the pathophysiological functions of ß-catenin in diabetic angiogenesis.

Distinct epigenetic modulation of differentially expressed genes in the adult mouse brain following prenatal exposure to low-dose bisphenol A.

Bisphenol A (BPA) is a common component in the manufacture of daily plastic consumer goods. Recent studies have suggested that prenatal exposure to BPA can increase the susceptibility of offspring to mental illness, although the underlying mechanisms remain unclear. In this study, we performed transcriptomic and epigenomic profiling in the adult mouse brain following prenatal exposure to low-dose BPA. We observed a sex-specific transcriptional dysregulation in the cortex, with more significant differentially expressed genes was observed in adult cortex from male offspring. Moreover, the upregulated genes primarily influenced neuronal functions, while the downregulated genes were significantly associated with energy metabolism pathways. More evidence supporting impaired mitochondrial function included a decreased ATP level and a reduced number of mitochondria in the cortical neuron of the BPA group. We further investigated the higher-order chromatin regulatory patterns of DEGs by incorporating published Hi-C data. Interestingly, we found that upregulated genes exhibited more distal interactions with multiple enhancers, while downregulated genes displayed relatively short-range interactions among adjacent genes. Our data further revealed decreased H3K9me3 signal on the distal enhancers of upregulated genes, whereas increased DNA methylation and H3K27me3 signals on the promoters of downregulated genes. In summary, our study provides compelling evidence for the potential health risks associated with prenatal exposure to BPA, and uncovers sex-specific transcriptional changes with a complex interplay of multiple epigenetic mechanisms.

Transcriptomic profiling of the developing brain revealed cell-type and brain-region specificity in a mouse model of prenatal stress.

BACKGROUND: Prenatal stress (PS) is considered as a risk factor for many mental disorders. PS-induced transcriptomic alterations may contribute to the functional dysregulation during brain development. Here, we used RNA-seq to explore changes of gene expression in the mouse fetal brain after prenatal exposure to chronic unpredictable mild stress (CUMS). RESULTS: We compared the stressed brains to the controls and identified groups of significantly differentially expressed genes (DEGs). GO analysis on up-regulated DEGs revealed enrichment for the cell cycle pathways, while down-regulated DEGs were mostly enriched in the neuronal pathways related to synaptic transmission. We further performed cell-type enrichment analysis using published scRNA-seq data from the fetal mouse brain and revealed cell-type-specificity for up- and down-regulated DEGs, respectively. The up-regulated DEGs were highly enriched in the radial glia, while down-regulated DEGs were enriched in different types of neurons. Cell deconvolution analysis further showed altered cell fractions in the stressed brain, indicating accumulation of neuroblast and impaired neurogenesis. Moreover, we also observed distinct brain-region expression pattern when mapping DEGs onto the developing Allen brain atlas. The up-regulated DEGs were primarily enriched in the dorsal forebrain regions including the cortical plate and hippocampal formation. Surprisingly, down-regulated DEGs were found excluded from the cortical region, but highly expressed on various regions in the ventral forebrain, midbrain and hindbrain. CONCLUSION: Taken together, we provided an unbiased data source for transcriptomic alterations of the whole fetal brain after chronic PS, and reported differential cell-type and brain-region vulnerability of the developing brain in response to environmental insults during the pregnancy.

Effect of Admission and Discharge Times on Hospital Mortality in Patients With Sepsis.

OBJECTIVES: To assess whether the time of admission/discharge time from the ICU and weekend admission are independently associated with hospital mortality in critically ill patients with sepsis. DESIGN: Retrospective study. Each 24-hour period (08:00 to 07:59 hr) was split into three time periods, defined as "day" (08:00 to 16:59 hr), "evening" (17:00 to 23:59 hr), and "night" (00:00 to 07:59 hr). Weekends were defined as 17:00 hours on Friday to 07:59 hours on Monday. Multivariate logistic regression models were conducted to assess the association between the ICU admission/discharge time, weekend admission, and hospital mortality. SETTING: Single-center ICUs in China. PATIENTS: Characteristics and clinical outcomes of 1,341 consecutive septic patients admitted to the emergency ICU, general ICU, or cardiovascular ICU in a tertiary teaching hospital were collected. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: ICU mortality rates were 5.8%, 11.9%, and 10.6%, and hospital mortality rates were 7.3%, 15.6%, and 17.1% during the day, evening, and night time, respectively. Hospital mortality was adjusted for patient to nurse (P/N) ratio, disease severity, Charlson index, age, gender, mechanical ventilation, and shock. Notably, ICU admission time and weekend admission were not predictors of mortality after adjustment. The P/N ratio at admission was significantly associated with mortality ( p < 0.05). The P/N ratio and compliance with the Surviving Sepsis Campaign (SSC) were significantly correlated. After risk adjustment for illness severity at time of ICU discharge and Charlson index, the time of discharge was no longer a significant predictor of mortality. CONCLUSIONS: ICU admission/discharge time and weekend admission were not independent risk factors of hospital mortality in critically ill patients with sepsis. The P/N ratio at admission, which can affect the compliance rate with SSC, was a predictor of hospital survival. Unstable state on transfer from the ICU was the main risk factor for in-hospital death. These findings may have implications for the management of septic patients.

Improved cell seeding efficiency and cell distribution in porous hydroxyapatite scaffolds by semi-dynamic method.

Tissue engineering is a promising technique for the repair of bone defects. An efficient and homogeneous distribution of cell seeding into scaffold is a crucial but challenging step in the technique. Murine bone marrow mesenchymal stem cells were seeded into porous hydroxyapatite scaffolds of two morphologies by three methods: static seeding, semi-dynamic seeding, or dynamic perfusion seeding. Seeding efficiency, survival, distribution, and proliferation were quantitatively evaluated. To investigate the performance of the three seeding methods for larger/thicker scaffolds as well as batch seeding of numerous scaffolds, three scaffolds were stacked to form assemblies, and seeding efficiencies and cell distribution were analyzed. The semi-dynamic seeding and static seeding methods produced significantly higher seeding efficiencies, vitalities, and proliferation than did the dynamic perfusion seeding. On the other hand, the semi-dynamic seeding and dynamic perfusion seeding methods resulted in more homogeneous cell distribution than did the static seeding. For stacked scaffold assemblies, the semi-dynamic seeding method also created superior seeding efficiency and longitudinal cell distribution homogeneity. The semi-dynamic seeding method combines the high seeding efficiency of static seeding and satisfactory distribution homogeneity of dynamic seeding while circumventing their disadvantages. It may contribute to improved outcomes of bone tissue engineering.

Macropore Regulation of Hydroxyapatite Osteoinduction via Microfluidic Pathway.

Macroporous characteristics have been shown to play a key role in the osteoinductivity of hydroxyapatite ceramics, but the physics underlying the new bone formation and distribution in such scaffolds still remain elusive. The work here has emphasized the osteoinductive capacity of porous hydroxyapatite scaffolds containing different macroporous sizes (200-400 µm, 1200-1500 µm) and geometries (star shape, spherical shape). The assumption is that both the size and shape of a macropore structure may affect the microfluidic pathways in the scaffolds, which results in the different bone formations and distribution. Herein, a mathematical model and an animal experiment were proposed to support this hypothesis. The results showed that the porous scaffolds with the spherical macropores and large pore sizes (1200-1500 µm) had higher new bone production and more uniform new bone distribution than others. A finite element analysis suggested that the macropore shape affected the distribution of the medium-high velocity flow field, while the macropore size effected microfluid speed and the value of the shear stress in the scaffolds. Additionally, the result of scaffolds implanted into the dorsal muscle having a higher new bone mass than the abdominal cavity suggested that the mechanical load of the host tissue could play a key role in the microfluidic pathway mechanism. All these findings suggested that the osteoinduction of these scaffolds depends on both the microfluid velocity and shear stress generated by the macropore size and shape. This study, therefore, provides new insights into the inherent osteoinductive mechanisms of bioceramics, and may offer clues toward a rational design of bioceramic scaffolds with improved osteoinductivity.

Advanced glycation end products induce endothelial hyperpermeability via ß-catenin phosphorylation and subsequent up-regulation of ADAM10.

Endothelial hyperpermeability is the initial event in the development of diabetic microvascular complications, and advanced glycation end products (AGEs) are suggested to cause much of the endothelial hyperpermeability associated with diabetes mellitus, but the molecular mechanism remains to be characterized. ß-catenin reportedly plays dual functions in maintaining normal endothelial permeability by serving both as an adhesive component and a signal transduction component. Here, we found that AGEs induced the phosphorylation of ß-catenin at residues Y654 and Y142 and the endothelial hyperpermeability was reversed when the two residues were blocked. In mechanism, phosphorylation of Y654 was blocked by Src inactivation, whereas phosphorylation of Y142 was reduced by a focal adhesion kinase inhibitor. ß-catenin Y654 phosphorylation induced by AGEs facilitated the dissociation of vascular endothelial (VE)-cadherin/ß-catenin and the impairment of adherens junctions (AJs), whereas ß-catenin Y142 phosphorylation favoured the dissociation of ß-catenin and α-catenin. Further investigation revealed that ß-catenin Y142 phosphorylation was required for AGEs-mediated ß-catenin nuclear translocation, and this nuclear-located ß-catenin subsequently activated the TCF/LEF pathway. This pathway promotes the transcription of the Wnt target, ADAM10 (a disintegrin and metalloprotease 10), which mediates VE-cadherin shedding and leads to further impairment of AJs. In summary, our study showed the role of ß-catenin Y654 and Y142 phosphorylation in AGEs-mediated endothelial hyperpermeability through VE-cadherin/ß-catenin/α-catenin dissociation and up-regulation of ADAM10, thereby advancing our understanding of the underlying mechanisms of AGEs-induced microvascular hyperpermeability.

Development and validation of a score to predict mortality in ICU patients with sepsis: a multicenter retrospective study.

BACKGROUND: Early and accurate identification of septic patients at high risk for ICU mortality can help clinicians make optimal clinical decisions and improve the patients' outcomes. This study aimed to develop and validate (internally and externally) a mortality prediction score for sepsis following admission in the ICU. METHODS: We extracted data retrospectively regarding adult septic patients from one teaching hospital in Wenzhou, China and a large multi-center critical care database from the USA. Demographic data, vital signs, laboratory values, comorbidities, and clinical outcomes were collected. The primary outcome was ICU mortality. Through multivariable logistic regression, a mortality prediction score for sepsis was developed and validated. RESULTS: Four thousand two hundred and thirty six patients in the development cohort and 8359 patients in three validation cohorts. The Prediction of Sepsis Mortality in ICU (POSMI) score included age ≥ 50 years, temperature < 37 °C, Respiratory rate > 35 breaths/min, MAP ≤ 50 mmHg, SpO2 < 90%, albumin ≤ 2 g/dL, bilirubin ≥ 0.8 mg/dL, lactate ≥ 4.2 mmol/L, BUN ≥ 21 mg/dL, mechanical ventilation, hepatic failure and metastatic cancer. In addition, the area under the receiver operating characteristic curve (AUC) for the development cohort was 0.831 (95% CI, 0.813-0.850) while the AUCs ranged from 0.798 to 0.829 in the three validation cohorts. Moreover, the POSMI score had a higher AUC than both the SOFA and APACHE IV scores. Notably, the Hosmer-Lemeshow (H-L) goodness-of-fit test results and calibration curves suggested good calibration in the development and validation cohorts. Additionally, the POSMI score still exhibited excellent discrimination and calibration following sensitivity analysis. With regard to clinical usefulness, the decision curve analysis (DCA) of POSMI showed a higher net benefit than SOFA and APACHE IV in the development cohort. CONCLUSION: POSMI was validated to be an effective tool for predicting mortality in ICU patients with sepsis.

Rabbit thyroid extracellular matrix as a 3D bioscaffold for thyroid bioengineering: a preliminary in vitro study.

BACKGROUND: Advances in regenerative medicine technologies have been strongly proposed in the management of thyroid diseases. Mechanistically, the adoption of thyroid bioengineering requires a scaffold that shares a similar three-dimensional (3D) space structure, biomechanical properties, protein component, and cytokines to the native extracellular matrix (ECM). METHODS: 24 male New Zealand white rabbits were used in this experimental study. The rabbit thyroid glands were decellularized by immersion/agitation decellularization protocol. The 3D thyroid decellularization scaffolds were tested with histological and immunostaining analyses, scanning electron microscopy, DNA quantification, mechanical properties test, cytokine assay and cytotoxicity assays. Meanwhile, the decellularization scaffold were seeded with human thyroid follicular cells, cell proliferation and thyroid peroxidase were determined to explore the biocompatibility in vitro. RESULTS: Notably, through the imaging studies, it was distinctly evident that our protocol intervention minimized cellular materials and maintained the 3D spatial structure, biomechanical properties, ECM composition, and biologic cytokine. Consequently, the decellularization scaffold was seeded with human thyroid follicular cells, thus strongly revealing its potential in reinforcing cell adhesion, proliferation, and preserve important protein expression. CONCLUSIONS: The adoption of our protocol to generate a decellularized thyroid scaffold can potentially be utilized in transplantation to manage thyroid diseases through thyroid bioengineering.

Advanced glycation end products induce immature angiogenesis in in vivo and ex vivo mouse models.

Proliferative diabetic retinopathy (PDR) is a progressive disease predominantly involving pathological angiogenesis and is characterized by the development of immature, fragile, and easily hemorrhagic new vessels. Advanced glycation end products (AGEs) and the receptor for AGEs (RAGE) play important roles in the progression of diabetic retinopathy. Our previous studies demonstrated that AGEs promoted HUVEC angiogenesis by inducing moesin phosphorylation via RhoA/Rho-associated protein kinase (ROCK) pathway. The aim of this study was to further confirm AGE-induced angiogenesis in vivo and the involvement of RAGE, ROCK, and moesin phosphorylation in this process. We performed the study in an AGE-treated mouse model with various angiogenesis assays in multiple in vivo and ex vivo models. The results demonstrated that AGEs promoted significant neovascularization in whole mount retina and mouse aortic ring of adult and postnatal mice and in Matrigel plug as well, which were consistently accompanied by increased moesin phosphorylation. The increase of AGE-evoked neovascularization and moesin phosphorylation were both attenuated by RAGE knockout or ROCK inhibitor Y27632 administration in mice. We also revealed the pathological characteristics of AGE-promoted angiogenesis by demonstrating the decrease of pericyte coverage and the disarranged endothelial alignment in microvessels. In conclusion, this study provides in vivo evidences that AGEs induce immature angiogenesis by binding to RAGE, activating the RhoA/ROCK signal pathway and inducing moesin phosphorylation.NEW & NOTEWORTHY Advanced glycation end product (AGE)-induced formation of neovessels and phosphorylation of moesin in retina and aortic ring required AGE receptors. AGEs increased neovessels and the phosphorylation of moesin in retina and aortic ring via RhoA/ROCK pathway. AGE-induced immature angiogenesis in AGE-treated mouse retina and aortic ring. The AGE-RAGE axis and moesin could be candidate targets for overcoming relative diseases.

Amiodarone induces epithelial-mesenchymal transition in A549 cells via activation of TGF-ß1.

Amiodarone is a high effectiveness anti-arrhythmia agent which is able to induce pulmonary fibrosis. Many studies have shown that the epithelial-mesenchymal transition (EMT) was a significant process in pulmonary fibrosis. So far, there are no studies about whether EMT was associated with amiodarone-induced pulmonary fibrosis, which was therefore explored in this study. In addition, the underlying mechanisms of amiodarone-induced pulmonary fibrosis were examined in vitro. We found the EMT marker (α-SMA) was significantly increased, while the E-cadherin was significantly decreased in adenocarcinomic human alveolar basal epithelial cells (A549) after amiodarone treatment, suggesting that the epithelial cells were an important source of mesenchymal cells. Transforming growth factor beta1 (TGF-ß1) was also increased significantly after amiodarone treatment. In conclusion, this study suggested amiodarone could induce pulmonary fibrosis via EMT, and the TGF-ß1 may be a key profibrotic cytokine in mechanisms of amiodarone-induced pulmonary fibrosis.

ß-Catenin phosphorylation at Y654 and Y142 is crucial for high mobility group box-1 protein-induced pulmonary vascular hyperpermeability.

OBJECTIVE: Endothelial hyperpermeability is a hallmark of acute lung injury in response to sepsis. The imbalance between adherence junction (AJ) mediated cell-cell adherence forces and stress fiber driven contractile forces contributes to increased endothelial permeability. Here, we spotlight the effects of ß-catenin Y654 andY142 phosphorylation on HMGB1-mediated endothelial barrier leakage. APPROACH AND RESULTS: Our results showed that phospho-deficiencies at both ß-catenin Y654and Y142ameliorated pulmonary vascular dysfunction in male C57 mice receiving a cecal ligation and puncture operation. In vitro analysis indicated that high mobility group box-1 protein (HMGB1) triggered ß-catenin Y654 and Y142 phosphorylation, causing ß-catenin translocation and adherence junction (AJ) disruptions as well as cytoskeleton rearrangement. In addition,ß-catenin Y654 dephosphorylation attenuated HMGB1-mediated dissociation of VE-cadherin/ß-catenin and, hence, partially prevented endothelial hyperpermeability. ß-catenin Y142 dephosphorylation abolished HMGB1-induced uncoupling of ß-catenin and α-catenin, suppressed cytoskeletal reassembly and, hence, alleviated endothelial hyperpermeability. Further investigation demonstrated that RAGE and Src were required forß-catenin Y654 phosphorylation in response to HMGB1, while FAK was responsible for HMGB1-triggered ß-catenin Y142 phosphorylation. CONCLUSIONS: In sum, this study revealed the role of ß-catenin Y654 and Y142 phosphorylation in HMGB1-mediated endothelial hyperpermeability through dysregulation between adherence and contractile forces. This result advances understanding of the mechanisms underlying pulmonary vascular hyperpermeability in sepsis.

Slit2/Robo4 signaling pathway modulates endothelial hyper-permeability in a two-event in vitro model of transfusion-related acute lung injury.

Transfusion-related acute lung injury (TRALI) remains the leading cause of transfusion-related mortality. Endothelium semipermeable barrier function plays a critical role in the pathophysiology of transfusion-related acute lung injury (TRALI). Recently, Roundabout protein 4 (Robo4), interaction with its ligand Slit 2, was appreciated as a modulator of endothelial permeability and integrity. However, not much is known about the role of Slit2/Robo4 signaling pathway in the pathophysiology of TRALI. In this study, the TRALI model was performed by the "two-event" model of polymorphonuclear neutrophils (PMN)-mediated pulmonary microvascular endothelial cells (PMVECs) damage. We investigated the expression of Slit2/Robo4 and VE-cadherin and examined the pulmonary endothelial hyper-permeability in TRALI model. We found that the expression of Slit2/Robo4 and VE-cadherin were significantly decreased in a time-dependent manner, whereas the PMVECs permeability was gradually increased over time in TRALI model. Moreover, the treatment with Slit2-N, an active fragment of Slit2, increased the expression of Slit2/Robo4 and VE-cadherin to protect PMVECs from PMN-mediated pulmonary endothelial hyper-permeability. These results indicate that targeting Slit2/Robo4 signaling pathway may modulate the permeability as well as protect the integrity of endothelial barrier. In addition, Slit2-N appears to be a promising candidate for developing novel therapies against TRALI.

A dynamic model and some strategies on how to prevent and control hepatitis c in mainland China.

BACKGROUND: Hepatitis C virus (HCV) is a leading cause of chronic liver disease. As yet there is no approved vaccine protects against contracting hepatitis C. HCV seriously affects many people's health in the world. METHODS: In this article, an epidemiological model is proposed and discussed to understand the transmission and prevalence of hepatitis C in mainland China. This research concentrates on hepatitis C data from Chinese Center for Disease Control and Prevention (China's CDC). The optimal parameters of the model are obtained by calculating the minimum chi-square value. Sensitivity analyses of the basic reproduction number and the endemic equilibrium are conducted to evaluate the effectiveness of control measures. RESULTS: Vertical infection is not the most important factor that causes hepatitis C epidemic, but contact transmission is. The proportion of acute patients who are transformed into chronic patients is about 82.62%. The possibility of the hospitalized patients who are restored to health is about 76.24%. There are about 92.32% of acute infected are not treated. The reproduction number of hepatitis C in mainland China is estimated as approximately 1.6592. CONCLUSION: We find that small changes of transmission infection rate of acutely infected population, transmission infection rate of exposed population, transition rate for the acutely infected, and rate of progression to acute stage from the exposed can achieve the purpose of controlling HCV through sensitivity analysis. Finally, based on the results of sensitivity analysis, we find out several preventions and control strategies to control the Hepatitis C.

Selective occlusion of the hepatic artery and portal vein improves liver hypertrophy for staged hepatectomy.

BACKGROUND: To evaluate the safety and feasibility of selective occlusion of the hepatic artery and portal vein (SOAP) for staged hepatectomy (SOAPS) in patients with hepatocellular carcinoma (HCC) METHODS: From December 2014 to August 2018, 9 patients with unresectable HCC were chosen to undergo SOAPS. SOAP without liver partition was performed in the first stage. The second stage was performed when future liver remnant (FLR) was equal to or bigger than 40% of the standard liver volume (SLV). The growth rate of FLR, perioperative outcomes, and survival data was recorded. RESULTS: In the first stage, all the 9 patients completed SOAP. Two cases received radiological interventional method and 7 cases received open operation. None of them developed liver failure and died following SOAP. After SOAP, FLR increased 145.0 ml (115.0 to 210 ml) and 37.1% (25.6 to 51.7%) on average. The average time interval between the two stages was 14.1 days (8 to 18 days). In the second stage, no in-hospital deaths occurred after SOAPS. One patient suffered from liver failure after SOAPS, and artificial liver support was adopted and his total bilirubin level returned to normal after postoperative day 35. The alpha-fetoprotein level of 8 patients reduced to normal within 2 months after SOAPS. Among 9 patients, 5 patients survived, 4 patients died of intrahepatic recurrence, lung metastasis, or bone metastasis. In the 5 survived cases, bone metastasis and intrahepatic recurrence were found in 1 patient, intrahepatic recurrence was found in another patient, and the remaining 3 patients were free of recurrence. The median disease-free survival time and overall survival time were 10.4 and 13.9 months, respectively. CONCLUSION: SOAP can facilitate rapid and sustained FLR hypertrophy, and SOAPS is safe and effective in patients with unresectable HCC.

Graphite paste electrodes modified with a sulfo-functionalized metal-organic framework (type MIL-101) for voltammetric sensing of dopamine.

The metal-organic frameworks MIL-101 and sulfo-MIL-101 were used to modify graphite paste electrodes (GPEs) to obtain sensors for determination of dopamine (DA). Taking advantage of the catalytic activity of metal-organic frameworks (MOFs) and of the electrical conductivity of graphite, the modified GPEs show enhanced voltammetric responses, and the GPE modified with the sulfo-MOF displays superior sensitivity when operated at a working potential of -0.4 to 0.8 V (vs. Ag/AgCl). The sensor works in the 0.07 to100 µM DA concentration range and has a 43 nM detection limit. It is concluded that the sulfo group provides open sites for efficient electrostatic and hydrogen bonding interactions, which facilitates electron transfer. Graphical abstractSchematic representation of the structure of the sulfo-functionalized MOF (sulfo-MIL-101) and the different voltammetric signals of dopamine at the graphite paste electrodes (GPEs) modified with sulfo-MIL-101 and the parent MOF (MIL-101).

Mdia1 is Crucial for Advanced Glycation End Product-Induced Endothelial Hyperpermeability.

BACKGROUND/AIMS: Disruption of endothelial barrier integrity in response to advanced glycation end products (AEGs) stimulation contributes to vasculopathy associated with diabetes mellitus. Mammalian diaphanous-related formin (mDia1) has been reported to bind to the cytoplasmic domain of the receptor for advanced glycation end products (RAGE), which induces a series of cellular processes. This study directly evaluated the participation of mDia1 in AGE-induced hyperpermeability and revealed the precise intracellular signal transductions of this pathological process. METHODS: Human umbilical vein endothelial cells (HUVECs) were used in the in vitro studies. Trans-endothelial electric resistance and permeability coefficient for dextran (Pd) were measured to analyze cell permeability. Western blotting, immunofluorescence staining and flow cytometry assay were performed to investigate the underlying mechanism. Dextran flux across the mesentery in mice was monitored to investigate in vivo microvascular permeability. RESULTS: we found that AGEs evoked Nox4 membrane translocation, reactive oxygen species production, phosphorylation of Src and VE-cadherin, dissociation of adherens junctions and eventual endothelial hyperpermeability through RAGE-mDia1 binding. Cells overexpressing mDia1 by recombinant adenovirus infection showed stronger cellular responses induced by AGEs. Down-regulation of mDia1 by infection with an adenovirus encoding siRNA or blockade of RAGE-mDia1 binding by transfection with RAGE mutant plasmids into HUVECs abolished these AGE-induced effects. Furthermore, knockdown of mDia1 using an adenovirus or genetical knockout of RAGE in C57 mice rescued AGE-evoked microvascular hyperpermeability. CONCLUSION: Our study revealed that mDia1 plays a critical role in AGE-induced microvascular hyperpermeability through binding to RAGE.

Role of TLR4-p38 MAPK-Hsp27 signal pathway in LPS-induced pulmonary epithelial hyperpermeability.

BACKGROUND: The breakdown of alveolar barrier dysfunction contributes to Lipopolysaccharide stimulated pulmonary edema and acute lung injury. Actin cytoskeleton has been implicated to be critical in regulation of epithelial barrier. Here, we performed in vivo and in vitro study to investigate role of TLR4-p38 MAPK-Hsp27 signal pathway in LPS-induced ALI. METHODS: For in vivo studies, 6-8-week-old C57 mice were used, Bronchoalveolar lavage Fluid /Blood fluorescent ratio, wet-to-dry lung weight ratio, as well as protein concentrations and neutrophil cell counts in BALF were detected as either directly or indirectly indicators of pulmonary alveolar barrier dysfunction. And hematoxylin and eosin staining was performed to estimate pulmonary injury. The in vitro explorations of transepithelial permeability were achieved through transepithelial electrical resistance measurement and testing of FITC-Dextran transepithelial flux in A549. In addition, cytoskeletal rearrangement was tested through F-actin immunostaining. And SB203580 was used to inhibit p38 MAPK activation, while siRNA was administered to genetically knockdown specific protein. RESULTS: We showed that LPS triggered activation of p38 MAPK, rearrangement of cytoskeleton which resulted in severe epithelial hyperpermeability and lung edema. A549 pretreated with TLR4 siRNA、p38 MAPK siRNA and its inhibitor SB203580 displayed a lower permeability and fewer stress fibers formation after LPS stimulation, accompanied with lower phosphorylation level of p38 MAPK and Hsp27, which verified the involvement of TLR4-p38 MAPK-Hsp27 in LPS-evoked alveolar epithelial injury. Inhibition of p38 MAPK activity with SB203580 in vivo attenuated pulmonary edema formation and hyperpermeability in response to LPS. CONCLUSIONS: Our study demonstrated that LPS increased alveolar epithelial permeability both in vitro and in vivo and that TLR4- p38 MAPK- Hsp27 signal pathway dependent actin remolding was involved in this process.

[Mechanical Reinforcement Strategy of Calcium Phosphate Cements by Loading Polymers].

Calcium phosphate cement (CPC) is well known for the excellent bioactivity and biocompatibility, however, CPC has been used only for the repair of non-load bearing bone defects due to its brittle nature and low flexural strength. Polymer reinforced CPC has been considered as one of the most effective strategies for mechanical reinforcement. This paper summarizes various kinds of polymers loaded CPC:fiber reinforcement, microsphere reinforcement and dual setting cements. It is aimed to analyze the advantages, disadvantages and principles of the polymers reinforced CPC, and so as to lay a foundation for the further research of improving and manufacturing the CPC with ideal mechanical properties.