Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Objective:To explore the clinical efficacy of liver transplantation for Wilson's disease(WD).Methods:From January 1999 to November 2021, clinical data were retrospectively reviewed for 16 recipients with WD undergoing liver transplantation.There were 9 males and 7 females with an age range of 29.5(14~54)years.They were followed up by telephone, outpatient services and hospitalization.The starting point of follow-up was operation date.And recipient death was an endpoint.Postoperative survival, improvement of neuropsychiatric symptom, changes of corneal K-F ring, altered levels of liver function and serum copper-protein at Month 1 post-operation were observed.The follow-up deadline was November 24, 2021.Results:15 recipients underwent classical orthotopic liver transplantation and the other one recipient underwent living-related liver transplantation.No perioperative deaths occurred.All 16 recipients were followed up for 122(6~260)months.The 1-, 5-, and 10-year survival rates were 93.8%、85.2%and 75.8%, respectively.Among 10 recipients with corneal K-F ring positive with varying degrees after operation and was disappeared in 2 recipients at 7 and 11 months.Among 5 recipients with neuropsychiatric manifestation, 4 recipients showed ameliorative neuropsychic symptoms with varying degrees after operation and 1 recipient died.All the levels of liver function and serum copper-protien of all recipients recovered obviously in 1 month and the 1-, 5-, and 10-year post-operation.Conclusions:Classical orthotopic liver transplantation and living-related liver transplantation not only effectively improves copper metabolism of patient with WD and relieves their severe neurological manifestation, but also improves their life and prolongs survival, which is worthy of clinical promotion.

Objective To assess the effects of vascular endothelial growth factor-C (VEGF-C)/vascular endothelial growth factor receptor-3 (VEGFR-3) signaling on nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression in human osteosarcoma MG63 cells and the subsequent impact on the proliferation of human umbilical vein endothelial cells (HUVECs). MethodsMG63 cells were treated with VEGF-C alone (VEGF-C group), VEGF-C + iNOS inhibitor aminoguanidine (AG; AG group), and VEGF-C + VEGFR-3 inhibitor MAZ51 (MAZ51 group); untreated MG63 cells were used as controls. NO production was evaluated by a colorimetric method involving nitrate reductase. Meanwhile, mRNA and protein levels of iNOS were examined by reverse transcription polymerase chain reaction (RT-PCR) and Western blot. To explore the effect of VEGF-C/VEGFR-3/iNOS signaling of MG63 cells on proliferation of HUVECs, we set up six groups: HUVECs, HUVECs+MG63, HUVECs+VEGF-C, HUVECs+MG63+VEGF-C, HUVECs+MG63+VEGF-C+AG, and HUVECs+MG63+VEGF-C+MAZ51 groups. The proliferation of HUVEC cells was assessed by Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay, and proliferating cell nuclear antigen (PCNA) expression quantitation. ResultsVEGF-C treatment enhanced iNOS expression at both gene and protein levels (mRNA: LSD-

An eco-friendly and fast HPLC method was developed for the determination of adenosine, inosine, guanosine and uridine in Cordyceps and related products (fermented mycelia of Hirsutella sinensis andPaecilomyces hepiali). The sample was ultrasonically extracted using 0.5% phosphoric acid solutions for 2.5 min. Sample separation was performed on a Poroshell SB-Aq column (50 mm × 4.6 mm, 2.7 μm) using eco-friendly mobile phase consisting of formic acid and ammonium formate aqueous solution at a flow rate of 1.0 mL·min
Adenosine ; Chromatography, High Pressure Liquid ; Cordyceps ; Nucleosides

RAS, a member of the small GTPase family, functions as a binary switch by shifting between inactive GDP-loaded and active GTP-loaded state. RAS gain-of-function mutations are one of the leading causes in human oncogenesis, accounting for ∼19% of the global cancer burden. As a well-recognized target in malignancy, RAS has been intensively studied in the past decades. Despite the sustained efforts, many failures occurred in the earlier exploration and resulted in an 'undruggable' feature of RAS proteins. Phosphorylation at several residues has been recently determined as regulators for wild-type and mutated RAS proteins. Therefore, the development of RAS inhibitors directly targeting the RAS mutants or towards upstream regulatory kinases supplies a novel direction for tackling the anti-RAS difficulties. A better understanding of RAS phosphorylation can contribute to future therapeutic strategies. In this review, we comprehensively summarized the current advances in RAS phosphorylation and provided mechanistic insights into the signaling transduction of associated pathways. Importantly, the preclinical and clinical success in developing anti-RAS drugs targeting the upstream kinases and potential directions of harnessing allostery to target RAS phosphorylation sites were also discussed.

OBJECTIVE: To retrospectively analyze the risk factors of avascular necrosis of femoral head (ANFH) after internal fixation in young and mid-aged adults. METHODS: From January 2007 to December 2017, femoral neck fracture patients (18-60 years old) treated by reduction and internal fixation were retrospectively studied in Peking University Third Hospital. We recorded their gender, age, body mass index (BMI), American Society of Anesthesiology (ASA) grade, reason of injury, fracture side, interval between injury and surgery, location of fracture line, Garden classification, Pauwels classification, reduction method (open or closed), internal fixation and reduction quality. The diagnosis of ANFH was confirmed based on X-ray and MRI images during the follow-up. The internal fixation method included cannulated compression screw (CCS) or dynamic hip screw (DHS, with or without anti-rotation screw). χ² test and Logistic regression analysis were used to analyze the relationship between the various factors and postoperative ANFH. RESULTS: A total of 113 patients were included in this study, including 63 males and 50 females with an average age of (43.17 ± 12.34) years. They were followed up by (25.08 ± 16.17) months. ASA grade included grade I (21 cases), grade II (55 cases) and grade III (37 cases). The reasons of injury included low-energy trauma (76 cases) and high-energy (37 cases). The fracture line included subcapital type (37 cases), transverse type (74 cases) and basal type (2 cases). Garden classification included type I (3 cases), type II (46 cases), type III (39 cases) and type IV (25 cases). Pauwels classification included type I (21 cases), type II (55 cases) and type III (37 cases). Interval between injury and surgery was (3.88 ± 3.66) days, 108 patients and 5 patients performed closed and open reduction respectively. 63 patients performed CCS, and 50 patients performed DHS. The reduction quality included grade A (91 cases), grade B (18 cases) and grade C (4 cases). 18 patients developed ANFH after surgery, the incidence rate was 15.93% (18/113). The result of χ² test showed the reason of injury (OR=0.19, P < 0.01), Garden classification (OR=0.13, P < 0.01), Pauwels classification (OR=0.12, P = 0.02), internal fixation method (OR=3.29, P = 0.04) and reduction quality (OR=0.33, P < 0.01) were significantly associated with ANFH. These five factors were further included into the Logistic regression analysis, and its results showed that the reason of injury (OR=4.11, P = 0.03) and Garden classification (OR=4.85, P = 0.04) were statistically significant. CONCLUSION The reason of injury, Garden classification, Pauwels classification, internal fixation and reduction quality may increase the risk of ANFH after surgery, and the reason of injury and Garden classification were much more significant.
Adolescent ; Adult ; Female ; Femoral Neck Fractures ; Femur Head Necrosis ; Fracture Fixation, Internal ; Fracture Healing ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Risk Factors ; Young Adult

Objective To investigate the effects and mechanism of remifentanil on renal ischemia/reperfusion(IR) injury via mediating Fas apoptosis signal pathway in rats.Methods Sprague-Dawley rats were divided into 3 groups (n =20 each) by using the random number table method:sham operation group (S group),IR control group (IR group),experimental group (Rgroup).The renal IR model was prepared by clamping the bilateral renal arteries for 45 min followedby reperfusion in IR group and R group.In R group,remifentanil was infused at 1.0μg·kg-1 ·min-1 via the tail vein starting from 15 min before ischemia until 30 min of reperfusion.In S group and IR group,the same volume of physiological saline was given.At 15 min before ischemia and at 3 h,12 h,24 h of reperfusion,the renal tissue samples were obtained for detecting the apoptosis rate by flow cytometry,determining the level of Fas mRNA expression by RT-PCR,the level of caspase-8 and caspase-3 activation by Western blotting,and scoring the number of kidney tubules injury by Paller'method.Results In IR group,the renal tubular injury score,the apoptosis rate,the expression of Fas mRNA and the activation of caspase-3 in renal tissue increased at 3 h after reperfusion,and those continued to increase at 12 h after reperfusion and reached the peak at 24 h after reperfusion (P＜0.01),and the activity of caspase-8 increased at 3 b,reached the peak at 12 h after reperfusion and decreased at 24 h after reperfusion (P＜0.01).As compared with S group,the renal tubular injury score,apoptosis rate,the expression of Fas mRNA and the activation of caspase-3 at 3 h,12 h and 24 h of reperfusion and the activation of caspase-8 at 12 h,24 h of reperfusion were all increased in IR group and R group (P＜0.05 or 0.01).As compared with IR group,the renal tubular injury score,apoptosis rate,the expression of Fas mRNA and the activation of caspase-8 and caspase-3 at 3 h,12 h and 24 h of reperfusion were decreased in R group (P＜0.05 or 0.01).Conclusion Remifentanil inhibits cell apoptosis and alleviates renal IR damage by reducing the expression of Fas receptor and the activation of caspase-8 and caspase-3,and regulating the apoptotic signal pathway of Fas.

Objective To investigate the effect of Wnt5a on inducing differentiation of Cp15-5a cell to myocardial cell.Methods Recombinant adenovirus wnt5a (Ad-wnt5a) and Ad-GFP was amplified with human embryo kidney 293 cells (HEK293 cells),and then transfected into CP15-5a cells and 3 experiment groups were set up:wnt5a group,GFP group and blank control group.Flow cytometry was used to detect the transfection efficiency of Ad-wnt5a and Ad-GFP.One week after transfection,the expressions of genes GATA binding protein 4 (GATA4) and myocardial enhancement factor 2C (MEF2C) were analyzed by realtime quantitative PCR (qRT-PCR).Two weeks after transfection,the expressions of cardiac-specific connexin 43 (Cx43) and cardiac troponin T (cTnT) in Ad-wnt5a-induced CP15-5a cells were detected by Western blotting and immunofluorescence techniques.The sodium current expression (INa) was detected by whole cell patch clamp techniques.Results The transfection efficiency of Ad-wnt5a and Ad-GFP was 42.8％ and 44.3％,respectively.One week after transduction,the expressions of GATA4 and MEF2C were significantly higher in wnt5a group (1.717 ± 0.220 and 1.847 ± 0.190) than in GFP group (1.003 ± 0.087 and 0.456 ± 0.042,P＜0.05) and blank control group (0.961 ± 0.063 and 0.500 ± 0.095,P＜0.05),while no significant difference existed between GFP group and blank control group.Two weeks after transduction,the expressions of CX43 and cTnT were significantly higher in wnt5a group (1.597 ± 0.267 and 0.727 ± 0.100) than in GFP group (0.723 ± 0.047 and 0.217 ± 0.021,P＜0.05) and blank control group (0.783 ± 0.1333 and 0.253 ± 0.102,P＜0.01),while no significant difference existed between GFP group and blank control group.INa was detected in the wnt5a group compared with GFP group and blank control group.Conclusion wnt5a may induce differentiation of cp 15-5a cell into myocardial cell.