Integrated multi-omic analysis identifies fatty acid binding protein 4 as a biomarker and therapeutic target of ischemia-reperfusion injury in steatotic liver transplantation.

BACKGROUND AND AIMS: Due to a lack of donor grafts, steatotic livers are used more often for liver transplantation (LT). However, steatotic donor livers are more sensitive to ischemia-reperfusion (IR) injury and have a worse prognosis after LT. Efforts to optimize steatotic liver grafts by identifying injury targets and interventions have become a hot issue. METHODS: Mouse LT models were established, and 4D label-free proteome sequencing was performed for four groups: normal control (NC) SHAM, high-fat (HF) SHAM, NC LT, and HF LT to screen molecular targets for aggravating liver injury in steatotic LT. Expression detection of molecular targets was performed based on liver specimens from 110 donors to verify its impact on the overall survival of recipients. Pharmacological intervention using small-molecule inhibitors on an injury-related target was used to evaluate the therapeutic effect. Transcriptomics and metabolomics were performed to explore the regulatory network and further integrated bioinformatics analysis and multiplex immunofluorescence were adopted to assess the regulation of pathways and organelles. RESULTS: HF LT group represented worse liver function compared with NC LT group, including more apoptotic hepatocytes (P < 0.01) and higher serum transaminase (P < 0.05). Proteomic results revealed that the mitochondrial membrane, endocytosis, and oxidative phosphorylation pathways were upregulated in HF LT group. Fatty acid binding protein 4 (FABP4) was identified as a hypoxia-inducible protein (fold change > 2 and P < 0.05) that sensitized mice to IR injury in steatotic LT. The overall survival of recipients using liver grafts with high expression of FABP4 was significantly worse than low expression of FABP4 (68.5 vs. 87.3%, P < 0.05). Adoption of FABP4 inhibitor could protect the steatotic liver from IR injury during transplantation, including reducing hepatocyte apoptosis, reducing serum transaminase (P < 0.05), and alleviating oxidative stress damage (P < 0.01). According to integrated transcriptomics and metabolomics analysis, cAMP signaling pathway was enriched following FABP4 inhibitor use. The activation of cAMP signaling pathway was validated. Microscopy and immunofluorescence staining results suggested that FABP4 inhibitors could regulate mitochondrial membrane homeostasis in steatotic LT. CONCLUSIONS: FABP4 was identified as a hypoxia-inducible protein that sensitized steatotic liver grafts to IR injury. The FABP4 inhibitor, BMS-309403, could activate of cAMP signaling pathway thereby modulating mitochondrial membrane homeostasis, reducing oxidative stress injury in steatotic donors.

Older liver grafts from donation after circulatory death are associated with impaired survival and higher incidence of biliary non-anastomotic structure.

BACKGROUND: Grafts from older donors after circulatory death were associated with inferior outcome in liver transplants in the past. But it has seemed to remain controversial in the last decade, as a result of modified clinical protocols, selected recipients, and advanced technology of organ perfusion and preservation. The present study aimed to examine the impact of older donor age on complications and survival of liver transplant using grafts from donation after circulatory death (DCD). METHODS: A total of 944 patients who received DCD liver transplantation from 2015 to 2020 were included and divided into two groups: using graft from older donor (aged ≥ 65 years, n = 87) and younger donor (age < 65 years, n = 857). Propensity score matching (PSM) was applied to eliminate selection bias. RESULTS: A progressively increased proportion of liver transplants with grafts from older donors was observed from 1.68% to 15.44% during the study period. The well-balanced older donor (n = 79) and younger donor (n = 79) were 1:1 matched. There were significantly more episodes of biliary non-anastomotic stricture (NAS) in the older donor group than the younger donor group [15/79 (19.0%) vs. 6/79 (7.6%); P = 0.017]. The difference did not reach statistical significance regarding early allograft dysfunction (EAD) and primary non-function (PNF). Older livers had a trend toward inferior 1-, 2-, 3-year graft and overall survival compared with younger livers, but these differences were not statistically significant (63.1%, 57.6%, 57.6% vs. 76.9%, 70.2%, 67.7%, P = 0.112; 64.4%, 58.6%, 58.6% vs. 76.9%, 72.2%, 72.2%, P = 0.064). The only risk factor for poor survival was ABO incompatible transplant (P = 0.008) in the older donor group. In the subgroup of ABO incompatible cases, it demonstrated a significant difference in the rate of NAS between the older donor group and the younger donor group [6/8 (75.0%) vs. 3/14 (21.4%); P = 0.014]. CONCLUSIONS: Transplants with grafts from older donors (aged ≥ 65 years) after circulatory death are more frequently associated with inferior outcome compared to those from younger donors. Older grafts from DCD are more likely to develop NAS, especially in ABO incompatible cases.

[Causes and Countermeasures of Complications After Bariatric Surgery].

Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy characterized by simple operation and few postoperative complications have gradually become the two most commonly used surgical methods in clinical practice.A series of complications often occur after bariatric surgery,including gallstone disease,anemia,malnutrition,gastroesophageal reflux disease,kidney stones,and birth defects in offspring of women of childbearing age.There are controversies regarding the causes and countermeasures of these complications.This article mainly reviews the risk factors and countermeasures for the complications after bariatric surgery.

Cellular crosstalk during liver regeneration: unity in diversity.

The liver is unique in its ability to regenerate from a wide range of injuries and diseases. Liver regeneration centers around hepatocyte proliferation and requires the coordinated actions of nonparenchymal cells, including biliary epithelial cells, liver sinusoidal endothelial cells, hepatic stellate cells and kupffer cells. Interactions among various hepatocyte and nonparenchymal cells populations constitute a sophisticated regulatory network that restores liver mass and function. In addition, there are two different ways of liver regeneration, self-replication of liver epithelial cells and transdifferentiation between liver epithelial cells. The interactions among cell populations and regenerative microenvironment in the two modes are distinct. Herein, we first review recent advances in the interactions between hepatocytes and surrounding cells and among nonparenchymal cells in the context of liver epithelial cell self-replication. Next, we discuss the crosstalk of several cell types in the context of liver epithelial transdifferentiation, which is also crucial for liver regeneration. Video abstract.

The critical role of therapeutic plasma exchange in ABO-incompatible liver transplantation.

BACKGROUND: The shortage of donor liver restricts liver transplantation (LT). Nowadays, donor liver with ABO blood group incompatibility between donor and recipient has become an option to expand the source of donor liver. Although it is now possible to perform ABO-incompatible (ABO-I) LT, antibody-mediated rejection (AMR) has been recognized as the primary cause of desperate outcomes after ABO-I LT. Anti-A/B antibody is the trigger of immune response to ABO-I LT graft injury. Therapeutic plasma exchange (TPE) can quickly reduce the titer of plasma antibodies and effectively inhibit humoral immunity. DATA SOURCES: We searched PubMed and CNKI databases using search terms "therapeutic plasma exchange", "ABO-incompatible liver transplantation", "ABO-I LT", "liver transplantation", "LT", "antibody-mediated rejection", and "AMR". Additional publications were identified by a manual search of references from key articles. The relevant publications published before September 30, 2020 were included in this review. RESULTS: Different centers have made different attempts on whether to use TPE, when to use TPE and how often to use TPE. However, the control standard of lectin revision level is always controversial, the target titer varies significantly from center to center, and the standard target titer has not yet been established. TPE has several schemes to reduce antibody titers, but there is a lack of clinical trials that provide standardized procedures. CONCLUSIONS: TPE is essential for ABO-I LT. Hence, further research and clinical trials should be conducted to determine the best regimen for TPE to remove ABO antibodies and prevent AMR.

The effects of salinity on coupled nitrification and aerobic denitrification in an estuarine system.

Salinity has significant effects on nitrification and denitrification processes, particularly in estuarine systems. A dissolved oxygen-enriched river and its estuary in northern China were selected to investigate the impact of salinity gradients (0.6, 4, 7.6, 11.4 and 14.7‰) obtained from the mixing of river samples and estuarine samples with different proportions on coupled nitrification and aerobic denitrification via incubation experiments (35 and 10 °C). Results indicated that: (a) nitrification and coupled nitrification-aerobic denitrification occurred for all treatments, which resulted in NO3- being either accumulated or removed at the end of the incubation; (b) a suitable range of salinity is 4.0-11.4‰ for nitrification and 4.0-7.6‰ for coupled nitrification-aerobic denitrification; and (c) the relatively higher temperature (35 °C) can effectively stimulate N transformation processes compared to the lover temperature (10 °C) in the incubation experiment.

Assessing the Effects of Acidification on N Dynamics in Jiyun River System of Tianjin, China.

Alterations in pH have significant effects on nitrification and denitrification processes in aquatic systems. The Jiyun River in northern China experiences significant acid precipitation, and as such was selected to investigate the effects of decreasing pH (river pH at 8.2, pH at 6 and 5) on N dynamics via incubation experiments (35 and 10°C). Statistical results indicated that the NO3 (-) concentrations of the control (pH at 8.2) were either significantly lower (at 35°C) or significantly higher (at 10°C) than the treatments of pH at 6 and 5 at the alpha level of 0.05 in the incubation. However, the NO3 (-) concentrations of the two pH treatments showed significant difference during part of the reaction stage at 35°C and no difference at 10°C. Analysis indicated that nitrification and coupled nitrification-aerobic denitrification occurred for all treatments, which resulted in NO3 (-) being either accumulated or removed at the end of the incubation.

Effect of Co-Doping of Al3+, In3+, and Y3+ on the Electrical Properties of Zinc Oxide Varistors under Pre-Synthesizing BiSbO4.

Under the premise of using the solid-phase method to pre-sinter Bi2O3 and Sb2O3 into BiSbO4 as a substitute for equal amounts of Bi2O3 and Sb2O3 in the formula, the effects of co-doping with In(NO3)3, Al(NO3)3, and Y(NO3)3 on the microstructure and electrical properties of ZnO varistors were studied. The experimental results show that with an increase in In3+-doped molar concentration, the leakage current of the ZnO varistor shows a rapid decrease and then a slow increase trend. However, the nonlinear coefficient is the opposite of it. With the combined effect of the rare earth element Y3+, the average grain size is significantly reduced, which leads to an increase in the voltage gradient. At the same time, a certain amount of doped In3+ and Al3+ is dissolved into the grains, resulting in a decrease in grain resistance and thus a low level of residual voltage. The varistor with 0.6 mol% In3+, 0.1 mol% Al3+, and 0.9 mol% Y3+ doping ratios exhibits excellent overall performance. The nonlinear coefficient is 62.2, with the leakage current being 1.46 µA/cm2 and the voltage gradient being 558 V/mm, and the residual voltage ratio is 1.73. The prepared co-doped ZnO varistors will provide better protection for metal oxide surge arresters.

The Role of Astrocytes in Migraine with Cortical Spreading Depression: Protagonists or Bystanders? A Narrative Review.

Cortical spreading depression (CSD) is a slow wave of cortical depolarization closely associated with migraines with an aura. Previously, it was thought that CSD depolarization was mainly driven by neurons, with characteristic changes in neuronal swelling and increased extracellular potassium (K+) and glutamate. However, the role of astrocytes, a member of the neurovascular unit, in migraine with CSD has recently received increasing attention. In the early stages of CSD, astrocytes provide neurons with energy support and clear K+ and glutamate from synaptic gaps. However, in the late stages of CSD, astrocytes release large amounts of lactic acid to exacerbate hypoxia when the energy demand exceeds the astrocytes' compensatory capacity. Astrocyte endfoot swelling is a characteristic of CSD, and neurons are not similarly altered. It is primarily due to K+ influx and abnormally active calcium (Ca2+) signaling. Aquaporin 4 (AQP-4) only mediates K+ influx and has little role as an aquaporin. Astrocytes endfoot swelling causes perivascular space closure, slowing the glymphatic system flow and exacerbating neuroinflammation, leading to persistent CSD. Astrocytes are double-edged swords in migraine with CSD and may be potential targets for CSD interventions.

Research progress of astragaloside IV in treating acute kidney injury.

Acute kidney injury (AKI) is one of the most common clinical critical illnesses, with decreased glomerular filtration rate, retention of nitrogen products, water and electrolyte disorders, and acid-base imbalance as the main clinical manifestations. Presently, there is no effective treatment for acute kidney injury, but the main treatment is to cure the primary disease, remove risk factors, maintain acid-base and water-electrolyte balance, and undergo kidney replacement. However, the mortality rate is still high. Investigations and studies showed that the mortality rate of patients with acute kidney injury in the ICU is 5-80% [1]. In recent years, Chinese medicine has been widely used in acute kidney injury treatment due to its complete dialectical system and rich experience. Astragalus is a commonly used medicine in traditional Chinese medicine to treat acute kidney injury. Astragaloside IV is the main active component of traditional Chinese medicine, Astragalus membranaceus. This article summarizes the relevant studies on treating acute kidney injury with astragaloside IV.

Influence of intraoperative blood salvage and autotransfusion on tumor recurrence after deceased donor liver transplantation: a large nationwide cohort study.

BACKGROUND AND AIMS: The practice of intraoperative blood salvage and autotransfusion (IBSA) during deceased donor liver transplantation (DDLT) for hepatocellular carcinoma (HCC) can potentially reduce the need for allogeneic blood transfusion. However, implementing IBSA remains debatable due to concerns about its possible detrimental effects on oncologic recurrence. METHODS: This study retrospectively enrolled nationwide recipients of DDLT for HCC between 2015 and 2020. The focus was on comparing the cumulative recurrence rate and the recurrence-free survival rate. Propensity score matching was conducted repeatedly for further subgroup comparison. Recipients were categorized based on the Milan criteria, macrovascular invasion, and pre-transplant α-Fetoprotein (AFP) level to identify subgroups at risk of HCC recurrence. RESULTS: A total of 6196 and 329 patients were enrolled in the non-IBSA and IBSA groups in this study. Multivariable competing risk regression analysis identified IBSA as independent risk factors for HCC recurrence (P<0.05). Post-matching, the cumulative recurrence rate and recurrence-free survival rate revealed no significant difference in the IBSA group and non-IBSA group (22.4% vs. 16.5%, P=0.12; 60.3% vs. 60.9%, P=0.74). Recipients beyond Milan criteria had higher, albeit not significant, risk of HCC recurrence if receiving IBSA (33.4% vs. 22.5%, P=0.14). For recipients with macrovascular invasion, the risk of HCC recurrence has no significant difference between the two groups (32.2% vs. 21.3%, P=0.231). For recipients with an AFP level<20 ng/mL, the risk of HCC recurrence was comparable in the IBSA group and the non-IBSA group (12.8% vs. 18.7%, P=0.99). Recipients with an AFP level ≥20 ng/mL, the risk of HCC recurrence was significantly higher in the IBSA group. For those with an AFP level≥400 ng/mL, the impact of IBSA on the cumulative recurrence rate was even more pronounced (49.8% vs. 21.9%, P=0.011). CONCLUSIONS: IBSA does not appear to be associated with worse outcomes for recipients with HCC exceeding the Milan criteria or with macrovascular invasion. IBSA could be confidently applied for recipients with a pre-transplant AFP level<20 ng/mL. For recipients with AFP levels≥20 ng/mL, undertaking IBSA would increase the risk of HCC recurrence.

Evaluation of liver regeneration after hemi-hepatectomy by combining computed tomography and post-operative liver function.

Background: Accurate evaluation of postoperative liver regeneration is essential to prevent postoperative liver failure. Aims: To analyze the predictors that affect liver regeneration after hemi-hepatectomy. Method: Patients who underwent hemi-hepatectomy in Hangzhou First People's Hospital and Hangzhou Shulan Hospital from January 2016 to December 2021 were enrolled in this study. The regeneration index (RI) was calculated by the following equation: RI = [(postoperative total liver volume {TLVpost} - future liver remnant volume {FLRV}/FLRV] × 100 %. Hepatic dysfunction was defined according to the "TBilpeak>7" standard, which was interpreted as (peak) total bilirubin (TBil) >7.0 mg/dL. Good liver regeneration was defined solely when the RI surpassed the median with hepatic dysfunction. Logistic regression analyses were performed to estimate prognostic factors affecting liver regeneration. Result: A total of 153 patients were enrolled, with 33 in the benign group and 120 patients in the malignant group. In the entire study population, FLRV% [OR 4.087 (1.405-11.889), P = 0.010], international normalized ratio (INR) [OR 2.763 (95%CI, 1.008-7.577), P = 0.048] and TBil [OR 2.592 (95%CI, 1.177-5.710), P = 0.018] were independent prognostic factors associated with liver regeneration. In the benign group, only the computed tomography (CT) parameter FLRV% [OR, 11.700 (95%CI, 1.265-108.200), P = 0.030] predicted regeneration. In the malignant group, parenchymal hepatic resection rate (PHRR%) [OR 0.141 (95%CI, 0.040-0.499), P = 0.002] and TBil [OR 3.384 (95%CI, 1.377-8.319), P = 0.008] were independent prognostic factors. Conclusion: FLRV%, PHRR%, TBil and INR were predictive factors associated with liver regeneration.

Protective effect of unsaturated fatty acids on cognitive impairment in CKD patients: Results from the National Health and Nutrition Examination Survey (2011-2014).

BACKGROUND: It is still unknown whether unsaturated fatty acids (UFA) have the same effect on preventing cognitive impairment in chronic kidney disease (CKD) patients as in healthy people. OBJECTIVE: To investigate the protective effect of dietary UFA intake and proportion on cognitive impairment in patients with CKD. METHODS: We extracted data from the National Health and Nutrition Examination Survey (NHANES, 2011-2014) on participants with a previous diagnosis of CKD and at least one complete cognitive assessment (Consortium to Establish a Registry for Alzheimer's Disease test, Animal Fluency Test and Digit Symbol Substitution Test). We used the lower quartile of the total scores of these three tests as the cut-off point, and divided the participants into two groups of normal cognitive performance and low cognitive performance to extract participants' intake of various UFA from the NHANES dietary module.

Causality between sarcopenia-related traits and major depressive disorder: A bi-directional, two-sample Mendelian randomized study.

Observational studies have demonstrated an association between sarcopenia and depression. However, these studies may be influenced by confounding factors, and the causal relationship between sarcopenia and major depressive disorder (MDD) remains unclear. This study aimed to apply the Mendelian randomization (MR) method to address confounding factors and assess the causal effect of sarcopenia on MDD. A two-way, two-sample MR method was employed in this study. Instrumental variables of genome-wide significance level were obtained from the open large-scale genome-wide association study summary data. MR analysis was conducted using inverse variance weighted, MR-Egger, and weighted median methods. The reliability of the results was verified using the heterogeneity test, pleiotropy test, and leave-one-out method for sensitivity analysis. Grip strength (right-hand grip strength: odds ratio [OR] = 0.880, 95% confidence interval [CI] 0.786-0.987, P = .027; left-hand grip strength: OR = 0.814, 95% CI 0.725-0.913, P < .001) and usual walking pace (OR = 0.673, 95% CI 0.506-0.896, P = .007) exhibited a direct causal effect on MDD. MDD had a significant causal effect on appendicular lean mass (ß = -0.065, 95% CI -0.110, -0.019, P = .005). There was a causal relationship between sarcopenia-related traits and MDD. Loss of muscle strength, rather than skeletal muscle mass, is correlated with an increased risk of MDD. Furthermore, individuals with MDD are more likely to experience loss of skeletal muscle mass.

Artificial intelligence can accurately distinguish IgA nephropathy from diabetic nephropathy under Masson staining and becomes an important assistant for renal pathologists.

Introduction: Hyperplasia of the mesangial area is common in IgA nephropathy (IgAN) and diabetic nephropathy (DN), and it is often difficult to distinguish them by light microscopy alone, especially in the absence of clinical data. At present, artificial intelligence (AI) is widely used in pathological diagnosis, but mainly in tumor pathology. The application of AI in renal pathological is still in its infancy. Methods: Patients diagnosed as IgAN or DN by renal biopsy in First Affiliated Hospital of Zhejiang Chinese Medicine University from September 1, 2020 to April 30, 2022 were selected as the training set, and patients who diagnosed from May 1, 2022 to June 30, 2022 were selected as the test set. We focused on the glomerulus and captured the field of the glomerulus in Masson staining WSI at 200x magnification, all in 1,000 × 1,000 pixels JPEG format. We augmented the data from training set through minor affine transformation, and then randomly split the training set into training and adjustment data according to 8:2. The training data and the Yolov5 6.1 algorithm were used to train the AI model with constant adjustment of parameters according to the adjusted data. Finally, we obtained the optimal model, tested this model with test set and compared it with renal pathologists. Results: AI can accurately detect the glomeruli. The overall accuracy of AI glomerulus detection was 98.67% and the omission rate was only 1.30%. No Intact glomerulus was missed. The overall accuracy of AI reached 73.24%, among which the accuracy of IgAN reached 77.27% and DN reached 69.59%. The AUC of IgAN was 0.733 and that of DN was 0.627. In addition, compared with renal pathologists, AI can distinguish IgAN from DN more quickly and accurately, and has higher consistency. Discussion: We constructed an AI model based on Masson staining images of renal tissue to distinguish IgAN from DN. This model has also been successfully deployed in the work of renal pathologists to assist them in their daily diagnosis and teaching work.

Non-destructive high-throughput measurement of elastic-viscous properties of maize using a novel ultra-micro sensor array and numerical validation.

Maize is the world's most produced cereal crop, and the selection of maize cultivars with a high stem elastic modulus is an effective method to prevent cereal crop lodging. We developed an ultra-compact sensor array inspired by earthquake engineering and proposed a method for the high-throughput evaluation of the elastic modulus of maize cultivars. A natural vibration analysis based on the obtained Young's modulus using finite element analysis (FEA) was performed and compared with the experimental results, which showed that the estimated Young's modulus is representative of the individual Young's modulus. FEA also showed the hotspot where the stalk was most deformed when the corn was vibrated by wind. The six tested cultivars were divided into two phenotypic groups based on the position and number of hotspots. In this study, we proposed a non-destructive high-throughput phenotyping technique for estimating the modulus of elasticity of maize stalks and successfully visualized which parts of the stalks should be improved for specific cultivars to prevent lodging.

MELK promotes HCC carcinogenesis through modulating cuproptosis-related gene DLAT-mediated mitochondrial function.

Cuproptosis caused by copper overload is mediated by a novel regulatory mechanism that differs from previously documented mechanisms regulating cell death. Cells dependent on mitochondrial respiration showed increased sensitivity to a copper ionophore elesclomol that induced cuproptosis. Maternal embryonic leucine zipper kinase(MELK) promotes tumorigenesis and tumor progression through the PI3K/mTOR pathway, which exerts its effects partly by targeting the pyruvate dehydrogenase complex(PDHc) and reprogramming the morphology and function of mitochondria. However, the role of MELK in cuproptosis remains unclear. Here, we validated that elevated MELK expression enhanced the activity of PI3K/mTOR signaling and subsequently promoted Dihydrolipoamide S-Acetyltransferase (DLAT) expression and stabilized mitochondrial function. This regulatory effect helped to improve mitochondrial respiration, eliminate excessive intracellular reactive oxygen species (ROS), reduce intracellular oxidative stress/damage and the possibility of mitochondria-induced cell fate alternations, and ultimately promote the progression of HCC. Meanwhile, elesclomol reduced translocase of outer mitochondrial membrane 20(TOM 20) expression and increased DLAT oligomers. Moreover, the above changes of MELK to HCC were abolished by elesclomol. In conclusion, MELK enhanced the levels of the cuproptosis-related signature(CRS) gene DLAT (especially the proportion of DLAT monomer) by activating the PI3K/mTOR pathway, thereby promoting elesclomol drug resistance, altering mitochondrial function, and ultimately promoting HCC progression.

Stratified Analysis of Survival Benefit for ABO-incompatible Deceased-donor Liver Transplantation: Multicenter Propensity Score-matched Study.

Background and Aims: Liver transplantation (LT) using ABO-incompatible (ABOi) grafts can extend the donor pool to a certain extent and hence reduce the waiting time for transplantation. However, concerns of the impending prognosis associated with this option, especially for patients with liver failure and higher model for end-stage liver disease (MELD) scores, who tend to be more fragile during the waiting period before LT. Methods: Recipients undergoing LT for acute-on-chronic liver failure or acute liver failure were retrospectively enrolled at four institutions. Overall survival was compared and a Cox regression analysis was performed. Propensity score matching was performed for further comparison. Patients were stratified by MELD score and cold ischemia time (CIT) to determine the subgroups with survival benefits. Results: Two hundred ten recipients who underwent ABOi LT and 1,829 who underwent ABO compatible (ABOc) LT were enrolled. The 5-year overall survival rate was significantly inferior in the ABOi group compared with the ABOc group after matching (50.6% vs. 75.7%, p<0.05). For patients with MELD scores ≤30, using ABOi grafts achieved a comparable overall survival rate as using ABOc grafts (p>0.05). Comparison of the survival rates revealed no statistically significant difference for patients with MELD scores ≥40 (p>0.05). For patients with MELD scores of 31-39, the overall survival rate was significantly inferior in the ABOi group compared with the ABOc group (p<0.001); however, the rate was increased when the liver graft CIT was<8 h. Conclusions: For recipients with MELD scores ≤30, ABOi LT had a prognosis comparable to that of ABOc LT and can be regarded as a feasible option. For recipients with MELD scores ≥40, ABOi should be adopted with caution in emergency cases. For recipients with MELD scores of 31-39, the ABOi LT prognosis was worse. However, those patients benefited from receiving ABOi grafts with a CIT of <8 h.

Quantitative proteomic profiling of hepatocellular carcinoma at different serum alpha-fetoprotein level.

PURPOSE: Hepatocellular carcinoma (HCC) is characterized by a poor long-term prognosis and high mortality rate. Serum alpha-fetoprotein (AFP) levels show great prognostic value in patients undergoing hepatectomy. This study aims to explore proteomic profiling in HCC samples based on AFP subgroups and identify potential key targets involved in HCC progression. METHODS: Twelve paired tumor and adjacent noncancerous tissue samples were collected from patients with HCC who underwent primary curative resection from January 2012 to December 2013. Clinical information was curated from four tissue microarrays to conduct survival analysis based on serum AFP levels. TMT-based quantitative proteomic analyses and bioinformatics analyses were performed to comprehensively profile molecular features. Immunohistochemistry was carried out to validate protein expression of identified targets. Kaplan-Meier survival analysis was performed to assess the overall survival and recurrence-free survival based on protein expressions. RESULTS: AFP (400 ng/mL) was a turning point in prognosis, metabolic- and invasion-associated pathways. The mass spectrometry analysis yielded a total of 5573 identified proteins. Annotations of 151 differentially expressed proteins in tumors and 95 proteins in paracancerous tissues (1.2-fold) showed similarities in biological processes, cellular components, molecular functions. Furthermore, differentially expressed hub proteins with five innovatively nominated druggable targets (C1QBP, HSPE1, GLUD2 for tumors and CHDH, ITGAL for paracancerous tissues), of which four (C1QBP, HSPE1, CHDH, ITGAL) targets were associated with poor overall survival (all Log-rank P < 0.05). CONCLUSIONS: Our quantitative proteomics analyses identified four key prognostic biomarkers in HCC and provide opportunities for translational medicine and new treatment.

CLIC1 Drives Angiogenesis in Hepatocellular Carcinoma by Modulating VEGFA.

Background: Chloride intracellular channel 1 (CLIC1) is upregulated in hepatocellular carcinoma (HCC). The present study aimed to investigate the role of CLIC1 in HCC angiogenesis. Materials and Methods: Immunohistochemistry (IHC) was used to test the expression of CLIC1 and CD34 in 67 pairs of HCC and paracarcinoma tissues. The prognosis data of the patients were used to analyze the clinical relevance of CLIC1. We built a coculture system of HCC cells and endothelial cells to explore the migration of endothelial cells. Conditioned media (CMs) from HCC cells was then collected to assess endothelial cell migration. Experiments were then conducted to confirm the relationship between CLIC1 and angiogenesis in a subcutaneous tumor model. Results: CLIC1 expression was higher in HCC tumor tissues than in paracarcinoma tissues. Patients with increased CLIC1 expression showed a higher microvascular density (MVD; P = .013). Kaplan-Meier curves indicated that patients with lower expression of CLIC1 had better overall survival (P < .001) and recurrence-free survival (P = .046). Vascular endothelial growth factor A (VEGFA) in CMs from CLIC1-knockdown cells was lower than in the control group, while VEGFA in CMs from CLIC1 overexpression cells was higher than in the control group. CMs from CLIC1 overexpression cell lines promote the in vitro migration of EA.hy926 cells. Meanwhile, adding Bevacizumab to CMs from CLIC1 overexpression cells significantly inhibited this migration. The growth of xenograft tumors derived from CLIC1-knockdown Huh7 cells was restrained compared with the control group (P < .001). IHC staining showed MVD was higher in tumors with CLIC1 overexpression. Conclusion: CLIC1 is a promising biomarker for predicting the prognosis of HCC patients, and expression of CLIC1 correlates with angiogenesis in HCC through regulating VEGFA.