Progress of PD-1/PD-L1 signaling in immune response to liver transplantation for hepatocellular carcinoma.

Primary liver cancer is one of the most common malignant tumors in China. The vast majority of primary liver cancer are hepatocellular carcinoma. Due to its high incidence and mortality from HCC, HCC has always been a feared type of cancer. Liver transplantation, as one of the important means to treat advanced liver cancer, has brought new hope to patients. However, as patients have been in a state of immunosuppression after liver transplantation, these patients face new problems of HCC recurrence and metastasis. A increasing number of studies have proved that blocking the PD-1/PD-L1 signaling pathway and restoring the immune killing inhibition of T cells can produce better therapeutic effects on tumors and chronic infectious diseases. As a promising treatment in the field of tumor immunotherapy, PD-1/PD-L1 inhibitors have achieved important results in liver cancer patients, but their application in liver transplantation patients is still highly controversial. This paper will introduce the mechanism of action of PD-1/PD-L1 signaling pathway and the current basic and clinical studies of PD-1/PD-L1 signaling pathway associated with immune response in HCC transplantation.

Red cell distribution width-to-lymphocyte ratio: A novel predictor for HBV-related liver cirrhosis.

To evaluate the diagnostic power of red cell distribution width-to-lymphocyte ratio (RLR) for HBV-related liver cirrhosis via a retrospective cohort study.Seven hundred fifty healthy controls, 327 chronic hepatitis B (CHB) patients, and 410 patients with HBV-related liver cirrhosis (HBV-LC) were enrolled in this study. RLR, lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), red cell distribution width (RDW), AST to platelet ratio index (APRI), and fibrosis index based on the 4 factors (FIB-4) were compared between the 3 groups. The predictive powers of RLR and RDW for HBV-related liver cirrhosis and patient prognosis were evaluated using AUROC.Patients with HBV-related liver cirrhosis had higher RLR, FIB-4, NLR, RDW, APRI, and lower LMR compared with the control and CHB groups. RLR in the HBV-LC group was significantly higher than both CHB and control groups (both P < .05). While RLR in the CHB group was also higher than the control group, the difference was not statistically significant (P > .05). The AUROC of RLR for predicting HBV-related liver cirrhosis was 0.87, and was superior to RDW (0.81), FIB-4 (0.79), and APRI (0.60). With an optimized cut-off value (10.87), RLR had the highest sensitivity (0.88) and specificity (0.72), and was superior to RDW (0.86, 0.64), FIB-4 (0.80, 0.65), and APRI (0.85, 0.48) as a biomarker. For all 3 groups, RLR was negatively correlated (all P < .05) with serum platelet (PLT) and was positively correlated (all P < .05) with FIB-4 and APRI. There was no significant statistical difference in RLR for patients in HBV-LC group who had different prognosis (P > .05).The RLR, a routinely available, inexpensive, and easily calculated measure, can be used as a predictor of HBV-related liver cirrhosis, but not as a predictor of prognosis for patients with liver cirrhosis. Use of RLR may reduce the need for frequent liver biopsies in CHB patients.

Seroprevalence of AIH-related autoantibodies in patients with acute hepatitis E viral infection: a prospective case-control study in China.

The seroprevalenc of autoimmune hepatitis (AIH)-related antibodies in patients, particularly Asians, with acute hepatitis E (AHE) is unclear. In this study, we investigated whether acute hepatitis E virus (HEV) infection is associated with the seroprevalence of AIH-related autoantibodies and assessed their impact on the disease characteristics. AIH-related autoantibodies were detected by indirect immunofluorescence in 198 AHE patients and 50 type 1 AIH patients. The positivity rates of against nuclear antigen (ANA) and smooth muscles antibody (SMA) in AHE patients were 37.4% and 22.7%, and the total positivity rate was 50%. Compared to those in AIH patients, the positivity rates of ANA-H and SMA-AA were significantly lower (35.1% vs. 82.1% and 4.4% vs. 88.4%). Female gender and the ALT level, but not immunosuppressive or antiviral drugs, were independently predictive of the presence of AIH-related autoantibodies in AHE patients. Fifty-two patients positive for AIH-related autoantibodies were followed up for 12 months. During this period, 33 of them became negative and 19 remained positive, albeit with significantly decreased titres. In conclusions, the seroprevalence of AIH-related autoantibodies in AHE patients was elevated, particularly in females, but their subspecificities and titres differed from those of type 1 AIH. Acute HEV infection may be related to AIH.Abbreviations: AIH: autoimmune hepatitis; AHE: acute hepatitis E; ANA: against nuclear antigen; SMA: smooth muscles antibody; ANA-H: ANA with homogeneous pattern; SMA-AA: SMA with anti-actin pattern; Anti-LKM1: anti- liver-kidney microsomes-1 antibody; ANCA: anti-neutrophil cytoplasmic antibody; AMA: anti-mitochondrial antibody; Anti-SLA: anti-soluble liver antigen; Anti-LC1: anti-liver cytoplasmic type 1 antibody; pANCA: perinuclear antineutrophil cytoplasmic antibody.

HEV-LFS : A novel scoring model for patients with hepatitis E virus-related liver failure.

A noninvasive assessment method for acute or acute-on-chronic liver failure in patients with hepatitis E virus (HEV) infection is urgently needed. We aimed to develop a scoring model for diagnosing HEV patients who developed liver failure (HEV-LF) at different stages. A cross-sectional set of 350 HEV-LF patients were identified and enrolled, and the Guidelines for Diagnosis and Treatment of Liver Failure in China and the Asian Pacific Association for the Study of the Liver were adopted as references. HEV-LFS , a novel scoring model that incorporates data on cholinesterase (CHE), urea nitrogen (UREA), platelets and international normalized ratio was developed using a derived dataset. For diagnosing HEV-LF stages F1 to F3, the HEV-LFS scoring model (F1: 0.87; F2: 0.90; F3: 0.92) had a significantly higher AUROC than did the CLIF-C-ACLFs (F1: 0.65; F2: 0.56; F3: 0.51) and iMELD (F1: 0.70; F2: 0.57; F3: 0.51) scoring models, of which the HEV-LFS scoring model had the best sensitivity and specificity. In addition, the HEV-LFS scoring model was correlated with mortality, length of hospitalization and ICU stay. As the GDTLF score increased, the CHE level decreased and the UREA increased gradually. Encouragingly, a calibration curve showed good agreement between the derivation and validation sets. Notably, we also established a nomogram to facilitate the practical operability of the HEV-LFS scoring model in clinical settings. In conclusion, both CHE and UREA may be indicators for HEV-LF patients. The HEV-LFS scoring model is an efficient and accessible model for classifying HEV-LF at different stages.

[Retracted] Serum­free­medium­type mesenchymal stem cell culture supernatant exerts a protective effect on A549 lung epithelial cells in acute lung injury induced by H2O2.

The authors wish to retract their research article entitled 'Serum­free­medium­type mesenchymal stem cell culture supernatant exerts a protective effect on A549 lung epithelial cells in acute lung injury induced by H2O2', published in Oncology Reports 40, 3033­3039, 2018. After the publication of this article, the authors have become concerned that there were flaws in their study design that have called into question the reported results. On repeating certain of the experiments, the authors found that the Nrf2­Keap1­ARE signaling pathway only has a role in the lung epithelial cell injury model, whereas it does not serve a role in the A549 model. Further studies are required to validate the role of the Nrf2­Keap1­ARE signaling pathway and the apoptosis­associated proteins. In particular, the results presented in Fig. 5, showing the difference between Bax and Bcl­2, appear to be incorrect. For these reasons, the authors have decided to retract the article from the publication. All the named authors on the paper agree to this retraction. The authors sincerely apologize for any inconvenience that might result from the retraction of this article. [the original article was published in the Oncology Reports 40: 3033­3039, 2018; DOI: 10.3892/or.2018.6656].

Benzbromarone as a possible cause of acute kidney injury in patients with urolithiasis: Two case reports.

RATIONALE: Reports of acute kidney injury (AKI) associated with benzbromarone use in patients with hyperuricemia (HUA) are rare so far. PATIENT CONCERNS: We describe 2 unique clinical patterns in which benzbromarone was a possible cause of AKI following self-medication for HUA. In case 1, a 45-year-old man developed AKI after taking 100 mg of benzbromarone. His serum creatinine (Scr) increased to 2.3 mg/dL on day 2 after benzbromarone administration. Ultrasound showed multiple small stones in both kidneys, and the 24-hour urine uric acid level was 3128 mg. In case 2, a 17-year-old male student presented with AKI after self-administration of 50 mg of benzbromarone. His Scr increased to 6.8 mg/dL on day 3 after benzbromarone administration. Ultrasound showed multiple stones in the left kidney. DIAGNOSIS: Both patients underwent renal biopsy, with findings of acute tubular interstitial nephropathy in case 1 and acute tubular damage in case 2. Drug-induced AKI was considered. INTERVENTIONS: Both cases were treated supportively with intravenous hydration only. In both patients, the Scr level recovered within 0.5 months and renal function was normal 3 months after discharge. LESSONS: Oral benzbromarone is widely used in Asian counties to treat HUA and the adverse effects are mostly mild. However, clinicians should be alert for benzbromarone-induced AKI. Moreover, uricosuric drugs should only be used after exclusion of urolithiasis and other contraindications.

The Protective Effects and the Involved Mechanisms of Tanshinone IIA on Sepsis-Induced Brain Damage in Mice.

To evaluate the protective effect of tanshinone IIA on sepsis using a mouse model as well as to preliminarily explore the mechanism behind its application. The mouse model of sepsis was established using the cecal ligation and puncture (CLP) method. Eighty mice were randomly divided into four groups: Sham operation group (Sham group), model group (CLP group), tanshinone IIA group (DS group), and dexamethasone group (DEX group). ELISA method was used to detect the levels of TNF-α and IL-6 in the hippocampal tissue of mouse. Western blot method was used to detect the expression levels of PSD-95, SYP, and Iba-1 in the hippocampus tissue. Immunohistochemistry was used to detect the expression level and distribution of astrocytes (GFAP antibody). Morris water maze test was used to determine the ability of learning and memory in mice. Tanshinone IIA could improve the postoperative survival and 7-day survival rate in the septic mice after operation, which shortens the escape latency and increases the number of crossing platform in the septic mice. It also reduces the expression of TNF-α, IL-6, and Iba-1 in the peripheral blood/hippocampus and the number of astrocytes in hippocampal CA3 area after 7 days of sepsis in mice. However, tanshinone IIA increases the expression levels of SYP and PSD-95 in the hippocampus of septic mice on the seventh day after operation. Tanshinone IIA has a protective effect on the nerve of septic mice, and its mechanism may be related to the anti-inflammatory effects of the peripheral and hippocampal parts as well as inhibiting the over-activation of astrocytes and microglia.

Correlation between tripartite motif-containing protein 44 protein expression and the prognosis of postoperative patients exhibiting skin squamous cell carcinoma.

Tripartite motif-containing protein 44 (TRIM44) plays an important role in the development and progression of some human cancers; however, its role in skin squamous cell carcinoma (SCC) remains unknown. The aim of the present study was to investigate TRIM44 expression and clinicopathological significance of TRIM44 in SCC.Immunohistochemistry (IHC) technique, reverse transcriptase-polymerase chain reaction (RT-PCR) and western blot were performed to evaluate differences in TRIM44 protein expression in SCC and normal skin tissues.IHC showed that the positive rate of TRIM44 staining in SCC tissues 26.00% (9/30), while the positive rate of normal control group was 83.33% (25/30). The positive rate of TRIM44 staining in SCC tissues is significantly lower than normal skin tissue (P <.01). RT-PCR showed that the positive rates of TRIM44 mRNA expression in SCC tissues were 16.67% (5/30), but the positive rate of normal control group was 86.67% (26/30). TRIM44 mRNA expression in SCC group was significantly lower than that in the normal group (P <.01). Kaplan-Meier survival analysis showed that low expression was associated with poor overall survival in SCC patients (P =.004). Multi-factor survival analysis indicated that both low TRIM44 expression and tumor stage were independent factors affecting the overall survival of patients with SCC (P =.038 and P =.001, respectively). Low expression of TRIM44 in SCC was associated with staging (P =.009 and P =.008, respectively) and metastasis (P =.003 and P =.004, respectively).The levels of TRIM44 protein and TRIM44 mRNA in SCC are both lowly expressed which is strongly associated with tumor staging, metastasis, and poor survival. And it also is an independent factor affecting the overall survival of patients with SCC.

Serum­free­medium­type mesenchymal stem cell culture supernatant exerts a protective effect on A549 lung epithelial cells in acute lung injury induced by H2O2.

The aim of the present study was to investigate the mechanisms and protective effect of serum­free­medium­type fetal placental mesenchymal stem cell (fPMSC) culture supernatant on A549 lung epithelial cells following treatment with hydrogen peroxide (H2O2). A549 lung epithelial cells were stimulated with different concentrations of H2O2, and the survival rate of the cells was examined by Cell Counting Kit­8 (CCK­8) assay. It was concluded that the H2O2 concentration when the cell survival rate was at 50% was the optimum condition to create an oxidative damage model. Hoechst 33258 staining and western blot analysis was used to validate the A549 lung epithelial cell model. Serum­free medium was used to culture fPMSCs, and A549 lung epithelial cells treated with H2O2 were cultured with passage 3 MSC supernatant for 24 h. This was termed the supernatant group. Simultaneously, a damage group that was stimulated with H2O2 only, and a vitamin C (VC) group that was treated with H2O2 followed by 100 µmol/l VC in culture medium was also established. The apoptosis of the three groups was detected by flow cytometry, and western blotting was used to detect apoptosis­associated and nuclear factor erythroid 2­like 2 (Nrf2)­kelch­like ECH­associated protein 1 (Keap1)­antioxidant response element/oxidative stress­associated protein expression. Following the CCK­8 test, 600 µmol/l H2O2 was selected to stimulate the A549 lung epithelial cells for 24 h, which resulted in a A549 cell survival rate of 56.41±3.31%. Hoechst 33258 staining and western blotting also confirmed the reliability of the model. Flow cytometry demonstrated that the apoptotic rate of the cells in the VC and supernatant groups was reduced compared with that in the injury group. The difference between the supernatant group and the injury group was statistically significant. The detection of apoptosis­associated proteins by western blotting revealed that the expression of apoptosis regulator BAX and Caspase­3 in the VC and supernatant groups was decreased. Furthermore, the expression of B­cell lymphoma­2 was increased compared with that in the injury group, and the difference was statistically significant (P<0.05). Compared with that in the injury group, the expression of Nrf2 increased in the VC and supernatant groups, whereas the expression of Keap1 was decreased, and the difference was statistically significant (P<0.05). In conclusion, fPMSC supernatant exhibited an antioxidant capacity in A549 lung epithelial cells treated with H2O2 as a model of acute lung injury. The supernatant was found to reduce oxidative damage and inhibit apoptosis.

Blocking beta 2-adrenergic receptor inhibits dendrite ramification in a mouse model of Alzheimer's disease.

Dendrite ramification affects synaptic strength and plays a crucial role in memory. Previous studies revealed a correlation between beta 2-adrenergic receptor dysfunction and Alzheimer's disease (AD), although the mechanism involved is still poorly understood. The current study investigated the potential effect of the selective ß2-adrenergic receptor antagonist, ICI 118551 (ICI), on Aß deposits and AD-related cognitive impairment. Morris water maze test results demonstrated that the performance of AD-transgenic (TG) mice treated with ICI (AD-TG/ICI) was significantly poorer compared with NaCl-treated AD-TG mice (AD-TG/NaCl), suggesting that ß2-adrenergic receptor blockage by ICI might reduce the learning and memory abilities of mice. Golgi staining and immunohistochemical staining revealed that blockage of the ß2-adrenergic receptor by ICI treatment decreased the number of dendritic branches, and ICI treatment in AD-TG mice decreased the expression of hippocampal synaptophysin and synapsin 1. Western blot assay results showed that the blockage of ß2-adrenergic receptor increased amyloid-ß accumulation by downregulating hippocampal α-secretase activity and increasing the phosphorylation of amyloid precursor protein. These findings suggest that blocking the ß2-adrenergic receptor inhibits dendrite ramification of hippocampal neurons in a mouse model of AD.

NPY Impairs Cell Viability and Mitochondrial Membrane Potential Through Ca2+ and p38 Signaling Pathways in Neonatal Rat Cardiomyocytes.

NPY is involved in stress cardiomyopathy. However, the associated mechanism for NPY-induced stress cardiomyopathy remains unclear. In this study, we aimed to explore potential cell signaling pathways that are related to NPY-mediated cell viability in neonatal rat cardiomyocytes. We found that NPY induced cell viability suppression in cultured cardiomyocytes in a dose-dependent manner. After NPY treatment, expression of CaN and p-CAMKII increased significantly, and phosphorylation of p38 but not ERK and JNK was changed. Moreover, NPY treatment significantly increased PGC-1α (the key factor of mitochondrial biogenesis and energy metabolism) expression but decreased mitochondrial membrane potential in cultured cardiomyocytes. More importantly, the blockage of CaN, CAMKII, and p38 signaling pathways by their inhibitors could rescue the reduced cell viability and mitochondrial membrane potential in NPY-treated cardiomyocytes. Collectively, our data demonstrated that NPY mediated cell viability and mitochondrial membrane potential in cardiomyocytes through CaN, CAMKII, and p38 signaling pathways.