Human monoclonal antibodies against Staphylococcus aureus A protein identified by high-throughput single-cell sequencing of phase I clinical volunteers' B cells.

Methicillin-resistant Staphylococcus aureus, poses a significant threat through infections in both community and hospital settings. To address this challenge, we conducted a phase I clinical trial study involving a recombinant Staphylococcus aureus vaccine. Utilizing peripheral blood lymphocytes from 64 subjects, we isolated antigen-specific memory B cells for subsequent single-cell sequencing. Among the 676 identified antigen-binding IgG1+ clones, we selected the top 10 antibody strains for construction within expression vectors. Successful expression and purification of these monoclonal antibodies led to the discovery of a highly expressed human antibody, designated as IgG-6. This antibody specifically targets the pentameric form of the Staphylococcus aureus protein A (SpA5). In vivo assessments revealed that IgG-6 provided prophylactic protection against MRSA252 infection. This study underscores the potential of human antibodies as an innovative strategy against Staphylococcus aureus infections, offering a promising avenue for further research and clinical development.

Real-world data on the clinicopathological traits and outcomes of hospitalized liver hemangioma patients: a multicenter study.

BACKGROUND: There is currently a lack of consensus regarding the clinical features, diagnosis, treatment indications and options, and risk assessment of hepatic hemangioma patients. METHODS: This was a multicenter, real-world study that analyzed a large number of hepatic hemangioma cases in China and included patient data on epidemiology, diagnosis, treatment methods, and outcomes. RESULTS: A total of 5,143 patients hospitalized for hepatic hemangioma were included, of whom 34.42% were male and 65.58% were female. The age distribution was concentrated between 30 and 60 years old, accounting for 87.41% of the patients. Among the hepatic hemangioma patients, 60.8% had only one tumor, with the most common pathological type being cavernous hemangioma (96.07% of cases). The treatment motivations and indications included anxiety, obvious clinical symptoms, rapid tumor growth, unclear diagnoses and acute emergencies. Overall, 41.4% of the patients were treated for psychological reasons, while 30.59% were treated because they presented obvious (primarily nonspecific) clinical symptoms. Hepatic resection was the main therapeutic method and was based on various indications. There were a small number of patients with Kasabach-Merritt syndrome, according to its generally recognized definition. CONCLUSIONS: Most patients in this study who were hospitalized for hepatic hemangioma did not meet the indications for requiring treatment. Surveillance is the recommended course of action for definitively diagnosed hepatic hemangioma, and a new classification system is needed to standardize the diagnosis of this condition.

Roles of BATF/JUN/IRF4 complex in tacrolimus mediated immunosuppression on Tfh cells in acute rejection after liver transplantation.

Rejection injury is a serious complication after liver transplantation (LTx). Tacrolimus (Tac) is a key immunosuppressive agent in the prevention of liver rejection after transplantation. The basic leucine zipper ATF-like transcription factor (BATF)/JUN/interferon regulatory factor 4 (IRF4) complex serves critical functions in the immune response. This study aimed to explore the role of the BATF/JUN/IRF4 complex in rejection after LTx by treatment with Tac. Herein, DA and Lewis (LEW) rats were used to construct the LTx animal model. The recipient LEW rats were treated with Tac or saline, subcutaneously. Splenic mononuclear cells were treated with Tac at 1 and 10 nM after stimulation with interleukin-6 (IL-6), and the expression of factors associated with the nuclear factor of activated T cells (NFAT)-BATF/JUN/IRF4 and IL-21 were detected. The results demonstrated that Tac prolonged the allografts survival and attenuated inflammation injury, and decreased the percentage frequencies of T follicular helper (Tfh) cells in peripheral blood mononuclear cells and inhibited B-cell lymphoma 6 (Bcl-6) and IL-6 expression in Tfh cells. In addition, Tac inhibited the expression of the BATF/JUN/IRF4 complex, Bcl-6 and IL-21 NFATc1 and NFATc2 were inhibited by Tac, and interacted with the promoter of BATF and IRF4. In conclusion, the attenuation of rejection injury may be dependent on the NFAT-BATF/JUN/IRF4-IL-21 axis, and the BATF/JUN/IRF4 complex participates in the inhibition of IL-21-producing Tfh cells after treatment with Tac. These findings suggest that the BATF/JUN/IRF4 complex-IL-21 axis may be used as a potential target for attenuating rejection injury after LTx.

MicroRNA-125a-3p overexpression promotes liver regeneration through targeting proline-rich acidic protein 1.

INTRODUCTION AND OBJECTIVES: Liver regeneration plays a valuable significance for hepatectomies, and is mainly attributed to hepatocyte proliferation. MicroRNA-125a-3p was reported to be highly associated with liver regeneration process. We studied the underlying mechanism of the functional role of miR-125a-3p in liver regeneration. MATERIALS AND METHODS: The miR-125a-3p mimics and inhibitor vector were constructed and transfected into primary human liver HL-7702 cells, the transfected cell viability was detected using cell counting kit-8 (CCK-8). Cell cycle distribution was analyzed by flow cytometry. With Targetscan and OUGene prediction, the potential targets of miR-125 were verified by real-time quantitative PCR (qPCR) and luciferase reporter assays in turn. The overexpression vector of proline-rich acidic protein 1 (PRAP1) was constructed and co-transfected with miR-125a-3p mimics into HL-7702 cells, detecting the changes of proliferative capacity and cell cycle distribution. Western blot and qPCR performed to analyze gene expressions. RESULTS: Overexpressed miR-125a-3p notably increased the hepatocyte viability at 48h, and decreased the number of G1 phase cells (p<0.05). However, miR-125a-3p inhibition suppressed the development of hepatocytes. PRAP1 was the target of miR-125a-3p. After co-transfection with PRAP1 vector, hepatocyte viability was decrease and the G1 phase cell number was increased (p<0.05). More importantly, overexpressed PRAP1 notably decreased the mRNA and protein levels of cyclin D1, cyclin-dependent kinase 2 (CDK2) and cell division cycle 25A (CDC25A). CONCLUSION: The elevated miR-125a-3p positively correlated with hepatocyte viability and cell cycle progression due to the modulation of PRAP1, and miR-125a-3p may contribute to improving liver regeneration.

Effect of the intermittent Pringle maneuver on liver damage after hepatectomy: a retrospective cohort study.

BACKGROUND: The Pringle maneuver (PM) interrupts the blood flow through the hepatic artery and portal vein to help control bleeding. This study analyzes the effects of the intermittent Pringle maneuver (IPM) on the surgical process and postoperative liver injury. METHODS: This study retrospectively evaluated 182 hepatocellular carcinoma patients who underwent hepatectomy. In the IPM group, hepatic blood flow was intermittently interrupted via clamping, with cycles of 10 minutes of inflow occlusion followed by 5 minutes of reperfusion that were repeated until the end of the surgery. In the non-IPM group, liver resection was performed without hepatic vascular blockage. RESULTS: For postoperative complications, the incidence rates of ascites and pleural effusion in the IPM group were significantly lower than those in the non-IPM group. The postoperative hospitalization time in the IPM group was significantly lower than that in the non-IPM group (p=0.0008). On the first day after the operation, the platelet count was significantly lower (p=0.0381) but the prothrombin time (PT) (p=0.0195) and activated partial thromboplastin time (APTT) (p=0.0071) were significantly higher in the non-IPM group than those in the IPM group. At discharge, only albumin was significantly higher in the non-IPM group than that in the IPM group (p=0.0303). Regression analysis showed that a prolonged interruption time was related to increased ALT and AST levels on the first day after surgery, but not on the seventh day or at discharge. CONCLUSION: The IPM does not cause additional liver damage during hepatectomy, and use of the IPM results in shorter hospital stays compared to surgery without using the IPM. The results of this study require further confirmation because of the retrospective design.

Roles of the tacrolimus-dependent transcription factor IRF4 in acute rejection after liver transplantation.

Acute rejection is a serious and life-threatening complication of liver transplantation (LTx). Tacrolimus (TAC) is a potent immunosuppressant used in experimental and clinical transplantation. Interferon regulatory factor 4 (IRF4) plays key roles as a transcription factor in the immune response. This study explored the role of IRF4 in acute rejection after LTx using TAC treatment. Here, LTx was performed in DA (RT1(n)) and Lewis (LEW) (RT1(l)) rats. The recipients were immunosuppressed with TAC (1.5mg/kg/day subcutaneously) or saline. Liver grafts were harvested 1, 3, 5, 7, and 10 days after LTx for histology, immunohistochemistry, western blotting and real-time PCR. Splenic mononuclear cells were activated with different doses of TAC. The nuclear factor of activated T cells (NFAT) signal pathway and CD4+ T subset-related transcription factors were assessed. The results showed that TAC treatment prolonged the survival of liver allografts in recipients, significantly attenuated hepatic tissue injury and improved liver function. IRF4 expression in grafts was down-regulated after TAC treatment. TAC inhibited the expression of IRF4, NFAT, Foxp3 and RORγt in splenic mononuclear cells in vitro. In conclusions, our studies showed that TAC attenuated acute rejection responses after LTx. This attenuation might depend on the TAC-NFAT-IRF4 signal pathway, which is crucial for the function of T helper subsets (Treg and Th17 cells) in acute rejection after LTx. These findings contribute to our understanding of the immune pharmacological mechanism of TAC to prevent rejection in LTx rats.

Vitamin E intake and pancreatic cancer risk: a meta-analysis of observational studies.

BACKGROUND: Some epidemiological studies have suggested that vitamin E intake reduces the risk of pancreatic cancer; however, this conclusion has not been supported by all the published studies. We conducted a meta-analysis to assess the relationship between vitamin E intake and the risk of pancreatic cancer by combining the results from published articles. MATERIAL/METHODS: We searched the published studies that reported the relationship between vitamin E intake and pancreatic cancer risk using the PubMed, Web of Science, and Embase databases through December 31st, 2014. Based on a fixed-effects or random-effects model, the RR and 95% CI were used to assess the combined risk. RESULTS: In total, 10 observational studies (6 case-control studies and 4 cohort studies) were included. The overall RR (95% CI) of pancreatic cancer for the highest vs. the lowest level of vitamin E intake was 0.81 (0.73, 0.89). We found little evidence of heterogeneity (I2=19.8%, P=0.255). In the subgroup analyses, we found an inverse association between vitamin E intake and pancreatic cancer risk both in the case-control and cohort studies. Additionally, this inverse association was not modified by different populations. CONCLUSIONS: In our meta-analysis, there was an inverse association between vitamin E intake and the risk of pancreatic cancer. A high level of vitamin E might be a protective factor for populations at risk for pancreatic cancer.

Type 1 innate lymphoid cells contribute to the pathogenesis of chronic hepatitis B.

Innate lymphoid cells (ILCs) function in producing effector cytokines in response to pathogenic infections. However, the roles and related mechanisms of the ILC subpopulations, ILC1 and ILC2, which mirror Th1 and Th2 in adaptive immunity, remain unclear. In this study, we found the markedly elevated levels of the ILC1 transcription factor T-bet, the effector cytokine IFN-γ and the IL/receptor signaling molecules IL-12/IL-12R, which are indispensable for ILC1 differentiation, in the helper ILCs of chronic hepatitis B (CHB) patients. The elevated level of the ILC1 population was significantly associated with hepatic damage in CHB patients, and was not related to telbivudine treatment. In contrast, although we also observed elevated levels of ILC2-related factors, including IL-33, ST2, GATA3 and IL-13 in helper ILCs, the extent of elevation shown by each was lower than that shown by the ILC1-related factors. Furthermore, the activity of the ILC2s did not correlate with either HBV copies or liver damage. The findings of this study suggest potential pro-inflammatory roles for ILC1s in CHB pathogenesis, potentiating these cells and their related molecules as targets of diagnostic, prognostic and/or therapeutic strategies for hepatitis B.

Predictive value of indocyanine green retention rate with respect to complications of radiofrequency ablation in 878 patients with hepatocellular carcinoma.

BACKGROUND AND AIMS: Radiofrequency ablation (RFA) is a minimally invasive technique used for the treatment of hepatocellular carcinoma (HCC). It may produce complications. The indocyanine green (ICG) retention rate at 15 min (ICGR15) has been used to predict complications after hepatectomy. In this study, the prediction of the value of ICGR15 for complications of RFA to the patients with HCC was evaluated. METHODS: Some 878 cases of HCC treated between June 2009 and June 2013 were evaluated. All patients were treated by percutaneous radiofrequency ablation. Patients were divided into two groups: a complication group (85 cases) and a complication-free group (793 cases). ICGR15 and other baseline characteristics of the two groups were compared. A logistic regression model was used to analyse the merits of assessing liver reserve to predict complications post-RFA. RESULTS: Complications such as intra-abdominal haemorrhage and pleural effusion occurred in 85 (9.68%) patients after RFA. Patients in the two groups did not differ with regard to baseline parameters. Patients in the two groups did differ significantly in ICGR15 and tumour site (p < 0.05). Tumour site was found to have a significant impact on the rate of complications post-RFA. There was no significant difference in ICGR15 values among patients with the same Child-Pugh scores or in the same tumour site. CONCLUSIONS: The present results demonstrated that RFA is minimally invasive and suitable for the treatment of HCC. They also showed that ICGR15 did not independently predict for liklihood of post-RFA complications, after controlling for tumour site. Patients with tumours located subcapsularly or near the porta hepatis were found to have significantly higher rates of post-operative complications after RFA than to patients with tumours in the liver parenchyma.

Prediction of the prognosis after liver transplantation in severe hepatitis B-induced liver failure and clinical decision for liver transplantation.

BACKGROUND: Severe hepatitis B-induced liver failure (SHBLF) patients who require liver transplantation represent a particular challenge. We sought to explore the prognostic factors and establish a new scoring model, the SHBLF prognosis model (SHBLFPM), which can aid in clinical decision making. MATERIALS AND METHODS: A total of 98 patients who underwent liver transplantation for SHBLF in our center were retrospectively recruited between January 1, 1999, and December 31, 2010. The clinical and biochemical data were analyzed using the Cox proportional hazards model and log-rank test. The receiver operating characteristic curves were obtained for the King's College Hospital (KCH) criterion, the model for end-stage liver disease (MELD), and the new model; the areas under the curves were compared using a z-test. RESULTS: The independent factors predicting the prognosis were the age of the patient (AP, P = 0.017), hepatic encephalopathy (HE, P = 0.013), the serum total bilirubin concentration (TBiL, P < 0.001), and the international normalized ratio for prothrombin time (INR, P = 0.001), as identified using a multivariate Cox regression analysis. The area under the curve of the new regression model (0.881) was significantly larger than that of the MELD (0.783) and KCH scores (0.596) (P < 0.05). Patients with a preoperative SHBLFPM score <23.57 had a significantly better prognosis than those with higher scores (P < 0.001). CONCLUSIONS: Age of patient, hepatic encephalopathy, serum total bilirubin concentration, and international normalized ratio for prothrombin time are independent factors affecting the posttransplantation mortality of SHBLF patients. SHBLFPM may be a criterion for the clinical decision for liver transplantation in SHBLF patients with a greater prognostic predictive ability than the MELD and KCH models.