Role of international normalized ratio in nonpulmonary sepsis screening: An observational study.

BACKGROUND: Currently, there is a lack of sepsis screening tools that can be widely used worldwide. Pulmonary sepsis can be of sufficient concern to physicians due to their noticeable symptoms, which usually rely less on screening tools. AIM: To investigate the efficiency of the international normalized ratio (INR) for the early rapid recognition of adult nonpulmonary infectious sepsis. METHODS: This is a prospective observational study. A total of 108 sepsis patients and 106 nonsepsis patients were enrolled according to relevant inclusion and exclusion criteria. Commonly used clinical indicators, such as white blood cell, neutrophil count, lymphocyte count, neutrophil-lymphocyte count ratio (NLCR), platelets (PLT), prothrombin time, INR, activated partial thromboplastin time, and quick Sequential "Sepsis-related" Organ Failure Assessment (qSOFA) scores were recorded within 24 h after admission. The diagnostic performances of these clinical indicators were analyzed and compared through multivariate logistic regression analysis, Spearman correlation, and receiver operating characteristic curve analysis. RESULTS: The INR value of the sepsis group was significantly higher than that of the nonsepsis group. INR has superior diagnostic efficacy for sepsis, with an area under the curve value of 0.918, when those preexisting diseases which significantly affect coagulation function were excluded. The diagnostic efficacy of the INR was more significant than that of NLCR, PLT, and qSOFA (P < 0.05). Moreover, INR levels of 1.17, 1.20, and 1.22 could be used to categorize the relative risk of nonpulmonary infections sepsis into three categories: low, medium and high risk, respectively. CONCLUSION: The INR is a promising and easily available biomarker for diagnosis, and it can be used as one of the indicators for early screening of adult nonpulmonary infectious sepsis. When its value is higher than the optimal cutoff value (1.22), high vigilance is required for adult nonpulmonary infectious sepsis.

Integrative Characterization of Immune-relevant Genes in Hepatocellular Carcinoma.

BACKGROUND AND AIMS: Tumor microenvironment plays an essential role in cancer development and progression. Cancer immunotherapy has become a promising approach for the treatment of hepatocellular carcinoma (HCC). We aimed to analyze the HCC immune microenvironment characteristics to identify immune-related genetic changes. METHODS: Key immune-relevant genes (KIRGs) were obtained through integrating the differentially expressed genes of The Cancer Genome Atlas, immune genes from the Immunology Database and Analysis Portal, and immune differentially expressed genes determined by single-sample gene set enrichment analysis scores. Cox regression analysis was performed to mine therapeutic target genes. A regulatory network based on KIRGs, transcription factors, and immune-related long non-coding RNAs (IRLncRNAs) was also generated. The outcomes of risk score model were validated in a testing cohort and in clinical samples using tissue immunohistochemistry staining. Correlation analysis between risk score and immune checkpoint genes and immune cell infiltration were investigated. RESULTS: In total, we identified 21 KIRGs, including programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA4), and found IKBKE, IL2RG, EDNRA, and IGHA1 may be equally important to PD-1 or CTLA4. Meanwhile, KIRGs, various transcription factors, and IRLncRNAs were integrated to reveal that the NRF1-AC127024.5-IKBKE axis might be involved in tumor immunity regulation. Furthermore, the immune-related risk score model was established according to KIRGs and key IRLncRNAs, and verified more obvious discriminating power in the testing cohort. Correlation analysis indicated TNFSF4 , LGALS9 , KIAA1429 , IDO2, and CD276 were closely related to the risk score, and CD4 T cells, macrophages, and neutrophils were the primary immune infiltration cell types. CONCLUSIONS: Our results highlight the importance of immune genes in the HCC microenvironment and further unravel the underlying molecular mechanisms in the development of HCC.

α-ketoglutarate attenuates ischemia-reperfusion injury of liver graft in rats.

OBJECTIVE: The α-ketoglutarate (αKG), a metabolite of glutaminolysis, is reported to orchestrate macrophages activation. This study aims to clarify whether the αKG / glutaminolysis metabolism can suppress Kupffer cells (KCs) activation during liver transplantation and attenuate hepatic ischemia-reperfusion injury (IRI). METHODS: Donor livers were perfused with DM-αKG (a cell-permeable analog of αKG) or BPTES (an inhibitor of glutaminase 1) via portal vein during cold preservation, and controls were perfused with UW solution. Then, a rat model of liver transplantation was performed. Serum levels of alanine transaminase (ALT), total bilirubin (TBIL) and inflammatory cytokines, as well as histology, were analyzed after 24 h. KCs were isolated from grafts. RT-PCR and immunofluorescence were used to evaluate polarization-specific marker genes. Western bolt was employed to assess the expression of phosphorylation of glycogen synthase kinase 3ß (p-GSK3ß) and suppressor of cytokine signaling 1 (SOCS1). EMSA was utilized to quantify the NF-κB transcriptional activity. RESULTS: Compared with controls, DM-αKG perfusion decreased ALT and TBIL levels, alleviated liver damage, and reduced apoptosis, while BPTES group showed higher ALT and TBIL levels, severe damage and more apoptosis. Furthermore, DM-αKG perfusion suppressed NF-κB activity, up-regulated the expression of p-GSK3ß and SOCS1 in KCs, and shifted the M1/M2 balance toward an anti-inflammatory profile. Besides, DM-αKG suppressed serum pro-inflammatory cytokines secretion and increased IL-10. CONCLUSIONS: αKG produced by glutaminolysis protects liver graft from IRI by regulating the inflammatory response and modifying the polarization of KCs.

VEGF-C attenuates ischemia reperfusion injury of liver graft in rats.

BACKGROUND: Vascular endothelial growth factor receptor-3 (VEGFR-3) / vascular endothelial growth factor -c (VEGF-C) signaling is reported to negatively regulate TLR4-triggered inflammation of macrophages. This study aims to clarify whether the VEGFR-3/VEGF-C signaling can suppress Kupffer cells (KCs) activation and attenuate hepatic ischemia-reperfusion injury (IRI) after liver transplantation. METHODS: A rat model of liver transplantation was performed. Donor livers were perfused with VEGF-C injection via portal vein during cold preservation, and controls were perfused with UW solution. Serum levels of alanine transaminase (ALT), total bilirubin (TBIL) and inflammatory cytokines, as well as histology were analyzed after 24 h. KCs were isolated from grafts, RT-PCR and immunofluorescence were used to evaluate polarization-specific marker genes, western bolt was employed to assess the expression of suppressor of cytokine signaling 1(SOCS1) and phosphorylated glycogen synthase kinase 3ß (p-GSK3ß), and EMSA was utilized to quantify the NF-κB transcriptional activity. RESULTS: Compared with controls, VEGF-C perfusion reduced ALT and TBIL levels and alleviated liver damage. Furthermore, VEGF-C perfusion suppressed serum proinflammatory cytokines secretion and increased IL-10.In addition, the VEGFR-3 mRNA of KCs was increased after reperfusion. VEGF-C perfusion suppressed NF-κB activity and up-regulated the expression of SOCS1 and p-GSK3ß in KCs, and shifted the M1/M2 balance toward an anti-inflammatory profile. CONCLUSION: Exogenous VEGF-C protects liver graft from IRI by regulating the inflammatory response and modifying polarization of KCs.

Liver X Receptors Activation Attenuates Ischemia Reperfusion Injury of Liver Graft in Rats.

Purpose: Suppression of the Toll like receptor 4 (TLR4)-nuclear factor-κB (NF-κB) signaling was critical in protection against liver IRI. Previous studies revealed that Liver X receptors (LXRs) activation could antagonize TLR4-NF-κB signaling. The purpose of this study is to determine whether LXRs agonist GW3965 can suppress the TLR4-NF-κB signaling during liver transplantation and protect ischemia-reperfusion injury (IRI). Materials and Methods: Sprague Dawley (SD) rats were used to perform orthotropic liver transplantation. Donors were pretreatment with GW3965 (0.3 mg/kg) through caudal vein injection 30 min before the surgery. The followings were analyzed after transplantation: alanine aminotransferase (ALT), interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) level in serum, ATP binding cassette transporter A1 (Abca1) expression, NF-κB transcriptional activity, apoptosis and histological injury. Results: GW3965 pretreatment significantly ameliorated the degree of IRI associated with the effects of upregulating Abca1 expression, inhibiting NF-κB transcriptional activity, and downregulating TNF-α and IL-6 level. Conclusion: LXRs activation attenuated hepatic IRI by preventing TLR4-NF-κB signaling.

NBD peptides protect against ischemia reperfusion after orthotopic liver transplantation in rats.

BACKGROUND: NBD (NEMO binding domain) peptides could selectively inhibit the inflammation induced NF-κB activity, while sparing the protective functions of basal NF-κB activity. The aim of this study was to determine whether NBD peptides inhibited the transcriptional activity of nuclear factor-κB (NF-κB) during liver transplant ischemia-reperfusion injury (IRI), without affecting its basal function. MATERIALS AND METHODS: Sprague Dawley (SD) rats were performed orthotropic liver transplantation according to the Kamada technique. Donors were given NBD peptides (8 mg/kg, intraperitoneal) 2 h before surgery (n = 24) and the controls were treated with the same volume of physiologic saline (n = 24). An additional 16 animals in normal condition (did not undergo any surgery) were also divided into two groups and given the same treatment as above to assess the effect of NBD peptides on basal function. We analyzed levels of alanine aminotransferase (ALT), tumor necrosis factor (TNF-α), IKK (IκB kinase) complex phosphorylation, IκBα degradation, NF-κB transcriptional activity, apoptosis, and performed a morphologic study of liver tissues at 3, 6, and 24 h after portal vein reperfusion and in normal condition (n = 8). RESULTS: Pretreatment with NBD peptides significantly improved liver function, attenuating liver parenchymal cell damage, apoptosis by down-regulating TNF-α level, inhibiting IKK complex phosphorylation, IκBα degradation, and NF-κB transcriptional activity, but had no effect in normal condition. CONCLUSION: NBD peptides attenuated hepatic IRI by preventing NF-κB activation, without affecting basal NF-κB activity.