Immunostaining of PD-1/PD-Ls in liver tissues of patients with hepatitis and hepatocellular carcinoma

AIM: To investigate the expression of programmed death (PD)-1,PD ligand 1 (PD-L1) and PD-L2 in liver tissues in the context of chronic hepatitis and hepatocellular carcinoma (HCC).METHODS: Liver biopsies and HCC specimens from patients were collected and histologically examined.The expression of PD-1,PD-L1,and PD-L2 in biopsy specimens of chronic hepatitis and HCC specimens was evaluated by immunohistochemical staining.The association between the expression level of PD-1,PD-L1,and PD-L2 and clinical and pathological variables was analyzed statistically.RESULTS: Expression of PD-1 was found in liverinfiltrating lymphocytes.In contrast,PD-L1 and PD-L2 were expressed in non-parenchyma liver cells and tumor cells.The expression of PD-L1 was significantly correlated with hepatitis B virus infection (1.42 ± 1.165 vs 0.50 ± 0.756,P = 0.047) and with the stage of HCC (7.50 ± 2.121 vs 1.75 ± 1.500 vs 3.00 ± 0.001,P = 0.018).PD-1 and PD-Ls were significantly up-regulated in HCC specimens (1.40 ± 1.536 vs 5.71 ± 4.051,P = 0.000;1.05 ± 1.099 vs 4.29 ± 3.885,P = 0.004;1.80 ± 1.473 vs 3.81 ± 3.400,P = 0.020).CONCLUSION: PD-L1 may contribute to negative regulation of the immune response in chronic hepatitis B.PD-1 and PD-Ls may play a role in immune evasion of tumors.

Leptin administration exacerbates thioacetamide-induced liver fibrosis in mice

AIM： To investigate the effects of leptin administration on liver fibrosis induced by thioacetamide （TAA）. METHODS： Twenty-four male C57BI/6 mice were randomly allocated into four groups, which were intra-peritoneally given saline （2 mL/kg）, leptin （1 mg/kg）, TAA （200 mg/kg）, TAA （200 mg/kg） plus leptin （1 mg/kg） respectively, thrice a week. All mice were killed after 4 wk. The changes in biochemical markers, such as the levels of alanine aminotransferase （ALT） and aspartate aminotransferase （AST） in serum and superoxide dismutase （SOD）, malondialdehyde （MDA） in liver were determined. For histological analysis, liver tissues were fixed with 10% buffered formalin, embedded with paraffin. Hematoxylin-eosin （HE） staining and picric acid-Sirius red dyeing were performed. The level of α1（I） procollagen mRNA in liver tissues was analyzed by RT-PCR. RESULTS： Apparent liver fibrosis was found in TAA group and TAA plus leptin group. Compared to saline group, the levels of ALT and AST in serum and MDA in liver increased in TAA group （205.67±27.69 U/L vs 50.67±10.46 U/L, 177.50±23.65 U/L vs76.33±12.27 U/L, 2.60±0.18 nmol/mg pro vs 1.91±0.14 nmol/mg pro, P〈0.01） and in TAA plus leptin group （256.17±22.50 U/L vs 50.67±10.46 U/L, 234.17±27.37 U/L vs76.33±12.27 U/L, 2.97±0.19 nmol/mg pro vs 1.91±0.14 nmol/mg pro, P〈0.01）. The level of SOD in livers decreased （51.80±8.36 U/mg pro vs 81.52±11.40 U/mg pro, 35.78±6.11 U/mg pro vs81.52± 11.40 U/mg pro, P〈0.01） and the level of α1（I） procollagen mRNA in liver tissues also increased （0.28±0.04 vs0.11± 0.02, 0.54±0.07 vs0.11±0.02, P〈0.01）. But no significant changes were found in leptin group and saline group. Compared to TAA group, ALT, AST, MDA, and α1（I） procollagen mRNA and grade of liver fibrosis in TAA plus leptin group increased （256.17±22.50 U/L vs 205.67± 27.69 U/L, P〈0.05; 234.17±27.37 U/L vs 177.50±23.65 U/L, P〈0.05; 2.97±0.19 nmol/mg pro vs 2.60±0.18 nmol/mgpro, P〈0.05, 0.54±0.07 vs0.28±0.04, P〈0.01, 3.17 vs 2.00, P〈0.05）, and the level of SOD in liver decreased （35.78±6.11 U/rag pro vs 51.80±8.36 U/rag pro, P〈0.05）. There were similar changes in the degree of type I collagen deposition confirmed by picric acid-Sirius red dyeing. CONCLUSION： Leptin can exacerbate the degree of TAA - induced liver fibrosis in mice. Leptin may be an important factor in the development of liver fibrosis.

A Diagnostic Tool for Identification of Etiologies of Fever of Unknown Origin in Adult Patients

The diagnosis and treatment of fever of unknown origin (FUO) are huge challenges to clinicians.Separating the etiologies of FUO into infectious and non-infectious disease is conducive to clinical physicians not only on making decisions rapidly concerning the prescription of suitable antibiotics but also on further analysis of the final diagnosis.In order to develop and validate a diagnostic tool to efficiently distinguish the etiologies of adult FUO patients as infectious or non-infectious disease,FUO patients from the departments of infectious disease and internal medicine in three Chinese tertiary hospitals were enrolled retrospectively and prospectively.By using polynomial logistic regression analysis,the diagnostic formula and the associated scoring system were developed.The variables included in this diagnostic formula were from clinical evaluations and common laboratory examinations.The proposed tool could discriminate infectious and noninfectious causes of FUO with an area under receiver operating characteristic curve (AUC) of 0.83,sensitivity of 0.80 and specificity of 0.75.This diagnosis tool could predict the infectious and non-infectious causes of FUO in the validation cohort with an AUC of 0.79,sensitivity of 0.79 and specificity of 0.70.The results suggested that this diagnostic tool could be a reliable tool to discriminate between infectious and non-infectious causes of FUO.

Establishment of a Predictive Model Related to Pathogen Invasion for Infectious Diseases and Its Diagnostic Value in Fever of Unknown Origin

The present study aimed to establish a list of parameters indicative of pathogen invasion and develop a predictive model to distinguish the etiologies of fever of unknown origin (FUO) into infectious and non-infectious causes.From January 2014 to September 2017,431 patients with FUO were prospectively enrolled in the study population.This study established a list of 26 variables from the following 4aspects:host factors,epidemiological factors,behavioral factors,and iatrogenic factors.Predefined predicted variables were included in a multivariate logistic regression analysis to develop a predictive model.The predictive model and the corresponding scoring system were developed using data from the confirmed diagnoses and 9 variables were eventually identified.These factors were incorporated into the predictive model.This model discriminated between infectious and non-infectious causes of FUO with an AUC of 0.72,sensitivity of 0.71, and specificity of 0.63.The predictive model and corresponding scoring system based on factors concerning pathogen invasion appear to be reliable screening tools to discriminate between infectious and non-infectious causes of FUO.

Association Between Proton Pump Inhibitor Therapy and Spontaneous Bacterial Peritonitis Occurrence in Cirrhotic Patients:A Clinical Review

Spontaneous bacterial peritonitis(SBP)is one of the most common complications in patients with end-stage liver disease(ESLD),which increases the risk of short-term mortality.Proton pump inhibitors(PPIs)are frequently used in patients with ESLD,in which controversies about the risk of PPI treatment in the occurrence of SBP are largely raised and the pathogenic mechanism of PPI-associated SBP remains unclear.We conducted a systematic literature search through PubMed/MEDLINE for publications mainly from 1 January 2000 to 1 January 2021.Our narrative review summarized the adverse effect of specific PPI therapy on the occurrence and prognosis of SBP in cirrhotic patients,described the potential mechanisms by which PPI induces the development of SBP,and discussed the risk factors associated with the development of SBP and the strategy of PPI therapy in cirrhotic patients.Although controversy regarding the association between PPI use and the occurrence of SBP exists,PPIs use should be restricted to patients with clear benefit indications,and be cautious for elderly patients with severe liver damage.