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ImportancePrimary biliary cholangitis (PBC) is a classical autoimmune disease, which is highly influenced by genetic determinants. Many genome-wide association studies (GWAS) have reported that numerous genetic loci were significantly associated with PBC susceptibility. However, the effects of genetic determinants on liver cells and its immune microenvironment for PBC remain unclear.ObjectiveTo identify genetics-modulated functional liver cell subsets involved in the pathogenesis of PBC.Design, Setting, and ParticipantsIn this present study, 13,239 European participants were collected from IEU open GWAS project on PBC. There were 1,124,241 qualified SNPs used for GWAS analysis. Expression quantitative trait loci (eQTL) data across 49 tissues were downloaded from the GTEx database. Two single cell RNA sequencing (scRNA-seq) profiles and two bulk-based RNA transcriptomes were downloaded from the GEO database. Data collection and analyses were performed from August 2020 to June 2021.Main outcomes and measuresWe constructed a powerful computational framework to integrate GWAS summary statistics with scRNA-seq data to uncover genetics-modulated liver cell subpopulations.ResultsBased on our multi-omics integrative analysis, we found that 29 risk genes including ORMDL3, GSNK2B, and DDAH2 were significantly associated with PBC susceptibility. Gene-property analysis revealed that four immune cell types, including Cst3+ dendritic cell, Chil3+ macrophage, Trbc2+ T cell, and Gzma+ T cell, were significantly enriched by PBC-risk genes. By combining GWAS summary statistics with scRNA-seq data, we found that cholangiocytes exhibited a notable enrichment by PBC-related genetic association signals (Permuted P < 0.05). The risk gene of ORMDL3 showed the highest expression proportion in cholangiocytes than other liver cells (22.38%). Compared with ORMDL3+ cholangiocytes, there were 71 significantly highly-expressed genes among ORMDL3- cholangiocytes (FDR < 0.05), such as inflammatory cytokine genes CXCL8, CCL3, IFI16, and IRF1. These highly-expressed genes were significantly enriched in numerous biological pathways and functional terms associated with autoimmune diseases (FDR < 0.05).Conclusions and relevanceTo the best of our knowledge, this is the first study to integrate genetic information with single cell sequencing data for parsing genetics-influenced liver cells for PBC risk. We identified that ORMDL3- cholangiocytes play important immune-modulatory roles in the etiology of PBC.Key pointsQuestionAre genetics factors influenced liver cell subpopulations and its immune microenvironment for PBC?FindingsIn this comprehensive genomics study based on multi-omics data, genetic determinants were significantly enriched in cholangiocytes and immune cells including subsets of macrophage, dendritic cells, and T cells. ORMDL3- cholangiocytes have crucial immune-modulatory roles in developing PBC.MeaningFindings suggest that integration of single cell sequencing data with GWAS summary statistics contribute to pinpoint PBC-relevant cell types and risk genes.

Aim. To explore the therapeutic effects and mechanisms of interleukin 10 gene-modified bone marrow-derived dendritic cells (DC-IL10) on liver fibrosis. Methods. In vitro, BMDCs were transfected with lentiviral-interleukin 10-GFP (LV-IL10-GFP) at the MOI of 1 : 40. Then, the phenotype (MHCII, CD80, and CD86) and allo-stimulatory ability of DC-IL10 were identified by flow cytometry, and the levels of IL-10 and IL-12 (p70) secreted into the culture supernatants were quantified by ELISA. In vivo, DC-IL10 was injected into mice with CCl4-induced liver fibrosis through the tail vein. Lymphocytes were isolated to investigate the differentiation of T cells, and serum and liver tissue were collected for biochemical, cytokine, histopathologic, immune-histochemical, and Western blot analyzes. Results. In vitro, the expressions of MHCII, CD80, and CD86 in DC-IL10 were significantly suppressed, allogeneic CD4+T cells incubated with DC-IL10 showed a lower proliferative response, and the levels of IL-10 and IL-12 (p70) secreted into the DC-IL10 culture supernatants were significantly increased and decreased, respectively. In vivo, regulatory T cells (Tregs) were significantly increased, while ALT, AST, and inflammatory cytokines were significantly reduced in the DC-IL10 treatment group, and the degree of hepatic fibrosis was obviously reversed. The TGF-β/smad pathway was inhibited following DC-IL10 treatment compared to the liver fibrosis group. Conclusion. IL-10 genetic modification of BMDCs may maintain DC in the state of tolerance and allow DC to induce T cell hyporesponsiveness or tolerance. DC-IL10 suppressed liver fibrosis by inducing Treg production and inhibiting the TGF-β/smad signaling pathway.

ObjectivesNo data were available about in-flight transmission of SARS-CoV-2. Here, we report an in-flight transmission cluster of COVID-19 and describe the clinical characteristics of these patients.MethodsAfter a flight, laboratory-confirmed COVID-19 was reported in 12 patients. Ten patients were admitted to the designated hospital. Data were collected from 25th January to 28th February 2020. Clinical information was retrospectively collected.ResultsAll patients are passengers without flight attendants. The median age was 33 years, and 70% were females. None was admitted to intensive care unit, and no patients succumbed through 28th February. The median incubation period was 3.0 days and from illness onset to hospital admission was 2 days. The most common symptom was fever. Two patients were asymptomatic and negative for chest CT scan throughout the disease courses. On admission, initial RT-PCR were positive in 9 patients, however initial chest CT were positive in only half patients. The median lung “total severity score” of chest CT was 6. Notably, “Crazy-Paving” pattern, pleural effusion, and ground-glass nodules were also seen.ConclusionIt is potential for COVID-19 transmission by airplane, but the symptoms are mild. Passengers and attendants must be protected during the flight.

Immunomodulation is poised to revolutionize the treatment of cancer, autoimmune diseases, and many other inflammation-related disorders. The immune system in these conditions can be either activated or suppressed by nanocarriers loaded with bioactive molecules. Although immunomodulation via these therapeutics has long been recognized, and a broad range of nanocarriers have been designed to accommodate varied usages, less studies have focused on the effects of nanomaterial physicochemical properties on immune responses, especially the immunity altered by nanocarrier materials alone. Conclusions are sometimes seemly inconsistent due to the complexities of nanomaterials and the immune system. An in-depth understanding of the nanocarrier-induced immune responses is essential for clinical applications. In this review, we summarize recent studies of the immune responses influenced by nanomaterial physicochemical properties with an emphasis on the intrinsic features of nanomaterials that modulate the innate and adaptive immunities. We then provide our perspectives on the design of nanomaterials for immunomodulation.

// Naibin Yang 1 , Shanshan Li 2 , Guoxiang Li 1 , Shengguo Zhang 2 , Xinyue Tang 2 , Shunlan Ni 2 , Xiaomin Jian 3 , Cunlai Xu 4 , Jiayin Zhu 5 and Mingqin Lu 2 1 Department of Infection and Liver Diseases, Ningbo First Hospital, Ningbo, China 2 Department of Infection and Liver Diseases, The First Affiliated Hospital of Wenzhou Medical University, Institute of Liver Research, Wenzhou Medical University, Wenzhou, China 3 Department of The First Clinical Medical, Wenzhou Medical University, Wenzhou, China 4 Department of Respiration, Lishui People’s Hospital of Wenzhou Medical University, Lishui, China 5 Laboratory Animal Center, Wenzhou Medical University, Wenzhou, China Correspondence to: Mingqin Lu, email: // Keywords : extracellular vesicles, exosomes, miRNA, hepatocellular carcinoma, MSCs Received : April 28, 2016 Accepted : September 28, 2016 Published : October 04, 2016 Abstract Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. As vectors for intercellular information exchange, the potential role of extracellular vesicles (EVs) in HCC formation, progression and therapy has been widely investigated. In this review, we explore the current status of the researches in this field. Altogether there is undeniable evidence that EVs play a crucial role in HCC development, metastasis. Moreover, EVs have shown great potential as drug delivery systems (DDSs) for the treatment of HCC. Exosomal miRNAs derived from HCC cells can enhance transformed cell growth in recipient cells by modulating the expression of transforming growth factor-β activated kinase-1(TAK1) and downstream signaling molecules. Furthermore, vacuolar protein sortin 4 homolog A(VPS4A) and insulin-like growth factor(IGF)-1 regulate exosome-mediated miRNAs transfer. Immune cells- derived EVs containing integrin αMβ2 or CD147 may facilitate HCC metastasis. In addition, EVs-mediated shuttle of long non-coding RNAs (lncRNAs), specifically linc- VLDLR and linc-ROR promote chemoresistance of malignant cells. Heat shock proteins (HSPs)-harboring exosomes derived from HCC tumor cells increase the antitumor effect of natural killer (NK) cells, thus enhancing HCC immunotherapy. Indeed, inhibition of HCC tumor growth has been associated with tumor cell-derived exosomes (TEX)-pulsed dentritic cells (DCs). Exosomes are also essential in liver metastasis during colorectal carcinoma (CRC) and pancreatic ductal adenocarcinomas (PDAC). Therefore, as nucleic acid and drug delivery vehicles, EVs show a tremendous potential for effective treatment against HCC.

Acute liver failure is a devastating clinical syndrome with extremely terrible inflammation reaction, which is still lack of effective treatment in clinic. Suppressor of Cytokine Signaling 1 protein is inducible intracellular negative regulator of Janus kinases (JAK)/signal transducers and activators of transcription (STAT) pathway that plays essential role in inhibiting excessive intracellular signaling cascade and preventing autoimmune reaction. In this paper, we want to explore whether dendritic cells (DCs) with overexpression of SOCS1 have a therapeutic effect on experimental acute liver failure. Bone marrow derived dendritic cells were transfected with lentivirus encoding SOCS1 and negative control lentivirus, thereafter collected for costimulatory molecules analysis, allogeneic Mixed Lymphocyte Reaction and Western blot test of JAK/STAT pathway. C57BL/6 mice were randomly separated into normal control and treatment groups which respectively received tail vein injection of modified DCs, negative control DCs and normal saline 12 h earlier than acute liver failure induction. Our results indicated that DCs with overexpression of SOCS1 exhibited like regulatory DCs (DCregs) with low level of costimulatory molecules and poor allostimulatory ability in vitro, which was supposed to correlate with block of JAK2/STAT1 signaling. In vivo tests, we found that infusion of modified DCs increased survival rate of acute liver failure mice and alleviate liver injury via inhibition of TLR4/HMGB1 pathway. We concluded that DCs transduced with SOCS1 gene exhibit as DCregs through negative regulation of JAK2/STAT1 pathway and ameliorated lipopolysaccharide/ d -galactosamine induced acute liver failure via inhibition of TLR4 pathway.

Kinesin family member 20A (KIF20A) is an essential regulator of cytokinesis. In this study, by performing a retrospective study based on data from the Cancer Genome Atlas (TCGA)-Liver and Hepatocellular Carcinoma (LIHC) cohort, we tried to assess the independent prognostic value of KIF20A in terms of overall survival (OS) and recurrence-free survival (RFS). Results showed that normal liver tissues had very low KIF20A expression compared with normal tissues in other cohorts in TCGA. However, the primary HCC tissues (N = 371) had significantly elevated KIF20A expression than normal liver tissues (N = 50). Immunohistochemistry (IHC) data showed that normal hepatocytes had weak KIF20A staining. In comparison, some HCC tissues had medium and strong KIF20A expression, with nuclear-enhanced staining. By grouping patients with primary HCC (N = 365) into high and low KIF20A expression groups, we found that the high expression group had a substantially higher proportion of high-grade tumors (G3/G4) (34/65, 52.3% vs. 96/295, 32.5%, P = 0.0027), advanced tumors (stage III/IV) (28/61, 45.9% vs. 59/280, 21.1%, P < 0.0001) and death (44/67, 65.7% vs. 86/298, 28.9%, P < 0.0001) compared with the low expression group. Kaplan-Meier curves of OS and RFS indicated that high KIF20A expression was associated with worse survival outcomes. Subgroup analysis confirmed the associations in G1/G2, G3/G4 tumors and in early and advanced stages. Following univariate and multivariate analysis revealed that KIF20A expression was an independent prognostic indicator for poor OS (HR: 1.304, 95%CI: 1.157-1.469, P < 0.001) and RFS (HR: 1.144, 95%CI: 1.028-1.272, P < 0.001). Based on these findings, we infer that KIF20A was aberrantly expressed in HCC tissues and its expression might independently predict poor OS and RFS. © 2018 IUBMB Life, 70(4):328-335, 2018.

Aims. Acute-on-chronic liver failure (ACLF) and acute liver failure (ALF) are similar in many respects during their acute exacerbation; however, ACLF generally has a poorer prognosis. We aimed to investigate the role and dynamic changes of regulatory T cell (Treg) and T helper 17 (Th17) cell proportions during ACLF progress. Methods. All rats were classified into two groups randomly: ACLF group and ALF group (control group). The rat model of ACLF was preestablished by intraperitoneal injection of carbon tetrachloride for 2 months. Then acute liver injury was induced by combined D-galactosamine and lipopolysaccharide. Six time points were examined before or after acute induction. Liver samples were performed with hematoxylin-eosin and Masson staining; circulatory Treg and Th17 cell frequencies were determined using flow cytometry assays; serum levels of alanine aminotransferase, aspartate aminotransferase, interleukin-10 (IL-10), and interferon-γ (IFN-γ) were examined. Results. In group ACLF, both Th17 cell proportion and IFN-γ level presented upgrade firstly and then descend latter tendency; the trends of Treg cell proportion and IL-10 level were observed to gradually decrease and became stable. Conclusion. The Treg cells played an important role in the immunologic mechanism during the process of ACLF. And the function of Treg cells in ACLF was defective.

Endotoxin tolerance (ET) is suggested to attenuate the severity of acute liver failure (ALF) in mice, possibly through both innate and adaptive immunity. However, the involvement of regulatory dendritic cells (DCregs) in ET has not been fully elucidated. In this study, their effect on ALF in mice was investigated. Splenic DCregs from ET-exposed mice (ET-DCregs) showed lower expression levels of CD40, CD80, and MHC-II markers and stronger inhibition of allogenic T cells and regulation of IL-10 and IL-12 secretion than splenic DCregs from normal mice (nDCregs). Moreover, the mRNA and protein levels of TNF-α and P65 in splenic ET-DCregs were significantly lower than those in the splenic nDCregs. The survival rate was significantly increased and liver injury was mitigated in mice with ALF treated with splenic ET-DCregs. In addition, A20 expression was decreased in the liver of ALF mice, but elevated after infusion of splenic nDCregs and ET-DCregs, and a much higher elevation was observed after infusing the latter cells. The functionality of splenic DCregs was altered after ET exposure, contributing to protection of the livers against D-GalN/LPS-induced ALF.

To the EditorWe read with interest the recent article in this journal by Yao et al. [1] on cryptococcal meningitis (CM). In their study, the response rate to voriconazole was more favourable than t...

It has been reported that hypereosinophilic syndrome may be induced by antituberculosis drugs. We herein report the case of a 43-year-old man who had been on antituberculosis drugs for two months to treat tuberculous meningitis. During therapy, he suffered from drug rash with eosinophilia and systemic symptoms (DRESS) presenting as acute eosinophilic myocarditis, as confirmed on a histopathologic examination. According to the patient's medication history, clinical features and accessory examination findings, the eosinophilic myocarditis was thought to be possibly induced by isoniazid. Although further investigations are needed to confirm causality, isoniazid may be added to the list of drugs with the potential to cause DRESS syndrome.

Background Acute pancreatitis is a common complication of endoscopic retrograde cholangiopancreatography and benefit of pharmacological treatment is unclear. Although prophylactic use of corticosteroid for reduction of pancreatic injury after ERCP has been evaluated, discrepancy about beneficial effect of corticosteroid on pancreatic injury still exists. The aim of current study is to evaluate effectiveness and safety of corticosteroid in prophylaxis of post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP). Methods We employed the method recommended by the Cochrane Collaboration to perform a meta-analysis of seven randomized controlled trials (RCTs) of corticosteroid in prevention of post-ERCP pancreatitis (PEP) around the world. Results Most of the seven RCTs were of high quality. When the RCTs were analyzed, odds ratios (OR) for corticosteroid were 1.13 [95% CI (0.89~1.44), p = 0.32] for PEP, 1.61 [95% CI (0.74~3.52), p = 0.23] for severe PEP, 0.92 [95% CI (0.57~1.48), p = 0.73] for post-ERCP hyperamylasemia respectively. The results indicated that there were no beneficial effects of corticosteroid on acute pancreatitis and hyperamylasemia. No evidence of publication bias was found. Conclusion Corticosteroids cannot prevent pancreatic injury after ERCP. Therefore, their use in the prophylaxis of PEP is not recommended.