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BACKGROUND AND AIMS: Chronic liver congestion reflecting right-sided heart failure (RHF), Budd-Chiari syndrome, or Fontan-associated liver disease (FALD) is involved in liver fibrosis and HCC. However, molecular mechanisms of fibrosis and HCC in chronic liver congestion remain poorly understood. APPROACH AND RESULTS: Here, we first demonstrated that chronic liver congestion promoted HCC and metastatic liver tumor growth using murine model of chronic liver congestion by partial inferior vena cava ligation (pIVCL). As the initial step triggering HCC promotion and fibrosis, gut-derived lipopolysaccharide (LPS) appeared to induce LSECs capillarization in mice and in vitro. LSEC capillarization was also confirmed in patients with FALD. Mitogenic factor, sphingosine-1-phosphate (S1P), was increased in congestive liver and expression of sphingosine kinase 1, a major synthetase of S1P, was increased in capillarized LSECs after pIVCL. Inhibition of S1P receptor (S1PR) 1 (Ex26) and S1PR2 (JTE013) mitigated HCC development and liver fibrosis, respectively. Antimicrobial treatment lowered portal blood LPS concentration, LSEC capillarization, and liver S1P concentration accompanied by reduction of HCC development and fibrosis in the congestive liver. CONCLUSIONS: In conclusion, chronic liver congestion promotes HCC development and liver fibrosis by S1P production from LPS-induced capillarized LSECs. Careful treatment of both RHF and liver cancer might be necessary for patients with RHF with primary or metastatic liver cancer.
Subject(s)
Carcinoma, Hepatocellular , Heart Failure , Liver Neoplasms , Vascular Diseases , Animals , Carcinoma, Hepatocellular/pathology , Disease Models, Animal , Fibrosis , Humans , Lipopolysaccharides , Liver Cirrhosis/pathology , Liver Neoplasms/pathology , Lysophospholipids/metabolism , Mice , Receptors, Lysosphingolipid/metabolism , Sphingosine/analogs & derivatives , Sphingosine/metabolismABSTRACT
BACKGROUNDS AND AIMS: Toll-like receptor (TLR) agonists have been developed as adjuvants to efficiently induce antiviral immune responses. Specificity and potency of these compounds are essential requirements for clinical trial applications. In patients with hepatitis B virus (HBV) infections, sustained loss of hepatitis B surface antigen (HBsAg) is a therapeutic goal, which may be achievable by the sequential activation of follicular helper T cells (Tfh) and antibody-secreting B cells. We aimed to elucidate whether novel TLR7 agonist, GS-986, could activate immune responses involved in HBV elimination. METHODS: To clarify the impact of GS-986 on pDCs, we quantified the expression levels of surface markers and evaluated for Tfh induction in a culture model consisting of human pDCs with allogeneic naïve CD4+ T cells. In addition, we examined whether GS-986 could enhance HBs antibody production capacity using PBMC from CHB patients. RESULTS: pDCs from CHB patients had lower OX40L expression and as well as impaired capacity for Tfh induction compared with those from healthy donors. However, GS-986-stimulated pDCs from CHB patients expressed OX40L and produced IL-6 and IL-12, resulting in the induction of IL-21-producing Tfh cells (CXCR5+ PD-1+ CD4+ ) from naïve CD4+ T cells. The Tfh-inducing capacity of GS-986 was reduced in the presence of an anti-OX40L blocking antibody. Furthermore, GS-986 promoted HBsAg-specific antibody production in PBMCs from CHB patients. CONCLUSIONS: GS-986 is an adjuvant that stimulates pDCs to induce Tfh differentiation and antigen-specific B-cell production. This immune profile may be beneficial for therapeutic application as an immune modulator in CHB patients.
Subject(s)
Antiviral Agents , Hepatitis B, Chronic , Toll-Like Receptor 7 , Hepatitis B, Chronic/drug therapy , Humans , Toll-Like Receptor 7/agonists , Antiviral Agents/therapeutic use , Male , Female , Middle Aged , Up-Regulation , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/drug effects , Cell Differentiation , Dendritic Cells/drug effects , Dendritic Cells/metabolism , T Follicular Helper Cells/cytology , T Follicular Helper Cells/drug effects , Hepatitis B Surface Antigens/metabolism , Antibodies, Viral/metabolismABSTRACT
AIM: Congestive hepatopathy often leads to liver fibrosis and hepatocellular carcinoma. Imaging modalities provided clinical evidence that elevation of liver stiffness and tumor occurrence are mainly induced in the periphery of the liver in patients with congestive hepatopathy. However, clinical relevance of liver stiffness and liver fibrosis is unclear because liver congestion itself increases liver stiffness in congestive hepatopathy. It also unclear which factors configure such regional disparity of tumor development in patients with congestive hepatopathy. To answer these questions, we evaluated the macroscopic spatial distribution of liver fibrosis and tumors in the murine model of congestive hepatopathy. METHODS: Chronic liver congestion was induced by partial ligation of the suprahepatic inferior vena cava. Distribution of liver congestion, fibrosis, and tumors in partial ligation of the suprahepatic inferior vena cava mice were assessed by histological findings, laser microdissection (LMD)-based qPCR and enhanced computed tomography. LMD-based RNA-sequencing was performed to identify causal factors that promote tumor development in congestive hepatopathy. RESULTS: Liver fibrosis was mainly induced in the periphery of the liver and co-localized with distribution of liver congestion. Liver tumors were also induced in the periphery of the liver where liver congestion and fibrosis occurred. LMD-based RNA-sequencing revealed the upregulation of extracellular matrix/collagen fibril-, wound healing-, angiogenesis-, morphogenesis-, and cell motility-related signaling pathways in periphery of liver compared with liver center. CONCLUSIONS: Our findings showed the experimental relevance of liver congestion, fibrosis, and tumor development in congestive hepatopathy, and may provide important locational information. Macroscopic regional disparity observed in this murine model should be considered to manage patients with congestive hepatopathy.
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BACKGROUND: Hepatitis B surface antigen (HBsAg) loss is an ideal goal for chronic hepatitis B patients. Antiretroviral therapy (ART) in hepatitis B virus/human immunodeficiency virus-1 (HBV/HIV-1)-coinfected patients can lead to hepatic flare (HF) caused by immune reconstitution-induced inflammatory syndrome (IRIS). Here, we investigated the impact of IRIS-HF on HBsAg loss. METHODS: This was a retrospective study of 58 HBV/HIV-1-coinfected subjects HBsAg-positive for ≥6 months before ART initiation and followed for ≥1 year (median 9.9 years) after ART initiation. We examined humoral factors in sera from healthy volunteers, HIV-monoinfected patients, and HBV/HIV-1-coinfected patients with IRIS-HF or acute hepatitis B infection. RESULTS: During ART, HBsAg loss was observed in 20 of 58 HBV/HIV-1-coinfected patients (34.5%). Of the 58 patients, 15 (25.9%) developed IRIS-HF within 12 months of ART initiation. HBsAg loss was more frequent among patients who developed IRIS-HF (11/15, 73.3%) than those who did not (9/43, 20.9%). Multivariate analysis showed IRIS-HF was an independent predictor of subsequent HBsAg loss. Younger age and higher baseline HBV DNA titer were associated with IRIS-HF. Elevation of sCD163, not CXCL9, CXC10, CXCXL11, or CXCL13, was observed at IRIS-HF. CONCLUSIONS: IRIS-HF was associated with HBsAg loss in HBV/HIV-1-coinfected patients.
Subject(s)
Anti-HIV Agents , Coinfection , HIV Infections , Hepatitis B, Chronic , Immune Reconstitution Inflammatory Syndrome , Anti-HIV Agents/therapeutic use , Coinfection/immunology , Coinfection/virology , DNA, Viral , HIV Infections/complications , HIV Infections/drug therapy , HIV-1 , Hepatitis B Surface Antigens/blood , Hepatitis B virus/genetics , Hepatitis B, Chronic/complications , Humans , Retrospective StudiesABSTRACT
BACKGROUND: Pathological angiogenesis is involved in the development of hepatocellular carcinoma. In patients with chronic hepatitis C (CHC), the level of angiogenic factor angiopoietin (ANGP)-2 is reported to be increased in the blood, correlating with fibrosis. In this study, we aimed to clarify whether blood ANGP-2 is useful as a biomarker for liver angiogenesis and fibrosis in CHC patients and to further reveal the relationship between such pathology in a carbon tetrachloride (CCl4)-treated liver fibrosis mouse model. METHODS: Plasma levels of ANGP-2, expression of a liver sinusoidal endothelial cell (LSEC) marker (CD31), collagen deposition (Sirius Red staining) in the liver, clinical fibrosis markers (Mac-2 binding protein glycosylation isomer, virtual touch quantification, and liver stiffness measurement), and liver function (albumin bilirubin score) were examined in CHC patients. To determine the effects of an anti-angiogenic agent on liver fibrosis in vivo, sorafenib was administered to the CCl4-treated mice (BALB/c male). RESULTS: The plasma levels of ANGP-2 were increased in CHC patients compared to healthy volunteers and decreased by the eradication of hepatitis C with direct-acting antivirals. In addition, plasma ANGP-2 levels were correlated with CD31 expression, collagen deposition, clinical fibrosis markers, and liver function. Sorafenib inhibited liver angiogenesis and fibrosis in the CCl4-treated mice and was accompanied by decreased ANGP-2 expression in LSECs. CONCLUSIONS: ANGP-2 may serve as a useful biomarker for liver angiogenesis and fibrosis in CHC patients. In addition, angiogenesis and fibrosis may be closely related.
Subject(s)
Angiopoietin-2 , Hepatitis C, Chronic , Angiopoietin-2/therapeutic use , Animals , Antiviral Agents/therapeutic use , Carbon Tetrachloride , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/pathology , Humans , Liver/pathology , Liver Cirrhosis/pathology , Male , Mice , Mice, Inbred BALB C , Neovascularization, PathologicABSTRACT
AIM: In patients with liver cirrhosis, high levels of serum myostatin are associated with poor prognosis. We aimed to clarify the influence of myostatin on the prognosis of patients with non-alcoholic fatty liver disease-hepatocellular carcinoma (NAFLD-HCC) without cirrhosis and on the progression of liver fibrosis. METHODS: Serum myostatin levels were evaluated in 234 patients who underwent primary surgical resection for single HCC. To clarify the impact of myostatin on liver fibrosis, we established human primary liver fibroblasts from resected livers, and cultured them in the presence of myostatin. RESULTS: The median age was 67.4 years, the median L3 skeletal muscle mass index was 44.4 cm2 /m2 , and the median body mass index was 23.4 kg/m2 . Eighty-two (35.0%) patients had sarcopenia (L3 skeletal muscle mass index: men <42, women <38 cm2 /m2 ). The etiologies of liver disease were hepatitis B virus (n = 61), hepatitis C virus (n = 86), and non-B non-C hepatitis (n = 87) including NAFLD (n = 74). High preoperative serum myostatin and vascular invasion were independent predictors of poor overall survival (OS). High serum myostatin was associated with poor OS in patients with no sarcopenia (n = 152). In patients without advanced liver fibrosis (Fibrosis stage, 0-2; n = 58), high levels of serum myostatin were also associated with poor OS, regardless of sarcopenia. Serum myostatin levels were increased with the progression of liver fibrosis. Liver fibroblasts were activated and produced collagen following stimulation with myostatin. CONCLUSIONS: In patients with NAFLD-HCC without advanced liver fibrosis, high levels of serum myostatin were associated with poor OS. Myostatin activated primary fibroblasts and stimulated collagen production.
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AIM: Non-alcoholic fatty liver disease (NAFLD) is a leading cause of liver disease worldwide. Because liver fibrosis is associated with the long-term prognosis of patients with NAFLD, there is an urgent need for non-invasive markers of liver fibrosis. Sialic acid-binding immunoglobulin-like lectin-7 (Siglec-7) is an immunomodulatory molecule expressed on various immune cells, including macrophages, which plays a key role in liver inflammation and fibrosis in NAFLD. We aimed to determine whether serum levels of soluble Siglec-7 (sSiglec-7) could have utility at a marker of fibrosis in this patient population. METHODS: We examined serum samples from 93 NAFLD patients and 19 healthy donors for macrophage-associated protein, including sSiglec-7, soluble CD163, and YKL-40, and examined their correlation with liver fibrosis scores, tissue elastography, and histological findings. Independent factors associated with advanced fibrosis were analyzed using a logistic regression model and a decision tree. To clarify the source of sSiglec-7, we examined its expression in liver tissue-derived macrophages and cultured monocyte-derived macrophages. RESULTS: Serum sSiglec-7 levels were significantly higher in NAFLD patients compared with healthy donors, and correlated positively with sCD163 and YKL-40 levels. Serum sSiglec-7 was an independent diagnostic marker with high specificity (96.3%) for advanced fibrosis (F3 and F4) in NAFLD patients. Siglec-7 was mainly expressed on CCR2+ macrophages in the liver, and sSiglec-7 production by monocyte-derived macrophages in vitro was increased after stimulation by pro-inflammatory factors. CONCLUSIONS: Elevated serum sSiglec-7 could serve as an independent marker with high specificity for advanced liver fibrosis in patients with NAFLD.
Subject(s)
Liver Transplantation , Age Factors , Aged , Humans , Living Donors , Postoperative ComplicationsSubject(s)
Laparoscopy , Liver Neoplasms , Neoplasms , Hepatectomy , Hepatic Veins/diagnostic imaging , Hepatic Veins/surgery , Humans , Liver Neoplasms/surgery , ThrombectomyABSTRACT
INTRODUCTION: During laparoscopic cholecystectomy for acute cholecystitis, it is often difficult to keep the surgical view dry because of inflammation-related tissue fragility and susceptibility to bleeding. The resulting inadequate surgical view can lead to bile duct or vascular injury. Soft coagulation systems are used to achieve hemostasis during various surgeries; however, the usefulness of soft coagulation during laparoscopic cholecystectomy for acute cholecystitis is unclear. We here demonstrate the usefulness and feasibility of blunt dissection and soft coagulation during this procedure. MATERIALS AND SURGICAL TECHNIQUE: We used blunt dissection and soft coagulation when performing laparoscopic cholecystectomy on two patients with acute cholecystitis. As with conventional laparoscopic cholecystectomy, four ports were inserted. After cutting the serosa by electrocautery, blunt dissection using soft coagulation was performed, exposing the inner subserosa. Maintaining this layer using blunt dissection with soft coagulation achieved a sufficiently clear view for safety. After resecting the cystic artery and duct, the gallbladder bed was also dissected by blunt dissection with soft coagulation. Blood loss was <20 mL in both patients. DISCUSSION: Blunt dissection with soft coagulation may be a useful and feasible means of keeping the surgical view dry and minimizing blood loss during laparoscopic cholecystectomy for acute cholecystitis.
Subject(s)
Cholecystectomy, Laparoscopic , Cholecystitis, Acute , Dissection , Electrocoagulation , Humans , Cholecystectomy, Laparoscopic/methods , Cholecystitis, Acute/surgery , Electrocoagulation/methods , Dissection/methods , Female , Male , Middle Aged , Feasibility Studies , Aged , Hemostasis, Surgical/methods , AdultABSTRACT
AIM: Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most prevalent liver diseases and is characterized by steatosis and the accumulation of bioactive lipids. This study aims to understand the specific lipid species responsible for the progression of liver fibrosis in MASH. METHODS: Changes in bioactive lipid levels were examined in the livers of MASH mice fed a choline-deficient diet (CDD). Additionally, sphingosine kinase (SphK)1 mRNA, which generates sphingosine 1 phosphate (S1P), was examined in the livers of patients with MASH. RESULTS: CDD induced MASH and liver fibrosis were accompanied by elevated levels of S1P and increased expression of SphK1 in capillarized liver sinusoidal endothelial cells (LSECs) in mice. SphK1 mRNA also increased in the livers of patients with MASH. Treatment of primary cultured mouse hepatic stellate cells (HSCs) with S1P stimulated their activation, which was mitigated by the S1P receptor (S1PR)2 inhibitor, JTE013. The inhibition of S1PR2 or its knockout in mice suppressed liver fibrosis without reducing steatosis or hepatocellular damage. CONCLUSION: S1P level is increased in MASH livers and contributes to liver fibrosis via S1PR2.
Subject(s)
Fatty Liver , Hepatic Stellate Cells , Liver Cirrhosis , Lysophospholipids , Phosphotransferases (Alcohol Group Acceptor) , Sphingosine-1-Phosphate Receptors , Sphingosine , Animals , Sphingosine/analogs & derivatives , Sphingosine/metabolism , Lysophospholipids/metabolism , Liver Cirrhosis/metabolism , Liver Cirrhosis/pathology , Liver Cirrhosis/genetics , Liver Cirrhosis/etiology , Mice , Hepatic Stellate Cells/metabolism , Hepatic Stellate Cells/pathology , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Phosphotransferases (Alcohol Group Acceptor)/genetics , Humans , Sphingosine-1-Phosphate Receptors/metabolism , Fatty Liver/metabolism , Fatty Liver/pathology , Male , Mice, Knockout , Mice, Inbred C57BL , Liver/metabolism , Liver/pathology , Choline Deficiency/complications , Choline Deficiency/metabolism , Endothelial Cells/metabolism , Endothelial Cells/pathology , Receptors, Lysosphingolipid/metabolism , Receptors, Lysosphingolipid/genetics , Pyrazoles , PyridinesABSTRACT
Meckel's diverticulum (MD) is a commonly encountered congenital gastrointestinal abnormality. Although the frequency of MD-related complications such as inflammation or bleeding is relatively high, small bowel obstruction induced by axial torsion of the MD is rare. Therefore, we herein report such a case along with a review of the literature. A 34-year-old female with right lower quadrant pain, nausea, and vomiting was admitted to our hospital with the diagnosis of adhesive small bowel obstruction due to a cesarean section performed five years previously. A long intestinal tube was placed, and the patient's clinical symptoms and X-ray findings showed relief of the small bowel obstruction. However, she developed severe right lower quadrant pain after contrast examination through the long intestinal tube despite the fact that the contrast agent had smoothly reached the terminal ileum. Blood tests and enhanced computed tomography (CT) showed a remarkable elevation of inflammatory markers, the appearance of ascites, and closed-loop-like and abscess-like appearances near the site of the caliber change. With a diagnosis of internal hernia, the patient underwent emergency laparotomy by means of a midline incision. Purulent ascites was observed within the abdominal cavity. Small bowel obstruction caused by a single band was observed in the right lower quadrant. Further exploration revealed an inflammatory MD with neck torsion and a mesodiverticular band (MDB). Simple mesodiverticular band resection by electrocautery and diverticulectomy by linear stapler were performed. The postoperative course was uneventful, and the patient was discharged on postoperative day 7. In the case of juvenile-onset small bowel obstruction, axial torsion of the MD should be considered as a differential diagnosis. Herein, we report such a difficult diagnostic case and the first English literature review of small bowel obstruction due to axial torsion of the MD.
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BACKGROUND: NASH is an increasingly common cause of chronic liver disease and can progress to cirrhosis and HCC. Although exercise suppresses inflammation during acute hepatitis, its impact on the progression of chronic liver disease remains unclear. Here, we investigated the effects of exercise on disease progression and intrahepatic immune cell composition in a mouse model of NASH. METHOD: Mice were assigned to 4 groups: 2 control groups (normal diet) and 2 NASH groups (western diet and low-dose carbon tetrachloride injection). One of each group remained sedentary and one was exercised on a treadmill for 12 weeks (60 min/d, 5 times/wk). All mice were then analyzed for liver histomorphology, steatosis, inflammation, and fibrosis; liver, adipose tissue, and skeletal muscle expression of genes related to metabolism and inflammation; and intrahepatic immune cell composition. RESULT: Compared with the normal diet mice, NASH mice exhibited enhanced liver steatosis, inflammation, and fibrosis; upregulated expression of liver lipogenesis-related and inflammation-related genes; and increased frequencies of intrahepatic F4/80 int CD11b hi bone marrow-derived macrophages and programmed death receptor-1 (PD-1) + CD8 + T cells. Expression of inflammatory cytokines and the frequencies of bone marrow-derived macrophages and PD-1 + CD8 + T cells correlated positively with liver steatosis, inflammation, and fibrosis. Exercise was shown to reduce NASH-induced hepatic steatosis, liver inflammation, and fibrosis; induce alterations in metabolism-related genes and inflammatory cytokines in the liver; and suppress accumulation of liver bone marrow-derived macrophages and PD-1 + CD8 + T cells. In addition, we showed that exercise induced increased expression of IL-15 in muscle and its deficiency exacerbated the pathology of NASH. CONCLUSIONS: Exercise alters the intrahepatic immune cell profile and protects against disease progression in a mouse model of NASH.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Non-alcoholic Fatty Liver Disease , Animals , Mice , Non-alcoholic Fatty Liver Disease/genetics , Programmed Cell Death 1 Receptor , Liver Neoplasms/pathology , Inflammation , Fibrosis , Cytokines/metabolism , Disease ProgressionABSTRACT
Congestive hepatopathy (CH) with chronic passive congestion is characterized by the progression of liver fibrosis without prominent inflammation and hepatocellular damage. Currently, the lack of reliable biomarkers for liver fibrosis in CH often precludes the clinical management of patients with CH. To explore fibrosis biomarkers, we performed proteome analysis on serum exosomes isolated from patients with CH after the Fontan procedure. Exosomal cluster of differentiation (CD)44 levels were increased in patients with CH compared to healthy volunteers and was accompanied by increases in serum levels of soluble CD44 and CD44 expression in the liver. To address the roles of CD44 in CH, we established a mouse model of chronic liver congestion by partial inferior vena cava ligation (pIVCL) that mimics CH by fibrosis progression with less inflammation and cellular damage. In the pIVCL mice, enhanced CD44 expression in hepatic stellate cells (HSCs) and deposition of its ligand hyaluronan were observed in the liver. Blood levels of soluble CD44 were correlated with liver fibrosis. The blockade of CD44 with specific antibody inhibited liver fibrosis in pIVCL mice and was accompanied by a reduction in S100 calcium-binding protein A4 expression following activation of HSCs. Conclusion: Chronic liver congestion promotes fibrosis through CD44. This identifies CD44 as a novel biomarker and therapeutic target of liver fibrosis in patients with CH.
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Overall response rates of systemic therapies against advanced hepatocellular carcinoma (HCC) remain unsatisfactory. Thus, searching for new immunotherapy targets is indispensable. NK cells are crucial effectors and regulators in the tumor microenvironment and a determinant of responsiveness to checkpoint inhibitors. We revealed the landscape of NK cell phenotypes in HCC patients to find potential immunotherapy targets. Using single cell mass cytometry, we analyzed 32 surface markers on CD56dim and CD56bright NK cells, which included Sialic acid-binding immunoglobulin-type lectins (Siglecs). We compared peripheral NK cells between HCC patients and healthy volunteers. We also compared NK cells, in terms of their localizations, on an individual patient bases between peripheral and intrahepatic NK cells from cancerous and noncancerous liver tissues. In the HCC patient periphery, CD160+CD56dim NK cells that expressed Siglec-7, NKp46, and NKp30 were reduced, while CD49a+CD56dim NK cells that expressed Siglec-10 were increased. CD160 and CD49a on CD56dim NK cells were significantly correlated to other NK-related markers in HCC patients, which suggested that CD160 and CD49a were signature molecules. CD49a+ CX3CR1+ Siglec-10+ NK cells had accumulated in HCC tissues. Considering further functional analyses, CD160, CD49a, CX3CR1, and Siglec-10 on CD56dim NK cells may be targets for immunotherapies of HCC patients.
Subject(s)
Antigens, CD/metabolism , Carcinoma, Hepatocellular , Killer Cells, Natural , Liver Neoplasms , Liver , Neoplasm Proteins/metabolism , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Cytophotometry , Female , Humans , Killer Cells, Natural/metabolism , Killer Cells, Natural/pathology , Liver/metabolism , Liver/pathology , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , MaleABSTRACT
Non-alcoholic fatty liver disease (NAFLD) is a progressive disorder that can develop into liver fibrosis and hepatocellular carcinoma. Natural killer (NK) cells have been shown to protect against liver fibrosis and tumorigenesis, suggesting that they may also play a role in the pathogenesis of NAFLD. Sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of inhibitory and activating receptors expressed by many cell types, including NK cells. Here, we investigated the phenotypic profiles of peripheral blood and intrahepatic NK cells, including expression of Siglecs and immune checkpoint molecules, and their association with NK cell function in patients with NAFLD. Immune cells in the peripheral blood of 42 patients with biopsy-proven NAFLD and 13 healthy volunteers (HVs) were identified by mass cytometry. The function of various NK cell subpopulations was assessed by flow cytometric detection of intracellular IFN-γ and CD107a/LAMP-1, a degranulation marker, after in vitro stimulation. We found that peripheral blood from NAFLD patients, regardless of fibrosis stage, contained significantly fewer total CD56+ NK cell and CD56dim NK cell populations compared with HVs, and the CD56dim cells from NAFLD patients were functionally impaired. Among the Siglecs examined, NK cells predominantly expressed Siglec-7 and Siglec-9, and both the expression levels of Siglec-7 and Siglec-9 on NK cells and the frequencies of Siglec-7+CD56dim NK cells were reduced in NAFLD patients. Notably, Siglec-7 levels on CD56dim NK cells were inversely correlated with PD-1, CD57, and ILT2 levels and positively correlated with NKp30 and NKp46 levels. Further subtyping of NK cells identified a highly dysfunctional Siglec-7-CD57+PD-1+CD56dim NK cell subset that was increased in patients with NAFLD, even those with mild liver fibrosis. Intrahepatic NK cells from NAFLD patients expressed elevated levels of NKG2D and CD69, suggesting a more activated phenotype than normal liver NK cells. These data identify a close association between NK cell function and expression of Siglec-7, CD57, and PD-1 that could potentially be therapeutically targeted in NAFLD.
Subject(s)
Antigens, Differentiation, Myelomonocytic/immunology , CD57 Antigens/immunology , Killer Cells, Natural/immunology , Lectins/immunology , Non-alcoholic Fatty Liver Disease/immunology , Programmed Cell Death 1 Receptor/immunology , Adult , Aged , Female , Flow Cytometry , Humans , Interferon-gamma/immunology , Killer Cells, Natural/pathology , Lysosomal-Associated Membrane Protein 1/immunology , Lysosomal Membrane Proteins/immunology , Male , Middle Aged , Non-alcoholic Fatty Liver Disease/pathologyABSTRACT
INTRODUCTION: Dual-hemostat techniques for port closure have previously been reported, but their safety and efficacy have not been evaluated. Here, we describe the dual-hemostat port closure technique employed at our institution, which uses a customized surgical suture for safe and certain port closure, and we assess the incidence rate of trocar-site hernia (TSH) after laparoscopic cholecystectomy. METHODS: From March 1999 to March 2017 at our institution, 316 patients underwent elective laparoscopic cholecystectomy performed by a single experienced surgeon. We routinely used a dual-hemostat technique with a customized surgical suture to achieve safe and certain port closure. We assessed the incidence rate of TSH after laparoscopic cholecystectomy (defined as a reoperation for a TSH or clinical hernia at the port site) based on follow-up data from patient questionnaires and clinical examinations. RESULTS: After 67 patients were excluded because of death, unknown address, or conversion to open cholecystectomy, 249 eligible patients received questionnaires, of which 173 were returned (response rate, 69.5%). From these responses, TSH was suspected in three patients, but only one underwent reoperation for TSH after laparoscopic cholecystectomy. Thus, the incidence rate of TSH after laparoscopic cholecystectomy was 0.6% (1/173). CONCLUSIONS: Our single-center experience demonstrated that our port closure technique using a dual-hemostat technique with customized surgical suture provides an appropriate option for laparoscopic cholecystectomy, especially given its ease and low incidence of TSH.
Subject(s)
Cholecystectomy, Laparoscopic/instrumentation , Cholecystectomy, Laparoscopic/methods , Hernia, Ventral/surgery , Incisional Hernia/surgery , Wound Closure Techniques/instrumentation , Cholecystectomy, Laparoscopic/adverse effects , Hernia, Ventral/etiology , Humans , Incisional Hernia/etiology , Surgical Instruments , SuturesABSTRACT
BACKGROUND: Small bowel adenocarcinomas are rare malignant tumors that account for less than 2% of gastrointestinal malignancies. In addition, tumor incarceration in an inguinal hernia is also rare entity. We herein report a first case of small bowel adenocarcinoma incarcerated within an inguinal hernia. CASE PRESENTATION: A 75-year-old man with asymptomatic anemia (hemoglobin, 8.6 g/dl) had a checkup at our hospital. Colonoscopy revealed bleeding through the ileocecal valve and an annular stricture by a tumor in the ileum. Endoscopic biopsy revealed a well-differentiated adenocarcinoma of the small bowel. Enhanced computed tomography showed a hypervascular solid tumor incarcerated within a right inguinal hernia. With a diagnosis of small bowel adenocarcinoma incarcerated within a right inguinal hernia, the patient underwent elective laparotomy with midline excision. The small bowel tumor, located at 30 cm from the terminal ileum, was incarcerated within a right inguinal hernia, and the small bowel was adherent to the hernia sac. A 24-cm segment of the distal ileum and regional lymph nodes were resected. The hernia sac was ligated, and the bottom of the hernia sac was resected. The hernia orifice was closed by tissue repair technique via a standard oblique incision in the right inguinal region. Postoperatively, the patient remains well with no evidence of tumor or hernia recurrence as of 1 year after operation. CONCLUSIONS: We reported to our knowledge the first case of small bowel adenocarcinoma incarcerated within an inguinal hernia.
ABSTRACT
Global implementation of a birth-dose hepatitis B (HB) vaccine has significantly reduced the prevalence of hepatitis B virus (HBV) carriers. Durable and sufficient titers of antibodies to hepatitis B surface antigen (anti-HBs) are desirable for vaccinees to gain resistance to HBV exposure. However, the existence of primary nonresponders and vaccinees who lost anti-HBs over time remains a challenge for the strategy of HBV elimination. We thus aim to clarify the mechanisms of acquisition and maintenance of vaccine-induced anti-HBs in healthy adults. We retrospectively analyzed the vaccination records of 3,755 first-time HB-vaccinated students and also traced the acquired antibody transition of 392 first-time vaccinees for 10 consecutive years. To understand the cellular and humoral immune response, we prospectively examined peripheral blood from 47 healthy first-time HB-vaccinated students, 62 booster-vaccinated health care workers, and 20 individuals who maintained their anti-HBs. In responders, a significant increase of follicular helper T (Tfh) cells, activated plasmablasts, and plasma cells was observed in first-time-vaccinated but not booster-vaccinated persons. We also discovered memory B cells and antibody-secreting cells were more abundant in individuals who maintained anti-HBs. According to vaccination records, higher anti-HBs antibody titer acquisition was related to the longer term maintenance of anti-HBs, the level of which was positively correlated with prevaccination levels of serum interferon-γ and related chemokines. The second series of vaccination as a booster provided significantly higher anti-HBs antibody titers compared to the initial series. Conclusion: Coordinated activation of Tfh and B-cell lineages after HB vaccination is involved in the acquisition and maintenance of anti-HBs. Our findings support the rationale of preconditioning the immune status of recipients to ensure durable vaccine responses.