Risk Factors for a Narrow Safety Margin after Endoscopic Submucosal Dissection for Early Gastric Cancer.

INTRODUCTION: A narrow safety margin (NSM) after endoscopic submucosal dissection (ESD) is a well-recognized risk factor for local recurrence in early gastric cancer (EGC). However, only a few studies have investigated the risk factors for the development of NSM. METHODS: The medical records and pathologic specimens of patients with EGC who underwent ESD from January 2020 to December 2020 at a single tertiary hospital (Daejeon, South Korea) were reviewed. RESULTS: A total of 218 patients were enrolled and 29 had NSM (<3 mm). When comparing the NSM and the control groups, the size of the lesion, the depth of invasion, and the operating endoscopist were found to be risk factors for the development of NSM. The increased length of the subepithelial spread of the lesion was associated with a narrower safety margin. Logistic regression analysis revealed that lesion size was a risk factor for NSM, and a marginally significant difference between endoscopists was found. CONCLUSIONS: Multiple factors may need to be considered during ESD, including lesion size, invasion depth, operating endoscopist, and subepithelial spread.

CT-based Hounsfield unit values reflect the degree of steatohepatitis in patients with low-grade fatty liver disease.

BACKGROUND/AIMS: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Ultrasound, the most used tool for diagnosing NAFLD, is operator-dependent and shows suboptimal performance in patients with mild steatosis. However, few studies have been conducted on whether alternative noninvasive methods are useful for diagnosing mild hepatic steatosis. Also, little is known about whether noninvasive tests are useful for grading the severity of hepatic steatosis or the degree of intrahepatic inflammation. Therefore, we aimed to evaluate whether the HSI, the FLI and HU values in CT could be used to discriminate mild hepatic steatosis and to evaluate the severity of hepatic steatosis or the degree of intrahepatic inflammation in patients with low-grade fatty liver disease using liver biopsy as a reference standard. METHODS: Demographic, laboratory, CT imaging, and histological data of patients who underwent liver resection or biopsy were analyzed. The performance of the HSI, HU values and the FLI for diagnosing mild hepatic steatosis was evaluated by calculating the area under the receiver operating characteristic curve. Whether the degree of hepatic steatosis and intrahepatic inflammation could be predicted using the HSI, HU values or the FLI was also analyzed. Moreover, we validate the results using magnetic resonance imaging proton density fat fraction as an another reference standard. RESULTS: The AUROC for diagnosing mild hepatic steatosis was 0.810 (p < 0.001) for the HSI, 0.732 (p < 0.001) for liver HU value, 0.802 (p < 0.001) for the difference between liver and spleen HU value (L-S HU value) and 0.813 (p < 0.001) for the FLI. Liver HU and L-S HU values were negatively correlated with the percentage of hepatic steatosis and NAFLD activity score (NAS) and significantly different between steatosis grades and between NAS grades. The L-S HU value was demonstrated the good performance for grading the severity of hepatic steatosis and the degree of intrahepatic inflammation. CONCLUSIONS: The HU values on CT are feasible for stratifying hepatic fat content and evaluating the degree of intrahepatic inflammation, and the HSI and the FLI demonstrated good performance with high sensitivity and specificity in diagnosing mild hepatic steatosis.

Outcomes of laparoscopic radiofrequency ablation versus percutaneous radiofrequency ablation for hepatocellular carcinoma.

BACKGROUND: Few studies have compared the therapeutic outcomes in patients with HCC who underwent laparoscopic radiofrequency ablation (LRFA) versus percutaneous radiofrequency ablation (PRFA) for hepatocellular carcinoma (HCC). Therefore, this study compared the recurrence and survival outcomes of the two RFA methods in patients with HCC. METHODS: Recurrence and overall survival outcomes were evaluated in 307 patients who underwent LRFA (n = 151) or PRFA (n = 156) as a treatment method for de novo HCC. Inverse probability of treatment weighting (IPTW) analysis was performed to reduce the impact of treatment selection bias. RESULTS: There were no significant differences in major baseline characteristics between the LRFA and PRFA groups. However, the proportion of cirrhotic patients was higher in the LRFA group, whereas the LRFA group had more tumors and a more advanced tumor-node-metastasis stage. Moreover, the mean tumor size was significantly larger in the LRFA group than in the PRFA group. In a multivariate analysis, serum albumin level, more than three tumors, and the RFA method were identified as significant predictors of recurrence-free survival. Moreover, for the overall survival of HCC patients, serum albumin levels, days of hospital stay during RFA, and the RFA method were independent predictors. In the IPTW-adjusted analysis, the LRFA group showed significantly higher recurrence-free survival and overall survival. CONCLUSIONS: Our study revealed that compared with PRFA, LRFA was associated with longer recurrence-free survival and favorable overall survival in patients with HCC. Therefore, LRFA should be considered the primary therapy in patients with HCC eligible for RFA.

Metabotropic Glutamate Receptor 5 in Natural Killer Cells Attenuates Liver Fibrosis by Exerting Cytotoxicity to Activated Stellate Cells.

BACKGROUND AND AIMS: The important roles of glutamate and metabotropic glutamate receptor 5 (mGluR5) in HSCs have recently been reported in various liver diseases; however, the mechanism linking the glutamine/glutamate metabolism and mGluR5 in liver fibrosis remains unclear. Here, we report that mGluR5 activation in natural killer (NK) cells attenuates liver fibrosis through increased cytotoxicity and interferon-γ (IFN-γ) production in both mice and humans. APPROACH AND RESULTS: Following 2-week injection of carbon tetrachloride (CCl4 ) or 5-week methionine-deficient and choline-deficient diet, liver fibrosis was more aggravated in mGluR5 knockout mice with significantly decreased frequency of NK cells compared with wild-type mice. Consistently, NK cell-specific mGluR5 knockout mice had aggravated CCl4 -induced liver fibrosis with decreased production of IFN-γ. Conversely, in vitro activation of mGluR5 in NK cells significantly increased the expression of anti-fibrosis-related genes including Ifng, Prf1 (perforin), and Klrk1 (killer cell lectin like receptor K1) and the production of IFN-γ through the mitogen-activated extracellular signal-regulated kinase/extracellular signal-related kinase pathway, contributing to the increased cytotoxicity against activated HSCs. However, we found that the uptake of glutamate was increased in activated HSCs, resulting in shortage of extracellular glutamate and reduced stimulation of mGluR5 in NK cells. Consequently, this could enable HSCs to evade NK cell cytotoxicity in advanced liver fibrosis. In vivo, pharmacologic activation of mGluR5 accelerated CCl4 -induced liver fibrosis regression by restoring NK cell cytotoxicity. In humans, mGluR5 activation enhanced the cytotoxicity of NK cells isolated from healthy donors, but not from patients with cirrhosis with significantly reduced mGluR5 expression in NK cells. CONCLUSIONS: mGluR5 plays important roles in attenuating liver fibrosis by augmenting NK cell cytotoxicity, which could be used as a potential therapeutic target for liver fibrosis.

Typhoid fever presenting with gastric ulcer bleeding.

BACKGROUND: Enteric fever is a systemic disease caused by Salmonella enterica serovar Typhi or Salmonella enterica serovar Paratyphi, characterized by high fever and abdominal pain. Most patients with enteric fever improve within a few days after antibiotic treatment. However, some patients do not recover as easily and develop fatal life-threatening complications, including intestinal hemorrhage. Lower gastrointestinal bleeding has been reported in 10% of cases. However, upper gastrointestinal bleeding has rarely been reported in patients with enteric fever. We present a case of gastric ulcer hemorrhage caused by enteric fever. CASE PRESENTATION: A 32-year-old woman, complaining of fever lasting four days and right upper quadrant pain and melena that started one day before admission, consulted our hospital. Abdominal computed tomography revealed mild hepatomegaly and gastroscopy revealed multiple active gastric ulcers with flat black hemorrhagic spots. The melena of the patient stopped on the third day. On the fifth admission day, she developed hematochezia. At that time, Salmonella enterica serovar Typhi was isolated from the blood culture. The antibiotic regimen was switched to ceftriaxone. Her hematochezia spontaneously resolved the following day. Finally, the patient was discharged on the 12th admission day without clinical symptoms. However, her fever recurred one month after discharge, and she was readmitted and Salmonella enterica serovar Typhi was confirmed again via blood culture. She was treated with ceftriaxone for one month, and was discharged without complications. CONCLUSION: Our case showed that although rare, active gastric ulcers can develop in patients with enteric fever. Therefore, upper and lower gastrointestinal bleeding should be suspected in patients with enteric fever, especially showing relapsing bacteremia.

Effect of Diminutive Adenoma with High-Grade Dysplasia on Surveillance Colonoscopy Interval.

BACKGROUND: Colonoscopy surveillance guidelines set the surveillance schedule based on polyp characteristics. Polyps with high-grade dysplasia (HGD) require 3 years of follow-up regardless of size. However, it is unclear whether patients with diminutive polyps (≤5 mm) with HGD have a higher risk. We evaluated the effect of diminutive adenoma with HGD on adenoma occurrence. METHODS: From January 2015 to December 2017, patients who underwent index and surveillance colonoscopy were retrospectively screened. The patients were grouped into no adenoma group, low-risk (patients with ≤2 low-grade dysplasia [LGD]), diminutive HGD, and high-risk (HGD >5 mm, ≥3 adenomas) groups according to the index colonoscopy results. Each group was analyzed using logistic analysis. RESULTS: The mean follow-up period was 22.47 months. Altogether, 610 (50.45%) patients had LGD and 152 (12.5%) had HGD. Among them, 61 (5.0%) patients had a diminutive polyp with HGD. Analysis of the risks of developing advanced adenoma in the surveillance colonoscopy showed that compared to the no adenoma group, the diminutive HGD group did not show a significant risk (odds ratio [OR] = 1.503 [0.449-5.027], p = 0.509), while the high-risk group showed a significant risk (OR = 2.044 [1.015-4.114], p = 0.045). CONCLUSIONS: Diminutive adenoma with HGD increased the risk of adenoma on surveillance colonoscopy, and in the case of advanced adenoma, the risk was increased, but it was not statistically significant.

Mitochondrial Double-Stranded RNA in Exosome Promotes Interleukin-17 Production Through Toll-Like Receptor 3 in Alcohol-associated Liver Injury.

BACKGROUND AND AIMS: Mitochondrial double-stranded RNA (mtdsRNA) and its innate immune responses have been reported previously; however, mtdsRNA generation and its effects on alcohol-associated liver disease (ALD) remain unclear. Here, we report that hepatic mtdsRNA stimulates toll-like receptor 3 (TLR3) in Kupffer cells through the exosome (Exo) to enhance interleukin (IL)-17A (IL-17A) production in ALD. APPROACH AND RESULTS: Following binge ethanol (EtOH) drinking, IL-17A production primarily increased in γδ T cells of wild-type (WT) mice, whereas the production of IL-17A was mainly facilitated by CD4+ T cells in acute-on-chronic EtOH consumption. These were not observed in TLR3 knockout (KO) or Kupffer cell-depleted WT mice. The expression of polynucleotide phosphorylase, an mtdsRNA-restricting enzyme, was significantly decreased in EtOH-exposed livers and hepatocytes of WT mice. Immunostaining revealed that mtdsRNA colocalized with the mitochondria in EtOH-treated hepatocytes from WT mice and healthy humans. Bioanalyzer analysis revealed that small-sized RNAs were enriched in EtOH-treated Exos (EtOH-Exos) rather than EtOH-treated microvesicles in hepatocytes of WT mice and humans. Quantitative real-time PCR and RNA sequencing analyses indicated that mRNA expression of mitochondrial genes encoded by heavy and light strands was robustly increased in EtOH-Exos from mice and humans. After direct treatment with EtOH-Exos, IL-1ß expression was significantly increased in WT Kupffer cells but not in TLR3 KO Kupffer cells, augmenting IL-17A production of γδ T cells in mice and humans. CONCLUSIONS: EtOH-mediated generation of mtdsRNA contributes to TLR3 activation in Kupffer cells through exosomal delivery. Consequently, increased IL-1ß expression in Kupffer cells triggers IL-17A production in γδ T cells at the early stage that may accelerate IL-17A expression in CD4+ T cells in the later stage of ALD. Therefore, mtdsRNA and TLR3 may function as therapeutic targets in ALD.

Subepithelial spread of early gastric cancer is common and extends more than expected.

BACKGROUNDS: The clinical significance of subepithelial (SE) spread from early gastric cancer (EGC) is poorly understood. Thus, we evaluated the proportion and extent of SE spread from EGC, as well as related risk factors. METHODS: We reviewed medical records and pathological specimens from patients with EGC who underwent surgery or endoscopic resection between January 2016 and December 2016 at Chungnam National University Hospital. RESULTS: A total of 404 patients were reviewed and SE spread was identified for 142 patients (35.1%). The presence of SE spread was associated with gender, histological type, location, endoscopic appearance, color change, presence of lymphovascular invasion, and invasion depth. Multivariable analysis revealed that SE spread was only independently associated with histological type. The distance of SE spread was significantly different between histological types, and the maximum distance was 17 mm. CONCLUSION: More than 30% of our patients with EGC had SE spread, which could reach up to 17 mm. Given the proportion of SE spread in these cases, a wider resection margin may be safe during endoscopic resection or surgery.

Subepithelial Spread of Early Gastric Signet Ring Cell Carcinoma: How Far They Can Reach?

INTRODUCTION: Although signet ring cell carcinoma (SRC) is a poorly differentiated cancer subtype, recent studies suggest that endoscopic resection can be applied in small, mucosal early gastric SRC. However, other studies report frequent positive lines at the lateral resection margin after endoscopic treatment. Subepithelial spread beneath normal mucosa can exist in SRC, and such lesions may be the cause of positive margins after endoscopic resection. Thus, we conducted a retrospective study in order to evaluate the significance of subepithelial spread in early gastric SRC. METHOD: Medical records of early gastric SRC patients who underwent surgery or endoscopic resection from January 2011 to December 2016 at a single tertiary hospital (Daejeon, South Korea) were reviewed to examine subepithelial spread and clinical datum. Two expert pathologists reviewed all pathologic specimens, and only patients showing a pure SRC component were included. RESULTS: Eighty-six patients were initially enrolled, and subepithelial spread existed in 62 patients (72.1%). The mean distance of subepithelial spread was 1,132.1 µm, and the maximal distance was 6,000 µm. Only discoloration was significantly associated with the presence of a subepithelial spread (p < 0.05, χ2 test, and logistic regression test). Distance of subepithelial spread did not correlate with total lesion size. CONCLUSION: Subepithelial spread of early gastric SRC occurs frequently and can reach up to 6 mm. Lesion discoloration may be associated with the presence of subepithelial spread. Our results suggest that careful decision of the margin is needed when performing endoscopic resection of early gastric SRC.

Dual oxidase 1 and NADPH oxidase 2 exert favorable effects in cervical cancer patients by activating immune response.

BACKGROUND: Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived reactive oxygen species (ROS) not only can promote cancer progression, but also they have recently emerged as mediators of the mucosal immune system. However, the roles and clinical relevance of the collective or individual NADPH oxidase (NOX) family genes in cervical cancer have not been studied. METHODS: We investigated the clinical significance of the NOX family genes using data from 307 patients with cervical cancer obtained from The Cancer Genome Atlas. Bioinformatics and experimental analyses were performed to examine NOX family genes in cervical cancer patients. RESULTS: Dual Oxidase1 (DUOX1) and Dual Oxidase 2 (DUOX2) mRNA levels were upregulated 57.9- and 67.5-fold, respectively, in cervical cancer patients. The protein expression of DUOX1, DUOX2, and NOX2 also identified in cervical squamous cell carcinoma tissues. Especially, DUOX1 and DUOX2 mRNA levels were significantly increased in patients infected with human papillomavirus (HPV) 16. Moreover, high DUOX1 mRNA levels were significantly associated with both favorable overall survival and disease-free survival in cervical cancer patients. High NOX2 mRNA levels was significantly associated with favorable overall survival. Gene set enrichment analyses revealed that high DUOX1 and NOX2 expression was significantly correlated with the enrichment of immune pathways related to interferon (IFN)-alpha, IFN-gamma, and natural killer (NK) cell signaling. Cell-type identification by estimating relative subsets of known RNA transcript analyses indicated that the fraction of innate immune cells, including NK cells, monocytes, dendritic cells, and mast cells, was elevated in patients with high DUOX1 expression. CONCLUSIONS: DUOX1 and NOX2 expression are associated with mucosal immunity activated in cervical squamous cell carcinoma and predicts a favorable prognosis in cervical cancer patients.

Cytochrome P450 4A11 expression in tumor cells: A favorable prognostic factor for hepatocellular carcinoma patients.

BACKGROUND AND AIM: Elevated cytochrome p450 (CYP) 4A gene expression has been linked to the aggravation of various cancers and affects various regulated metabolites. In hepatocellular carcinoma (HCC), the clinicopathological value of CYP4A has not yet been explored, although CYP4A is expressed at high levels in the liver. The goal of this study was to evaluate the clinicopathological value of CYP4A11 expression in HCC. METHODS: We performed immunohistochemical analysis of CYP4A11 and correlated the results with clinicopathological features of HCC (n = 155). Western blotting and reverse transcription-polymerase chain reaction against CYP4A11 and CYP4A22 were also performed for 15 and 20 pairs of fresh-frozen primary HCC and non-neoplastic liver tissue, respectively. Moreover, we analyzed the underlying mechanism by comparing the high and low CYP4A11 mRNA expression groups using gene set enrichment analysis. RESULTS: CYP4A11 expression level was higher in non-neoplastic hepatocytes than those in HCC cells (P < 0.001), and CYP4A11 expression positively correlated with favorable prognostic factors, including tumor size, histological grade, and pathological tumor stage (P = 0.007, P = 0.005, and P = 0.007). Multivariate analysis revealed that CYP4A11 expression was an independent prognostic factor of overall and disease-free survival (P = 0.002 and P = 0.033). Based on gene set enrichment analysis, high CYP4A11 mRNA expression negatively correlated with the expression of cell cycle-related genes. CONCLUSION: These findings support the notion that CYP4A11 expression is a favorable prognostic factor of HCC and suggest potential predictive diagnostic and prognostic roles of CYP4A11 expression in HCC.

Clinical Significance of the Thioredoxin System and Thioredoxin-Domain-Containing Protein Family in Hepatocellular Carcinoma.

BACKGROUND: Oxidative stress occurs due to the excessive generation of cellular reactive oxygen species and antioxidant system dysfunction. The thioredoxin (TXN) system and TXN-domain-containing protein (TXNDC) family form networks maintaining the cellular reducing environment. Recently, the importance of these genes in the tumor environment has been emphasized. AIM: To investigate the clinical significance of TXNs and TXNDC family members in HCC. METHODS: Genomic data from 367 hepatocellular carcinoma (HCC) patients who underwent hepatic resections were analyzed to determine genetic alterations in mRNA and protein levels between patients and healthy controls. In addition, functional enrichment and survival analyses were performed. RESULTS: HCC patients were shown to have enhanced expression of TXN, TXNRD1, and TXNDC7/9/14 mRNA and protein compared with controls. In accordance with the survival analyses, strong associations were found that patients with TXN, TXNRD1, and TXNDC1/7/9 alterations were proven to have poor prognosis in overall survival. Moreover, gene set enrichment analysis and network analyses revealed that positive correlations were found in mRNA expression of TXN, TXNRD1, and TXNDC7/9 genes with upregulation of the tumor-promoting genes, specifically mTORC1, E2F targets, and Myc targets. On the other hand, elevated expressions of TXNIP and TXNDC11 genes were correlated with suppression of the above tumor-promoting genes. CONCLUSIONS: TXN system and TXNDC family gene panel obtained from the resected tissue of the HCC patients could be used to predict survival prognosis of HCC, and these genes could be considered as potential therapeutic targets for improving HCC survival.

Expression of NOX Family Genes and Their Clinical Significance in Colorectal Cancer.

BACKGROUND: The NADPH oxidase (NOX) family is overexpressed in many cancers and is associated with cancer cell proliferation and metastasis; however, little is known about the role of the NOX family in colorectal cancer (CRC). AIMS: To identify the expression of the NOX family in CRC and to investigate the relationship between the expression of NOXs with the prognosis of the patients. METHODS: In the TCGA data portal, mRNA expression data were obtained from 41 normal samples and 458 CRC samples to analyze mRNA expression and gene alteration. We compared the survival differences according to the degree of expression of NOX family in CRC patients and performed Gene Set Enrichment Analysis (GSEA). RESULTS: The mRNA expression of NOX1, 3, 4, and DUOX1, 2 was significantly increased in the colorectal adenocarcinoma. Especially, the higher T and N stage, the more NOX4 expression was significantly increased. Survival analyses showed that NOX4 and NOX5 were associated with poor prognosis; however, NOX1 and DUOX2 were significantly associated with better prognosis. In the results of GSEA of CRC patients, the NOX4 gene was significantly associated with Angiogenesis, EMT and notch signaling. CONCLUSIONS: The NOX family is overexpressed in CRC and is associated with the prognosis of the patient. Therefore, NOX family can predict CRC patient survival and the role of the NOX family as a molecular target in the treatment of CRC.

Exosome-mediated activation of toll-like receptor 3 in stellate cells stimulates interleukin-17 production by γδ T cells in liver fibrosis.

UNLABELLED: During liver injury, hepatocytes secrete exosomes that include diverse types of self-RNAs. Recently, self-noncoding RNA has been recognized as an activator of Toll-like receptor 3 (TLR3). However, the roles of hepatic exosomes and TLR3 in liver fibrosis are not yet fully understood. Following acute liver injury and early-stage liver fibrosis induced by a single or 2-week injection of carbon tetrachloride (CCl4 ), increased interleukin (IL)-17A production was detected primarily in hepatic γδ T cells in wild-type (WT) mice. However, liver fibrosis and IL-17A production by γδ T cells were both significantly attenuated in TLR3 knockout (KO) mice compared with WT mice. More interestingly, IL-17A-producing γδ T cells were in close contact with activated hepatic stellate cells (HSCs), suggesting a role for HSCs in IL-17A production by γδ T cells. In vitro treatments with exosomes derived from CCl4 -treated hepatocytes significantly increased the expression of IL-17A, IL-1ß, and IL-23 in WT HSCs but not in TLR3 KO HSCs. Furthermore, IL-17A production by γδ T cells was substantially increased upon coculturing with exosome-treated WT HSCs or conditioned medium from TLR3-activated WT HSCs. However, similar increases were not detected when γδ T cells were cocultured with exosome-treated HSCs from IL-17A KO or TLR3 KO mice. Using reciprocal bone marrow transplantation between WT and TLR3 KO mice, we found that TLR3 deficiency in HSCs contributed to decreased IL-17A production by γδ T cells, as well as liver fibrosis. CONCLUSION: In liver injury, the exosome-mediated activation of TLR3 in HSCs exacerbates liver fibrosis by enhancing IL-17A production by γδ T cells, which might be associated with HSC stimulation by unknown self-TLR3 ligands from damaged hepatocytes. Therefore, TLR3 might be a novel therapeutic target for liver fibrosis. (Hepatology 2016;64:616-631).

Advantages of Laparoscopic Radiofrequency Ablation Over Percutaneous Radiofrequency Ablation in Hepatocellular Carcinoma.

BACKGROUND: Inoperable hepatocellular carcinoma (HCC) can be treated with laparoscopic radiofrequency ablation (LRFA), which is generally a more accurate and accessible procedure than percutaneous RFA (PRFA). However, few studies have compared survival outcomes between LRFA and PRFA in patients with HCC. AIMS: This study aimed to compare the efficacy of LRFA and PRFA for HCC treatment. METHODS: Patients who underwent PRFA or LRFA as an initial treatment modality between April 2005 and April 2016 were enrolled in this study. The overall and recurrence-free survival rates were examined for each patient. Additionally, propensity score matching was performed for both groups. RESULTS: The baseline characteristics of patients in the PRFA and LRFA groups showed several minor differences. Multivariate analysis showed that the RFA method was not a critical determinant of recurrence-free or overall survival (p = 0.069 and p = 0.406). Among patients who underwent RFA as the initial treatment modality, there was no significant effect between either RFA procedures on survival. After propensity score matching, univariate analysis showed a significant difference in overall survival between PRFA and LRFA (p = 0.031). Multivariate analysis showed that LRFA is a strong factor that contributed to an improved overall survival in HCC patients (hazard ratio 0.108, p = 0.040). Furthermore, our data showed that LRFA was able to limit multiple intrahepatic recurrences, as well as prevent marginal recurrence. CONCLUSIONS: LRFA appears to be superior to PRFA in terms of survival. LRFA may help reduce mortality in HCC patients.

Protective effects of ginsenoside F2 on 12-O-tetradecanoylphorbol-13-acetate-induced skin inflammation in mice.

Topical use of ginsenosides, the major bioactive substances in Panax ginseng, has been used for the treatment of irritated skin complaints. However, the protective mechanisms of ginsenosides remain unclear. In the present study, we investigated the anti-inflammatory role of ginsenoside F2 (GF2) on the skin inflammation. To induce irritant dermatitis, 12-O-tetradecanoylphorbol-13-acetate (TPA) was applied on the surface of the mouse ears with or without treatments of GF2 and dexamethasone for 24 h. Protective effects of GF2 on edema and inflammation were assessed by measuring ear thickness, weights of skin punch, and inflammatory responses. In gross findings, treatments with GF2 significantly decreased skin thickness and weight compared to those of TPA-treated groups, which was comparable with the protective effects of dexamethasone. In addition, expression of inflammatory mediators was remarkably reduced in GF2-treated ears compared to that of vehicle-treated ears of mice. Interestingly, immunohistochemistry and flow cytometry analyses revealed that TPA treatment significantly increased infiltration of interleukin-17 (IL-17) producing dermal γδ T cells, while frequencies of γδ T cells was decreased by GF2 treatment, subsequently ameliorating inflammation in skin. Concomitantly, TPA-mediated skin inflammation was significantly ameliorated in IL-17A knock out mice. Furthermore, GF2 treatment inhibited infiltration and generation of reactive oxygen species (ROS) of neutrophils in damaged ears compared with vehicle-treated mice. These results clearly suggest that GF2 treatment ameliorates TPA-induced dermal inflammation by inhibiting production of IL-17 and ROS in γδ T cells and neutrophils, respectively. Therefore, as a natural compound, application of GF2 may be a novel therapeutic approach for treating skin inflammation.

Comparison of Glecaprevir/Pibrentasvir and Sofosbuvir/Ledipasvir in Patients with Hepatitis C Virus Genotype 1 and 2 in South Korea.

Background/Aims: This study compared the effectiveness and safety of glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/ledipasvir (SOF/LDV) in real-life clinical practice. Methods: The data from genotype 1 or 2 chronic hepatitis C patients treated with GLE/PIB or sofosbuvir + ribavirin or SOF/LDV in South Korea were collected retrospectively. The analysis included the treatment completion rate, sustained virologic response at 12 weeks (SVR12) test rate, treatment effectiveness, and adverse events. Results: Seven hundred and eighty-two patients with genotype 1 or 2 chronic hepatitis C who were treated with GLE/PIB (n=575) or SOF/LDV (n=207) were included in this retrospective study. The baseline demographic and clinical characteristics revealed significant statistical differences in age, genotype, ascites, liver cirrhosis, and hepatocellular carcinoma between the GLE/PIB and SOF/LDV groups. Twenty-two patients did not complete the treatment protocol. The treatment completion rate was high for both regimens without statistical significance (97.7% vs. 95.7%, p=0.08). The overall SVR12 of intention-to-treat analysis was 81.2% vs. 80.7% without statistical significance (p=0.87). The overall SVR12 of per protocol analysis was 98.7% vs. 100% without statistical significance (p=0.14). Six patients treated with GLE/PIB experienced treatment failure. They were all male, genotype 2, and showed a negative hepatitis C virus RNA level at the end of treatment. Two patients treated with GLE/PIB stopped medication because of fever and abdominal discomfort. Conclusions: Both regimens had similar treatment completion rates, effectiveness, and safety profiles. Therefore, the SOF/LDV regimen can also be considered a viable DAA for the treatment of patients with genotype 1 or 2 chronic hepatitis C.

Programmed Death 1 and Cytotoxic T-Lymphocyte-Associated Protein 4 Gene Expression in Peripheral Blood Mononuclear Cells Can Serve as Prognostic Biomarkers for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a highly aggressive form of liver cancer with poor prognosis. The lack of reliable biomarkers for early detection and accurate diagnosis and prognosis poses a significant challenge to its effective clinical management. In this study, we investigated the diagnostic and prognostic potential of programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression in peripheral blood mononuclear cells (PBMCs) in HCC. PD-1 and CTLA-4 gene expression was analyzed comparatively using PBMCs collected from HCC patients and healthy individuals. The results revealed higher PD-1 gene expression levels in patients with multifocal tumors, lymphatic invasion, or distant metastasis than those in their control counterparts. However, conventional serum biomarkers of liver function do not exhibit similar correlations. In conclusion, PD-1 gene expression is associated with OS and PFS and CTLA-4 gene expression is associated with OS, whereas the serum biomarkers analyzed in this study show no significant correlation with survival in HCC. Hence, PD-1 and CTLA-4 expressed in PBMCs are considered potential prognostic biomarkers for patients with HCC that can facilitate prediction of malignancy, response to currently available HCC treatments, and overall survival.

CD11b(+) Gr1(+) bone marrow cells ameliorate liver fibrosis by producing interleukin-10 in mice.

UNLABELLED: Clinical trials and animal models suggest that infusion of bone marrow cells (BMCs) is effective therapy for liver fibrosis, but the underlying mechanisms are obscure, especially those associated with early effects of BMCs. Here, we analyzed the early impact of BMC infusion and identified the subsets of BMCs showing antifibrotic effects in mice with carbon tetrachloride-induced liver fibrosis. An interaction between BMCs and activated hepatic stellate cells (HSCs) was investigated using an in vitro coculturing system. Within 24 hours, infused BMCs were in close contact with activated HSCs, which was associated with reduced liver fibrosis, enhanced hepatic expression of interleukin (IL)-10, and expanded regulatory T cells but decreased macrophage infiltration in the liver at 24 hours after BMC infusion. In contrast, IL-10-deficient (IL-10(-/-) ) BMCs failed to reproduce these effects in fibrotic livers. Intriguingly, in isolated cells, CD11b(+) Gr1(high) F4/80(-) and CD11b(+) Gr1(+) F4/80(+) BMCs expressed more IL-10 after coculturing with activated HSCs, leading to suppressed expression of collagen and α-smooth muscle actin in HSCs. Moreover, these effects were either enhanced or abrogated, respectively, when BMCs were cocultured with IL-6(-/-) and retinaldehyde dehydrogenase 1(-/-) HSCs. Similar to murine data, human BMCs expressed more IL-10 after coculturing with human HSC lines (LX-2 or hTERT), and serum IL-10 levels were significantly elevated in patients with liver cirrhosis after autologous BMC infusion. CONCLUSION: Activated HSCs increase IL-10 expression in BMCs (CD11b(+) Gr1(high) F4/80(-) and CD11b(+) Gr1(+) F4/80(+) cells), which in turn ameliorates liver fibrosis. Our findings could enhance the design of BMC therapy for liver fibrosis.