Aberrant Upregulation of Indoleamine 2,3-Dioxygenase 1 Promotes Proliferation and Metastasis of Hepatocellular Carcinoma Cells via Coordinated Activation of AhR and ß-Catenin Signaling.

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. Chronic liver inflammation due to hepatitis virus infection and other major effectors is a major risk factor of HCC. Indoleamine 2,3-dioxygenase 1 (IDO1), a heme enzyme highly expressed upon stimulation with proinflammatory cytokines such as interferon-γ (IFN-γ), is activated to modulate the tumor microenvironment and potentially crucial in the development of certain cancer types. Earlier studies have majorly reported an immunomodulatory function of IDO1. However, the specific role of IDO1 in cancer cells, particularly HCC, remains to be clarified. Analysis of The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA LIHC) dataset in the current study revealed a significant correlation between IDO1 expression and HCC. We further established inducible IDO1-expressing cell models by coupling lentivirus-mediated knockdown and IFN-γ induction of IDO1 in normal and HCC cells. In functional assays, proliferation and motility-related functions of HCC cells were compromised upon suppression of IDO1, which may partially be rescued by its enzymatic product, kynurenine (KYN), while normal hepatocytes were not affected. Aryl hydrocarbon receptor (AhR), a reported endogenous KYN receptor, is suggested to participate in tumorigenesis. In mechanistic studies, IDO1 activation promoted both AhR and ß-catenin activity and nuclear translocation. Immunofluorescence staining and co-immunoprecipitation assays further disclosed interactions between AhR and ß-catenin. In addition, we identified a Src-PTEN-PI3K/Akt-GSK-3ß axis involved in ß-catenin stabilization and activation following IDO1-mediated AhR activation. IDO1-induced AhR and ß-catenin modulated the expression of proliferation- and EMT-related genes to facilitate growth and metastasis of HCC cells. Our collective findings provide a mechanistic basis for the design of more efficacious IDO1-targeted therapy for HCC.

Aboriginal Taiwanese hepatitis B carriers have more favorable viral factors than Han Chinese carriers.

Several viral factors are associated with disease progression in hepatitis B virus (HBV) carriers. Compared with Taiwanese Han Chinese, Taiwanese aborigines have a higher prevalence of chronic HBV infection and a higher standardized mortality rate of chronic liver diseases but a lower standardized mortality rate of hepatocellular carcinoma (HCC). The aim of this study was to investigate whether aboriginal Taiwanese HBV carriers have more favorable viral factors which reduce the risk for HCC than Han Chinese carriers. Blood samples from 3,488 HBV carriers (1,527 aborigines and 1,961 Han Chinese) were assayed for aminotransferases, hepatitis B e antigen (HBeAg), HBV DNA, and HBV genotype. Aboriginal HBV carriers had a lower HBeAg-positive rate (5.3% vs. 10.2%, P < 0.0001) and a lower viral load of HBV DNA > 2,000 IU/ml (27.4% vs. 36.7%, P < 0.0001) but a higher rate of alcohol consumption (40.0% vs. 19.3%, P < 0.0001) than Han Chinese carriers. The prevalence of HBV genotype B in aboriginal carriers (92.7%) was significantly higher than that in Han Chinese carriers (72.7%) in all age groups (P < 0.05). In addition, patients with rare genotype D infections were clustered in a township in southern Taiwan. In conclusion, aboriginal Taiwanese HBV carriers have more favorable viral factors than Han Chinese carriers, which may be partly responsible for the lower standardized mortality rate of HCC in Taiwanese aborigines.

The disconnect in hepatitis screening: participation rates, awareness of infection status, and treatment-seeking behavior.

BACKGROUND: Over 325 million people in the world are infected with hepatitis B or C virus. Chronic hepatitis is responsible for 78% of cases of hepatocellular carcinoma and an estimated 1.3 million preventable deaths a year. As "silent killers", liver diseases are often asymptomatic and go undiagnosed until their terminal stage. Knowledge of infection status via screening is thus a vital part of preventing spread and seeking early treatment. Recently there has been a worldwide push to eliminate hepatitis. The objective of this study is to assess hepatitis B and C self-reported awareness of infection status vs correct awareness (compared to blood test results) and follow-up rates in Taiwan to inform global health promotion efforts that utilize screening interventions to prevent chronic liver diseases. METHODS: De-identified data from a Liver Foundation's nationwide community-outreach free blood screening programs was utilized, including 50 909 participants' data from 74 sites with a questionnaire (demographics, screening history, hepatitis awareness, monitoring behavior) and blood test results. Chi square tests were applied using R programing to examine the impacts of demographic variables on infection prevalence, awareness, and behavior relating to hepatitis. RESULTS: Among all participants, 41.1% indicated having had a hepatitis screening, of which only 60.8% knew their results. Around 69.7% and 66.5% self-reported awareness of their hepatitis B and C status respectively; 12.8% and 26.4% of individuals who tested positive for HBsAg and Anti-HCV respectively incorrectly thought they were not infected. Of those who self-reported awareness of their positive infection, 43.4% and 26.6% did not follow up with a health care professional for monitoring or treatment; the top reasons were "no symptoms", "too busy", and "don't know where to follow up". Rural populations showed higher infection prevalence but lower screening rates and self-reported awareness. CONCLUSIONS: Intervention programs must address the substantial number of people that do not recall if they were screened or do not know the results of a screening. Discrepancies between self-reported awareness, correct awareness, and follow-up and disparities across demographic groups deserve further scrutiny. Global hepatitis eradication initiatives should reconsider how screening, test results, and education are presented in order to improve awareness and prevent chronic infection that could develop into life-threatening liver diseases.

One-year weight management lowers lipopolysaccharide-binding protein and its implication in metainflammation and liver fibrosis.

BACKGROUND: Studies showed that the endotoxemia-related biomarker, lipopolysaccharide-binding protein (LBP), is associated with obesity and fatty liver. The level of LBP is reduced after surgical weight loss. This study aimed to verify the change of serum LBP levels after one-year medical weight management in subjects with obesity. METHODS AND FINDINGS: A total of 62 subjects with obesity, 39 subjects with overweight, and 21 subjects with normal body mass index were enrolled for a one-year weight management program. Basic information, body composition analysis, clinical data, serum LBP level, and abdominal ultrasonography findings were collected. At baseline, the serum LBP levels of the obese and overweight subjects were significantly higher than that of the normal group (30.9±7.4 and 29.6±6.3 versus 23.1±5.6 µg/mL, respectively, p<0.001). Serum LBP in subjects with obesity was significantly reduced to 26.5±7.1 µg/mL (p-value < 0.001) after one year. In the multivariate analyses, LBP was associated with high sensitive C-reactive protein (hs-CRP) and non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS) before weight management in the obese group. Moreover, the change of LBP in response to weight management was significantly related to the changes of hs-CRP, leukocyte count and NFS by multivariate linear regression analysis also in the obese group. CONCLUSION: The serum level of the endotoxemia-related biomarker, LBP, decreases after one-year weight management in the obese subjects. In addition to serving as a metainflammatroy biomarker like hs-CRP, LBP may also be a potential biomarker as a non-invasive biomarker for the evaluation of liver fibrosis in NAFLD.

High Serum Lipopolysaccharide-Binding Protein Level in Chronic Hepatitis C Viral Infection Is Reduced by Anti-Viral Treatments.

BACKGROUND: Lipopolysaccharide-binding protein (LBP) has been reported to associate with metabolic diseases, such as obesity, diabetes, and non-alcoholic fatty liver disease. Since chronic hepatitis C virus (HCV) infection is associated with metabolic derangements, the relationship between LBP and HCV deserves additional studies. This study aimed to determine the serum LBP level in subjects with or without HCV infection and investigate the change of its level after anti-viral treatments with or without interferon. METHODS AND FINDINGS: We recruited 120 non-HCV subjects, 42 and 17 HCV-infected subjects respectively treated with peginterferon α-2a/ribavirin and direct-acting antiviral drugs. Basic information, clinical data, serum LBP level and abdominal ultrasonography were collected. All the subjects provided written informed consent before being enrolled approved by the Research Ethics Committee of the National Taiwan University Hospital. Serum LBP level was significantly higher in HCV-infected subjects than non-HCV subjects (31.0 ± 8.8 versus 20.0 ± 6.4 µg/mL; p-value < 0.001). After multivariate analyses, LBP at baseline was independently associated with body mass index, hemoglobin A1c, alanine aminotransferase (ALT) and HCV infection. Moreover, the baseline LBP was only significantly positively associated with ALT and inversely with fatty liver in HCV-infected subjects. The LBP level significantly decreased at sustained virologic response (27.4 ± 6.6 versus 34.6 ± 7.3 µg/mL, p-value < 0.001; 15.9 ± 4.4 versus 22.2 ± 5.7 µg/mL, p-value = 0.001), regardless of interferon-based or -free therapy. CONCLUSIONS: LBP, an endotoxemia associated protein might be used as an inflammatory biomarker of both infectious and non-infectious origins in HCV-infected subjects.

Duodenojejunal Bypass Leads to Altered Gut Microbiota and Strengthened Epithelial Barriers in Rats.

BACKGROUND: Gastrointestinal bypass changes the gut microbiota and decreases systemic endotoxemia in obese subjects. Epithelial barrier integrity is crucial for confining enteric bacteria in the lumen and preventing gut-derived endotoxemia. The effect of bypass surgery on intestinal barrier functions remains poorly understood. This study aimed to evaluate the changes in intestinal permeability and gut barrier between rats receiving Roux-en-Y duodenojejunal bypass (DJB) or sham operation (SO). METHODS: Eighteen Sprague-Dawley rats were assigned to DJB or SO groups. Tissues of the alimentary, biliopancreatic, and common limbs in the small intestine, and the colon, were collected 2 weeks after operation. Mucosa-associated bacteria were quantified by colony forming units. Intestinal permeability was determined by mucosal-to-serosal dextran flux measured in Ussing chambers. Expression of occludin and proliferating cell nuclear antigen (PCNA) in the intestinal mucosa was examined by western blots. RESULTS: Enteric bacterial numbers were increased in the alimentary and common limbs after DJB. Reduced dextran permeability was found in the alimentary limb, common limb, and colon after DJB. Moreover, increased villus height and crypt depth were found to be associated with higher mucosal levels of occludin and PCNA levels in the alimentary and common limbs after DJB. CONCLUSIONS: DJB in rats altered gut microbiota and reduced intestinal permeability due to increased epithelial proliferation and tight junctional protein expression. Our results show that bypass surgery led to fortification of the intestinal barrier functions, which may provide an explanation for the decreased risk of systemic endotoxemia in postoperative patients.

Diabetes Associated Markers After Bariatric Surgery: Fetuin-A, but Not Matrix Metalloproteinase-7, Is Reduced.

BACKGROUND: Recent studies showed that fetuin-A and matrix metalloproteinase-7 (MMP-7) are type 2 diabetes mellitus (T2DM)-associated markers. Bariatric surgery not only reduces body weight but also improves T2DM. This study aimed to investigate the changes of fetuin-A and MMP-7 in obese subjects with and without T2DM after bariatric surgery. METHODS: We enrolled 130 obese subjects that received bariatric surgery, including 41 Roux-en-Y gastric bypass (RYGB), 67 mini-gastric bypass (MGB), and 22 sleeve gastrectomy (SG) patients. Forty-three patients suffered from T2DM prior to surgery. The fasting serum fetuin-A and MMP-7 levels were measured before and 1 year after surgery. RESULTS: Only five of 43 patients remained diabetic after surgery. Preoperative T2DM patients had higher fetuin-A and MMP-7 levels than non-T2DM subjects. RYGB, MGB, and SG all decreased the fetuin-A levels 1 year after the operation. The MMP-7 levels were not changed after RYGB, MGB, or SG. In multivariate analyses, the preoperative fetuin-A was significantly related to the diastolic blood pressure (DBP) and glycosylated hemoglobin (HbA1c), while the postoperative fetuin-A was independently related to the waist-to-hip ratio and HbA1c. Moreover, the preoperative MMP-7 level was significantly related to age, DBP, aspartate transaminase, alanine transaminase, and gamma-glutamyl transferase (rGT), while the postoperative MMP-7 level was independently related to age and rGT. CONCLUSIONS: The fetuin-A and MMP-7 levels are both higher in obese T2DM than non-T2DM subjects. The level of fetuin-A is reduced after RYGB, MGB, and SG, but the level of MMP-7 remains unchanged.

Mini-laparotomy implantation of peritoneal dialysis catheters: outcome and rescue.

BACKGROUND: Continuous ambulatory peritoneal dialysis is one of the main treatments for end-stage renal disease. To correct mechanical outflow obstruction after open surgical methods of catheter insertion, laparoscopic techniques are widely employed. ♢ METHODS: Between January 2001 and December 2006, 228 open Tenckhoff catheter implantations were carried out by mini-laparotomy in 218 patients at our medical center. The procedures were all performed by an experienced surgeon, and the postoperative care, patient education, and long-term follow-up were all conducted by the same peritoneal dialysis team. ♢ RESULTS: Infection of the exit site or tunnel was the most common complication (27/228, 11.8%), followed by peritonitis (18/228, 7.9%) and refractory mechanical catheter obstruction (9/228, 3.9%). The main causes of catheter removal were successful renal transplantation (21/228, 9.2%), peritonitis (18/228, 7.9%), and infection of the exit site or tunnel (7/228, 3.1%). In the 9 cases of refractory mechanical catheter obstruction, laparoscopic surgery was performed to identify the pathology and to rescue the catheter at the same time. Omental wrapping was the major cause (8/9) of catheter obstruction, with blood clot in the lumen and tube migration occurring in the remaining case (1/9). Partial omentectomy was performed in 5 patients to prevent recurrent obstruction. Neither technique failure nor operation-related complications were noted in our laparoscopic rescue group. For 20 of the 25 patients with refractory infection of the exit site or tunnel, the salvage technique of partial re-plantation was performed, with an 85% (17/20) technique survival rate. ♢ CONCLUSIONS: With an experienced surgeon and a good postoperative care team, open paramedian placement is a simple, safe, and effective method for Tenckhoff catheter insertion, with a low complication rate. Laparoscopic surgery is effective as rescue for mechanical obstruction, and partial re-plantation is effective as salvage for exit-site or tunnel infection.

Sentinel lymphadenectomy for circumscribed cutaneous T-cell lymphoma.

BACKGROUND: Sentinel lymphadenectomy has been associated with fewer complications in evaluating regional lymph nodes from melanoma or squamous cell carcinoma. It may also be employed in other malignancies such as localized cutaneous lymphoma. This is the first report demonstrating sentinel lymphadenectomy may be useful on primary cutaneous anaplastic large-cell lymphoma. OBJECTIVE: The objective was to assess the efficacy of sentinel lymphadenectomy on primary cutaneous anaplastic large-cell lymphoma. METHODS: Sentinel lymphadenectomy was performed on a patient with a localized CD30+ primary cutaneous anaplastic large-cell lymphoma. After preoperative lymphoscintigraphy, sentinel lymph node was identified by the gamma probe, excised totally, and sent for histopathologic examination. RESULTS: Sentinel lymphadenectomy was negative for tumor metastasis to sentinel lymph node. Total excision was performed without systemic chemotherapy or immunotherapy. This patient remained tumor-free 36 months after operation. CONCLUSION: Sentinel lymphadenectomy on patients with circumscribed restricted primary cutaneous lymphoma may be beneficial for staging and prognostication of the disease.