Nicha Wongjarupong

Hepatic stellate cell–derived platelet‐derived growth factor receptor‐alpha‐enriched extracellular vesicles promote liver fibrosis in mice through SHP2

Liver fibrosis is characterized by the activation and migration of hepatic stellate cells (HSCs), followed by matrix deposition. Recently, several studies have shown the importance of extracellular vesicles (EVs) derived from liver cells, such as hepatocytes and endothelial cells, in liver pathobiology. While most of the studies describe how liver cells modulate HSC behavior, an important gap exists in the understanding of HSC‐derived signals and more specifically HSC‐derived EVs in liver fibrosis. Here, we investigated the molecules released through HSC‐derived EVs, the mechanism of their release, and the role of these EVs in fibrosis. Mass spectrometric analysis showed that platelet‐derived growth factor (PDGF) receptor‐alpha (PDGFRα) was enriched in EVs derived from PDGF‐BB‐treated HSCs. Moreover, patients with liver fibrosis had increased PDGFRα levels in serum EVs compared to healthy individuals. Mechanistically, in vitro tyrosine720‐to‐phenylalanine mutation on the PDGFRα sequence abolished enrichment of PDGFRα in EVs and redirected the receptor toward degradation. Congruently, the inhibition of Src homology 2 domain tyrosine phosphatase 2, the regulatory binding partner of phosphorylated tyrosine720, also inhibited PDGFRα enrichment in EVs. EVs derived from PDGFRα‐overexpressing cells promoted in vitro HSC migration and in vivo liver fibrosis. Finally, administration of Src homology 2 domain tyrosine phosphatase 2inhibitor, SHP099, to carbon tetrachloride–administered mice inhibited PDGFRα enrichment in serum EVs and reduced liver fibrosis. Conclusion: PDGFRα is enriched in EVs derived from PDGF‐BB‐treated HSCs in an Src homology 2 domain tyrosine phosphatase 2–dependent manner and these PDGFRα‐enriched EVs participate in development of liver fibrosis. (Hepatology 2018;68:333‐348).

Model combining pre-transplant tumor biomarkers and tumor size shows more utility in predicting hepatocellular carcinoma recurrence and survival than the BALAD models

AIM To assess the performance of BALAD, BALAD-2 and their component biomarkers in predicting outcome of hepatocellular carcinoma (HCC) patients after liver transplant. METHODS BALAD score and BALAD-2 class are derived from bilirubin, albumin, alpha-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP (AFP-L3), and des-gamma-carboxyprothrombin (DCP). Pre-transplant AFP, AFP-L3 and DCP were measured in 113 patients transplanted for HCC from 2000 to 2008. Hazard ratios (HR) for recurrence and death were calculated. Univariate and multivariate regression analyses were conducted. C-statistics were used to compare biomarker-based to predictive models. RESULTS During a median follow-up of 12.2 years, 38 patients recurred and 87 died. The HRs for recurrence in patients with elevated AFP, AFP-L3, and DCP defined by BALAD cut-off values were 2.42 (1.18-5.00), 1.86 (0.98-3.52), and 2.83 (1.42-5.61), respectively. For BALAD, the HRs for recurrence and death per unit increased score were 1.48 (1.15-1.91) and 1.59 (1.28-1.97). For BALAD-2, the HRs for recurrence and death per unit increased class were 1.45 (1.06-1.98) and 1.38 (1.09-1.76). For recurrence prediction, the combination of three biomarkers had the highest c-statistic of 0.66 vs. 0.64, 0.61, 0.53, and 0.53 for BALAD, BALAD-2, Milan, and UCSF, respectively. Similarly, for death prediction, the combination of three biomarkers had the highest c-statistic of 0.66 vs 0.65, 0.61, 0.52, and 0.50 for BALAD, BALAD-2, Milan, and UCSF. A new model combining biomarkers with tumor size at the time of transplant (S-LAD) demonstrated the highest predictive capability with c-statistics of 0.71 and 0.69 for recurrence and death. CONCLUSION BALAD and BALAD-2 are valid in transplant HCC patients, but less predictive than the three biomarkers in combination or the three biomarkers in combination with maximal tumor diameter (S-LAD).

Blood stream infection is associated with cerebrovascular accident in patients with left ventricular assist device: a systematic review and meta-analysis

Cerebrovascular accident (CVA) is one of the major complications and a leading cause of death in patients with a left ventricular assist device (LVAD). Multiple studies of have shown that patients with blood stream infection (BSI) are more likely to develop CVA compared to patients without BSI. However, there is no meta-analysis to confirm this association. Studies were systematically acquired from MEDLINE and EMBASE electronic databases. Included studies assessed patients with heart failure requiring LVAD and reported the number of patients who had BSI post LVAD, incidence of ischemic CVA, hemorrhagic CVA, or any CVA. Pooled effect size was calculated with a random-effect model, weighted for the inverse of variance. Heterogeneity was assessed with I2. Six studies were analyzed. Participants with LVAD who developed BSI were more likely to have a CVA compared to participants without BSI (RR 3.43, 95% CI 2.49–4.72, I2 = 0). In four studies, there was an association between BSI and increased incidence of hemorrhagic CVA post LVAD (RR 5.28, 95% CI 2.65–10.53) with minimal heterogeneity (I2 = 30%). In three studies, participants with BSI were more likely to develop ischemic CVA (RR 2.18, 95% CI 1.23–3.84) compared to patients without BSI. This meta-analysis suggested that there maybe an association between blood stream infection and cerebrovascular accident in patients with LVAD.

Outcome and validation of a new clinically based staging system for predicting survival of perihilar cholangiocarcinoma patients: Clinical staging system for cholangiocarcinoma

Currently available staging systems for cholangiocarcinoma (CCA) are not applicable to patients with unresectable stage. A new clinical staging system for perihilar CCA (pCCA) subtype has been recently developed in a US cohort, with a good performance in predicting survival of all pCCA patients. We aimed to determine outcomes of pCCA patients and evaluate predictive performance of this staging system in an Asian population.