Citations

AbstractThe Hippo pathway effector YAP is implicated in the pathogenesis of cholangiocarcinoma (CCA). The Hippo pathway relies on signaling cross talk for its regulation. Given the importance of platelet derived growth factor receptor (PDGFR) signaling in CCA biology, our aim was to examine potential YAP regulation by PDGFR. We employed human and mouse CCA specimens and cell lines for these studies. Initially, we confirmed upregulation of PDGFRβ and PDGFR ligands in human and mouse CCA specimens and cell lines. YAP, a transcriptional co‐activator, was localized to the nucleus in human CCA specimens and a cell line, as well as patient derived xenografts (PDX). PDGFR pharmacologic inhibition led to a redistribution of YAP from the nucleus to cytosol and downregulation of YAP target genes in a human CCA cell line. siRNA silencing of PDGFR‐β similarly downregulated YAP target genes. YAP activation (nuclear localization and target gene expression) was regulated by Src family kinases (SFKs) downstream of PDGFR. SFK activity resulted in phosphorylation of YAP on tyrosine357 (YAPY357). The importance of YAPY357 phosphorylation in regulating YAP activation was confirmed utilizing the SB‐1 cell line, a mouse cell line expressing YAP S127A precluding canonical serine phosphorylation. PDGFR inhibition decreased cellular abundance of the survival protein Mcl‐1, a known YAP target gene, and accordingly increased cell death in CCA cells in vitro and in vivo. These preclinical data demonstrate that a PDGFR‐SFK cascade regulates YAP activation via tyrosine phosphorylation in CCA. Inhibiting this cascade may provide a viable therapeutic strategy for this human malignancy.

AbstractBackground & AimsHepatocellular carcinoma (HCC) is the second leading cause of cancer‐related death worldwide. Most studies addressing the epidemiology of HCC originate from developed countries. This study reports the preliminary findings of a multinational approach to characterize HCC in South America.MethodsWe evaluated 1336 HCC patients seen at 14 centres in six South American countries using a retrospective study design with participating centres completing a template chart of patient characteristics. The diagnosis of HCC was made radiographically or histologically for all cases according to institutional standards. Methodology of surveillance for each centre was following AASLD or EASL recommendations.ResultsSixty‐eight percent of individuals were male with a median age of 64 years at time of diagnosis. The most common risk factor for HCC was hepatitis C infection (HCV, 48%), followed by alcoholic cirrhosis (22%), Hepatitis B infection (HBV, 14%) and NAFLD (9%). We found that among individuals with HBV‐related HCC, 38% were diagnosed before age 50. The most commonly provided therapy was transarterial chemoembolization (35% of HCCs) with few individuals being considered for liver transplant (<20%). Only 47% of HCCs were diagnosed during surveillance, and there was no difference in age of diagnosis between those diagnosed incidentally vs by surveillance. Nonetheless, being diagnosed during surveillance was associated with improved overall survival (P = .01).ConclusionsOur study represents the largest cohort to date reporting characteristics and outcomes of HCC across South America. We found an important number of HCCs diagnosed outside of surveillance programmes, with associated increased mortality in those patients.

Objective: To evaluate the relationship between donor sex and hepatocellular carcinoma (HCC) recurrence after living donor liver transplantation. Background: HCC shows a male predominance in incidence and recurrence after tumor resection due to sex differences in hepatic sex hormone receptors. There have been no studies evaluating the importance of donor sex on post-transplant HCC recurrence. Methods: Of 384 recipients of livers, from living donors, for HCC: 104/120 who received grafts from female donors were matched with 246/264 who received grafts from male donors using propensity score matching, with an unfixed matching ratio based on factors like tumor biology. Survival analysis was performed with death as a competing risk event. The primary outcome was overall HCC recurrence. Results: The median follow-up time was 39 months. Before matching, recurrence probability at 1/2/5 years after transplantation was 6.1/9.7/12.7% in recipients with female donors and 11.7/19.2/25.3% in recipients with male donors. Recurrence risk was significantly higher with male donors in univariable analysis (hazard ratio [HR] = 2.04 [1.15–3.60], P = 0.014) and multivariable analysis (HR=2.10 [1.20–3.67], P = 0.018). In the matched analysis, recurrence risk was also higher with male donors (HR=1.92 [1.05–3.52], P = 0.034): both in intrahepatic recurrence (HR=1.92 [1.05–3.51], P = 0.034) and extrahepatic recurrence (HR=1.93 [1.05–3.52], P = 0.033). Multivariable analysis confirmed the significance of donor sex (HR=2.08 [1.11–3.91], P = 0.023). Interestingly, the significance was lost when donor age was >40 years. Two external cohorts validated the significance of donor sex. Conclusions: Donor sex appears to be an important graft factor modulating HCC recurrence after living donor liver transplantation.

AbstractNeurogenesis in the subependymal zone (SEZ) declines across the human lifespan, and reduced local neurotrophic support is speculated to be a contributing factor. While tyrosine receptor kinase B (TrkB) signalling is critical for neuronal differentiation, maturation and survival, little is known about subependymal TrkB expression changes during postnatal human life. In this study, we used quantitative PCR and in situ hybridisation to determine expression of the cell proliferation marker Ki67, the immature neuron marker doublecortin (DCX) and both full‐length (TrkB‐TK+) and truncated TrkB receptors (TrkB‐TK‐) in the human SEZ from infancy to middle age (n = 26–35, 41 days to 43 years). We further measured TrkB‐TK+ and TrkB‐TK‐ mRNAs in the SEZ from young adulthood into ageing (n = 50, 21–103 years), and related their transcript levels to neurogenic and glial cell markers. Ki67, DCX and both TrkB splice variant mRNAs significantly decreased in the SEZ from infancy to middle age. In contrast, TrkB‐TK‐ mRNA increased in the SEZ from young adulthood into ageing, whereas TrkB‐TK+ mRNA remained stable. TrkB‐TK‐ mRNA positively correlated with expression of neural precursor (glial fibrillary acidic protein delta and achaete‐scute homolog 1) and glial cell markers (vimentin and pan glial fibrillary acidic protein). TrkB‐TK+ mRNA positively correlated with expression of neuronal cell markers (DCX and tubulin beta 3 class III). Our results indicate that cells residing in the human SEZ maintain their responsiveness to neurotrophins; however, this capability may change across postnatal life. We suggest that TrkB splice variants may differentially influence neuronal and glial differentiation in the human SEZ.

Shear wave elasticity imaging determines the mechanical parameters of soft tissue by analyzing measured shear waves induced by an acoustic radiation force. Currently, the widely used time-of-flight method calculates the correlation between shear waveforms at adjacent lateral observation points to estimate the shear elasticity value. Although this method provides accurate estimates of the shear elasticity in purely elastic media, our experience suggests that this approach overestimates the shear elasticity values in viscoelastic media because the effects of diffraction, attenuation, and dispersion are not taken into account. To address this problem, we have developed an approach that directly accounts for all of these effects when estimating the shear elasticity. This new approach simulates shear waveforms using a Green’s function-based approach with a Voigt model, while the shear elasticity and viscosity values are estimated using an optimization-based approach by comparing measured shear waveforms with simulated shear waveforms in the time-domain. This operation is then performed on a point-by-point basis to generate images. The results indicate that there is good agreement between the simulated and measured shear velocity waveforms, and that this approach yields improved images of the shear elasticity and shear viscosity. [Work supported, in part, by NIH Grant R01DK092255.]

Summary Hepatitis B virus ( HBV ) infection in the United States is the most common among Asians followed by non‐Hispanic blacks. However, there have been few studies that describe HBV infection and immunity by racial group. Our study aimed to assess racial/ethnic disparities in the prevalence and awareness of HBV infection and immunity using nationally representative data. In the National Health and Nutrition Examination Survey 2011‐2014, 14 722 persons had HBV serology testing. We estimated the prevalence of HBV infection, past exposure, and immunity by selected characteristics and calculated adjusted odds ratios using survey‐weighted generalized logistic regression. Awareness of infection and vaccination history was also investigated. The overall prevalence of chronic HBV infection, past exposure and vaccine‐induced immunity was 0.34% [95% CI 0.24‐0.43], 4.30% [95% CI 3.80‐4.81], and 24.4% [95% CI 23.4‐25.4], respectively. The prevalence of chronic infection was 2.74% [95% CI 1.72‐3.76] in Asians, 0.64% [95% CI 0.35‐0.92] in non‐Hispanic blacks, and 0.15% [95% CI 0.06‐0.24] in non‐Asian, non‐blacks. Only 26.2% of those with chronic infection were aware of their infection. The prevalence of the past exposure was 21.5% [95% CI 19.3‐23.7] in Asians, 8.92% [95% CI 7.84‐9.99] in non‐Hispanic blacks, 2.05% [95% CI 1.49‐2.63] in non‐Hispanic whites and 4.47% [95% CI 3.25‐5.70] in Hispanics. Prevalence of vaccine‐induced immunity by each race was 34.1% [95% CI : 32.0‐36.2] in Asians, 25.5% [95% CI : 24.0‐27.0] in non‐Hispanic blacks, 24.0% [95% CI : 22.6‐25.4] in non‐Hispanic whites and 22.2% [95% CI : 21.3‐23.3] in Hispanics. There are considerable racial/ethnic disparities in HBV infection, exposure and immunity. More active and sophisticated healthcare policies on HBV management may be warranted.

ObjectivesTo develop and validate a nomogram to estimate the pretest probability of malignancy in Chinese patients with solid solitary pulmonary nodule (SPN).Materials and MethodsA primary cohort of 1798 patients with pathologically confirmed solid SPNs after surgery was retrospectively studied at five institutions from January 2014 to December 2015. A nomogram based on independent prediction factors of malignant solid SPN was developed. Predictive performance also was evaluated using the calibration curve and the area under the receiver operating characteristic curve (AUC).ResultsThe mean age of the cohort was 58.9 ± 10.7 years. In univariate and multivariate analysis, age; history of cancer; the log base 10 transformations of serum carcinoembryonic antigen value; nodule diameter; the presence of spiculation, pleural indentation, and calcification remained the predictive factors of malignancy. A nomogram was developed, and the AUC value (0.85; 95%CI, 0.83‐0.88) was significantly higher than other three models. The calibration cure showed optimal agreement between the malignant probability as predicted by nomogram and the actual probability.ConclusionsWe developed and validated a nomogram that can estimate the pretest probability of malignant solid SPNs, which can assist clinical physicians to select and interpret the results of subsequent diagnostic tests.