Faculty Bibliography

BACKGROUND:F-THK5117, we previously reported that the ventricular CSF clearance of the PET tracer was reduced in AD and associated with elevated brain Aβ levels. METHODS:C-PiB to estimate CSF clearance calculated from early dynamic PET frames in 9 normal controls and 15 AD participants. RESULTS:F-THK5351) and brain Aβ load (r =  - 0.64, n = 24, p < 0.01). With a larger sample size, we extended our observations to show that reduced CSF clearance is associated with reductions in cortical thickness and cognitive performance. CONCLUSIONS:Overall, the findings support the hypothesis that failed CSF clearance is a feature of AD that is related to Aβ deposition and to the pathology of AD. Longitudinal studies are needed to determine whether failed CSF clearance is a predictor of progressive amyloidosis or its consequence.

AIMS/OBJECTIVE:Lymphoepithelioma-like carcinomas (LELCs) are uncommon epithelial cancers characteristically showing two distinct components consisting of malignant epithelial cells and prominent dense lymphoid infiltrate. Hepatic LELCs consist of two types, the lymphoepithelioma-like hepatocellular carcinoma and lymphoepithelioma-like cholangiocarcinoma (LEL-CCA), with the latter being strongly associated with Epstein-Barr virus (EBV). METHODS AND RESULTS/RESULTS:We present a series of three cases of intrahepatic biliary EBV-associated LEL tumours in which the biliary epithelial component showed a distinctly benign appearance, instead of the usual malignant epithelial features of a typical CCA or EBV-associated LEL-CCA. In the lesions, the biliary epithelium showed interconnecting glands or cords of cells. All had a very low proliferation (Ki-67) index. Immunohistochemistry for IDH1 and TP53 performed on two cases was negative and molecular tests for EGFR and KRAS gene mutations performed on one were negative. Prognosis was very good in all three cases, with patients alive with no evidence of disease 24-62 months after surgery. Intriguingly, all three cases had co-infection of HBV and EBV. These cases are also discussed in the context of the 63 cases of LEL-CCA available in the literature, with a focus on epidemiology, clinicopathological features and potential research interests. CONCLUSIONS:Based on the distinct clinicopathological features and unique survival benefits, we believe these tumours represent the benign end of the spectrum of EBV-associated lymphoepithelial biliary carcinomas. Whether these tumours require a revision of the current nomenclature to 'lymphoepithelioma-like neoplasm of the biliary tract with probable low malignant potential' will require more detailed analysis with larger case-series.

Despite significant research efforts, treatment options for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain limited. This is due in part to a lack of therapeutics that increase host defense to the virus. Replication of SARS-CoV-2 in lung tissue is associated with marked infiltration of macrophages and activation of innate immune inflammatory responses that amplify tissue injury. Antagonists of the androgen (AR) and glucocorticoid (GR) receptors have shown efficacy in models of COVID-19 and in clinical studies because the cell surface proteins required for viral entry, angiotensin converting enzyme 2 (ACE2) and the transmembrane protease, serine 2 (TMPRSS2), are transcriptionally regulated by these receptors. We postulated that the GR and AR modulator, PT150, would reduce infectivity of SARS-CoV-2 and prevent inflammatory lung injury in the Syrian golden hamster model of COVID-19 by down-regulating expression of critical genes regulated through these receptors. Animals were infected intranasally with 2.5 × 10⁴ TCID₅₀/ml equivalents of SARS-CoV-2 (strain 2019-nCoV/USA-WA1/2020) and PT150 was administered by oral gavage at 30 and 100 mg/Kg/day for a total of 7 days. Animals were examined at 3, 5 and 7 days post-infection (DPI) for lung histopathology, viral load and production of proteins regulating the progression of SARS-CoV-2 infection. Results indicated that oral administration of PT150 caused a dose-dependent decrease in replication of SARS-CoV-2 in lung, as well as in expression of ACE2 and TMPRSS2. Lung hypercellularity and infiltration of macrophages and CD4⁺ T-cells were dramatically decreased in PT150-treated animals, as was tissue damage and expression of IL-6. Molecular docking studies suggest that PT150 binds to the co-activator interface of the ligand-binding domain of both AR and GR, thereby acting as an allosteric modulator and transcriptional repressor of these receptors. Phylogenetic analysis of AR and GR revealed a high degree of sequence identity maintained across multiple species, including humans, suggesting that the mechanism of action and therapeutic efficacy observed in Syrian hamsters would likely be predictive of positive outcomes in patients. PT150 is therefore a strong candidate for further clinical development for the treatment of COVID-19 across variants of SARS-CoV-2.

Background: Glisson's capsule is the layer of connective tissue that surrounds the liver. During fibrosis, mesothelial cells from this layer migrate inwards into the liver and contribute to the myofibroblast population and to the progression of liver fibrosis1. Changes to the capsule itself are less well understood. An increase in capsule thickness in alcoholic cirrhosis and HCV has been reported2. The aim of this study was to characterize the changes in the matrix components of the capsule and to determine whether these correlate with severity of disease or etiology.
Method(s): Human liver samples were collected from autopsies and liver transplants. Collagen, hyaluronic acid and proteoglycans were assessed by immunohistochemistry. Elastic fibers were assessed by Van Gieson staining. Collagen organization was visualized using 3D second harmonic generation imaging.
Result(s): We examined 12 normal samples, 5 mild to moderate steatosis samples and 15 cirrhotic samples from patients with variety of disease etiologies including NASH, PSC, HCV and ethanol induced cirrhosis. Capsule thickness was significantly increased in cirrhotic patient samples compared to normal controls irrespective of the etiology (69.62 +/- 9.99 and 171.269 +/- 16.65 mum mean +/- SEM respectively), but mild to moderate steatosis had no effect on thickness (62.15 +/- 4.97 mean +/- SEM). There was an increase in collagen, hyaluronic acid and elastic fiber deposition. In normal and in mild to moderate steatosis, collagen fiber width significantly decreased in the inner layers of the capsule (outer 5.74 +/- 0.095, inner 4.98 +/-0.099 and outer 5.55 +/- 0.14, inner 4.8 +/- 0.13 nm mean +/- SEM respectively) . This change however is lost in cirrhotic samples and collagen width remains relatively thick (outer 5.69 +/- 0.091, inner 5.3 +/- 0.12 nm mean +/- SEM). 3D collagen organization is also altered in cirrhosis. In the normal human liver, collagen is organized into layered sheets of one orientation with limited overlap between different orientations; however, in cirrhotic samples, this is disrupted and considerable overlap is observed between different fiber orientations.
Conclusion(s): The composition and organization of key matrix components is significantly changed in Glisson's capsule in cirrhotic patients, but not patients with mild to moderate steatosis. These changes likely impact the stiffness and other mechanics of the capsule, particularly its ability to expand in response to changes in liver blood flow. Work is ongoing to characterize capsule mechanics, but the work here makes clear that altered matrix content and organization in cirrhosis is not limited to the parenchyma of the liver. 1. Li Y, Wang J, Asahina K. Proc Natl Acad Sci U S A. 2013;110(6):2324-2329. doi:10.1073/pnas.1214136110 2. Balog S, Li Y, Ogawa T, et al. Hepatology. 2020;71(1):291-305. doi:10.1002/hep.30809

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Hepatocellular carcinoma (HCC) is a malignancy with variable biologic aggressiveness based on the tumor grade, presence or absence of vascular invasion, and pathologic and molecular classification. Knowledge and understanding of the prognostic implications of different pathologic and molecular phenotypes of HCC are emerging, with therapeutics that promise to provide improved outcomes in what otherwise remains a lethal cancer. Imaging has a central role in diagnosis of HCC. However, to date, the imaging algorithms do not incorporate prognostic features or subclassification of HCC according to its biologic aggressiveness. Emerging data suggest that some imaging features and further radiologic, pathologic, or radiologic-molecular phenotypes may allow prediction of the prognosis of patients with HCC. An invited commentary by Bashir is available online. Online supplemental material is available for this article. ^©RSNA, 2021.