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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.

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.

Content available: Author Interview and Audio Recording.

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

In the background of chronic liver disease, hepatocellular carcinoma develops via a complex, multistep process called hepatocarcinogenesis. This article reviews the causes contributing to the process. Emphasis is made on the imaging manifestations of the pathologic changes seen at many stages of hepatocarcinogenesis, from regenerative nodules to dysplastic nodules and then to hepatocellular carcinoma.

INTRODUCTION/BACKGROUND:Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 virus, is a predominantly respiratory tract infection with the capacity to affect multiple organ systems. Abnormal liver tests, mainly transaminase elevations, have been reported in hospitalized patients. We describe a syndrome of cholangiopathy in patients recovering from severe COVID-19 characterized by marked elevation in serum alkaline phosphatase (ALP) accompanied by evidence of bile duct injury on imaging. METHODS:We conducted a retrospective study of COVID-19 patients admitted to our institution from March 1, 2020, to August 15, 2020, on whom the hepatology service was consulted for abnormal liver tests. Bile duct injury was identified by abnormal liver tests with serum ALP > 3x upper limit of normal and abnormal findings on magnetic resonance cholangiopacreatography. Clinical, laboratory, radiological, and histological findings were recorded in a Research Electronic Data Capture database. RESULTS:Twelve patients were identified, 11 men and 1 woman, with a mean age of 58 years. Mean time from COVID-19 diagnosis to diagnosis of cholangiopathy was 118 days. Peak median serum alanine aminotransferase was 661 U/L and peak median serum ALP was 1855 U/L. Marked elevations of erythrocyte sedimentation rate, C-reactive protein, and D-dimers were common. Magnetic resonance cholangiopacreatography findings included beading of intrahepatic ducts (11/12, 92%), bile duct wall thickening with enhancement (7/12, 58%), and peribiliary diffusion high signal (10/12, 83%). Liver biopsy in 4 patients showed acute and/or chronic large duct obstruction without clear bile duct loss. Progressive biliary tract damage has been demonstrated radiographically. Five patients were referred for consideration of liver transplantation after experiencing persistent jaundice, hepatic insufficiency, and/or recurrent bacterial cholangitis. One patient underwent successful living donor liver transplantation. DISCUSSION/CONCLUSIONS:Cholangiopathy is a late complication of severe COVID-19 with the potential for progressive biliary injury and liver failure. Further studies are required to understand pathogenesis, natural history, and therapeutic interventions.

Bodies have continuous reticular networks, comprising collagens, elastin, glycosaminoglycans, and other extracellular matrix components, through all tissues and organs. Fibrous coverings of nerves and blood vessels create structural continuity beyond organ boundaries. We recently validated fluid flow through human fibrous tissues, though whether these interstitial spaces are continuous through the body or discontinuous, confined within individual organs, remains unclear. Here we show evidence for continuity of interstitial spaces using two approaches. Non-biological particles (tattoo pigment, colloidal silver) were tracked within colon and skin interstitial spaces and into adjacent fascia. Hyaluronic acid, a macromolecular component of interstitial spaces, was also visualized. Both techniques demonstrate interstitial continuity within and between organs including within perineurium and vascular adventitia traversing organs and the spaces between them. We suggest that there is a body-wide network of fluid-filled interstitial spaces that has significant implications for molecular signaling, cell trafficking, and the spread of malignant and infectious disease.