Human quad liver-on-chip system as a tool toward bridging the gap between animals and humans regarding toxicology and pharmacology of a cannabidiol-rich cannabis extract.

Cannabidiol (CBD) is a major phytocannabinoid from . It is currently widely available and widely used in the USA, but despite its rapid progress to market, the pharmacology and toxicology of both CBD and cannabidiol-rich cannabis extracts (CRCE) remain largely unknown. The goals of this study were to investigate the potential of a novel human microphysiological system to emulate CRCE-induced hepatotoxicity and pharmacological properties demonstrated in animal models.

Inter-strain variability in responses to a single administration of the cannabidiol-rich cannabis extract in mice.

Cannabidiol (CBD) has gained widespread popularity; however, its pharmacological and toxicological profiles in the context of human genetic diversity remain largely unexplored. Here, we investigated the variability in metabolism and toxicity of CBD-rich cannabis extract (CRCE) in genetically diverse mouse models: C57BL/6J, B6C3F/J, and NZO/HlLtJ strains. Mice received a single dose of CRCE containing 57.

Hepatic pyruvate and alanine metabolism are critical and complementary for maintenance of antioxidant capacity and resistance to oxidative insult.

Objective: Mitochondrial pyruvate is a critical intermediary metabolite in gluconeogenesis, lipogenesis, and NADH production. As a result, the mitochondrial pyruvate carrier (MPC) complex has emerged as a promising therapeutic target in metabolic diseases. Clinical trials are currently underway.

Budesonide, an anti-inflammatory drug, exacerbate clostridioides difficile colitis in mice.

Background And Aims: Clostridioides difficile infection (CDI) induces intense acute inflammatory responses through toxin release. A combination of antibiotic and anti-inflammatory agents is sometimes recommended in severe, non-responsive cases, although clinical trials have been inconclusive, raising concerns about potential complications. This study aims to investigate the effect of budesonide and mesalamine in the treatment of CDI in a murine model, by evaluating the combination of fidaxomicin and these anti-inflammatory drugs.

Impacts of Transitioning to an Online Curriculum at a Graduate School in South Korea Due to the COVID-19 Pandemic.

This study focuses on the impacts of implementing an online curriculum at a graduate school in South Korea in response to the COVID-19 pandemic. A framework distinguishing impacts to academic, educational, and institutional stakeholders from the virtualization of curricula as well as general COVID-19 prevention measures is invoked to help understand the impacts of these changes. These impacts are sourced from general graduate school operations, course evaluations for two compulsory courses, and unofficial interviews with students and professors.

Radiation Effects on Methamphetamine Pharmacokinetics and Pharmacodynamics in Rats.

Background And Objectives: Whole-body radiation exposure has been shown to alter the pharmacokinetics of certain drugs in both animal models and humans, but little is known about the effect of radiation on psychoactive medications. These drugs may have altered pharmacokinetics when administered during or after space travel or therapeutic or accidental radiation exposure, resulting in reduced efficacy or increased toxicity.

Methods: Methamphetamine was used to determine the effects of acutely administered 1, 3, and 6 Gy radiation on drug pharmacokinetics and pharmacodynamics.

Exogenous phosphatidic acid reduces acetaminophen-induced liver injury in mice by activating hepatic interleukin-6 signaling through inter-organ crosstalk.

We previously demonstrated that endogenous phosphatidic acid (PA) promotes liver regeneration after acetaminophen (APAP) hepatotoxicity. Here, we hypothesized that exogenous PA is also beneficial. To test that, we treated mice with a toxic APAP dose at 0 h, followed by PA or vehicle (Veh) post-treatment.

Adenosine deaminase 2 produced by infiltrative monocytes promotes liver fibrosis in nonalcoholic fatty liver disease.

Elevated circulating activity of adenosine deaminase 2 (ADA2) is associated with liver fibrosis in nonalcoholic fatty liver disease (NAFLD). In the liver of NAFLD patients, ADA2-positive portal macrophages are significantly associated with the degree of liver fibrosis. These liver macrophages are CD14- and CD16-positive and co-express chemokine receptors CCR2, CCR5, and CXCR3, indicating infiltrative monocyte origin.

Multi-Class Cell Detection Using Spatial Context Representation.

In digital pathology, both detection and classification of cells are important for automatic diagnostic and prognostic tasks. Classifying cells into subtypes, such as tumor cells, lymphocytes or stromal cells is particularly challenging. Existing methods focus on morphological appearance of individual cells, whereas in practice pathologists often infer cell classes through their spatial context.

Characterizing T2 iso- and hypo-intense renal masses on MRI: Can templated algorithms improve accuracy?

Purpose: To assess if a templated algorithm can improve the diagnostic performance of MRI for characterization of T2 isointense and hypointense renal masses.

Methods: In this retrospective study, 60 renal masses with histopathologic diagnoses that were also confirmed as T2 iso- or hypointense on MRI were identified (mean ± standard deviation, range: 3.9 ± 2.

Dietary Methionine Supplementation Exacerbates Gastrointestinal Toxicity in a Mouse Model of Abdominal Irradiation.

Background And Purpose: Identification of appropriate dietary strategies for prevention of weight and muscle loss in cancer patients is crucial for successful treatment and prolonged patient survival. High-protein oral nutritional supplements decrease mortality and improve indices of nutritional status in cancer patients; however, high-protein diets are often rich in methionine, and experimental evidence indicates that a methionine-supplemented diet (MSD) exacerbates gastrointestinal toxicity after total body irradiation. Here, we sought to investigate whether MSD can exacerbate gastrointestinal toxicity after local abdominal irradiation, an exposure regimen more relevant to clinical settings.

Epithelial Cell Biomarkers Are Predictive of Response to Biologic Agents in Crohn's Disease.

Background: Therapeutic efficacy of biologics has remained at about 50% for 2 decades. In Crohn's disease (CD) patients, we examined the predictive value of an epithelial cell biomarker, ileal microvillar length (MVL), for clinical response to ustekinumab (UST) and vedolizumab (VDZ) and its relationship to another biomarker, intestinal epithelial cell (IEC) pyroptosis, with respect to response to VDZ.

Method: Ileal biopsies from the UNITI-2 randomized controlled trial were analyzed for MVL as a predictor of clinical response to UST.

Clostridioides difficile Toxin A Remodels Membranes and Mediates DNA Entry Into Cells to Activate Toll-Like Receptor 9 Signaling.

Background & Aims: Clostridioides difficile toxin A (TcdA) activates the innate immune response. TcdA co-purifies with DNA. Toll-like receptor 9 (TLR9) recognizes bacterial DNA to initiate inflammation.

Potential Probiotic or Trigger of Gut Inflammation - The Janus-Faced Nature of Cannabidiol-Rich Cannabis Extract.

Cannabidiol (CBD) is the major non-psychotropic phytocannabinoid present in . In 2018, Congress designated certain plant material as "hemp," thus removing it from the DEA's list of controlled substances. As a result, CBD-containing hemp extracts and other CBD products are now widely available and heavily marketed, yet their FDA regulatory status is still hotly debated.

Endoscopic ultrasound guided liver biopsy: Recent evidence.

Liver biopsy (LB) is an essential tool in diagnosing, evaluating and managing various diseases of the liver. As such, histopathological results are critical as they establish or aid in diagnosis, provide information on prognosis, and guide the appropriate selection of medical therapy for patients. Indications for LB include evaluation of persistent elevation of liver chemistries of unclear etiology, diagnosis of chronic liver diseases such as Wilson's disease, autoimmune hepatitis, small duct primary sclerosing cholangitis, work up of fever of unknown origin, amyloidosis and more.

Identification of Serum Biomarkers to Distinguish Hazardous and Benign Aminotransferase Elevations.

The standard circulating biomarker of liver injury in both clinical settings and drug safety testing is alanine aminotransferase (ALT). However, ALT elevations sometimes lack specificity for tissue damage. To identify novel serum biomarkers with greater specificity for injury, we combined unique animal models with untargeted proteomics, followed by confirmation with immunoblotting.

Mucosal Biomarker of Innate Immune Activation Predicts Response to Vedolizumab in Crohn's Disease.

Objective: Mucosal barrier dysfunction plays a crucial role in intestinal inflammation in Crohn's disease (CD). Intestinal epithelial cell (IEC) death resulting from innate immune activation, termed pyroptosis, was recently found to be a cause of this barrier defect. The aim of this study was to determine the predictive value of pretreatment ileal biopsy pyroptosis as a biomarker for clinical response to vedolizumab in CD.

Paradoxical Patterns of Sinusoidal Obstruction Syndrome-Like Liver Injury in Aged Female CD-1 Mice Triggered by Cannabidiol-Rich Cannabis Extract and Acetaminophen Co-Administration.

The goal of this study was to investigate the potential for a cannabidiol-rich cannabis extract (CRCE) to interact with the most common over-the-counter drug and the major known cause of drug-induced liver injury-acetaminophen (APAP)-in aged female CD-1 mice. Gavaging mice with 116 mg/kg of cannabidiol (CBD) [mouse equivalent dose (MED) of 10 mg/kg of CBD] in CRCE delivered with sesame oil for three consecutive days followed by intraperitoneally (i.p.

Multispectral light scattering endoscopic imaging of esophageal precancer.

Esophageal adenocarcinoma is the most rapidly growing cancer in America. Although the prognosis after diagnosis is unfavorable, the chance of a successful outcome increases tremendously if detected early while the lesion is still dysplastic. Unfortunately, the present standard-of-care, endoscopic surveillance, has major limitations, since dysplasia is invisible, often focal, and systematic biopsies typically sample less than one percent of the esophageal lining and therefore easily miss malignancies.

Intraobserver and Interobserver Variability in the Assessment of Dysplasia in Ampullary Mucosal Biopsies.

Endoscopic mucosal biopsies of the ampulla of Vater (AmpBx) are obtained to histologically assess for dysplasia or carcinoma. However, biopsy material is often scant and a host of factors can induce histologic changes that pose diagnostic challenges. We sought to investigate observer variability in interpretation of AmpBx and the impact clinical data may have on diagnostic interpretation.

ZIP4 Promotes Pancreatic Cancer Progression by Repressing ZO-1 and Claudin-1 through a ZEB1-Dependent Transcriptional Mechanism.

ZIP4 is overexpressed in human pancreatic cancer and promotes tumor growth. However, little is known about the role of ZIP4 in advanced stages of this dismal neoplasm. Our goal is to study the underlying mechanism and define a novel signaling pathway controlled by ZIP4-modulating pancreatic tumor metastasis.

Pathologic Features of Infectious Gastritis.

This manuscript presents a review of infectious causes of gastritis aimed at the practicing anatomic pathologist. We shall highlight unique histologic findings and clinical attributes that will assist those analyzing endoscopically obtained mucosal biopsies of the stomach or resection specimens.

Prediction of the histopathologic findings of intrahepatic cholangiocarcinoma: qualitative and quantitative assessment of diffusion-weighted imaging.

Objective: To correlate qualitative and quantitative diffusion weighted imaging (DWI) characteristics of intrahepatic cholangiocarcinoma (ICC) with histopathologic tumour grade and fibrosis content.

Methods: Fifty-one patients (21M/30F; mean age 61y) with ICC and MRI including DWI were included in this IRB-approved multicentre retrospective study. Qualitative tumour features were assessed.

Distinct roles of ecto-nucleoside triphosphate diphosphohydrolase-2 (NTPDase2) in liver regeneration and fibrosis.

Ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDases) are cell surface-located transmembrane ecto-enzymes of the CD39 superfamily which regulate inflammation and tissue repair by catalyzing the phosphohydrolysis of extracellular nucleotides and modulating purinergic signaling. In the liver, NTPDase2 is reportedly expressed on portal fibroblasts, but its functional role in regulating tissue regeneration and fibrosis is incompletely understood. Here, we studied the role of NTPDase2 in several models of liver injury using global knockout mice.