Overexpression of wild-type HRAS drives non-alcoholic steatohepatitis to hepatocellular carcinoma in mice

Hepatocellular carcinoma(HCC),a prevalent solid carcinoma of significant concern,is an aggressive and often fatal disease with increasing global incidence rates and poor therapeutic outcomes.The etiology and pathological progression of non-alcoholic steatohepatitis(NASH)-related HCC is multifactorial and multistage.However,no single animal model can accurately mimic the full NASH-related HCC pathological progression,posing considerable challenges to transition and mechanistic studies.Herein,a novel conditional inducible wild-type human HRAS overexpressed mouse model(HRAS-HCC)was established,demonstrating 100%morbidity and mortality within approximately one month under normal dietary and lifestyle conditions.Advanced symptoms of HCC such as ascites,thrombus,internal hemorrhage,jaundice,and lung metastasis were successfully replicated in mice.In-depth pathological features of NASH-related HCC were demonstrated by pathological staining,biochemical analyses,and typical marker gene detections.Combined murine anti-PD-1 and sorafenib treatment effectively prolonged mouse survival,further confirming the accuracy and reliability of the model.Based on protein-protein interaction(PPI)network and RNA sequencing analyses,we speculated that overexpression of HRAS may initiate the THBS1-COL4A3 axis to induce NASH with severe fibrosis,with subsequent progression to HCC.Collectively,our study successfully duplicated natural sequential progression in a single murine model over a very short period,providing an accurate and reliable preclinical tool for therapeutic evaluations targeting the NASH to HCC continuum.

Advances in magnetic nanoparticle-based magnetic resonance imaging contrast agents

Magnetic resonance imaging(MRI)has revolutionized medical imaging diagnostics with the advantages of non-invasive nature,absence of ionizing radiation,unrestricted penetration depth,high-resolution imaging of soft tissues,organs and blood vessels,and multi-parameter and multi-sequence imaging.Contrast agents(CAs)are crucial for enhancing image quality,detecting molecular-level changes,and providing comprehensive diagnostic information in contrast enhanced MRI.However,the performance of clinical Gd-based CAs represents a limitation to the improvement of MRI sensitivity,specificity,and versatility,thereby impeding the achievement of satisfactory imaging outcomes.In recent years,the development of magnetic nanoparticle-based CAs has emerged as a promising avenue to enhance the capabilities of MRI.Here,we review the advances in magnetic nanoparticle-based MRI CAs,including blood pool CAs,biochemically-targeted CAs,stimulus-responsive CAs,and ultra-high field MRI CAs,as well as the use of CAs for cell labeling and tracking.Additionally,we offer insights into the future prospects and challenges associated with the integration of these nanoparticles into clinical practice.

Animal models for COVID-19:advances,gaps and perspectives

COVID-19,caused by SARS-CoV-2,is the most consequential pandemic of this century.Since the outbreak in late 2019,animal models have been playing crucial roles in aiding the rapid development of vaccines/drugs for prevention and therapy,as well as understanding the pathogenesis of SARS-CoV-2 infection and immune responses of hosts.However,the current animal models have some deficits and there is an urgent need for novel models to evaluate the virulence of variants of concerns(VOC),antibodydependent enhancement(ADE),and various comorbidities of COVID-19.This review summarizes the clinical features of COVID-19 in different populations,and the characteristics of the major animal models of SARS-CoV-2,including those naturally susceptible animals,such as non-human primates,Syrian hamster,ferret,minks,poultry,livestock,and mouse models sensitized by genetically modified,AAV/adenoviral transduced,mouse-adapted strain of SARS-CoV-2,and by engraftment of human tissues or cells.Since understanding the host receptors and proteases is essential for designing advanced genetically modified animal models,successful studies on receptors and proteases are also reviewed.Several improved alternatives for future mouse models are proposed,including the reselection of alternative receptor genes or multiple gene combinations,the use of transgenic or knock-in method,and different strains for establishing the next generation of genetically modified mice.