Objective The high global prevalence of adenovirus serotype 5(Ad5)infection,particularly in developing coun-tries,has led to widespread pre-existing neutralizing antibodies(NAbs)against this serotype.These NAbs may substantially im-pair the efficacy of Ad5-based therapeutics,necessitating the development of novel strategies to circumvent neutralizing antibody interference.Methods A novel Ad5-based vector was engineered via homologous recombination,wherein the hexon hypervari-able region(HVR)1,2,and 5 of Ad5 were strategically replaced with their counterparts from the less prevalent adenovirus sero-type 35(Ad35).This chimeric design aimed to reduce vector neutralization by Ad5-specific NAbs while preserving infectivi-ty.Results The hexon HVR-modified Ad5 vector exhibited reduced neutralization by pre-existing Ad5 antibodies while retai-ning efficient infectivity in tumor cells.In animal models,thesemodified vectors demonstrated excellent oncolyticability and still maintained strong tumor-killing activity in nude mice that received passive immunization with Ad5 neutralizing antibody ser-um.Conclusion The hexon HVR-modified Ad5 vectors demonstrate effective tumor infection rates and oncolytic efficacy in the presence of pre-existing Ad5 NAbs,suggesting promising clinical potential.

Objective The high global prevalence of adenovirus serotype 5(Ad5)infection,particularly in developing coun-tries,has led to widespread pre-existing neutralizing antibodies(NAbs)against this serotype.These NAbs may substantially im-pair the efficacy of Ad5-based therapeutics,necessitating the development of novel strategies to circumvent neutralizing antibody interference.Methods A novel Ad5-based vector was engineered via homologous recombination,wherein the hexon hypervari-able region(HVR)1,2,and 5 of Ad5 were strategically replaced with their counterparts from the less prevalent adenovirus sero-type 35(Ad35).This chimeric design aimed to reduce vector neutralization by Ad5-specific NAbs while preserving infectivi-ty.Results The hexon HVR-modified Ad5 vector exhibited reduced neutralization by pre-existing Ad5 antibodies while retai-ning efficient infectivity in tumor cells.In animal models,thesemodified vectors demonstrated excellent oncolyticability and still maintained strong tumor-killing activity in nude mice that received passive immunization with Ad5 neutralizing antibody ser-um.Conclusion The hexon HVR-modified Ad5 vectors demonstrate effective tumor infection rates and oncolytic efficacy in the presence of pre-existing Ad5 NAbs,suggesting promising clinical potential.

Signal transducer and activator of transcription 3 (STAT3) and Chemokine CX3C ligand 1 (Fractalkine/CX3CL1) play important roles in vascular inflammation and injury. To study if STAT3 promotes vascular endothelial cell proliferation and migration through fractalkine, we overexpressed or knocked down STAT3 in vascular endothelial cells, and used quantitative real-time PCR and Western blotting to determine the effect of STAT3 on fractalkine expression. The wild type and STAT3 binding site mutant fractalkine promoter luciferase reporter plasmids were constructed, and luciferase activity assays were used to explore the effect of STAT3 on the transcriptional activity of the fractalkine promoter. MTT assays were used to detect the effect of overexpression or knockdown of STAT3 or fractalkine on the proliferation rate of vascular endothelial cells. Scratch assays were used to detect the effect of overexpression or knockdown of STAT3 or fractalkine on vascular endothelial cell migration. There results showed that overexpression of STAT3 could promote fractalkine expression, and knockdown of STAT3 could down-regulate fractalkine expression. STAT3 could directly bind to the promoter of fractalkine to promote its transcriptional activity via binding the GAS site of the fractalkine promoter. Knockdown of STAT3 could inhibit the migration of vascular endothelial cell, and overexpression of fractalkine antagonized this inhibition. Our data concluded that STAT3 promotes the proliferation and migration of vascular endothelial cell by binding the GAS site of the fractalkine promoter to promote fractalkine transcriptional activity and expression.
Cell Proliferation ; Chemokine CX3CL1 ; Endothelial Cells ; Promoter Regions, Genetic ; STAT3 Transcription Factor