Biodistribution and inflammatory profiles of novel penton and hexon double-mutant serotype 5 adenoviruses

The use of adenovirus serotype 5 (Ad5) vectors in the clinical setting is severely hampered by the profound liver tropism observed after intravascular delivery coupled with the pronounced inflammatory and innate immune response elicited by these vectors. Liver transduction by circulating Ad5 virions is mediated by a high-affinity interaction between the capsid hexon protein and blood coagulation factor X (FX), whilst penton-α(v)integrin interactions are thought to contribute to the induction of anti-Ad5 inflammatory and innate immune responses. To overcome these limitations, we sought to develop and characterise for the first time novel Ad5 vectors possessing mutations ablating both hexon:FX and penton:integrin interactions. As expected, intravascular administration of the FX binding-ablated Ad5HVR5*HVR7*E451Q vector (AdT*) resulted in significantly reduced liver transduction in vivo compared to Ad5. In macrophage-depleted mice, increased spleen uptake of AdT* was accompanied by an elevation in the levels of several inflammatory mediators. However ablation of the penton RGD motif in the AdT* vector background (AdT*RGE) resulted in a significant 5-fold reduction in spleen uptake and attenuated the antiviral inflammatory response. A reduction in spleen uptake and inflammatory activation was also observed in animals after intravascular administration of Ad5RGE compared to the parental Ad5 vector, with reduced co-localisation of the viral beta-galactosidase transgene with MAdCAM-1+ sinus-lining endothelial cells. Our detailed assessment of these novel adenoviruses indicates that penton base RGE mutation in combination with FX binding-ablation may be a viable strategy to attenuate the undesired liver uptake and pro-inflammatory responses to Ad5 vectors after intravascular deliver

Evaluation of the Sublingual Route for Administration of Influenza H5N1 Virosomes in Combination with the Bacterial Second Messenger c-di-GMP

Avian influenza A H5N1 is a virus with pandemic potential. Mucosal vaccines are attractive as they have the potential to block viruses at the site of entry, thereby preventing both disease and further transmission. The intranasal route is safe for the administration of seasonal live-attenuated influenza vaccines, but may be less suitable for administration of pandemic vaccines. Research into novel mucosal routes is therefore needed. In this study, a murine model was used to compare sublingual administration with intranasal and intramuscular administration of influenza H5N1 virosomes (2 µg haemagglutinin; HA) in combination with the mucosal adjuvant (3′,5′)-cyclic dimeric guanylic acid (c-di-GMP). We found that sublingual immunisation effectively induced local and systemic H5N1-specific humoral and cellular immune responses but that the magnitude of response was lower than after intranasal administration. However, both the mucosal routes were superior to intramuscular immunisation for induction of local humoral and systemic cellular immune responses including high frequencies of splenic H5N1-specific multifunctional (IL-2+TNF-α+) CD4+ T cells. The c-di-GMP adjuvanted vaccine elicited systemic haemagglutination inhibition (HI) antibody responses (geometric mean titres ≥40) both when administered sublingually, intranasally and inramuscularly. In addition, salivary HI antibodies were elicited by mucosal, but not intramuscular vaccination. We conclude that the sublingual route is an attractive alternative for administration of pandemic influenza vaccines

A randomized trial of photoselective vaporization of the prostate using the 80-w potassium-titanyl-phosphate laser vs transurethral prostatectomy, with a 1-year follow-up

OBJECTIVE To compare the potassium-titanyl-phosphate GreenlightTM 80-W laser ablation system for photovaporization of the prostate (PVP; Laserscope, San Jose, CA, USA) with transurethral resection of the prostate (TURP), as many technologies have been proposed as equivalent or superior to TURP without gaining widespread acceptance, due to lack of data from randomized trials. PATIENTS AND METHODS In all, 120 patients were randomized to undergo either TURP or PVP after a full urological evaluation, which was repeated at 1, 3, 6 and 12 months after surgery. Irrigation use, duration of catheterization (DOC), length of hospital stay (LOS), blood loss, cost and operative time were also assessed. RESULTS Both groups showed a significant increase in mean (sd) maximum urinary flow rate from baseline (P < 0.05); in the TURP group from 8.9 (3.0) to 19.4 (8.7) mL/s (154%), and in the PVP group from 8.8 (2.5) to 18.6 (8.2) mL/s (136%). The International Prostate Symptom Score (IPSS) decreased from 25.4 (5.7) to 10.9 (9.4) in the TURP group (53%), and from 25.3 (5.9) to 8.9 (7.6) in the PVP group (61%). The trends were similar for the bother and Quality of Life scores. There was no difference in sexual function as measured by Baseline Sexual Function Questionnaires. The DOC was significantly less in the PVP than the TURP group (P < 0.001), with a mean (range) of 13 (0-24) h vs 44.7 (6-192) h. The situation was similar for LOS (P < 0.001), with a mean (range) of 1.09 (1-2) and 3.6 (3-9) days in the PVP and TURP groups, respectively. Adverse events and complications were less frequent in the PVP group. Costs were also 22% less in the PVP group. CONCLUSIONS This trial shows that PVP is an effective technique when compared to TURP, producing equivalent improvements in flow rates and IPSS with the advantages of markedly reduced LOS, DOC and adverse events. A long-term follow-up is being undertaken to ensure durability of these results

Corrigendum to "RPN (Radius, Position of tumour, iNvasion of renal sinus) Classification and Nephrometry Scoring System: An Internationally Developed Clinical Classification To Describe the Surgical Difficulty for Renal Masses for Which Robotic Partial Nephrectomy Is Planned" [Eur. Urol. Open Sci. 54 (2023) 33-42].

[This corrects the article DOI: 10.1016/j.euros.2023.05.007.]