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Background: Previous studies have demonstrated enhanced efficacy of vaccine formulations that incorporate the chemokine macrophage inflammatory protein 3α (MIP-3α) to direct vaccine antigens to immature dendritic cells. To address the reduction in vaccine efficacy associated with a mutation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutants, we have examined the ability of receptor-binding domain vaccines incorporating MIP-3α to sustain higher concentrations of antibody when administered intramuscularly (IM) and to more effectively elicit lung T-cell responses when administered intranasally (IN). Methods: BALB/c mice aged 6-8 weeks were immunized intramuscularly or intranasally with DNA vaccine constructs consisting of the SARS-CoV-2 receptor-binding domain alone or fused to the chemokine MIP-3α. In a small-scale (n = 3/group) experiment, mice immunized IM with electroporation were followed up for serum antibody concentrations over a period of 1 year and for bronchoalveolar antibody levels at the termination of the study. Following IN immunization with unencapsulated plasmid DNA (n = 6/group), mice were evaluated at 11 weeks for serum antibody concentrations, quantities of T cells in the lungs, and IFN-γ- and TNF-α-expressing antigen-specific T cells in the lungs and spleen. Results: At 12 months postprimary vaccination, recipients of the IM vaccine incorporating MIP-3α had significantly, approximately threefold, higher serum antibody concentrations than recipients of the vaccine not incorporating MIP-3α. The area-under-the-curve analyses of the 12-month observation interval demonstrated significantly greater antibody concentrations over time in recipients of the MIP-3α vaccine formulation. At 12 months postprimary immunization, only recipients of the fusion vaccine had concentrations of serum-neutralizing activity deemed to be effective. After intranasal immunization, only recipients of the MIP-3α vaccine formulations developed T-cell responses in the lungs significantly above those of PBS controls. Low levels of serum antibody responses were obtained following IN immunization. Conclusion: Although requiring separate IM and IN immunizations for optimal immunization, incorporating MIP-3α in a SARS-CoV-2 vaccine construct demonstrated the potential of a stable and easily produced vaccine formulation to provide the extended antibody and T-cell responses that may be required for protection in the setting of emerging SARS-CoV-2 variants. Without electroporation, simple, uncoated plasmid DNA incorporating MIP-3α administered intranasally elicited lung T-cell responses. [ABSTRACT FROM AUTHOR]

BackgroundPrevious studies have demonstrated enhanced efficacy of vaccine formulations that incorporate the chemokine macrophage inflammatory protein 3α (MIP-3α) to direct vaccine antigens to immature dendritic cells. To address the reduction in vaccine efficacy associated with a mutation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutants, we have examined the ability of receptor-binding domain vaccines incorporating MIP-3α to sustain higher concentrations of antibody when administered intramuscularly (IM) and to more effectively elicit lung T-cell responses when administered intranasally (IN).MethodsBALB/c mice aged 6–8 weeks were immunized intramuscularly or intranasally with DNA vaccine constructs consisting of the SARS-CoV-2 receptor-binding domain alone or fused to the chemokine MIP-3α. In a small-scale (n = 3/group) experiment, mice immunized IM with electroporation were followed up for serum antibody concentrations over a period of 1 year and for bronchoalveolar antibody levels at the termination of the study. Following IN immunization with unencapsulated plasmid DNA (n = 6/group), mice were evaluated at 11 weeks for serum antibody concentrations, quantities of T cells in the lungs, and IFN-γ- and TNF-α-expressing antigen-specific T cells in the lungs and spleen.ResultsAt 12 months postprimary vaccination, recipients of the IM vaccine incorporating MIP-3α had significantly, approximately threefold, higher serum antibody concentrations than recipients of the vaccine not incorporating MIP-3α. The area-under-the-curve analyses of the 12-month observation interval demonstrated significantly greater antibody concentrations over time in recipients of the MIP-3α vaccine formulation. At 12 months postprimary immunization, only recipients of the fusion vaccine had concentrations of serum-neutralizing activity deemed to be effective. After intranasal immunization, only recipients of the MIP-3α vaccine formulations developed T-cell responses in the lungs significantly above those of PBS controls. Low levels of serum antibody responses were obtained following IN immunization.ConclusionAlthough requiring separate IM and IN immunizations for optimal immunization, incorporating MIP-3α in a SARS-CoV-2 vaccine construct demonstrated the potential of a stable and easily produced vaccine formulation to provide the extended antibody and T-cell responses that may be required for protection in the setting of emerging SARS-CoV-2 variants. Without electroporation, simple, uncoated plasmid DNA incorporating MIP-3α administered intranasally elicited lung T-cell responses.

The development of paclitaxel-loaded polymeric nanoparticles for the treatment of brain tumors was investigated. Poly(lactide-glycolide) (PLGA) nanoparticles containing 10% w/w paclitaxel with a particle size of 216 nm were administered through intranasal and intravenous routes to male Sprague–Dawley rats at a dose of 5 mg/kg. Both routes of administration showed appreciable accumulation of paclitaxel in brain tissue, liver, and kidney without any sign of toxicity. The anti-proliferative effect of the nanoparticles on glioblastoma tumor cells was comparable to that of free paclitaxel. [ABSTRACT FROM AUTHOR]

Highly pathogenic viruses in the Filoviridae family are causative agents of filovirus disease (FVD). Ebola virus (EBOV) is one such member and, of all filoviruses, represents the largest threat to global public health. The study of FVD has been hampered by the lack of tools to study filovirus infection outside maximum containment laboratories. Recombinant vesicular stomatitis virus (VSV) lacking its native glycoprotein and expressing a filovirus glycoprotein (VSV-filo GP) has improved our understanding of GP-mediated host-cell interactions as well as adaptive and humoral immune responses in in vitro and in vivo studies. Furthermore, mouse models suitable for these studies are readily available. Here, we describe multiple injection routes for investigating filovirus GP-mediated infection and pathogenesis using VSV-filo GP and interferon α/β receptor-deficient (Ifnar -/- ) mice as models. These tools can be safely used outside maximum containment laboratories, are cost effective, and easy to manipulate., (© 2025. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Left ventricular noncompaction (LVNC) is a recently described rare type of congenital cardiomyopathy with a poor long-term prognosis. We performed dental extraction for a 6-year-old female patient with LVNC who had risk of endocarditis due to dental disease along with a history of being uncooperative with dental care. For this case, we utilized intranasal (IN) midazolam conscious sedation, which enables a rapid sedation onset and is considered appropriate for child patients with a high level of anxiety, as movement is effectively decreased, making dental surgery possible. In cases with a small number of teeth, IN midazolam conscious sedation provides a safe condition for high-risk or anxious children undergoing treatment. [ABSTRACT FROM AUTHOR]

Abstract: Lectin-functionalized, polyethylene glycol–block-poly-(d,l)-lactic-co-glycolic acid nanoparticles loaded with haloperidol were prepared with narrow size distributions and sizes <135nm. The nanoparticles exhibited high Solanum tuberosum lectin (STL) conjugation efficiencies, encapsulation efficiencies, and drug loading capacities. The in vitro release of haloperidol was 6–8% of the loaded amount in endo-lysosomal conditions over 96h, demonstrating minimal drug leakage and the potential for the efficient drug transport to the targeted brain tissue. The haloperidol released upon erosion was successful in displacing [3H] N-propylnorapomorphine and binding to bovine striatal dopamine D2 receptors. Both haloperidol-loaded nanoparticle formulations were found to be highly effective at inducing catalepsy. Intranasal administration of STL-functionalized nanoparticles increased the brain tissue haloperidol concentrations by 1.5–3-fold compared to non-STL-functionalized particles and other routes of administration. This formulation demonstrates promise in the reduction of the drug dose necessary to produce a therapeutic effect with antipsychotic drugs for the treatment of schizophrenia. [Copyright &y& Elsevier]

Highlights: [•] We examine advances in drug development gained from genetically engineered mouse models (GEMMs) for NSCLC. [•] GEMMs with KRAS, EGFR and ALK addicted NSCLC are being used to understand resistance and establish new therapies. [•] Co-clinical trials enable the real-time integration of GEMM and human data for rapid evaluation of treatments. [•] GEMMs have the potential to assist in the discovery of non-invasive biomarkers. [•] GEMMs that recapitulate human disease will assist in bringing new drugs to the clinic for direct patient benefit. [Copyright &y& Elsevier]

Purpose: Vaccines targeting tumor associated antigens are in development for bladder cancer. Most of these cancers are nonmuscle invasive at diagnosis and confined in the mucosa and submucosa. However, to our knowledge how vaccination may induce the regression of tumors at such mucosal sites has not been examined previously. We compared different immunization routes for the ability to induce vaccine specific antitumor CD8 T cells in the bladder and bladder tumor regression in mice. Materials and Methods: In the absence of a murine bladder tumor model expressing a tumor antigen relevant for human use we established an orthotopic model expressing the HPV-16 tumor antigen E7 as a model. We used an adjuvant E7 polypeptide to induce CD8 T cell mediated tumor regression. Results: Subcutaneous and intravaginal but not intranasal vaccination induced a high number of TetE7+CD8+ T cells in the bladder as well as bladder tumor regression. The entry of vaccine specific T cells in the bladder was not the only key since persistent regression of established bladder tumors by intravaginal or subcutaneous immunization was associated with tumor infiltration of total CD4 and CD8 T cells. This resulted in an increase in TetE7+CD8+ T cells and a decrease in T regulatory cells, leading to an increased number of effector interferon-γ secreting vaccine specific CD8 T cells in the regressing bladder tumor. Conclusions: These data show that immunization routes should be tailored to each mucosal tumor site. Subcutaneous or intravaginal vaccination may be of additional value to treat patients with bladder cancer. [ABSTRACT FROM AUTHOR]

Highlights: [•] Allopregnanolone is a regenerative therapeutic candidate that promotes neurogenesis and restoration of cognitive function. [•] Endogenous allopregnanolone is important for normal brain development and is reduced with aging and Alzheimer's. [•] Intermittent allopregnanolone reduces Alzheimer's pathology; increases cholesterol homeostasis, white matter generation. [•] Formulation and route of administration allow for fine-tuning of pharmacokinetics and safety profile. [•] Treatment regimen must synergize with systems biology of regeneration and prevention/reduction of Alzheimer's. [ABSTRACT FROM AUTHOR]

Background: Use of intranasal (IN) dexmedetomidine for procedural sedation has been reported in recent years. Good patient selection is important to ensure high success rates. We aimed to identify factors that influence the successful use of IN dexmedetomidine in non-invasive investigations., Methods: All paediatric patients who received IN dexmedetomidine for investigations between 01 July 2019 to 01 July 2020 were included. Baseline demographics, time to reach adequate sedation level, duration of sedation, dose, indications for sedation and need for rescue sedatives were recorded. Procedures were classified into "long" or "short" according to completion time. Successful sedation was defined by completion of investigations by IN dexmedetomidine alone., Results: Of 105 patients included, median age was 20.0 months, and median weight 11.0 kg. Magnetic resonance imaging (56, 53.3%) was the most common indication. Sixty (57.1%) were successfully sedated using IN dexmedetomidine alone. Automated auditory brainstem response, computerised tomography and mercaptoacetyltriglycine-3 renogram scans had the highest success rate (83.3%, 83.3%, and 100% respectively). On multivariate analysis, short procedures had an adjusted odds ratio of 5.30 (95% CI: 1.69-16.61; P=0.004) compared to long procedures., Conclusions: IN dexmedetomidine is effective for procedural sedation for paediatric patients. The most important predictor for sedation success was indication of sedation and duration of procedures., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at: http://dx.doi.org/10.21037/tp-20-358). The authors have no conflicts of interest to declare., (2021 Translational Pediatrics. All rights reserved.)

Acute pain is one of the most common symptoms in children admitted to the Pediatric Emergency Department (PED) and its management represents a real clinical challenge for pediatricians. Different painful procedures can be very stressful for young children and their perception of pain can be enhanced by emotional factors, such as anxiety, distress, or anger. Adequate procedural sedation reduces anxiety and emotional trauma for the patient, but it reduces also stress for operators and the time for procedures. We have reviewed the literature on this topic and the drugs covered in these papers were: midazolam, fentanyl, ketamine, and dexmedetomidine. There are several routes of administering for these drugs to provide analgesia and anxiolysis to children: oral, parenteral, or intranasal (IN). Intravenous (IV) sedation, since it involves the use of needles, can be stressful; instead, IN route is a non-invasive procedure and generally well tolerated by children and it has become increasingly widespread. Some medications can be administered by a mucosal atomizer device (MAD) or by drops. The benefits of the atomized release include less drug loss in the oropharynx, higher cerebrospinal fluid levels, better patient acceptability, and better sedative effects. IN midazolam has a sedative, anxiolytic and amnesic effect, but without analgesic properties. Fentanyl and ketamine are mainly used for pain control. Dexmedetomidine has anxiolytic and analgesic properties. In conclusion, IN analgo-sedation is a simple, rapid and painless option to treat pain and anxiety in the PED requiring brief training on the administration process and experience in sedation., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-5177). The series “Pain Therapy” was commissioned by the editorial office without any funding or sponsorship. AR served as the unpaid Guest Editor of the series and serves as an unpaid editorial board member of Annals of Translational Medicine from Nov 2019 to Oct 2021. The other authors have no other conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)