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In a previous study we demonstrated that intranasal (i.n.) vaccination promotes a Th17 biased immune response. Here, we show that co-administration of a pegylated derivative of α-galactosylceramide (αGCPEG) with an antigen, even in the presence of Th17-polarizing compounds, results in a strong blocking of Th17 differentiation. Additional studies demonstrated that this phenomenon is specifically dependent on soluble factors, like IL-4 and IFNγ, which are produced by NKT cells. Even NK1.1 negative NKT cells, which by themselves produce IL-17A, are able to block Th17 differentiation. It follows that the use of αGCPEG as adjuvant would enable to tailor Th17 responses, according to the specific clinical needs. This knowledge expands our understanding of the role played by NKT cells in overall control of the cytokine microenvironment, as well as in the overall shaping of adaptive immune responses.

In a previous study we demonstrated that intranasal (i.n.) vaccination promotes a Th17 biased immune response. Here, we show that co-administration of a pegylated derivative of [alpha]-galactosylceramide ([alpha]GCPEG) with an antigen, even in the presence of Th17-polarizing compounds, results in a strong blocking of Th17 differentiation. Additional studies demonstrated that this phenomenon is specifically dependent on soluble factors, like IL-4 and IFN[gamma], which are produced by NKT cells. Even NK1.1 negative NKT cells, which by themselves produce IL-17A, are able to block Th17 differentiation. It follows that the use of [alpha]GCPEG as adjuvant would enable to tailor Th17 responses, according to the specific clinical needs. This knowledge expands our understanding of the role played by NKT cells in overall control of the cytokine microenvironment, as well as in the overall shaping of adaptive immune responses.

The outcomes of prolonged weaning in a specialist weaning centre range from successful weaning to death. We aimed to identify indicators of the different outcomes. We analysed 915 patients who underwent prolonged weaning at Thoraxklinik Heidelberg from Dec. 2008 to Dec. 2023. 73.2% were successfully weaned, 36.1% without (3a) and 37.1% with subsequent non-invasive ventilation (3b). 20.2% were discharged with IMV (3cI) and 6.6% died (3cII). The length of stay was significantly longer in the group discharged with IMV. Patients in weaning category 3a had fewer comorbidities, also as cause of IMV and were less obese (each at least OR ≤ 0.6, p  ≤ 0.02). IMV before admission in days was significantly shorter, FiO 2 higher and pCO 2 lower, although with a weak effect (OR between 1.014 and 0.971). Indicators of category 3b were younger age (weak effect, OR 0.977), BMI ≥ 30 kg/m 2 (OR 2.470, p  < 0,001), higher pCO 2 (OR 1.044), cause of IMV AECOPD (OR 2.803), pre-diagnosis of COPD (OR 2.073) and nosocomial pneumonia (OR 1.857), whereas patients with malignancy (OR 0.438) and CIP (critical illness polyneuropathy, OR 0.523) were less likely to fall into this category. Indicators of category 3cI were duration of previous IMV with a weak effect (OR 1.006), neuromuscular disease as the cause of IMV (OR 6.023), restrictive thoracic disease (OR 2.330), renal insufficiency (OR 1.977) and CIP (OR 1.744), absence of nosocomial pneumonia (OR 0.366). Only BMI ≤ 20 kg/m 2 (OR 3.611), renal insufficiency (OR 1.253) and pre-diagnosed malignancy (OR 1.785) were indicators of category 3cII. The relevant indicators from multivariate analyses were transferred into ROC (receiver operating characteristic) curves and show an acceptable AUC (area under curve) between 0.72 and 0.79 for each of the four outcomes. There are specific indicators for each weaning outcome and an early assessment of each patient’s individual risk profile can help plan further outpatient care, shorten length of stay in the ventilator weaning unit and generate capacities for other patients in need of prolonged weaning.

► We investigated transfollicular vaccination via intact skin using nanoparticles(NP). ► Polymeric NP from PLGA+- chitosan were loaded with ovalbumin (OVA). ► OVA/NP stimulated proliferation of CD4+ &/or CD8+ T-cells more than OVA/solution. ► NP improved (×2–3) follicular delivery of OVA on pig ears compared to OVA/solution. ► Consequently using OVA/NP one may reduce the dose compared to OVA/solution. Transfollicular vaccination aims to reach the peri-follicular antigen presenting cells without impairing the stratum corneum (SC) barrier. This would be an optimal vaccination strategy under critical hygienic conditions. Nanoparticles (NPs) are the ideal vehicles for transfollicular delivery of vaccines as they are able to (i) penetrate deeper into the hair follicles than molecules in solution, (ii) can help to stabilize protein based antigen and (iii) improve and modulate the immune response. This study investigates the potential of transfollicular delivery of polymeric NPs using ovalbumin (OVA) as a model antigen. NPs were prepared by a double emulsion method from pharmaceutically well characterized biocompatible and biodegradable polymers poly(lactide-co-glycolide) (PLGA) or chitosan-coated PLGA (Chit-PLGA) using polyvinyl alcohol as stabilizer. The NP formulations are available as freeze dried product which can be re-constituted with water or cell culture medium before use to yield any desired OVA/NP concentration. OVA was protected from cleavage or aggregation inside the NPs and retained its biological activity to 74% (PLGA) and 64% (Chit-PLGA). Thus, when applying a typical dose of 8.5μl/cm2 NP formulation (50mg NPs/ml, 54.3±0.047 and 66.5±0.044μg OVA/mg NPs for PLGA and Chit-PLGA NPs, respectively) an effective dose of 17μg/cm2 (PLGA) or 18μg/cm2 (Chit-PLGA) of active OVA is administered. In a cell culture assay encapsulated OVA stimulated the proliferation of CD4+ (PLGA and Chit-PLGA) and CD8+ T-cells (only Chit-PLGA) to a larger extent than OVA in solution. An adoptive transfer experiment demonstrated that the model antigen OVA can be delivered via the transfollicular route. This preliminary experiment is a proof of concept that by this transfollicular immunization approach it is possible to deliver antigens, thereby stimulating antigen-specific T cells. Both NP formulations improved the delivery efficiency of OVA into the hair follicles on excised pig ears by a factor of 2–3 compared to OVA solution. This delivery efficiency could further be increased by increasing the number of NPs applied per skin area by a factor of ≈2–2.4. Consequently formulation of OVA into PLGA and Chit-PLGA NPs may offer to reduce the dose which needs to be applied for transfollicular immunization.

IntroductionDespite a large number of trials, the role of bevacizumab (BEV) in the treatment of recurrent high-grade gliomas is still controversial. Evidence regarding an effect on overall survival in this context is ultimately inconclusive. At the Department of Radiation Oncology at Erlangen, Germany we treated a large cohort of patients with recurrent gliomas where bevacizumab use was determined exclusively by the health care provider’s approval of reimbursement.Methods61 patients (between 06/2008 and 01/2014) with recurrent high-grade gliomas had reimbursement requests for BEV sent to their health insurance. 37 patients out of 61 (60.7%) had their requests approved and therefore received bevacizumab (BEV-arm) as part of their treatment. The remaining 24 (39.3%) patients received standard therapy without bevacizumab (non-BEV-arm). Survival endpoints were defined with reference to the first BEV request to the health insurance provider.ResultsMedian overall survival (OS) for the whole cohort was 7.0 months. OS was significantly better for BEV vs. Non-BEV patients (median, 10.3 vs. 4.2 months, logrank p = 0.023). There was an increased BEV benefit in cases of higher-order recurrences (first order recurrence BEV vs. Non-BEV, 12.5 vs. 10.2 months, p = 0.578) (second or higher order of recurrence, 9.9 vs. 2.6 months, p = 0.010). On multivariate analysis for overall survival the prognostic impact of bevacizumab (HR = 0.43, p = 0.034) remained significant.ConclusionOur results suggest an influence of BEV on overall survival in a heavily pretreated patient population suffering from high-grade gliomas with BEV benefit being greatest in case of second or later recurrence.

Prions are transmissible agents that cause lethal neurodegeneration in humans and other mammals. Prions bind avidly to metal surfaces such as steel wires and, when surface-bound, can initiate infection of brain or cultured cells with remarkable efficiency. While investigating the properties of metal-bound prions by using the scrapie cell assay to measure infectivity, we observed, at low frequency, positive assay results in control groups in which metal wires had been coated with uninfected mouse brain homogenate. This phenomenon proved to be reproducible in rigorous and exhaustive control experiments designed to exclude prion contamination. The infectivity generated in cell culture could be readily transferred to mice and had strain characteristics distinct from the mouse-adapted prion strains used in the laboratory. The apparent \"spontaneous generation\" of prions from normal brain tissue could result if the metal surface, possibly with bound cofactors, catalyzed de novo formation of prions from normal cellular prion protein. Alternatively, if prions were naturally present in the brain at levels not detectable by conventional methods, metal surfaces might concentrate them to the extent that they become quantifiable by the scrapie cell assay.