A new vicious cycle involving glutamate excitotoxicity, oxidative stress and mitochondrial dynamics

Glutamate excitotoxicity leads to fragmented mitochondria in neurodegenerative diseases, mediated by nitric oxide and S-nitrosylation of dynamin-related protein 1, a mitochondrial outer membrane fission protein. Optic atrophy gene 1 (OPA1) is an inner membrane protein important for mitochondrial fusion. Autosomal dominant optic atrophy (ADOA), caused by mutations in OPA1, is a neurodegenerative disease affecting mainly retinal ganglion cells (RGCs). Here, we showed that OPA1 deficiency in an ADOA model influences N-methyl-D-aspartate (NMDA) receptor expression, which is involved in glutamate excitotoxicity and oxidative stress. Opa1enu/+ mice show a slow progressive loss of RGCs, activation of astroglia and microglia, and pronounced mitochondrial fission in optic nerve heads as found by electron tomography. Expression of NMDA receptors (NR1, 2A, and 2B) in the retina of Opa1enu/+ mice was significantly increased as determined by western blot and immunohistochemistry. Superoxide dismutase 2 (SOD2) expression was significantly decreased, the apoptotic pathway was activated as Bax was increased, and phosphorylated Bad and BcL-xL were decreased. Our results conclusively demonstrate that not only glutamate excitotoxicity and/or oxidative stress alters mitochondrial fission/fusion, but that an imbalance in mitochondrial fission/fusion in turn leads to NMDA receptor upregulation and oxidative stress. Therefore, we propose a new vicious cycle involved in neurodegeneration that includes glutamate excitotoxicity, oxidative stress, and mitochondrial dynamics

Tumor Volume Estimation and Quasi- Continuous Administration for Most Effective Bevacizumab Therapy

Bevacizumab is an exogenous inhibitor which inhibits the biological activity of human VEGF. Several studies have investigated the effectiveness of bevacizumab therapy according to different cancer types but these days there is an intense debate on its utility. We have investigated different methods to find the best tumor volume estimation since it creates the possibility for precise and effective drug administration with a much lower dose than in the protocol.We have examined C38 mouse colon adenocarcinoma and HT-29 human colorectal adenocarcinoma. In both cases, three groups were compared in the experiments. The first group did not receive therapy, the second group received one 200 μg bevacizumab dose for a treatment period (protocol-based therapy), and the third group received 1.1 μg bevacizumab every day (quasi-continuous therapy). Tumor volume measurement was performed by digital caliper and small animal MRI. The mathematical relationship between MRI-measured tumor volume and mass was investigated to estimate accurate tumor volume using caliper-measured data. A two-dimensional mathematical model was applied for tumor volume evaluation, and tumor- and therapy-specific constants were calculated for the three different groups. The effectiveness of bevacizumab administration was examined by statistical analysis.In the case of C38 adenocarcinoma, protocol-based treatment did not result in significantly smaller tumor volume compared to the no treatment group; however, there was a significant difference between untreated mice and mice who received quasi-continuous therapy (p = 0.002). In the case of HT-29 adenocarcinoma, the daily treatment with one-twelfth total dose resulted in significantly smaller tumors than the protocol-based treatment (p = 0.038). When the tumor has a symmetrical, solid closed shape (typically without treatment), volume can be evaluated accurately from caliper-measured data with the applied two-dimensional mathematical model.Our results provide a theoretical background for a much more effective bevacizumab treatment using optimized administration

An anti-TNF--α antibody mimetic to treat ocular inflammation

Infliximab is an antibody that neutralizes TNF-α and is used principally by systemic administration to treat many inflammatory disorders. We prepared the antibody mimetic Fab-PEG-Fab (FpFinfliximab) for direct intravitreal injection to assess whether such formulations have biological activity and potential utility for ocular use. FpFinfliximab was designed to address side effects caused by antibody degradation and the presence of the Fc region. Surface plasmon resonance analysis indicated that infliximab and FpFinfliximab maintained binding affinity for both human and murine recombinant TNF-α. No Fc mediated RPE cellular uptake was observed for FpFinfliximab. Both Infliximab and FpFinfliximab suppressed ocular inflammation by reducing the number of CD45+ infiltrate cells in the EAU mice model after a single intravitreal injection at the onset of peak disease. These results offer an opportunity to develop and formulate for ocular use, FpF molecules designed for single and potentially multiple targets using bi-specific FpFs

Prognostic value of advanced lung cancer inflammation index in head and neck squamous cell carcinoma

Purpose: The advanced lung cancer inflammation index (ALI) is a useful tool for prediction of outcome in several malignancies. However, to date, its significance in head and neck cancer patients has not been evaluated. Methods: We retrospectively analyzed data from 93 patients who were diagnosed with head and neck squamous cell carcinoma (HNSCC) and treated with surgical resection and postoperative radiotherapy between 2002 and 2012. The aim of this study was to investigate whether the preoperative ALI is a prognostic indicator for disease-free survival and overall survival in HNSCC patients. Results: A low ALI was significantly associated with a worse 5-year disease-free survival (47.0 vs. 83.5%, p < 0.001), and overall survival (44.4 vs. 73.6%, p = 0.008). Multivariate analysis showed that low ALI was independently associated with disease-free survival (p < 0.001) and overall survival (p = 0.02). Conclusion: The ALI could serve as an easily available prognostic indicator for disease-free and overall survival prediction in patients with HNSCC. © 2019, Springer-Verlag GmbH Germany, part of Springer Nature

Beeinflussung der Prüfungsergebnisse durch ein Repetitorium als Vorbereitung auf das mündliche HNO-Rigorosum und Einfluss des Geschlechts der PrüferInnen - eine retrospektive Aufarbeitung von 3961 Prüfungen

Revision courses should repeat already acquired knowledge and skills and mostly provide a basis for passing the following exam.Aim: The aim of the study is to investigate the influence of a previously attended revision course on the grades achieved in a final exam (Ear, Nose and Throat Diseases). Additionally we ask the question whether the gender of the examiners plays a role concerning the marks or not.Methods: 3961 exams at the Department of Ear, Nose and Throat (ENT) Diseases in Vienna were investigated, 725 with revision course (experimental group) and 3236 without previous revision course (comparison group). The revision courses were performed in a standardized way concerning form and content, interactive and case based.Both groups were examined uniform in regard to topics and time duration. 16 male and 6 female examiners were involved. The grading followed a five-level scale. The examination marks were calculated in the arithmetic mean and median value for the entire sample, gender dependence was calculated according to the Wilcoxon-Mann-Whitney-Test. The inferential statistics included single- and multiple factorial analyses of variance as well as uni- and multivariate regression models.Results: The experimental group achieved a grade average of 2.54 compared with 2.46 for the comparison group. Splitting up into male and female examiners, an average of 2.54 and 2.58 resp. for the experimental group and 2.44 and 2.61 resp. for the comparison group resulted. Female examiner marked significantly lower grades in comparison to their male colleagues (P= 0.001926). Conclusions: The ENT revision course did not improve the grade averages of the final ENT exam. Female examiners grade stricter than male examiners. There was no difference concerning grades 4 (pass) and 5 (fail) but female examiners grade less with mark 1.Repetitorien sind Lehrveranstaltungen, die bereits erworbenes Wissen und Kenntnisse wiederholen und meist als Vorbereitung zum Bestehen eines Examens dienen.Zielsetzung: Zweck der Studie ist es, die Beeinflussung des Ergebnisses bei der mündlichen Gesamtprüfung (Rigorosum) im Fach Hals-Nasen-Ohrenheilkunde zu untersuchen, wenn zuvor ein interaktives mündliches Repetitorium besucht wurde. Zudem wird der Frage nachgegangen, ob es Unterschiede zwischen weiblichen und männlichen Prüfern bei der Notenvergabe gibt.Methode: 3961 Einzelprüfungen an der Universitätsklinik für HNO-Krankheiten in Wien wurden untersucht, 725 mit Repetitorium (Versuchsgruppe) und 3236 ohne Repetitorium (Vergleichsgruppe). Das Repetitorium wurde als inhaltlich standardisiertes Wahlfach interaktiv und fallorientiert gestaltet.Beide Gruppen wurden nach einheitlichen Kriterien (Inhalte, Dauer) geprüft. 16 männliche Prüfer und 6 weibliche Prüferinnen waren tätig. Die Benotung erfolgte in einer 5-teiligen Skala und wurde als arithmetischer Durchschnittswert mit Median, die Geschlechtsabhängigkeit der Notenvergabe wurde mit dem Wilcoxon-Rangsummentest berechnet. Die schließende Statistik bestand aus ein- und multifaktoriellen Varianzanalysen sowie uni- und multivarianten Regressionsmodellen.Ergebnisse: Die Versuchsgruppe erzielte einen Notendurchschnitt von 2,54 gegenüber jener der Vergleichsgruppe mit 2,46. Nach Aufteilung in männliche und weibliche Prüfer ergibt sich ein Notendurchschnitt für die Versuchsgruppe von 2,54 bzw. 2,58 und für die Vergleichsgruppe von 2,44 bzw. 2,61. Der Unterschied ist statistisch signifikant (p=0,001926).Schlussfolgerung: Das HNO-Repetitorium hat nicht zu einer Verbesserung des Notendurchschnittes bei der nachfolgenden mündlichen Prüfung über Inhalte des gesamten Faches geführt. Weibliche Prüfer benoten strenger als männliche. Der wesentliche Unterschied zwischen männlichen und weiblichen PrüferInnen in der Notengebung besteht bei der Vergabe der Noten 1 und 2 und nicht bei der Note 5 (nicht bestanden)