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Neue Veröffentlichungen:
Die Sicherheit und Wirksamkeit der Immunrekonstitutionstherapie in der Regelversorgung der Multiplen Sklerose
(2024) Pfeuffer, Steffen
Die Immuntherapie der Multiplen Sklerose hat sich in der vergangenen Dekade erheblich gewandelt. Eine vormals nur unzureichend behandelbare Erkrankung wird nunmehr mit dem Therapieziel „Krankheitsstillstand“ behandelt. Unter den in ihren jeweiligen randomisiert-kontrollierten Studien erfolgreich geprüften und in der Folge zugelassenen Medikamenten nehmen die „Immunrekonstitutionstherapeutika“ eine Sonderrolle ein, da sie ihre hohe Wirksamkeit kombinieren sie mit dem Vorteil langfristiger Therapiefreiheit. Allerdings verbleiben auch nach den Zulassungsstudien relevante Fragen ungeklärt. Einerseits beinhalteten die klinischen Studien überwiegend therapienaive und junge Patienten, andererseits war zum Zeitpunkt der jeweiligen Studien der Großteil der heute verfügbaren Medikamente noch nicht verfügbar. Dementsprechend fehlen belastbare Informationen zur Sicherheit und Wirksamkeit von heute selbstverständlichen Therapiesequenzen.
Im Rahmen der vorgelegten kumulativen Habilitationsschrift werden die gewonnenen Erkenntnisse multizentrischer Kohortenstudien des Verfassers zu den verfügbaren Immunrekonstitutionstherapeutika (Alemtuzumab, Cladribin, Ocrelizumab) dargestellt. Die Einflüsse der Vorbehandlung mit Sphingosin-1-Rezeptormodulatoren auf die Sicherheit und Wirksamkeit der Behandlungen mit Alemtuzumab (reduzierte Wirksamkeit und erhöhtes Risiko sekundärer Autoimminutät) und Ocrelizumab (reduzierte Wirksamkeit) werden dargestellt und eingeordnet. Ebenso werden die Einflüsse der Therapiesequenzen auf die Wirksamkeit und Sicherheit einer Therapie mit Cladribin (erhöhtes Risiko von Lymphopenien und Herpesvirus-Reaktivierungen) erörtert. Ferner werden in der vorgelegten Schrift weitere, in der Regelversorgung neu beobachtete/erweiterte unerwünschte Ereignisse (neuartige Autoimmunphänomene unter Therapie mit Alemtuzumab und Erkrankungen der Haut unter Therapie mit Alemtuzumab&Cladribin) diskutiert.
Im Rahmen der vorgelegten kumulativen Habilitationsschrift werden die gewonnenen Erkenntnisse multizentrischer Kohortenstudien des Verfassers zu den verfügbaren Immunrekonstitutionstherapeutika (Alemtuzumab, Cladribin, Ocrelizumab) dargestellt. Die Einflüsse der Vorbehandlung mit Sphingosin-1-Rezeptormodulatoren auf die Sicherheit und Wirksamkeit der Behandlungen mit Alemtuzumab (reduzierte Wirksamkeit und erhöhtes Risiko sekundärer Autoimminutät) und Ocrelizumab (reduzierte Wirksamkeit) werden dargestellt und eingeordnet. Ebenso werden die Einflüsse der Therapiesequenzen auf die Wirksamkeit und Sicherheit einer Therapie mit Cladribin (erhöhtes Risiko von Lymphopenien und Herpesvirus-Reaktivierungen) erörtert. Ferner werden in der vorgelegten Schrift weitere, in der Regelversorgung neu beobachtete/erweiterte unerwünschte Ereignisse (neuartige Autoimmunphänomene unter Therapie mit Alemtuzumab und Erkrankungen der Haut unter Therapie mit Alemtuzumab&Cladribin) diskutiert.
Shadowing during intraoperative optical coherence tomography-assisted vitreoretinal surgery: clinical significance and reduction strategy
(2024) Carlos Reyna, Kevin Erick Gabriel
Purpose: To analyze the clinical significance of signal shadowing during intraoperative optical coherence tomography (iOCT)-assisted vitreoretinal surgery caused by intraocular instruments, intraocular dyes, and vitreous substitutes, and to objectively quantify its impact on iOCT imaging in order to produce strategies to mitigate its negative effects.
Methods: This is a retrospective observational study of postoperative image analysis from one hundred seventeen (117) patients who underwent iOCT-assisted vitrectomy. The image data were assigned to three groups: intraocular instruments, intraocular dyes, and vitreous substitutes. The data was then processed using graphic software to measure the grade of picture quality distortion and compared to paired image controls without clinically perceptive interference; consequently, analyzed statistically. Newly designed vitreoretinal instrument prototypes aimed at reducing baseline interference were also similarly tested.
Results: The intraocular portion of all studied vitreoretinal instruments caused a high average gray level interference compared to controls ranging from 32% to 68% reduction, obscuring the area of interest significantly. The tips of the instruments produced low-grade shadowing, allowing the underlying tissue to be distinguished. The analyzed dyes demonstrated a wide interference range: ICG (-75.12%), and triamcinolone (-26.13%) showed dose-dependent high shadowing, while VITREODYNE™ (49.3%) and brilliant blue (15.0%) exhibited no perceived distortions whilst increasing average gray levels. All analyzed vitreous substitutes (air, SF6, C3F8, PFCL, and silicone oil) showed an insignificant shadowing effect on iOCT. The novel instrument prototypes showed an average gray level reduction of only 9.01%.
Conclusions: Certain dyes and vitreous substitutes produce a negligible shadowing effect compared to controls and other dyes, giving an advantage during real-time iOCT imaging. All analyzed intraocular instruments showed a significant interference that should prompt the development of new imaging techniques or the implementation of materials with low-grade interference to overcome a clinically relevant shadowing effect on iOCT, maximizing the technology’s visual accuracy and in vivo surgical diagnostic aid proficiency.
Identification of Growth Factors and Regulatory Cytokines during Postnatal Cell Cycle Exit in Cardiomyocytes
(2024) Adibi, Paniz
During the embryonic development, the cardiac growth is mainly promoted by cardiomyocyte proliferation. In mice the cardiomyocyte proliferation declines continuously after birth, such that in adults cardiac myocytes are largely unable to divide. If an exposure to an extrauterine environment induces postanal cell cycle arrest, cardiomyocyte numbers per heart might be reduced following preterm birth compared to term deliveries. This might affect cardiovascular health later in life. Thus, in this thesis, we evaluated the onset of cell cycle withdrawal in mouse hearts in the period immediately after birth. We performed independent immunofluorescence (IF) staining for Ki67, and phospho-Histone H3 together with Caveolin 3 as a cardiomyocyte marker in murine ventricular myocardium at two latest fetal stages (E17.5 and E18.5), shortly after birth (NB18.5 and NB19.5), a day after delivery (NB18.5+1 and NB19.5+1), and two days after birth (NB19.5+2). Both E18.5 and NB18.5 mice share an identical gestational age, however, only the NB18.5 mice were briefly exposed to the extrauterine environment. Thus, comparing E18.5 and NB18.5 hearts allows for the evaluation of the birth influence on cardiac growth regulation. Moreover, in the entire analytical steps, the mouse gestational age and sex were precisely monitored. Our IF data revealed no remarkable variations in the cardiac cell cycle activity between E17.5 and E18.5 stages. Nonetheless, shortly after birth, the cell cycle activity rate (Ki67) in cardiac cells, as well as mitosis rate in cardiomyocyte and non-myocyte (phospho-Histone H3 and Caveolin 3) were noticeably reduced in mouse ventricular myocardium at NB18.5 and NB19.5 compared to E18.5 (p<0.05). Comparing the cardiac proliferation rate in NB18.5 and NB19.5 hearts, out data suggested that the cell cycle activity was gender and gestational age-independent. Furthermore, at one day after birth compared to immediately after delivery, the mitosis rate in cardiomyocytes and non-myocytes dropped significantly, whereas the cardiac cell cycle activity remained unchanged during the early postnatal stages. Notably, within the first week after birth factors such as the metabolic switch, oxidative stress and DNA damage, as well as the activity of the cardiac growth regulating signalling pathways and the availability of cell cycle regulators influence the murine postnatal cardiac cell cycle arrest. However, assessing the availability of glycolysis-involved enzymes (HK-II, ALDOA, PKM1/2, LDHA, and Eno-II), levels of antioxidative enzymes (SOD2, TRX2 and hyperoxidized PRDX-SO3), and the degree of oxidative DNA-damage (using IF staining for 8´-Oxo-7,8-dihydroguanine and MEF2A/C) in perinatal mouse ventricular myocardium, we observed no noticeable modifications in the level of these factor at NB18.5 compared to E18.5. Thus, it is very unlikely that these factors would be associated in the cell cycle arrest in CMs shortly after birth. Interestingly, via western blot and IF approaches, we revealed that coincidence with the birth-associated cell cycle arrest in CMs, the levels of type-D Cyclins and activity of MAP-kinase, AKT, and mTORC1 were significantly reduced in mouse ventricular myocardium at NB18.5 compared to E18.5. These pathways are partially regulated by growth factors and cytokines. Accordingly, we hypothesized that immediately after a separation from an intrauterine environment, an alteration in the availability of growth factors and cytokines promote the postnatal cardiac cell cycle arrest. Indeed, our in silico approaches revealed that out of 161 studied growth factors and cytokines, 68% exhibited an altered RNA expression level in neonatal compared to fetal mouse and human hearts. Via proteomics analyses (antibody-array screenings and ELISA experiments), we unveiled that concomitant with the birth-associated cardiac cell cycle arrest, the level of the growth factors and cytokines including Angptl3, IGF-1, IGFBP6, and PDGFAA declined remarkably, whereas Adiponectin, CRP, IGFBP1, Osteopontin, and Resistin levels were noticeably accelerated in mouse hearts at NB18.5 compared to shortly before delivery (at E18.5). Consequently, to promote the cell cycle activity in cultured primary cardiomyocytes isolated from neonatal mouse hearts, the cells were incubated with either medium (negative control), or Angptl3, or PDGFAA, and thereby the BrdU incorporation rates were assessed. While the Angptl3 treatment did not influence the cell cycle activity in cardiomyocytes, an incubation of primary cardiomyocytes with PDGFAA enhanced the rate of cardiomyocytes exhibiting a BrdU-incorporation to twice its value observed in negative controls. Collectively, it seems that PDGFAA might promote proliferation in cardiomyocyte, which needs to be elucidated in future. In this context, the outcome of this thesis can have beneficial clinical implications in preterm-born humans as well as cardiac regeneration studies in humans.
Mediator-based electron transfer pathways in microorganisms
(2024) Gemünde, André
Challenges in industrial biotechnology arise, among other things, when dissolved O2 is required as an electron acceptor in aqueous fermentation media. These challenges mainly consist of the low solubility of the gas at cultivation temperatures, increased foaming, and the risk of explosion when combined with H2 as a substrate. Electrodes could replace O2 as electron acceptors, thereby enabling gas fermentation with Cupriavidus necator, a β-proteobacterium used for the production of basic chemicals from H2/CO2 mixtures. Although electron transfer between microorganisms and electrodes has already been demonstrated using soluble mediators, knowledge of their precise interaction is still lacking to fully replace O2. The aim of this dissertation was to develop screening and reactor systems and to identify key components in the metabolism of C. necator influencing the extracellular electron transfer.
To this end, a 300 mL bioelectrochemical reactor was designed and initially characterized with Vibrio natriegens. The mediator-based and direct electron transfer of the organism was demonstrated, showing a measurable impact on product and biomass yield. As a measure of the efficiency of the artificial mediated electron transfer process, the percentage of O2 replaced by anodic electron transfer was introduced.
Furthermore, a 3.5 mL screening system was developed that enables online measurement of cell density and the redox state of the mediators. Pseudomonas putida was used for verification, as its ferricyanide mediated electron transfer is already described in the literature. The screening of 14 mediators with variable redox potentials in combination with C. necator in the developed system revealed a potential window for mediator reduction, along with a current production of -365 to 206 mV vs. Ag/AgCl, with ferricyanide proving most efficient with a total of 8.4 reduction and oxidation cycles (turnovers). The established 300 mL reactors were then used for the electrochemical cultivation of C. necator to elucidate the electron transfer. Cytochrome c reductase, cytochrome c oxidase, and nitrate/nitrite reductase were identified as key complexes in ferricyanide reduction through RT-qPCR, specific inhibition, and deletion mutants.
This work lays the foundation for screening mediators with microorganisms that are validated in larger reactors and also provides a basis for optimizing ferricyanide-mediated electron transfer in C. necator and other organisms.
uniforum 38 (2025) Nr. 1
(2025)
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