The sodium iodide symporter (NIS) as theranostic gene: its emerging role in new imaging modalities and non-viral gene therapy

Cloning of the sodium iodide symporter (NIS) in 1996 has provided an opportunity to use NIS as a powerful theranostic transgene. Novel gene therapy strategies rely on image-guided selective NIS gene transfer in non-thyroidal tumors followed by application of therapeutic radionuclides. This review highlights the remarkable progress during the last two decades in the development of the NIS gene therapy concept using selective non-viral gene delivery vehicles including synthetic polyplexes and genetically engineered mesenchymal stem cells. In addition, NIS is a sensitive reporter gene and can be monitored by high resolution PET imaging using the radiotracers sodium [ 124 I]iodide ([ 124 I]NaI) or [ 18 F]tetrafluoroborate ([ 18 F]TFB). We performed a small preclinical PET imaging study comparing sodium [ 124 I]iodide and in-house synthesized [ 18 F]TFB in an orthotopic NIS-expressing glioblastoma model. The results demonstrated an improved image quality using [ 18 F]TFB. Building upon these results, we will be able to expand the NIS gene therapy approach using non-viral gene delivery vehicles to target orthotopic tumor models with low volume disease, such as glioblastoma

Disease severity in hospitalized COVID-19 patients: comparing routine surveillance with cohort data from the LEOSS study in 2020 in Germany

Introduction Studies investigating risk factors for severe COVID-19 often lack information on the representativeness of the study population. Here, we investigate factors associated with severe COVID-19 and compare the representativeness of the dataset to the general population. Methods We used data from the Lean European Open Survey on SARS-CoV-2 infected patients (LEOSS) of hospitalized COVID-19 patients diagnosed in 2020 in Germany to identify associated factors for severe COVID-19, defined as progressing to a critical disease stage or death. To assess the representativeness, we compared the LEOSS cohort to cases of hospitalized patients in the German statutory notification data of the same time period. Descriptive methods and Poisson regression models were used. Results Overall, 6672 hospitalized patients from LEOSS and 132,943 hospitalized cases from the German statutory notification data were included. In LEOSS, patients above 76 years were less likely represented (34.3% vs. 44.1%). Moreover, mortality was lower (14.3% vs. 21.5%) especially among age groups above 66 years. Factors associated with a severe COVID-19 disease course in LEOSS included increasing age, male sex (adjusted risk ratio (aRR) 1.69, 95% confidence interval (CI) 1.53–1.86), prior stem cell transplantation (aRR 2.27, 95% CI 1.53–3.38), and an elevated C-reactive protein at day of diagnosis (aRR 2.30, 95% CI 2.03–2.62). Conclusion We identified a broad range of factors associated with severe COVID-19 progression. However, the results may be less applicable for persons above 66 years since they experienced lower mortality in the LEOSS dataset compared to the statutory notification data.Peer Reviewe

Mobile Air Quality Studies (MAQS) - an international project

Due to an increasing awareness of the potential hazardousness of air pollutants, new laws, rules and guidelines have recently been implemented globally. In this respect, numerous studies have addressed traffic-related exposure to particulate matter using stationary technology so far. By contrast, only few studies used the advanced technology of mobile exposure analysis. The Mobile Air Quality Study (MAQS) addresses the issue of air pollutant exposure by combining advanced high-granularity spatial-temporal analysis with vehicle-mounted, person-mounted and roadside sensors. The MAQS-platform will be used by international collaborators in order 1) to assess air pollutant exposure in relation to road structure, 2) to assess air pollutant exposure in relation to traffic density, 3) to assess air pollutant exposure in relation to weather conditions, 4) to compare exposure within vehicles between front and back seat (children) positions, and 5) to evaluate "traffic zone"- exposure in relation to non-"traffic zone"-exposure. Primarily, the MAQS-platform will focus on particulate matter. With the establishment of advanced mobile analysis tools, it is planed to extend the analysis to other pollutants including including NO2, SO2, nanoparticles, and ozone

Bioassays to Monitor Taspase1 Function for the Identification of Pharmacogenetic Inhibitors

Background: Threonine Aspartase 1 (Taspase1) mediates cleavage of the mixed lineage leukemia (MLL) protein and leukemia provoking MLL-fusions. In contrast to other proteases, the understanding of Taspase1's (patho)biological relevance and function is limited, since neither small molecule inhibitors nor cell based functional assays for Taspase1 are currently available. Methodology/Findings: Efficient cell-based assays to probe Taspase1 function in vivo are presented here. These are composed of glutathione S-transferase, autofluorescent protein variants, Taspase1 cleavage sites and rational combinations of nuclear import and export signals. The biosensors localize predominantly to the cytoplasm, whereas expression of biologically active Taspase1 but not of inactive Taspase1 mutants or of the protease Caspase3 triggers their proteolytic cleavage and nuclear accumulation. Compared to in vitro assays using recombinant components the in vivo assay was highly efficient. Employing an optimized nuclear translocation algorithm, the triple-color assay could be adapted to a high-throughput microscopy platform (Z'factor = 0.63). Automated high-content data analysis was used to screen a focused compound library, selected by an in silico pharmacophor screening approach, as well as a collection of fungal extracts. Screening identified two compounds, N-[2-[(4-amino-6-oxo-3H-pyrimidin-2-yl)sulfanyl]ethyl]benzenesulfonamideand 2-benzyltriazole-4,5-dicarboxylic acid, which partially inhibited Taspase1 cleavage in living cells. Additionally, the assay was exploited to probe endogenous Taspase1 in solid tumor cell models and to identify an improved consensus sequence for efficient Taspase1 cleavage. This allowed the in silico identification of novel putative Taspase1 targets. Those include the FERM Domain-Containing Protein 4B, the Tyrosine-Protein Phosphatase Zeta, and DNA Polymerase Zeta. Cleavage site recognition and proteolytic processing of these substrates were verified in the context of the biosensor. Conclusions: The assay not only allows to genetically probe Taspase1 structure function in vivo, but is also applicable for high-content screening to identify Taspase1 inhibitors. Such tools will provide novel insights into Taspase1's function and its potential therapeutic relevance

Optimization of soot deposition by high-temperature prepolarization of a resistive particulate matter sensor

For the purposes of the onboard diagnosis (OBD) of diesel particulate filters (DPFs) in diesel exhaust treatment systems, a particulate matter (PM) sensor is applied downstream from the DPFs to detect small amounts of diesel soot that passed through the filter. The state-of-the-art technology is a sensor based on the resistive measurement principle, i.e., charged soot particles are attracted by electrophoretic forces, deposited on an interdigital electrode (IDE) structure and conductive soot bridges that reduce the overall resistance are formed. This paper reports how the response time of a resistively working particulate matter sensor can be shortened up to 30 % by the optimization of soot deposition that is initiated by a change in the sensor operation strategy. The measurement voltage is applied for prepolarization during the sensor regeneration phase rather than during the cooling phase before the measurement is commonly done. Experiments were performed at diesel engine test benches to examine this context and simulations of the electric field above and below the IDE structure. The data are used to deduct a model, including the solid state chemistry of the sensor's ceramic materials, the effect of impurities on the electric field properties and the interconnection with the soot deposition, which defines the sensor's response

Resolving the base of the pyramid inclusion paradox through supplier development

Gefördert im Rahmen des Projekts DEALInternational Center for Development and Decent Work (ICDD), Grant/Award Number: 57160015; Bundesministerium für Forschung und Technologie, Grant/Award Number: 031A247A-

Handreichung zur Patient*innenbeteiligung an klinischer Forschung

Die Handreichung zur Patient*innenbeteiligung an klinischer Forschung wurde entwickelt, um die Patient*innenbeteiligung an klinischen Studien im deutschsprachigen Raum zu stärken und Forschende bei der aktiven Beteiligung von Patient*innen zu unterstützen. Unter Beteiligung verstehen wir die aktive Einbindung von Patient*innen in die Planung, Durchführung und Translation klinischer Studien. Wir grenzen den Begriff ab von ähnlichen Konzepten wie bspw. der partizipativen Gesundheitsforschung – für diese treffen wir keine Aussagen. Der Fokus liegt auf Hinweisen und Anregungen für die praktische Umsetzung von Beteiligung an klinischen Studien. Je nach Situation sind ganz unterschiedliche Formen und Intensitäten der Beteiligung denkbar, die Inhalte der Handreichung sollten entsprechend an die eigene Situation angepasst werden. Die vorliegende Handreichung richtet sich unmittelbar an klinisch Forschende, die an einer aktiven Patient*innenbeteiligung interessiert sind und diese umsetzen möchten. Forschungsfördernde und Gutachter*innen können sie als Orientierung bei der Bewertung der Patient*innenbeteiligung in Forschungsanträgen nutzen. Darüber hinaus kann die Handreichung auch Patient*innen( vertreter*innen) unterstützen, die sich aktiv an klinischer Forschung beteiligen wollen. Die vorliegende Handreichung soll eine praktische Unterstützung für die Planung und Umsetzung von Patient*innenbeteiligung darstellen. Entsprechend ist sie aufgebaut: In Kapitel 1 wird in das Thema der Patient*innenbeteiligung eingeführt. Kapitel 2 gibt einen kurzen Einblick in die Erfahrungen zweier Patientinnen mit Patient*innenbeteiligung. Kapitel 3 widmet sich der Planung, Kapitel 4 der Durchführung von Patient*innenbeteiligung. Kapitel 5 gibt einen Ausblick auf Handlungsbedarfe und Entwicklungspotentiale

Handreichung zur Patient*innenbeteiligung an klinischer Forschung

Dies ist die aktualisierte Handreichung zur Patient*innenbeteiligung an klinischer Forschung. Die Handreichung wurde entwickelt, um die Patient*innenbeteiligung an klinischen Studien im deutschsprachigen Raum zu stärken und Forschende bei der aktiven Beteiligung von Patient*innen zu unterstützen. Unter Beteiligung verstehen wir die aktive Einbindung von Patient*innen in die Planung, Durchführung und Translation klinischer Studien. Wir grenzen den Begriff ab von ähnlichen Konzepten wie bspw. der partizipativen Gesundheitsforschung – für diese treffen wir keine Aussagen. Der Fokus liegt auf Hinweisen und Anregungen für die praktische Umsetzung von Beteiligung an klinischen Studien. Je nach Situation sind ganz unterschiedliche Formen und Intensitäten der Beteiligung denkbar, die Inhalte der Handreichung sollten entsprechend an die eigene Situation angepasst werden. Die vorliegende Handreichung richtet sich unmittelbar an klinisch Forschende, die an einer aktiven Patient*innenbeteiligung interessiert sind und diese umsetzen möchten. Forschungsfördernde und Gutachter*innen können sie als Orientierung bei der Bewertung der Patient*innenbeteiligung in Forschungsanträgen nutzen. Darüber hinaus kann die Handreichung auch Patient*innen( vertreter*innen) unterstützen, die sich aktiv an klinischer Forschung beteiligen wollen. Die vorliegende Handreichung soll eine praktische Unterstützung für die Planung und Umsetzung von Patient*innenbeteiligung darstellen. Entsprechend ist sie aufgebaut: In Kapitel 1 wird in das Thema der Patient*innenbeteiligung eingeführt. Kapitel 2 gibt einen kurzen Einblick in die Erfahrungen zweier Patientinnen mit Patient*innenbeteiligung. Kapitel 3 widmet sich der Planung, Kapitel 4 der Durchführung von Patient*innenbeteiligung. Kapitel 5 gibt einen Ausblick auf Handlungsbedarfe und Entwicklungspotentiale

Contactin-associated protein 2 autoantibodies can be associated with multifocal motor-like neuropathy: a case report

Autoantibodies against contactin-associated protein 2 (CASPR2) are usually associated with autoimmune encephalitis and neuromyotonia. Their association with inflammatory neuropathies has been described in case reports albeit all with distal symmetric manifestation. Here, we report a patient who developed distal arm paresis, dominantly of the right arm, over the course of 1 year. Electroneurography showed a conduction block of motor nerve conduction, nerve ultrasonography a swelling of the right median and ulnar nerve and flow cytometry an increase in natural killer (NK cells) in the blood and natural killer T (NKT) cells in the cerebrospinal fluid (CSF), therefore indicating a multifocal motor neuropathy-like (MMN-like) phenotype. CASPR2 autoantibodies were detected in serum and CSF. Through immunotherapy with intravenous immunoglobulins the patient showed clinical and neurographic improvement. We therefore describe the first association of CASPR2 autoantibodies with a MMN-like clinical manifestation, extending the spectrum of CASPR2-associated diseases