Automobilantriebe im Wandel

Der Automobilantrieb ist eng mit dem globalen wirtschaftlichen Erfolg und dessen Wachstum verbunden. Nie zuvor konnten größere Distanzen von so vielen Individuen und Gütern in so kurzer Zeit zurückgelegt werden. Aufgrund der aktuellen wirtschaftlichen und ökologischen Lage sind die Automobilbauer gefordert Antriebe zu entwickeln, die möglichst geringe Emissionen mit einem maximalen Wirkungsgrad und dennoch großen Reichweiten ermöglichen. Dabei verfügt der Automobilmarkt über eine große Vielfalt und aufgrund der zunehmenden Anforderungen und regional abhängigen Randbedingungen (Gesetze, Emissionsanforderungen, etc.), sowie den Interessenkonflikten bei den Herstellern, über eine hohe Komplexität. Auch der zukünftige Endverbraucher hat Anforderungen an sein Fahrzeug. Wie groß ist die Reichweite eines Elektrofahrzeugs? Wie kann diese bei Bedarf gesteigert werden? Sind diese Antriebe wirklich effizient? Um diese Fragen beantworten zu können, muss der aktuelle Stand der Technik näher beleuchtet werden, so dass die teilweise geringen Unterschiede, gerade bei Hybridsystemen, nachvollzogen werden können und um die individuellen Vorteile greifbarer zu machen. Letztendlich wird klar, dass sich der Antrieb verändern wird und trotz, oder gerade wegen der zunehmenden Elektrifizierung und Hybridisierung, wird dennoch der Verbrennungsmotor die dominante Antriebsquelle über einen längeren Zeitraum bleiben

Clonal Type I Interferon–producing and Dendritic Cell Precursors Are Contained in Both Human Lymphoid and Myeloid Progenitor Populations

Because of different cytokine responsiveness, surface receptor, and transcription factor expression, human CD11c− natural type I interferon–producing cells (IPCs) and CD11c+ dendritic cells were thought to derive through lymphoid and myeloid hematopoietic developmental pathways, respectively. To directly test this hypothesis, we used an in vitro assay allowing simultaneous IPC, dendritic cell, and B cell development and we tested lymphoid and myeloid committed hematopoietic progenitor cells for their developmental capacity. Lymphoid and common myeloid and granulocyte/macrophage progenitors were capable of developing into both functional IPCs, expressing gene transcripts thought to be associated with lymphoid lineage development, and into dendritic cells. However, clonal progenitors for both populations were about fivefold more frequent within myeloid committed progenitor cells. Thus, in humans as in mice, natural IPC and dendritic cell development robustly segregates with myeloid differentiation. This would fit with natural interferon type I–producing cell and dendritic cell activity in innate immunity, the evolutionary older arm of the cellular immune system

Addition of romiplostim to conditioning prior to HSCT allows chemotherapy reduction while maintaining engraftment levels

Allogeneic hematopoietic stem cell transplantation (HSCT) offers a curative treatment approach for certain benign and malignant hematologic diseases. The actual HSCT is preceded by a conditioning therapy that reduces host-vs-HSCT graft rejection and creates niche space for transplanted hematopoietic stem and progenitor cells (HSPCs). Conditioning consists of chemotherapy with or without irradiation and is a major cause of side effects in HSCT. However, reduction of the intensity of cytotoxic conditioning leads to higher rates of engraftment failure and increased rates of relapse. We here tested if the addition of an HSC cycling inducing agent during conditioning allows to diminish the dose of conditioning drugs without reducing subsequent transplanted HSC engraftment in a mouse HSCT model. The thrombopoietin receptor agonist romiplostim was shown to induce cell cycling activity in hematopoietic stem cells (HSCs). We thus tested if the addition of romiplostim to the clinically applied conditioning chemotherapy regimen cyclophosphamide and busulfan leads to increased efficacy of the chemotherapeutic regimen. We found that romiplostim not only sensitizes HSCs to chemotherapy but also enables a reduction of the main chemotherapeutic component busulfan by half while HSC engraftment levels are maintained in long-term, serial transplantation assays

Humanized mice: are we there yet?

Animal models have been instrumental in increasing the understanding of human physiology, particularly immunity. However, these animal models have been limited by practical considerations and genetic diversity. The creation of humanized mice that carry partial or complete human physiological systems may help overcome these obstacles. The National Institute of Allergy and Infectious Diseases convened a workshop on humanized mouse models for immunity in Bethesda, MD, on June 13–14, 2005, during which researchers discussed the benefits and limitations of existing animal models and offered insights into the development of future humanized mouse models

Nutrient mass balance of the seagrass Posidonia oceanica: the importance of nutrient retranslocation

The seasonal nutrient mass balance of the dominant seagrass of the Mediterranean, Posidonia oceanica (L.) Delde, was evaluated in NE Spain in order to test the hypothesis that the effect of seasonal nutrient imbalance can be reduced by the reutilization of internal nutrient pools. To this end we investigated the seasonal and age-dependent variability of nitrogen and phosphorus concentration of the leaves, inferring from these data values of seasonal nitrogen and phosphorus incorporation, uptake, losses and retranslocation. Incorporation of nitrogen and phosphorus in leaves peaked in June and was lowest in September, thus following the seasonal growth pattern of the plant. Retranslocation of nitrogen and phosphorus was high from May to September and close to zero during the rest of the year. Losses of nitrogen and phosphorus were highest at the end of summer, associated with the major biomass losses. Nitrogen uptake by leaves reached maximum values in winter and was lowest during August-September, while phosphorus uptake was highest in spring and lowest in August-September. On an annual basis nitrogen and phosphorus uptake accounted for 60 and 41 % of the total nutrient incorporation, respectively, while retranslocation of nutrients from old tissues accounted for the remaining 40 and 59%. Although roots and rhizomes function as sources of nutrients at the beginning of the summer, their contribution to the seasonal nutrient budget seemed to be minor.This work was supported by grant STEP-0063-C of the ECC.Peer reviewe

Flt3 Ligand Regulates Dendritic Cell Development from Flt3+ Lymphoid and Myeloid-committed Progenitors to Flt3+ Dendritic Cells In Vivo

Stimulation of Flt3 receptor tyrosine kinase through its cognate ligand expands early hematopoietic progenitor and dendritic cells (DCs) in humans and mice. The exact developmental stages at which hematopoietic progenitors express Flt3, are responsive to its ligand, and subsequently develop to DCs, are not known. Here we show that common lymphoid and common myeloid progenitors, as well as steady state DCs in thymus, spleen, and epidermis, express Flt3. The receptor is down-regulated once definitive B cell, T cell, and megakaryocyte/erythrocyte commitment occurs, and Flt3 is not detectable on other steady state hematopoietic cell populations. Upon in vivo Flt3 ligand (Flt3L) administration, Flt3+ progenitor cells and their progeny DCs are expanded, whereas Flt3− downstream progenitors are not, or are only slightly increased. Transplantation of common lymphoid and common myeloid progenitors and subsequent Flt3L injection increases progeny DCs of both precursor populations. These findings provide a definitive map of Flt3 expression in the hematopoietic hierarchy and directly demonstrate that Flt3L can drive DC development along both the lymphoid and myeloid developmental pathways from Flt3+ progenitors to Flt3+ DCs

Activation of the Flt3 signal transduction cascade rescues and enhances type I interferon–producing and dendritic cell development

Flt3 ligand (Flt3L) is a nonredundant cytokine in type I interferon–producing cell (IPC) and dendritic cell (DC) development, and IPC and DC differentiation potential is confined to Flt3+ hematopoietic progenitor cells. Here, we show that overexpression of human Flt3 in Flt3− (Flt3−Lin−IL-7Rα−Thy1.1−c-Kit+) and Flt3+ (Flt3+Lin−IL-7Rα−Thy1.1−c-Kit+) hematopoietic progenitors rescues and enhances their IPC and DC differentiation potential, respectively. In defined hematopoietic cell populations, such as Flt3− megakaryocyte/erythrocyte-restricted progenitors (MEPs), enforced Flt3 signaling induces transcription of IPC, DC, and granulocyte/macrophage (GM) development–affiliated genes, including STAT3, PU.1, and G-/M-/GM-CSFR, and activates differentiation capacities to these lineages. Moreover, ectopic expression of Flt3 downstream transcription factors STAT3 or PU.1 in Flt3− MEPs evokes Flt3 receptor expression and instructs differentiation into IPCs, DCs, and myelomonocytic cells, whereas GATA-1 expression and consecutive megakaryocyte/erythrocyte development is suppressed. Based on these data, we propose a demand-regulated, cytokine-driven DC and IPC regeneration model, in which high Flt3L levels initiate a self-sustaining, Flt3-STAT3– and Flt3-PU.1–mediated IPC and DC differentiation program in Flt3+ hematopoietic progenitor cells

Real-world outcomes in elderly ALL patients with and without allogeneic hematopoietic stem cell transplantation: a single-center evaluation over 10 years

Elderly patients (EP) of 60 years and above with acute lymphoblastic leukemia (ALL) have a dismal prognosis, but pediatric-inspired chemotherapy and allogeneic stem cell transplantation (allo HCT) are used reluctantly due to limited data and historical reports of high treatment-related mortality in EP. We analyzed 130 adult ALL patients treated at our center between 2009 and 2019, of which 26 were EP (range 60-76 years). Induction with pediatric-inspired protocols was feasible in 65.2% of EP and resulted in complete remission in 86.7% compared to 88.0% in younger patients (YP) of less than 60 years. Early death occurred in 6.7% of EP. Three-year overall survival (OS) for Ph - B-ALL was significantly worse for EP (n = 16) than YP (n = 64) with 30.0% vs 78.1% (p ≤ 0.001). Forty-nine patients received allo HCT including 8 EP, for which improved 3-year OS of 87.5% was observed, whereas EP without allo HCT died after a median of 9.5 months. In Ph + B-ALL, 3-year OS did not differ between EP (60.0%, n = 7) and YP (70.8%, n = 19). Non-relapse mortality and infection rate were low in EP (14.3% and 12.5%, respectively). Our data indicate that selected EP can be treated effectively and safely with pediatric regimens and might benefit from intensified therapy including allo HCT. Keywords: Acute lymphoblastic leukemia; Allogeneic hematopoietic stem cell transplantation; Elderly; Treatmen

Introducing innovative cellular therapies into the clinic: a 2-year retrospective experience of a chimeric antigen receptor T-cell programme at a single centre in Switzerland

AIM OF THE STUDY Chimeric antigen receptor T (CAR-T) cells are a powerful form of immune-cell therapy for patients with relapsed/refractory B-cell lymphoma and acute B lymphoblastic leukaemia. CAR-T cells have been commercially available in Switzerland since 2018. Because of the complexity and costs of this treatment it is critical to review patient outcomes in real-world settings, to examine whether the promising results from pivotal trials can be reproduced and to identify clinical parameters that determine their efficacy. METHODS Here we present results of a retrospective study analysing outcomes of patients treated with CAR-T cells in a single academic centre in Switzerland during the first two years after commercial approval (BASEC-No. 2020-02271). Cytokine release syndrome (CRS), immune-cell associated neurotoxicity syndrome (ICANS), responses to treatment, ancillary laboratory studies and administrative specifics of CAR-T treatment were examined and are discussed. RESULTS From October 2018 to August 2020 CAR-T cell therapy was evaluated in 34 patients, mostly with relapsed/refractory aggressive B-cell lymphoma (87% had refractory disease). Thirty-one patients underwent leukapheresis. Three of 31 patients (9.6%) died of rapid disease progression before the CAR-T cell product was delivered, two patients were enrolled into a clinical trial, three patients were not given CAR-T cells for other reasons. Ultimately, 23 patients were infused with a commercial CAR-T cell product and included in this analysis. Fourteen (61%) patients received bridging therapy while waiting for a median of 41 days (range 31-62) for delivery of the CAR-T cell product. Toxicity and severe side effects were rare (CRS >3 in 13%, ICANS > grade 3 in 10% of patients), manageable and resolved completely thereafter. The best overall response rate was 65%, with complete responses in 38% of lymphoma patients. At 12 months postinfusion, 61% of patients were alive and 35% progression free. With a median follow-up of 14 months, 13/23 (56%) patients were alive at the time of writing. CONCLUSION CAR-T cell therapy proved to be safe and manageable under adequate hospital conditions. Outcomes resemble results from pivotal trials. The majority of patients was heavily pretreated and refractory at the time of CAR-T cell infusion. Patient selection, time point of leukapheresis, bridging strategies and timing of CAR-T cell infusion may be critical to further improve outcomes

BRAF inhibitor treatment of classical hairy cell leukemia allows successful vaccination against SARS-CoV-2

In classical hairy cell leukemia (HCL), standard treatments including purine analogs achieve a durable response (up to 90%), but lead to severe immunosuppression and long-lasting depletion of CD4 + T lymphocytes. The BRAF inhibitor vemurafenib is effective in HCL, but its use in first-line treatment is restricted to select clinical situations (e.g. active infection). Its impact on immune function or response to vaccines in HCL is unclear. We treated four HCL patients with vemurafenib during the COVID-19 pandemic and monitored immune reconstitution and response to SARS-CoV-2 immunization. All patients responded to HCL treatment with normalization of peripheral blood counts. No severe infections occurred. As an indication of limited immunosuppression by vemurafenib, stable CD4 + and CD8 + T lymphocyte counts and immunoglobulin levels were observed. Three out of four patients received SARS-CoV-2 vaccination (Pfizer-BioNTech) during treatment with vemurafenib. IgG antibody levels against the spike-protein of SARS-CoV-2 were detected (40-818 AE/ml). Our data suggest that vemurafenib has limited effects on cellular and humoral immune function in HCL, which allows for successful SARS-CoV-2 vaccination. These data support the use of BRAF inhibitors during the current pandemic where continued immune response is necessary for minimizing the COVID-19-related risk of non-vaccinated patients