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(1) Background: High-dose chemotherapy (HDCT) before autologous stem cell transplantation (ASCT) in acute myeloid leukemia (AML) patients predominantly combines busulfan with cyclophosphamide or melphalan. Treosulfan compares favorably regarding lower inter-individual bioavailability and neurotoxicity, but so far, had not been studied before ASCT in AML. (2) Methods: This single-center study investigated AML patients undergoing ASCT in CR1 between November 2017 and September 2020. The first 16 patients received busulfan 16 mg/kg b.w. (days −5 to −2) and melphalan 140 mg/m2 (day −1) (BuMel). In a subsequent (TreoMel) cohort, 20 patients received treosulfan 14 g/m2 (days −4 to −2) and melphalan. Plasma concentrations of busulfan and treosulfan were determined by mass spectrometry. (3) Results: Neutrophil engraftment and platelet recovery were similar, and PFS and OS were comparable. In only the BuMel cohort, patients reported central nervous toxicities, including seizures (6%) and encephalopathy (12%). The mean AUC for busulfan was 1471.32 μM*min, and for treosulfan it was 836.79 mg/L*h, with ranges of 804.1–2082 μM*min and 454.2–1402 mg/L*h. The peak values for busulfan ranged between 880.19–1734 μg/L and for treosulfan between 194.3–489.25 mg/L. (4) Conclusions: TreoMel appears to be safe and effective for pre-ASCT treatment in AML patients. Due to considerable interindividual biovariability, pharmacologic monitoring may also be warranted for the use of treosulfan.

Background Immunosuppressive therapies derived from solid organ transplantation are effective in promoting survival of vascularized composite allotransplantation (VCA), but they cause serious side effects that are difficult to justify for this non–life-saving procedure. Unlike solid organ transplantation, hand and face transplants offer the possibility of site-specific immunosuppression for reducing systemic exposure while increasing intra-graft concentrations of the drug. Therefore, in this study, we tested whether a single intra-graft injection tacrolimus could promote VCA survival. Methods Brown Norway-to-Lewis hind limb transplantations were performed, and animals were left untreated (group I), treated with a daily injection of 1-mg/kg tacrolimus for 21 days (group 2) or injected with 7-mg tacrolimus directly into the transplanted limb on day 1 (group III). Graft rejection was monitored, and animals were sacrificed at grade 3 rejection or 200 days after transplantation. Results Intra-graft injection of tacrolimus significantly prolonged allograft survival as compared to untreated animals or animals treated with systemic tacrolimus. Half of the intra-graft–treated rats rejected their graft on average at day 70.5. Interestingly, the other half remained rejection-free for more than 200 days without signs of kidney or liver toxicity. In these animals, tacrolimus was detected in the VCA skin but not in the blood until day 200. Long-term survival was not linked to induction of donor-specific tolerance but to a higher level of lymphocyte chimerism. Conclusions Intra-graft delivery of tacrolimus may promote VCA survival by increasing tissue drug availability and promoting the establishment of transient chimerism and thus long-term graft acceptance.

A reduced immune surveillance due to immune deficiency or treatment with immunosuppressive drugs is associated with a higher risk to develop aggressive Non-Hodgkin's lymphoma (NHL). Nevertheless, NHL also develops in immunocompetent patients indicating an escape from the immune system. T cell function in advanced aggressive lymphoma is not well characterized and the molecular mechanisms how malignant B cells influence T cell function are ill-defined. We therefore studied T cell function in Eμ-myc transgenic mice that develop an aggressive B cell lymphoma with some similarities to human Burkitt-lymphoma (BL). In advanced lymphoma, the number of T cells was severely reduced and the remaining CD4+ and CD8+ T cells lost the capacity to produce effector cytokines and expand upon re-stimulation. T cells in lymphoma-bearing mice were characterized by the expression of the immune inhibitory molecules programmed death (PD)-1, 2B4 and lymphocyte activation protein (LAG)-3. The proto-oncogene c-Myc not only drives cell proliferation and disease progression but also induces apoptosis of the malignant cells. We found that apoptotic lymphoma cells release purine metabolites that inhibit T cell function. Taken together, our data document that the characteristic high cell turnover and apoptotic rate in aggressive NHL induce a severe T cell dysfunction mediated by several immune-inhibitory mechanisms including ligation of inhibitory ligands and purine metabolites. Blocking a single mechanism only partially restored T cell function and did not increase survival of lymphoma mice.

Astronomical research at present requires that a telescope with an aperture diameter of between 50 and 100 metres be constructed within the next 10 years or so. This new generation of telescopes will be called OWL (Overwhelmingly Large), and it represents one order of magnitude increase in size over today's telescopes. Selection of an ideal site for this giant telescope is dependent on many climatological, meteorological and geomorphological parameters (Grenon 1990). Among these are cloud cover, atmospheric humidity, aerosol content, airflow direction and strength, air temperature, topography, and seismicity. Even relatively minor changes in weather patterns can have a significant effect on seeing conditions (Beniston et al. 2002).

Selection of an ideal site for the new generation of Overwhelmingly Large (OWL) telescopes is dependent on many climatological and meteorological parameters. Among these are cloud cover, atmospheric humidity, aerosol content, air temperature, airflow direction, strength and turbulence. Even relatively minor changes in weather patterns can have a significant effect on seeing conditions. A composite climatological database has been designed and built for the site selection task at the Department of Geosciences, University of Fribourg, Switzerland. The database is mainly composed of ECMWF and NCEP-NCAR reanalysis data at a global resolution of between 1° and 2.5° latitude / longitude. Using a Java based interface, codenamed "FriOWL", and programmed in the style of a Geographical Information System, all of this relevant information can be interrogated in order to find the best possible sites for the new telescope. Perhaps the most important variable in site selection is the interaction between air-flow and topography, as atmospheric turbulence greatly affects the image quality produced by the telescope. Global climate is changing and it will continue to do throughout the 21st century. Therefore, it is important to ascertain the effect of global warming on potential sites. An ideal site in today’s climate may not prove ideal within 20 to 50 years. It is therefore planned to update the database with future climate data, using output from global climate models. High resolution modeling of the critical parameters at preferred sites under future climates is also planned.