221 research outputs found
Optimization of the indications for allogeneic stem cell transplantation in Acute Myeloid Leukemia based on interactive diagnostic strategies
The indications for allogeneic stem cell transplantation (SCT) in Acute Myeloid Leukemia (AML) represent a real challenge due to the clinical and genetic heterogeneity of the disorder. Therefore, an optimized indication for SCT in AML first requires the determination of the individual relapse risk based on diverse chromosomal and molecular prognosis-defining aberrations. A broad panel of diagnostic methods is needed to allow such subclassification and prognostic stratification: cytomorphology, cytogenetics, molecular genetics, and immunophenotyping by multiparameter flow cytometry. These methods should not be seen as isolated techniques but as parts of an integral network with hierarchies and interactions. Examples for a poor risk constellation as a clear indication for allogeneic SCT are provided by anomalies of chromosome 7, complex aberrations, or FLT3-length mutations. In contrast, the favorable reciprocal translocations such as the t(15;17)/PML-RARA or t(8;21)/AML1-ETO are not indications for SCT in first remission due to the rather good prognosis after standard therapy. Further, the indication for SCT should include the results of minimal residual disease (MRD) diagnostics by polymerase chain reaction (PCR) or flow cytometry. New aspects for a safe and fast risk stratification as basis for an optimized indication for SCT in AML might be provided by novel technologies such as microarray-based gene expression profiling. Keywords: Acute Myeloid Leukemia (AML), Allogeneic Stem Cell Transplantation (SCT), Indication, Cytogenetics, Polymerase Chain Reaction (PCR
Self-pulsation at 480 GHz from a two-color discrete mode laser diode
A discrete mode Fabry-PĂ©rot laser is designed and fabricated to achieve two-color lasing. We demonstrate beating between the two laser modes and self-pulsation at 480 GHz
Inverse scattering approach to multiwavelength Fabry-PĂ©rot laser design
A class of multiwavelength Fabry-Pérot lasers is introduced where the spectrum is tailored through a patterning of the cavity effective index. The cavity geometry is obtained using an inverse scattering approach and can be designed such that the spacing of discrete Fabry-Pérot lasing modes is limited only by the bandwidth of the inverted gain medium. A specific two-color semiconductor laser with a mode spacing in the THz region is designed, and measurements are presented demonstrating the simultaneous oscillation of the two wavelengths. The nonperiodic effective index profile of the particular two-color device considered is shown to be related to a Moiré or superstructure grating
IL-10 dampens antitumor immunity and promotes liver metastasis via PD-L1 induction
Background & Aims: The liver is one of the organs most commonly affected by metastasis. The presence of liver metastases has been reported to be responsible for an immunosuppressive microenvironment and diminished immunotherapy efficacy. Herein, we aimed to investigate the role of IL-10 in liver metastasis and to determine how its modulation could affect the efficacy of immunotherapy in vivo. Methods: To induce spontaneous or forced liver metastasis in mice, murine cancer cells (MC38) or colon tumor organoids were injected into the cecum or the spleen, respectively. Mice with complete and cell type-specific deletion of IL-10 and IL-10 receptor alpha were used to identify the source and the target of IL-10 during metastasis formation. Programmed death ligand 1 (PD-L1)-deficient mice were used to test the role of this checkpoint. Flow cytometry was applied to characterize the regulation of PD-L1 by IL-10. Results: We found that Il10-deficient mice and mice treated with IL-10 receptor alpha antibodies were protected against liver metastasis formation. Furthermore, by using IL-10 reporter mice, we demonstrated that Foxp3+ regulatory T cells (Tregs) were the major cellular source of IL-10 in liver metastatic sites. Accordingly, deletion of IL-10 in Tregs, but not in myeloid cells, led to reduced liver metastasis. Mechanistically, IL-10 acted on Tregs in an autocrine manner, thereby further amplifying IL-10 production. Furthermore, IL-10 acted on myeloid cells, i.e. monocytes, and induced the upregulation of the immune checkpoint protein PD-L1. Finally, the PD-L1/PD-1 axis attenuated CD8-dependent cytotoxicity against metastatic lesions. Conclusions: Treg-derived IL-10 upregulates PD-L1 expression in monocytes, which in turn reduces CD8+ T-cell infiltration and related antitumor immunity in the context of colorectal cancer-derived liver metastases. These findings provide the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastases. Impact and implications: Liver metastasis diminishes the effectiveness of immunotherapy and increases the mortality rate in patients with colorectal cancer. We investigated the role of IL-10 in liver metastasis formation and assessed its impact on the effectiveness of immunotherapy. Our data show that IL-10 is a pro-metastatic factor involved in liver metastasis formation and that it acts as a regulator of PD-L1. This provides the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastasis.</p
IL-10 dampens antitumor immunity and promotes liver metastasis via PD-L1 induction
Background & Aims: The liver is one of the organs most commonly affected by metastasis. The presence of liver metastases has been reported to be responsible for an immunosuppressive microenvironment and diminished immunotherapy efficacy. Herein, we aimed to investigate the role of IL-10 in liver metastasis and to determine how its modulation could affect the efficacy of immunotherapy in vivo. Methods: To induce spontaneous or forced liver metastasis in mice, murine cancer cells (MC38) or colon tumor organoids were injected into the cecum or the spleen, respectively. Mice with complete and cell type-specific deletion of IL-10 and IL-10 receptor alpha were used to identify the source and the target of IL-10 during metastasis formation. Programmed death ligand 1 (PD-L1)-deficient mice were used to test the role of this checkpoint. Flow cytometry was applied to characterize the regulation of PD-L1 by IL-10. Results: We found that Il10-deficient mice and mice treated with IL-10 receptor alpha antibodies were protected against liver metastasis formation. Furthermore, by using IL-10 reporter mice, we demonstrated that Foxp3+ regulatory T cells (Tregs) were the major cellular source of IL-10 in liver metastatic sites. Accordingly, deletion of IL-10 in Tregs, but not in myeloid cells, led to reduced liver metastasis. Mechanistically, IL-10 acted on Tregs in an autocrine manner, thereby further amplifying IL-10 production. Furthermore, IL-10 acted on myeloid cells, i.e. monocytes, and induced the upregulation of the immune checkpoint protein PD-L1. Finally, the PD-L1/PD-1 axis attenuated CD8-dependent cytotoxicity against metastatic lesions. Conclusions: Treg-derived IL-10 upregulates PD-L1 expression in monocytes, which in turn reduces CD8+ T-cell infiltration and related antitumor immunity in the context of colorectal cancer-derived liver metastases. These findings provide the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastases. Impact and implications: Liver metastasis diminishes the effectiveness of immunotherapy and increases the mortality rate in patients with colorectal cancer. We investigated the role of IL-10 in liver metastasis formation and assessed its impact on the effectiveness of immunotherapy. Our data show that IL-10 is a pro-metastatic factor involved in liver metastasis formation and that it acts as a regulator of PD-L1. This provides the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastasis.</p
An Efficient Vector System to Modify Cells Genetically
The transfer of foreign genes into mammalian cells has been essential for understanding the functions of genes and mechanisms of genetic diseases, for the production of coding proteins and for gene therapy applications. Currently, the identification and selection of cells that have received transferred genetic material can be accomplished by methods, including drug selection, reporter enzyme detection and GFP imaging. These methods may confer antibiotic resistance, or be disruptive, or require special equipment. In this study, we labeled genetically modified cells with a cell surface biotinylation tag by co-transfecting cells with BirA, a biotin ligase. The modified cells can be quickly isolated for downstream applications using a simple streptavidin bead method. This system can also be used to screen cells expressing two sets of genes from separate vectors
Clonal competition in BcrAbl-driven leukemia: how transplantations can accelerate clonal conversion
Carbon sequestration and biodiversity following 18 years of active tropical forest restoration
Vast areas of degraded tropical forest, combined with increasing interest in mitigating climate change and conserving biodiversity, demonstrate the potential value of restoring tropical forest. However, there is a lack of long-term studies assessing active management for restoration. Here we investigate Above-Ground Biomass (AGB), forest structure, and biodiversity, before degradation (in old-growth forest), after degradation (in abandoned agricultural savanna grassland), and within a forest that is actively being restored in Kibale National Park, Uganda. In 1995 degraded land in Kibale was protected from fire and replanted with native seedlings (39 species) at a density of 400 seedlings ha-1. Sixty-five plots (50 m Ă 10 m) were established in restoration areas in 2005 and 50 of these were re-measured in 2013, allowing changes to be assessed over 18 years. Degraded plots have an Above Ground Biomass (AGB) of 5.1 Mg dry mass ha-1, of which 80% is grass. By 2005 AGB of trees â„10 cm DBH was 9.5 Mg ha-1, increasing to 40.6 Mg ha-1 by 2013, accumulating at a rate of 3.9 Mg ha-1 year-1. A total of 153 planted individuals ha-1 (38%) remained by 2013, contributing 28.9 Mg ha-1 (70%) of total AGB. Eighteen years after restoration, AGB in the plots was 12% of old-growth (419 Mg ha-1). If current accumulation rates continue restoration forest would reach old-growth AGB in a further 96 years. Biodiversity of degraded plots prior to restoration was low with no tree species and 2 seedling species per sample plot (0.05 ha). By 2005 restoration areas had an average of 3 tree and 3 seedling species per sample plot, increasing to 5 tree and 9 seedling species per plot in 2013. However, biodiversity was still significantly lower than old-growth forest, at 8 tree and 16 seedling species in an equivalent area. The results suggest that forest restoration is beneficial for AGB accumulation with planted stems storing the majority of AGB. Changes in biodiversity appear slower; possibly due to low stem turnover. Overall this restoration treatment is an effective means of restoring degraded land in the area, as can be seen from the lack of regeneration in degraded plots, which remain low-AGB and diversity, largely due to the impacts of fire and competition with grasses
PhD and Career â Do academics with a doctoral degree in Switzerland find adequate jobs?
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