Differential redox-regulation and mitochondrial dynamics in normal and leukemic hematopoietic stem cells:A potential window for leukemia therapy

The prognosis for many patients with acute myeloid leukemia (AML) is poor, mainly due to disease relapse driven by leukemia stem cells (LSCs). Recent studies have highlighted the unique metabolic properties of LSCs, which might represent opportunities for LSC-selective targeting. LSCs characteristically have low levels of reactive oxygen species (ROS), which apparently result from a combination of low mitochondria] activity and high activity of ROS-removing pathways such as autophagy. Due to this low activity, LSCs are highly dependent on mitochondrial regulatory mechanisms. These include the anti-apoptotic protein BCL-2, which also has crucial roles in regulating the mitochondrial membrane potential, and proteins involved in mitophagy. Here we review the different pathways that impact mitochondrial activity and redox-regulation, and highlight their relevance for the functionality of both HSCs and LSCs. Additionally, novel AML therapy strategies that are based on interference with those pathways, including the promising BCL-2 inhibitor Venetoclax, are summarized

Drought sensitivity of Empetrum nigrum shrub growth at the species' southern lowland distribution range margin

The ongoing warming of the Earth's atmosphere is projected to cause a northward shift of species' distributions, as they track their climatic optimum. In the rapidly warming Arctic, this has already led to an increase of shrubs in tundra ecosystems. While this northern expansion of woody biomass has been studied relatively extensively over the last decade, little research has been devoted to shrub growth responses at the southern margins of Northern Hemisphere shrubs. Here, we studied shoot length growth, its responses to climate over the period 2010-2017, and differences in leaf C and N content of the evergreen dwarf shrub Empetrum nigrum, as well as the vegetation composition and soil parameters at four sites located along a gradient of increasing dune age on the island Spiekeroog, northern Germany. The sites are located in the tri-national UNESCO world heritage site, the Wadden Sea. E. nigrum has a predominantly circum-arctic-boreal distribution and its southern distribution margin in European lowlands runs through northern Germany, where it is retreating northwards. We found a negative response to autumn (surface) temperatures and previous summer surface temperatures and/or a positive response to summer precipitation of E. nigrum growth, except at the oldest dune with the strongest E. nigrum dominance. Growth rates and plant species diversity declined with dune age. Our results suggest that E. nigrum growth is drought sensitive at its European southern range margin. We hypothesize that this sensitivity may form the basis for its northward retreat, which is supported by recent observations of E. nigrum dieback in Germany after the extreme drought in 2018 and model projections

CITED2 affects leukemic cell survival by interfering with p53 activation

CITED2 (CBP/p300-interacting-transactivator-with-an-ED-rich-tail 2) is a regulator of the acetyltransferase CBP/p300 and elevated CITED2 levels are shown in a number of acute myeloid leukemia (AML). To study the in vivo role of CITED2 in AML maintenance, AML cells were transduced with a lentiviral construct for RNAi-mediated knockdown of CITED2. Mice transplanted with CITED2-knockdown AML cells (n = 4) had a significantly longer survival compared to mice transplanted with control AML cells (P <0.02). In vitro, the reduction of CITED2 resulted in increased p53-mediated apoptosis and CDKN1A expression, whereas BCL2 levels were reduced. The activation of p53 upon CITED2 knockdown is not a direct consequence of increased CBP/p300-activity towards p53, since no increased formation of CBP/p300/p53 complexes was demonstrated and inhibition of CBP/p300-activity could not rescue the phenotype of CITED2-deficient cells. Instead, loss of CITED2 had an inhibitory effect on the AKT-signaling pathway, which was indicated by decreased levels of phosphorylated AKT and altered expression of the AKT-pathway regulators PHLDA3 and SOX4. Notably, simultaneous upregulation of BCL2 or downregulation of the p53-target gene PHLDA3 rescued the apoptotic phenotype in CITED2-knockdown cells. Furthermore, knockdown of CITED2 led to a decreased interaction of p53 with its inhibitor MDM2, which results in increased amounts of total p53 protein. In summary, our data indicate that CITED2 functions in pathways regulating p53 activity and therefore represents an interesting target for AML therapy, since de novo AML cases are characterized by an inactivation of the p53 pathway or deregulation of apoptosis-related genes

Effect of the 3D Structure and Grain Boundaries on Lithium Transport in Garnet Solid Electrolytes

Lithium metal anodes are vital enablers for high-energy all-solid-state batteries (ASSBs). To promote ASSBs in practical applications, performance limitations such as the high lithium interface resistance and the grain boundary resistance in the solid electrolyte (SE) need to be understood and reduced by optimization of the cell design. In this work, we use our 3D microstructure-resolved simulation approach combined with a modified grain boundary transport model for the SE to shed some light on the aforementioned limitations in garnet ASSBs. Using high-resolution volume images of the SE electrode sample, we are able to reconstruct the SE microstructure. Using a grain segmentation algorithm, we further distinguish individual grains and account for the influence of the SE grain size and grain boundaries. We focus our simulation work on the trilayer cell architecture, consisting of two porous SE electrodes separated by a dense layer. Even though the highly porous SE electrodes reduce the lithium interface resistance by providing a higher active surface area, the increased electrode tortuosity also reduces the effective ionic conductivity in the SE. We confirm via impedance simulation studies and validation against experimental results that with increasing SE electrode porosity, the lithium transport becomes limited by grain boundaries. We also correlate the area-specific resistance to different lithium infiltration stages in the trilayer cell by spatially resolving the current density distribution. This analysis allows us to suggest a plausible deposition mechanism, and moreover, we identify current density hot spots in the proximity of the dense layer. These hot spots might lead to dendrite formation and long-term cell failure. The joint theoretical and experimental study gives guidelines for cell design and optimization which allow further improvement of the trilayer architecture

The price of tumor control

Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects

Host taxon-derived Sarcoptes mite in European wild animals revealed by microsatellite markers

Ten markers specific to Sarcoptes mites were used in applying microsatellite genotyping to individual Sarcoptes mites collected in three European countries from 15 wild mammal populations belonging to 10 host species. The results showed that geographical separation had real biological significance for the definition of mite sub-populations, and that the degree of genetic exchange occurring between mites from different localities was apparently related to the geographical distance between locations. Wild host-derived mite populations were found to be clustered into three main groups: herbivore-, carnivore- and omnivore-derived Sarcoptes populations, with the omnivore-derived group located halfway between the herbivore- and carnivore-derived Sarcoptes populations. The separation between these three mite groups was better supported than the geographical separations; nevertheless, a kind of sub-clustering was detected within each of these three groups that separates mite populations into their geographical localities (countries). The lack of gene flow between Sarcoptes populations may have improved parasitic adaptations and led to what we refer to as a host-taxon-derived (carnivore host-, herbivore host- and omnivore host-derived) Sarcoptes mite found on European wild animals. Our results demonstrate that Sarcoptes is not a single panmictic population, even within each geographical location. This finding will have important ramifications for the study of the genetic structure of populations, life cycles, diagnosis and the monitoring protocols of the ubiquitous Sarcoptes mite, and could thus contribute to a better understanding of its associated epidemiology, which is of pivotal interest for wildlife biological conservation. © 2010 Elsevier Ltd. All rights reserved.Peer Reviewe

第985回千葉医学会例会・第二内科例会

Magnetic resonance spectroscopy (MRS) provides the unique ability to monitor several disease-related pathological processes via their characteristic metabolic markers in vivo. In the present study metabolic compositions were assessed every six months over the period of two years in 36 patients with Multiple Sclerosis (MS) including 21 relapsing-remitting (RR), 15 secondary progressive (SP) patients and 12 normal subjects. The concentrations of the main MRS-detectable metabolites N-acetylaspartate and N-acetylaspartylglutamate (tNAA), creatine and phosphocreatine (tCr), choline containing compounds (Cho), myo-Inositol (Ins), glutamine and glutamate (Glx) and their ratios were calculated in the normal appearing white matter (NAWM) and in selected non-enhancing white matter (WM) lesions. Association between metabolic concentrations in the NAWM and disability were investigated. Concentration of tNAA, a marker for neuroaxonal integrity, did not show any difference between the investigated groups. However, the patients with SPMS showed significant reduction of tNAA in the NAWM over the investigation period of two years indicating diffuse neuroaxonal loss during the disease course. Furthermore, we found a significant increase of Ins, Ins/tCr and Ins/tNAA in WM lesions independently from the course of the disease suggesting ongoing astrogliosis in silent-appearing WM lesions. Analyzing correlations between MRS metabolites in the NAWM and patients clinical status we found the positive correlation of Ins/tNAA with disability in patients with RRMS. In SPMS positive correlation of Cho with disability was found