Combined Application of Pan-AKT Inhibitor MK-2206 and BCL-2 Antagonist Venetoclax in B-Cell Precursor Acute Lymphoblastic Leukemia

Aberrant PI3K/AKT signaling is a hallmark of acute B-lymphoblastic leukemia (B-ALL) resulting in increased tumor cell proliferation and apoptosis deficiency. While previous AKT inhibitors struggled with selectivity, MK-2206 promises meticulous pan-AKT targeting with proven anti-tumor activity. We herein, characterize the effect of MK-2206 on B-ALL cell lines and primary samples and investigate potential synergistic effects with BCL-2 inhibitor venetoclax to overcome limitations in apoptosis induction. MK-2206 incubation reduced AKT phosphorylation and influenced downstream signaling activity. Interestingly, after MK-2206 mono application tumor cell proliferation and metabolic activity were diminished significantly independently of basal AKT phosphorylation. Morphological changes but no induction of apoptosis was detected in the observed cell lines. In contrast, primary samples cultivated in a protective microenvironment showed a decrease in vital cells. Combined MK-2206 and venetoclax incubation resulted in partially synergistic anti-proliferative effects independently of application sequence in SEM and RS4;11 cell lines. Venetoclax-mediated apoptosis was not intensified by addition of MK-2206. Functional assessment of BCL-2 inhibition via Bax translocation assay revealed slightly increased pro-apoptotic signaling after combined MK-2206 and venetoclax incubation. In summary, we demonstrate that the pan-AKT inhibitor MK-2206 potently blocks B-ALL cell proliferation and for the first time characterize the synergistic effect of combined MK-2206 and venetoclax treatment in B-ALL.     

Verstärken mit textilbewehrtem Beton

Strengthening with Textile Reinforced Concrete The strengthening by textile reinforced concrete noticeably increases both the ultimate load bearing behaviour as well as the serviceability. This will be shown in the paper using experimental results and numerical simulations of strengthened concrete members.     

Identification of Novel Genes Involved in Hyperglycemia in Mice

Current attempts to prevent and manage type 2 diabetes have been moderately effective, and a better understanding of the molecular roots of this complex disease is important to develop more successful and precise treatment options. Recently, we initiated the collective diabetes cross, where four mouse inbred strains differing in their diabetes susceptibility were crossed with the obese and diabetes-prone NZO strain and identified the quantitative trait loci (QTL) Nidd13/NZO, a genomic region on chromosome 13 that correlates with hyperglycemia in NZO allele carriers compared to B6 controls. Subsequent analysis of the critical region, harboring 644 genes, included expression studies in pancreatic islets of congenic Nidd13/NZO mice, integration of single-cell data from parental NZO and B6 islets as well as haplotype analysis. Finally, of the five genes (Acot12, S100z, Ankrd55, Rnf180, and Iqgap2) within the polymorphic haplotype block that are differently expressed in islets of B6 compared to NZO mice, we identified the calcium-binding protein S100z gene to affect islet cell proliferation as well as apoptosis when overexpressed in MIN6 cells. In summary, we define S100z as the most striking gene to be causal for the diabetes QTL Nidd13/NZO by affecting β-cell proliferation and apoptosis. Thus, S100z is an entirely novel diabetes gene regulating islet cell function.     

The Inhibitory Response to PI3K/AKT Pathway Inhibitors MK-2206 and Buparlisib Is Related to Genetic Differences in Pancreatic Ductal Adenocarcinoma Cell Lines

The aberrant activation of the phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT) pathway is common in pancreatic ductal adenocarcinomas (PDAC). The application of inhibitors against PI3K and AKT has been considered as a therapeutic option. We investigated PDAC cell lines exposed to increasing concentrations of MK-2206 (an AKT1/2/3 inhibitor) and Buparlisib (a pan-PI3K inhibitor). Cell proliferation, metabolic activity, biomass, and apoptosis/necrosis were evaluated. Further, whole-exome sequencing (WES) and RNA sequencing (RNA-seq) were performed to analyze the recurrent aberrations and expression profiles of the inhibitor target genes and the genes frequently mutated in PDAC (Kirsten rat sarcoma virus (KRAS), Tumor protein p53 (TP53)). MK-2206 and Buparlisib demonstrated pronounced cytotoxic effects and limited cell-line-specific effects in cell death induction. WES revealed two sequence variants within the direct target genes (PIK3CA c.1143C > G in Colo357 and PIK3CD c.2480C > G in Capan-1), but a direct link to the Buparlisib response was not observed. RNA-seq demonstrated that the expression level of the inhibitor target genes did not affect the efficacy of the corresponding inhibitors. Moreover, increased resistance to MK-2206 was observed in the analyzed cell lines carrying a KRAS variant. Further, increased resistance to both inhibitors was observed in SU.86.86 carrying two TP53 missense variants. Additionally, the presence of the PIK3CA c.1143C > G in KRAS-variant-carrying cell lines was observed to correlate with increased sensitivity to Buparlisib. In conclusion, the present study reveals the distinct antitumor effects of PI3K/AKT pathway inhibitors against PDAC cell lines. Aberrations in specific target genes, as well as KRAS and TP53, individually or together, affect the efficacy of the two PI3K/AKT pathway inhibitors.     

Resting respiratory sinus arrhythmia buffers against rejection sensitivity via emotion control.

Emerging evidence suggests that high resting heart rate variability in the respiratory frequency band, or respiratory sinus arrhythmia (RSA) may capture individual differences in the capacity to engage in situationally appropriate regulation of affect and behavior. The authors therefore hypothesized that high RSA may act as a protective factor against difficulties controlling negative affect and hostile behaviors in conflicts with romantic partners in highly rejection-sensitive individuals--a population otherwise vulnerable to these responses. Results were consistent with this hypothesis such that highly rejection-sensitive participants reported less emotion control and more hostility in conflicts only if they were also low in RSA. Furthermore, emotion control mediated the joint effect of rejection-sensitivity and RSA on hostile conflict behavior. These results are consistent with the argument that resting RSA is a marker of flexible responding in the context of highly emotional situations, and further suggest that it may serve as a protective factor particularly in vulnerable populations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sorption-induced effects of humic substances on mass transfer of organic pollutants through aqueous diffusion boundary layers: the example of water/air exchange

This study examines the effect of dissolved humic substances (DHS) on the rate of water-gas exchange of organic compounds under conditions where diffusion through the aqueous boundary layer is rate-determining. A synthetic surfactant was applied for comparison. Mass-transfer coefficients were determined from the rate of depletion of the model compounds by means of an apparatus containing a stirred aqueous solution with continuous purging of the headspace above the solution. In addition, experiments with continuous passive dosing of analytes into the water phase were conducted to simulate a system where thermodynamic activity of the chemical in the aqueous phase is identical in the presence and absence of DHS. The experimental results show that DHS and surfactants can affect water-gas exchange rates by the superposition of two mechanisms: (1) hydrodynamic effects due to surface film formation ("surface smoothing"), and (2) sorption-induced effects. Whether sorption accelerates or retards mass transfer depends on its effect on the thermodynamic activity of the pollutant in the aqueous phase. Mass transfer will be retarded if the activity (or freely dissolved concentration) of the pollutant is decreased due to sorption. If it remains unchanged (e.g., due to fast equilibration with a sediment acting as a large source phase), then DHS and surfactant micelles can act as an additional shuttle for the pollutants, enhancing the flux through the boundary layer.     

Comparing properties of substrate-constrained and freestanding epitaxial Ni–Mn–Ga films

In order to use the magnetic shape memory alloy Ni–Mn–Ga with its high achievable strain of up to 10% for microactuators, freestanding epitaxial films are required. Here we show that these conditions can be fulfilled when using chromium as a sacrificial layer. The low misfit towards Ni–Mn–Ga enables epitaxial growth. Furthermore, Cr can afterwards be removed selectively by wet-chemical etching and during deposition no significant interdiffusion is observed. The structure, microstructure and magnetic properties of micrometer thick films are not affected by the etching process. Films are ferromagnetic at room temperature and we observe the coexistence of non-modulated (NM) and seven layered modulated (14 M) martensite. Tensile stress–strain measurement of a freestanding bridge reveals a broad strain plateau of 12% at a twinning stress of 25 MPa, indicating reorientation of NM variants.     

Watershed and lake influences on the energetic base of coastal wetland food webs across the Great Lakes Basin

We examined factors that influence the energy base of Great Lakes coastal wetland food webs across a basin-wide gradient of landscape disturbance. Wetland nutrient concentrations were positively correlated with a principal components-based metric of agricultural practices. Hydraulic residence time influenced the energy base of wetland food webs, with high residence-time systems based mostly on plankton and low residence-time systems based mostly upon benthos. In systems with plankton, the importance of planktonic carbon to the resident fish community generally increased with residence time. A stronger relationship was apparent with an index of nutrient loading that combined residence time and nutrient concentration as the predictor (R² = 0.289, p = 0.026). Shifts toward plankton-based food webs occurred at relatively low levels of loading. In riverine wetlands without plankton, contributions of detrital carbon to fish communities decreased significantly in response to watershed disturbance that reflected nutrient loading. In a third class of wetlands the wetland-resident fish communities were not entirely supported by within-wetland carbon sources and were significantly subsidized by nearshore habitats, which provided 35 (± 22) to 73 (± 9) % of fish community carbon. When lake-run migrant fish were included in the analyses, nearshore subsidies to all 30 wetland food webs ranged from 3 (± 2) to 79 (± 12) %. We obtained similar ranges when examining nearshore contributions to a single wetland species, northern pike. These results illustrate the spatial scale and the degree to which the energetics of coastal wetland food webs are influenced by interactions with their watersheds and Great Lakes.     

Experiment planning using high-level component models at W7-X

The superconducting stellarator Wendelstein 7-X (W7-X) is a fusion device, which is capable of steady state operation. Furthermore W7-X is a very complex technical system. To cope with these requirements a modular and strongly hierarchical component-based control and data acquisition system has been designed.The behavior of W7-X is characterized by thousands of technical parameters of the participating components. The intended sequential change of those parameters during an experiment is defined in an experiment program. Planning such an experiment program is a crucial and complex task. To reduce the complexity an abstract, more physics-oriented high-level layer has been introduced earlier. The so-called high-level (physics) parameters are used to encapsulate technical details.This contribution will focus on the extension of this layer to a high-level component model. It completely describes the behavior of a component for a certain period of time. It allows not only defining simple value ranges but also complex dependencies between physics parameters. This can be: dependencies within components, dependencies between components or temporal dependencies.Component models can now be analyzed to generate various views of an experiment. A first implementation of such an analyze process is already finished. A graphical preview of a planned discharge can be generated from a chronological sequence of component models. This allows physicists to survey complex planned experiment programs at a glance.