Charakterisierung der Glucocorticoid-induzierten Zellantwort humaner ALL-Zelllinien nach zusätzlicher Modulation des Ubiquitin-Proteasom-Signalweges zur Überwindung der Glucocorticoid-Resistenz

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Modelling Shear Flows with SPH and Grid Based Methods

Given the importance of shear flows for astrophysical gas dynamics, we study the evolution of the Kelvin-Helmholtz instability (KHI) analytically and numerically. We derive the dispersion relation for the two-dimensional KHI including viscous dissipation. The resulting expression for the growth rate is then used to estimate the intrinsic viscosity of four numerical schemes depending on code-specific as well as on physical parameters. Our set of numerical schemes includes the Tree-SPH code VINE, an alternative SPH formulation developed by Price (2008), and the finite-volume grid codes FLASH and PLUTO. In the first part, we explicitly demonstrate the effect of dissipation-inhibiting mechanisms such as the Balsara viscosity on the evolution of the KHI. With VINE, increasing density contrasts lead to a continuously increasing suppression of the KHI (with complete suppression from a contrast of 6:1 or higher). The alternative SPH formulation including an artificial thermal conductivity reproduces the analytically expected growth rates up to a density contrast of 10:1. The second part addresses the shear flow evolution with FLASH and PLUTO. Both codes result in a consistent non-viscous evolution (in the equal as well as in the different density case) in agreement with the analytical prediction. The viscous evolution studied with FLASH shows minor deviations from the analytical prediction.Comment: 16 pages, 17 figure

Flow-Driven Cloud Formation and Fragmentation: Results From Eulerian and Lagrangian Simulations

The fragmentation of shocked flows in a thermally bistable medium provides a natural mechanism to form turbulent cold clouds as precursors to molecular clouds. Yet because of the large density and temperature differences and the range of dynamical scales involved, following this process with numerical simulations is challenging. We compare two-dimensional simulations of flow-driven cloud formation without self-gravity, using the Lagrangian Smoothed Particle Hydrodynamics (SPH) code VINE and the Eulerian grid code Proteus. Results are qualitatively similar for both methods, yet the variable spatial resolution of the SPH method leads to smaller fragments and thinner filaments, rendering the overall morphologies different. Thermal and hydro-dynamical instabilities lead to rapid cooling and fragmentation into cold clumps with temperatures below 300K. For clumps more massive than 1 Msun/pc, the clump mass function has an average slope of -0.8. The internal velocity dispersion of the clumps is nearly an order of magnitude smaller than their relative motion, rendering it subsonic with respect to the internal sound speed of the clumps, but supersonic as seen by an external observer. For the SPH simulations most of the cold gas resides at temperatures below 100K, while the grid-based models show an additional, substantial component between 100 and 300K. Independently of the numerical method our models confirm that converging flows of warm neutral gas fragment rapidly and form high-density, low-temperature clumps as possible seeds for star formation.Comment: 9 pages, 8 figures, MNRAS accepte

Genetic Variation in ABCC4 and CFTR and Acute Pancreatitis during Treatment of Pediatric Acute Lymphoblastic Leukemia

Background: Acute pancreatitis (AP) is a serious, mechanistically not entirely resolved side effect of L-asparaginase-containing treatment for acute lymphoblastic leukemia (ALL). To find new candidate variations for AP, we conducted a genome-wide association study (GWAS). Methods: In all, 1,004,623 single-nucleotide variants (SNVs) were analyzed in 51 pediatric ALL patients with AP (cases) and 1388 patients without AP (controls). Replication used independent patients. Results: The top-ranked SNV (rs4148513) was located within the ABCC4 gene (odds ratio (OR) 84.1; p = 1.04 × 10−14). Independent replication of our 20 top SNVs was not supportive of initial results, partly because rare variants were neither present in cases nor present in controls. However, results of combined analysis (GWAS and replication cohorts) remained significant (e.g., rs4148513; OR = 47.2; p = 7.31 × 10−9). Subsequently, we sequenced the entire ABCC4 gene and its close relative, the cystic fibrosis associated CFTR gene, a strong AP candidate gene, in 48 cases and 47 controls. Six AP-associated variants in ABCC4 and one variant in CFTR were detected. Replication confirmed the six ABCC4 variants but not the CFTR variant. Conclusions: Genetic variation within the ABCC4 gene was associated with AP during the treatment of ALL. No association of AP with CFTR was observed. Larger international studies are necessary to more conclusively assess the risk of rare clinical phenotypes

Benchmarking whole exome sequencing in the German Network for Personalized Medicine

Introduction Whole Exome Sequencing (WES) has emerged as an efficient tool in clinical cancer diagnostics to broaden the scope from panel-based diagnostics to screening of all genes and enabling robust determination of complex biomarkers in a single analysis. Methods To assess concordance, six formalin-fixed paraffin-embedded (FFPE) tissue specimens and four commercial reference standards were analyzed by WES as matched tumor-normal DNA at 21 NGS centers in Germany, each employing local wet-lab and bioinformatics investigating somatic and germline variants, copy-number alteration (CNA), and different complex biomarkers. Somatic variant calling was performed in 494 diagnostically relevant cancer genes. In addition, all raw data were re-analyzed with a central bioinformatic pipeline to separate wet- and dry-lab variability. Results The mean positive percentage agreement (PPA) of somatic variant calling was 76% and positive predictive value (PPV) 89% compared a consensus list of variants found by at least five centers. Variant filtering was identified as the main cause for divergent variant calls. Adjusting filter criteria and re-analysis increased the PPA to 88% for all and 97% for clinically relevant variants. CNA calls were concordant for 82% of genomic regions. Calls of homologous recombination deficiency (HRD), tumor mutational burden (TMB), and microsatellite instability (MSI) status were concordant for 94%, 93%, and 93% respectively. Variability of CNAs and complex biomarkers did not increase considerably using the central pipeline and was hence attributed to wet-lab differences. Conclusion Continuous optimization of bioinformatic workflows and participating in round robin tests are recommend

Central amazonian floodplain forests: Tree adaptations in a pulsing system

Amazonian floodplain forests are characterized by an annual flood pulse with changes of the water table that exceed 10 meters. Seedlings and adult trees are waterlogged or submerged for continuous periods lasting up to seven months per year. The monomodal flood pulse of the rivers causes drastic changes in the bioavailability of nutrients, oxygen levels, and concentrations of phytotoxins. The aquatic phase occurs during a period in which temperature and light conditions are optimal for plant growth and development, implying the need for adaptations. Not only do trees persist in a dormant state, they grow vigorously during most of the year, including the aquatic period. The regularity of flooding may have enhanced the evolution of specific traits, which partially are well known from floodplain trees in other tropical and in temperate regions. Different kinds of adaptations are found at the level of structural, physiological, and phenological traits. Combinations of adaptations regarding seed germination, seedling development, and traits of roots, shoots, and leaves result in a variety of growth strategies among trees. These lead to specific species distributions and zonations along the flooding gradient and within Amazonian floodplain systems (nutrient-rich white-water várzea and nutrient-poor black-water igapó). © 2004 The New York Botanical Garden

Hepatic sinusoidal obstruction syndrome and short-term application of 6-thioguanine in pediatric acute lymphoblastic leukemia

Long-term treatment with 6-thioguanine (6-TG) for pediatric acute lymphoblastic leukemia (ALL) is associated with high rates of hepatic sinusoidal obstruction syndrome (SOS). Nevertheless, current treatment continues to use short-term applications of 6-TG with only sparse information on toxicity. 6-TG is metabolized by thiopurine methyltransferase (TPMT) which underlies clinically relevant genetic polymorphism. We analyzed the association between hepatic SOS reported as a serious adverse event (SAE) and short-term 6-TG application in 3983 pediatric ALL patients treated on trial AIEOP-BFM ALL 2000 (derivation cohort) and defined the role of TPMT genotype in this relationship. We identified 17 patients (0.43%) with hepatic SOS, 13 of which with short-term exposure to 6-TG (P < 0.0001). Eight of the 13 patients were heterozygous for low-activity TPMT variants, resulting in a 22.4-fold (95% confidence interval 7.1–70.7; P ≤ 0.0001) increased risk of hepatic SOS for heterozygotes in comparison to TPMT wild-type patients. Results were supported by independent replication analysis. All patients with hepatic SOS after short-term 6-TG recovered and did not demonstrate residual symptoms. Thus, hepatic SOS is associated with short-term exposure to 6-TG during treatment of pediatric ALL and SOS risk is increased for patients with low-activity TPMT genotypes

Definition and Prognostic Value of Ph-like and IKZF1plus Status in Children With Down Syndrome and B-cell Precursor Acute Lymphoblastic Leukemia

Children with Down syndrome have an augmented risk for B-cell acute lymphoblastic leukemia (DS-ALL), which is associated with lower survival than in non-DS-ALL. It is known that cytogenetic abnormalities common in childhood ALL are less frequent in DS-ALL, while other genetic aberrancies (ie, CRLF2 overexpression and IKZF1 deletions) are increased. A possible cause for the lower survival of DS-ALL that we herewith evaluated for the first time was the incidence and prognostic value of the Philadelphia-like (Ph-like) profile and the IKZF1plus pattern. These features have been associated with poor outcome in non-DS ALL and therefore introduced in current therapeutic protocols. Forty-six out of 70 DS-ALL patients treated in Italy from 2000 to 2014 displayed Ph-like signature, mostly characterized by CRLF2 (n = 33) and IKZF1 (n = 16) alterations; only 2 cases were positive for ABL-class or PAX5-fusion genes. Moreover, in an Italian and German joint cohort of 134 DS-ALL patients, we observed 18% patients positive for IKZF1plus feature. Ph-like signature and IKZF1 deletion were associated with poor outcome (cumulative incidence of relapse: 27.7 ± 6.8% versus 13 ± 7%; P = 0.04 and 35.2 ± 8.6% versus 17 ± 3.9%; P = 0.007, respectively), which further worsens when IKZF1 deletion was co-occurring with P2RY8::CRLF2, qualifying for the IKZF1plus definition (13/15 patients had an event of relapse or treatment-related death). Notably, ex vivo drug screening revealed sensitivity of IKZF1plus blasts for drugs active against Ph-like ALL such as Birinapant and histone deacetylase inhibitors. We provided data in a large setting of a rare condition (DS-ALL) supporting that these patients, not associated with other high-risk features, need tailored therapeutic strategies