23 research outputs found
Deutsches MobilitÀtspanel (MOP) - wissenschaftliche Begleitung und erste Auswertungen. Bericht 2008
Genomic CDKN2A/2B deletions in adult Ph+ ALL are adverse despite allogeneic stem cell transplantation
We investigated the role of copy number alterations to refine risk stratification in adult Philadelphia chromosome positive (Ph)+ ALL treated with tyrosine kinase inhibitors (TKI) and allogeneic stem cell transplantation (aSCT). 97 Ph+ ALL patients (median age 41 years, range 18-64 years) within the prospective multicenter GMALL studies 06/99 (n=8) and 07/2003 (n=89) were analysed. All patients received TKI and aSCT in first complete remission (CR1). Copy number analysis was performed with SNP arrays and validated by multiplex ligation-dependent probe amplification (MLPA). The frequencies of recurrently deleted genes were: IKZF1, 76%, CDKN2A/2B, 45%, PAX5, 43%, BTG1, 18%, EBF1, 13%, ETV6, 5%, RB, 14%. In univariate analyses, the presence of CDKN2A/2B deletions had a negative impact on all endpoints: overall survival (p=0.023), disease free survival (p=0.012) and remission duration (p=0.036). The negative predictive value of CDKN2A/2B deletions was retained in multivariable analysis along with other factors such as timing of TKI therapy, intensity of conditioning, achieving remission after induction phase I and BTG1 deletions. We therefore conclude that acquired genomic CDKN2A/2B deletions identify a subgroup of Ph+ ALL patients, who have an inferior prognosis despite aSCT in CR1. Their poor outcome was attributable primarily to a high relapse rate after aSCT
The genetic architecture of the human cerebral cortex
The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder
âItâs your problem, not mineâ: does competence have anything to do with desire and aspiration to self-direct?
Targeting the Surface of the Protein 14â3â3 by Ultrasmall (1.5 nm) Gold Nanoparticles Carrying the Specific Peptide CRaf
The surface of ultrasmall gold nanoparticles with an average diameter of 1.55â
nm was conjugated with a 14â3â3 proteinâbinding peptide derived from CRaf. Each particle carries 18 CRaf peptides, leading to an overall stoichiometry of Au(115)Craf(18). The binding to the protein 14â3â3 was probed by isothermal titration calorimetry (ITC) and fluorescence polarization spectroscopy (FP). The dissociation constant (K (D)) was measured as 5.0â
ÎŒM by ITC and 0.9â
ÎŒM by FP, which was close to the affinity of dissolved CRaf to 14â3â3Ï. In contrast to dissolved CRaf, which alone did not enter HeLa cells, CRAFâconjugated gold nanoparticles were well taken up by HeLa cells, opening the opportunity to target the protein inside a cell
Long-term relapse-free survival in a phase 2 study of blinatumomab for the treatment of patients with minimal residual disease in B-lineage acute lymphoblastic leukemia
High-Throughput Screening To Identify Inhibitors Which Stabilize Inactive Kinase Conformations in p38α
Small molecule kinase inhibitors are an attractive means to modulate kinase activities in medicinal chemistry and chemical biology research. In the physiological setting of a cell, kinase function is orchestrated by a plethora of regulatory processes involving the structural transition of kinases between inactive and enzymatically competent conformations and vice versa. The development of novel kinase inhibitors is mainly fostered by high-throughput screening initiatives where the small molecule perturbation of the phosphorylation reaction is measured to identify inhibitors. Such setups require enzymatically active kinase preparations and present a risk of solely identifying classical ATP-competitive Type I inhibitors. Here we report the high-throughput screening of a library of similar to 35000 small organic molecules with an assay system that utilizes enzymatically inactive human p38 alpha MAP kinase to detect stabilizers of the pharmacologically more desirable DFG-out conformation. We used protein X-ray crystallography to characterize the binding mode of hit compounds and reveal structural features which explain how these ligands stabilize and/or induce the DFG-out conformation. Lastly, we show that although some of the hit compounds were confirmed by protein X-ray crystallography, they were not detected in classic phosphorylation assays, thus validating the unique sensitivity of the assay system used in this study and highlighting the potential of screening with inactive kinase preparations