Overcoming Steroid Resistance in Pediatric Acute Lymphoblastic Leukemia—The State-of-the-Art Knowledge and Future Prospects

Acute lymphoblastic leukemia (ALL) is the most common malignancy among children. Despite the enormous progress in ALL therapy, resulting in achieving a 5-year survival rate of up to 90%, the ambitious goal of reaching a 100% survival rate is still being pursued. A typical ALL treatment includes three phases: remission induction and consolidation and maintenance, preceded by a prednisone prephase. Poor prednisone response (PPR) is defined as the presence of ≥1.0 × 10⁹ blasts/L in the peripheral blood on day eight of therapy and results in significantly frequent relapses and worse outcomes. Hence, identifying risk factors of steroid resistance and finding methods of overcoming that resistance may significantly improve patients’ outcomes. A mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK-ERK) pathway seems to be a particularly attractive target, as its activation leads to steroid resistance via a phosphorylating Bcl-2-interacting mediator of cell death (BIM), which is crucial in the steroid-induced cell death. Several mutations causing activation of MAPK-ERK were discovered, notably the interleukin-7 receptor (IL-7R) pathway mutations in T-cell ALL and rat sarcoma virus (Ras) pathway mutations in precursor B-cell ALL. MAPK-ERK pathway inhibitors were demonstrated to enhance the results of dexamethasone therapy in preclinical ALL studies. This report summarizes steroids’ mechanism of action, resistance to treatment, and prospects of steroids therapy in pediatric ALL.     

Cyclic Fatigue-Crack Propagation in Magnesia-Partially-Stabilized Zirconia Ceramics

The subcritical growth of fatigue cracks under (tension-tension) cyclic loading is demonstrated for ceramic materials, based on experiments using compact C(T) specimens of a MgO-partially-stabilized zirconia (PSZ), heat-treated to vary the fracture toughness K _c from ∼3 to 16 MPa·m^1/2 and tested in inert and moist environments. Analogous to behavior in metals, cyclic fatigue-crack rates (over the range 10⁻¹¹ to 10⁻⁵ m/cycle) are found to be a function of the stress-intensity range, environment, fracture toughness, and load ratio, and to show evidence of fatigue crack closure. Unlike toughness behavior, growth rates are not dependent on through0-thickness constraint. Under variable-amplitude cyclic loading, crack-growth rates show transient accelerations following low-high block overloads and transient retardations following high-low block overloads or single tensile overloads, again analogous to behavior commonly observed in ductile metals. Cyclic crack-growth rates are observed at stress intensities as low as 50% of K _c , and are typically some 7 orders of magnitude faster than corresponding stress-corrosion crack-growth rates under sustained-loading conditions. Possible mechanisms for cyclic crack advance in ceramic materials are examined, and the practical implications of such "ceramic fatigue" are briefly discussed.     

Enzymes in organic synthesis. 2. Synthesis of enantiomerically pure prostaglandin intermediates by Enzymatic Hydrolysis of (1SR, 5RS, 6RS, 7RS)-7-acetoxy-6-acetoxymethyl-2-oxabicyclo[3.3.0]octan-3-one

Subtilisin DY as well as alkaline protease from Bacillus licheniformis 41 p catalyze the hydrolysis of (1SR, 5RS, 6RS, 7RS)-7-acetoxy-6-acetoxymethyl-2-oxabicyclo[3.3.0]octan-3-one ( rac-1 ) with practically useful enantio- and regioselectivity. Under the hitherto found optimal conditions (1S, 5R, 6R, 7R)-7-hydroxy-6-hydroxymethyl-2-oxabicyclo[3.3.0]octan-3-one ( 4 ), an important intermediate in prostaglandin syntheses, could be prepared in a yield of 16% with an enantiomeric excess of 99%. The enantiomer ( ent-4 ) was obtained with the same enantiomeric excess in 20% yield. The chemical yields are related to the racemic starting material rac-1 .     

Komplikationen bei der Initiierung kationischer Polymerisationen mit Lewis-Säuren - Modellrechnungen an Antimon-(V)-halogeniden

Complications in the Initiation of Cationic Polymerizations by Lewis Acids - Model Calculations for Antimony(V)halogenids Quantum-chemical CNDO/2-calculations including geometry-optimization show that complex anions (X₅Sb-Z-SbY₅)⊖ are formed as a result of interaction between Lewis acids SbX₅ and anions SbY₅Z⊖ (X, Y, Z = F, Cl, Br). This interaction is very strong in the case of X, Z = F and Y = Br. When the complex anions decompose the simple anions with the greatest number of fluorine ligands are formed. The interaction between the two different Lewis acids SbX₅ and SbY₅ yields a random distribution of the ligands of both acids. During formation of the ions SbX₄⊕ and SbXY₅⊖ the anion with the greatest number of fluorine ligands is formed. The probability of the conversion Sb(V)-Sb(III) is higher for SbCl₅ than for SbCl₆⊖.     

Three-dimensional simulation with a CFD tool of the airflow phenomena in single floor double-skin facade equipped with a venetian blind

Nowadays different kinds of double-skin facades are developed and used in new architectural projects. The aim of these facades is, on the one hand, to increase internal comfort and, on the other hand, to decrease energy consumption. In order to optimise the overall performance of the double-skin façades, their detailed behaviour needs to be better understood. The prediction of the airflow within the channel (between the two glazings) is very important for understanding of the double-skin facades behaviour, especially in summer conditions. A comprehensive modelling of a compact double-skin facade equipped with a venetian blind and forced ventilation is proposed here. The modelling is done using the CFD (computational fluid dynamics) approach to assess the air movement within the ventilated facade channel. Three-dimensional airflow is modelled using a homogeneous porous media representation, in order to reduce the size of the mathematical model. A parametric study is proposed here, analysing the impact of three parameters on the airflow development: slat tilt angle, blind position and air outlet position. The distance between the blind and the external glazing was found to have a major impact on the velocity profiles inside the double-skin facade channel.     

Hydroxyl Group Separation Distances in Anti-Freeze Compounds and Their Effects on Ice Nucleation

Since the discovery of biological antifreeze glycoproteins (AFGPs), which can inhibit ice nucleation, there has been considerable interest in understanding their mechanisms and mimicking them in synthetic polymers. In this study, we used molecular dynamics simulations of modified polyvinyl alcohol (PVA) compounds to show that the hydroxyl (OH) group distance is a key factor in whether certain compounds promote or inhibit ice nucleation. A hydroxyl distance smaller than ~2.8 Å but greater than ~7.1 Å in modified PVA (MPVA) compounds was associated with the promotion of ice nucleation, while a hydroxyl group separation distance of approximately ~5.0 Å was correlated with a delay in ice nucleation, owing to changes in the energy of the system. Thus, these results may help explain some of the mechanisms of current known anti-freeze compounds and may have implications for designing new anti-freeze compounds in the future.     

Preview benefit and parafoveal-on-foveal effects from word n + 2.

Using the gaze-contingent boundary paradigm with the boundary placed after word n, the experiment manipulated preview of word n + 2 for fixations on word n. There was no preview benefit for 1st-pass reading on word n + 2, replicating the results of K. Rayner, B. J. Juhasz, and S. J. Brown (2007), but there was a preview benefit on the 3-letter word n + 1, that is, after the boundary but before word n + 2. Additionally, both word n + 1 and word n + 2 exhibited parafoveal-on-foveal effects on word n. Thus, during a fixation on word n and given a short word n + 1, some information is extracted from word n + 2, supporting the hypothesis of distributed processing in the perceptual span. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Analysis of Volatiles Induced by Oviposition of Elm Leaf Beetle Xanthogaleruca luteola on Ulmus minor

Egg deposition of the elm leaf beetle Xanthogaleruca luteola causes the emission of volatiles from its food plant, Ulmus minor. These volatiles are exploited by the egg parasitoid, Oomyzus gallerucae, to locate its host. In contrast to other tritrophic systems, the release of volatiles is not induced by feeding but by egg deposition. Previous investigations showed that the release is systemic and can be triggered by jasmonic acid. Comparison of headspace analysis revealed similarities in the blend of volatiles emitted following egg deposition and feeding. The mixture consists of more than 40 compounds; most of the substances are terpenoids. Leaves next to those carrying eggs emit fewer compounds. When treated with jasmonic acid, leaves emit a blend that consists almost exclusively of terpenoids. Dichloromethane extracts of leaves treated with jasmonic acid were also investigated. After separation of extracts of jasmonate induced elm leaves on silica, we obtained a fraction of terpenoid hydrocarbons that was attractive to the parasitoids. This indicates that jasmonic acid stimulates the production of terpenoid hydrocarbons that convey information of egg deposition to the parasitoid.     

Tyrp1 Mutant Variants Associated with OCA3: Computational Characterization of Protein Stability and Ligand Binding

Oculocutaneous albinism type 3 (OCA3) is an autosomal recessive disorder caused by mutations in the TYRP1 gene. Tyrosinase-related protein 1 (Tyrp1) is involved in eumelanin synthesis, catalyzing the oxidation of 5,6-dihydroxyindole-2-carboxylic acid oxidase (DHICA) to 5,6-indolequinone-2-carboxylic acid (IQCA). Here, for the first time, four OCA3-causing mutations of Tyrp1, C30R, H215Y, D308N, and R326H, were investigated computationally to understand Tyrp1 protein stability and catalytic activity. Using the Tyrp1 crystal structure (PDB:5M8L), global mutagenesis was conducted to evaluate mutant protein stability. Consistent with the foldability parameter, C30R and H215Y should exhibit greater instability, and two other mutants, D308N and R326H, are expected to keep a native conformation. SDS-PAGE and Western blot analysis of the purified recombinant proteins confirmed that the foldability parameter correctly predicted the effect of mutations critical for protein stability. Further, the mutant variant structures were built and simulated for 100 ns to generate free energy landscapes and perform docking experiments. Free energy landscapes formed by Y362, N378, and T391 indicate that the binding clefts of C30R and H215Y mutants are larger than the wild-type Tyrp1. In docking simulations, the hydrogen bond and salt bridge interactions that stabilize DHICA in the active site remain similar among Tyrp1, D308N, and R326H. However, the strengths of these interactions and stability of the docked ligand may decrease proportionally to mutation severity due to the larger and less well-defined natures of the binding clefts in mutants. Mutational perturbations in mutants that are not unfolded may result in allosteric alterations to the active site, reducing the stability of protein-ligand interactions.