Expression of PIK3CA mutant E545K in the mammary gland induces heterogeneous tumors but is less potent than mutant H1047R.

The phosphoinositide 3-kinase (PI3K) signaling cascade is a key mediator of cellular growth, survival and metabolism and is frequently subverted in human cancer. The gene encoding for the alpha catalytic subunit of PI3K (PIK3CA) is mutated and/or amplified in ∼30% of breast cancers. Mutations in either the kinase domain (H1047R) or the helical domain (E545K) are most common and result in a constitutively active enzyme with oncogenic capacity. PIK3CA(H1047R) was previously demonstrated to induce tumors in transgenic mouse models; however, it was not known whether overexpression of PIK3CA(E545K) is sufficient to induce mammary tumors and whether tumor initiation by these two types of mutants differs. Here, we demonstrate that expression of PIK3CA(E545K) in the mouse mammary gland induces heterogenous mammary carcinomas but with a longer latency than PIK3CA(H1047R)-expressing mice. Our results suggest that the helical domain mutant PIK3CA(E545K) is a less potent inducer of mammary tumors due to less efficient activation of downstream Akt signaling

Magnetic Fourier Integral Operators

In some previous papers we have defined and studied a 'magnetic' pseudodifferential calculus as a gauge covariant generalization of the Weyl calculus when a magnetic field is present. In this paper we extend the standard Fourier Integral Operators Theory to the case with a magnetic field, proving composition theorems, continuity theorems in 'magnetic' Sobolev spaces and Egorov type theorems. The main application is the representation of the evolution group generated by a 1-st order 'magnetic' pseudodifferential operator (in particular the relativistic Schr\"{o}dinger operator with magnetic field) as such a 'magnetic' Fourier Integral Operator. As a consequence of this representation we obtain some estimations for the distribution kernel of this evolution group and a result on the propagation of singularities

TheMPO: A knowledge-based system for therapy planning in pediatric oncology

This article describes the knowledge-based system THEMPO (Therapy Management in Pediatric Oncology), which supports protocol-directed therapy planning and configuration in pediatric oncology. THEMPO provides a semantic network controlled by graph grammars to cover the different types of knowledge relevant in the domain, and offers a suite of acquisition tools for knowledge base authoring. Medical problem solvers, operating on the oncological network, reason about adequate therapeutic and diagnostic timetables for a patient. Furthermore, a corresponding patient record, also based on semantic networks and graph grammars, has been implemented to represent the course of therapy of an oncological patient

19F-labeling of the adenine H2-site to study large RNAs by NMR spectroscopy

In comparison to proteins and protein complexes, the size of RNA amenable to NMR studies is limited despite the development of new isotopic labeling strategies including deuteration and ligation of differentially labeled RNAs. Due to the restricted chemical shift dispersion in only four different nucleotides spectral resolution remains limited in larger RNAs. Labeling RNAs with the NMR-active nucleus [superscript 19]F has previously been introduced for small RNAs up to 40 nucleotides (nt). In the presented work, we study the natural occurring RNA aptamer domain of the guanine-sensing riboswitch comprising 73 nucleotides from Bacillus subtilis. The work includes protocols for improved in vitro transcription of 2-fluoroadenosine-5′-triphosphat (2F-ATP) using the mutant P266L of the T7 RNA polymerase. Our NMR analysis shows that the secondary and tertiary structure of the riboswitch is fully maintained and that the specific binding of the cognate ligand hypoxanthine is not impaired by the introduction of the [superscript 19]F isotope. The thermal stability of the [superscript 19]F-labeled riboswitch is not altered compared to the unmodified sequence, but local base pair stabilities, as measured by hydrogen exchange experiments, are modulated. The characteristic change in the chemical shift of the imino resonances detected in a 1H,15N-HSQC allow the identification of Watson–Crick base paired uridine signals and the [superscript 19]F resonances can be used as reporters for tertiary and secondary structure transitions, confirming the potential of [superscript 19]F-labeling even for sizeable RNAs in the range of 70 nucleotides.Deutsche Forschungsgemeinschaft (collaborative research center: SFB902

Shape-dependent universality in percolation

The shape-dependent universality of the excess percolation cluster number and cross-configuration probability on a torus is discussed. Besides the aspect ratio of the torus, the universality class depends upon the twist in the periodic boundary conditions, which for example are generally introduced when triangular lattices are used in simulations.Comment: 11 pages, 3 figures, to be published in Physica

Excess number of percolation clusters on the surface of a sphere

Monte Carlo simulations were performed in order to determine the excess number of clusters b and the average density of clusters n_c for the two-dimensional "Swiss cheese" continuum percolation model on a planar L x L system and on the surface of a sphere. The excess number of clusters for the L x L system was confirmed to be a universal quantity with a value b = 0.8841 as previously predicted and verified only for lattice percolation. The excess number of clusters on the surface of a sphere was found to have the value b = 1.215(1) for discs with the same coverage as the flat critical system. Finally, the average critical density of clusters was calculated for continuum systems n_c = 0.0408(1).Comment: 13 pages, 2 figure

Premature subclinical atherosclerosis in children and young adults with juvenile idiopathic arthritis.:A review considering preventive measures

Many studies show that Juvenile Idiopathic Arthritis (JIA) is associated with early subclinical signs of atherosclerosis. Chronic inflammation per se may be an important driver but other known risk factors, such as dyslipidemia, hypertension, insulin insensitivity, a physically inactive lifestyle, obesity, and tobacco smoking may also contribute substantially. We performed a systematic review of studies through the last 20 years on early signs of subclinical atherosclerosis in children and adolescents with JIA with the purpose of investigating whether possible risk factors, other than inflammation, were considered. We found 13 descriptive cross sectional studies with healthy controls, one intervention study and two studies on adults diagnosed with JIA. Only one study addressed obesity, and physical activity (PA) has only been assessed in one study on adults with JIA and only by self-reporting. This is important as studies on PA in children with JIA have shown that most patients are less physically active than their healthy peers, and as physical inactivity in several large studies of normal schoolchildren is found to be associated with increased clustering of risk factors for cardiovascular disease. It is thus possible that an inactive lifestyle in patients with JIA is an important contributor to development of the subclinical signs of atherosclerosis seen in children with JIA, and that promotion of an active lifestyle in childhood and adolescence may diminish the risk for premature atherosclerotic events in adulthood

Perspective Chapter: Negative Thermal Gradient Gas Chromatography

Gas chromatography is typically operated in isothermal mode for optimum separation of a mixture of compounds with a narrow boiling point range, or in temperature-programmed mode, which strives to achieve a compromise between separation efficiency and time. Temperature gradients also keep the peak widths nearly constant over a wide range of retention times, enhancing the detectability of the later eluting peaks. In this chapter, the use of negative thermal gradients for gas chromatography (NTGGC) – for the sake of simplicity, subsequently only denoted as thermal gradient-gas chromatography, TGGC – shall be discussed. (N)TGGC is achieved by producing a stationary temperature gradient along the relatively short GC column in a proprietary experimental setup that allows cooling on one end of the column and heating on the other. The sample is injected into the hot end of the GC column, and analytes move towards the colder end of the column. Along their passage through the column, they are focused by the increasingly lower temperature of the stationary phase. This leads to a focusing of the peaks as they reach the cold column end. With appropriate temperature programming, very fast (sub-minute) chromatography with excellent resolution can be achieved on short GC columns. The present contribution will both discuss the theory behind this unusual, but highly performant mode of gas chromatographic separation, and also the hardware aspects of this technique. Relevant examples will be presented which highlight both the speed and the separation power by which (N)TGGC excels in comparison with regular temperature-programmed GC