In Vitro Treatment of Melanoma Brain Metastasis by Simultaneously Targeting the MAPK and PI3K Signaling Pathways

Malignant melanoma is the most lethal form of skin cancer, with a high propensity to metastasize to the brain. More than 60% of melanomas have the BRAF^V600E mutation, which activates the mitogen-activated protein kinase (MAPK) pathway [1]. In addition, increased PI3K (phosphoinositide 3-kinase) pathway activity has been demonstrated, through the loss of activity of the tumor suppressor gene, PTEN [2]. Here, we treated two melanoma brain metastasis cell lines, H1_DL2, harboring a BRAF^V600E mutation and PTEN loss, and H3, harboring WT (wild-type) BRAF and PTEN loss, with the MAPK (BRAF) inhibitor vemurafenib and the PI3K pathway associated mTOR inhibitor temsirolimus. Combined use of the drugs inhibited tumor cell growth and proliferation in vitro in H1_DL2 cells, compared to single drug treatment. Treatment was less effective in the H3 cells. Furthermore, a strong inhibitory effect on the viability of H1_DL2 cells, when grown as 3D multicellular spheroids, was seen. The treatment inhibited the expression of pERK1/2 and reduced the expression of pAKT and p-mTOR in H1_DL2 cells, confirming that the MAPK and PI3K pathways were inhibited after drug treatment. Microarray experiments followed by principal component analysis (PCA) mapping showed distinct gene clustering after treatment, and cell cycle checkpoint regulators were affected. Global gene analysis indicated that functions related to cell survival and invasion were influenced by combined treatment. In conclusion, we demonstrate for the first time that combined therapy with vemurafenib and temsirolimus is effective on melanoma brain metastasis cells in vitro. The presented results highlight the potential of combined treatment to overcome treatment resistance that may develop after vemurafenib treatment of melanomas.     

High-end opto ASICs for DVD, data communication receivers and optical distance measurement

The designs with integrated photodiodes and low-noise amplifiers, presented in this paper, reach from DVD pickup units via high-speed glass and plastic fibre receivers to optical distance measurement. Furthermore, new developments in the fields of highly-parallel high-speed receivers for free-space optical interconnect and optical distance measurements are shown.     

A survey of multiple contractions

The AGM theory of belief contraction is extended tomultiple contraction, i.e. to contraction by a set of sentences rather than by a single sentence. There are two major variants: Inpackage contraction all the sentences must be removed from the belief set, whereas inchoice contraction it is sufficient that at least one of them is removed. Constructions of both types of multiple contraction are offered and axiomatically characterized. Neither package nor choice contraction can in general be reduced to contractions by single sentences; in the finite case choice contraction allows for reduction.     

Plastic displacement distributions of the Gaussian white noise excited elasto-plastic oscillator

Slepian model process approximate reasoning is used to obtain representative net and absolute yield displacement processes for the symmetric elasto-plastic oscillator of one degree of freedom excited by stationary Gaussian white noise. Yieldings occur in clumps with yield increments of alternating sign. Distributions are obtained in closed analytical form for the first yielding in a clump, the subsequent yieldings, and the accumulated net and absolute yielding from the entire clump. Moreover distributions of clump durations as well as interclump durations are obtained. All distribution parameters are theoretically calculated, that is, no parameters are obtained from estimation using simulated data. Extensive comparisons with simulated histograms show excellent fits. Also comparisons with published predictions from diffusion theory (Fokker-Planck equation based on the stochastic averaging method) show interesting features and good agreement. Finally an approximate general formula is given for the distribution of the time to the first passage of any given level of net or absolute yielding. This formula is a generalization of a corresponding formula valid for any compound Poisson process of finite second moments.     

Cognitive predictors of incident Alzheimer's disease: A prospective longitudinal study.

The present study examined whether cognitive variables measured at baseline could predict incident cases of Alzheimer's disease (AD) after a 3-year follow-up period. Twenty-six incident AD adults and 179 very old (M?=?83.5 years) adults without dementia participated in a population-based study. Cognitive performance was indexed by the Mini-Mental State Examination (MMSE) and multiple indices of memory and visuospatial and verbal performance. A logistic regression analysis that controlled for age, gender, and education indicated that MMSE scores were reliable indicators of who would develop AD. In addition, recall of organizable words, recognition of faces, and letter fluency were reliable predictors of subsequent dementia status after differences in MMSE performance were partialed out. Thus, although the MMSE is useful in predicting dementia, there is an additional advantage of assessing specific indices of cognitive functioning. Further, supportive episodic memory tasks may be more salient predictors of incident AD than tasks that offer less supportive encoding or retrieval conditions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Changes of disjunctively closed bases

An operator of contraction for a belief set (a theory) can be obtained by assigning to it a belief base and an operator of partial meet contraction for that base. It is argued that closure of the base under disjunction is an intuitively reasonable condition. Axiomatic characterizations are given of the contractions of belief sets that can be generated by (various types of) partial meet contraction on disjunctively closed bases. The corresponding revision operators are also characterized. Finally, some results are reported on operations on bases that are closed under material implication.I would like to thank Hans Rott and two anonymous referees for valuable comments and the Swedish Council for Research in the Humanities and Social Sciences for financial support.     

Physical datarepresentation in a multiprocessor database machine

By using a multiprocessor to implement the lowest level of a relational database we want to achieve fast execution of database operations such as join, find, and update. But the potential speed improvements provided by a multiprocessor can only be achieved if one can construct algorithms and corresponding physical data representations that can utilize the potential. By choosing a particular representation, the grid file, and analyzing its behaviour, we want to point out the difficulties encountered in trying to achieve speed improvements from a multiprocessor.     

Magnetic Anomalies and Electronic Structure of Ce<Subscript>2</Subscript>Cu<Subscript>2</Subscript>Mg and Ce<Subscript>2</Subscript>Pd<Subscript>2</Subscript>Mg

The intermetallic compounds RE ₂Cu₂Mg and RE ₂Pd₂Mg (RE=La, Ce) were prepared and characterized by magnetic susceptibility and heat-capacity measurements. They crystallize with an ordered U₃Si₂ type structure (space group P4/mbm) and the cerium compounds contain stable trivalent cerium ions, which undergo antiferromagnetic ordering at ∼7.5 and ∼4 K, respectively. In high magnetic fields Ce₂Cu₂Mg exhibits spin reorientation with critical field strength of 40 kOe at 5 K. The data are compared to the non-magnetic isotypic compounds La₂ T ₂Mg (T=Cu, Ni, Pd) and to the already reported intermediate valent Ce₂Ni₂Mg.     

Calculation of Decomposition Products from Components of Gunpowder by using ReaxFF Reactive Force Field Molecular Dynamics and Thermodynamic Calculations of Equilibrium Composition

The major combustion products from munitions containing nitro‐based propellants are water, carbon monoxide, carbon dioxide, hydrogen, and nitrogen. In addition, compounds including hydrogen cyanide, ammonia, methane, nitrogen oxides, benzene, acrylonitrile, toluene, furan, aromatic amines, benzopyrene, and various polycyclic aromatic hydrocarbons are detected in minor concentrations. The literature shows that the thermodynamic prediction of the major decomposition products agrees fairly well with the measurements. However, poor agreement is found for the minor species. We have studied the thermal decomposition products of the main gunpowder ingredients. Each of the components nitrocellulose, nitroglycerine, and the nitrate ester stabilizers diphenylamine and ethyl centralite were thermally decomposed with ReaxFF reactive force field molecular dynamics and equilibrium thermodynamics. The molecular dynamics results for the major decomposition products from nitrocellulose were partly consistent with measurements. Compared to the thermodynamic calculations, the molecular dynamics simulations agreed considerably better with experimental results for minor species like hydrogen cyanide. The nitrate ester stabilizers are the main sources for ammonia and aromatic combustion products, whereas hydrogen cyanide is produced from nitrocellulose as well as from the stabilizers when gunpowder is combusted.