Targeting treatment resistant breast cancer stem cells with FKBPL and its peptide derivative, AD-01, via the CD44 pathway

PURPOSE: FKBPL and its peptide derivative, AD-01, have already demonstrated tumour growth inhibition and CD44 dependent anti-angiogenic activity. Here we explore the ability of AD-01 to target CD44 positive breast cancer stem cells (BCSCs). EXPERIMENTAL DESIGN: Mammosphere assays and flow cytometry were utilized to analyse the effect of FKBPL overexpression/knockdown and AD-01 treatment ± other anti-cancer agents on BCSCs using breast cancer cell lines (MCF-7/MDA-231/ZR-75), primary patient samples and xenografts. Delays in tumour initiation were evaluated in vivo. The anti-stem cell mechanisms were determined using clonogenic assays, qPCR and immunofluorescence. RESULTS: AD-01 treatment was highly effective at inhibiting the BCSC population by reducing mammosphere forming efficiency (MFE) and ESA+/CD44+/CD24- or ALDH+ cell subpopulations in vitro and tumour initiation in vivo. The ability of AD-01 to inhibit the self-renewal capacity of BCSCs was confirmed; mammospheres were completely eradicated by the third generation. The mechanism appears to be due to AD-01-mediated BCSC differentiation demonstrated by a significant decrease in the number of holoclones and an associated increase in meroclones/paraclones; the stem cell markers, Nanog, Oct4 and Sox2, were also significantly reduced. Furthermore, we demonstrated additive inhibitory effects when AD-01 was combined with the Notch inhibitor, DAPT. AD-01 was also able to abrogate a chemo- and radiotherapy induced enrichment in BCSCs. Finally, FKBPL knockdown led to an increase in Nanog/Oct4/Sox2 and an increase in BCSCs, highlighting a role for endogenous FKBPL in stem cell signalling. CONCLUSIONS: AD-01 has dual anti-angiogenic and anti-BCSC activity which will be advantageous as this agent enters clinical trial.

Polyphosphate and pyrophosphate derivative of saccharides

The present invention provides, among other things, phosphorylated and pyrophosphate derivatives of mono-, di- and oligosaccharides, as well as structural derivatives of these compounds. These compounds have a variety of uses including for pharmaceutical applications. Also provided are methods of use in the treatment of disease, including diseases related to oxygen delivery

Capturing Goodwillie's Derivative

Recent work of Biedermann and Roendigs has translated Goodwillie's calculus of functors into the language of model categories. Their work focuses on symmetric multilinear functors and the derivative appears only briefly. In this paper we focus on understanding the derivative as a right Quillen functor to a new model category. This is directly analogous to the behaviour of Weiss's derivative in orthogonal calculus. The immediate advantage of this new category is that we obtain a streamlined and more informative proof that the n-homogeneous functors are classified by spectra with an action of the symmetric group on n objects. In a later paper we will use this new model category to give a formal comparison between the orthogonal calculus and Goodwillie's calculus of functors.

Probing a 3,4'-bis-guanidinium diaryl derivative as an allosteric inhibitor of the Ras pathway

Mutations in the Ras-pathway occur in 40–45% of colorectal cancer patients and these are refractory to treatment with anti-EGFR-targeted therapies. With this in mind, we have studied novel guanidinium- based compounds with demonstrated ability to inhibit protein kinases. We have performed docking stud- ies with several proteins involved in the Ras-pathway and evaluated 3,40-bis-guanidinium derivatives as inhibitors of B-Raf. Compound 3, the most potent in this series, demonstrated strong cytotoxicity in WTB-Raf colorectal cancer cells and also cells with V600EB-Raf mutations. Cell death was induced by apop- tosis, detected by cleavage of PARP. Compound 3 also potently inhibited ERK1/2 signalling, inhibited EGFR activation, as well as Src, STAT3 and AKT phosphorylation. Mechanistically, compound 3 did not inhibit ATP binding to B-Raf, but direct assay of B-Raf activity was inhibited in vitro. Summarizing, we have identified a novel B-Raf type-III inhibitor that exhibits potent cellular cytotoxicity

B-spline and neuro-fuzzy models design with function and derivative equalities

The design of neuro-fuzzy models is still a complex problem, as it involves not only the determination of the model parameters, but also its structure. Of special importance is the incorporation of a priori information in the design process. In this paper two known design algorithms for B-spline models will be updated to account for function and derivatives equality restrictions, which are important when the neural model is used for performing single or multi-objective optimization on-line.

DNA interaction and cytotoxicity studies of new ruthenium(II) cyclopentadienyl derivative complexescontaining heteroaromatic ligands

Four ruthenium(II) complexes with the formula [Ru(eta(5)-C(5)H(5))(PP)L][CF(3)SO(3)], being (PP = two triphenylphosphine molecules), L = 1-benzylimidazole, 1; (PP = two triphenylphosphine molecules), L = 2,2'bipyridine, 2; (PP = two triphenylphosphine molecules), L = 4-Methylpyridine, 3; (PP = 1,2-bis(diphenylphosphine) ethane), L = 4-Methylpyridine, 4, were prepared, in view to evaluate their potentialities as antitumor agents. The compounds were completely characterized by NMR spectroscopy and their crystal and molecular structures were determined by X-ray diffraction. Electrochemical studies were carried out giving for all the compounds quasi-reversible processes. The images obtained by atomic force microscopy (AFM) suggest interaction with pBR322 plasmid DNA. Measurements of the viscosity of solutions of free DNA and DNA incubated with different concentrations of the compounds confirmed this interaction. The cytotoxicity of compounds 1234 was much higher than that of cisplatin against human leukemia cancer cells (HL-60 cells). IC(50) values for all the compounds are in the range of submicromolar amounts. Apoptotic death percentage was also studied resulting similar than that of cisplatin. (C) 2010 Elsevier Inc. All rights reserved.

Derivative-free optimization and filter methods to solve nonlinear constrained problems

In real optimization problems, usually the analytical expression of the objective function is not known, nor its derivatives, or they are complex. In these cases it becomes essential to use optimization methods where the calculation of the derivatives, or the verification of their existence, is not necessary: the Direct Search Methods or Derivative-free Methods are one solution. When the problem has constraints, penalty functions are often used. Unfortunately the choice of the penalty parameters is, frequently, very difficult, because most strategies for choosing it are heuristics strategies. As an alternative to penalty function appeared the filter methods. A filter algorithm introduces a function that aggregates the constrained violations and constructs a biobjective problem. In this problem the step is accepted if it either reduces the objective function or the constrained violation. This implies that the filter methods are less parameter dependent than a penalty function. In this work, we present a new direct search method, based on simplex methods, for general constrained optimization that combines the features of the simplex method and filter methods. This method does not compute or approximate any derivatives, penalty constants or Lagrange multipliers. The basic idea of simplex filter algorithm is to construct an initial simplex and use the simplex to drive the search. We illustrate the behavior of our algorithm through some examples. The proposed methods were implemented in Java.

Analysis of diffusion process in fractured reservoirs using fractional derivative approach

The fractal geometry is used to model of a naturally fractured reservoir and the concept of fractional derivative is applied to the diffusion equation to incorporate the history of fluid flow in naturally fractured reservoirs. The resulting fractally fractional diffusion (FFD) equation is solved analytically in the Laplace space for three outer boundary conditions. The analytical solutions are used to analyze the response of a naturally fractured reservoir considering the anomalous behavior of oil production. Several synthetic examples are provided to illustrate the methodology proposed in this work and to explain the diffusion process in fractally fractured systems.

Strange Dynamics in a Fractional Derivative of Complex-Order Network of Chaotic Oscillators

We study the peculiar dynamical features of a fractional derivative of complex-order network. The network is composed of two unidirectional rings of cells, coupled through a "buffer" cell. The network has a Z3 × Z5 cyclic symmetry group. The complex derivative Dα±jβ, with α, β ∈ R+ is a generalization of the concept of integer order derivative, where α = 1, β = 0. Each cell is modeled by the Chen oscillator. Numerical simulations of the coupled cell system associated with the network expose patterns such as equilibria, periodic orbits, relaxation oscillations, quasiperiodic motion, and chaos, in one or in two rings of cells. In addition, fixing β = 0.8, we perceive differences in the qualitative behavior of the system, as the parameter c ∈ [13, 24] of the Chen oscillator and/or the real part of the fractional derivative, α ∈ {0.5, 0.6, 0.7, 0.8, 0.9, 1.0}, are varied. Some patterns produced by the coupled system are constrained by the network architecture, but other features are only understood in the light of the internal dynamics of each cell, in this case, the Chen oscillator. What is more important, architecture and/or internal dynamics?

Redirection of T cells by delivering a transgenic mouse-derived MDM2 tumor antigen-specific TCR and its humanized derivative is governed by the CD8 coreceptor and affects natural human TCR expression.

Retroviral transfer of T cell antigen receptor (TCR) genes selected by circumventing tolerance to broad tumor- and leukemia-associated antigens in human leukocyte antigen (HLA)-A*0201 (A2.1) transgenic (Tg) mice allows the therapeutic reprogramming of human T lymphocytes. Using a human CD8 x A2.1/Kb mouse derived TCR specific for natural peptide-A2.1 (pA2.1) complexes comprising residues 81-88 of the human homolog of the murine double-minute 2 oncoprotein, MDM2(81-88), we found that the heterodimeric CD8 alpha beta coreceptor, but not normally expressed homodimeric CD8 alpha alpha, is required for tetramer binding and functional redirection of TCR- transduced human T cells. CD8+T cells that received a humanized derivative of the MDM2 TCR bound pA2.1 tetramers only in the presence of an anti-human-CD8 anti-body and required more peptide than wild-type (WT) MDM2 TCR+T cells to mount equivalent cytotoxicity. They were, however, sufficiently effective in recognizing malignant targets including fresh leukemia cells. Most efficient expression of transduced TCR in human T lymphocytes was governed by mouse as compared to human constant (C) alphabeta domains, as demonstrated with partially humanized and murinized TCR of primary mouse and human origin, respectively. We further observed a reciprocal relationship between the level of Tg WT mouse relative to natural human TCR expression, resulting in T cells with decreased normal human cell surface TCR. In contrast, natural human TCR display remained unaffected after delivery of the humanized MDM2 TCR. These results provide important insights into the molecular basis of TCR gene therapy of malignant disease.

Does friendship give us non-derivative partial reasons ?

Une des façons d’approcher la question de l’existence de raisons partiales non-dérivatives d’une quelconque sorte consiste à expliquer ce que sont les raisons partiales et ensuite à chercher à savoir s’il y a des raisons de cette sorte. Si de telles raisons existent, alors il est au moins possible qu’il y ait des raisons partiales d’amitié. C’est cette approche que j’adopterai ici, et elle produit des résultats intéressants. Le premier a trait à la structure des raisons partiales. C’est au moins une condition nécessaire pour qu’une raison soit partiale qu’elle aie une composante relationnelle explicite. Cette composante, techniquement parlant, est un relatum dans la relation d’être une raison qui elle-même est une relation entre la personne à qui la raison s’applique et la personne concernée par l’action pour laquelle il y a une raison. La deuxième conclusion de ce texte est que cette composante relationnelle est aussi requise dans de nombreuses sortes de raisons admises comme impartiales. Afin d’éviter de banaliser la distinction entre raisons partiales et impartiales nous devons appliquer une condition suffisante additionnelle. Finalement, bien qu’il pourrait s’avérer possible de distinguer les raisons impartiales ayant une composante relationnelle des raisons partiales, cette approche suggère que la question de savoir si l’éthique est partiale ou impartiale devra se régler au niveau de l’éthique normative, ou à tout le moins, qu’elle ne pourra se régler au niveau du discours sur la nature des raisons d’agir.

A PVC Plasticized Sensor for Ni(II) Ion Based on a Simple Ethylenediamine Derivative

new PVC membrane ion selective electrode which is highly selective towards Ni(II) ions was constructed using a Schiff base containing a binaphthyl moiety as the ionophore. The sensor exhibited a good Nernstian response for nickel ions over the concentration range 1.0 × 10–1 – 5.0 × 10–6 M with a lower limit of detection of 1.3 × 10–6 M. It has a fast response time and can be used for a period of 4 months with a good reproducibility. The sensor is suitable for use in aqueous solutions in a wide pH range of 3.6 – 7.4 and works satisfactorily in the presence of 25% (v/v) methanol or ethanol. The sensor shows high selectivity to nickel ions over a wide variety of cations. It has been successfully used as an indicator electrode in the potentiometric titration of nickel ions against EDTA and also for the direct determination of nickel content in real samples: effluent samples, chocolates and hydrogenated oils.

A Nonparametric Approach to Pricing and Hedging Derivative Securities via Learning Networks

We propose a nonparametric method for estimating derivative financial asset pricing formulae using learning networks. To demonstrate feasibility, we first simulate Black-Scholes option prices and show that learning networks can recover the Black-Scholes formula from a two-year training set of daily options prices, and that the resulting network formula can be used successfully to both price and delta-hedge options out-of-sample. For comparison, we estimate models using four popular methods: ordinary least squares, radial basis functions, multilayer perceptrons, and projection pursuit. To illustrate practical relevance, we also apply our approach to S&P 500 futures options data from 1987 to 1991.