Oncogenic transformation of mesenchymal stem cells decreases Nrf2 expression favoring in vivo tumor growth and poorer survival

BACKGROUND: The transcription factor Nrf2 is a key regulator of the cellular antioxidant response, and its activation by chemoprotective agents has been proposed as a potential strategy to prevent cancer. However, activating mutations in the Nrf2 pathway have been found to promote tumorigenesis in certain models. Therefore, the role of Nrf2 in cancer remains contentious. METHODS: We employed a well-characterized model of stepwise human mesenchymal stem cell (MSC) transformation and breast cancer cell lines to investigate oxidative stress and the role of Nrf2 during tumorigenesis. The Nrf2 pathway was studied by microarray analyses, qRT-PCR, and western-blotting. To assess the contribution of Nrf2 to transformation, we established tumor xenografts with transformed MSC expressing Nrf2 (n = 6 mice per group). Expression and survival data for Nrf2 in different cancers were obtained from GEO and TCGA databases. All statistical tests were two-sided. RESULTS: We found an accumulation of reactive oxygen species during MSC transformation that correlated with the transcriptional down-regulation of antioxidants and Nrf2-downstream genes. Nrf2 was repressed in transformed MSC and in breast cancer cells via oncogene-induced activation of the RAS/RAF/ERK pathway. Furthermore, restoration of Nrf2 function in transformed cells decreased reactive oxygen species and impaired in vivo tumor growth (P = 0.001) by mechanisms that included sensitization to apoptosis, and a decreased hypoxic/angiogenic response through HIF-1α destabilization and VEGFA repression. Microarray analyses showed down-regulation of Nrf2 in a panel of human tumors and, strikingly, low Nrf2 expression correlated with poorer survival in patients with melanoma (P = 0.0341), kidney (P = 0.0203) and prostate (P = 0.00279) cancers. CONCLUSIONS: Our data indicate that oncogene-induced Nrf2 repression is an adaptive response for certain cancers to acquire a pro-oxidant state that favors cell survival and in vivo tumor growth

Interplay between geometry and flow distribution in an airway tree

Uniform fluid flow distribution in a symmetric volume can be realized through a symmetric branched tree. It is shown here, however, that the flow partitioning can be highly sensitive to deviations from exact symmetry if inertial effects are present. This is found by direct numerical simulation of the Navier-Stokes equations in a 3D tree geometry. The flow asymmetry is quantified and found to depend on the Reynolds number. Moreover, for a given Reynolds number, we show that the flow distribution depends on the aspect ratio of the branching elements as well as their angular arrangement. Our results indicate that physiological variability should be severely restricted in order to ensure uniform fluid distribution in a tree. This study suggests that any non-uniformity in the air flow distribution in human lungs should be influenced by the respiratory conditions, rest or hard exercise

Monitoring the Growth of an Orthotopic Tumour Xenograft Model: Multi-Modal Imaging Assessment with Benchtop MRI (1T), High-Field MRI (9.4T), Ultrasound and Bioluminescence

BACKGROUND: Research using orthotopic and transgenic models of cancer requires imaging methods to non-invasively quantify tumour burden. As the choice of appropriate imaging modality is wide-ranging, this study aimed to compare low-field (1T) magnetic resonance imaging (MRI), a novel and relatively low-cost system, against established preclinical techniques: bioluminescence imaging (BLI), ultrasound imaging (US), and high-field (9.4T) MRI. METHODS: A model of colorectal metastasis to the liver was established in eight mice, which were imaged with each modality over four weeks post-implantation. Tumour burden was assessed from manually segmented regions. RESULTS: All four imaging systems provided sufficient contrast to detect tumours in all of the mice after two weeks. No significant difference was detected between tumour doubling times estimated by low-field MRI, ultrasound imaging or high-field MRI. A strong correlation was measured between high-field MRI estimates of tumour burden and all the other modalities (p < 0.001, Pearson). CONCLUSION: These results suggest that both low-field MRI and ultrasound imaging are accurate modalities for characterising the growth of preclinical tumour models

The heats of formation of the haloacetylenes XCCY [X, Y = H, F, Cl]: basis set limit ab initio results and thermochemical analysis

The heats of formation of haloacetylenes are evaluated using the recent W1 and W2 ab initio computational thermochemistry methods. These calculations involve CCSD and CCSD(T) coupled cluster methods, basis sets of up to spdfgh quality, extrapolations to the one-particle basis set limit, and contributions of inner-shell correlation, scalar relativistic effects, and (where relevant) first-order spin-orbit coupling. The heats of formation determined using W2 theory are: \hof(HCCH) = 54.48 kcal/mol, \hof(HCCF) = 25.15 kcal/mol, \hof(FCCF) = 1.38 kcal/mol, \hof(HCCCl) = 54.83 kcal/mol, \hof(ClCCCl) = 56.21 kcal/mol, and \hof(FCCCl) = 28.47 kcal/mol. Enthalpies of hydrogenation and destabilization energies relative to acetylene were obtained at the W1 level of theory. So doing we find the following destabilization order for acetylenes: FCCF $>$ ClCCF $>$ HCCF $>$ ClCCCl $>$ HCCCl $>$ HCCH. By a combination of W1 theory and isodesmic reactions, we show that the generally accepted heat of formation of 1,2-dichloroethane should be revised to -31.8$\pm$0.6 kcal/mol, in excellent agreement with a very recent critically evaluated review. The performance of compound thermochemistry schemes such as G2, G3, G3X and CBS-QB3 theories has been analyzed.Comment: Mol. Phys., in press (E. R. Davidson issue

Tunable Semiconducting Polymer Nanoparticles with INDT-Based Conjugated Polymers for Photoacoustic Molecular Imaging.

Photoacoustic imaging combines both excellent spatial resolution with high contrast and specificity, without the need for patients to be exposed to ionizing radiation. This makes it ideal for the study of physiological changes occurring during tumorigenesis and cardiovascular disease. In order to fully exploit the potential of this technique, new exogenous contrast agents with strong absorbance in the near-infrared range, good stability and biocompatibility, are required. In this paper, we report the formulation and characterization of a novel series of endogenous contrast agents for photoacoustic imaging in vivo. These contrast agents are based on a recently reported series of indigoid π-conjugated organic semiconductors, coformulated with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, to give semiconducting polymer nanoparticles of about 150 nm diameter. These nanoparticles exhibited excellent absorption in the near-infrared region, with good photoacoustic signal generation efficiencies, high photostability, and extinction coefficients of up to three times higher than those previously reported. The absorption maximum is conveniently located in the spectral region of low absorption of chromophores within human tissue. Using the most promising semiconducting polymer nanoparticle, we have demonstrated wavelength-dependent differential contrast between vasculature and the nanoparticles, which can be used to unambiguously discriminate the presence of the contrast agent in vivo

Model validation for a noninvasive arterial stenosis detection problem

Copyright @ 2013 American Institute of Mathematical SciencesA current thrust in medical research is the development of a non-invasive method for detection, localization, and characterization of an arterial stenosis (a blockage or partial blockage in an artery). A method has been proposed to detect shear waves in the chest cavity which have been generated by disturbances in the blood flow resulting from a stenosis. In order to develop this methodology further, we use both one-dimensional pressure and shear wave experimental data from novel acoustic phantoms to validate corresponding viscoelastic mathematical models, which were developed in a concept paper [8] and refined herein. We estimate model parameters which give a good fit (in a sense to be precisely defined) to the experimental data, and use asymptotic error theory to provide confidence intervals for parameter estimates. Finally, since a robust error model is necessary for accurate parameter estimates and confidence analysis, we include a comparison of absolute and relative models for measurement error.The National Institute of Allergy and Infectious Diseases, the Air Force Office of Scientific Research, the Deopartment of Education and the Engineering and Physical Sciences Research Council (EPSRC)

Lubricating Bacteria Model for Branching growth of Bacterial Colonies

Various bacterial strains (e.g. strains belonging to the genera Bacillus, Paenibacillus, Serratia and Salmonella) exhibit colonial branching patterns during growth on poor semi-solid substrates. These patterns reflect the bacterial cooperative self-organization. Central part of the cooperation is the collective formation of lubricant on top of the agar which enables the bacteria to swim. Hence it provides the colony means to advance towards the food. One method of modeling the colonial development is via coupled reaction-diffusion equations which describe the time evolution of the bacterial density and the concentrations of the relevant chemical fields. This idea has been pursued by a number of groups. Here we present an additional model which specifically includes an evolution equation for the lubricant excreted by the bacteria. We show that when the diffusion of the fluid is governed by nonlinear diffusion coefficient branching patterns evolves. We study the effect of the rates of emission and decomposition of the lubricant fluid on the observed patterns. The results are compared with experimental observations. We also include fields of chemotactic agents and food chemotaxis and conclude that these features are needed in order to explain the observations.Comment: 1 latex file, 16 jpeg files, submitted to Phys. Rev.