The usefulness of mouse breast tumor models for testing and optimization of breast cancer vaccines at old age

Cancer is an age-related disease and with the graying of the society, there is an increasing need to optimize cancer management and therapy for application in elderly patients. Cancer vaccines that can be applied in both prevention and therapy are potentially less toxic than chemotherapy or radiation and could, therefore, be especially suitable for older more frail cancer patients. In this study, we used syngeneic metastatic (4TO7) and non-metastatic (64pT) breast tumor models to obtain valuable information on the potential usefulness of MAGE-encoding cancer vaccines in metastatic and non-metastatic breast cancer at old age. First, we tested a mouse Mage-b DNA vaccine in young mice and found a significant preventive effect on the development of metastases. However, little effect was observed on primary breast tumors. Second, we studied tumor progression in relation to aging and found significant smaller tumors in old compared to young mice. This was associated with an increase in the percentage of CD8(+) T cells in the inguinal lymph nodes at the site of the tumor at old age. These findings suggest that breast cancer immunotherapeutic approaches could be a valid strategy even in elderly patients.     

A method of analyzing of the “Dose-effect” dependence in multifactor medico-biological experiments

A conceptual-logical and mathematical approximation model has been created for the organism's response to external factors. The mathematical model of the “dose-effect” dependence for the combined effect of several factors is constructed using the basic equation of the Volterra mathematical theory of the struggle for existence. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 117, N ^o 3, pp. 328–331, March, 1994 Presented by L. A. Tiunov, Member of the Russian Academy of Medical Sciences     

Ultrastructural features of the myocardium of newborn mini-pigs after chronic parental alcoholization

Department of Mini-Pig Models, Research Laboratory of Experimental Biological Models, Academy of Medical Sciences of the USSR, Krasnogorsk, Moscow Region. (Presented by Academician of the Academy of Medical Sciences of the USSR A. P. Avtsyn.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 109, No. 4, pp. 398–400, April, 1990.     

Alternative common factor models for multivariate biometric analyses

In prior research we have shown how linear structural equation models and computer programs (e.g., LISREL) may be simply and directly used to provide alternatives for the traditional biometric twin design. We use structural equations and path models to define biometric group differences, we write traditional common-factor models in the same way, and then we take a detailed look at some alternative multivariate and biometric models. We contrast the biometricfactors covariance structure approach used by Loehlin and Vandenberg (1968), Martin and Eaves (1977), and others with the psychometric-factors approach used by McArdle et al. (1980) and others. We use the multivariate primary mental abilities data on monozygotic (MZ) and dizygotic (DZ) twins from Loehlin and Vandenberg (1968) to detail fundamental differences in model specification and results. We extend both multivariate biometric approaches using exploratory and confirmatory multiple-factor models. These comparisons show that each alternative multivariate methodology has useful features for empirical applications.This research has been supported by grants from the National Institute on Aging (AG02695, AG04704, and AG07137) to McArdle, and a Research Career Development Award (HD00694) to Goldsmith.     

Physics-Driven CFD Modeling of Complex Anatomical Cardiovascular Flows—A TCPC Case Study

Recent developments in medical image acquisition combined with the latest advancements in numerical methods for solving the Navier-Stokes equations have created unprecedented opportunities for developing simple and reliable computational fluid dynamics (CFD) tools for meeting patient-specific surgical planning objectives. However, for CFD to reach its full potential and gain the trust and confidence of medical practitioners, physics-driven numerical modeling is required. This study reports on the experience gained from an ongoing integrated CFD modeling effort aimed at developing an advanced numerical simulation tool capable of accurately predicting flow characteristics in an anatomically correct total cavopulmonary connection (TCPC). An anatomical intra-atrial TCPC model is reconstructed from a stack of magnetic resonance (MR) images acquired in vivo. An exact replica of the computational geometry was built using transparent rapid prototyping. Following the same approach as in earlier studies on idealized models, flow structures, pressure drops, and energy losses were assessed both numerically and experimentally, then compared. Numerical studies were performed with both a first-order accurate commercial software and a recently developed, second-order accurate, in-house flow solver. The commercial CFD model could, with reasonable accuracy, capture global flow quantities of interest such as control volume power losses and pressure drops and time-averaged flow patterns. However, for steady inflow conditions, both flow visualization experiments and particle image velocimetry (PIV) measurements revealed unsteady, complex, and highly 3D flow structures, which could not be captured by this numerical model with the available computational resources and additional modeling efforts that are described. Preliminary time-accurate computations with the in-house flow solver were shown to capture for the first time these complex flow features and yielded solutions in good agreement with the experimental observations. Flow fields obtained were similar for the studied total cardiac output range (1–3 l/min); however hydrodynamic power loss increased dramatically with increasing cardiac output, suggesting significant energy demand at exercise conditions. The simulation of cardiovascular flows poses a formidable challenge to even the most advanced CFD tools currently available. A successful prediction requires a two-pronged, physics-based approach, which integrates high-resolution CFD tools and high-resolution laboratory measurements.     

The adjuvant monophosphoryl lipid A increases the function of antigen-presenting cells

The induction of immune responses in vivo is typically performed with antigens administered in external adjuvants, like alum, complete Freund's adjuvant, LPS and, more recently, monophosphoryl lipid A (MPL). However, the role of the adjuvant is still poorly defined. The aim of this study was to test whether the MPL affects the function of antigen-presenting cells (APC) in vitro and in vivo. Antigen-pulsed APC [including macrophages, B cells and dendritic cells (DC)] were incubated or not with MPL, and their ability to sensitize naive T cells was tested in vitro and in vivo. The data show that MPL enhances the ability of macrophages and B cells to sensitize naive T cells, and confers to them the capacity to induce the development of T(h)1 and T(h)2. Administration of MPL i.v. in mice results in the redistribution of fully mature DC in the T cell area of the spleen. These observations suggest that MPL may induce an antigen-specific primary immune response by provoking the migration and maturation of DC that are the physiological adjuvant of the immune system.     

Impedance plethysmography: the origin of electrical impedance changes measured in the human calf

Electrical impedance plethysmography of the lower leg is now a widely used test for detection of deep vein thrombosis. The origin of the impedance signal is difficult to evaluate in the living subject, and experimental animals have important anatomic differences. A controlled study on human cadavers was therefore undertaken. Conductive and nonconductive fluids were injected into the lower legs of cadavers, while electrical impedance changes were recorded utilising a 4-electrode technique. X-ray studies confirmed the localisation of the injections. Results from ten cadavers showed that significant impedance changes occurred only in response to injections of saline in the region between the electrodes. Injections of nonconductive silicone oil caused a small increase in the measured impedance. It is concluded that electrical impedance plethysmography reflects changes in conductivity confined to the region between the electrodes; and that the ratio of deep to superficial impedance sensitivity is a function of the electrode spacing.     

Differential IL-12 responsiveness of T cells but not of NK cells from tumor-bearing mice in IL-12-responsive versus -unresponsive tumor models

While IL-12 administration induces tumor regression through stimulating T cells in tumor-bearing mice, this IL-12 effect is observed in some but not all tumor models. The present study aimed to compare IL-12 responsiveness of T cells from tumor-bearing mice in IL-12-responsive (CSA1M and OV-HM) and -unresponsive (Meth A) tumor models. Tumor regression in IL-12-responsive tumor models required the participation of T cells, but not of NK1.1(+) cells. Because a NK1.1(+) cell population was the major producer of IFN-gamma, comparable levels of IFN-gamma production were induced in IL-12-responsive and -unresponsive tumor-bearing mice. This indicates that the amount of IFN-gamma produced in tumor-bearing individuals does not correlate with the anti-tumor efficacy of IL-12. In contrast, IL-12 responsiveness of T cells differed between the responsive and unresponsive models: purified T cells from CSA1M/OV-HM-bearing or Meth A-bearing mice exhibited high or low IL-12 responsiveness respectively, when evaluated by the amounts of IFN-gamma produced in response to IL-12. T cells from CSA1M- or OV-HM-bearing but not from Meth A-bearing mice exhibited enhanced levels of mRNA for the IL-12 receptor (IL-12R). These results indicate that a fundamental difference exists in IL-12 responsiveness of T cells between IL-12-responsive and -unresponsive tumor models, and that such a difference is associated with the expression of IL-12R on T cells.     

Silicon neuron simulation with SPICE: tool for neurobiology and neural networks

The paper deals with computer simulations of ‘silicon neurons’, which are assemblies of CMOS circuits that generate the equivalents of the ionic currents and of the action potentials of real (biological) neurons. The circuit simulation program SPICE is used to simulate the generation of action potentials by a silicon neuron. Moreover, the equivalent circuits of silicon synapses are described and the behaviours of simple two- and three-neuron networks are analysed. Implications for the areas of neurobiology and formal neural networks are briefly considered.