Anticancer Photodynamic Therapy Using Ruthenium(II) and Os(II)-Based Complexes as Photosensitizers

Photodynamic therapy (PDT) is an approved procedure using a photosensitizer (PS) activated by light to selectively destroy malignant/premalignant cells. Transition metal complexes, such as Ru(II)- and Os(II)-based PSs (Theralase Technologies Inc., Ontario. Canada), are activated in a wide range of wavelengths, are resistant to photobleaching and have a high singlet oxygen quantum yield and ability to produce cytotoxic reactive oxygen species (ROS). Their design allows fine-tuning of the photophysical and photochemical properties. They demonstrate Type I and II photoreactions, and some are activated in hypoxia. High PDT potency and activation under NIR light and even X-ray may provide an advantage over the approved PSs. Their ability to associate with transferrin (Tf) as an endogenous delivery system increases photobleaching resistance, ROS production, selective cellular uptake, and PDT efficacy in combination with a decreased systemic toxicity. This makes these PSs attractive for systemic therapy of recurrent/progressive cancers. Their PDT efficacy has been demonstrated in various in vitro and in vivo clinically relevant models. The unique properties of the mentioned PSs allow bypassing such limitations of PDT as low specific uptake ratio, insufficiently broad absorption band, and low efficacy in hypoxia. One of these PSs (TLD-1433) was successful against non-muscle invasive urinary bladder cancer unresponsive to contemporary anticancer therapies

A distributed shear and flexural flexibility model with shear-flexure interaction for R/C members subjected to seismic loading

Α beam-column type finite element for seismic assessment of R/C frame structures is presented. This finite element consists of two interacting, distributed flexibility subelements representing inelastic flexural and shear response. Following this formulation, the proposed model is able to capture spread of flexural yielding, as well as spread of shear cracking, in R/C members. The model accounts for shear strength degradation with inelastic curvature demand, as well as coupling between inelastic flexural and shear deformations after flexural yielding, observed in many experimental studies. An empirical relationship is proposed for evaluating average shear distortion of R/C columns at onset of stirrup yielding. The proposed numerical model is validated against experimental results involving R/C columns subjected to cyclic loading. It is shown that the model can predict well the hysteretic response of R/C columns with different failure modes, i.e. flexure-critical elements, elements failing in shear after flexural yielding, and shear-critical R/C members

Seismic damage estimation of in-plane regular steel/concrete composite moment resisting frames

© 2016 Elsevier Ltd. Simple empirical expressions to estimate maximum seismic damage on the basis of four well known damage indices for planar regular steel/concrete composite moment resisting frames having steel I beams and concrete filled steel tube (CFT) columns are presented. These expressions are based on the results of an extensive parametric study concerning the inelastic response of a large number of frames to a large number of ordinary far-field type ground motions. Thousands of nonlinear dynamic analyses are performed by scaling the seismic records to different intensities in order to drive the structures to different levels of inelastic deformation. The statistical analysis of the created response databank indicates that the number of stories, beam strength ratio, material strength and ground motion characteristics strongly influence structural damage. Nonlinear regression analysis is employed in order to derive simple formulae, which reflect the influence of the aforementioned parameters and offer a direct estimation of the damage indices used in this study. More specifically, given the characteristics of the structure and the ground motion, one can calculate the maximum damage observed in column bases and beams. Finally, three examples serve to illustrate the use of the proposed expressions and demonstrate their accuracy and efficiency

Influence of earthquake ground-motion duration on damage estimation - application to steel moment resisting frames

This paper presents an analytical study evaluating the influence of ground motion duration on structural damage of 3-story, 9-story, and 20-story SAC steel moment resisting frame buildings designed for downtown Seattle, WA, USA, using pre-Northridge codes. Two-dimensional nonlinear finite element models of the buildings are used to estimate the damage induced by the ground motions. A set of 44 ground motions is used to study the combined effect of spectral acceleration and ground motion significant duration on drift and damage measures. In addition, 10 spectrally equivalent short-duration shallow crustal ground motions and long-duration subduction zone records are selected to isolate duration effect and assess its effect on the response. For each ground motion pair, incremental dynamic analyses are performed at at least 20 intensity levels and response measures such as peak interstory drift ratio and energy dissipated are tracked. These response measures are combined into two damage metrics that account for the ductility and energy dissipation. Results indicate that the duration of the ground motion influences, above all, the combined damage measures, although some effect on drift-based response measures is also observed for larger levels of drift. These results indicate that because the current assessment methodologies do not capture the effects of ground motion duration, both performance-based and code-based assessment methodologies should be revised to consider damage measures that are sensitive to duration

Modelling of R/C members accounting for shear failure localisation: Hysteretic shear model

Reinforced concrete (R/C) frame buildings designed according to older seismic codes represent a large part of the existing building stock worldwide. Their structural elements are often vulnerable to shear or flexure-shear failure, which can eventually lead to loss of axial load resistance of vertical elements and initiate vertical progressive collapse of a building. In this study, a hysteretic model capturing the local shear response of shear-deficient R/C elements is described in detail, with emphasis on post-peak behaviour; it differs from existing models in that it considers the localisation of shear strains after the onset of shear failure in a critical length defined by the diagonal failure planes. Additionally, an effort is made to improve the state of the art in post-peak shear response modelling, by compiling the largest database of experimental results for shear and flexure-shear critical R/C columns cycled well beyond the onset of shear failure and/or up to the onset of axial failure, and developing empirical relationships for the key parameters defining the local backbone post-peak shear response of such elements. The implementation of the derived local hysteretic shear model in a computationally efficient beam-column finite element model with distributed shear flexibility, which accounts for all deformation types, will be presented in a forthcoming paper

Seismic damage estimation of in-plane regular steel moment resisting and x-braced frames

Simple empirical expressions to estimate maximum seismic damage on the basis of five well known damage indices for planar regular moment resisting and x-braced steel frames are presented. They are based on the results of extensive parametric studies concerning the inelastic response of a large number of these frames to a large number of ground motions. Thousands of nonlinear dynamic analyses are performed by scaling the seismic records to different intensities in order to drive the structures to different levels of inelastic deformation and finally to collapse. The statistical analysis of the created response databank indicates that the number of stories, period of vibration, stiffness ratio, capacity factor (for moment resisting frames), brace slenderness ratio and column stiffness (for x-braced frames) and characteristics of the ground motion, such as characteristic period and spectral acceleration, strongly influence damage. Nonlinear regression analysis is employed in order to derive simple formulae, which reflect the influence of the aforementioned parameters and offer a direct estimation of the damage indices used in this study. More specifically, given the characteristics of the structure and the ground motion, one can calculate the maximum damage observed in column bases and beams (for moment resisting frames) or in braces (for x-braced frames). Finally, two examples serve to illustrate the use of the proposed expressions and demonstrate their accuracy and efficiency. © 2012 Springer Science+Business Media Dordrecht

Self-renewing resident arterial macrophages arise from embryonic CX3CR1+ precursors and circulating monocytes immediately after birth

Resident macrophages densely populate the normal arterial wall, yet their origins and the mechanisms that sustain them are poorly understood. Here we use gene-expression profiling to show that arterial macrophages constitute a distinct population among macrophages. Using multiple fate-mapping approaches, we show that arterial macrophages arise embryonically from CX3CR1+ precursors and postnatally from bone marrow–derived monocytes that colonize the tissue immediately after birth. In adulthood, proliferation (rather than monocyte recruitment) sustains arterial macrophages in the steady state and after severe depletion following sepsis. After infection, arterial macrophages return rapidly to functional homeostasis. Finally, survival of resident arterial macrophages depends on a CX3CR1-CX3CL1 axis within the vascular niche

Reverse Transendothelial Migration of Intimal CD11c+ Dendritic Cells: Role in Intracellular Pathogen Removal and Effect on Atherosclerotic Lesions.

Dendritic cells are antigen presenting cells that play a key role in the initiation of the adaptive immune response and in chronic inflammatory diseases such as atherosclerosis. Resident intimal CD11c+ cells are abundant in the normal arterial intima of mice, in regions predisposed to atherosclerosis. Upon induction of hypercholesterolemia, these cells engulf lipids and become the first foam cells in nascent lesions. However, their function in the normal aorta remains poorly understood. The purpose of this study is to show that their function is to protect the arterial intima against Chlamydia (C.) muridarum infection, and potentially against other intracellular and extracellular bacteria. This protection is achieved when intimal CD11c+ cells undergo reverse transendothelial migration (RTM) through the endothelium into the arterial circulation to remove the pathogen from the vessel wall. Systemic pathogens and stimulation of pattern recognition receptors trigger two waves of RTM of intimal CD11c+ cells, each was followed by recovery through proliferation of the remaining cells. Both waves of RTM were dependent on up-regulated expression of CCR7 and its ligand CCL19 by intimal CD11c+ cells. C. muridarum enters the arterial intima when infected circulating monocytes are recruited. The second wave of RTM removes the pathogen from the vessel wall. Inhibition of RTM (e.g. in Ccr7-/- mice) results in accumulation of C. muridarum in the vessel wall, which induces a local inflammatory response, that could be harmful to the arteria intima. Hypercholesterolemia and lipid loading of intimal CD11c+ cells by feeding Ldlr--/- mice high fat diet for one week results in inhibition of RTM of CD11c+ foam cells. Lipid loading did not affect CCR7 or CCL19 induction in intimal cells and incubation with CCL19 did not rescue RTM in atherosclerotic lesions. Studies in Asc-/- and Casp1-/- mice that are deficient in the production of cleaved IL-1ď ˘, as well as antibody blockade and rescue experiments revealed that RTM is dependent on IL-1ď ˘ production from the arterial endothelial cells. In addition, experiments with Il-1r1-/- mice suggest that RTM is dependent on receptor expression by the endothelial cells. Future studies will continue to investigate other factors and mechanisms that might play a role in RTM of intimal CD11c+ cells, and explore how they can be used to induce RTM in atherosclerotic lesions as a potential preventative therapy to reduce atherosclerotic plaque burden.Ph.D