Development of a scoring function for comparing simulated and experimental tumor spheroids

Progress continues in the field of cancer biology, yet much remains to be unveiled regarding the mechanisms of cancer invasion. In particular, complex biophysical mechanisms enable a tumor to remodel the surrounding extracellular matrix (ECM), allowing cells to invade alone or collectively. Tumor spheroids cultured in collagen represent a simplified, reproducible 3D model system, which is sufficiently complex to recapitulate the evolving organization of cells and interaction with the ECM that occur during invasion. Recent experimental approaches enable high resolution imaging and quantification of the internal structure of invading tumor spheroids. Concurrently, computational modeling enables simulations of complex multicellular aggregates based on first principles. The comparison between real and simulated spheroids represents a way to fully exploit both data sources, but remains a challenge. We hypothesize that comparing any two spheroids requires first the extraction of basic features from the raw data, and second the definition of key metrics to match such features. Here, we present a novel method to compare spatial features of spheroids in 3D. To do so, we define and extract features from spheroid point cloud data, which we simulated using Cells in Silico (CiS), a high-performance framework for large-scale tissue modeling previously developed by us. We then define metrics to compare features between individual spheroids, and combine all metrics into an overall deviation score. Finally, we use our features to compare experimental data on invading spheroids in increasing collagen densities. We propose that our approach represents the basis for defining improved metrics to compare large 3D data sets. Moving forward, this approach will enable the detailed analysis of spheroids of any origin, one application of which is informing in silico spheroids based on their in vitro counterparts. This will enable both basic and applied researchers to close the loop between modeling and experiments in cancer research

Compressive remodeling alters fluid transport properties of collagen networks - implications for tumor growth

Biomechanical alterations to the tumor microenvironment include accumulation of solid stresses, extracellular matrix (ECM) stiffening and increased fluid pressure in both interstitial and peri-tumoral spaces. The relationship between interstitial fluid pressurization and ECM remodeling in vascularized tumors is well characterized, while earlier biomechanical changes occurring during avascular tumor growth within the peri-tumoral ECM remain poorly understood. Type I collagen, the primary fibrous ECM constituent, bears load in tension while it buckles under compression. We hypothesized that tumor-generated compressive forces cause collagen remodeling via densification which in turn creates a barrier to convective fluid transport and may play a role in tumor progression and malignancy. To better understand this process, we characterized the structure-function relationship of collagen networks under compression both experimentally and computationally. Here we show that growth of epithelial cancers induces compressive remodeling of the ECM, documented in the literature as a TACS-2 phenotype, which represents a localized densification and tangential alignment of peri-tumoral collagen. Such compressive remodeling is caused by the unique features of collagen network mechanics, such as fiber buckling and cross-link rupture, and reduces the overall hydraulic permeability of the matrix.R01 HL098028 - NHLBI NIH HHS; U01 CA202123 - NCI NIH HHSPublished versio

Design of the ERIS calibration unit

The Enhanced Resolution Imager and Spectrograph (ERIS) is a new-generation instrument for the Cassegrain focus of the ESO UT4/VLT, aimed at performing AO-assisted imaging and medium resolution spectroscopy in the 1-5 micron wavelength range. ERIS consists of the 1-5 micron imaging camera NIX, the 1-2.5 micron integral field spectrograph SPIFFIER (a modified version of SPIFFI, currently operating on SINFONI), the AO module and the internal Calibration Unit (ERIS CU). The purpose of this unit is to provide facilities to calibrate the scientific instruments in the 1-2.5 micron and to perform troubleshooting and periodic maintenance tests of the AO module (e.g. NGS and LGS WFS internal calibrations and functionalities, ERIS differential flexures) in the 0.5 - 1 μm range. The ERIS CU must therefore be designed in order to provide, over the full 0.5 - 2.5 μm range, the following capabilities: 1) illumination of both the telescope focal plane and the telescope pupil with a high-degree of uniformity; 2) artificial point-like and extended sources onto the telescope focal plane, with high accuracy in both positioning and FWHM; 3) wavelength calibration; 4) high stability of these characteristics. In this paper the design of the ERIS CU, and the solutions adopted to fulfill all these requirements, is described. The ERIS CU construction is foreseen to start at the end of 2016

Contributi per una flora vascolare di Toscana. XII (739-812)

Vengono presentate nuove località e/o conferme relative a 74 taxa specifici e sottospecifici di piante vascolari della flora vascolare to- scana, appartenenti a 69 generi e 28 famiglie: Bunium, Trinia (Apia- ceae), Nerium (Apocynaceae), Lemna (Araceae), Artemisia, Bidens, Centaurea, Crupina, Gazania, Hieracium, Rhagadiolus, Symphyotri- chum, Tagetes, Tripleurospermum (Asteraceae), Impatiens (Balsami- naceae), Anredera (Basellaceae), Cynoglottis, Phacelia (Boraginaceae), Cardamine, Diplotaxis, Hornungia (Brassicaceae), Campanula, Lobe- lia (Campanulaceae), Cerastium, Dianthus, Polycarpon, Spergularia, Stellaria (Caryophyllaceae), Commelina (Commelinaceae), Fallopia (Convolvulaceae), Sempervivum (Crassulaceae), Dryopteris (Dryopte- ridaceae), Euphorbia (Euphorbiaceae), Lathyrus, Medicago, Ononis, Trigonella (Fabaceae), Geranium (Geraniaceae), Lycopus, Stachys (Lamiaceae), Malva (Malvaceae), Anacamptis, Cephalanthera, Epi- pactis, Orchis (Orchidaceae), Linaria (Plantaginaceae), Ceratochloa, Eragrostis, Festuca, Gastridium, Hyparrhenia, Molineriella, Phalaris, Phyllostachys, Setaria, Sporobolus, Stipellula (Poaceae), Anogramma (Pteridaceae), Anemonoides, Ranunculus (Ranunculaceae), Reseda (Resedaceae), Alchemilla, Kerria, Pyracantha, Rosa, Rubus (Rosa- ceae), Galium, Valantia (Rubiaceae), Thesium (Santalaceae). Infine, viene discusso lo status di conservazione delle entità e gli eventuali vincoli di protezione dei biotopi segnalati

The MAORY first-light adaptive optics module for E-ELT

The MAORY adaptive optics module is part of the first light instrumentation suite for the E-ELT. The MAORY project phase B is going to start soon. This paper contains a system-level overview of the current instrument design

Mechanical Role of Elastin in Arterial Development and Disease Progression

Abdominal and thoracic aortic aneurysms are focal dilatations of the aorta that typically assume a fusiform shape and often progress to rupture, which is increasingly responsible for mortality and morbidity in our aging population. Although aneurysmal pathogenesis remains unclear, loss of medial elastin, the primary component of elastic fibers in arteries, is one of the fundamental histopathologic features of aneurysmal degeneration of the thoracic and abdominal aorta. The present work of thesis was carried out at the Continuum Biomechanics Laboratory of Texas A&M University, under the supervision of Prof. Jay D. Humphrey. The main goal of this thesis is to study the role of collagen and elastin, with a particular focus on the latter, in determining the passive biaxial mechanical behavior of large arteries. In order to quantify the response of single arterial wall constituents under biaxial loading, a new, structurally-motivated “four fiber family” nonlinear constitutive relation was fitted to experimental data via nonlinear regression. Confidence intervals for material and structural parameters were determined using the nonparametric bootstrap method, which allows determination of the precision of the parameter estimation procedure with the least assumptions. This analysis was first applied to describe the mechanical behavior of both human abdominal aorta (AA) and abdominal aortic aneurysm (AAA). Results show that the model is able to capture the mechanical behavior of the arterial tissue in both groups and the estimated parameters provide structural information about modifications of the arterial wall with aging and aneurysmal disease. Motivated by these results, the same analysis was subsequently applied to describe the mechanical response of common carotid arteries excised from a mouse model (mgR/mgR) of Marfan syndrome and tested under biaxial loading. These animal models express fibrillin-1, a microfibrillar glycoprotein that appears to stabilize elastic fibers mechanically, at only 15 to 25% of normal levels. This genetic modification is usually associated with higher rates of thoracic aortic aneurysm (TAA). Elastase was used to degrade elastin in common carotid arteries excised at 7 to 9 weeks of age. In vitro biaxial mechanical and functional tests performed before and after exposure to elastase revealed that the fibrillin-1 deficient arteries exhibit biomechanical characteristics consistent with significant structural integrity of elastin. These findings support the hypothesis that it is a premature fatigue-induced damage to otherwise competent elastic fibers that render arteries in Marfan syndrome patients susceptible to lethal dilatation, dissection, and rupture

Development of a scoring function for comparing simulated and experimental tumor spheroids.

Progress continues in the field of cancer biology, yet much remains to be unveiled regarding the mechanisms of cancer invasion. In particular, complex biophysical mechanisms enable a tumor to remodel the surrounding extracellular matrix (ECM), allowing cells to invade alone or collectively. Tumor spheroids cultured in collagen represent a simplified, reproducible 3D model system, which is sufficiently complex to recapitulate the evolving organization of cells and interaction with the ECM that occur during invasion. Recent experimental approaches enable high resolution imaging and quantification of the internal structure of invading tumor spheroids. Concurrently, computational modeling enables simulations of complex multicellular aggregates based on first principles. The comparison between real and simulated spheroids represents a way to fully exploit both data sources, but remains a challenge. We hypothesize that comparing any two spheroids requires first the extraction of basic features from the raw data, and second the definition of key metrics to match such features. Here, we present a novel method to compare spatial features of spheroids in 3D. To do so, we define and extract features from spheroid point cloud data, which we simulated using Cells in Silico (CiS), a high-performance framework for large-scale tissue modeling previously developed by us. We then define metrics to compare features between individual spheroids, and combine all metrics into an overall deviation score. Finally, we use our features to compare experimental data on invading spheroids in increasing collagen densities. We propose that our approach represents the basis for defining improved metrics to compare large 3D data sets. Moving forward, this approach will enable the detailed analysis of spheroids of any origin, one application of which is informing in silico spheroids based on their in vitro counterparts. This will enable both basic and applied researchers to close the loop between modeling and experiments in cancer research

An Experimental–Computational Study of Catheter Induced Alterations in Pulse Wave Velocity in Anesthetized Mice

Computational methods for solving problems of fluid dynamics and fluid-solid-interactions have advanced to the point that they enable reliable estimates of many hemodynamic quantities, including those important for studying vascular mechanobiology or designing medical devices. In this paper, we use a customized version of the open source code SimVascular to develop a computational model of central artery hemodynamics in anesthetized mice that is informed with experimental data on regional geometries, blood flows and pressures, and biaxial wall properties. After validating a baseline model against available data, we then use the model to investigate the effects of commercially available catheters on the very parameters that they are designed to measure, namely, murine blood pressure and (pressure) pulse wave velocity (PWV). We found that a combination of two small profile catheters designed to measure pressure simultaneously in the ascending aorta and femoral artery increased the PWV due to an overall increase in pressure within the arterial system. Conversely, a larger profile dual-sensor pressure catheter inserted through a carotid artery into the descending thoracic aorta decreased the PWV due to an overall decrease in pressure. In both cases, similar reductions in cardiac output were observed due to increased peripheral vascular resistance. As might be expected, therefore, invasive transducers can alter the very quantities that are designed to measure, yet advanced computational models offer a unique method to evaluate or augment such measurements

Combining in vivo and in vitro biomechanical data reveals key roles of perivascular tethering in central artery function.

Considerable insight into effectors of cardiovascular function can be gleaned from controlled studies on mice, especially given the diverse models that are available. Toward this end, however, there is a need for consistent and complementary methods of in vivo and in vitro data analysis, synthesis, and interpretation. The overall objective of this study is twofold. First, we present new semi-automated methods to quantify in vivo measurements of vascular function in anesthetized mice as well as new approaches to synthesize these data with those from in vitro biaxial mechanical characterizations. Second, we contrast regional differences in biomechanical behaviors along the central vasculature by combining biaxial strains measured in vivo with data on the unloaded geometry and biaxial material properties measured in vitro. Results support the hypothesis that the healthy ascending aorta stores significant elastic energy during systole, which is available to work on the heart and blood during diastole, particularly during periods of physical exertion, and further suggest that perivascular tethering allows arteries to work at lower values of wall stress and material stiffness than often assumed. The numerous measurements of vascular function and properties provided herein can also serve as reference values for normal wild-type male and female mice, to which values for myriad genetic, surgical, and pharmacological models can be compared in future studies