3D Multi-Cell Simulation of Tumor Growth and Angiogenesis

We present a 3D multi-cell simulation of a generic simplification of vascular tumor growth which can be easily extended and adapted to describe more specific vascular tumor types and host tissues. Initially, tumor cells proliferate as they take up the oxygen which the pre-existing vasculature supplies. The tumor grows exponentially. When the oxygen level drops below a threshold, the tumor cells become hypoxic and start secreting pro-angiogenic factors. At this stage, the tumor reaches a maximum diameter characteristic of an avascular tumor spheroid. The endothelial cells in the pre-existing vasculature respond to the pro-angiogenic factors both by chemotaxing towards higher concentrations of pro-angiogenic factors and by forming new blood vessels via angiogenesis. The tumor-induced vasculature increases the growth rate of the resulting vascularized solid tumor compared to an avascular tumor, allowing the tumor to grow beyond the spheroid in these linear-growth phases. First, in the linear-spherical phase of growth, the tumor remains spherical while its volume increases. Second, in the linear-cylindrical phase of growth the tumor elongates into a cylinder. Finally, in the linear-sheet phase of growth, tumor growth accelerates as the tumor changes from cylindrical to paddle-shaped. Substantial periods during which the tumor grows slowly or not at all separate the exponential from the linear-spherical and the linear-spherical from the linear-cylindrical growth phases. In contrast to other simulations in which avascular tumors remain spherical, our simulated avascular tumors form cylinders following the blood vessels, leading to a different distribution of hypoxic cells within the tumor. Our simulations cover time periods which are long enough to produce a range of biologically reasonable complex morphologies, allowing us to study how tumor-induced angiogenesis affects the growth rate, size and morphology of simulated tumors

Differential associations of childhood adversity subtypes and psychopathology in men and women

AbstractIntroductionPrior evidence suggests that men and women might be differentially susceptible to distinct types of childhood adversity (CA), but research on gender-specific associations between CA subtypes and psychiatric symptoms is limited.ObjectivesTo test the gender-specific associations of CA subtypes and psychiatric symptoms in the general population.MethodsData from 791 twins and siblings from the TwinssCan project were used. Psychopathology and CA exposure were assessed using the Symptom Checklist-90 Revised (SCL-90) and the Childhood Trauma Questionnaire (CTQ), respectively. The associations between the total CTQ scores and SCL-90 scores (i.e. total SCL-90, psychoticism, paranoid ideation, anxiety, depression, somatization, obsessive-compulsive, interpersonal sensitivity, hostility, and phobic anxiety) were tested in men and women separately. The associations between the five CA subtypes (i.e. physical abuse, emotional abuse, sexual abuse, physical neglect, and emotional neglect) and total SCL-90 were tested in a mutually adjusted model. As exploratory analyses, the associations between all CA subtypes and the nine SCL-90 subdomain scores were similarly tested. The regression coefficients between men and women were compared using Chow’s test. All models were adjusted for age and family structure.ResultsTotal CTQ was significantly associated with total SCL-90 in men (B = 0.013, SE = 0.003, P < .001) and women (B = 0.011, SE = 0.002, P < .001). The associations with the nine symptom domains were also significant in both genders (P < .001). No significant gender differences in the regression coefficients of total CTQ were detected. The analyses of CA subtypes showed a significant association between emotional abuse and total SCL-90 in women (B = 0.173, SE = 0.030, P < .001) and men (B = 0.080, SE = 0.035, P = .023), but the association was significantly stronger in women (ꭓ2(1) = 4.10, P = .043). The association of sexual abuse and total SCL-90 was only significant in women (B = 0.217, SE = 0.053, P < .001). The associations of emotional neglect (B = 0.061, SE = 0.027, P = .026) and physical neglect (B = 0.167, SE = 0.043, P < .001) with total SCL-90 were only significant in men. The explorative analyses of SCL-90 subdomains revealed significant associations of emotional abuse with all nine symptom domains and of sexual abuse with seven symptom domains in women. Significant associations of physical neglect with six symptom domains and of emotional neglect with depression were also detected in men. No other significant associations between CT subtypes and total SCL-90 or symptom domain scores were observed in men and women.ConclusionsCA exposure was associated with diverse psychopathology similarly in both genders. However, women are more sensitive to abuse, but men are more sensitive to neglect. Gender-specific influences of CA subtypes on psychopathology should be considered in future studies

Microvasculature on a chip: study of the Endothelial Surface Layer and the flow structure of Red Blood Cells

International audienceMicrovasculatures-on-a-chip, i.e. in vitro models that mimic important features of microvessel networks, have gained increasing interest in recent years. Such devices have allowed investigating pathophysiological situations involving abnormal biophysical interactions between blood cells and vessel walls. Still, a central question remains regarding the presence, in such biomimetic systems, of the endothelial glycocalyx. The latter is a glycosaminoglycans-rich surface layer exposed to blood flow, which plays a crucial role in regulating the interactions between circulating cells and the endothelium. Here, we use confocal microscopy to characterize the layer expressed by endothelial cells cultured in microfluidic channels. We show that, under our culture conditions, endothelial cells form a confluent layer on all the walls of the circuit and display a glycocalyx that fully lines the lumen of the microchannels. Moreover, the thickness of this surface layer is found to be on the order of 600 nm, which compares well with measurements performed ex or in vivo on microcapillaries. Furthermore, we investigate how the presence of endothelial cells in the microchannels affects their hydrodynamic resistance and the near-wall motion of red blood cells. Our study thus provides an important insight into the physiological relevance of in vitro microvasculatures. Interactions between circulating blood components and vessel walls are central to the immune 1,2 and inflamma-tory 3,4 response, and to processes such as angiogenesis 5,6 or hemostasis 7. These interactions result from a complex and highly regulated interplay between specific biomolecular adhesion mechanisms at cell/wall interfaces 1,3,8 , chemoattractant expression 2,9 , mechanical properties of the cells 10,11 , and fluid stresses arising from hemody-namics 10–13. Anomalous interactions between blood cells and the endothelium, i.e. the cellular layer lining the internal lumen of blood vessels, are known to be associated with a number of blood and vascular disorders such as thrombosis, atherosclerosis, diabetes mellitus, or sickle cell anemia 3,14. In vitro studies have proven to be extremely useful in order to unravel the respective roles of mechanical, biochemical and biophysical factors that govern some vascular pathologies 15–18. These studies typically rely on microfluidic tools to create networks of channels that recapitulate the microvasculature properties. Such in vitro investigations present several important advantages for the rational studies of blood dynamics, cell trafficking and microvascular functions: (i) they solve technical and ethical issues encountered when working on animal models 19 , (ii) microchannels are made from transparent materials and facilitate the use of advanced and high-resolution microscopy techniques, and (iii) experiments are performed under tightly controlled fluid composition and flow conditions. However, these advantages often come at the cost of a partial loss of physiological relevance, in particular regarding cell/wall interactions. To overcome this limitation, several works have proposed designs of in vitro microvasculatures that mimic not only the architecture, but also the surface properties of blood microvessels: endothelial cells have been cultured in microcircuits, made of silicone elastomer or hydrogels, in order to form a confluent monolayer on their walls, thus providing perfusable channels bearing a model endothe-lium, while displaying two-or three-dimensional network architectures 20–31. Such in vitro microvasculatures have 1 Univ

Coronary microvascular dysfunction in cardiovascular disease:Lessons from large animal models

The coronary microvasculature is responsible for maintaining local matching of myocardial blood flow to myocardial demand of oxygen and nutrients. Long term adjustment of myocardial blood flow involves structural changes in microvascular density and diameter while fine-tuning of flow is achieved via adaptations in vascular smooth muscle tone in the coronary microvasculature.In the past several decades, considerable research efforts have been directed at understanding structural and functional microvascular adaptations involved in matching myocardial oxygen supply and demand and how these mechanisms are affected by various diseases. In this review we will discuss our current understanding of the mechanisms underlying the regulation of coronary microvascular tone under healthy physiological conditions, and the role of microvascular dysfunction in obstructive and non-obstructive coronary artery disease, as studied in large animal (particularly swine) models and confirmed in human studies. Future studies should be directed at further unraveling the mechanisms of coronary microvascular dysfunction in different disease entities in order to, and ultimately directed at improving microvascular function as a therapeutic target in patients with ischemic heart disease