Blood coagulation dynamics: mathematical modeling and stability results

The hemostatic system is a highly complex multicomponent biosystem that under normal physiologic conditions maintains the fluidity of blood. Coagulation is initiated in response to endothelial surface vascular injury or certain biochemical stimuli, by the exposure of plasma to Tissue Factor (TF), that activates platelets and the coagulation cascade, inducing clot formation, growth and lysis. In recent years considerable advances have contributed to understand this highly complex process and some mathematical and numerical models have been developed. However, mathematical models that are both rigorous and comprehensive in terms of meaningful experimental data, are not available yet. In this paper a mathematical model of coagulation and fibrinolysis in flowing blood that integrates biochemical, physiologic and rheological factors, is revisited. Three-dimensional numerical simulations are performed in an idealized stenosed blood vessel where clot formation and growth are initialized through appropriate boundary conditions on a prescribed region of the vessel wall. Stability results are obtained for a simplified version of the clot model in quiescent plasma, involving some of the most relevant enzymatic reactions that follow Michaelis-Menten kinetics, and having a continuum of equilibria.CEMAT/IST through FCT [PTDC/MAT/68166/2006]; Czech Science Foundation [201/09/0917]; Grant Agency of the Academy of Sciences of the CR [IAA100190804]; Ministry of Education of Czech Republic [6840770010]info:eu-repo/semantics/publishedVersio

Distribution of laminin and fibronectin isoforms in oral mucosa and oral squamous cell carcinoma

The expression of laminin and fibronectin isoforms varies with cellular maturation and differentiation and these differences may well influence cellular processes such as adhesion and motility. The basement membrane (BM) of fetal oral squamous epithelium contains the laminin chains, α2, α3, α5, β1, β2, β3, γ1 and γ2. The BM of adult normal oral squamous epithelium comprises the laminin chains, α3, α5, β1, β3, γ1 and γ2. A re-expression of the laminin α2 and β2 chains could be shown in adult hyperproliferative, dysplastic and carcinomatous lesions. In dysplasia and oral squamous cell carcinoma (OSCC), multifocal breaks of the BM are present as indicated by laminin chain antibodies. These breaks correlate to malignancy grade in their extent. Moreover, in the invasion front the α3 and γ2 chain of laminin-5 can immunohistochemically be found outside the BM within the cytoplasm of budding carcinoma cells and in the adjacent stroma. The correlation between the morphological pattern of invasive tumour clusters and a laminin-5 immunostaining in the adjacent stroma may suggest, first, that a laminin-5 deposition outside the BM is an immunohistochemical marker for invasion and second, that OSCC invasion is guided by the laminin-5 matrix. Expression of oncofetal fibronectins (IIICS de novo glycosylated fibronectin and ED-B fibronectin) could be demonstrated throughout the stromal compartment. However, the ED-B fibronectin synthesizing cells (RNA/RNA in situ hybridization) are confined to small stroma areas and to single stroma and inflammatory cells in the invasion front. A correlation of the number of ED-B fibronectin synthesizing cells to malignancy grade could not be seen. ED-B fibronectin mRNA-positive cells seem to be concentrated in areas of fibrous stroma recruitment with a linear alignment of stromal fibro-/myofibroblasts (desmoplasia). Double staining experiments (ED-B fibronectin in situ hybridization and α-smooth muscle actin immunohistochemistry) indicated that the stroma myofibroblasts are a preferential source of ED-B fibronectin. In conclusion, in OSCC, a fetal extracellular matrix conversion is demonstrable. Tumour cells (laminin α2 and β2 chain) and recruited stromal myofibroblasts (oncofetal ED-B fibronectin) contribute to the fetal extracellular matrix milieu. © 1999 Cancer Research Campaig

Digital realities & virtual ideals: Portraiture, idealism and the clash of subjectivities in the post-digital era

This is an accepted manuscript of an article published by Taylor and Francis in Photography and Culture on 26/02/2019, available online: https://doi.org/10.1080/17514517.2019.1565290 The accepted version of the publication may differ from the final published version.All portraits play host to a number of antithetical tensions, such as ‘private’ and ‘public’, ‘real’ and ‘ideal’, without which they would be reduced to a type of unassuming identification of subjects. Whereas in premodern times the artist was subject to the demands of the commissioner, after modernism the representational desires of the sitter began to clash with the creative intentions of the artist. Prior to the introduction of digital formats, this clash of subjectivities manifests itself in photography during the production of the work, the shooting of a portrait. Digital photography and post-production editing have expanded the methods for idealising external appearance; a desire stimulated by the recent technological acceleration of production and circulation of more ‘manipulated’ portraits than ever. In what ways, therefore, does the introduction of digital post-production editing and composite images affect this double-clash in portraiture, between the real and ideal, and the desires of the sitter against the intentions of the artist? Moreover, how does the evolution of self-portraiture in the ‘selfie’ affect the epistemological character of the genre? As such, is conceptual and aesthetic subservience a matter of technological possibility or creative determination

Glow discharge in low pressure plasma PVD: mathematical model and numerical simulations

In this paper we analyze the problem of glow discharge in low pressure plasma in industrial plant, for chambers of different shapes and various working parameters, like pressure and electric potential. The model described is based upon a static approximation of the AC configuration with two electrodes and a drift diffusion approximation for the current density of positive ions and electrons. A detailed discussion of the boundary conditions imposed is given, as well as the full description of the mathematical model. Numerical simulations were performed for a simple 1D model and two different 2D models, corresponding to two different settings of the industrial plant. The simpler case consists of a radially symmetric chamber, with one central electrode (cathode), based upon a DC generator. In this case, the steel chamber acts as the anode. The second model concerns a two dimensional horizontal cut of the most common plant configuration, with two electrodes connected to an AC generator. The case is treated in a "quasi-static" approximation. The three models show some common behaviours, particularly including the main expected features, such as dark spaces, glow regions and a wide "plasma region". Furthermore, the three shown models show some similarities with previously published results concerning 1D and simplified 2D models, as well as with some preliminary results of the full 3D case.Comment: 16 pages, 11 figures, in pres

Combination of temozolomide with immunocytokine F16–IL2 for the treatment of glioblastoma

Glioblastoma patients are still not cured by the treatments available at the moment. We investigated the therapeutic properties of temozolomide in combination with F16-IL2, a clinical-stage immunocytokine consisting of human interleukin (IL)-2 fused to the human antibody F16, specific to the A1 domain of tenascin-C

A chemically modified antibody mediates complete eradication of tumours by selective disruption of tumour blood vessels

These results reinforce the concept that vascular shutdown can induce a curative avalanche of tumour cell death. Immuno-photodynamic therapy may be particularly indicated for squamous cell carcinoma of the skin, which we show to be strongly positive for markers of angiogenesis

Characterisation and radioimmunotherapy of L19-SIP, an anti-angiogenic antibody against the extra domain B of fibronectin, in colorectal tumour models

Angiogenesis is a characteristic feature of tumours and other disorders. The human monoclonal antibody L19- SIP targets the extra domain B of fibronectin, a marker of angiogenesis expressed in a range of tumours. The aim of this study was to investigate whole body distribution, tumour localisation and the potential of radioimmunotherapy with the L19-small immunoprotein (SIP) in colorectal tumours. Two colorectal tumour models with highly different morphologies, the SW1222 and LS174T xenografts, were used in this study. Localisation and retention of the L19-SIP antibody at tumour vessels was demonstrated using immunohistochemistry and Cy3-labelled L19-SIP. Whole body biodistribution studies in both tumour models were carried out with 125I-labelled L19-SIP. Finally, 131I-labelled antibody was used to investigate the potential of radioimmunotherapy in SW1222 tumours. Using immunohistochemistry, we confirmed extra domain B expression in the tumour vasculature. Immunofluorescence demonstrated localisation and retention of injected Cy3-labelled L19-SIP at the abluminal side of tumour vessels. Biodistribution studies using a 125I-labelled antibody showed selective tumour uptake in both models. Higher recorded values for localisation were found in the SW1222 tumours than in the LS174T (7.9 vs 6.6 %ID g−1), with comparable blood clearance for both models. Based on these results, a radioimmunotherapy study was performed in the SW1222 xenograft using 131I-Labelled L19-SIP (55.5 MBq), which showed selective tumour uptake, tumour growth inhibition and improved survival. Radio- and fluorescence-labelled L19-SIP showed selective localisation and retention at vessels of two colorectal xenografts. Furthermore, 131I-L19-SIP shows potential as a novel treatment of colorectal tumours, and provides the foundation to investigate combined therapies in the same tumour models

High-K volcanism in the Afyon region, western Turkey: from Si-oversaturated to Si-undersaturated volcanism

Volcanic rocks of the Afyon province (eastern part of western Anatolia) make up a multistage potassic and ultrapotassic alkaline series dated from 14 to 12 Ma. The early-stage Si-oversaturated volcanic rocks around the Afyon city and further southward are trachyandesitic volcanic activity (14.23 ± 0.09 Ma). Late-stage Si-undersaturated volcanism in the southernmost part of the Afyon volcanic province took place in three episodes inferred from their stratigraphic relationships and ages. Melilite– leucitites (11.50 ± 0.03 Ma), spotted rachyandesites, tephryphonolites and lamproites (11.91 ± 0.13 Ma) formed in the first episode; trachyandesites in the second episode and finally phonotephrites, phonolite, basaltic trachyandesites and nosean-bearing trachyandesites during the last episode. The parameter Q [normative q-(ne + lc + kls + ol)] of western Anatolia volcanism clearly decreased southward with time becoming zero in the time interval 10–15 Ma. The magmatism experienced a sudden change in the extent of Si saturation after 14 Ma, during late-stage volcanic activity of Afyon volcanic province at around 12 Ma, though there was some coexistence of Si-oversaturated and Si-undersaturated magmas during the whole life of Afyon volcanic province

Optimal MHC-II-restricted tumor antigen presentation to CD4+ T helper cells: the key issue for development of anti-tumor vaccines

Present immunoprevention and immunotherapeutic approaches against cancer suffer from the limitation of being not “sterilizing” procedures, as very poor protection against the tumor is obtained. Thus newly conceived anti-tumor vaccination strategies are urgently needed. In this review we will focus on ways to provide optimal MHC class II-restricted tumor antigen presentation to CD4+ T helper cells as a crucial parameter to get optimal and protective adaptive immune response against tumor. Through the description of successful preventive or therapeutic experimental approaches to vaccinate the host against the tumor we will show that optimal activation of MHC class II-restricted tumor specific CD4+ T helper cells can be achieved in various ways. Interestingly, the success in tumor eradication and/or growth arrest generated by classical therapies such as radiotherapy and chemotherapy in some instances can be re-interpreted on the basis of an adaptive immune response induced by providing suitable access of tumor-associated antigens to MHC class II molecules. Therefore, focussing on strategies to generate better and suitable MHC class II–restricted activation of tumor specific CD4+ T helper cells may have an important impact on fighting and defeating cancer

Objectively assessed disease activity and drug persistence during ustekinumab treatment in a nationwide real-world Crohn's disease cohort

ObjectiveLong-term evidence on ustekinumab treatment response and persistence in patients with Crohn's disease in a real-world setting is scarce. We performed a retrospective nationwide chart review study of long-term clinical outcomes in Crohn's disease patients treated with ustekinumab.MethodsThe study was conducted in 17 Finnish hospitals and included adult Crohn's disease patients who received an initial intravenous dose of ustekinumab during 2017-2018. Disease activity data were collected at baseline, 16 weeks, and 1 year from health records.ResultsThe study included 155 patients. The disease was stricturing or penetrating in 69 and 59% had prior Crohn's disease-related surgeries, and 97% had a treatment history of at least one biologic agent. Of 93 patients with >= 1 year of follow-up, 77 (83%) were still on ustekinumab at 1 year. In patients with data available, from baseline to the 1-year follow-up the simple endoscopic score for Crohn's disease (SES-CD) decreased from 10 to 3 (P = 0.033), C-reactive protein from 7 to 5 mg/L, (P ConclusionsUstekinumab treatment in patients with highly refractory Crohn's disease resulted in high long-term treatment persistence and significantly reduced disease activity, assessed with objective markers for intestinal inflammatory activity.</div