This paper addresses the problem of virtual pedestrian autonomous navigation for crowd simulation. It describes a method for solving interactions between pedestrians and avoiding inter-collisions. Our approach is agent-based and predictive: each agent perceives surrounding agents and extrapolates their trajectory in order to react to potential collisions. We aim at obtaining realistic results, thus the proposed model is calibrated from experimental motion capture data. Our method is shown to be valid and solves major drawbacks compared to previous approaches such as oscillations due to a lack of anticipation. We first describe the mathematical representation used in our model, we then detail its implementation, and finally, its calibration and validation from real data.

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Despite tremendous results achieved by immune checkpoint inhibitors, most patients are not responders, mainly because of the lack of a pre-existing anti-tumor immune response. Thus, solutions to efficiently prime this immune response are currently under intensive investigations. Radiotherapy elicits cancer cell death, generating an antitumorspecific T cell response, turning tumors in personalized in situ vaccines, with potentially systemic effects (abscopal effect). Nonetheless, clinical evidence of sustained anti-tumor immunity as abscopal effect are rare. Methods: Hafnium oxide nanoparticles (NBTXR3) have been designed to increase energy dose deposit within cancer cells. We examined the effect of radiotherapy-activated NBTXR3 on anti-tumor immune response activation and abscopal effect production using a mouse colorectal cancer model. Results: We demonstrate that radiotherapy-activated NBTXR3 kill more cancer cells than radiotherapy alone, significantly increase immune cell infiltrates both in treated and in untreated distant tumors, generating an abscopal effect dependent on CD8+ lymphocyte T cells. Conclusion: These data show that radiotherapy-activated NBTXR3 could increase local and distant tumor control through immune system priming. Our results may have important implications for immunotherapeutic agent combination with radiotherapy.

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Polyethyleneimines (PEIs) are efficient non-viral vectors for gene transfer. Heparan sulfate proteoglycans have been proposed to be the cell-surface receptors for PEI⅐DNA complexes (polyplexes). Here, we investigated if syndecan-1 (SDC1) and syndecan-2 (SDC2) are involved in PEI-mediated transfection. Following addition of polyplexes to HEK293 cells, green fluorescent protein-tagged SDCs rapidly formed clusters with PEI that were dependent of lipid raft integrity. However, although SDC1 overexpression slightly enhanced PEI-mediated gene expression, SDC2 dramatically inhibited it. Confocal microscopy analysis showed that SDC1⅐polyplex endocytosis occurred within minutes after addition of polyplexes, whereas SDC2⅐polyplex endocytosis took hours. Expression of SDC1 cytoplasmic deletion mutants revealed that the SDC1 cytoplasmic tail is required for gene expression, but not for clustering or endocytosis, whereas overexpression of SDC1/SDC2 chimeras showed that the SDC2 ectodomain is responsible for the inhibitory effect on gene transfer. This study provides evidence that SDCs may have opposing effects on PEI-mediated transfection.

HIF-1 (hypoxia-inducible factor-1) is the main transcription factor involved in the adaptation of cells to hypoxia. In addition to regulation of HIF-1α protein level, HIF-1 activity is also enhanced by several pathways involving asparagine hydroxylation and phosphorylation. Here, we investigated the relationship between casein kinase 2 (CK2), p53 and HIF-1. An increase in p53 protein level and transcriptional activity was observed when CK2 was inhibited by different inhibitors under normoxia and hypoxia. This increase was in parallel with a decrease in HIF-1 activity without changes in HIF-1α protein level, indicating a regulation of its transcriptional activity. Similar results were obtained using CK2α siRNA. Ectopic overexpression of p53 also led to an inhibition of HIF-1 activity. Conversely, CK2 inhibition had no effect in p53-null cells indicating that the inhibitory effect of CK2 inhibitors requires the presence of p53. p53 activity was not required because overexpression of a p53 mutated in its DNA-binding domain exerted the same effect as wild-type p53 and because the effect of CK2 inhibitors was still observed when p53 activity was inhibited by pifithrin-α. Since CK2 activity is increased in hypoxic conditions, this process provides one more mechanism to ensure enhanced HIF-1 activity under such conditions.

The inter-␣ trypsin inhibitor (ITI) family is a group of proteins built up from different combinations of 1 light chain (ITI-L) and 3 highly homologous heavy chains (ITI-H1, -H2 and -H3). To investigate a potential role of the ITI family chains in cancer and metastasis spreading, we engineered human H460M cell lines expressing both the green fluorescent protein (GFP) and one of these chains. These clones were subcutaneously injected in athymic nude mice, and lung metastasis number and primary tumor weight were determined after 28 days. Expression of the ITI-L chain considerably decreased tumor weight and fluorescent lung metastasis number. ITI-H1 and ITI-H3 chain expression induced a significant decrease of metastasis number, whereas no decrease of tumor weight could be detected. Key words: inter-␣-trypsin inhibitor; green fluorescent protein; spontaneous lung metastases; primary tumorInhibition of the metastatic process represents an important challenge in cancer treatment, and potential therapeutic approaches include the inhibition of matrix metalloproteinases, 1 of the vascular endothelial cell growth factor (VEGF) pathway 2 or the activation of metastasis suppressor genes. 3 Although most of the molecules involved in the metastatic process have not been identified, it is now established that alteration of the extracellular matrix (ECM) plays an important role in cell migration and metastasis. 4 The major ECM component, hyaluronic acid (HA), is organized as a complex network of macromolecules involving hyaluronic acidbinding proteins (HABP) 5 and the ITI family. The most of ITI members are composed of variable associations of light (ITI-L) and heavy chains (ITI-H1, -H2, -H3), encoded by 4 different genes on 3 chromosomes, 6 -9 giving rise to a series of proteins covalently linked by a glycosaminoglycan 10 and differing in their chain composition. 11 Although the binding of ITI to HA is known for a long time, 12 involvement of heavy chains in this linkage was only recently demonstrated 13-15 together with a major role in the ECM stability of the mouse cumulus oocyte complex. 16 The ITI-L chain mRNA encodes 2 tandemly arranged proteins that separate after proteolytic cleavage: the ␣ 1 -microglobulin (␣ 1 m) that belongs to the lipocalin superfamily 17 and the bikunin that contains 2 Kunitz inhibitory domains responsible for the protease inhibitory activity of ITI molecules. 18 Different studies have suggested a potential antimetastatic effect of bikunin: (i) it inhibits in vitro tumor cell receptor-bound plasmin 19 and the invasiveness of malignant cells; 20,21 and (ii) injections of human purified bikunin efficiently reduced the number of metastases produced by the murine 3LL cell line. 22 We have therefore analyzed in the present study the antimetastatic effect of the different ITI chains using a model of fluorescent spontaneous lung metastases. 23 MATERIAL AND METHODS Cells lines and cultureThe H460M cell line, initially derived from the parental NCI-H460 cell line established from a large-cell carcinoma o...