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International audience; The purpose of this paper is to propose a time-step-robust cell-to-cell integration of particle trajectories in 3-D unstructured meshes in particle/mesh Lagrangian stochastic methods. The main idea is to dynamically update the mean fields used in the time integration by splitting, for each particle, the time step into sub-steps such that each of these sub-steps corresponds to particle cell residence times. This reduces the spatial discretization error. Given the stochastic nature of the models, a key aspect is to derive estimations of the residence times that do not anticipate the future of the Wiener process. To that effect, the new algorithm relies on a virtual particle, attached to each stochastic one, whose mean conditional behavior provides free-of-statistical-bias predictions of residence times. After consistency checks, this new algorithm is validated on two representative test cases: particle dispersion in a statistically uniform flow and particle dynamics in a non-uniform flow.; L’objectif de ce papier est de proposer un algorithme robuste en pas de temps permettant l’intégration face à face de la trajectoire de particules dans des maillage 3-D non-structurés pour des méthodes lagrangiennes stochastiques. L’idée principale est de mettre à jour de façon dynamique les champs moyens utilisés dans l’intégration temporelle. Pour ce faire, pour chaque particule, on subdivise le pas de temps en sous pas de temps, de façon à ce que chacun de ceux-ci correspondent au temps de résidence de la particule dans une cellule. Ce faisant on réduit l’erreur de discrétisation spatiale. Étant donnée la nature stochastique du modèle, un aspect prépondérant est de pouvoir dériver des estimations du temps de résidence des particules dans les cellules qui n’anticipent pas le futur des processus de Wiener. Dans ce but, le nouvel algorithme est basé sur une particule virtuelle attachée à chaque particule stochastique, dont le comportement conditionné moyen permet d’obtenir des temps de résidence qui ne sont entachés d’aucun biais statistique. Après une vérification de consistance, ce nouvel algorithme est validé sur deux cas de tests représentatifs : une dispersion de polluants dans un écoulement statistiquement uniforme et un écoulement non-uniforme dans lequel on traque la dynamique des particules.

The recombinant fusion protein aflibercept (ziv-aflibercept in the United States) binds VEGF-A, VEGF-B, and placental growth factor (PlGF). The monoclonal antibody bevacizumab binds VEGF-A. Recent studies hypothesized that dual targeting of VEGF/PlGF is more beneficial than targeting either ligand. We compared activity of aflibercept versus bevacizumab in 48 patient-derived xenograft (PDX) colorectal cancer models. Nude mice engrafted subcutaneously with PDX colorectal cancer tumors received biweekly aflibercept, bevacizumab, or vehicle injections. Differential activity between aflibercept and bevacizumab, determined by mouse (m), human (h), VEGF-A, and PlGF levels in untreated tumors, was measured. Aflibercept induced complete tumor stasis in 31 of 48 models and bevacizumab in 2 of 48. Based on statistical analysis, aflibercept was more active than bevacizumab in 39 of 48 models; in 9 of 39 of these models, bevacizumab was considered inactive. In 9 of 48 remaining models, aflibercept and bevacizumab had similar activity. Tumor levels of hVEGF-A (range 776–56,039 pg/mg total protein) were ∼16- to 1,777-fold greater than mVEGF-A (range 8–159 pg/mg total protein). Tumor levels of mPlGF (range 104–1,837 pg/mg total protein) were higher than hPlGF (range 0–543 pg/mg total protein) in 47 of 48 models. Tumor cells were the major source of VEGF; PlGF was primarily produced by tumor stroma. Because tumor levels of hVEGF-A were far greater than mVEGF-A, bevacizumab's inability to bind mVEGF-A is unlikely to explain higher and more consistent aflibercept activity. Neutralizing PlGF and VEGFR-1 activation may be a factor and should be investigated in future studies. In these colorectal cancer PDX models, aflibercept demonstrated greater antitumor activity than bevacizumab. Mol Cancer Ther; 13(6); 1636–44. ©2014 AACR.

PDF - 6591K, Tumor growth curves utilizing median ATVs of the 48 CRC PDXs: Tumor growth curves for all 48 patient-derived CRC tumors in mice engrafted SC, and which were treated with aflibercept SC injection (2x/week, 25 mg/kg), vehicle (SC injection, 2x/week), or bevacizumab (IV injection, 2x/week, 25 mg/kg) for a total of 3 weeks. Tumor measurements were recorded twice per week. Error bars represent MAD.

PDF - 44K, Distribution of the tumor origin across PDX models: Of the 48 PDX tumors, 8 were derived from primary patient tumors, 36 from metastatic sites, 1 from a site of recurring disease, and 1 of unknown anatomical origin. All of the primary tumors (8/8) were associated with phenotype A where aflibercept is more efficacious than bevacizumab. PDX tumors that originated from metastatic tumors were represented in both phenotypes A (30/39) and B (9/9).

PDF - 107K, Genomic characterization of PDX models: 48 PDX tumors comprising similar mutational patterns of KRAS, BRAF, PIK3CA, and PTEN have been reported in several other publications.

PDF - 6683K, Tumor growth curves utilizing mean ATVs of the 48 CRC PDXs: Tumor growth curves for all 48 patient-derived CRC tumors in mice engrafted SC, and which were treated with aflibercept SC injection (2x/week, 25 mg/kg), vehicle (SC injection, 2x/week), or bevacizumab (IV injection, 2x/week, 25 mg/kg) for a total of 3 weeks. Tumor measurements were recorded twice per week. Error bars represent standard error of the mean.

PDF - 115K, Legends to Supplementary Figures. Supplementary Table S1. Characteristics of 48 patient-derived colon cancer tumor xenografts. Supplementary Table S2. Evaluation of statistical differences between treatment(s) groups at the terminal point.

Supplementary Figure S2

Purpose:Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is a glycoprotein that has limited expression in normal adult tissues, but is overexpressed in carcinomas of the gastrointestinal tract, the genitourinary and respiratory systems, and breast cancer. As such, CEACAM5 is an attractive target for antibody-based therapies designed to selectively deliver cytotoxic drugs to certain epithelial tumors. Here, we describe preclinical data for a novel antibody–drug conjugate (ADC), SAR408701, which consists of an anti-CEACAM5 antibody (SAR408377) coupled to a maytansinoid agent DM4 via a cleavable linker.Experimental Design:The specificity and binding affinity of SAR408701 to human and cynomolgus monkey CEACAM5 were tested in vitro. The cytotoxic activity of SAR408701 was assessed in CEACAM5-expressing tumor cell lines and using patient-derived xenograft mouse models of CEACAM5-positive tumors. Pharmacokinetic-pharmacodynamic and pharmacokinetic-efficacy relationships were established. SAR408701 toxicity was evaluated in cynomolgus monkey.Results:SAR408701 bound selectively to human and cynomolgus monkey CEACAM5 with similar apparent Kd values (0.017 nmol/L and 0.024 nmol/L, respectively). Both in vitro and in vivo evaluations showed that SAR408701 has cytotoxic activity, leading to in vivo efficacy in single and repeated dosing. Single doses of SAR408701 induced significant increases in the tumor expression of phosphorylated histone H3, confirming the tubulin-targeting mechanism of action. The overall toxicity profile of SAR408701 in cynomolgus monkey was similar to that observed after intravenous administration of DM4 alone.Conclusions:On the basis of these preclinical data, the ADC SAR408701 is a promising candidate for development as a potential treatment for patients with CEACAM5-positive tumors.

Supplementary Materials

The purpose of this review is to analyze the physics at play in particle resuspension in order to bring insights into the rich complexity of this common but challenging concern. Following the more-is-different vision, this is performed by starting from a range of practical observations and experimental data. We then work our way through the investigation of the key mechanisms which play a role in the overall process. In turn, these mechanisms reveal an array of fundamental interactions, such as particle-fluid, particle-particle and particle-surface, whose combined effects create the tapestry of current applications. At the core of this analysis are descriptions of these physical phenomena and the different ways through which they are intertwined to build up various models used to provide quantitative assessment of particle resuspension. The physics of particle resuspension implies to hold together processes occurring at extremely different space and time scales and models are key in providing a single vehicle to lead us through such multiscale journeys. This raises questions on what makes up a model and one objective of the present work is to clarify the essence of a modeling approach. In spite of its ubiquitous nature, particle resuspension is still at the early stages of developments. Many extensions need to be worked out and revisiting the art of modeling is not a moot point. The need to consider more complex objects than small and spherical particles and, moreover, to come up with unified descriptions of mono- and multilayer resuspension put the emphasis on solid model foundations if we are to go beyond current limits. This is very much modeling in the making and new ideas are proposed to stimulate interest into this everyday but challenging issue in physics., Comment: 123 pages, 65 figures, submitted to Physics Reports

International audience; Mature soot aggregates exhibit a morphology which is currently mimicked by diffusion-limited aggregation (DLCA) codes, i.e. with a sticking probability = 1 when two aggregates collide. Nevertheless, nascent soot particles may grow in the reaction-limited aggregation regime (RLCA), i.e. with a sticking probability ≪ 1. Yet, it remains to be seen how fast the transition from RLCA to DLCA occurs for soot particles and what is the impact on aggregation kinetics, particle size distribution and morphology. This work intends to fill this gap by exploring the aggregation of soot particles formed in a laminar premixed flame through numerical simulations. Results show that the transition from RLCA to DLCA is very fast and produces a moderate impact on soot formation dynamics and morphology. However, soot particles mass bulk density is found to play an important role and should be considered in future simulations of soot formation in flames.

International audience; The present Letter addresses the resuspension of microscopic glass particles from a monolayer bed into a turbulent gas flow. With an intermediate surface coverage, here set to about 10% of the field of view, we report two distinct detachment mechanisms. At relatively low flow velocities, few loosely adhering particles move on the wall to eventually collide with neighboring particles resulting in a clustered resuspension. At higher fluid velocities, mostly individual particles resuspend due to their interaction with the turbulent flow. The resuspension curve, showing the remaining particle fraction as a function of the flow velocity, exhibits a strong bimodal character.

International audience; We clarify issues related to the expression of Lagrangian stochastic models used for atmospheric dispersion applications. Two aspects are addressed: the need to verify the well-mixed criterion and the correspondence between Eulerian and Lagrangian turbulence models when they are combined in practical simulations. In particular, it is recalled that the fulfillment of the well-mixed criterion depends only on the proper incorporation of the mean pressure-gradient term as the mean drift term of the Langevin equation. New consistency issues between duplicate fields within Eulerian/Lagrangian hybrid formulations are also brought out, especially regarding turbulence models, boundary conditions, and divergence-free condition. Such hybrid methods, where mean flow quantities calculated with an Eulerian approach are provided to the Lagrangian approach, are commonly used in atmospheric dispersion simulations for their numerical efficiency. Nevertheless, it is shown that serious inconsistencies can result from coupling Eulerian and Lagrangian models that do not correspond to the same level of description of the fluid turbulence.

International audience; This article presents a new data-driven spatial decomposition algorithm that allows to split a domain containing point particles into elementary cells, each cell containing a spatially-uniform distribution of particles. For that purpose, the algorithm relies on the use of statistical information for the spatial distribution of particles and then extracts an optimal spatial decomposition. After evaluating the convergence and accuracy of the algorithm on homogeneous and inhomogeneous cases, this optimal spatial decomposition is applied to study the case of particle agglomeration. Indeed in CFD context, recent developments on numerical simulations of particle agglomeration in complex and turbulent flows increasingly resort to Euler-Lagrange approaches. These methods are coupled with population balance equation (PBE)-like algorithms to compute agglomeration inside each cell of the Eulerian mesh. One of the key issues with such approaches is related to the respect of the spatially-uniform condition, i.e. agglomeration should be computed on a set of particles that are uniformly distributed locally in each cell. Yet, CFD simulations in realistic industrial/environmental cases often involve non-homogeneous concentrations of particles (due to local injection or accumulation in specific regions). We show that more accurate and mesh-independent predictions of particle agglomeration are made possible by the application of this new data-driven spatial decomposition algorithm.

xCT is a cystine/glutamate antiporter that exports intracellular glutamate for extracellular cystine. In the intracellular space, cystine is converted into cysteine which is subsequently used for glutathione (GSH) synthesis (a major antioxidant species). ARID1A is part of the SWI-SNF remodeling complex that binds on the xCT promoter and as such controls its gene expression. ARID1A deficiency which is highly prevalent in many cancers results in downregulation of xCT, impaired GSH biosynthesis and subsequent ROS induction, raising potential rationale to target xCT in ARID1A deficient cancers. By using a selective nanomolar range xCT inhibitor, we first showed that cell lines deficient for ARID1A were significantly more sensitive to the inhibition of xCT. Effects on proliferation could be reversed by N-acetylcysteine supplementation in the culture medium. In vivo, the xCT inhibitor confirmed its drug-like properties showing significant target engagement in an ARID1A deficient ovarian cell line xenograft model together with good PK and tolerability profiles. Altogether these studies have provided evidence that a specific drug-like inhibitor of xCT can be developed. This proprietary compound was used to confirm that in vitro the deficiency of ARID1A in ovarian cancer predicts sensitivity to xCT inhibition. Further in vivo pharmacological studies are required to confirm a specific molecular context predicting sensitivity towards xCT inhibition. Citation Format: Christophe Henry, Philippe Péron, Anne-Marie Blanchet, Arielle Genevois-Borella, Marc Trellu, Dorothée Bourges, Philippe Lienard, Alexandra Basset, Erwan Jouannot, Christophe Philippo, Laurent Debussche, Jürgen Moll. Pharmacological effects of selective xCT inhibition in ARID1A mutated cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 130.

International audience; Computational fluid dynamics simulations in practical industrial/environmental cases often involve non-homogeneous concentrations of particles. In Euler-Lagrange simulations, this can induce the propagation of numerical error when the number of collision/agglomeration events is computed using mean-field approaches. In fact, mean-field statistical collision models allow to sample the number of collision events using a priori information on the frequency of collisions (the collision kernel). Yet, since such methods often rely on the mesh used for the Eulerian simulation of the fluid phase, the particle number concentration within a given cell might not be homogeneous, leading to numerical errors. In this article, we apply the data-driven spatial decomposition (D2SD) algorithm to control such error in simulations of particle agglomeration. Significant improvements are made to design a fast D2SD version, minimizing the additional computational cost by developing re-meshing criteria. Through the application to some practical simulation cases, we show the importance of splitting the domain when computing agglomeration events in Euler/Lagrange simulations, so that within each elementary cell there is a spatially uniform distribution of particles.

The fragmentation of small, brittle, flexible, inextensible fibers is investigated in a fully-developed, homogeneous, isotropic turbulent flow. Such small fibers spend most of their time fully stretched and their dynamics follows that of stiff rods. They can then break through tensile failure, i.e. when the tension is higher than a given threshold. Fibers bend when experiencing a strong compression. During these rare and intermittent buckling events, they can break under flexural failure, i.e. when the curvature exceeds a threshold. Fine-scale massive simulations of both the fluid flow and the fiber dynamics are performed to provide statistics on these two fragmentation processes. This gives ingredients for the development of accurate macroscopic models, namely the fragmentation rate and daughter-size distributions, which can be used to predict the time evolution of the fiber size distribution. Evidence is provided for the generic nature of turbulent fragmentation and of the resulting population dynamics. It is indeed shown that the statistics of breakup is fully determined by the probability distribution of Lagrangian fluid velocity gradients. This approach singles out that the only relevant dimensionless parameter is a local flexibility which balances flow stretching to the fiber elastic forces., 19 pages, 9 figures

Human cytomegalovirus (HCMV) is a major human pathogen with seropositivity rates in the adult population ranging between 40% and 95%. HCMV infection is associated with severe pathology, such as life-threatening courses of infection in immunocompromised individuals and neonates. Current standard therapy with valganciclovir has the disadvantage of adverse side effects and viral drug resistance. A novel anti-HCMV drug, letermovir, has been approved recently, so that improved therapy options are available. Nevertheless, even more so far unexploited classes of compounds and molecular modes of action will be required for a next generation of antiherpesviral treatment strategies. In this study, we focused on the analysis of the antiviral potency of a novel class of compounds, i.e. pyrrolopyridine analogs, and identified both hit compounds and their target protein candidates. In essence, we provide novel evidence as follows: (i) screening hit SC88941 is highly active in inhibiting HCMV replication in primary human fibroblasts with an EC50 value of 0.20 ± 0.01 μM in the absence of cytotoxicity, (ii) inhibition occurs at the early-late stage of viral protein production and shows reinforcing effects upon LMV cotreatment, (iii) among the viruses analyzed, antiviral activity was most pronounced against β-herpesviruses (HCMV, HHV-6A) and intermediate against adenovirus (HAdV-2), (iv) induction of SC88941 resistance was not detectable, thus differed from the induction of ganciclovir resistance, (v) a linker-coupled model compound was used for mass spectrometry-based target identification, thus yielding several drug-binding target proteins and (vi) a first confocal imaging approach used for addressing intracellular effects of SC88941 indicated qualitative and quantitative alteration of viral protein expression and localization. Thus, our findings suggest a multifaceted pattern of compound-target binding in connection with an unusual mode of action, opening up further opportunities of antiviral drug development.

KAT6A and KAT6B are histone acetyl transferase (HAT) that are controlling gene expression by transferring acetyl groups to histones. Yu et al (Oncogene, 2017 36, 2910-2918) have shown that KAT6A has a role in breast cancer development by activating the ERα promoter and was found frequently amplified in 11% and is overexpressed in 15% of breast cancers. Altogether, these data support KAT6A as an attractive target in estrogen receptor driven breast cancer. KAT6B is a close homolog that shares 91% identity in the acetyl coA binding site. While the prevalence of gene amplification for KAT6B in breast cancer is only 1-2%, it is often overexpressed. In this study, we are exploring how KAT6A and KAT6B are contributing to ERα expression and the growth of KAT6A amplified breast cancer cell lines. To decipher each protein's role, we have designed specific siRNA against KAT6A and KAT6B and we tested their action either individually or in combination in the KAT6A gene amplified breast cancer cell lines T-47D, CAM-1 and ZR-75. Following treatment of T-47D, CAMA-1 and ZR75 cell lines with KAT6A or B siRNA we observed a decrease of ERα gene and protein expression for all siRNAs. The effect was more pronounced when using KAT6A over KAT6B and the effect of both siRNA A/B were additive. Phenotypically, the impact on cell line proliferation by applying clonogenic and incucyte assays, mirrors what is observed on ERα gene and protein expression. The effect on cellular proliferation of KAT6A is more prominent than KAT6B silencing, while the combined KAT6A + KAT6B silencing being more impactful than KAT6A silencing alone. In conclusion, our data show that KAT6A and KAT6B share similar function in the control of ER gene and protein expression. This study suggests that KAT6A and KAT6B may be paralogs, one compensating for the loss of the other. This translates into a more pronounced antiproliferative effect when both genes are silenced concomitantly. Citation Format: Isabelle Meaux, Dimitri Gorge-Bernat, Angele Paz, Catherine Geslin, Laurent Debussche, Jürgen Moll, Christophe Henry. Roles of KAT6A and KAT6B in the biology of estrogen positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2125.

Despite recent breakthrough in the treatment of multiple myeloma (MM) relapses are frequent, highlighting the need for novel approaches. Here we describe a novel anti-CD38/CD28xCD3 trispecific T cell engager (TCE) that targets CD38 expressed by malignant plasma cells and activates T cells by engaging CD3 and CD28 (1). Using bone marrow (BM) aspirates from MM patients, we confirmed that binding to malignant plasmocytes is primarily driven by the expression of CD38 and showed ex vivo that CD38/CD28xCD3 TCE induces a dose-dependent proliferation of CD4+ and CD8+ effector T cells. We also showed that MM patients' primary T cells were stimulated by CD38/CD28xCD3 TCE resulting in RPMI 8226 MM cell line lysis in co-culture assays. Killing of tumor cells was accompanied by MM effector CD8+ T cell degranulation and immunostimulatory cytokine production (IFN-γ and TNF-α). Finally, using MM patients' total BM cells, we showed that CD38/CD28xCD3 TCE induced the activation and cytokine production by cytotoxic CD8+ T cells and the CD38-dependent depletion of autologous primary malignant plasmocytes. Importantly, treatment of total BM cells with CD38/CD28xCD3 TCE also led to a CD38-dependent depletion of immunosuppressive myeloid derived suppressor cells (MDSC) that express CD38. Overall, these data show that CD38/CD28xCD3 trispecific TCE is active against primary myeloma cells and support the current evaluation of this next generation anti-CD38 multi-specific antibody in phase I clinical trial in patients with relapsed/refractory MM. (1) Wu, L., Seung, E., Xu, L. et al. Trispecific antibodies enhance the therapeutic efficacy of tumor-directed T cells through T cell receptor co-stimulation. Nat Cancer 1, 86-98 (2020). Citation Format: Nizar El-Murr, Sahar Kassem, Nadège Carrié, Christophe Henry, Angela Virone-Oddos, Zhi-yong Yang, Dmitri Wiederschain, Helgi Van de Velde, Marielle Chiron, Ludovic Martinet. Anti-CD38/CD28xCD3 trispecific T cell engager induces proliferation of primary T cells and mediates potent killing of primary malignant plasma cells isolated from Multiple Myeloma bone marrow aspirates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1887.

SAR442257 (CD38/CD28xCD3) is a trispecific T cell engager designed for the treatment of multiple myeloma (MM). Its cytotoxic activity and anti-tumor efficacy is dependent on the expression of CD38 by malignant plasma cells and the recruitment and activation of T cells via CD3 and CD28. Here we show that MM cells also express CD28 on their membrane and investigate how this expression impacts the cytotoxic activity of the trispecific antibody. Using CRISPR, CD28 knock-out (KO) models were generated from two MM cell lines that have different receptor densities of CD38 and CD28: KMS-11 (CD38 ~3 000/cell; CD28 ~35 000/cell) and RPMI8226 (CD38 ~129 000/cell; CD28 ~84 000/cell). T-cell-mediated cytotoxicity was evaluated in vitro using either effector CD8+ T cells or total PBMC isolated from healthy donors. Binding of SAR442257 to tumor cells in the presence of saturating concentrations of anti-CD38 antibodies was evaluated by flow cytometry using APC-labeled SAR442257 and FITC-labeled anti-CD38 antibodies. In vitro killing assays showed that SAR442257 is active on both CD38 high and CD38 low MM cell lines (EC50 in the pM range for WT cell lines; Table 1). Following CD28 KO, SAR442257 remained active but displayed reduced cytotoxic activity as compared to WT CD38+ CD28+ cells. The reduced cytotoxic activity was noticeable in both CD38 low and CD38 high MM models suggesting that the expression of CD28 by MM cells contributes to the cytotoxic activity of the trispecific antibody. We further show that when other anti-CD38 antibodies are bound to CD38, binding of SAR442257 to tumor cells and T-cell mediated cytotoxicity are rescued by CD28 as evidenced by loss of binding and cytotoxic activity in CD28KO cells. Overall, these data show that SAR442257 is active on both CD38 high and low MM models and that CD28 expressed on MM tumor cells can be directly targeted by SAR442257, enhancing its cytotoxicity and allowing it to bind MM cells when CD38 is occupied by other anti-CD38 antibodies Table 1.T cell mediated killing assays. EC50rel, Relative EC50; CI, Confidence interval.EC50rel (pM) [±CI95%]KMS-11RPMI8226WTCD28KOWTCD28KOEffector CD8+ T cells4.1 [2.9 ; 5.9]30.2 [16.9 ; 54.0]0.2 [0.1 ; 0.3]0.5 [0.3 ; 0.8]Total PBMC26.0 [7.8 ; 87]>250032.0 [14.8 ; 69.2]304.0 [118.0 ; 787.0] Citation Format: Nizar El-Murr, Christophe Henry, Elisa Francesconi, Florence Attenot, Angela Virone-Oddos, Laurent Vidard, Lan Wu, Zhi-Yong Yang, Marielle Chiron. CD28 expression on multiple myeloma cells enhances the cytotoxic activity of CD38/CD28xCD3 trispecific T cell engager [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5641.

This paper investigates the effect of inertia on the dynamics of elongated chains to go beyond the overdamped case that is often used to study such systems. For that purpose, numerical simulations are performed considering the motion of freely jointed bead-rod chains in an extensional flow in the presence of thermal noise. The coil-stretch transition and the tumbling instability are characterized as a function of three parameters: the Peclet number, the Stokes number, and the chain length. Numerical results show that the coil-stretch transition remains when inertia is present and that it depends nonlinearly on the Stokes and Peclet numbers. Theoretical and numerical analyses also highlight the role of intermediate stable configurations in the dynamics of elongated chains: chains can indeed remain trapped for a certain time in these configurations, especially while undergoing a tumbling event.

International audience; Small flexible fibers in a turbulent flow are found to be most of the time as straight as stiff rods. This is due to the cooperative action of flexural rigidity and fluid stretching. However, fibers might bend and buckle when they tumble and experience a strong-enough local compressive shear. Such events are similar to an activation process, where the role of temperature is played by the inverse of Young's modulus. Numerical simulations show that buckling occurs very intermittently in time. This results from unexpected long-range Lagrangian correlations of the turbulent shear.

This paper highlights the role played by surface roughness on the resuspension of nano- and micro-sized particles and, in particular, the need to extract more information from measurements of the surface profile than typical values such as the average roughness R a and the rms roughness R rms (usually obtained through AFM or SEM measures). For that purpose, standard experimental measurements of surface roughness are analysed. Then, numerical results obtained with a stochastic model for particle resuspension are analysed and compared to experimental data. This analysis reveals that particle resuspension can only be properly captured with more detailed representations of surface roughness that include information on the distribution of the curvature radius and surface coverage of roughness features.

The problem of accretion of small particles by a sphere embedded in a mean flow is studied in the case where the particles undergo inelastic collisions with the solid object. The collision efficiency, which gives the flux of particles experiencing at least one bounce on the sphere, is found to depend upon the sphere Reynolds number only through the value of the critical Stokes number below which no collision occurs. In the absence of molecular diffusion, it is demonstrated that multiple bounces do not provide enough energy dissipation for the particles to stick to the surface within a finite time. This excludes the possibility of any kind of inelastic collapse, so that determining an accretion efficiency requires modelling more precisely particle-surface microphysical interactions. A straightforward choice is to assume that the particles stick when their kinetic energy at impact is below a threshold. In this view, numerical simulations are performed in order to describe the statistics of impact velocities at various values of the Reynolds number. Successive bounces are shown to enhance accretion. These results are put together in order to provide a general qualitative picture on how the accretion efficiency depends upon the non dimensional parameters of the problem., Comment: 14 pages, 16 figures

This article deals with the resuspension phenomenon whereby particles adhering on a wall surface can be re-entrained by a flowing fluid. This is an area where significant progress has been achieved over the last years from an experimental, theoretical and numerical point of view. A first purpose of the present work is to report on the advances that have clarified our understanding of the physics of particle resuspension. It will be seen that new pictures have emerged about the physical processes involved in particle resuspension and, correspondingly, that new models have been proposed. A second purpose of the review is to put forward a general framework that allows both experimental analysis and new modelling ideas to be developed in terms of the fundamental interactions at play. These interactions are made up by the particle–fluid, particle–surface and particle–particle forces which are, in turn, related to the three specific fields of fluid dynamics, interface chemistry and surface roughness. Such a separation is helpful to highlight the actual physical processes while emphasising their relative importance in different situations and to provide useful guidelines for the necessary modelling efforts. In particular, it is stressed that new models which capture particle motion along a wall and simulate the complete particle dynamics represent an improvement over more classical static approaches. It is proposed that these new approaches be pursued and brought to higher levels of maturity. In this paper, attention is first focussed on the case where only a single layer of particles is sticking on the surface and, thus, can be re-entrained. A detailed review of the experimental works brings out the essential mechanisms and particle resuspension is shown to result from a balance between particle–fluid interactions and particle–surface interactions influenced by surface heterogeneities (roughness). The numerical models which have been proposed are then thoroughly discussed with respect to a new hierarchy of modelling approaches which is introduced. The present paper also outlines the mechanisms of multilayer particle resuspension which is still an open subject and where our present understanding remains preliminary. In this situation, resuspension is shown to be also governed by particle–fluid and particle–surface interactions but with the addition of particle–particle interactions (through cohesion forces or impaction). Finally, suggestions about the areas that still need to be addressed as well as about the issues that remain to be improved are addressed.

This paper presents a Lagrangian stochastic model to simulate colloid resuspension from rough surfaces. For that purpose, the extension of a recent proposition is discussed as well as the details of its numerical implementation. The basis of this model is a dynamical approach which reproduces explicitly the different steps involved in a three-stage scenario of particle resuspension where particles are set in motion (first stage); roll/slide along a rough surface due to varying force moments (second stage); and can be detached when a large-scale asperity is hit (third stage). The model treats separately hydrodynamic forces (drag force), adhesion forces (mainly due to interface chemical effects) and surface roughness through a two-level description (small-scale asperities and large-scale asperities) within a unified approach that combines the effects of fluid mechanics, interface chemistry and material properties. A description of the key points of the model brings forward the important role played by the number of small-scale asperities in contact with each particle; the pivot point around which particles can roll; the streamwise kinetic energy acquired as particles roll/slide along the surface; the probability to hit a large-scale asperity and the prediction of the actual detachment. Specific methods to simulate the trajectories of these stochastic processes are detailed and validated in a step-by-step manner with a specific emphasis put on the interplay between adhesion forces and particle dynamics. Finally, once each step has been separately assessed, the complete model is evaluated by comparing predictions to a realistic resuspension test-case for airborne colloids, showing that good and consistent numerical predictions are obtained with reasonable time steps.

Infection with human cytomegalovirus (HCMV) is a serious medical problem, particularly in immunocompromised individuals and neonates. The success of (val)ganciclovir therapy is hampered by low drug compatibility and induction of viral resistance. A novel strategy of antiviral treatment is based on the exploitation of cell-directed signaling, e. g. pathways with a known relevance for carcinogenesis and tumor drug development. Here we describe a principle for putative antiviral drugs based on targeting dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs). DYRKs constitute an evolutionarily conserved family of protein kinases with key roles in the control of cell proliferation and differentiation. Members of the DYRK family are capable of phosphorylating a number of substrate proteins, including regulators of the cell cycle, e.g. DYRK1B can induce cell cycle arrest, a critical step for the regulation of HCMV replication. Here we provide first evidence for a critical role of DYRKs during viral replication and the high antiviral potential of DYRK inhibitors (SC84227, SC97202 and SC97208, Harmine and AZ-191). Using established replication assays for laboratory and clinically relevant strains of HCMV, concentration-dependent profiles of inhibition were obtained. Mean inhibitory concentrations (EC50) of 0.98 ± 0.08 μM/SC84227, 0.60 ± 0.02 μM/SC97202, 6.26 ± 1.64 μM/SC97208, 0.71 ± 0.019 μM/Harmine and 0.63 ± 0.23 μM/AZ-191 were determined with HCMV strain AD169-GFP for the infection of primary human fibroblasts. A first analysis of the mode of antiviral action suggested a block of viral replication at the early-late stage of HCMV gene expression. Moreover, rhesus macaque cytomegalovirus (RhCMV), varicella-zoster virus (VZV) and herpes simplex virus (HSV-1) showed a similarly high sensitivity to these compounds. Thus, we conclude that DYRK signaling represents a promising target pathway for the development of novel anti-herpesviral strategies.

The purpose of this chapter is to provide an introduction to surface forces and to highlight their role in the context of particle deposition and resuspension. For that purpose, surface forces are first presented with a specific emphasis on the DLVO theory, which combines both van der Waals and electrostatic double-layer contributions within a single theory. The limitations and possible extensions of the DLVO theory are also briefly outlined, especially the role played by surface properties (such as surface roughness or surface charge heterogeneities). Then, the impact of such surface forces on particle deposition and resuspension is analysed with a brief review of some experimental results. Besides, the development of modelling approaches including the coupling and resulting effects of these various phenomena/mechanisms (with very different spatial- and time-scales) is illustrated with a thorough description of a one-point PDF modelling approach together with corresponding numerical results.

BRAF(V600E) mutant colon cancers (CCs) have a characteristic gene expression signature that is also found in some tumors lacking this mutation. Collectively, they are referred to as "BRAF-like" tumors and represent some 20% of CCs. We used a shRNA-based genetic screen focused on genes upregulated in BRAF(V600E) CCs to identify vulnerabilities of this tumor subtype that might be exploited therapeutically. Here, we identify RANBP2 (also known as NUP358) as essential for survival of BRAF-like, but not for non-BRAF-like, CC cells. Suppression of RANBP2 results in mitotic defects only in BRAF-like CC cells, leading to cell death. Mechanistically, RANBP2 silencing reduces microtubule outgrowth from the kinetochores, thereby inducing spindle perturbations, providing an explanation for the observed mitotic defects. We find that BRAF-like CCs display far greater sensitivity to the microtubule poison vinorelbine both in vitro and in vivo, suggesting that vinorelbine is a potential tailored treatment for BRAF-like CCs.

In this paper, the reentrainment of nanosized and microsized particles from rough walls under various electrostatic conditions and various hydrodynamic conditions (either in air or aqueous media) is numerically investigated. This issue arises in the general context of particulate fouling in industrial applications, which involves (among other phenomena) particle deposition and particle reentrainment. The deposition phenomenon has been studied previously and, in the present work, we focus our attention on resuspension. Once particles are deposited on a surface, the balance between hydrodynamic forces (which tend to move particles away from the surface) and adhesion forces (which maintain particles on the surface) can lead to particle removal. Adhesion forces are generally described using van der Waals attractive forces, but the limit of these models is that any dependence of adhesion forces on electrostatic forces (due to variations in pH or ionic strength) cannot be reproduced numerically. For this purpose, we develop a model of adhesion forces that is based on the DLVO (Derjaguin and Landau, Verwey and Overbeek) theory and which includes also the effect of surface roughness through the use of hemispherical asperities on the surface. We first highlight the effect of the curvature radius on adhesion forces. Then some numerical predictions of adhesion forces or adhesion energies are compared to experimental data. Finally, the overall effects of surface roughness and electrostatic forces are demonstrated with some applications of the complete reentrainment model in some simple test cases.

In this paper, we investigate the deposition of nanosized and microsized particles on rough surfaces under electrostatic repulsive conditions in an aqueous suspension. This issue arises in the general context of modeling particle deposition which, in the present work, is addressed as a two-step process: first particles are transported by the motions of the flow toward surfaces and, second, in the immediate vicinity of the walls, the forces between the incoming particles and the walls are determined using the classical DLVO theory. The interest of this approach is to take into account both hydrodynamical and physicochemical effects within a single model. Satisfactory results have been obtained in attractive conditions but some discrepancies have been revealed in the case of repulsive conditions, in line with other studies which have noted differences between predictions based on the DLVO theory and experimental measurements for similar repulsive conditions. Consequently, the aim of the present work is to focus on this particular range and, more specifically, to assess the influence of surface roughness on the DLVO potential energy. For this purpose, we introduce a new simplified model of surface roughness where spherical protruding asperities are placed randomly on a smooth plate. On the basis of this geometrical description, approximate DLVO expressions are used and numerical calculations are performed. We first highlight the existence of a critical asperity size which brings about the highest reduction of the DLVO interaction energy. Then, the influence of the surface covered by the asperities is investigated as well as retardation effects which can play a role in the reduction of the interaction energy. Finally, by considering the random distribution of the energy barrier of the DLVO potential due to the random geometrical configurations, the overall effect of surface roughness is demonstrated with one application of the complete deposition model in an industrial test case. These new numerical results show that nonzero deposition rates are now obtained even in repulsive conditions, which confirms that surface roughness is a relevant aspect to introduce in general approaches to deposition.

Tumor cells display enhanced requirements for energy and building blocks such as amino acids, nucleic acids and lipids to sustain their proliferation. Metabolic demands of cancer cells are often met in the context of limited access to nutrients and the need to maintain redox balance. Glutamine catabolism is considered critical to cancer cell survival by not only delivering carbon and nitrogen atoms needed for nucleic acid and amino acid precursors but also by serving as the source of antioxidants such as NADPH and glutathione. A vital step in the catabolism of glutamine is its conversion to glutamate by the mitochondrial enzyme glutaminase (GLS).In this study, we confirmed the significance of GLS and enhanced glutamine utilization in the basal subtype of breast cancer as evidenced by higher GLS to GLUL (Glutamine synthetase) ratio in a panel of breast cancers in The Cancer Genome Atlas (TCGA) database. Using inducible shRNA mediated gene knockdown, we discovered that loss of GLS function in triple-negative breast cancer (TNBC) cell lines led to profound tumor growth inhibition in vitro and in vivo. This anti-tumor effect of GLS knockdown was rescued either using shRNA resistant cDNAs encoding both GLS isoforms or by addition of an a-ketoglutarate analog thus confirming the critical role of GLS in TNBC. Along with these observations, we have found that pharmacological inhibition of GLS with the small molecule inhibitor CB-839 reduced cell growth and led to a decrease in mammalian target of rapamycin (mTOR) coupled with an increase in the stress response pathway driven by activating transcription factor 4 (ATF4). In line with the observed impact on mTOR pathway we found that GLS inhibition synergizes with mTOR inhibition. In conclusion, our preliminary investigation revealed that glutaminolysis is deregulated in a majority of TNBC cancer patients. Our target credentialing studies confirmed that GLS is essential for the survival of TNBC cell lines and xenografts tumors. The synergistic activity of GLS and mTOR inhibitors in this specific breast cancer subtype suggests a new therapeutic modality that may bring benefit to TNBC patients with high unmet need. Citation Format: Christophe Henry, Michael Lampa, Timothy He, Beatriz Ospina, Bailin Zhang, Gejing Deng, Claude Barberis, Dietmar Hoffmann, Jack Pollard, Adrian Francisco, Heike Arlt, Jason Reeves, Joshua Murtie, Christopher Winter, Victoria Richon, Hong Cheng, Carlos Garcia-Echeverria, Dmitri Wiederschain, Lakshmi Srinivasan. Basal-like breast cancer subtype is characterized by deregulated glutamine metabolism and is sensitive to GLS inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5472.

Performance of a voice prosthesis, used to restore speech in patients following total laryngectomy, was evaluated by measuring in vitro, as well as in vivo, airflow resistances. The pressure-flow characteristics of the device were analyzed using the standard pressure-flow diagram (to calculate airway resistance) and a Moody plot (to determine the different flow patterns). The flow rate and the pressure drop were measured with a Fleisch pneumotachograph and a variable reluctance transducer, respectively. Total device resistances were found in the range of 34–50 cm H2O/L/s when the flowrates ranged from 0.05 to 0.35 L/s. Comparison of these resistances with those of other commercially available devices showed that our voice prosthesis had the lowest resistance.

An original series of P-chirogenic aminophosphane-phosphinite (AMPP) ligands has been synthesized from (+)- or(–)-ephedrine in 23 to 61 % overall yields by a versatile three-step methodology. The AMPP ligands, bearing either one or two P-chirogenic centers, were used in the form of rhodium complexes for the catalyzed hydrogenation of α-acetamidocinnamate as a test reaction. Notably, even with AMPP ligands all derived from (+)-ephedrine, variation of the substituent on a P-center allowed the phenylalanine derivatives to be obtained in either (S) or (R) absolute configurations, with ee values ranging from 99 % (S) to 88 % (R). The asymmetric induction was analyzed with the aid of X-ray structures of AMPP complexes, and a new model for the enantioselectivity, taking into consideration the boat conformation and the steric and electronic dissymmetries at the dihydride rhodium-substrate complex, has been proposed. This model offers an alternative to the quadrant rule, well adapted to the C2-symmetry ligands and the chair conformation of their complex derivatives. In this work, the model, which schematizes the front side of the complex as a sextant in the direction of the cardinal points, fits with coordination of the substrate by the acetamido and the cinnamyl groups in the north and east (or west) parts, respectively. The enantioselectivity originates from the ligand residues located at the south-east or south-west parts of the dihydride rhodium intermediate. Computer modeling on several AMPP-rhodium complexes with PCModel confirms the proposed predicting model.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Particle deposition in turbulent flows is a phenomenon which can lead to fouling and affect normal operating conditions of key components of industrial processes. To explain the deposition mechanisms and predict the deposition rate, several models have been proposed in the literature. The model presented in this paper is based on a stochastic Lagrangian approach, where each particle is explicitly tracked, and where the velocity of the flow seen by particles is modeled by a stochastic process which depends on the mean fluid properties at particle locations. The interactions between particles and near-wall coherent structures are taken into account. Recent developments have shown that the model is not only able to reproduce single-particle deposition and resuspension but can also be applied to simulate the formation and the growth of multilayer deposits. Such deposits result from the competition between particle–fluid, particle–surface, and particle–particle interactions. Different morphologies of the deposit (monolayer, dendrites, multilayer) can exist according to the chemical properties of the particles and wall. A porous medium approach is used to take into account the effect of the deposit formed on the flow to obtain more realistic evolution.