Combined OX40 Agonist and PD-1 Inhibitor Immunotherapy Improves the Efficacy of Vascular Targeted Photodynamic Therapy in a Urothelial Tumor Model

Purpose: Vascular targeted photodynamic therapy (VTP) is a nonsurgical tumor ablation approach used to treat early-stage prostate cancer and may also be effective for upper tract urothelial cancer (UTUC) based on preclinical data. Toward increasing response rates to VTP, we evaluated its efficacy in combination with concurrent PD-1 inhibitor/OX40 agonist immunotherapy in a urothelial tumor-bearing model. Experimental design: In mice allografted with MB-49 UTUC cells, we compared the effects of combined VTP with PD-1 inhibitor/OX40 agonist with those of the component treatments on tumor growth, survival, lung metastasis, and antitumor immune responses. Results: The combination of VTP with both PD-1 inhibitor and OX40 agonist inhibited tumor growth and prolonged survival to a greater degree than VTP with either immunotherapeutic individually. These effects result from increased tumor infiltration and intratumoral proliferation of cytotoxic and helper T cells, depletion of Treg cells, and suppression of myeloid-derived suppressor cells. Conclusions: Our findings suggest that VTP synergizes with PD-1 blockade and OX40 agonist to promote strong antitumor immune responses, yielding therapeutic efficacy in an animal model of urothelial cancer.     

Equivariant quantization of orbifolds

Equivariant quantization is a new theory that highlights the role of symmetries in the relationship between classical and quantum dynamical systems. These symmetries are also one of the reasons for the recent interest in quantization of singular spaces, orbifolds, stratified spaces, etc. In this work, we prove the existence of an equivariant quantization for orbifolds. Our construction combines an appropriate desingularization of any Riemannian orbifold by a foliated smooth manifold, with the foliated equivariant quantization that we built in Poncin et al. (2009) [19]. Further, we suggest definitions of the common geometric objects on orbifolds, which capture the nature of these spaces and guarantee, together with the properties of the mentioned foliated resolution, the needed correspondences between singular objects of the orbifold and the respective foliated objects of its desingularization.     

A first approximation for quantization of singular spaces

Many mathematical models of physical phenomena that have been proposed in recent years require more general spaces than manifolds. When taking into account the symmetry group of the model, we get a reduced model on the (singular) orbit space of the symmetry group action. We investigate quantization of singular spaces obtained as leaf closure spaces of regular Riemannian foliations on compact manifolds. These contain the orbit spaces of compact group actions and orbifolds. Our method uses foliation theory as a desingularization technique for such singular spaces. A quantization procedure on the orbit space of the symmetry group–that commutes with reduction–can be obtained from constructions which combine different geometries associated with foliations and new techniques originated in Equivariant Quantization. The present paper contains the first of two steps needed to achieve these just detailed goals.     

Are the Interactions between Recombinant Prion Proteins and Polymeric Surfaces Related to the Hydrophilic/Hydrophobic Balance?

New non‐fouling tubes are developed and their influence on the adhesion of neuroproteins is studied. Recombinant prion proteins are considered as a single component representative of hydrophobic proteins. Samples are stored for 24 h at 4 °C in tubes coated with two different coatings: poly(N‐isopropylacrylamide) as a hydrophilic surface and a plasma‐fluorinated coating as a hydrophobic one. The protein adhesion is monitored by ELISA tests, XPS and confocal microscopy. It appears that the highest recovery of recombinant prion protein in the liquid phase is obtained with the hydrophilic surface while the hydrophobic character of the storage tube induces an important amount of biological loss. However, the recovery is not complete even for tubes coated with poly(N‐isopropylacrylamide).

     

Synthesis of a new polymer surface bearing grafted azo polymer chains

Azobenzene, a photosensitive chromophore that undergoes photoinduced and thermal cis–trans isomerization, can be applied in a nonlinear optical field. {4′‐[(Hydroxy)ethyl]amino}‐4‐nitroazobenzene (disperse red 1) corresponds to one of these azo compounds, which can be grafted to a polymer chain as a part of the main chain, as a dangling group, or onto the polymer surface. In the last case, disperse red 1 is transformed into an acrylic monomer and then grafted onto a polypropylene surface modified with a cold carbon dioxide‐plasma treatment. A method is proposed for quantifying the radicals formed during the plasma treatment and, consequently, for optimizing the grafting reaction. The best conditions (the nature of the solvent, temperature, monomer concentration, and duration) are given. Both IR and Raman spectroscopies were used as efficient techniques for grafting characterization. © 2001 John Wiley & Sons, Inc. J Polym Sci Part A: Polym Chem 39: 3052–3061, 2001     

Higher trace and Berezinian of matrices over a Clifford algebra

We define the notions of trace, determinant and, more generally, Berezinian of matrices over a (_Z2)ⁿ${\left({\mathbb{Z}}_2\right)}^n$-graded commutative associative algebra A$A$. The applications include a new approach to the classical theory of matrices with coefficients in a Clifford algebra, in particular of quaternionic matrices. In a special case, we recover the classical Dieudonné determinant of quaternionic matrices, but in general our quaternionic determinant is different. We show that the graded determinant of purely even (_Z2)ⁿ${\left({\mathbb{Z}}_2\right)}^n$-graded matrices of degree 0$0$ is polynomial in its entries. In the case of the algebra A=H$A=\mathbb{H}$ of quaternions, we calculate the formula for the Berezinian in terms of a product of quasiminors in the sense of Gelfand, Retakh, and Wilson. The graded trace is related to the graded Berezinian (and determinant) by a (_Z2)ⁿ${\left({\mathbb{Z}}_2\right)}^n$-graded version of Liouville’s formula.     

Experimental investigation of bubble and drop formation at submerged orifices

The aim of this study was to investigate bubble/drop formation at a single submerged orifice in stagnant Newtonian fluids and to gain qualitative understanding of the formation mechanism. The effects of various governing parameters were studied. Formation behavior of bubbles and drops in Newtonian aqueous solutions were investigated experimentally under different operating conditions with various orifices. The results show that the volume of the detached dispersed phase (bubble or drop) increases with the viscosity of the continuous phase (or dispersion medium), surface tension, orifice diameter, and dispersed phase flow rate. A PIV system was employed to measure the velocity flow field quantitatively during the bubble/drop formation, giving interesting information useful for the elucidation of the fundamental formation process at the orifice. It was revealed that the orifice shape strongly influences the size of the bubble formed. Furthermore, based on a simple mass balance, a general correlation successfully predicting both bubble and drop sizes has been proposed.     

Products in the category of -manifolds

We prove that the category of -manifolds has all finite products. Further, we show that a -manifold (resp., a -morphism) can be reconstructed from its algebra of global -functions (resp., from its algebra morphism between global -function algebras). These results are of importance in the study of Lie groups. The investigation is all the more challenging, since the completed tensor product of the structure sheafs of two -manifolds is not a sheaf. We rely on a number of results on (pre)sheaves of topological algebras, which we establish in the appendix.     

Dynamical deformation of a flat liquid–liquid interface

The passage of solid spheres through a liquid–liquid interface was experimentally investigated using a high-speed video and PIV (particle image velocimetry) system. Experiments were conducted in a square Plexiglas column of 0.1 m. The Newtonian Emkarox (HV45 50 and 65% wt) aqueous solutions were employed for the dense phase, while different silicone oils of different viscosity ranging from 10 to 100 mPa s were used as light phase. Experimental results quantitatively reveal the effect of the sphere’s size, interfacial tension and viscosity of both phases on the retaining time and the height of the liquid entrained behind the sphere. These data were combined with our previous results concerning the passage of a rising bubble through a liquid–liquid interface in order to propose a general relationship for the interface breakthrough for the wide range of Mo ₁/Mo ₂ ∈ [2 × 10⁻⁵–5 × 10⁴] and Re ₁/Re ₂ ∈ [2 × 10⁻³–5 × 10²].