Low Avidity T Cells Do Not Hinder High Avidity T Cell Responses Against Melanoma

The efficacy of T cells depends on their functional avidity, i. e., the strength of T cell interaction with cells presenting cognate antigen. The overall T cell response is composed of multiple T cell clonotypes, involving different T cell receptors and variable levels of functional avidity. Recently, it has been proposed that the presence of low avidity tumor antigen-specific CD8 T cells hinder their high avidity counterparts to protect from tumor growth. Here we analyzed human cytotoxic CD8 T cells specific for the melanoma antigen Melan-A/MART-1. We found that the presence of low avidity T cells did not result in reduced cytotoxicity of tumor cells, nor reduced cytokine production, by high avidity T cells. In vivo in NSG-HLA-A2 mice, the anti-tumor effect of high avidity T cells was similar in presence or absence of low avidity T cells. These data indicate that low avidity T cells are not hindering anti-tumor T cell responses, a finding that is reassuring because low avidity T cells are an integrated part of natural T cell responses

Subclinical coronary atherosclerosis identified by coronary computed tomographic angiography in asymptomatic morbidly obese patients

Obesity is a common public health problem and obese individuals in particular have a disproportionate incidence of acute coronary events. This study was undertaken to identify coronary artery lesions as well as associated clinical features, risk factors and demographics in patients with a body mass index (BMI) >40 kg/m2 without known coronary artery disease (CAD). Morbidly obese subjects were prospectively recruited to undergo coronary computed tomographic angiography (CCTA) using a dual-source computed tomography (CT) system. CAD was defined as the presence of any atherosclerotic lesion in any one coronary artery segment. The presence, location, and severity of atherosclerosis were related to patient characteristics. Forty-one patients (28 women, mean age, 50.4±10.0 years, mean BMI, 43.8±4.8 kg/m2) served as the study population. Of these, 25 patients (61%) had at least one coronary stenosis. All but 2 patients within the CAD cohort had coronary artery calcium (CAC) scores >0, and most plaques identified (75.4%) were non-calcified. There was a predilection of calcified and non-calcified atherosclerosis involving the left anterior descending (LAD) coronary artery compared with other coronary segments. Univariate predictors of CAD included older age, dyslipidemia, and diabetes. In this preliminary study of young morbidly obese patients, CCTA detected a high prevalence of calcified and non-calcified CAD, although the later predominated

Investigating the interaction of cellulose nanofibers derived from cotton with a sophisticated 3D human lung cell coculture

Cellulose nanofibers are an attractive component of a broad range of nanomaterials. Their intriguing mechanical properties and low cost, as well as the renewable nature of cellulose make them an appealing alternative to carbon nanotubes (CNTs), which may pose a considerable health risk when inhaled. Little is known, however, concerning the potential toxicity of aerosolized cellulose nanofibers. Using a 3D in vitro triple cell coculture model of the human epithelial airway barrier, it was observed that cellulose nanofibers isolated from cotton (CCN) elicited a significantly (p < 0.05) lower cytotoxicity and (pro-)inflammatory response than multiwalled CNTs (MWCNTs) and crocidolite asbestos fibers (CAFs). Electron tomography analysis also revealed that the intracellular localization of CCNs is different from that of both MWCNTs and CAFs, indicating fundamental differences between each different nanofibre type in their interaction with the human lung cell coculture. Thus, the data shown in the present study highlights that not only the length and stiffness determine the potential detrimental (biological) effects of any nanofiber, but that the material used can significantly affect nanofiber–cell interactions

Non-commutative Quantum Mechanics in Three Dimensions and Rotational Symmetry

We generalize the formulation of non-commutative quantum mechanics to three dimensional non-commutative space. Particular attention is paid to the identification of the quantum Hilbert space in which the physical states of the system are to be represented, the construction of the representation of the rotation group on this space, the deformation of the Leibnitz rule accompanying this representation and the implied necessity of deforming the co-product to restore the rotation symmetry automorphism. This also implies the breaking of rotational invariance on the level of the Schroedinger action and equation as well as the Hamiltonian, even for rotational invariant potentials. For rotational invariant potentials the symmetry breaking results purely from the deformation in the sense that the commutator of the Hamiltonian and angular momentum is proportional to the deformation.Comment: 21 page

Risk assessment of released cellulose nanocrystals – mimicking inhalatory exposure

Cellulose nanocrystals (CNCs) exhibit advantageous chemical and mechanical properties that render them attractive for a wide range of applications. During the life-cycle of CNC containing materials the nanocrystals could be released and become airborne, posing a potential inhalatory exposure risk towards humans. Absent reliable and dose-controlled models that mimic this exposure in situ is a central issue in gaining an insight into the CNC-lung interaction. Here, an Air Liquid Interface Cell Exposure system (ALICE), previously designed for studies of spherical nanoparticles, was used for the first time to establish a realistic physiological exposure test method for inhaled fiber shaped nano-objects; in this case, CNCs isolated from cotton. Applying a microscopy based approach the spatially homogenous deposition of CNCs was demonstrated as a prerequisite of the functioning of the ALICE. Furthermore, reliability and controllability of the system to nebulise high aspect ratio nanomaterials (HARN, e.g. CNCs) was shown. This opens the potential to thoroughly investigate the inhalatory risk of CNCs in vitro using a realistic exposure system

Complete curvature homogeneous pseudo-Riemannian manifolds

We exhibit 3 families of complete curvature homogeneous pseudo-Riemannian manifolds which are modeled on irreducible symmetric spaces and which are not locally homogeneous. All of the manifolds have nilpotent Jacobi operators; some of the manifolds are, in addition, Jordan Osserman and Jordan Ivanov-Petrova.Comment: Update paper to fix misprints in original versio

TIE-2-expressing monocytes are lymphangiogenic and associate specifically with lymphatics of human breast cancer.

In experimental mouse models of cancer, increasingly compelling evidence point toward a contribution of tumor associated macrophages (TAM) to tumor lymphangiogenesis. Corresponding experimental observations in human cancer remain scarce although lymphatic metastasis is widely recognized as a predominant route for tumor spread. We previously showed that, in malignant tumors of untreated breast cancer (BC) patients, TIE-2-expressing monocytes (TEM) are highly proangiogenic immunosuppressive cells and that TIE-2 and VEGFR signaling pathways drive TEM immunosuppressive function. We report here that, in human BC, TEM express the canonical lymphatic markers LYVE-1, Podoplanin, VEGFR-3 and PROX-1. Critically, both TEM acquisition of lymphatic markers and insertion into lymphatic vessels were observed in tumors but not in adjacent non-neoplastic tissues, suggesting that the tumor microenvironment shapes both TEM phenotype and spatial distribution. We assessed the lymphangiogenic activity of TEM isolated from dissociated primary breast tumors in vitro and in vivo using endothelial cells (EC) sprouting assay and corneal vascularization assay, respectively. We show that, in addition to their known hemangiogenic function, TEM isolated from breast tumor display a lymphangiogenic activity. Importantly, TIE-2 and VEGFR pathways display variable contributions to TEM angiogenic and lymphangiogenic activities across BC patients; however, combination of TIE-2 and VEGFR kinase inhibitors abrogated these activities and overcame inter-patient variability. These results highlight the direct contribution of tumor TEM to the breast tumor lymphatic network and suggest a combined use of TIE-2 and VEGFR kinase inhibitors as a therapeutic approach to block hem- and lymphangiogenesis in BC

Curvature homogeneous spacelike Jordan Osserman pseudo-Riemannian manifolds

Let s be at least 2. We construct Ricci flat pseudo-Riemannian manifolds of signature (2s,s) which are not locally homogeneous but whose curvature tensors never the less exhibit a number of important symmetry properties. They are curvature homogeneous; their curvature tensor is modeled on that of a local symmetric space. They are spacelike Jordan Osserman with a Jacobi operator which is nilpotent of order 3; they are not timelike Jordan Osserman. They are k-spacelike higher order Jordan Osserman for $2\le k\le s$; they are k-timelike higher order Jordan Osserman for $s+2\le k\le 2s$, and they are not k timelike higher order Jordan Osserman for $2\le s\le s+1$.Comment: Update bibliography, fix minor misprint

Geometric Phase, Curvature, and Extrapotentials in Constrained Quantum Systems

We derive an effective Hamiltonian for a quantum system constrained to a submanifold (the constraint manifold) of configuration space (the ambient space) by an infinite restoring force. We pay special attention to how this Hamiltonian depends on quantities which are external to the constraint manifold, such as the external curvature of the constraint manifold, the (Riemannian) curvature of the ambient space, and the constraining potential. In particular, we find the remarkable fact that the twisting of the constraining potential appears as a gauge potential in the constrained Hamiltonian. This gauge potential is an example of geometric phase, closely related to that originally discussed by Berry. The constrained Hamiltonian also contains an effective potential depending on the external curvature of the constraint manifold, the curvature of the ambient space, and the twisting of the constraining potential. The general nature of our analysis allows applications to a wide variety of problems, such as rigid molecules, the evolution of molecular systems along reaction paths, and quantum strip waveguides.Comment: 27 pages with 1 figure, submitted to Phys. Rev.