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  • 1
    Abstract: Recent evidence has revealed that oncogenic mutations may confer immune escape. A better understanding of how an oncogenic mutation affects immunosuppressive programmed death ligand 1 (PD-L1) expression may help in developing new therapeutic strategies. We show that oncogenic JAK2 (Janus kinase 2) activity caused STAT3 (signal transducer and activator of transcription 3) and STAT5 phosphorylation, which enhanced PD-L1 promoter activity and PD-L1 protein expression in JAK2(V617F)-mutant cells, whereas blockade of JAK2 reduced PD-L1 expression in myeloid JAK2(V617F)-mutant cells. PD-L1 expression was higher on primary cells isolated from patients with JAK2(V617F)-myeloproliferative neoplasms (MPNs) compared to healthy individuals and declined upon JAK2 inhibition. JAK2(V617F) mutational burden, pSTAT3, and PD-L1 expression were highest in primary MPN patient-derived monocytes, megakaryocytes, and platelets. PD-1 (programmed death receptor 1) inhibition prolonged survival in human MPN xenograft and primary murine MPN models. This effect was dependent on T cells. Mechanistically, PD-L1 surface expression in JAK2(V617F)-mutant cells affected metabolism and cell cycle progression of T cells. In summary, we report that in MPN, constitutive JAK2/STAT3/STAT5 activation, mainly in monocytes, megakaryocytes, and platelets, caused PD-L1-mediated immune escape by reducing T cell activation, metabolic activity, and cell cycle progression. The susceptibility of JAK2(V617F)-mutant MPN to PD-1 targeting paves the way for immunomodulatory approaches relying on PD-1 inhibition.
    Type of Publication: Journal article published
    PubMed ID: 29467301
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    ISSN: 1432-0959
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Extended Thermodynamics is an elegant and powerful material theory which yields, when applied, a symmetric hyperbolic system of evolution equations for the independent field variables. This system is obtained by imposing general physical principles, such as that of material objectivity and the entropy principle. With respect to thermodynamic equilibrium, the latter is carried through to second order. However, the following question arises: If this principle is imposed to even higher order terms, could it then yield restrictions also on the lower order terms, beyond those previously obtained in the literature? In this paper the entropy principle is applied to fourth order so that constitutive functions up to this order are obtained. In the process of computations many complicated equations involving only the lower order terms are deduced, which must be satisfied as identities. These equations, after long and tedious calculations, turn indeed out to be identically satisfied. This fact cannot be casual, thus confirming that this theory is trustworthy.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    ISSN: 1432-0959
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Relativistic Extended Thermodynamics is a very important scientific achievement of the last decades, and has inspired many subsequent authors to apply its methodology to lots of other possible applications. In short it furnishes field equations which are “closed” by imposing the relativity principle and the entropy principle up to second order, with respect to equilibrium; the linear closure is explicitly reported. Here these principles are imposed up to fourth order; the second order closure is explicitly reported, while the subsequent ones are reported as implicit functions. It is also proved that no internal inconsistencies are generated by the theory. In fact, in the process of computations many complicated conditions on the lower order terms are deduced, but they turn out to be identically satisfied.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-0959
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: The field equations of covariant Maxwell electrodynamics are a set I of 8 equations for the determination of 6 variables, i.e., the independent components of the skew-symmetric Maxwell tensor $F^{\alpha \beta}$ . Obviously 2 of these equations are not evolutive; however they cannot be eliminated without losing manifest covariance. This paper presents a new hyperbolic set S of 8 equations in the 8 variables $F^{\alpha \beta}, x, y $ , where $x, y$ are new auxiliary quantities. The solutions of S with $x = y = 0$ are those of the set I. Moreover, S is expressed in covariant form and is equivalent to a symmetric hyperbolic system.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-0959
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract The Blotekjaer hydrodynamical model for charge carriers transport in semiconductors is reconsidered from the viewpoint of extended thermodynamics. In particular the Blotekjaer original closure of the moment equations is shown to be equivalent to that obtained by applying the entropy principle.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    ISSN: 1432-0959
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract A system of equations is provided that may be used in the study of relativistic charged particle beams. The equations are based upon the equations of the kinetic theory for first, second and third order moments and the system is closed by letting the third order moment depend on the lower order ones. The form of that dependence is formally equal to the explicit constitutive function given by extended thermodynamics. However, here the contributions to the third order moment can be classed as being different in order of magnitude, because there is a smallness parameter characterizing the small dispersion of the particle beam. The resulting system of equations is quite specific, it is fully covariant and it is equivalent to a symmetric hyperbolic system thus ensuring existence and uniqueness of solutions.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-0959
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract Previous relativistic theories of thermodynamics of fluid mixtures can be extended to include more independent variables. Here the particular case is considered of a 3-constituent mixture consisting of a non-conducting fluid and two charged fluids; extension to the general case is straightforward. A set of field equations is found for the determination of the fields, following the methods of extended thermodynamics. These equations are restricted by the entropy principle and by material objectivity, obtaining in this way a closed hyperbolic system of field equations. As a byproduct of these principles, interesting stringent inequalities are obtained for the relaxation times arising from the production terms.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-0959
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract. Previous relativistic theories of thermodynamics of fluid mixtures can be extended to include more independent variables. Here the particular case is considered of a 3-constituent mixture consisting of a non-conducting fluid and two charged fluids; extension to the general case is straightforward. A set of field equations is found for the determination of the fields, following the methods of extended thermodynamics. These equations are restricted by the entropy principle and by material objectivity, obtaining in this way a closed hyperbolic system of field equations. As a byproduct of these principles, interesting stringent inequalities are obtained for the relaxation times arising from the production terms.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    ISSN: 1432-0959
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract The field equations of covariant Maxwell electrodynamics are a set I of 8 equations for the determination of 6 variables, i.e., the independent components of the skew-symmetric Maxwell tensorF αβ . Obviously 2 of these equations are not evolutive; however they cannot be eliminated without losing manifest covariance. This paper presents a new hyperbolic set S of 8 equations in the 8 variablesF αβ ,x, y, wherex, y are new auxiliary quantities. The solutions of S withx =y = 0 are those of the set I. Moreover, S is expressed in covariant form and is equivalent to a symmetric hyperbolic system.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    College Park, Md. : American Institute of Physics (AIP)
    Journal of Mathematical Physics 32 (1991), S. 544-550 
    ISSN: 1089-7658
    Source: AIP Digital Archive
    Topics: Mathematics , Physics
    Notes: Eddington factors are a common ingredient in many techniques for solving radiation hydrodynamics problems. Usually they are introduced in a phenomenological or ad hoc manner. In this paper a fundamental approach is devised for justifying Eddington factors on the basis of mathematical requirements arising from nonequilibrium thermodynamics.
    Type of Medium: Electronic Resource
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