Targeting TMEM176B Enhances Antitumor Immunity and Augments the Efficacy of Immune Checkpoint Blockers by Unleashing Inflammasome Activation.

Although immune checkpoint blockers have yielded significant clinical benefits in patients with different malignancies, the efficacy of these therapies is still limited. Here, we show that disruption of transmembrane protein 176B (TMEM176B) contributes to CD8+ T cell-mediated tumor growth inhibition by unleashing inflammasome activation. Lack of Tmem176b enhances the antitumor activity of anti-CTLA-4 antibodies through mechanisms involving caspase-1/IL-1β activation. Accordingly, patients responding to checkpoint blockade therapies display an activated inflammasome signature. Finally, we identify BayK8644 as a potent TMEM176B inhibitor that promotes CD8+ T cell-mediated tumor control and reinforces the antitumor activity of both anti-CTLA-4 and anti-PD-1 antibodies. Thus, pharmacologic de-repression of the inflammasome by targeting TMEM176B may enhance the therapeutic efficacy of immune checkpoint blockers.Uruguay INNOVA 2, Fondo Maria Viñas and Clemente Estable from ANII, as well as grants from CABBIO, PEDECIBA, ECOS-SUD and FOCEM (MERCOSUR Structural Convergence Fund), COF 03/11 to MH, The Harry J Lloyd Foundation to MRG and the Instituto Nacional del Cancer to YDM, Agencia de Promoción Científica y Tecnológica to GAR and MRG, Fundación Bunge & Born and Fundación Sales to GA

DESIGN AND ANALYSIS OF PAIRED COMPARISON EXPERIMENTS INVOLVING MIXTURES

2019110

Statistical inference for damaged Poisson distribution

For non-negative integer-valued random variables, the concept of "damaged" observations was introduced, for the first time, by Rao and Rubin [Rao, C. R., Rubin, H. (1964). On a characterization of the Poisson distribution. Sankhya 26:295-298] in 1964 on a paper concerning the characterization of Poisson distribution. In 1965, Rao [Rao, C. R. (1965). On discrete distribution arising out of methods of ascertainment. Sankhya Ser. A. 27:311-324] discusses some results related with inferences for parameters of a Poisson Model when it has occurred partial destruction of observations. A random variable is said to be damaged if it is unobservable, due to a damage mechanism which randomly reduces its magnitude. In subsequent years, considerable attention has been given to characterizations of distributions of such random variables that satisfy the "Rao-Rubin" condition. This article presents some inference aspects of a damaged Poisson distribution, under reasonable assumption that, when an observation on the random variable is made, it is also possible to determine whether or not some damage has occurred. In other words, we do not know how many items are damaged, but we can identify the existence of damage. Particularly it is illustrated the situation in which it is possible to identify the occurrence of some damage although it is not possible to determine the amount of items damaged. Maximum likelihood estimators of the underlying parameters and their asymptotic covariance matrix are obtained. Convergence of the estimates of parameters to the asymptotic values are studied through Monte Carlo simulations.33225926

On some fractional Green's functions

In this paper we discuss some fractional Green's functions associated with the fractional differential equations which appear in several fields of science, more precisely, the so-called wave reaction-diffusion equation and some of its particular cases. The methodology presented is the juxtaposition of integral transforms, in particular, the Laplace and the Fourier integral transforms. Some recent results involving the reaction-diffusion equation are pointed out.50