One CD4+TCR and One CD8+TCR Targeting Autochthonous Neoantigens Are Essential and Sufficient for Tumor Eradication.

PURPOSE: To achieve eradication of solid tumors, we examined how many neoantigens need to be targeted with how many T-cell receptors (TCR) by which type of T cells. EXPERIMENTAL DESIGN: Unmanipulated, naturally expressed (autochthonous) neoantigens were targeted with adoptively transferred TCR-engineered autologous T cells (TCR-therapy). TCR-therapy used CD8+ T-cell subsets engineered with TCRs isolated from CD8+ T cells (CD8+TCR-therapy), CD4+ T-cell subsets engineered with TCRs isolated from CD4+ T cells (CD4+TCR-therapy), or combinations of both. The targeted tumors were established for at least 3 weeks and derived from primary autochthonous cancer cell cultures, resembling natural solid tumors and their heterogeneity as found in humans. RESULTS: Relapse was common with CD8+TCR-therapy even when targeting multiple different autochthonous neoantigens on heterogeneous solid tumors. CD8+TCR-therapy was only effective against homogenous tumors artificially derived from a cancer cell clone. In contrast, a combination of CD8+TCR-therapy with CD4+TCR-therapy, each targeting one neoantigen, eradicated large and established solid tumors of natural heterogeneity. CD4+TCR-therapy targeted a mutant neoantigen on tumor stroma while direct cancer cell recognition by CD8+TCR-therapy was essential for cure. In vitro data were consistent with elimination of cancer cells requiring a four-cell cluster composed of TCR-engineered CD4+ and CD8+ T cells together with antigen-presenting cells and cancer cells. CONCLUSIONS: Two cancer-specific TCRs can be essential and sufficient to eradicate heterogeneous solid tumors expressing unmanipulated, autochthonous targets. We demonstrate that simplifications to adoptive TCR-therapy are possible without compromising efficacy.

Evolution and interpolation of double parton distributions using Chebyshev grids.

Double parton distributions are the nonperturbative ingredients needed for computing double parton scattering processes in hadron-hadron collisions. They describe a variety of correlations between two partons in a hadron and depend on a large number of variables, including two independent renormalization scales. This makes it challenging to compute their scale evolution with satisfactory numerical accuracy while keeping computational costs at a manageable level. We show that this problem can be solved using interpolation on Chebyshev grids, extending the methods we previously developed for ordinary single-parton distributions. Using an implementation of these methods in the C++ library ChiliPDF, we study for the first time the evolution of double parton distributions beyond leading order in perturbation theory.

Normal Values of Right Atrial Size and Function According to Age, Sex, and Ethnicity: Results of the World Alliance Societies of Echocardiography Study.

BACKGROUND: The World Alliance Societies of Echocardiography study is a multicenter, international, prospective, cross-sectional study whose aims were to evaluate healthy adult individuals to establish age- and sex-normative values of echocardiographic parameters and to determine whether differences exist among people from different countries and of different ethnicities. The present report focuses on two-dimensional (2D) and three-dimensional (3D) right atrial (RA) size and function. METHODS: Transthoracic 2D and 3D echocardiographic images were obtained in 2,008 healthy adult individuals evenly distributed among subgroups according to sex (1,033 men, 975 women) and age 18 to 40 years (n = 854), 41 to 65 years (n = 653), and >65 years (n = 501). For ethnicity, 34.9% were white, 41.6% Asian, and 9.7% black. Images were analyzed in a core laboratory according to current American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines. RA measurements included 2D dimensions, 2D and 3D RA volumes (RAVs) indexed to body surface area (BSA), emptying fraction (EmF), and global longitudinal strain, including total/reservoir, passive/conduit, and active/contractile phases. Differences among age and sex categories and among countries were also examined. RESULTS: RAVs were larger in men (even after BSA indexing), while 3D total EmF and global longitudinal strain magnitudes were higher in women. For both sexes, there were no significant age-related differences in 2D RAV measurements, but 3D RAV values differed minimally with age, remaining significant after BSA indexing. RA total EmF and reservoir strain and passive EmF and conduit strain magnitude were lower in older groups for both sexes. Interestingly, whereas RA active EmF increased with age, contractile strain magnitude decreased. Considerable geographic variations were identified: Asians of both sexes had significantly lower BSA than non-Asians, and their 2D and 3D end-systolic RAVs were significantly smaller even after BSA indexing. Of note, 2D end-systolic RAVs in this group were considerably lower than normal values provided in the current guidelines. CONCLUSIONS: There is significant sex, age, and geographic variability in normal RA size and function parameters. Current guideline-recommended normal ranges for RA size and function parameters should be adjusted geographically on the basis of the results of this study.

Automated cell cluster analysis provides insight into multi-cell-type interactions between immune cells and their targets.

Understanding interactions between immune cells and their targets is an important step on the path to fully characterizing the immune system, and in doing so, learning how it combats disease. Many studies of these interactions have a narrow focus, often looking only at a binary result of whether or not a specific treatment was successful or only focusing on the interactions between two individual cells. Therefore, in an effort to more comprehensively study multicellular interactions among immune cells and their targets, we used in vitro longitudinal time-lapse imaging and developed an automated cell cluster analysis tool, or macro, to investigate the formation of cell clusters. In particular, we investigated the behavior of cancer-specific CD8+ and CD4+ T cells on how they interact around their targets: cancer cells and antigen-presenting cells. The macro that we established allowed us to examine these large-scale clustering behaviors taking place between those four cell types. Thus, we were able to distinguish directed immune cell clustering from random cell movement. Furthermore, this macro can be generalized to be applicable to systems consisting of any number of differently labeled species and can be used to track clustering behaviors and compare them to randomized simulations.

Erratum to: Elements of a theory for multiparton interactions in QCD.

[This corrects the article DOI: 10.1007/JHEP03(2012)089.].