Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes, as well as differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor’s clonal evolution during treatment.

Understanding the cellular constituents of the prostate is essential for identifying the cell of origin for prostate adenocarcinoma. Here we describe a comprehensive single-cell atlas of the adult mouse prostate epithelium, which displays extensive heterogeneity. We observe distal lobe-specific luminal epithelial populations (LumA, LumD, LumL, and LumV), a proximally-enriched luminal population (LumP) that is not lobe-specific, and a periurethral population (PrU) that shares both basal and luminal features. Functional analyses suggest that LumP and PrU cells have multipotent progenitor activity in organoid formation and tissue reconstitution assays. Furthermore, we show that mouse distal and proximal luminal cells are most similar to human acinar and ductal populations, that a PrU-like population is conserved between species, and that the mouse lateral prostate is most similar to the human peripheral zone. Our findings elucidate new prostate epithelial progenitors, and help resolve long-standing questions about anatomical relationships between the mouse and human prostate.

Journal of High Energy Physics 2011.8 (2011): 152 reproduced by permission of Scuola Internazionale Superiore di Studi Avanzati (SISSA)We study the deformation induced by fluxes and instanton effects on Yukawa couplings involving 7-brane intersections in local F-theory constructions. In the absence of non-perturbative effects, holomorphic Yukawa couplings do not depend on open string fluxes. On the other hand instanton effects (or gaugino condensation on distant 7-branes) do induce corrections to the Yukawas. The leading order effect may also be captured by the presence of closed string (1,2) IASD fluxes, which give rise to a non-commutative structure. We check that even in the presence of these non-perturbative effects the holomorphic Yukawas remain independent of magnetic fluxes. Although fermion mass hierarchies may be obtained from these non-perturbative effects, they would give identical Yukawa couplings for D-quark and Lepton masses in SU(5) F-theory GUT's, in contradiction with experiment. We point out that this problem may be solved by appropriately normalizing the wavefunctions. We show in a simple toy model how the presence of hypercharge flux may then be responsible for the difference between D-quarks and Lepton masses in local SU(5) GUT'sThis work has been partially supported by the grants FPA 2009-09017, FPA 2009-07908, Consolider-CPAN (CSD2007-00042) from the MICINN, HEPHACOS-S2009/ESP1473 from the C.A. de Madrid and the contract “UNILHC” PITN-GA-2009-237920 of the European Commission. F.M. is supported by the MICINN Ramón y Cajal programme through the grant RYC-2009-0509

Abstract:We analyse soft supersymmetry breaking in type IIB de Sitter string vacua after moduli stabilisation, focussing on models in which the Standard Model is sequestered from the supersymmetry breaking sources and the spectrum of soft-terms is hierarchically smaller than the gravitino mass m 3/2 . Due to this feature, these models are compatible with gauge coupling unification and TeV scale supersymmetry with no cosmological moduli problem. We determine the influence on soft-terms of concrete realisations of de Sitter vacua constructed from supersymmetric effective actions. One of these scenarios provides the first study of soft-terms for consistent string models embedded in a compact Calabi-Yau manifold with all moduli stabilised. Depending on the moduli dependence of the Kähler metric for matter fields and on the mechanism responsible to obtain a de Sitter vacuum, we find two scenarios for phenomenology: (i) a split-supersymmetry scenario where gaugino masses are suppressed with respect to scalar masses:(ii) a typical MSSM scenario where all soft-terms are of the same order: M 1/2 ∼ m 0 ∼ m 3/2 ǫ ≪ m 3/2 . Background fluxes determine the numerical coefficients of the soft-terms allowing for small variations of parameters as is necessary to confront data and to interpolate between different scenarios. We comment on different stringy origins of the µ-term and potential sources of desequestering.