The immune response influences the clinical course of colorectal cancer (CRC). Analyzing the invasive margin of human CRC liver metastases, we identified a mechanism of immune cell exploitation by tumor cells. While two distinct subsets of myeloid cells induce an influx of T cells into the invasive margin via CXCL9/CXCL10, CCL5 is produced by these T cells and stimulates pro-tumoral effects via CCR5. CCR5 blockade in patient-derived functional in vitro organotypic culture models showed a macrophage repolarization with anti-tumoral effects. These anti-tumoral effects were then confirmed in a phase I trial with a CCR5 antagonist in patients with liver metastases of advanced refractory CRC. Mitigation of tumor-promoting inflammation within the tumor tissue and objective tumor responses in CRC were observed.

The U2AF35-related protein Urp has been implicated previously in splicing of the major class of U2-type introns. Here we show that Urp is also required for splicing of the minor class of U12-type introns. Urp is recruited in an ATP-dependent fashion to the U12-type intron 39 splice site, where it promotes formation of spliceosomal complexes. Remarkably, Urp also contacts the 39 splice site of a U2-type intron, but in this case is specifically required for the second step of splicing. Thus, through recognition of a common splicing element, Urp facilitates distinct steps of U2-and U12-type intron splicing.Supplemental material is available at http://www.genesdev.org.Received July 26, 2010; revised version accepted September 10, 2010.Pre-mRNA splicing occurs in a dynamic ribonucleoprotein (RNP) complex termed the spliceosome, which is composed of numerous proteins and small nuclear RNP particles (snRNPs). For the major class of introns, called U2-type introns, splicing occurs in a spliceosome that contains four U snRNPs: U1, U2, U5, and U4/U6 snRNPs (Black 2003). A small subset of introns, called U12-type introns, is spliced through the conventional two-step pathway, but by a different spliceosome that contains U5, U11, and U12 snRNPs, and an alternative form of U4/U6 snRNP called U4atac/U6atac (Will and Luhrmann 2005). On U12-type introns, the 59 and 39 splice sites and branchpoint are highly conserved and differ from those of the conventional U2-type introns (Hall and Padgett 1994;Sharp and Burge 1997), and the characteristic polypyrimidine (Py) tract is typically absent (Burge et al. 1998).Spliceosome assembly of U2-type introns is initiated by binding of U2AF to the Py tract/39 splice site. U2AF is a heterodimer composed of a large (65-kDa) and a small (35-kDa) subunit (Zamore et al. 1992). The large subunit, U2AF65, binds specifically to the Py tract, whereas the small subunit, U2AF35, contacts the AG dinucleotide at the 39 splice site (Merendino et al. 1999;Wu et al. 1999;Zorio and Blumenthal 1999). This contact results, at least in part, from a sequence-specific RNA-binding activity of U2AF35 that recognizes the 39 splice site AG. For introns with weak Py tracts, the U2AF35-39 splice site interaction is critical for U2AF binding and splicing.Genome sequence analysis and expression studies have revealed the existence of several U2AF35-related proteins (U2AF35-RPs). Each U2AF35-RP contains a common core, consisting of a noncanonical RNA recognition motif called the U2AF homology motif (UHM) (Kielkopf et al. 2004) and two flanking zinc finger domains, but differs at the N and/or C termini. In mammals, there are at least three U2AF35-RPs: U2AF26 and two highly similar proteins, U2AF1-RS1 and U2AF1-RS2 (also called Urp) (Kitagawa et al. 1995;Tronchere et al. 1997). U2AF26 is nearly identical to U2AF35, but lacks the C-terminal arginine-serine-rich (RS) domain that is present in U2AF35 (Shepard et al. 2002). U2AF26 associates with U2AF65 and can functionally substitute for U2AF35 in both constitutive and enhancer-...

Linguistic field research depends on collecting phrases and sentences as well as their geographical and social characteristics. The traditional method of field research -researchers asking questions and filling forms-is time-consuming, costly, and not free of biases. This article presents metropolitalia, a Web-based crowdsourcing platform for linguistic field research aiming at overcoming some of the drawbacks of traditional linguistic field research. metropolitalia is built upon Agora, a market for trading with phrases and speculating on their characteristics in a playful manner. Two games are run under Agora, Borsa Parole and Poker Parole, that aim at collecting complementary data and meta-data: Borsa Parole incites players to express their own knowledge or, rather, beliefs, Poker Parole incites players to make conjectures on the beliefs of others, thus enhancing the primary meta-data collected with Borsa Parole with secondary, or reflexive, metadata needed for language perception studies. This article describes Agora with both games and reports on first evaluations of the data gathered so far.

Patients with advanced, recurrent or metastatic cancer have poor prognosis despite treatment advancements. Vesicular stomatitis virus (VSV)-GP (BI 1831169) is a chimeric VSV with its neurotropic glycoprotein G replaced by the non-neurotropic glycoprotein (GP) of the lymphocytic choriomeningitis virus. This live, recombinant oncolytic virus has demonstrated preclinical efficacy as a viral-based immunotherapy due to its interferon-dependent tumor specificity, potent oncolysis and stimulation of antitumor immune activity. Co-administration of the immune checkpoint inhibitor, ezabenlimab (BI 754091), alongside VSV-GP may synergistically enhance antitumor immune activity. Here, we describe the rationale and design of the first-in-human, phase I, dose-escalation study of VSV-GP alone and in combination with the immune checkpoint inhibitor ezabenlimab in patients with advanced, metastatic or relapsed and refractory solid tumors ( NCT05155332 ).