Repression of Esophageal Neoplasia and Inflammatory Signaling by Anti-miR-31 Delivery In Vivo.

BACKGROUND: Overexpression of microRNA-31 (miR-31) is implicated in the pathogenesis of esophageal squamous cell carcinoma (ESCC), a deadly disease associated with dietary zinc deficiency. Using a rat model that recapitulates features of human ESCC, the mechanism whereby Zn regulates miR-31 expression to promote ESCC is examined. METHODS: To inhibit in vivo esophageal miR-31 overexpression in Zn-deficient rats (n = 12-20 per group), locked nucleic acid-modified anti-miR-31 oligonucleotides were administered over five weeks. miR-31 expression was determined by northern blotting, quantitative polymerase chain reaction, and in situ hybridization. Physiological miR-31 targets were identified by microarray analysis and verified by luciferase reporter assay. Cellular proliferation, apoptosis, and expression of inflammation genes were determined by immunoblotting, caspase assays, and immunohistochemistry. The miR-31 promoter in Zn-deficient esophagus was identified by ChIP-seq using an antibody for histone mark H3K4me3. Data were analyzed with t test and analysis of variance. All statistical tests were two-sided. RESULTS: In vivo, anti-miR-31 reduced miR-31 overexpression (P = .002) and suppressed the esophageal preneoplasia in Zn-deficient rats. At the same time, the miR-31 target Stk40 was derepressed, thereby inhibiting the STK40-NF-κΒ-controlled inflammatory pathway, with resultant decreased cellular proliferation and activated apoptosis (caspase 3/7 activities, fold change = 10.7, P = .005). This same connection between miR-31 overexpression and STK40/NF-κΒ expression was also documented in human ESCC cell lines. In Zn-deficient esophagus, the miR-31 promoter region and NF-κΒ binding site were activated. Zn replenishment restored the regulation of this genomic region and a normal esophageal phenotype. CONCLUSIONS: The data define the in vivo signaling pathway underlying interaction of Zn deficiency and miR-31 overexpression in esophageal neoplasia and provide a mechanistic rationale for miR-31 as a therapeutic target for ESCC

Microenvironment in neuroblastoma: Isolation and characterization of tumor-derived mesenchymal stromal cells

Background: It has been proposed that mesenchymal stromal cells (MSCs) promote tumor progression by interacting with tumor cells and other stroma cells in the complex network of the tumor microenvironment. We characterized MSCs isolated and expanded from tumor tissues of pediatric patients diagnosed with neuroblastomas (NB-MSCs) to define interactions with the tumor microenvironment. Methods: Specimens were obtained from 7 pediatric patients diagnosed with neuroblastoma (NB). Morphology, immunophenotype, differentiation capacity, proliferative growth, expression of stemness and neural differentiation markers were evaluated. Moreover, the ability of cells to modulate the immune response, i.e. inhibition of phytohemagglutinin (PHA) activated peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cytotoxic function, was examined. Gene expression profiles, known to be related to tumor cell stemness, Wnt pathway activation, epithelial-mesenchymal transition (EMT) and tumor metastasis were also evaluated. Healthy donor bone marrow-derived MSCs (BM-MSC) were employed as controls. Results: NB-MSCs presented the typical MSC morphology and phenotype. They showed a proliferative capacity superimposable to BM-MSCs. Stemness marker expression (Sox2, Nanog, Oct3/4) was comparable to BM-MSCs. NB-MSC in vitro osteogenic and chondrogenic differentiation was similar to BM-MSCs, but NB-MSCs lacked adipogenic differentiation capacity. NB-MSCs reached senescence phases at a median passage of P7 (range, P5-P13). NB-MSCs exhibited greater immunosuppressive capacity on activated T lymphocytes at a 1:2 (MSC: PBMC) ratio compared with BM-MSCs (p = 0.018). NK cytotoxic activity was not influenced by co-culture, either with BM-MSCs or NB-MSCs. Flow-cytometry cell cycle analysis showed that NB-MSCs had an increased number of cells in the G0-G1 phase compared to BM-MSCs. Transcriptomic profiling results indicated that NB-MSCs were enriched with EMT genes compared to BM-MSCs. Conclusions: We characterized the biological features, the immunomodulatory capacity and the gene expression profile of NB-MSCs. The NB-MSC gene expression profile and their functional properties suggest a potential role in promoting tumor escape, invasiveness and metastatic traits of NB cancer cells. A better understanding of the complex mechanisms underlying the interactions between NB cells and NB-derived MSCs should shed new light on potential novel therapeutic approaches

EVALITA 2020: Overview of the 7th evaluation campaign of natural language processing and speech tools for Italian

The Evaluation Campaign of Natural Language Processing and Speech Tools for Italian (EVALITA) is the biennial initiative aimed at promoting the development of language and speech technologies for the Italian language. EVALITA is promoted by the Italian Association of Computational Linguistics (AILC) and it is endorsed by the Italian Association for Artificial Intelligence (AIxIA) and the Italian Association for Speech Sciences (AISV). EVALITA provides a shared framework where different systems and approaches can be scientifically evaluated and compared with each other with respect to a large variety of tasks, suggested and organized by the Italian research community. The proposed tasks represent scientific challenges where methods, resources, and systems can be tested against shared benchmarks representing linguistic open issues or real world applications, possibly in a multilingual and/or multi-modal perspective. The collected data sets provide big opportunities for scientists to explore old and new problems concerning NLP in Italian as well as to develop solutions and to discuss the NLP-related issues within the community. Some tasks are traditionally present in the evaluation campaign, while others are completely new. This paper introduces the tasks proposed at EVALITA 2020 and provides an overview to the participants and systems whose descriptions and obtained results are reported in these Proceedings

3D structure of individual mammalian genomes studied by single cell Hi-C

The folding of genomic DNA from the beads-on-a-string like structure of nucleosomes into higher order assemblies is critically linked to nuclear processes. We have calculated the first 3D structures of entire mammalian genomes using data from a new chromosome conformation capture procedure that allows us to first image and then process single cells. This has allowed us to study genome folding down to a scale of <100 kb and to validate the structures. We show that the structures of individual topological-associated domains and loops vary very substantially from cell-to-cell. By contrast, A/B compartments, lamin-associated domains and active enhancers/promoters are organized in a consistent way on a genome-wide basis in every cell, suggesting that they could drive chromosome and genome folding. Through studying pluripotency factor- and NuRD-regulated genes, we illustrate how single cell genome structure determination provides a novel approach for investigating biological processes.We thank the Wellcome Trust (082010/Z/07/Z), the EC FP7 4DCellFate project (277899) and the MRC (MR/M010082/1) for financial support

Study of the B +→ J / ψ Λ ¯ p decay in proton-proton collisions at √s = 8 TeV

A study of the B +→ J / ψ Λ ¯ p decay using proton-proton collision data collected at s = 8 TeV by the CMS experiment at the LHC, corresponding to an integrated luminosity of 19.6 fb−1, is presented. The ratio of branching fractions B(B+→J/ψΛ¯p)/B(B+→J/ψK∗(892)+) is measured to be (1.054 ± 0.057(stat) ± 0.035(syst) ± 0.011(B))%, where the last uncertainty reflects the uncertainties in the world-average branching fractions of Λ ¯ and K*(892) + decays to reconstructed final states. The invariant mass distributions of the J / ψ Λ ¯ , J/ψp, and Λ ¯ p systems produced in the B +→ J / ψ Λ¯ p decay are investigated and found to be inconsistent with the pure phase space hypothesis. The analysis is extended by using a model-independent angular amplitude analysis, which shows that the observed invariant mass distributions are consistent with the contributions from excited kaons decaying to the Λ ¯ p system. [Figure not available: see fulltext.

Measurement of the top quark Yukawa coupling from t t kinematic distributions in the lepton+jets final state in proton-proton collisions at s =13 TeV MEASUREMENT of the TOP QUARK YUKAWA COUPLING from ... SIRUNYAN et al.

Results are presented for an extraction of the top quark Yukawa coupling from top quark-antiquark (tt) kinematic distributions in the lepton plus jets final state in proton-proton collisions, based on data collected by the CMS experiment at the LHC at s=13 TeV, corresponding to an integrated luminosity of 35.8 fb-1. Corrections from weak boson exchange, including Higgs bosons, between the top quarks can produce large distortions of differential distributions near the energy threshold of tt production. Therefore, precise measurements of these distributions are sensitive to the Yukawa coupling. Top quark events are reconstructed with at least three jets in the final state, and a novel technique is introduced to reconstruct the tt system for events with one missing jet. This technique enhances the experimental sensitivity in the low invariant mass region, Mtt. The data yields in Mtt, the rapidity difference |yt-yt|, and the number of reconstructed jets are compared with distributions representing different Yukawa couplings. These comparisons are used to measure the ratio of the top quark Yukawa coupling to its standard model predicted value to be 1.07-0.43+0.34 with an upper limit of 1.67 at the 95% confidence level

Search for a heavy Higgs boson decaying to a pair of W bosons in proton-proton collisions at √s = 13 TeV

A search for a heavy Higgs boson in the mass range from 0.2 to 3.0 TeV, decaying to a pair of W bosons, is presented. The analysis is based on proton-proton collisions at s = 13 TeV recorded by the CMS experiment at the LHC in 2016, corresponding to an integrated luminosity of 35.9 fb−1. The W boson pair decays are reconstructed in the 2ℓ2ν and ℓν2q final states (with ℓ = e or μ). Both gluon fusion and vector boson fusion production of the signal are considered. Interference effects between the signal and background are also taken into account. The observed data are consistent with the standard model (SM) expectation. Combined upper limits at 95% confidence level on the product of the cross section and branching fraction exclude a heavy Higgs boson with SM-like couplings and decays up to 1870 GeV. Exclusion limits are also set in the context of a number of two-Higgs-doublet model formulations, further reducing the allowed parameter space for SM extensions. [Figure not available: see fulltext.