1,464 research outputs found
Measurement of Collins asymmetries in inclusive production of charged pion pairs in e+e− annihilation at BABAR
No full textWe present measurements of Collins asymmetries in the inclusive process e+e−→ππX, where π stands for charged pions, at a center-of-mass energy of 10.6 GeV. We use a data sample of 468 fb−1 collected by the BABAR experiment at the PEP-II B factory at SLAC, and consider pairs of charged pions produced in opposite hemispheres of hadronic events. We observe clear asymmetries in the distributions of the azimuthal angles in two distinct reference frames. We study the dependence of the asymmetry on several kinematic variables, finding that it increases with increasing pion momentum and momentum transverse to the analysis axis, and with increasing angle between the thrust and beam axis
NaCl enhances CD8+ T cell effector functions in cancer immunotherapy
No full textCD8+ T cells control tumors but inevitably become dysfunctional in the tumor microenvironment. Here, we show that sodium chloride (NaCl) counteracts T cell dysfunction to promote cancer regression. NaCl supplementation during CD8+ T cell culture induced effector differentiation, IFN-γ production and cytotoxicity while maintaining the gene networks responsible for stem-like plasticity. Accordingly, adoptive transfer of tumor-specific T cells resulted in superior anti-tumor immunity in a humanized mouse model. In mice, a high-salt diet reduced the growth of experimental tumors in a CD8+ T cell-dependent manner by inhibiting terminal differentiation and enhancing the effector potency of CD8+ T cells. Mechanistically, NaCl enhanced glutamine consumption, which was critical for transcriptional, epigenetic and functional reprogramming. In humans, CD8+ T cells undergoing antigen recognition in tumors and predicting favorable responses to checkpoint blockade immunotherapy resembled those induced by NaCl. Thus, NaCl metabolism is a regulator of CD8+ T cell effector function, with potential implications for cancer immunotherapy
Circulating mucosal-associated invariant T cells identify patients responding to anti-PD-1 therapy
No full textImmune checkpoint inhibitors are used for treating patients with metastatic melanoma. Since the response to treatment is variable, biomarkers are urgently needed to identify patients who may benefit from such therapy. Here, we combine single-cell RNA-sequencing and multiparameter flow cytometry to assess changes in circulating CD8+ T cells in 28 patients with metastatic melanoma starting anti-PD-1 therapy, followed for 6 months: 17 responded to therapy, whilst 11 did not. Proportions of activated and proliferating CD8+ T cells and of mucosal-associated invariant T (MAIT) cells are significantly higher in responders, prior to and throughout therapy duration. MAIT cells from responders express higher level of CXCR4 and produce more granzyme B. In silico analysis support MAIT presence in the tumor microenvironment. Finally, patients with >1.7% of MAIT among peripheral CD8+ population show a better response to treatment. Our results thus suggest that MAIT cells may be considered a biomarker for patients responding to anti-PD-1 therapy
Two subsets of stem-like CD8+ memory T cell progenitors with distinct fate commitments in humans
No full textT cell memory relies on the generation of antigen-specific progenitors with stem-like properties. However, the identity of these progenitors has remained unclear, precluding a full understanding of the differentiation trajectories that underpin the heterogeneity of antigen-experienced T cells. We used a systematic approach guided by single-cell RNA-sequencing data to map the organizational structure of the human CD8+ memory T cell pool under physiological conditions. We identified two previously unrecognized subsets of clonally, epigenetically, functionally, phenotypically and transcriptionally distinct stem-like CD8+ memory T cells. Progenitors lacking the inhibitory receptors programmed death-1 (PD-1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) were committed to a functional lineage, whereas progenitors expressing PD-1 and TIGIT were committed to a dysfunctional, exhausted-like lineage. Collectively, these data reveal the existence of parallel differentiation programs in the human CD8+ memory T cell pool, with potentially broad implications for the development of immunotherapies and vaccines
HELLS regulates transcription in T-cell lymphomas by reducing unscheduled R-loops and by facilitating RNAPII progression
No full textChromatin modifiers are emerging as major determinants of many types of cancers, including Anaplastic Large Cell Lymphomas (ALCL), a family of highly heterogeneous T-cell lymphomas for which therapeutic options are still limited. HELLS is a multifunctional chromatin remodeling protein that affects genomic instability by participating in the DNA damage response. Although the transcriptional function of HELLS has been suggested, no clues on how HELLS controls transcription are currently available. In this study, by integrating different multi-omics and functional approaches, we characterized the transcriptional landscape of HELLS in ALCL. We explored the clinical impact of its transcriptional program in a large cohort of 44 patients with ALCL. We demonstrated that HELLS, loaded at the level of intronic regions of target promoters, facilitates RNA Polymerase II (RNAPII) progression along the gene bodies by reducing the persistence of co-transcriptional R-loops and promoting DNA damage resolution. Importantly, selective knockdown of HELLS sensitizes ALCL cells to different chemotherapeutic agents, showing a synergistic effect. Collectively, our work unveils the role of HELLS in acting as a gatekeeper of ALCL genome stability providing a rationale for drug design.Graphical Abstrac
DYKE DAVIDOFF MASSON SYNDROME:PROFILO DI SVILUPPO NEURO-COGNITIVO A 4 ANNI IN UN PAZIENTE CON DIAGNOSI IN EPOCA NEONATALE
No full textipoplasia emisferica, DDMS, dilatazione ventricolar
Frataxin deficiency increases cyclooxygenase 2 and prostaglandins in cell and animal models of Friedreich's ataxia
No full text© The Author 2014. Published by Oxford University Press
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.An inherited deficiency of the mitochondrial protein frataxin causes Friedreich's ataxia (FRDA); the mechanism by which this deficiency triggers neuro- and cardio-degeneration is unclear. Microarrays of neural tissue of animal models of the disease showed decreases in antioxidant genes, and increases in inflammatory genes. Cyclooxygenase (COX)-derived oxylipins are important mediators of inflammation. We measured oxylipin levels using tandem mass spectrometry and ELISAs in multiple cell and animal models of FRDA. Mass spectrometry revealed increases in concentrations of prostaglandins, thromboxane B2, 15-HETE and 11-HETE in cerebellar samples of knockin knockout mice. One possible explanation for the elevated oxylipins is that frataxin deficiency results in increased COX activity. While constitutive COX1 was unchanged, inducible COX2 expression was elevated over 1.35-fold (P < 0.05) in two Friedreich's mouse models and Friedreich's lymphocytes. Consistent with higher COX2 expression, its activity was also increased by 58% over controls. COX2 expression is driven by multiple transcription factors, including activator protein 1 and cAMP response element-binding protein, both of which were elevated over 1.52-fold in cerebella. Taken together, the results support the hypothesis that reduced expression of frataxin leads to elevation of COX2-mediated oxylipin synthesis stimulated by increases in transcription factors that respond to increased reactive oxygen species. These findings support a neuroinflammatory mechanism in FRDA, which has both pathomechanistic and therapeutic implications.The study was supported by NIH grants NS077777, EY012245 and AG025532 to G.A.C., and USDA-ARS Intramural Projects 5306-51530-019-00D and 1 U24 DK097154-01 to J.W.N. Funding to pay the Open Access publication charges for this article was provided by the NIH
Study of the reaction e+e−→ψ(2S)π+π− via initial-state radiation at BaBar
No full textWe study the process e+e−→ψ(2S)π+π− with initial-state-radiation events produced at the PEP-II asymmetric-energy collider. The data were recorded with the BABAR detector at center-of-mass energies at and near the Υ(nS) (n=2,3,4) resonances and correspond to an integrated luminosity of 520 fb−1. We investigate the ψ(2S)π+π− mass distribution from 3.95 to 5.95 GeV/c2, and measure the center-of-mass energy dependence of the associated e+e−→ψ(2S)π+π− cross section. The mass distribution exhibits evidence of two resonant structures. A fit to the ψ(2S)π+π− mass distribution corresponding to the decay mode ψ(2S)→J/ψπ+π− yields a mass value of 4340±16 (stat) ±9 (syst) MeV/c2 and a width of 94±32 (stat) ±13 (syst) MeV for the first resonance, and for the second a mass value of 4669±21 (stat) ±3 (syst) MeV/c2 and a width of 104±48 (stat) ±10 (syst) MeV. In addition, we show the π+π− mass distributions for these resonant regions
Dielectron production at midrapidity at low transverse momentum in peripheral and semi-peripheral Pb–Pb collisions at √sNN = 5.02 TeV
No full textThe first measurement of the e+e− pair production at low lepton pair transverse momentum (p T,ee) and low invariant mass (m ee) in non-central Pb–Pb collisions at sNN = 5.02 TeV at the LHC is presented. The dielectron production is studied with the ALICE detector at midrapidity (|η e | < 0.8) as a function of invariant mass (0.4 ≤ m ee < 2.7 GeV/c 2) in the 50–70% and 70–90% centrality classes for p T,ee < 0.1 GeV/c, and as a function of p T,ee in three m ee intervals in the most peripheral Pb–Pb collisions. Below a p T,ee of 0.1 GeV/c, a clear excess of e+e− pairs is found compared to the expectations from known hadronic sources and predictions of thermal radiation from the medium. The m ee excess spectra are reproduced, within uncertainties, by different predictions of the photon–photon production of dielectrons, where the photons originate from the extremely strong electromagnetic fields generated by the highly Lorentz-contracted Pb nuclei. Lowest-order quantum electrodynamic (QED) calculations, as well as a model that takes into account the impact-parameter dependence of the average transverse momentum of the photons, also provide a good description of the p T,ee spectra. The measured 〈pT,ee2〉 of the excess p T,ee spectrum in peripheral Pb–Pb collisions is found to be comparable to the values observed previously at RHIC in a similar phase-space region. [Figure not available: see fulltext.]
GAA repeat expansion mutation mouse models of Friedreich ataxia exhibit oxidative stress leading to progressive neuronal and cardiac pathology
No full textFriedreich ataxia (FRDA) is a neurodegenerative disorder caused by an unstable GAA repeat expansion mutation within intron 1 of the FXN gene. However, the origins of the GAA repeat expansion, its unstable dynamics within different cells and tissues, and its effects on frataxin expression are not yet completely understood. Therefore, we have chosen to generate representative FRDA mouse models by using the human FXN GAA repeat expansion itself as the genetically modified mutation. We have previously reported the establishment of two lines of human FXN YAC transgenic mice that contain unstable GAA repeat expansions within the appropriate genomic context. We now describe the generation of FRDA mouse models by crossbreeding of both lines of human FXN YAC transgenic mice with heterozygous Fxn knockout mice. The resultant FRDA mice that express only human-derived frataxin show comparatively reduced levels of frataxin mRNA and protein expression, decreased aconitase activity, and oxidative stress, leading to progressive neurodegenerative and cardiac pathological phenotypes. Coordination deficits are present, as measured by accelerating rotarod analysis, together with a progressive decrease in locomotor activity and increase in weight. Large vacuoles are detected within neurons of the dorsal root ganglia (DRG), predominantly within the lumbar regions in 6-month-old mice, but spreading to the cervical regions after 1 year of age. Secondary demyelination of large axons is also detected within the lumbar roots of older mice. Lipofuscin deposition is increased in both DRG neurons and cardiomyocytes, and iron deposition is detected in cardiomyocytes after 1 year of age. These mice represent the first GAA repeat expansion-based FRDA mouse models that exhibit progressive FRDA-like pathology and thus will be of use in testing potential therapeutic strategies, particularly GAA repeat-based strategies. © 2006 Elsevier Inc. All rights reserved
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