ISOTOPE : ISOform-guided prediction of epiTOPEs in cancer

Immunotherapies provide effective treatments for previously untreatable tumors and identifying tumor-specific epitopes can help elucidate the molecular determinants of therapy response. Here, we describe a pipeline, ISOTOPE (ISOform-guided prediction of epiTOPEs In Cancer), for the comprehensive identification of tumor-specific splicing-derived epitopes. Using RNA sequencing and mass spectrometry for MHC-I associated proteins, ISOTOPE identified neoepitopes from tumor-specific splicing events that are potentially presented by MHC-I complexes. Analysis of multiple samples indicates that splicing alterations may affect the production of self-epitopes and generate more candidate neoepitopes than somatic mutations. Although there was no difference in the number of splicing-derived neoepitopes between responders and non-responders to immune therapy, higher MHC-I binding affinity was associated with a positive response. Our analyses highlight the diversity of the immunogenic impacts of tumor-specific splicing alterations and the importance of studying splicing alterations to fully characterize tumors in the context of immunotherapies. ISOTOPE is available at https://github.com/comprna/ISOTOPE

Naturally presented HLA class I-restricted epitopes from the neurotrophic factor S100-? are targets of the autoimmune response in type 1 diabetes

Type 1 diabetes (T1D) results from the destruction of pancreatic beta-cells by the immune system, and CD8(+) T lymphocytes are critical actors in this autoimmune response. Pancreatic islets are surrounded by a mesh of nervous cells, the peri-insular Schwann cells, which are also targeted by autoreactive T lymphocytes and express specific antigens, such as the neurotrophic factor S100-beta. Previous work has shown increased proliferative responses to whole S100-beta in both human T1D patients and the nonobese diabetic (NOD) mouse model. We describe for the first time naturally processed and presented epitopes (NPPEs) presented by class I human leukocyte antigen-A*02:01 (A2.1) molecules derived from S100-beta. These NPPEs triggered IFN-gamma responses more frequently in both newly diagnosed and long-term T1D patients compared with healthy donors. Furthermore, the same NPPEs are recognized during the autoimmune response leading to diabetes in A2.1-transgenic NOD mice as early as 4 wk of age. Interestingly, when these NPPEs are used to prevent diabetes in this animal model, an acceleration of the disease is observed together with an exacerbation in insulitis and an increase in S100-beta-specific cytotoxicity in vaccinated animals. Whether these can be used in diabetes prevention needs to be carefully evaluated in animal models before use in future clinical assays.-Calvino-Sampedro, C., Gomez-Tourino, I., Cordero, O. J., Reche, P. A., Gomez-Perosanz, M., Sanchez-Trincado, J. L., Rodriguez, M. A., Sueiro, A. M., Vinuela, J. E., Calvino, R. V. Naturally presented HLA class I-restricted epitopes from the neurotrophic factor S100-beta are targets of the autoimmune response in type 1 diabetes

HDAC7 is a major contributor in the pathogenesis of infant t(4;11) proB acute lymphoblastic leukemia

This paper was funded by grants to MP by the Spanish Ministry of Science, Innovation and Universities (SAF2017-87990-R and EUR2019-103835) and elaborated at the Josep Carreras Leukaemia Research Institute (IJC, Badalona, Barcelona) and IDIBELL Research Institute (L’Hospitalet de Llobregat, Barcelona). OdB is funded by a Juan de la Cierva—Formación fellowship from the Spanish Ministry of Science, Innovation and Universities (FJCI-2017-32430). AM is funded by the Spanish Ministry of Science, Innovation and Universities, which is part of the Agencia Estatal de Investigación (AEI), through grant PRE2018-083183 (cofunded by the European Social Fund). Work in PM and CB’s lab was supported by the European Research Council (CoG-2014646903), the Spanish Ministry of Economy and Competitiveness (SAF-2016-80481-R), Uno entre Cien Mil Foundation, the Leo Messi Foundation, the Asociación Española Contra el Cáncer (AECC-CI-2015), and the ISCIII/FEDER (PI17/01028).

SUPPA2:fast, accurate, and uncertainty-aware differential splicing analysis across multiple conditions

Supplementary methods. (PDF 315 kb

Immune cell profiling of the cerebrospinal fluid enables the characterization of the brain metastasis microenvironment

Brain metastases are the most common tumor of the brain with a dismal prognosis. A fraction of patients with brain metastasis benefit from treatment with immune checkpoint inhibitors (ICI) and the degree and phenotype of the immune cell infiltration has been used to predict response to ICI. However, the anatomical location of brain lesions limits access to tumor material to characterize the immune phenotype. Here, we characterize immune cells present in brain lesions and matched cerebrospinal fluid (CSF) using single-cell RNA sequencing combined with T cell receptor genotyping. Tumor immune infiltration and specifically CD8 + T cell infiltration can be discerned through the analysis of the CSF. Consistently, identical T cell receptor clonotypes are detected in brain lesions and CSF, confirming cell exchange between these compartments. The analysis of immune cells of the CSF can provide a non-invasive alternative to predict the response to ICI, as well as identify the T cell receptor clonotypes present in brain metastasis. The use of CSF for diagnosis of metastatic brain tumors could be of clinical and patient benefit. Here the authors undertake a single-cell RNA analysis of CSF and brain to determine whether the phenotype in the CSF is reflective of the phenotype in the tumo

VVVX-Gaia Discovery of a Low Luminosity Globular Cluster in the Milky Way Disk

© 2020 ESOMilky Way globular clusters (MW GCs) are difficult to identify at low Galactic latitudes because of high differential extinction and heavy star crowding. The new deep near-IR images and photometry from the VISTA Variables in the Via L\'actea Extended Survey (VVVX) allow us to chart previously unexplored regions. Our long term aim is to complete the census of MW GCs. The immediate goals are to estimate the astrophysical parameters, measuring their reddenings, extinctions, distances, total luminosities, proper motions, sizes, metallicities and ages. We use the near-IR VVVX survey database, in combination with Gaia DR2 optical photometry, and with the Two Micron All Sky Survey (2MASS) photometry. We report the detection of a heretofore unknown Galactic Globular Cluster at RA = 14:09:00.0; DEC=-65:37:12 (J2000). We calculate a reddening of E(J-K_s)=(0.3 +/- 0.03) mag and an extinction of A_Ks=(0.15 +/- 0.01) mag for this new GC. Its distance modulus and corresponding distance were measured as (m-M)=(15.93 +/- 0.03) mag and D=(15.5 +/- 1.0) kpc, respectively. We estimate the metallicity and age by comparison with known GCs and by fitting PARSEC and Dartmouth isochrones, finding $[Fe/H]=(-0.70\pm0.2)$ dex and t=(11.0 +/- 1.0) Gyr. The mean GC PMs from Gaia are mu_alpha^(star)=(-4.68 +/- 0.47) mas yr^(-1) and mu_delta=(-1.34 \pm 0.45) mas yr^(-1). The total luminosity of our cluster is estimated to be M_Ks=(-7.76 +/- 0.5) mag. We have found a new low-luminosity, old and metal-rich globular cluster, situated in the far side of the Galactic disk, at R_G=11.2 kpc from the Galactic centre, and at z=1.0 kpc below the plane. Interestingly, the location, metallicity and age of this globular cluster are coincident with the Monoceros Ring (MRi) structure.Peer reviewe

The Astropy Problem

The Astropy Project (http://astropy.org) is, in its own words, "a community effort to develop a single core package for Astronomy in Python and foster interoperability between Python astronomy packages." For five years this project has been managed, written, and operated as a grassroots, self-organized, almost entirely volunteer effort while the software is used by the majority of the astronomical community. Despite this, the project has always been and remains to this day effectively unfunded. Further, contributors receive little or no formal recognition for creating and supporting what is now critical software. This paper explores the problem in detail, outlines possible solutions to correct this, and presents a few suggestions on how to address the sustainability of general purpose astronomical software

The Fourteenth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the extended Baryon Oscillation Spectroscopic Survey and from the second phase of the Apache Point Observatory Galactic Evolution Experiment

The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since July 2014. This paper describes the second data release from this phase, and the fourteenth from SDSS overall (making this, Data Release Fourteen or DR14). This release makes public data taken by SDSS-IV in its first two years of operation (July 2014-2016). Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey (eBOSS); the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data driven machine learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS website (www.sdss.org) has been updated for this release, and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020, and will be followed by SDSS-V.Comment: SDSS-IV collaboration alphabetical author data release paper. DR14 happened on 31st July 2017. 19 pages, 5 figures. Accepted by ApJS on 28th Nov 2017 (this is the "post-print" and "post-proofs" version; minor corrections only from v1, and most of errors found in proofs corrected

Impaired Condensin Complex and Aurora B kinase underlie mitotic and chromosomal defects in hyperdiploid B-cell ALL

B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric cancer, and high-hyperdiploidy (HyperD) identifies the most common subtype of pediatric B-ALL. Despite HyperD is an initiating oncogenic event affiliated to childhood B-ALL, the mitotic and chromosomal defects associated to HyperD B-ALL (HyperD-ALL) remain poorly characterized. Here, we have used 54 primary pediatric B-ALL samples to characterize the cellular-molecular mechanisms underlying the mitotic/chromosome defects predicated to be early pathogenic contributors in HyperD-ALL. We report that HyperD-ALL blasts are low proliferative and show a delay in early mitosis at prometaphase, associated to chromosome alignment defects at the metaphase plate leading to robust chromosome segregation defects and non-modal karyotypes. Mechanistically, biochemical, functional and mass-spectrometry assays revealed that condensin complex is impaired in HyperD-ALL cells, leading to chromosome hypocondensation, loss of centromere stiffness and mis-localization of the chromosome passenger complex proteins Aurora B Kinase (AURKB) and Survivin in early mitosis. HyperD-ALL cells show chromatid cohesion defects and impaired spindle assembly checkpoint (SAC) thus undergoing mitotic slippage due to defective AURKB and impaired SAC activity, downstream of condensin complex defects. Chromosome structure/condensation defects and hyperdiploidy were reproduced in healthy CD34+ stem/progenitor cells upon inhibition of AURKB and/or SAC. Collectively, hyperdiploid B-ALL is associated to defective condensin complex, AURKB and SAC