Ex Vivo Expanded Multi-Specific Cytotoxic T Lymphocytes Derived from HIV+ Patients and HIV Negative Donors Using GMP Compliant Methodologies Recognize Multiple HIV Antigens and Suppress HIV Replication

Coderch de Sentmenat, José Antoni

Interval dosing with the HDAC inhibitor vorinostat effectively reverses HIV latency

BACKGROUND. The histone deacetylase (HDAC) inhibitor vorinostat (VOR) can increase HIV RNA expression in vivo within resting CD4+ T cells of aviremic HIV+ individuals. However, while studies of VOR or other HDAC inhibitors have reported reversal of latency, none has demonstrated clearance of latent infection. We sought to identify the optimal dosing of VOR for effective serial reversal of HIV latency

HIV-Specific T Cells Generated from HIV-Naive Adult and Cord Blood Donors Target a Range of Viral Epitopes\u27 Implications for a Cure Strategy after Allogeneic Stem Cell Transplant

Adoptive T cell therapy has been successful in boosting viral-specific immunity post-HSCT, preventing viral rebound of CMV and EBV. However, therapeutic use of T cells to boost HIV-specific T cell immunity in HIV+ patients has met limited success. Despite multiple attempts to eradicate HIV with allogeneic-HSCT, there is only one case of functional HIV cure. We hypothesized that broadly HIV-specific CD8 and CD4 T-cells (HXTCs) could be expanded from patients on ARVs, as well as HIV-negative adult and cord blood donors (dHXTC), employing a non–HLA restricted approach for the treatment of HIV+ individuals after autologous or allogeneic HSCT. We have expanded autologous HXTCs from HIV+ subjects under NCT02208167. To extend this approach to the allogeneic HSCT setting, we generated dHXTCs from HIV-naive adults (n=9) and cord blood donors (n=11). IFNg-ELISPOT showed dHXTCs from adult donors were specific against Gag, Nef, and Pol (mean=220 IFNg SFC/1e5 cells) versus irrelevant antigen actin (mean=6 SFC/105cells)(n=9). Similarly, we are able to produce cord dHXTCs (n=11) that showed specificity to Gag (mean=78 SFC/105cells), Nef (mean=96 SFC/105cells), or Pol (mean=174 SFC/105cells), compared to CTL-only (mean=2 SFC/105cells) in IFNg-ELISPOT. dHXTCs were polyfunctional producing proinflammatory TNFα, IL2, IL6, IL8, and perforin responses (p In summary, HIV-specific T cells can be expanded from HIV+ and HIVneg donors for clinical use. Focusing on donors with HLA types that are associated with well characterized HIV responses (e.g. HLA A02) or associated with delayed progression to AIDS (e.g.HLA B27, B51, B57) may allow us to identify HLA-restricted epitopes critical for the successful development of a potent HIV-specific T cell therapeutic. Hence, the administration of dHXTCs derived from naive donors could offer a unique curative strategy post-allogeneic stem cell transplant

Chernobyl Accident : Assessing the Data

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10(-8) with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer

Measurement of inclusive and differential cross sections for single top quark production in association with a W boson in proton-proton collisions at s \sqrt{s} = 13 TeV

International audienceMeasurements of the inclusive and normalised differential cross sections are presented for the production of single top quarks in association with a W boson in proton-proton collisions at a centre-of-mass energy of 13 TeV. The data used were recorded with the CMS detector at the LHC during 2016–2018, and correspond to an integrated luminosity of 138 fb$^{−1}$. Events containing one electron and one muon in the final state are analysed. For the inclusive measurement, a multivariate discriminant, exploiting the kinematic properties of the events is used to separate the signal from the dominant $\textrm{t}\overline{\textrm{t}}$ background. A cross section of $79.2\pm 0.9{\left(\textrm{stat}\right)}_{-8.0}^{+7.7}\left(\textrm{syst}\right)\pm 1.2\left(\textrm{lumi}\right)$ pb is obtained, consistent with the predictions of the standard model. For the differential measurements, a fiducial region is defined according to the detector acceptance, and the requirement of exactly one jet coming from the fragmentation of a bottom quark. The resulting distributions are unfolded to particle level and agree with the predictions at next-to-leading order in perturbative quantum chromodynamics.[graphic not available: see fulltext

Search for pair production of vector-like quarks in leptonic final states in proton-proton collisions at s \sqrt{s} = 13 TeV

A search is presented for vector-like $\mathrm{T}$ and $\mathrm{B}$ quark-antiquark pairs produced in proton-proton collisions at a center-of-mass energy of 13 TeV. Data were collected by the CMS experiment at the CERN LHC in 2016-2018, with an integrated luminosity of 138 fb$^{-1}$. Events are separated into single-lepton, same-sign charge dilepton, and multilepton channels. In the analysis of the single-lepton channel a multilayer neural network and jet identification techniques are employed to select signal events, while the same-sign dilepton and multilepton channels rely on the high-energy signature of the signal to distinguish it from standard model backgrounds. The data are consistent with standard model background predictions, and the production of vector-like quark pairs is excluded at 95% confidence level for $\mathrm{T}$ quark masses up to 1.54 TeV and $\mathrm{B}$ quark masses up to 1.56 TeV, depending on the branching fractions assumed, with maximal sensitivity to decay modes that include multiple top quarks. The limits obtained in this search are the strongest limits to date for $\mathrm{T} \overline{\mathrm{T}}$ production, excluding masses below 1.48 TeV for all decays to third generation quarks, and are the strongest limits to date for $\mathrm{B} \overline{\mathrm{B}}$ production with $\mathrm{B}$ quark decays to tW.A search is presented for vector-like T and B quark-antiquark pairs produced in proton-proton collisions at a center-of-mass energy of 13 TeV. Data were collected by the CMS experiment at the CERN LHC in 2016–2018, with an integrated luminosity of 138 fb$^{−1}$. Events are separated into single-lepton, same-sign charge dilepton, and multi-lepton channels. In the analysis of the single-lepton channel a multilayer neural network and jet identification techniques are employed to select signal events, while the same-sign dilepton and multilepton channels rely on the high-energy signature of the signal to distinguish it from standard model backgrounds. The data are consistent with standard model background predictions, and the production of vector-like quark pairs is excluded at 95% confidence level for T quark masses up to 1.54 TeV and B quark masses up to 1.56 TeV, depending on the branching fractions assumed, with maximal sensitivity to decay modes that include multiple top quarks. The limits obtained in this search are the strongest limits to date for $\textrm{T}\overline{\textrm{T}}$ production, excluding masses below 1.48 TeV for all decays to third generation quarks, and are the strongest limits to date for $\textrm{B}\overline{\textrm{B}}$ production with B quark decays to tW.[graphic not available: see fulltext]A search is presented for vector-like T and B quark-antiquark pairs produced in proton-proton collisions at a center-of-mass energy of 13 TeV. Data were collected by the CMS experiment at the CERN LHC in 2016-2018, with an integrated luminosity of 138 fb$^{-1}$. Events are separated into single-lepton, same-sign charge dilepton, and multilepton channels. In the analysis of the single-lepton channel a multilayer neural network and jet identification techniques are employed to select signal events, while the same-sign dilepton and multilepton channels rely on the high-energy signature of the signal to distinguish it from standard model backgrounds. The data are consistent with standard model background predictions, and the production of vector-like quark pairs is excluded at 95% confidence level for T quark masses up to 1.54 TeV and B quark masses up to 1.56 TeV, depending on the branching fractions assumed, with maximal sensitivity to decay modes that include multiple top quarks. The limits obtained in this search are the strongest limits to date for $\mathrm{T\overline{T}}$ production, excluding masses below 1.48 TeV for all decays to third generation quarks, and are the strongest limits to date for $\mathrm{B\overline{B}}$ production with B quark decays to tW

Measurement of the Higgs boson inclusive and differential fiducial production cross sections in the diphoton decay channel with pp collisions at s \sqrt{s} = 13 TeV

International audienceThe measurements of the inclusive and differential fiducial cross sections of the Higgs boson decaying to a pair of photons are presented. The analysis is performed using proton-proton collisions data recorded with the CMS detector at the LHC at a centre-of-mass energy of 13 TeV and corresponding to an integrated luminosity of 137 fb$^{−1}$. The inclusive fiducial cross section is measured to be ${\sigma}_{\textrm{fid}}={73.4}_{-5.3}^{+5.4}{\left(\textrm{stat}\right)}_{-2.2}^{+2.4}\left(\textrm{syst}\right)$ fb, in agreement with the standard model expectation of 75.4 ± 4.1 fb. The measurements are also performed in fiducial regions targeting different production modes and as function of several observables describing the diphoton system, the number of additional jets present in the event, and other kinematic observables. Two double differential measurements are performed. No significant deviations from the standard model expectations are observed.[graphic not available: see fulltext

Search for nonresonant Higgs boson pair production in the four leptons plus two b jets final state in proton-proton collisions at s=\sqrt{s} = 13 TeV

The first search for nonresonant production of Higgs boson pairs (HH) with one H decaying into four leptons and the other into a pair of b quarks is presented, using proton-proton collisions recorded at a center-of-mass energy of $\sqrt{s} =$ 13 TeV by the CMS experiment. The analyzed data correspond to an integrated luminosity of 138 fb$^{-1}$. A 95% confidence level upper limit of 32.4 is set on the signal strength modifier $\mu$, defined as the ratio of the observed HH production rate in the ${\mathrm{H}\mathrm{H}} \to\mathrm{Z}\mathrm{Z}^{*}\mathrm{b}\mathrm{\bar{b}}\to 4\ell\mathrm{b}\mathrm{\bar{b}}$ decay channel to the standard model expectation. Possible modifications of the H trilinear coupling $\lambda_\text{HHH}$ with respect to the standard model (SM) value are investigated. The coupling modifier $\kappa_{\lambda}$, defined as $\lambda_\text{HHH}$ divided by its SM prediction, is constrained to be within the observed (expected) range $-$8.8 ($-$9.8) $< \kappa_{\lambda} <$ 13.4 (15.0) at 95% confidence level.The first search for nonresonant production of Higgs boson pairs (HH) with one H decaying into four leptons and the other into a pair of b quarks is presented, using proton-proton collisions recorded at a center-of-mass energy of $\sqrt{s}$ = 13 TeV by the CMS experiment. The analyzed data correspond to an integrated luminosity of 138 fb$^{−1}$. A 95% confidence level upper limit of 32.4 is set on the signal strength modifier μ, defined as the ratio of the observed HH production rate in the $\textrm{HH}\to {\textrm{ZZ}}^{\ast}\textrm{b}\overline{\textrm{b}}\to 4\ell \textrm{b}\overline{\textrm{b}}$ decay channel to the standard model (SM) expectation. Possible modifications of the H trilinear coupling λ$_{HHH}$ with respect to the SM value are investigated. The coupling modifier κ$_{λ}$, defined as λ$_{HHH}$ divided by its SM prediction, is constrained to be within the observed (expected) range −8.8 (−9.8) < κ$_{λ}$< 13.4 (15.0) at 95% confidence level.[graphic not available: see fulltext]The first search for nonresonant production of Higgs boson pairs (HH) with one H decaying into four leptons and the other into a pair of b quarks is presented, using proton-proton collisions recorded at a center-of-mass energy of $\sqrt{s}$ = 13 TeV by the CMS experiment. The analyzed data correspond to an integrated luminosity of 138 fb$^{-1}$. A 95% confidence level upper limit of 32.4 is set on the signal strength modifier $\mu$, defined as the ratio of the observed HH production rate in the HH $\to$ ZZ*b$\mathrm{\bar{b}}$ $\to$ 4$\ell$b$\mathrm{\bar{b}}$ decay channel to the standard model expectation. Possible modifications of the H trilinear coupling $\lambda_\text{HHH}$ with respect to the standard model (SM) value are investigated. The coupling modifier $\kappa_{\lambda}$, defined as $\lambda_\text{HHH}$ divided by its SM prediction, is constrained to be within the observed (expected) range -8.8 (-9.8) $<$ $\kappa_{\lambda}$ $<$ 13.4 (15.0) at 95% confidence level