ORCID Profile
0000-0003-3273-9419
Current Organisations
University of Tennessee
,
Peter MacCallum Cancer Centre
,
University of Melbourne
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Publisher: Elsevier BV
Date: 12-2017
Publisher: American Physical Society (APS)
Date: 26-04-2022
Publisher: Elsevier BV
Date: 09-2020
Publisher: Springer Science and Business Media LLC
Date: 11-11-2020
DOI: 10.1038/S41416-020-01158-Z
Abstract: Intrinsic and acquired drug resistance represent fundamental barriers to the cure of high-grade serous ovarian carcinoma (HGSC), the most common histological subtype accounting for the majority of ovarian cancer deaths. Defects in homologous recombination (HR) DNA repair are key determinants of sensitivity to chemotherapy and poly-ADP ribose polymerase inhibitors. Restoration of HR is a common mechanism of acquired resistance that results in patient mortality, highlighting the need to identify new therapies targeting HR-proficient disease. We have shown promise for CX-5461, a cancer therapeutic in early phase clinical trials, in treating HR-deficient HGSC. Herein, we screen the whole protein-coding genome to identify potential targets whose depletion cooperates with CX-5461 in HR-proficient HGSC. We demonstrate robust proliferation inhibition in cells depleted of DNA topoisomerase 1 (TOP1). Combining the clinically used TOP1 inhibitor topotecan with CX-5461 potentiates a G2/M cell cycle checkpoint arrest in multiple HR-proficient HGSC cell lines. The combination enhances a nucleolar DNA damage response and global replication stress without increasing DNA strand breakage, significantly reducing clonogenic survival and tumour growth in vivo. Our findings highlight the possibility of exploiting TOP1 inhibition to be combined with CX-5461 as a non-genotoxic approach in targeting HR-proficient HGSC.
Publisher: Springer Science and Business Media LLC
Date: 09-08-2023
Abstract: Measurements of the inclusive and differential fiducial cross sections for the Higgs boson production in the H → ZZ → 4 ℓ ( ℓ = e , μ ) decay channel are presented. The results are obtained from the analysis of proton-proton collision data recorded by the CMS experiment at the CERN LHC at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 138 fb − 1 . The measured inclusive fiducial cross section is 2 . 73 ± 0 . 26 fb, in agreement with the standard model expectation of 2 . 86 ± 0 . 1 fb. Differential cross sections are measured as a function of several kinematic observables sensitive to the Higgs boson production and decay to four leptons. A set of double-differential measurements is also performed, yielding a comprehensive characterization of the four leptons final state. Constraints on the Higgs boson trilinear coupling and on the bottom and charm quark coupling modifiers are derived from its transverse momentum distribution. All results are consistent with theoretical predictions from the standard model.
Publisher: Springer Science and Business Media LLC
Date: 07-2022
Abstract: A search for physics beyond the standard model (SM) in final states with an electron or muon and missing transverse momentum is presented. The analysis uses data from proton-proton collisions at a centre-of-mass energy of 13 TeV, collected with the CMS detector at the LHC in 2016–2018 and corresponding to an integrated luminosity of 138 fb − 1 . No significant deviation from the SM prediction is observed. Model-independent limits are set on the production cross section of W’ bosons decaying into lepton-plus-neutrino final states. Within the framework of the sequential standard model, with the combined results from the electron and muon decay channels a W’ boson with mass less than 5.7 TeV is excluded at 95% confidence level. Results on a SM precision test, the determination of the oblique electroweak W parameter, are presented using LHC data for the first time. These results together with those from the direct W’ resonance search are used to extend existing constraints on composite Higgs scenarios. This is the first experimental exclusion on compositeness parameters using results from LHC data other than Higgs boson measurements.
Publisher: Springer Science and Business Media LLC
Date: 2021
Abstract: Modifications to the distribution of charged particles with respect to high transverse momentum ( p T ) jets passing through a quark-gluon plasma are explored using the CMS detector. Back-to-back dijets are analyzed in lead-lead and proton-proton collisions at $$ \\sqrt{s_{\\mathrm{NN}}} $$ s NN = 5 . 02 TeV via correlations of charged particles in bins of relative pseudorapidity and angular distance from the leading and subleading jet axes. In comparing the lead-lead and proton-proton collision results, modifications to the charged-particle relative distance distribution and to the momentum distributions around the jet axis are found to depend on the dijet momentum balance x j , which is the ratio between the subleading and leading jet p T . For events with x j ≈ 1, these modifications are observed for both the leading and subleading jets. However, while subleading jets show significant modifications for events with a larger dijet momentum imbalance, much smaller modifications are found for the leading jets in these events.
Publisher: Elsevier BV
Date: 2021
Publisher: Springer Science and Business Media LLC
Date: 12-2021
Abstract: A measurement of the top quark mass is performed using a data s le enriched with single top quark events produced in the t channel. The study is based on proton- proton collision data, corresponding to an integrated luminosity of 35.9 fb − 1 , recorded at $$ \\sqrt{s} $$ s = 13 TeV by the CMS experiment at the LHC in 2016. Candidate events are selected by requiring an isolated high-momentum lepton (muon or electron) and exactly two jets, of which one is identified as originating from a bottom quark. Multivariate discriminants are designed to separate the signal from the background. Optimized thresholds are placed on the discriminant outputs to obtain an event s le with high signal purity. The top quark mass is found to be $$ {172.13}_{-0.77}^{+0.76} $$ 172.13 − 0.77 + 0.76 GeV, where the uncertainty includes both the statistical and systematic components, reaching sub-GeV precision for the first time in this event topology. The masses of the top quark and antiquark are also determined separately using the lepton charge in the final state, from which the mass ratio and difference are determined to be $$ {0.9952}_{-0.0104}^{+0.0079} $$ 0.9952 − 0.0104 + 0.0079 and $$ {0.83}_{-1.35}^{+1.79} $$ 0.83 − 1.35 + 1.79 GeV, respectively. The results are consistent with CPT invariance.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22521222.V1
Abstract: Supplemental Table 1, 2, 3. Supplemental Materials and Methods.
Publisher: Springer Science and Business Media LLC
Date: 13-09-2022
Abstract: A search is presented for a heavy W′ boson resonance decaying to a B or T vector-like quark and a t or a b quark, respectively. The analysis is performed using proton-proton collisions collected with the CMS detector at the LHC. The data correspond to an integrated luminosity of 138 fb − 1 at a center-of-mass energy of 13 TeV. Both decay channels result in a signature with a t quark, a Higgs or Z boson, and a b quark, each produced with a significant Lorentz boost. The all-hadronic decays of the Higgs or Z boson and of the t quark are selected using jet substructure techniques to reduce standard model backgrounds, resulting in a distinct three-jet W′ boson decay signature. No significant deviation in data with respect to the standard model background prediction is observed. Upper limits are set at 95% confidence level on the product of the W′ boson cross section and the final state branching fraction. A W′ boson with a mass below 3.1 TeV is excluded, given the benchmark model assumption of democratic branching fractions. In addition, limits are set based on generalizations of these assumptions. These are the most sensitive limits to date for this final state.
Publisher: Springer Science and Business Media LLC
Date: 03-2021
DOI: 10.1140/EPJC/S10052-020-08817-8
Abstract: The production of Z boson pairs in proton–proton ( $${\\mathrm{p}} {\\mathrm{p}} $$ p p ) collisions, $${{\\mathrm{p}} {\\mathrm{p}} \\rightarrow ({\\mathrm{Z}}/\\gamma ^*)({\\mathrm{Z}}/\\gamma ^*) \\rightarrow 2\\ell 2\\ell '}$$ p p → ( Z / γ ∗ ) ( Z / γ ∗ ) → 2 ℓ 2 ℓ ′ , where $${\\ell ,\\ell ' = {\\mathrm{e}}}$$ ℓ , ℓ ′ = e or $${{\\upmu }}$$ μ , is studied at a center-of-mass energy of 13 $$\\,\\text {TeV}$$ TeV with the CMS detector at the CERN LHC. The data s le corresponds to an integrated luminosity of 137 $$\\,\\text {fb}^{-1}$$ fb - 1 , collected during 2016–2018. The $${\\mathrm{Z}} {\\mathrm{Z}} $$ Z Z production cross section, $$\\sigma _{\\text {tot}} ({\\mathrm{p}} {\\mathrm{p}} \\rightarrow {\\mathrm{Z}} {\\mathrm{Z}} ) = 17.4 \\pm 0.3 \\,\\text {(stat)} \\pm 0.5 \\,\\text {(syst)} \\pm 0.4 \\,\\text {(theo)} \\pm 0.3 \\,\\text {(lumi)} \\text { pb} $$ σ tot ( p p → Z Z ) = 17.4 ± 0.3 (stat) ± 0.5 (syst) ± 0.4 (theo) ± 0.3 (lumi) pb , measured for events with two pairs of opposite-sign, same-flavor leptons produced in the mass region $${60 m_{\\ell ^+\\ell ^-} 120\\,\\text {GeV}}$$ 60 m ℓ + ℓ - 120 GeV is consistent with standard model predictions. Differential cross sections are also measured and agree with theoretical predictions. The invariant mass distribution of the four-lepton system is used to set limits on anomalous $${\\mathrm{Z}} {\\mathrm{Z}} {\\mathrm{Z}} $$ Z Z Z and $${{\\mathrm{Z}} {\\mathrm{Z}} \\gamma }$$ Z Z γ couplings.
Publisher: Cold Spring Harbor Laboratory
Date: 05-02-2021
DOI: 10.1101/2021.02.04.429849
Abstract: Patients with colorectal cancer (CRC) frequently develop liver metastases during the course of their disease. A substantial proportion of them receive neoadjuvant FOLFOX (5-Fluorouracil, Oxaliplatin, Leucovorin) prior to surgery in an attempt to enable successful surgical removal of their metastases and to reduce the risk of recurrence. Yet, the majority of patients progress during treatment or recur following surgery, and molecular mechanisms that contribute to FOLFOX resistance remain poorly understood. Here, using a combination of phenotypic, transcriptomic and genomic analyses of both tumor s les derived from patients with metastatic CRC and matching patient-derived tumor organoids (PDTOs), we characterize a novel FOLFOX resistance mechanism and identify inhibitors that target this mechanism to resensitize metastatic organoids to FOLFOX. Resistant PDTOs, identified after in vitro exposure to FOLFOX, exhibited elevated expression of E2F pathway, S phase, G 2 /M and spindle assembly checkpoints (SAC) genes. Similar molecular features were detected in CRLM from patients with progressive disease while under neoadjuvant FOLFOX treatment, highlighting the relevance of this finding. FOLFOX resistant PDTOs displayed inactivating mutations of TP53 and exhibited transcriptional features of P53 pathway downregulation. We found that they accumulated in early S-phase and underwent significant DNA damage during FOLFOX exposure, thereafter arresting in G 2 /M while they repaired their DNA after FOLFOX withdrawal. In parallel, results of a large kinase inhibitor screen indicated that drugs targeting regulators of the DNA damage response, G 2 M checkpoint and SAC had cytotoxic effects on PDTOs generated from patients whose disease progressed during treatment with FOLFOX. Corroborating this finding, CHK1 and WEE1 inhibitors were found to synergize with FOLFOX and sensitize previously resistant PDTOs. Additionally, targeting the SAC master regulator MPS1 using empesertib after exposure to FOLFOX, when cells accumulate in G 2 M, was also very effective to kill FOLFOX-resistant PDTOs. Our results indicate that targeted and timely inhibition of specific cell cycle checkpoints shows great potential to improve response rates to FOLFOX in patients with metastatic CRC, for whom therapeutic alternatives remain extremely limited.
Publisher: American Physical Society (APS)
Date: 10-09-2021
Publisher: American Physical Society (APS)
Date: 09-11-2020
Publisher: American Physical Society (APS)
Date: 17-09-2021
Publisher: American Physical Society (APS)
Date: 16-11-2020
Publisher: IOP Publishing
Date: 15-09-2020
Publisher: Elsevier BV
Date: 08-2021
Publisher: Springer Science and Business Media LLC
Date: 07-2021
Abstract: Measurements of Higgs boson production cross sections and couplings in events where the Higgs boson decays into a pair of photons are reported. Events are selected from a s le of proton-proton collisions at $$ \\sqrt{s} $$ s = 13 TeV collected by the CMS detector at the LHC from 2016 to 2018, corresponding to an integrated luminosity of 137 fb − 1 . Analysis categories enriched in Higgs boson events produced via gluon fusion, vector boson fusion, vector boson associated production, and production associated with top quarks are constructed. The total Higgs boson signal strength, relative to the standard model (SM) prediction, is measured to be 1 . 12±0 . 09. Other properties of the Higgs boson are measured, including SM signal strength modifiers, production cross sections, and its couplings to other particles. These include the most precise measurements of gluon fusion and vector boson fusion Higgs boson production in several different kinematic regions, the first measurement of Higgs boson production in association with a top quark pair in five regions of the Higgs boson transverse momentum, and an upper limit on the rate of Higgs boson production in association with a single top quark. All results are found to be in agreement with the SM expectations.
Publisher: Elsevier BV
Date: 09-2021
Publisher: Springer Science and Business Media LLC
Date: 05-2020
DOI: 10.1140/EPJC/S10052-020-7858-1
Abstract: A measurement is presented of differential cross sections for t -channel single top quark and antiquark production in proton–proton collisions at a centre-of-mass energy of 13 $$\\,\\text {Te}\\text {V}$$ Te by the CMS experiment at the LHC. From a data set corresponding to an integrated luminosity of 35.9 $$\\,\\text {fb}^{-1}$$ fb - 1 , events containing one muon or electron and two or three jets are analysed. The cross section is measured as a function of the top quark transverse momentum ( $$p_{\\mathrm{T}} $$ p T ), rapidity, and polarisation angle, the charged lepton $$p_{\\mathrm{T}} $$ p T and rapidity, and the $$p_{\\mathrm{T}} $$ p T of the $$\\text {W}{}{}$$ W boson from the top quark decay. In addition, the charge ratio is measured differentially as a function of the top quark, charged lepton, and $$\\text {W}{}{}$$ W boson kinematic observables. The results are found to be in agreement with standard model predictions using various next-to-leading-order event generators and sets of parton distribution functions. Additionally, the spin asymmetry, sensitive to the top quark polarisation, is determined from the differential distribution of the polarisation angle at parton level to be $$0.440 \\pm 0.070$$ 0.440 ± 0.070 , in agreement with the standard model prediction.
Publisher: Public Library of Science (PLoS)
Date: 16-10-2018
Publisher: Elsevier BV
Date: 02-2021
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854361.V1
Abstract: IL3Rα/βc transcript and protein expression ratio in AML patient s les.
Publisher: Springer Science and Business Media LLC
Date: 06-2020
Publisher: Springer Science and Business Media LLC
Date: 05-2022
DOI: 10.1140/EPJC/S10052-022-10315-Y
Abstract: Using a data s le of $$\\sqrt{s}=13\\,\\text {TeV}$$ s = 13 TeV proton-proton collisions collected by the CMS experiment at the LHC in 2017 and 2018 with an integrated luminosity of $$103\\text {~fb}^{-1}$$ 103 fb - 1 , the $$\\text {B}^{0}_{\\mathrm{s}} \\rightarrow \\uppsi (\\text {2S})\\text {K}_\\mathrm{S}^{0}$$ B s 0 → ψ ( 2S ) K S 0 and $$\\text {B}^{0} \\rightarrow \\uppsi (\\text {2S})\\text {K}_\\mathrm{S}^{0} \\uppi ^+\\uppi ^-$$ B 0 → ψ ( 2S ) K S 0 π + π - decays are observed with significances exceeding 5 standard deviations. The resulting branching fraction ratios, measured for the first time, correspond to $${\\mathcal {B}}(\\text {B}^{0}_{\\mathrm{s}} \\rightarrow \\uppsi (\\text {2S})K_\\mathrm{S}^{0})/{\\mathcal {B}}(\\text {B}^{0}\\rightarrow \\uppsi (\\text {2S})K_\\mathrm{S}^{0}) = (3.33 \\pm 0.69 (\\text {stat})\\, \\pm 0.11\\,(\\text {syst}) \\pm 0.34\\,(f_{\\mathrm{s}}/f_{\\mathrm{d}})) \\times 10^{-2}$$ B ( B s 0 → ψ ( 2S ) K S 0 ) / B ( B 0 → ψ ( 2S ) K S 0 ) = ( 3.33 ± 0.69 ( stat ) ± 0.11 ( syst ) ± 0.34 ( f s / f d ) ) × 10 - 2 and $${\\mathcal {B}}(\\text {B}^{0} \\rightarrow \\uppsi (\\text {2S})\\text {K}_\\mathrm{S}^{0} \\uppi ^{+} \\uppi ^{-})/ {\\mathcal {B}}(\\text {B}^{0} \\rightarrow \\uppsi (\\text {2S})\\text {K}^{0}_{\\mathrm{S}}) = 0.480 \\pm 0.013\\,(\\text {stat}) \\pm 0.032\\,(\\text {syst})$$ B ( B 0 → ψ ( 2S ) K S 0 π + π - ) / B ( B 0 → ψ ( 2S ) K S 0 ) = 0.480 ± 0.013 ( stat ) ± 0.032 ( syst ) , where the last uncertainty in the first ratio is related to the uncertainty in the ratio of production cross sections of $$\\hbox {B}^{0}_{\\mathrm{s}}$$ B s 0 and $$\\hbox {B}^{0}$$ B 0 mesons, $$f_{\\mathrm{s}}/f_{\\mathrm{d}}$$ f s / f d .
Publisher: Springer Science and Business Media LLC
Date: 19-01-2023
DOI: 10.1038/S41567-022-01838-Y
Abstract: Protons consist of three valence quarks, two up-quarks and one down-quark, held together by gluons and a sea of quark-antiquark pairs. Collectively, quarks and gluons are referred to as partons. In a proton-proton collision, typically only one parton of each proton undergoes a hard scattering – referred to as single-parton scattering – leaving the remainder of each proton only slightly disturbed. Here, we report the study of double- and triple-parton scatterings through the simultaneous production of three J/ ψ mesons, which consist of a charm quark-antiquark pair, in proton-proton collisions recorded with the CMS experiment at the Large Hadron Collider. We observed this process – reconstructed through the decays of J/ ψ mesons into pairs of oppositely charged muons – with a statistical significance above five standard deviations. We measured the inclusive fiducial cross-section to be $$27{2}_{-104}^{+141}\\,{{{\\rm{(stat)}}}}\\,\\pm 17\\,{{{\\rm{(syst)}}}}\\,{{{\\rm{fb}}}}\\,$$ 27 2 − 104 + 141 (stat) ± 17 (syst) fb , and compared it to theoretical expectations for triple-J/ ψ meson production in single-, double- and triple-parton scattering scenarios. Assuming factorization of multiple hard-scattering probabilities in terms of single-parton scattering cross-sections, double- and triple-parton scattering are the dominant contributions for the measured process.
Publisher: American Physical Society (APS)
Date: 30-11-2020
Publisher: American Physical Society (APS)
Date: 02-11-2021
Publisher: American Physical Society (APS)
Date: 14-06-2022
Publisher: American Physical Society (APS)
Date: 30-11-2021
Publisher: American Physical Society (APS)
Date: 30-11-2020
Publisher: Springer Science and Business Media LLC
Date: 13-05-2015
DOI: 10.1038/NATURE14474
Abstract: The standard model of particle physics describes the fundamental particles and their interactions via the strong, electromagnetic and weak forces. It provides precise predictions for measurable quantities that can be tested experimentally. The probabilities, or branching fractions, of the strange B meson (B(s)(0)) and the B0 meson decaying into two oppositely charged muons (μ+ and μ−) are especially interesting because of their sensitivity to theories that extend the standard model. The standard model predicts that the B(s)(0) →µ+µ− and B(0) →µ+µ− decays are very rare, with about four of the former occurring for every billion mesons produced, and one of the latter occurring for every ten billion B0 mesons. A difference in the observed branching fractions with respect to the predictions of the standard model would provide a direction in which the standard model should be extended. Before the Large Hadron Collider (LHC) at CERN started operating, no evidence for either decay mode had been found. Upper limits on the branching fractions were an order of magnitude above the standard model predictions. The CMS (Compact Muon Solenoid) and LHCb (Large Hadron Collider beauty) collaborations have performed a joint analysis of the data from proton–proton collisions that they collected in 2011 at a centre-of-mass energy of seven teraelectronvolts and in 2012 at eight teraelectronvolts. Here we report the first observation of the B(s)(0) → µ+µ− decay, with a statistical significance exceeding six standard deviations, and the best measurement so far of its branching fraction. Furthermore, we obtained evidence for the B(0) → µ+µ− decay with a statistical significance of three standard deviations. Both measurements are statistically compatible with standard model predictions and allow stringent constraints to be placed on theories beyond the standard model. The LHC experiments will resume taking data in 2015, recording proton–proton collisions at a centre-of-mass energy of 13 teraelectronvolts, which will approximately double the production rates of B(s)(0) and B0 mesons and lead to further improvements in the precision of these crucial tests of the standard model.
Publisher: Oxford University Press (OUP)
Date: 03-2003
DOI: 10.1095/BIOLREPROD.102.005934
Abstract: Specific changes in milk composition during lactation in the tammar wallaby (Macropus eugenii) were correlated with the ages of the developing pouch young (PY). The present experiment was designed to test the hypothesis that the sucking pattern of the PY determines the course of mammary development in the tammar wallaby. To test this hypothesis, groups of 60-day-old PY were fostered repeatedly onto one group of host mothers so that a constant sucking stimulus on the mammary gland was maintained for 56 days to allow the lactational stage to progress 42 days ahead of the age of the young. Analysis of the milk in fostered and control groups showed the timing of changes in the concentration of protein and carbohydrate were essentially unaffected by altering the sucking regime. The only change in milk protein secretion was a small delay in the timing of down-regulation of the secretion of whey acidic protein and early lactation protein in the host tammars. In addition, the rates of growth and development of the foster PY were significantly increased relative to those of the control PY because of ingesting more milk with a higher energy content and different composition than normal for their age. The present study demonstrates that the lactating tammar wallaby regulates both milk composition and the rate of milk production and that these determine the rates of PY growth and development, irrespective of the age of the PY.
Publisher: Elsevier BV
Date: 03-2018
Publisher: Springer Science and Business Media LLC
Date: 03-05-2022
Abstract: Results are presented from a search for physics beyond the standard model in proton-proton collisions at $$ \\sqrt{s} $$ s = 13 TeV in channels with two Higgs bosons, each decaying via the process H → b $$ \\overline{\\mathrm{b}} $$ b ¯ , and large missing transverse momentum. The search uses a data s le corresponding to an integrated luminosity of 137 fb − 1 collected by the CMS experiment at the CERN LHC. The search is motivated by models of supersymmetry that predict the production of neutralinos, the neutral partners of the electroweak gauge and Higgs bosons. The observed event yields in the signal regions are found to be consistent with the standard model background expectations. The results are interpreted using simplified models of supersymmetry. For the electroweak production of nearly mass-degenerate higgsinos, each of whose decay chains yields a neutralino $$ \\left({\\overset{\\sim }{\\upchi}}_1^0\\right) $$ χ ~ 1 0 that in turn decays to a massless goldstino and a Higgs boson, $$ \\left({\\overset{\\sim }{\\upchi}}_1^0\\right) $$ χ ~ 1 0 masses in the range 175 to 1025 GeV are excluded at 95% confidence level. For the strong production of gluino pairs decaying via a slightly lighter $$ \\left({\\overset{\\sim }{\\upchi}}_2^0\\right) $$ χ ~ 2 0 to H and a light $$ \\left({\\overset{\\sim }{\\upchi}}_1^0\\right) $$ χ ~ 1 0 , gluino masses below 2330 GeV are excluded.
Publisher: American Physical Society (APS)
Date: 18-08-2022
Publisher: IOP Publishing
Date: 05-2021
DOI: 10.1088/1748-0221/16/05/P05014
Abstract: The performance is presented of the reconstruction and identification algorithms for electrons and photons with the CMS experiment at the LHC. The reported results are based on proton-proton collision data collected at a center-of-mass energy of 13 TeV and recorded in 2016–2018, corresponding to an integrated luminosity of 136 fb^-1. Results obtained from lead-lead collision data collected at √(s NN )=5.02 TeV are also presented. Innovative techniques are used to reconstruct the electron and photon signals in the detector and to optimize the energy resolution. Events with electrons and photons in the final state are used to measure the energy resolution and energy scale uncertainty in the recorded events. The measured energy resolution for electrons produced in Z boson decays in proton-proton collision data ranges from 2 to 5%, depending on electron pseudorapidity and energy loss through bremsstrahlung in the detector material. The energy scale in the same range of energies is measured with an uncertainty smaller than 0.1 (0.3)% in the barrel (endcap) region in proton-proton collisions and better than 1 (3)% in the barrel (endcap) region in heavy ion collisions. The timing resolution for electrons from Z boson decays with the full 2016–2018 proton-proton collision data set is measured to be 200 ps.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22522815
Abstract: Supplementary Methods, Figures, and Tables
Publisher: Hindawi Limited
Date: 08-06-2021
DOI: 10.1111/CMI.13368
Abstract: The Dot/Icm system of Legionella pneumophila is essential for virulence and delivers a large repertoire of effectors into infected host cells to create the Legionella containing vacuole. Since the secretion of effectors via the Dot/Icm system does not occur in the absence of host cells, we hypothesised that host factors actively participate in Dot/Icm effector translocation. Here we employed a high-throughput, genome-wide siRNA screen to systematically test the effect of silencing 18,120 human genes on translocation of the Dot/Icm effector, RalF, into HeLa cells. For the primary screen, we found that silencing of 119 genes led to increased translocation of RalF, while silencing of 321 genes resulted in decreased translocation. Following secondary screening, 70 genes were successfully validated as 'high confidence' targets. Gene set enrichment analysis of siRNAs leading to decreased RalF translocation, showed that ubiquitination was the most highly overrepresented category in the pathway analysis. We further showed that two host factors, the E2 ubiquitin-conjugating enzyme, UBE2E1, and the E3 ubiquitin ligase, CUL7, were important for supporting Dot/Icm translocation and L. pneumophila intracellular replication. In summary, we identified host ubiquitin pathways as important for the efficiency of Dot/Icm effector translocation by L. pneumophila, suggesting that host-derived ubiquitin-conjugating enzymes and ubiquitin ligases participate in the translocation of Legionella effector proteins and influence intracellular persistence and survival.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22521240.V1
Abstract: Figure S1 shows TP53 mutation alone is not predictive of cancer cell response to PRIMA-1.
Publisher: Elsevier BV
Date: 09-2021
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532957.V1
Abstract: Supplemetary Material and Tables S1 - S7
Publisher: EMBO
Date: 14-12-2020
Publisher: Elsevier BV
Date: 08-2021
Publisher: Springer Science and Business Media LLC
Date: 06-01-2017
DOI: 10.1038/CDD.2016.119
Publisher: Springer Science and Business Media LLC
Date: 06-2020
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854355.V1
Abstract: Key interactions between distinct residues in the IL-3R ternary complex crystal structure.
Publisher: American Physical Society (APS)
Date: 14-01-2021
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532963.V1
Abstract: Supplementary Figure 6: Pik3ca+/HR and Ptenfl/fl prostate cancers acquire CRPC, while Pik3ca+/HR Ptenfl/fl mutants are resistant to castration. (A) Representative H& E images of Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl anterior (AP) and ventral (VP) prostate lobes post-castration (scale bar: 50 um, n = 3). (B) Representative IHC images of Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl prostate tissue stained to detect Androgen receptor (AR) 2 weeks post-castration compared to uncastrated, age-matched controls (scale bar: 50 um, n = 3). Mice were castrated when prostate carcinoma was prevalent Pik3ca+/HR = 400 d old, Ptenfl/fl = 200 d old and Pik3ca+/HR Ptenfl/fl = 100 d old. Insert displays positive AR nuclei (arrows) in Pik3ca+/HR Ptenfl/fl compound mutants (scale bar: 5 um). (C) Bar chart displaying total prostate weight normalised to body weight for Pik3ca+/HR mice 0, 2 and 42 weeks post-castration (n = 8, 7 and 7, respectively). Error bars: SEM, *P .05 compared to 0 weeks post-castration, or as indicated, one-way ANOVA with Tukey's multiple comparison test. (D) Representative H& E images of Pik3ca+/HR mice 0, 2 and 42 weeks post-castration (scale bar: 100 um). Mice were castrated at 100 d of age.
Publisher: Springer Science and Business Media LLC
Date: 2021
DOI: 10.1140/EPJC/S10052-020-08701-5
Abstract: A search is presented for supersymmetric partners of the top quark (top squarks) in final states with two oppositely charged leptons (electrons or muons), jets identified as originating from $${\\text {b}}$$ b quarks, and missing transverse momentum. The search uses data from proton-proton collisions at $$\\sqrt{s}=13\\,\\text {TeV} $$ s = 13 TeV collected with the CMS detector, corresponding to an integrated luminosity of 137 $$\\,{\\text {fb}}^{-1}$$ fb - 1 . Hypothetical signal events are efficiently separated from the dominant top quark pair production background with requirements on the significance of the missing transverse momentum and on transverse mass variables. No significant deviation is observed from the expected background. Exclusion limits are set in the context of simplified supersymmetric models with pair-produced lightest top squarks. For top squarks decaying exclusively to a top quark and a lightest neutralino, lower limits are placed at $$95\\%$$ 95 % confidence level on the masses of the top squark and the neutralino up to 925 and 450 $$\\,\\text {GeV}$$ GeV , respectively. If the decay proceeds via an intermediate chargino, the corresponding lower limits on the mass of the lightest top squark are set up to 850 $$\\,\\text {GeV}$$ GeV for neutralino masses below 420 $$\\,\\text {GeV}$$ GeV . For top squarks undergoing a cascade decay through charginos and sleptons, the mass limits reach up to 1.4 $$\\,\\text {TeV}$$ TeV and 900 $$\\,\\text {GeV}$$ GeV respectively for the top squark and the lightest neutralino.
Publisher: Springer Science and Business Media LLC
Date: 07-2022
Abstract: The associated production of a W and a Z boson is studied in final states with multiple leptons produced in proton-proton (pp) collisions at a centre-of-mass energy of 13 TeV using 137 fb − 1 of data collected with the CMS detector at the LHC. A measurement of the total inclusive production cross section yields σ tot (pp → WZ) = 50 . 6 ± 0 . 8 (stat) ± 1 . 5 (syst) ± 1 . 1 (lumi) ± 0 . 5 (theo) pb. Measurements of the fiducial and differential cross sections for several key observables are also performed in all the final-state lepton flavour and charge compositions with a total of three charged leptons, which can be electrons or muons. All results are compared with theoretical predictions computed up to next-to-next-to-leading order in quantum chromodynamics plus next-to-leading or- der in electroweak theory and for various sets of parton distribution functions. The results include direct measurements of the charge asymmetry and the W and Z vector boson polarization. The first observation of longitudinally polarized W bosons in WZ production is reported. Anomalous gauge couplings are searched for, leading to new constraints on beyond-the-standard-model contributions to the WZ triple gauge coupling.
Publisher: Elsevier BV
Date: 10-2020
Publisher: Springer Science and Business Media LLC
Date: 07-2020
DOI: 10.1140/EPJC/S10052-020-7917-7
Abstract: Normalised multi-differential cross sections for top quark pair ( $$\\hbox {t}{\\bar{\\hbox {t}}}$$ t t ¯ ) production are measured in proton-proton collisions at a centre-of-mass energy of 13 $$\\,{\\text {TeV}}$$ TeV using events containing two oppositely charged leptons. The analysed data were recorded with the CMS detector in 2016 and correspond to an integrated luminosity of $$35.9{\\,{\\text {fb}}^{-1}} $$ 35.9 fb - 1 . The double-differential $$\\hbox {t}{\\bar{\\hbox {t}}}$$ t t ¯ cross section is measured as a function of the kinematic properties of the top quark and of the $$\\hbox {t}{\\bar{\\hbox {t}}}$$ t t ¯ system at parton level in the full phase space. A triple-differential measurement is performed as a function of the invariant mass and rapidity of the $$\\hbox {t}{\\bar{\\hbox {t}}}$$ t t ¯ system and the multiplicity of additional jets at particle level. The data are compared to predictions of Monte Carlo event generators that complement next-to-leading-order (NLO) quantum chromodynamics (QCD) calculations with parton showers. Together with a fixed-order NLO QCD calculation, the triple-differential measurement is used to extract values of the strong coupling strength $$\\alpha _{S}$$ α S and the top quark pole mass ( $$m_{{\\text {t}}}^{{\\text {pole}}}$$ m t pole ) using several sets of parton distribution functions (PDFs). The measurement of $$m_{{\\text {t}}}^{{\\text {pole}}}$$ m t pole exploits the sensitivity of the $$\\hbox {t}{\\bar{\\hbox {t}}}$$ t t ¯ invariant mass distribution to $$m_{{\\text {t}}}^{{\\text {pole}}}$$ m t pole near the production threshold. Furthermore, a simultaneous fit of the PDFs, $$\\alpha _{S}$$ α S , and $$m_{{\\text {t}}}^{{\\text {pole}}}$$ m t pole is performed at NLO, demonstrating that the new data have significant impact on the gluon PDF, and at the same time allow an accurate determination of $$\\alpha _{S}$$ α S and $$m_{{\\text {t}}}^{{\\text {pole}}}$$ m t pole . The values $$\\alpha _{S}(m_{{\\text {Z}}}) = 0.1135{}^{+0.0021}_{-0.0017}$$ α S ( m Z ) = 0.1135 - 0.0017 + 0.0021 and $$m_{{\\text {t}}}^{{\\text {pole}}} = 170.5 \\pm 0.8 \\,{\\text {GeV}} $$ m t pole = 170.5 ± 0.8 GeV are extracted, which account for experimental and theoretical uncertainties, the latter being estimated from NLO scale variations. Possible effects from Coulomb and soft-gluon resummation near the $$\\hbox {t}{\\bar{\\hbox {t}}}$$ t t ¯ production threshold are neglected in these parameter extractions. A rough estimate of these effects indicates an expected correction of $$m_{{\\text {t}}}^{{\\text {pole}}}$$ m t pole of the order of $$+1 \\,{\\text {GeV}} $$ + 1 GeV , which can be regarded as additional theoretical uncertainty in the current $$m_{{\\text {t}}}^{{\\text {pole}}}$$ m t pole extraction.
Publisher: American Physical Society (APS)
Date: 28-06-2022
Publisher: Springer Science and Business Media LLC
Date: 11-2021
Abstract: The production cross sections for prompt open-charm mesons in proton-proton collisions at a center-of-mass energy of 13 TeV are reported. The measurement is performed using a data s le collected by the CMS experiment corresponding to an integrated luminosity of 29 nb − 1 . The differential production cross sections of the D ∗ ± , D ± , and D 0 $$ \left({\overline{\mathrm{D}}}^0\right) $$ D ¯ 0 mesons are presented in ranges of transverse momentum and pseudorapidity 4 p T 100 GeV and |η| 2 . 1, respectively. The results are compared to several theoretical calculations and to previous measurements.
Publisher: IOP Publishing
Date: 20-08-2020
Publisher: Springer Science and Business Media LLC
Date: 24-01-2014
DOI: 10.1038/CDD.2013.203
Publisher: American Physical Society (APS)
Date: 25-02-2022
Publisher: IOP Publishing
Date: 05-05-2020
Publisher: Springer Science and Business Media LLC
Date: 06-2020
DOI: 10.1140/EPJC/S10052-020-7834-9
Abstract: Anisotropies in the initial energy density distribution of the quark-gluon plasma created in high energy heavy ion collisions lead to anisotropies in the azimuthal distributions of the final-state particles known as collective anisotropic flow. Fourier harmonic decomposition is used to quantify these anisotropies. The higher-order harmonics can be induced by the same order anisotropies (linear response) or by the combined influence of several lower order anisotropies (nonlinear response) in the initial state. The mixed higher-order anisotropic flow and nonlinear response coefficients of charged particles are measured as functions of transverse momentum and centrality in $$\\mathrm {PbPb}$$ PbPb collisions at nucleon-nucleon center-of-mass energies $$\\sqrt{\\smash [b]{s_{_{\\mathrm {NN}}}}} = 2.76$$ s NN = 2.76 and 5.02 $$\\,\\text {TeV}$$ TeV with the CMS detector. The results are compared with viscous hydrodynamic calculations using several different initial conditions, as well as microscopic transport model calculations. None of the models provides a simultaneous description of the mixed higher-order flow harmonics and nonlinear response coefficients.
Publisher: Elsevier BV
Date: 09-2022
Publisher: Public Library of Science (PLoS)
Date: 26-10-2016
Publisher: Springer Science and Business Media LLC
Date: 11-2020
Abstract: Decays of the 125 GeV Higgs boson into a Z boson and a ρ 0 (770) or ϕ(1020) meson are searched for using proton-proton collision data collected by the CMS experiment at the LHC at $$ \\sqrt{s} $$ s = 13 TeV. The analysed data set corresponds to an integrated luminosity of 137 fb − 1 . Events are selected in which the Z boson decays into a pair of electrons or a pair of muons, and the ρ and ϕ mesons decay into pairs of pions and kaons, respectively. No significant excess above the background model is observed. As different polarization states are possible for the decay products of the Z boson and ρ or ϕ mesons, affecting the signal acceptance, scenarios in which the decays are longitudinally or transversely polarized are considered. Upper limits at the 95% confidence level on the Higgs boson branching fractions into Zρ and Zϕ are determined to be 1.04–1.31% and 0.31–0.40%, respectively, where the ranges reflect the considered polarization scenarios these values are 740–940 and 730–950 times larger than the respective standard model expectations. These results constitute the first experimental limits on the two decay channels.
Publisher: Springer Science and Business Media LLC
Date: 08-2020
DOI: 10.1140/EPJC/S10052-020-8166-5
Abstract: Central exclusive and semiexclusive production of "Equation missing" pairs is measured with the CMS detector in proton-proton collisions at the LHC at center-of-mass energies of 5.02 and 13TeV. The theoretical description of these nonperturbative processes, which have not yet been measured in detail at the LHC, poses a significant challenge to models. The two pions are measured and identified in the CMS silicon tracker based on specific energy loss, whereas the absence of other particles is ensured by calorimeter information. The total and differential cross sections of exclusive and semiexclusive central "Equation missing" production are measured as functions of invariant mass, transverse momentum, and rapidity of the "Equation missing" system in the fiducial region defined as transverse momentum "Equation missing" and pseudorapidity "Equation missing" . The production cross sections for the four resonant channels "Image missing" , "Equation missing" , "Image missing" , and "Image missing" are extracted using a simple model. These results represent the first measurement of this process at the LHC collision energies of 5.02 and 13TeV.
Publisher: Springer Science and Business Media LLC
Date: 02-2022
Abstract: A search for flavor-changing neutral current interactions of the top quark (t) and the Higgs boson (H) is presented. The search is based on a data s le corresponding to an integrated luminosity of 137 fb − 1 recorded by the CMS experiment at the LHC in proton-proton collisions at $$ \\sqrt{s} $$ s = 13 TeV. Events containing exactly one lepton (muon or electron) and at least three jets, among which at least two are identified as originating from the hadronization of a bottom quark, are analyzed. A set of deep neural networks is used for kinematic event reconstruction, while boosted decision trees distinguish the signal from the background events. No significant excess over the background predictions is observed, and upper limits on the signal production cross sections are extracted. These limits are interpreted in terms of top quark decay branching fractions ( $$ \\mathcal{B} $$ B ) to the Higgs boson and an up (u) or a charm quark (c). Assuming one nonvanishing extra coupling at a time, the observed (expected) upper limits at 95% confidence level are $$ \\mathcal{B} $$ B (t → Hu) 0 . 079 (0 . 11)% and $$ \\mathcal{B} $$ B (t → Hc) 0 . 094 (0 . 086)%.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532969.V1
Abstract: Supplementary Figure 4: Pik3caH1047R heterozygous oncogenic mutation causes p110alpha-dependent prostate cancer. Representative H& E images (scale bar: 100 um) for Pik3ca+/HR and Ptenfl/fl dorsolateral prostate and histograms displaying phenotype incidence for anterior (B) and ventral (C) prostate lobes from Pik3ca+/HR and Ptenfl/fl mice treated with vehicle, p110alpha�inhibitor (A66), p110beta inhibitor (TGX-221), pan-PI3K inhibitor (BKM120) or A66 + TGX-221 for 4 weeks. ND = not done. A66 and TGX-221 were generated in house by P.R.S. (University of Auckland, New Zealand) (14) and BKM120 was obtained from SYNkinase (Australia).
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854334
Abstract: Increasing IL3Rα/βc ratios lead to hexameric receptor assembly and augmented quiescence.
Publisher: Cold Spring Harbor Laboratory
Date: 20-11-2019
DOI: 10.1101/849307
Abstract: Limited effective therapeutic options are available for patients with recurrent high-grade serous carcinoma (HGSC), the most common histological subtype accounting for the majority of ovarian cancer deaths. We have shown efficacy in poly-ADP ribose polymerase (PARP) inhibitor-resistant HGSC for the RNA Polymerase I (Pol I) transcription inhibitor CX-5461 through its ability to activate a nucleolar-associated DNA damage response (DDR). Here, we screen the protein-coding genome to identify potential targets whose inhibition enhances the efficacy of CX-5461. We identify a network of cooperating inhibitory interactions, including components of homologous recombination (HR) DNA repair and DNA topoisomerase 1 (TOP1). We highlight that CX-5461 combined with topotecan, a TOP1 inhibitor used as salvage therapy in HGSC, induces robust cell cycle arrest and cell death in a panel of HR-proficient HGSC cell lines. The combination potentiates a nucleolar-associated DDR via recruitment of phosphorylated replication protein A (RPA) and ataxia telangiectasia and Rad3 related protein (ATR). CX-5461 plus low-dose topotecan cooperate to potently inhibit xenograft tumour growth, indicating the potential for this strategy to improve salvage therapeutic regimens to treat HGSC.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854331
Abstract: Increasing IL3Rα/βc ratios and enforced hexamer signaling lead to reduced differentiation in in vivo engraftments.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709870.V1
Abstract: Key interactions between distinct residues in the IL-3R ternary complex crystal structure.
Publisher: Springer Science and Business Media LLC
Date: 12-2021
Abstract: A search for new top quark interactions is performed within the framework of an effective field theory using the associated production of either one or two top quarks with a Z boson in multilepton final states. The data s le corresponds to an integrated luminosity of 138 fb − 1 of proton-proton collisions at $$ \\sqrt{s} $$ s = 13 TeV collected by the CMS experiment at the LHC. Five dimension-six operators modifying the electroweak interactions of the top quark are considered. Novel machine-learning techniques are used to enhance the sensitivity to effects arising from these operators. Distributions used for the signal extraction are parameterized in terms of Wilson coefficients describing the interaction strengths of the operators. All five Wilson coefficients are simultaneously fit to data and 95% confidence level intervals are computed. All results are consistent with the SM expectations.
Publisher: Springer Science and Business Media LLC
Date: 11-2021
Abstract: A measurement of the cross section of the associated production of a single top quark and a W boson in final states with a muon or electron and jets in proton-proton collisions at $$ \\sqrt{s} $$ s = 13 TeV is presented. The data correspond to an integrated luminosity of 36 fb − 1 collected with the CMS detector at the CERN LHC in 2016. A boosted decision tree is used to separate the tW signal from the dominant t $$ \\overline{\\mathrm{t}} $$ t ¯ background, whilst the subleading W+jets and multijet backgrounds are constrained using data-based estimates. This result is the first observation of the tW process in final states containing a muon or electron and jets, with a significance exceeding 5 standard deviations. The cross section is determined to be 89 ± 4 (stat) ± 12 (syst) pb, consistent with the standard model.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532975.V1
Abstract: Supplementary Figure 2: Heterozygous Pik3caH1047R oncogenic mutation causes invasive prostate cancer in mice that is phenotypically distinct to Pten-null prostate cancer. (A) Sequencing cDNA isolated from PBiCre+/- Pik3ca+/HR prostate tissue confirmed heterozygosity at known silent base changes within mutant exon 20 adjacent to exon 19, indicating recombination has occurred. (B) allele-specific PCR of cDNA isolated from PBiCre+/- prostate tissue expressing either Pik3ca+/+ (Wt) or Pik3ca+/HR alleles (as previously described (13)) revealed the presence of the mutant exon 20 in PBiCre+/- Pik3ca+/HR prostate cDNA, but not in PBiCre+/- Wt prostate cDNA. (C) Representative H& E images of PBiCre+/- Wt, Pik3ca+/HR and Ptenfl/fl ventral and anterior prostate epithelium at 400 d (scale bar: 100 um). Phenotype incidence plots for PBiCre+/- Wt, Pik3ca+/HR and Ptenfl/fl ventral (D) and anterior (E) prostate lobes. VP = Ventral prostate, AP = anterior prostate, PIN = prostate intraepithelial neoplasia. (F) IHC to detect SMA in Wt, Pik3ca+/HR and Ptenfl/fl mice at 400 d (scale bar: 50 um). (G) Quantitation of PCNA-positive nuclei in PBiCre+/- Pik3ca+/HR and Ptenfl/fl prostate hyperplastic lesions. *P .001, one-way ANOVA with Tukey's multiple comparison test, n = 3. Error bars: SEM.
Publisher: American Association for Cancer Research (AACR)
Date: 26-07-2021
DOI: 10.1158/1535-7163.MCT-21-0067
Abstract: APR-246 (eprenetapopt) is in clinical development with a focus on hematologic malignancies and is promoted as a mutant-p53 reactivation therapy. Currently, the detection of at least one TP53 mutation is an inclusion criterion for patient selection into most APR-246 clinical trials. Preliminary results from our phase Ib/II clinical trial investigating APR-246 combined with doublet chemotherapy [cisplatin and 5-fluorouracil (5-FU)] in metastatic esophageal cancer, together with previous preclinical studies, indicate that TP53 mutation status alone may not be a sufficient biomarker for APR-246 response. This study aims to identify a robust biomarker for response to APR-246. Correlation analysis of the PRIMA-1 activity (lead compound to APR-246) with mutational status, gene expression, protein expression, and metabolite abundance across over 700 cancer cell lines (CCL) was performed. Functional validation and a boutique siRNA screen of over 850 redox-related genes were also conducted. TP53 mutation status was not consistently predictive of response to APR-246. The expression of SLC7A11, the cystine/glutamate transporter, was identified as a superior determinant of response to APR-246. Genetic regulators of SLC7A11, including ATF4, MDM2, wild-type p53, and c-Myc, were confirmed to also regulate cancer-cell sensitivity to APR-246. In conclusion, SLC7A11 expression is a broadly applicable determinant of sensitivity to APR-246 across cancer and should be utilized as the key predictive biomarker to stratify patients for future clinical investigation of APR-246.
Publisher: Elsevier BV
Date: 11-2022
Publisher: American Physical Society (APS)
Date: 22-06-2020
Publisher: Elsevier BV
Date: 05-2021
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709858.V1
Abstract: Increasing IL3Rα/βc ratios lead to hexameric receptor assembly and augmented quiescence.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854334.V1
Abstract: Increasing IL3Rα/βc ratios lead to hexameric receptor assembly and augmented quiescence.
Publisher: American Association for Cancer Research (AACR)
Date: 20-08-0006
DOI: 10.1158/2159-8290.23854328.V1
Abstract: Data collection and refinement statistics for the IL-3R ternary complex crystal structure.
Publisher: Cold Spring Harbor Laboratory
Date: 21-01-2021
DOI: 10.1101/2021.01.21.427535
Abstract: The nucleolar surveillance pathway (NSP) monitors nucleolar fidelity and responds to nucleolar stresses (i.e., inactivation of ribosome biogenesis) by mediating the inhibitory binding of ribosomal proteins (RPs) to mouse double minute 2 homolog (MDM2), a nuclear-localised E3 ubiquitin ligase, which results in p53 accumulation. Inappropriate activation of the NSP has been implicated in the pathogenesis of collection of human diseases termed “ribosomopathies”, while drugs that selectively activate the NSP are now in trials for cancer. Despite the clinical significance, the precise molecular mechanism(s) regulating the NSP remain poorly understood. Using genome-wide loss of function screens, we demonstrate the ribosome biogenesis (RiBi) axis as the most potent class of genes whose disruption stabilises p53. Furthermore, we identified a novel suite of genes critical for the NSP, including a novel mammalian protein implicated in 5S ribonucleoprotein particle (5S-RNP) biogenesis, HEATR3. By selectively disabling the NSP, we unexpectedly demonstrate that a functional NSP is required for the ability of all nuclear acting stresses tested, including DNA damage, to robustly induce p53 accumulation. Together, our data demonstrates that the NSP has evolved as the dominant central integrator of stresses that regulate nuclear p53 abundance, thus ensuring RiBi is hardwired to cellular proliferative capacity.
Publisher: Springer Science and Business Media LLC
Date: 05-12-2022
DOI: 10.1140/EPJC/S10052-022-10897-7
Abstract: Measurements of the associated production of a W boson and a charm ( $${\\text {c}}$$ c ) quark in proton–proton collisions at a centre-of-mass energy of 8 $$\\,\\text {TeV}$$ TeV are reported. The analysis uses a data s le corresponding to a total integrated luminosity of 19.7 $$\\,\\text {fb}^{-1}$$ fb - 1 collected by the CMS detector at the LHC. The W bosons are identified through their leptonic decays to an electron or a muon, and a neutrino. Charm quark jets are selected using distinctive signatures of charm hadron decays. The product of the cross section and branching fraction $$\\sigma (\\text {p}\\text {p}\\rightarrow \\text {W}+ {\\text {c}}+ \\text {X}) {\\mathcal {B}}(\\text {W}\\rightarrow \\ell \\upnu )$$ σ ( pp → W + c + X ) B ( W → ℓ ν ) , where $$\\ell = \\text {e}$$ ℓ = e or $$\\upmu $$ μ , and the cross section ratio $$\\sigma (\\text {p}\\text {p}\\rightarrow {{\\text {W}}^{+} + \\bar{{\\text {c}}} + \\text {X}}) / \\sigma (\\text {p}\\text {p}\\rightarrow {{\\text {W}}^{-} + {\\text {c}}+ \\text {X}})$$ σ ( pp → W + + c ¯ + X ) / σ ( pp → W - + c + X ) are measured in a fiducial volume and differentially as functions of the pseudorapidity and of the transverse momentum of the lepton from the W boson decay. The results are compared with theoretical predictions. The impact of these measurements on the determination of the strange quark distribution is assessed.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532957
Abstract: Supplemetary Material and Tables S1 - S7
Publisher: Springer Science and Business Media LLC
Date: 06-2020
Publisher: Springer Science and Business Media LLC
Date: 05-2021
Abstract: Measurements of the differential cross sections of Z + jets and γ + jets production, and their ratio, are presented as a function of the boson transverse momentum. Measurements are also presented of the angular distribution between the Z boson and the closest jet. The analysis is based on pp collisions at a center-of-mass energy of 13 TeV corresponding to an integrated luminosity of 35.9 fb − 1 recorded by the CMS experiment at the LHC. The results, corrected for detector effects, are compared with various theoretical predictions. In general, the predictions at higher orders in perturbation theory show better agreement with the measurements. This work provides the first measurement of the ratio of the differential cross sections of Z + jets and γ + jets production at 13 TeV, as well as the first direct measurement of Z bosons emitted collinearly with a jet.
Publisher: Springer Science and Business Media LLC
Date: 13-07-2022
DOI: 10.1038/S41418-022-01037-5
Abstract: High-throughput methodologies are the cornerstone of screening approaches to identify novel compounds that regulate immune cell function. To identify novel targeted therapeutics to treat immune disorders and haematological malignancies, there is a need to integrate functional cellular information with the molecular mechanisms that regulate changes in immune cell phenotype. We facilitate this goal by combining quantitative methods for dissecting complex simultaneous cell phenotypic effects with genomic analysis. This combination strategy we term Multiplexed Analysis of Cells sequencing (MAC-seq), a modified version of Digital RNA with perturbation of Genes (DRUGseq). We applied MAC-seq to screen compounds that target the epigenetic machinery of B cells and assess altered humoral immunity by measuring changes in proliferation, survival, differentiation and transcription. This approach revealed that polycomb repressive complex 2 (PRC2) inhibitors promote antibody secreting cell (ASC) differentiation in both murine and human B cells in vitro. This is further validated using T cell-dependent immunization in mice. Functional dissection of downstream effectors of PRC2 using arrayed CRISPR screening uncovered novel regulators of B cell differentiation, including Mybl1 , Myof , Gas7 and Atoh8 . Together, our findings demonstrate that integrated phenotype-transcriptome analyses can be effectively combined with drug screening approaches to uncover the molecular circuitry that drives lymphocyte fate decisions.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532960
Abstract: Supplementary Figure 7: Characterization of Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl prostate tumors. Representative images of IHC to detect (A) PCNA and (B) Cleaved-caspase 3 (CC3) in Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl prostate tissue 2 weeks post-castration compared to uncastrated, age-matched controls (scale bar: 50 um, n = 3). Mice were castrated when prostate carcinoma was prevalent Pik3ca+/HR = 400 d old, Ptenfl/fl = 200 d old and Pik3ca+/HR Ptenfl/fl =100 d old. Quantitative RT-PCR to detect (C) Nkx3.1 and (D) Pbsn mRNA in Wt prostate and Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl stage-matched prostate carcinomas (n = 5). Error bars: SEM, *P .05 compared to Wt, or as indicated, one-way ANOVA with Tukey's multiple comparison test. (E) Western Blotting of protein lysates isolated from Wt prostate and stage-matched Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl prostate carcinomas to detect total AKT, p-AKT Thr308 and p-AKT Ser473 (n = 3).
Publisher: Springer Science and Business Media LLC
Date: 05-2021
Abstract: Jet production in lead-lead (PbPb) and proton-proton (pp) collisions at a nucleon-nucleon center-of-mass energy of 5.02 TeV is studied with the CMS detector at the LHC, using PbPb and pp data s les corresponding to integrated luminosities of 404 μ b − 1 and 27.4 pb − 1 , respectively. Jets with different areas are reconstructed using the anti- k T algorithm by varying the distance parameter R . The measurements are performed using jets with transverse momenta ( p T ) greater than 200 GeV and in a pseudorapidity range of |η| 2. To reveal the medium modification of the jet spectra in PbPb collisions, the properly normalized ratio of spectra from PbPb and pp data is used to extract jet nuclear modification factors as functions of the PbPb collision centrality, p T and, for the first time, as a function of R up to 1.0. For the most central collisions, a strong suppression is observed for high- p T jets reconstructed with all distance parameters, implying that a significant amount of jet energy is scattered to large angles. The dependence of jet suppression on R is expected to be sensitive to both the jet energy loss mechanism and the medium response, and so the data are compared to several modern event generators and analytic calculations. The models considered do not fully reproduce the data.
Publisher: American Physical Society (APS)
Date: 05-07-2022
Publisher: Springer Science and Business Media LLC
Date: 05-06-2017
DOI: 10.1038/ONC.2017.175
Abstract: Activation of Ras signalling occurs in ~30% of human cancers however, activated Ras alone is not sufficient for tumourigenesis. In a screen for tumour suppressors that cooperate with oncogenic Ras ( Ras V12 ) in Drosophila , we identified genes involved in the autophagy pathway. Bioinformatic analysis of human tumours revealed that several core autophagy genes, including GABARAP , correlate with oncogenic KRAS mutations and poor prognosis in human pancreatic cancer, supporting a potential tumour-suppressive effect of the pathway in Ras-driven human cancers. In Drosophila, we demonstrate that blocking autophagy at any step of the pathway enhances Ras V12 -driven epithelial tissue overgrowth via the accumulation of reactive oxygen species and activation of the Jun kinase stress response pathway. Blocking autophagy in Ras V12 clones also results in non-cell-autonomous effects with autophagy, cell proliferation and caspase activation induced in adjacent wild-type cells. Our study has implications for understanding the interplay between perturbations in Ras signalling and autophagy in tumourigenesis, which might inform the development of novel therapeutics targeting Ras-driven cancers.
Publisher: American Physical Society (APS)
Date: 07-10-2020
Publisher: IOP Publishing
Date: 03-06-2020
Publisher: IOP Publishing
Date: 03-2022
DOI: 10.1088/1748-0221/17/03/P03014
Abstract: Many measurements at the LHC require efficient identification of heavy-flavour jets, i.e. jets originating from bottom (b) or charm (c) quarks. An overview of the algorithms used to identify c jets is described and a novel method to calibrate them is presented. This new method adjusts the entire distributions of the outputs obtained when the algorithms are applied to jets of different flavours. It is based on an iterative approach exploiting three distinct control regions that are enriched with either b jets, c jets, or light-flavour and gluon jets. Results are presented in the form of correction factors evaluated using proton-proton collision data with an integrated luminosity of 41.5 fb -1 at √s = 13 TeV, collected by the CMS experiment in 2017. The closure of the method is tested by applying the measured correction factors on simulated data sets and checking the agreement between the adjusted simulation and collision data. Furthermore, a validation is performed by testing the method on pseudodata, which emulate various mismodelling conditions. The calibrated results enable the use of the full distributions of heavy-flavour identification algorithm outputs, e.g. as inputs to machine-learning models. Thus, they are expected to increase the sensitivity of future physics analyses.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 03-10-2017
DOI: 10.1126/SCISIGNAL.AAL2987
Abstract: Lymphatic vessels constitute a specialized vasculature that is involved in development, cancer, obesity, and immune regulation. The migration of lymphatic endothelial cells (LECs) is critical for vessel growth (lymphangiogenesis) and vessel remodeling, processes that modify the lymphatic network in response to developmental or pathological demands. Using the publicly accessible results of our genome-wide siRNA screen, we characterized the migratome of primary human LECs and identified in idual genes and signaling pathways that regulate LEC migration. We compared our data set with mRNA differential expression data from endothelial and stromal cells derived from two in vivo models of lymphatic vessel remodeling, viral infection and contact hypersensitivity-induced inflammation, which identified genes selectively involved in regulating LEC migration and remodeling. We also characterized the top candidates in the LEC migratome in primary blood vascular endothelial cells to identify genes with functions common to lymphatic and blood vascular endothelium. On the basis of these analyses, we showed that
Publisher: IOP Publishing
Date: 08-06-2020
DOI: 10.1088/1748-0221/15/06/P06009
Abstract: Measurements are presented of the reduction of signal output due to radiation damage for two types of plastic scintillator tiles used in the hadron endcap (HE) calorimeter of the CMS detector. The tiles were exposed to particles produced in proton-proton (pp) collisions at the CERN LHC with a center-of-mass energy of 13 TeV, corresponding to a delivered luminosity of 50 fb −1 . The measurements are based on readout channels of the HE that were instrumented with silicon photomultipliers, and are derived using data from several sources: a laser calibration system, a movable radioactive source, as well as hadrons and muons produced in pp collisions. Results from several irradiation c aigns using 60 Co sources are also discussed. The damage is presented as a function of dose rate. Within the range of these measurements, for a fixed dose the damage increases with decreasing dose rate.
Publisher: Springer Science and Business Media LLC
Date: 16-05-2022
Abstract: A search is presented for single production of a vector-like T quark with charge 2 / 3 e , in the decay channel featuring a top quark and a Z boson, with the top quark decaying hadronically and the Z boson decaying to neutrinos. The search uses data collected by the CMS experiment in proton-proton collisions at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 137 fb − 1 recorded at the CERN LHC in 2016–2018. The search is sensitive to a T quark mass between 0.6 and 1.8 TeV with decay widths ranging from negligibly small up to 30% of the T quark mass. Reconstruction strategies for the top quark are based on the degree of Lorentz boosting of its final state. At 95% confidence level, the upper limit on the product of the cross section and branching fraction for a T quark of small decay width varies between 15 and 602 fb, depending on its mass. For a T quark with decay widths between 10 and 30% of its mass, this upper limit ranges between 16 and 836 fb. For most of the studied range, the results provide the best limits to date. This is the first search for single T quark production based on the full Run 2 data set of the LHC.
Publisher: Springer Science and Business Media LLC
Date: 04-2021
Abstract: Angular distributions of the decay B + → K ∗ (892) + μ + μ − are studied using events collected with the CMS detector in $$ \\sqrt{\\mathrm{s}} $$ s = 8 TeV proton-proton collisions at the LHC, corresponding to an integrated luminosity of 20.0 fb − 1 . The forward-backward asymmetry of the muons and the longitudinal polarization of the K ∗ (892) + meson are determined as a function of the square of the dimuon invariant mass. These are the first results from this exclusive decay mode and are in agreement with a standard model prediction.
Publisher: Elsevier BV
Date: 08-2022
Publisher: Elsevier BV
Date: 03-2022
Publisher: Springer Science and Business Media LLC
Date: 16-05-2022
Abstract: The production cross section of a top quark pair in association with a photon is measured in proton-proton collisions in the decay channel with two oppositely charged leptons ( e ± μ ∓ , e + e − , or μ + μ − ). The measurement is performed using 138 fb − 1 of proton-proton collision data recorded by the CMS experiment at $$ \\sqrt{s} $$ s = 13 TeV during the 2016–2018 data-taking period of the CERN LHC. A fiducial phase space is defined such that photons radiated by initial-state particles, top quarks, or any of their decay products are included. An inclusive cross section of 175 . 2 ± 2 . 5(stat) ± 6 . 3(syst) fb is measured in a signal region with at least one jet coming from the hadronization of a bottom quark and exactly one photon with transverse momentum above 20 GeV. Differential cross sections are measured as functions of several kinematic observables of the photon, leptons, and jets, and compared to standard model predictions. The measurements are also interpreted in the standard model effective field theory framework, and limits are found on the relevant Wilson coefficients from these results alone and in combination with a previous CMS measurement of the t $$ \\overline{t} $$ t ¯ γ production process using the lepton+jets final state.
Publisher: Elsevier BV
Date: 12-2022
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532969
Abstract: Supplementary Figure 4: Pik3caH1047R heterozygous oncogenic mutation causes p110alpha-dependent prostate cancer. Representative H& E images (scale bar: 100 um) for Pik3ca+/HR and Ptenfl/fl dorsolateral prostate and histograms displaying phenotype incidence for anterior (B) and ventral (C) prostate lobes from Pik3ca+/HR and Ptenfl/fl mice treated with vehicle, p110alpha�inhibitor (A66), p110beta inhibitor (TGX-221), pan-PI3K inhibitor (BKM120) or A66 + TGX-221 for 4 weeks. ND = not done. A66 and TGX-221 were generated in house by P.R.S. (University of Auckland, New Zealand) (14) and BKM120 was obtained from SYNkinase (Australia).
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709864.V1
Abstract: The IL-3R dodecamer activates STAT1 to induce cell differentiation.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532966
Abstract: Supplementary Figure 5: Pik3caH1047R mutation and Pten-deletion synergize to promote prostate cancer by increasing mTORC1/2 signaling. Histograms displaying phenotype incidence for anterior (A) and ventral (B) prostate lobes at 56 and 100 days of age. (C) Representative IHC images of Pik3ca+/HR Ptenfl/fl prostate tumors at 100 d stained to detect CK8, CK5 and SMA (n = 3, scale bar: 50 um). (D) Bar chart displaying total prostate weight normalised to body weight for Wt (n = 7), Pik3ca+/HR (n = 8), Ptenfl/fl (n = 8) and Pik3ca+/HR Ptenfl/fl (n = 7) 100 d old mice. Error bars: SEM, *P .05 compared to Wt or as indicated, one-way ANOVA with Tukey's multiple comparison test. (E) Quantitation of the apoptotic marker Cleaved-Caspase-3 (CC3) positive nuclei and (F) representative IHC images of CC3 staining in Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl stage-matched invasive prostate carcinoma (scale bar: 50 um, n = 3, one-way ANOVA with Tukey's multiple comparison test. Error bars: SEM). (G) Representative IHC images of Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl stage-matched invasive prostate carcinoma stained to detect p-AKT Thr308, p-RPS6 Ser235/236, p-4E-BP1 Thr37/46, p-AKT Ser473 and p-NDRG1 Thr346 (scale bar: 50 um). (H) Representative images of RNA in situ hybridisation (ISH) to detect positive (housekeeping gene PPIB, peptidylprolyl isomerase B) and negative (bacterial gene dapB) control probes to confirm RNA quality and the absence of background signal respectively (scale bar: 50 um, insert scale bar: 5 um).
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854340.V1
Abstract: Enrichment of the IL-3R hexamer versus dodecamer gene signature in primitive normal and leukemic stem cells.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854328
Abstract: Data collection and refinement statistics for the IL-3R ternary complex crystal structure.
Publisher: Elsevier BV
Date: 02-2020
Publisher: IOP Publishing
Date: 10-2020
Publisher: Springer Science and Business Media LLC
Date: 04-2021
Abstract: A search for phenomena beyond the standard model in final states with two oppositely charged same-flavor leptons and missing transverse momentum is presented. The search uses a data s le of proton-proton collisions at $$ \\sqrt{s} $$ s = 13 TeV, corresponding to an integrated luminosity of 137 fb − 1 , collected by the CMS experiment at the LHC. Three potential signatures of physics beyond the standard model are explored: an excess of events with a lepton pair, whose invariant mass is consistent with the Z boson mass a kinematic edge in the invariant mass distribution of the lepton pair and the nonresonant production of two leptons. The observed event yields are consistent with those expected from standard model backgrounds. The results of the first search allow the exclusion of gluino masses up to 1870 GeV, as well as chargino (neutralino) masses up to 750 (800) GeV, while those of the searches for the other two signatures allow the exclusion of light-flavor (bottom) squark masses up to 1800 (1600) GeV and slepton masses up to 700 GeV, respectively, at 95% confidence level within certain supersymmetry scenarios.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854325
Abstract: Summary of the key interactions in the IL-3R ternary complex in the IL-3R ternary complex crystal structure.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532963
Abstract: Supplementary Figure 6: Pik3ca+/HR and Ptenfl/fl prostate cancers acquire CRPC, while Pik3ca+/HR Ptenfl/fl mutants are resistant to castration. (A) Representative H& E images of Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl anterior (AP) and ventral (VP) prostate lobes post-castration (scale bar: 50 um, n = 3). (B) Representative IHC images of Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl prostate tissue stained to detect Androgen receptor (AR) 2 weeks post-castration compared to uncastrated, age-matched controls (scale bar: 50 um, n = 3). Mice were castrated when prostate carcinoma was prevalent Pik3ca+/HR = 400 d old, Ptenfl/fl = 200 d old and Pik3ca+/HR Ptenfl/fl = 100 d old. Insert displays positive AR nuclei (arrows) in Pik3ca+/HR Ptenfl/fl compound mutants (scale bar: 5 um). (C) Bar chart displaying total prostate weight normalised to body weight for Pik3ca+/HR mice 0, 2 and 42 weeks post-castration (n = 8, 7 and 7, respectively). Error bars: SEM, *P .05 compared to 0 weeks post-castration, or as indicated, one-way ANOVA with Tukey's multiple comparison test. (D) Representative H& E images of Pik3ca+/HR mice 0, 2 and 42 weeks post-castration (scale bar: 100 um). Mice were castrated at 100 d of age.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.C.6749895.V2
Abstract: Abstract Leukemia stem cells (LSC) possess distinct self-renewal and arrested differentiation properties that are responsible for disease emergence, therapy failure, and recurrence in acute myeloid leukemia (AML). Despite AML displaying extensive biological and clinical heterogeneity, LSC with high interleukin-3 receptor (IL3R) levels are a constant yet puzzling feature, as this receptor lacks tyrosine kinase activity. Here, we show that the heterodimeric IL3Rα/βc receptor assembles into hexamers and dodecamers through a unique interface in the 3D structure, where high IL3Rα/βc ratios bias hexamer formation. Importantly, receptor stoichiometry is clinically relevant as it varies across the in idual cells in the AML hierarchy, in which high IL3Rα/βc ratios in LSCs drive hexamer-mediated stemness programs and poor patient survival, while low ratios mediate differentiation. Our study establishes a new paradigm in which alternative cytokine receptor stoichiometries differentially regulate cell fate, a signaling mechanism that may be generalizable to other transformed cellular hierarchies and of potential therapeutic significance. Significance: Stemness is a hallmark of many cancers and is largely responsible for disease emergence, progression, and relapse. Our finding that clinically significant stemness programs in AML are directly regulated by different stoichiometries of cytokine receptors represents a hitherto unexplained mechanism underlying cell-fate decisions in cancer stem cell hierarchies. i a href="ancerdiscovery/article/doi/10.1158/2159-8290.CD-13-8-ITI" target="_blank" This article is highlighted in the In This Issue feature, p. 1749 /a /i /
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.C.6749895.V1
Abstract: Abstract Leukemia stem cells (LSC) possess distinct self-renewal and arrested differentiation properties that are responsible for disease emergence, therapy failure, and recurrence in acute myeloid leukemia (AML). Despite AML displaying extensive biological and clinical heterogeneity, LSC with high interleukin-3 receptor (IL3R) levels are a constant yet puzzling feature, as this receptor lacks tyrosine kinase activity. Here, we show that the heterodimeric IL3Rα/βc receptor assembles into hexamers and dodecamers through a unique interface in the 3D structure, where high IL3Rα/βc ratios bias hexamer formation. Importantly, receptor stoichiometry is clinically relevant as it varies across the in idual cells in the AML hierarchy, in which high IL3Rα/βc ratios in LSCs drive hexamer-mediated stemness programs and poor patient survival, while low ratios mediate differentiation. Our study establishes a new paradigm in which alternative cytokine receptor stoichiometries differentially regulate cell fate, a signaling mechanism that may be generalizable to other transformed cellular hierarchies and of potential therapeutic significance. Significance: Stemness is a hallmark of many cancers and is largely responsible for disease emergence, progression, and relapse. Our finding that clinically significant stemness programs in AML are directly regulated by different stoichiometries of cytokine receptors represents a hitherto unexplained mechanism underlying cell-fate decisions in cancer stem cell hierarchies. /
Publisher: MDPI AG
Date: 24-12-2022
Abstract: Technical advances in microscopy and automation have enabled image-based phenotypic screening of spheroids and organoids to become increasingly high throughput and high content at the same time. In particular, matrix-embedded 3D structures can recapitulate many aspects of parent (e.g., patient) tissues. Live-cell imaging of growing structures allows tremendous insight into population heterogeneity during drug treatment. However, screening for targeted markers and more detailed morphological analyses typically require fixation of 3D structures, and standard formaldehyde (FA) incubation conditions can dissolve collagen-based extracellular matrices such as Matrigel. The dislocation and clumping of the spheroids make image-based segmentation very difficult and the tracking of structures from the live cell stage to their fixed cell location virtually impossible. In this method, we present a fixation and staining protocol that is gentle enough to maintain 3D structures exactly in their live-cell location and does not alter their morphology. This opens up analytical strategies that connect the spheroid’s growth kinetics and heterogeneity of treatment responses with the more targeted fixed cell stains. Furthermore, we optimized the automated seeding and imaging of spheroids so that screening and phenotypic characterization can be performed in high-throughput at either low or high magnification and yield the same result, independent of the microscope used.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854355
Abstract: Key interactions between distinct residues in the IL-3R ternary complex crystal structure.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854352
Abstract: IL3Rα P248 at the IL-3R assembly interface is critical for cell differentiation.
Publisher: American Physical Society (APS)
Date: 26-08-2021
Publisher: Elsevier BV
Date: 11-2022
Publisher: Springer Science and Business Media LLC
Date: 12-2021
Abstract: The production cross section of a top quark pair in association with a photon is measured in proton-proton collisions at a center-of-mass energy of 13 TeV. The data set, corresponding to an integrated luminosity of 137 fb − 1 , was recorded by the CMS experiment during the 2016–2018 data taking of the LHC. The measurements are performed in a fiducial volume defined at the particle level. Events with an isolated, highly energetic lepton, at least three jets from the hadronization of quarks, among which at least one is b tagged, and one isolated photon are selected. The inclusive fiducial t $$ \overline{\mathrm{t}} $$ t ¯ γ cross section, for a photon with transverse momentum greater than 20 GeV and pseudorapidity |η| 1 . 4442, is measured to be 798 ± 7(stat) ± 48(syst) fb, in good agreement with the prediction from the standard model at next-to-leading order in quantum chromodynamics. The differential cross sections are also measured as a function of several kinematic observables and interpreted in the framework of the standard model effective field theory (EFT), leading to the most stringent direct limits to date on anomalous electromagnetic dipole moment interactions of the top quark and the photon.
Publisher: American Physical Society (APS)
Date: 09-2023
Publisher: Springer Science and Business Media LLC
Date: 03-2017
DOI: 10.1038/SDATA.2017.9
Abstract: Many cell types undergo migration during embryogenesis and disease. Endothelial cells line blood vessels and lymphatics, which migrate during development as part of angiogenesis, lymphangiogenesis and other types of vessel remodelling. These processes are also important in wound healing, cancer metastasis and cardiovascular conditions. However, the molecular control of endothelial cell migration is poorly understood. Here, we present a dataset containing siRNA screens that identify known and novel components of signalling pathways regulating migration of lymphatic endothelial cells. These components are compared to signalling in blood vascular endothelial cells. Further, using high-content microscopy, we captured a dataset of images of migrating cells following transfection with a genome-wide siRNA library. These datasets are suitable for the identification and analysis of genes involved in endothelial cell migration and morphology, and for computational approaches to identify signalling networks controlling the migratory response and integration of cell morphology, gene function and cell signaling. This may facilitate identification of protein targets for therapeutically modulating angiogenesis and lymphangiogenesis in the context of human disease.
Publisher: IOP Publishing
Date: 19-10-2020
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.C.6749895
Abstract: Abstract Leukemia stem cells (LSC) possess distinct self-renewal and arrested differentiation properties that are responsible for disease emergence, therapy failure, and recurrence in acute myeloid leukemia (AML). Despite AML displaying extensive biological and clinical heterogeneity, LSC with high interleukin-3 receptor (IL3R) levels are a constant yet puzzling feature, as this receptor lacks tyrosine kinase activity. Here, we show that the heterodimeric IL3Rα/βc receptor assembles into hexamers and dodecamers through a unique interface in the 3D structure, where high IL3Rα/βc ratios bias hexamer formation. Importantly, receptor stoichiometry is clinically relevant as it varies across the in idual cells in the AML hierarchy, in which high IL3Rα/βc ratios in LSCs drive hexamer-mediated stemness programs and poor patient survival, while low ratios mediate differentiation. Our study establishes a new paradigm in which alternative cytokine receptor stoichiometries differentially regulate cell fate, a signaling mechanism that may be generalizable to other transformed cellular hierarchies and of potential therapeutic significance. Significance: Stemness is a hallmark of many cancers and is largely responsible for disease emergence, progression, and relapse. Our finding that clinically significant stemness programs in AML are directly regulated by different stoichiometries of cytokine receptors represents a hitherto unexplained mechanism underlying cell-fate decisions in cancer stem cell hierarchies. i a href="ancerdiscovery/article/doi/10.1158/2159-8290.CD-13-8-ITI" target="_blank" This article is highlighted in the In This Issue feature, p. 1749 /a /i /
Publisher: Springer Science and Business Media LLC
Date: 04-08-2022
Abstract: A measurement of the forward-backward asymmetry of pairs of oppositely charged leptons (dimuons and dielectrons) produced by the Drell-Yan process in proton-proton collisions is presented. The data s le corresponds to an integrated luminosity of 138 fb − 1 collected with the CMS detector at the LHC at a center-of-mass energy of 13 TeV. The asymmetry is measured as a function of lepton pair mass for masses larger than 170 GeV and compared with standard model predictions. An inclusive measurement across both channels and the full mass range yields an asymmetry of 0 . 612 ± 0 . 005 (stat) ± 0 . 007 (syst). As a test of lepton flavor universality, the difference between the dimuon and dielectron asymmetries is measured as well. No statistically significant deviations from standard model predictions are observed. The measurements are used to set limits on the presence of additional gauge bosons. For a Z′ boson in the sequential standard model the observed (expected) 95% confidence level lower limit on the Z′ mass is 4.4 TeV (3.7 TeV).
Publisher: American Physical Society (APS)
Date: 21-06-2022
Publisher: American Physical Society (APS)
Date: 13-07-2022
Publisher: Cold Spring Harbor Laboratory
Date: 28-02-2018
DOI: 10.1101/273284
Abstract: Docetaxel and cabazitaxel are taxane chemotherapy treatments for metastatic castration-resistant prostate cancer (CRPC). However, therapeutic resistance remains a major issue. MicroRNAs are short non-coding RNAs that can silence multiple genes, regulating several signalling pathways simultaneously. Therefore, synthetic microRNAs may have therapeutic potential in CRPC by regulating genes involved in taxane response and minimise compensatory mechanisms that cause taxane resistance. To identify microRNAs that can improve the efficacy of taxanes in CRPC, we performed a genome-wide screen of 1280 microRNAs in the CRPC cell lines PC3 and DU145 in combination with docetaxel or cabazitaxel treatment. Mimics of miR-217 and miR-181b-5p enhanced apoptosis significantly in PC3 cells in the presence of these taxanes. These mimics downregulated at least a thousand different transcripts, which were enriched for genes with cell proliferation and focal adhesion functions. In idual knockdown of a selection of 46 genes representing these transcripts resulted in toxic or taxane sensitisation effects, indicating that these genes may be mediating the effects of the microRNA mimics. A range of these genes are expressed in CRPC metastases, suggesting that these microRNA mimics may be functional in CRPC. With further development, these microRNA mimics may have therapeutic potential to improve taxane response in CRPC patients.
Publisher: Springer Science and Business Media LLC
Date: 06-10-2023
Publisher: American Association for the Advancement of Science (AAAS)
Date: 16-09-2022
Abstract: The mechanism of action of eprenetapopt (APR-246, PRIMA-1 MET ) as an anticancer agent remains unresolved, although the clinical development of eprenetapopt focuses on its reported mechanism of action as a mutant-p53 reactivator. Using unbiased approaches, this study demonstrates that eprenetapopt depletes cellular antioxidant glutathione levels by increasing its turnover, triggering a nonapoptotic, iron-dependent form of cell death known as ferroptosis. Deficiency in genes responsible for supplying cancer cells with the substrates for de novo glutathione synthesis ( SLC7A11 , SHMT2 , and MTHFD1L ), as well as the enzymes required to synthesize glutathione ( GCLC and GCLM ), augments the activity of eprenetapopt. Eprenetapopt also inhibits iron-sulfur cluster biogenesis by limiting the cysteine desulfurase activity of NFS1, which potentiates ferroptosis and may restrict cellular proliferation. The combination of eprenetapopt with dietary serine and glycine restriction synergizes to inhibit esophageal xenograft tumor growth. These findings reframe the canonical view of eprenetapopt from a mutant-p53 reactivator to a ferroptosis inducer.
Publisher: American Physical Society (APS)
Date: 21-05-2020
Publisher: American Physical Society (APS)
Date: 06-07-2022
Publisher: Springer Science and Business Media LLC
Date: 11-2020
Abstract: The ratios of the production cross sections between the excited ϒ(2S) and ϒ(3S) mesons and the ϒ(1S) ground state, detected via their decay into two muons, are studied as a function of the number of charged particles in the event. The data are from proton-proton collisions at $$ \\sqrt{s} $$ s = 7 TeV, corresponding to an integrated luminosity of 4.8 fb − 1 , collected with the CMS detector at the LHC. Evidence of a decrease in these ratios as a function of the particle multiplicity is observed, more pronounced at low transverse momentum $$ {p}_{\\mathrm{T}}^{\\upmu \\upmu} $$ p T μμ . For ϒ(nS) mesons with $$ {p}_{\\mathrm{T}}^{\\upmu \\upmu} $$ p T μμ 7 GeV, where most of the data were collected, the correlation with multiplicity is studied as a function of the underlying event transverse sphericity and the number of particles in a cone around the ϒ(nS) direction. The ratios are found to be multiplicity independent for jet-like events. The mean $$ {p}_{\\mathrm{T}}^{\\upmu \\upmu} $$ p T μμ values for the ϒ(nS) states as a function of particle multiplicity are also measured and found to grow more steeply as their mass increases.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532978
Abstract: Supplementary Figure 1: PIK3CA mutations are predominantly missense mutations and PTEN mutation/loss predicts for poor prostate cancer patient survival. (A) Pie chart depicting the frequency of missense/nonsense mutations, in-frame deletions and fusion events in PIK3CA identified in the 9 prostate cancer genomic datasets assessed in Fig. 1A (3-10). (B) Kaplan-Meier plot comparing TCGA provisional prostate adenocarcinoma dataset with PTEN homozygous deletion, loss or mutation compared to the general population. PTEN age-adjusted COXPH HR: 0.47, P = 0.0026* (n = 492, s les with sequencing and CNA data only). Data was obtained from the TCGA data portal (tcga-data.nci.nih.gov/). PTEN copy number loss criteria Log R ratio {less than or equal to} -0.48, probe number {greater than or equal to} 10. Silent mutations were excluded.
Publisher: Springer Science and Business Media LLC
Date: 06-10-2023
Publisher: American Physical Society (APS)
Date: 31-08-2021
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532972
Abstract: Supplementary Figure 3: Characterization of Pik3ca-mutated and Pten-deleted prostate hyperplasia and carcinoma. (A) IHC to detect the apoptotic marker Cleaved-Caspase-3 (CC3) in Wt, Pik3ca+/HR and Ptenfl/fl mice at 400 d (scale bar: 50 um). (B) Quantitation of CC3-positive nuclei in Wt, Pik3ca+/HR and Ptenfl/fl prostate epithelium (n = 3, *P .05 compared to Wt, or as indicated, one-way ANOVA with Tukey's multiple comparison test, ns = not significant. Error bars: SEM). (C) IHC to detect CK5 and CK8 in Pik3ca+/HR and Ptenfl/fl carcinomas (representative images from 3 prostates per genotype, scale bar: 50 um). (D) Representative IHC images to detect PTEN, mTORC1 signaling components (p-AKT Thr308, p-RPS6 Ser235/236 and p-4E-BP1 Thr37/46) and mTORC2 substrates (p-AKT Ser473 and p-NDRG1 Thr346) in Pik3ca+/HR and Ptenfl/fl hyperplastic lesions (n = 3, scale bar: 50 um). IHC quantitation for (E) p-AKT Thr308, (F) p-RPS6 Ser235/236, (G) p-4E-BP1 Thr37/46, (H) p-AKT Ser473 and (I) p-NDRG1 Thr346 in Pik3ca+/HR and Ptenfl/fl prostate hyperplastic lesions (n = 3, Error bars: SEM, *P 0.05, unpaired, two-tailed t-test).
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22521231.V1
Abstract: Figure S4 shows the effects of p53 overexpression and repression on SLC7A11 mRNA expression.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532975
Abstract: Supplementary Figure 2: Heterozygous Pik3caH1047R oncogenic mutation causes invasive prostate cancer in mice that is phenotypically distinct to Pten-null prostate cancer. (A) Sequencing cDNA isolated from PBiCre+/- Pik3ca+/HR prostate tissue confirmed heterozygosity at known silent base changes within mutant exon 20 adjacent to exon 19, indicating recombination has occurred. (B) allele-specific PCR of cDNA isolated from PBiCre+/- prostate tissue expressing either Pik3ca+/+ (Wt) or Pik3ca+/HR alleles (as previously described (13)) revealed the presence of the mutant exon 20 in PBiCre+/- Pik3ca+/HR prostate cDNA, but not in PBiCre+/- Wt prostate cDNA. (C) Representative H& E images of PBiCre+/- Wt, Pik3ca+/HR and Ptenfl/fl ventral and anterior prostate epithelium at 400 d (scale bar: 100 um). Phenotype incidence plots for PBiCre+/- Wt, Pik3ca+/HR and Ptenfl/fl ventral (D) and anterior (E) prostate lobes. VP = Ventral prostate, AP = anterior prostate, PIN = prostate intraepithelial neoplasia. (F) IHC to detect SMA in Wt, Pik3ca+/HR and Ptenfl/fl mice at 400 d (scale bar: 50 um). (G) Quantitation of PCNA-positive nuclei in PBiCre+/- Pik3ca+/HR and Ptenfl/fl prostate hyperplastic lesions. *P .001, one-way ANOVA with Tukey's multiple comparison test, n = 3. Error bars: SEM.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854346
Abstract: The IL-3R dodecamer activates STAT1 to induce cell differentiation.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854340
Abstract: Enrichment of the IL-3R hexamer versus dodecamer gene signature in primitive normal and leukemic stem cells.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709852.V1
Abstract: Data collection and refinement statistics for the IL-3R ternary complex crystal structure.
Publisher: American Physical Society (APS)
Date: 31-08-2021
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22521225.V1
Abstract: Gene List from siRNA screen with APR-246 growth inhibition in H1299 p53-null (Sheet 1) and p53-R273H (Sheet 2)
Publisher: Springer Science and Business Media LLC
Date: 03-2021
Abstract: Events containing one or more top quarks produced with additional prompt leptons are used to search for new physics within the framework of an effective field theory (EFT). The data correspond to an integrated luminosity of 41.5 fb − 1 of proton-proton collisions at a center-of-mass energy of 13 TeV at the LHC, collected by the CMS experiment in 2017. The selected events are required to have either two leptons with the same charge or more than two leptons jets, including identified bottom quark jets, are also required, and the selected events are ided into categories based on the multiplicities of these objects. Sixteen dimension-six operators that can affect processes involving top quarks produced with additional charged leptons are considered in this analysis. Constructed to target EFT effects directly, the analysis applies a novel approach in which the observed yields are parameterized in terms of the Wilson coefficients (WCs) of the EFT operators. A simultaneous fit of the 16 WCs to the data is performed and two standard deviation confidence intervals for the WCs are extracted the standard model expectations for the WC values are within these intervals for all of the WCs probed.
Publisher: Elsevier BV
Date: 08-2021
DOI: 10.1016/J.JMII.2020.07.010
Abstract: Human papilloma viruses (HPV) are the main culprit in cervical and oropharyngeal cancers. HPV positive (+) cancers are regarded as 'oncogene addicted', displaying an absolute requirement for the continued expression of the oncogenes for their viability owing their survival, and thus making these genes salient targets for developing specific therapeutic agents. There is a strong association between HPV and oropharyngeal squamous cell carcinomas (OPSCC), a subset of head and neck cancers (HNCs). Alarmingly, HPV-associated OPSCC are on the rise globally, and the number of cases of HPV + OPSCCs surpasses that of cervical cancer in the USA. Here, we show that major HPV oncogenes, E6 and E7, are essential for the survival of HPV positive (+) OPSCCs, making these oncogenes salient targets for HPV-driven OPSCCs. HPV E7 is known to interact with STING, a component of the viral DNA-sensing cGAS-STING machinery which activates a pro-typical anti-viral type I interferon (IFN) response. Our recent work showed that E7 from HPV type 16 is responsible for the blockade of cGAS-STING responses in HPV + OPSCC cells. In this study, we show that CRISPR/Cas9-mediated loss of E7 from HPV + OPSCC cells, SCC2 and SCC104, restored cGAS-STING responses. Future work could involve HPV oncogene targeting leading to HPV + OPSCC tumour regression and that the combined use of STING agonists would induce favourable tumour clearance by activating appropriate anti-tumour responses.
Publisher: Elsevier BV
Date: 12-2022
Publisher: Springer Science and Business Media LLC
Date: 04-2021
Abstract: Measurements are presented of differential cross sections for the production of Z bosons in association with at least one jet initiated by a charm quark in pp collisions at $$ \sqrt{s} $$ s = 13 TeV. The data recorded by the CMS experiment at the LHC correspond to an integrated luminosity of 35.9 fb − 1 . The final states contain a pair of electrons or muons that are the decay products of a Z boson, and a jet consistent with being initiated by a charm quark produced in the hard interaction. Differential cross sections as a function of the transverse momentum p T of the Z boson and p T of the charm jet are compared with predictions from Monte Carlo event generators. The inclusive production cross section 405 . 4 ± 5 . 6 (stat) ± 24 . 3 (exp) ± 3 . 7 (theo) pb, is measured in a fiducial region requiring both leptons to have pseudorapidity |η| 2 . 4 and p T 10 GeV, at least one lepton with p T 26 GeV, and a mass of the pair in the range 71–111 GeV, while the charm jet is required to have p T 30 GeV and |η| 2 . 4. These are the first measurements of these cross sections in proton-proton collisions at 13 TeV.
Publisher: Springer Science and Business Media LLC
Date: 07-2021
Abstract: A search is presented for physics beyond the standard model (SM) using electron or muon pairs with high invariant mass. A data set of proton-proton collisions collected by the CMS experiment at the LHC at $$ \\sqrt{s} $$ s = 13 TeV from 2016 to 2018 corresponding to a total integrated luminosity of up to 140 fb − 1 is analyzed. No significant deviation is observed with respect to the SM background expectations. Upper limits are presented on the ratio of the product of the production cross section and the branching fraction to dileptons of a new narrow resonance to that of the Z boson. These provide the most stringent lower limits to date on the masses for various spin-1 particles, spin-2 gravitons in the Randall-Sundrum model, as well as spin-1 mediators between the SM and dark matter particles. Lower limits on the ultraviolet cutoff parameter are set both for four-fermion contact interactions and for the Arkani-Hamed, Dimopoulos, and Dvali model with large extra dimensions. Lepton flavor universality is tested at the TeV scale for the first time by comparing the dimuon and dielectron mass spectra. No significant deviation from the SM expectation of unity is observed.
Publisher: American Physical Society (APS)
Date: 06-07-2022
Publisher: American Physical Society (APS)
Date: 24-11-2020
Publisher: Springer Science and Business Media LLC
Date: 09-2020
Abstract: A search for new physics in events with two highly Lorentz-boosted Z bosons and large missing transverse momentum is presented. The analyzed proton-proton collision data, corresponding to an integrated luminosity of 137 fb − 1 , were recorded at $$ \\sqrt{s} $$ s = 13 TeV by the CMS experiment at the CERN LHC. The search utilizes the substructure of jets with large radius to identify quark pairs from Z boson decays. Backgrounds from standard model processes are suppressed by requirements on the jet mass and the missing transverse momentum. No significant excess in the event yield is observed beyond the number of background events expected from the standard model. For a simplified supersymmetric model in which the Z bosons arise from the decay of gluinos, an exclusion limit of 1920 GeV on the gluino mass is set at 95% confidence level. This is the first search for beyond-standard-model production of pairs of boosted Z bosons plus large missing transverse momentum.
Publisher: American Physical Society (APS)
Date: 05-10-2020
Publisher: American Physical Society (APS)
Date: 31-05-2022
Publisher: Elsevier BV
Date: 12-2016
Publisher: Springer Science and Business Media LLC
Date: 2022
Abstract: Measurements of jet substructure describing the composition of quark- and gluon-initiated jets are presented. Proton-proton (pp) collision data at $$ \\sqrt{s} $$ s = 13 TeV collected with the CMS detector are used, corresponding to an integrated luminosity of 35.9 fb − 1 . Generalized angularities are measured that characterize the jet substructure and distinguish quark- and gluon-initiated jets. These observables are sensitive to the distributions of transverse momenta and angular distances within a jet. The analysis is performed using a data s le of dijet events enriched in gluon-initiated jets, and, for the first time, a Z+jet event s le enriched in quark-initiated jets. The observables are measured in bins of jet transverse momentum, and as a function of the jet radius parameter. Each measurement is repeated applying a “soft drop” grooming procedure that removes soft and large angle radiation from the jet. Using these measurements, the ability of various models to describe jet substructure is assessed, showing a clear need for improvements in Monte Carlo generators.
Publisher: Springer Science and Business Media LLC
Date: 05-07-2017
Publisher: Springer Science and Business Media LLC
Date: 26-04-2022
Abstract: The top quark pair production cross section is measured in proton-proton collisions at a center-of-mass energy of 5.02 TeV. The data were collected in a special LHC low-energy and low-intensity run in 2017, and correspond to an integrated luminosity of 302 pb − 1 . The measurement is performed using events with one electron and one muon of opposite charge, and at least two jets. The measured cross section is 60 . 7 ± 5 . 0 (stat) ± 2 . 8 (syst) ± 1 . 1 (lumi) pb. A combination with the result in the single lepton + jets channel, based on data collected in 2015 at the same center-of-mass energy and corresponding to an integrated luminosity of 27.4 pb − 1 , is then performed. The resulting measured value is 63 . 0 ± 4 . 1 (stat) ± 3 . 0 (syst+lumi) pb, in agreement with the standard model prediction of $$ {66.8}_{-3.1}^{+2.9} $$ 66.8 − 3.1 + 2.9 pb.
Publisher: American Physical Society (APS)
Date: 05-10-2021
Publisher: American Physical Society (APS)
Date: 05-10-2020
Publisher: Springer Science and Business Media LLC
Date: 06-2018
DOI: 10.1140/EPJC/S10052-018-5950-6
Abstract: The nuclear modification factors of $${\mathrm {J}/\psi }$$ J / ψ and $$\psi \text {(2S)}$$ ψ (2S) mesons are measured in $$\text {PbPb}$$ PbPb collisions at a centre-of-mass energy per nucleon pair of $$\sqrt{\smash [b]{s_{_{\text {NN}}}}} = 5.02\,\text {Te}\text {V} $$ s NN = 5.02 TeV . The analysis is based on $$\text {PbPb}$$ PbPb and $$\mathrm {p}\mathrm {p}$$ p p data s les collected by CMS at the LHC in 2015, corresponding to integrated luminosities of 464 $$\,\mu \mathrm {b}^{-1}$$ μ b - 1 and 28 $$\,\text {pb}^\text {-1}$$ pb -1 , respectively. The measurements are performed in the dimuon rapidity range of $$|y | 2.4$$ | y | 2.4 as a function of centrality, rapidity, and transverse momentum ( $$p_{\mathrm {T}}$$ p T ) from $$p_{\mathrm {T}} =3$$ p T = 3 $${\,\text {Ge}\text {V}/}\text {c}$$ GeV / c in the most forward region and up to 50 $${\,\text {Ge}\text {V}/}\text {c}$$ GeV / c . Both prompt and nonprompt (coming from b hadron decays) $${\mathrm {J}/\psi }$$ J / ψ mesons are observed to be increasingly suppressed with centrality, with a magnitude similar to the one observed at $$\sqrt{\smash [b]{s_{_{\text {NN}}}}} = 2.76\,\text {Te}\text {V} $$ s NN = 2.76 TeV for the two $${\mathrm {J}/\psi }$$ J / ψ meson components. No dependence on rapidity is observed for either prompt or nonprompt $${\mathrm {J}/\psi }$$ J / ψ mesons. An indication of a lower prompt $${\mathrm {J}/\psi }$$ J / ψ meson suppression at $$p_{\mathrm {T}} 25$$ p T 25 $${\,\text {Ge}\text {V}/}\text {c}$$ GeV / c is seen with respect to that observed at intermediate $$p_{\mathrm {T}}$$ p T . The prompt $$\psi \text {(2S)}$$ ψ (2S) meson yield is found to be more suppressed than that of the prompt $${\mathrm {J}/\psi }$$ J / ψ mesons in the entire $$p_{\mathrm {T}}$$ p T range.
Publisher: Springer Science and Business Media LLC
Date: 11-2021
Abstract: A search is presented for new particles produced at the LHC in proton-proton collisions at $$ \\sqrt{s} $$ s = 13 TeV, using events with energetic jets and large missing transverse momentum. The analysis is based on a data s le corresponding to an integrated luminosity of 101 fb − 1 , collected in 2017–2018 with the CMS detector. Machine learning techniques are used to define separate categories for events with narrow jets from initial-state radiation and events with large-radius jets consistent with a hadronic decay of a W or Z boson. A statistical combination is made with an earlier search based on a data s le of 36 fb − 1 , collected in 2016. No significant excess of events is observed with respect to the standard model background expectation determined from control s les in data. The results are interpreted in terms of limits on the branching fraction of an invisible decay of the Higgs boson, as well as constraints on simplified models of dark matter, on first-generation scalar leptoquarks decaying to quarks and neutrinos, and on models with large extra dimensions. Several of the new limits, specifically for spin-1 dark matter mediators, pseudoscalar mediators, colored mediators, and leptoquarks, are the most restrictive to date.
Publisher: Springer Science and Business Media LLC
Date: 26-04-2022
Abstract: A direct search for electroweak production of charginos and neutralinos is presented. Events with three or four leptons, with up to two hadronically decaying τ leptons, or two same-sign light leptons are analyzed. The data s le consists of 137 fb − 1 of proton-proton collisions with a center of mass energy of 13 TeV, recorded with the CMS detector at the LHC. The results are interpreted in terms of several simplified models. These represent a broad range of production and decay scenarios for charginos and neutralinos. A parametric neural network is used to target several of the models with large backgrounds. In addition, results using orthogonal search regions are provided for all the models, simplifying alternative theoretical interpretations of the results. Depending on the model hypotheses, charginos and neutralinos with masses up to values between 300 and 1450 GeV are excluded at 95% confidence level.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22521228
Abstract: Figure S5 shows MYC directly regulates SLC7A11 levels and APR-246 sensitivity.
Publisher: IOP Publishing
Date: 07-2022
DOI: 10.1088/1748-0221/17/07/P07023
Abstract: A new algorithm is presented to discriminate reconstructed hadronic decays of tau leptons ( τ h ) that originate from genuine tau leptons in the CMS detector against τ h candidates that originate from quark or gluon jets, electrons, or muons. The algorithm inputs information from all reconstructed particles in the vicinity of a τ h candidate and employs a deep neural network with convolutional layers to efficiently process the inputs. This algorithm leads to a significantly improved performance compared with the previously used one. For ex le, the efficiency for a genuine τ h to pass the discriminator against jets increases by 10–30% for a given efficiency for quark and gluon jets. Furthermore, a more efficient τ h reconstruction is introduced that incorporates additional hadronic decay modes. The superior performance of the new algorithm to discriminate against jets, electrons, and muons and the improved τ h reconstruction method are validated with LHC proton-proton collision data at √ s = 13 TeV.
Publisher: American Association for Cancer Research (AACR)
Date: 25-07-2022
DOI: 10.1158/2767-9764.CRC-21-0139
Abstract: Inhibiting the androgen receptor (AR), a ligand-activated transcription factor, with androgen deprivation therapy is a standard-of-care treatment for metastatic prostate cancer. Paradoxically, activation of AR can also inhibit the growth of prostate cancer in some patients and experimental systems, but the mechanisms underlying this phenomenon are poorly understood. This study exploited a potent synthetic androgen, methyltestosterone (MeT), to investigate AR agonist-induced growth inhibition. MeT strongly inhibited growth of prostate cancer cells expressing AR, but not AR-negative models. Genes and pathways regulated by MeT were highly analogous to those regulated by DHT, although MeT induced a quantitatively greater androgenic response in prostate cancer cells. MeT potently downregulated DNA methyltransferases, leading to global DNA hypomethylation. These epigenomic changes were associated with dysregulation of transposable element expression, including upregulation of endogenous retrovirus (ERV) transcripts after sustained MeT treatment. Increased ERV expression led to accumulation of double-stranded RNA and a “viral mimicry” response characterized by activation of IFN signaling, upregulation of MHC class I molecules, and enhanced recognition of murine prostate cancer cells by CD8+ T cells. Positive associations between AR activity and ERVs/antiviral pathways were evident in patient transcriptomic data, supporting the clinical relevance of our findings. Collectively, our study reveals that the potent androgen MeT can increase the immunogenicity of prostate cancer cells via a viral mimicry response, a finding that has potential implications for the development of strategies to sensitize this cancer type to immunotherapies. Our study demonstrates that potent androgen stimulation of prostate cancer cells can elicit a viral mimicry response, resulting in enhanced IFN signaling. This finding may have implications for the development of strategies to sensitize prostate cancer to immunotherapies.
Publisher: Springer Science and Business Media LLC
Date: 08-07-2019
DOI: 10.1038/S41418-019-0384-8
Abstract: Exquisite regulation of PI3K/AKT/mTORC1 signaling is essential for homeostatic control of cell growth, proliferation, and survival. Aberrant activation of this signaling network is an early driver of many sporadic human cancers. Paradoxically, sustained hyperactivation of the PI3K/AKT/mTORC1 pathway in nontransformed cells results in cellular senescence, which is a tumor-suppressive mechanism that must be overcome to promote malignant transformation. While oncogene-induced senescence (OIS) driven by excessive RAS/ERK signaling has been well studied, little is known about the mechanisms underpinning the AKT-induced senescence (AIS) response. Here, we utilize a combination of transcriptome and metabolic profiling to identify key signatures required to maintain AIS. We also employ a whole protein-coding genome RNAi screen for AIS escape, validating a subset of novel mediators and demonstrating their preferential specificity for AIS as compared with OIS. As proof of concept of the potential to exploit the AIS network, we show that neurofibromin 1 (NF1) is upregulated during AIS and its ability to suppress RAS/ERK signaling facilitates AIS maintenance. Furthermore, depletion of NF1 enhances transformation of p53-mutant epithelial cells expressing activated AKT, while its overexpression blocks transformation by inducing a senescent-like phenotype. Together, our findings reveal novel mechanistic insights into the control of AIS and identify putative senescence regulators that can potentially be targeted, with implications for new therapeutic options to treat PI3K/AKT/mTORC1-driven cancers.
Publisher: Springer Science and Business Media LLC
Date: 12-2020
DOI: 10.1140/EPJC/S10052-020-08562-Y
Abstract: Measurements are presented of the single-diffractive dijet cross section and the diffractive cross section as a function of the proton fractional momentum loss $$\xi $$ ξ and the four-momentum transfer squared t . Both processes $${\text{ p }{}{}} {\text{ p }{}{}} \rightarrow {\text{ p }{}{}} {\text{ X }} $$ p p → p X and $${\text{ p }{}{}} {\text{ p }{}{}} \rightarrow {\text{ X }} {\text{ p }{}{}} $$ p p → X p , i.e. with the proton scattering to either side of the interaction point, are measured, where $${\text{ X }} $$ X includes at least two jets the results of the two processes are averaged. The analyses are based on data collected simultaneously with the CMS and TOTEM detectors at the LHC in proton–proton collisions at $$\sqrt{s} = 8\,\text {Te}\text {V} $$ s = 8 Te during a dedicated run with $$\beta ^{*} = 90\,\text {m} $$ β ∗ = 90 m at low instantaneous luminosity and correspond to an integrated luminosity of $$37.5{\,\text {nb}^{-1}} $$ 37.5 nb - 1 . The single-diffractive dijet cross section $$\sigma ^{{\text{ p }{}{}} {\text{ X }}}_{\mathrm {jj}}$$ σ jj p X , in the kinematic region $$\xi 0.1$$ ξ 0.1 , $$0.03 |t | 1\,\text {Ge}\text {V} ^2$$ 0.03 | t | 1 Ge 2 , with at least two jets with transverse momentum $$p_{\mathrm {T}} 40\,\text {Ge}\text {V} $$ p T 40 Ge , and pseudorapidity $$|\eta | 4.4$$ | η | 4.4 , is $$21.7 \pm 0.9\,\text {(stat)} \,^{+3.0}_{-3.3}\,\text {(syst)} \pm 0.9\,\text {(lumi)} \,\text {nb} $$ 21.7 ± 0.9 (stat) - 3.3 + 3.0 (syst) ± 0.9 (lumi) nb . The ratio of the single-diffractive to inclusive dijet yields, normalised per unit of $$\xi $$ ξ , is presented as a function of x , the longitudinal momentum fraction of the proton carried by the struck parton. The ratio in the kinematic region defined above, for x values in the range $$-2.9 \le \log _{10} x \le -1.6$$ - 2.9 ≤ log 10 x ≤ - 1.6 , is $$R = (\sigma ^{{\text{ p }{}{}} {\text{ X }}}_{\mathrm {jj}}/\Delta \xi )/\sigma _{\mathrm {jj}} = 0.025 \pm 0.001\,\text {(stat)} \pm 0.003\,\text {(syst)} $$ R = ( σ jj p X / Δ ξ ) / σ jj = 0.025 ± 0.001 (stat) ± 0.003 (syst) , where $$\sigma ^{{\text{ p }{}{}} {\text{ X }}}_{\mathrm {jj}}$$ σ jj p X and $$\sigma _{\mathrm {jj}}$$ σ jj are the single-diffractive and inclusive dijet cross sections, respectively. The results are compared with predictions from models of diffractive and nondiffractive interactions. Monte Carlo predictions based on the HERA diffractive parton distribution functions agree well with the data when corrected for the effect of soft rescattering between the spectator partons.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22521225
Abstract: Gene List from siRNA screen with APR-246 growth inhibition in H1299 p53-null (Sheet 1) and p53-R273H (Sheet 2)
Publisher: Elsevier BV
Date: 08-2021
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22521222
Abstract: Supplemental Table 1, 2, 3. Supplemental Materials and Methods.
Publisher: American Physical Society (APS)
Date: 09-03-2022
Publisher: American Physical Society (APS)
Date: 20-05-2022
Publisher: Springer Science and Business Media LLC
Date: 2022
Abstract: A measurement of inclusive four-jet production in proton-proton collisions at a center-of-mass energy of 13 TeV is presented. The transverse momenta of jets within |η| 4 . 7 are required to exceed 35, 30, 25, and 20 GeV for the first-, second-, third-, and fourth-leading jet, respectively. Differential cross sections are measured as functions of the jet transverse momentum, jet pseudorapidity, and several other observables that describe the angular correlations between the jets. The measured distributions show sensitivity to different aspects of the underlying event, parton shower modeling, and matrix element calculations. In particular, the interplay between angular correlations caused by parton shower and double-parton scattering contributions is shown to be important. The double-parton scattering contribution is extracted by means of a template fit to the data, using distributions for single-parton scattering obtained from Monte Carlo event generators and a double-parton scattering distribution constructed from inclusive single-jet events in data. The effective double-parton scattering cross section is calculated and discussed in view of previous measurements and of its dependence on the models used to describe the single- parton scattering background.
Publisher: American Physical Society (APS)
Date: 19-03-2021
Publisher: Springer Science and Business Media LLC
Date: 02-2022
Abstract: Inclusive and differential cross sections of single top quark production in association with a Z boson are measured in proton-proton collisions at a center-of-mass energy of 13 TeV with a data s le corresponding to an integrated luminosity of 138 fb − 1 recorded by the CMS experiment. Events are selected based on the presence of three leptons, electrons or muons, associated with leptonic Z boson and top quark decays. The measurement yields an inclusive cross section of $$ {87.9}_{-7.3}^{+7.5}{\\left(\\mathrm{stat}\\right)}_{-6.0}^{+7.3}\\left(\\mathrm{syst}\\right) $$ 87.9 − 7.3 + 7.5 stat − 6.0 + 7.3 syst fb for a dilepton invariant mass greater than 30 GeV, in agreement with standard model (SM) calculations and represents the most precise determination to date. The ratio between the cross sections for the top quark and the top antiquark production in association with a Z boson is measured as $$ {2.37}_{-0.42}^{+0.56}{\\left(\\mathrm{stat}\\right)}_{-0.13}^{+0.27}\\left(\\mathrm{syst}\\right) $$ 2.37 − 0.42 + 0.56 stat − 0.13 + 0.27 syst . Differential measurements at parton and particle levels are performed for the first time. Several kinematic observables are considered to study the modeling of the process. Results are compared to theoretical predictions with different assumptions on the source of the initial-state b quark and found to be in agreement, within the uncertainties. Additionally, the spin asymmetry, which is sensitive to the top quark polarization, is determined from the differential distribution of the polarization angle at parton level to be 0 . 54 ± 0 . 16 (stat) ± 0 . 06 (syst), in agreement with SM predictions.
Publisher: American Physical Society (APS)
Date: 24-04-2020
Publisher: Springer New York
Date: 2018
DOI: 10.1007/978-1-4939-7568-6_17
Abstract: This chapter details a compendium of protocols that collectively enable the reader to perform a pooled shRNA and/or CRISPR screen-with methods to identify and validate positive controls and subsequent hits establish a viral titer in the cell line of choice create and screen libraries, sequence strategies, and bioinformatics resources to analyze outcomes. Collectively, this provides an overarching resource from the start to finish of a screening project, making this technology possible in all laboratories.
Publisher: American Physical Society (APS)
Date: 05-08-2020
Publisher: MDPI AG
Date: 30-04-2020
Abstract: Background: Breast cancer (BC) is a heterogeneous disease for which the commonly used chemotherapeutic agents primarily include the anthracyclines (doxorubicin, epirubicin), microtubule inhibitors (paclitaxel, docetaxel, eribulin), and alkylating agents (cyclophosphamide). While these drugs can be highly effective, metastatic tumours are frequently refractory to treatment or become resistant upon tumour relapse. Methods: We undertook a cell polarity/epithelial mesenchymal plasticity (EMP)-enriched short hairpin RNA (shRNA) screen in MDA-MB-468 breast cancer cells to identify factors underpinning heterogeneous responses to three chemotherapeutic agents used clinically in breast cancer: Doxorubicin, docetaxel, and eribulin. shRNA-transduced cells were treated for 6 weeks with the EC10 of each drug, and shRNA representation assessed by deep sequencing. We first identified candidate genes with depleted shRNA, implying that their silencing could promote a response. Using the Broad Institute’s Connectivity Map (CMap), we identified partner inhibitors targeting the identified gene families that may induce cell death in combination with doxorubicin, and tested them with all three drug treatments. Results: In total, 259 shRNAs were depleted with doxorubicin treatment (at p 0.01), 66 with docetaxel, and 25 with eribulin. Twenty-four depleted hairpins overlapped between doxorubicin and docetaxel, and shRNAs for TGFB2, RUNX1, CCDC80, and HYOU1 were depleted across all the three drug treatments. Inhibitors of MDM/TP53, TGFBR, and FGFR were identified by CMap as the top pharmaceutical perturbagens and we validated the combinatorial benefits of the TGFBR inhibitor (SB525334) and MDM inhibitor (RITA) with doxorubicin treatment, and also observed synergy between the inhibitor SB525334 and eribulin in MDA-MB-468 cells. Conclusions: Taken together, a cell polarity/EMP-enriched shRNA library screen identified relevant gene products that could be targeted alongside current chemotherapeutic agents for the treatment of invasive BC.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2019
DOI: 10.1158/2159-8290.23854361
Abstract: IL3Rα/βc transcript and protein expression ratio in AML patient s les.
Publisher: Elsevier BV
Date: 09-2020
Publisher: Springer Science and Business Media LLC
Date: 2021
Abstract: Evidence for Higgs boson decay to a pair of muons is presented. This result combines searches in four exclusive categories targeting the production of the Higgs boson via gluon fusion, via vector boson fusion, in association with a vector boson, and in association with a top quark-antiquark pair. The analysis is performed using proton-proton collision data at $$ \\sqrt{s} $$ s = 13 TeV, corresponding to an integrated luminosity of 137 fb − 1 , recorded by the CMS experiment at the CERN LHC. An excess of events over the back- ground expectation is observed in data with a significance of 3.0 standard deviations, where the expectation for the standard model (SM) Higgs boson with mass of 125.38 GeV is 2.5. The combination of this result with that from data recorded at $$ \\sqrt{s} $$ s = 7 and 8 TeV, corresponding to integrated luminosities of 5.1 and 19.7 fb − 1 , respectively, increases both the expected and observed significances by 1%. The measured signal strength, relative to the SM prediction, is $$ {1.19}_{-0.39}^{+0.40}{\\left(\\mathrm{stat}\\right)}_{-0.14}^{+0.15}\\left(\\mathrm{syst}\\right) $$ 1.19 − 0.39 + 0.40 stat − 0.14 + 0.15 syst . This result constitutes the first evidence for the decay of the Higgs boson to second generation fermions and is the most precise measurement of the Higgs boson coupling to muons reported to date.
Publisher: Elsevier BV
Date: 05-2021
Publisher: Springer Science and Business Media LLC
Date: 03-2022
DOI: 10.1038/S41467-022-28705-X
Abstract: Despite the success of therapies targeting oncogenes in cancer, clinical outcomes are limited by residual disease that ultimately results in relapse. This residual disease is often characterized by non-genetic adaptive resistance, that in melanoma is characterised by altered metabolism. Here, we examine how targeted therapy reprograms metabolism in BRAF-mutant melanoma cells using a genome-wide RNA interference (RNAi) screen and global gene expression profiling. Using this systematic approach we demonstrate post-transcriptional regulation of metabolism following BRAF inhibition, involving selective mRNA transport and translation. As proof of concept we demonstrate the RNA processing kinase U2AF homology motif kinase 1 (UHMK1) associates with mRNAs encoding metabolism proteins and selectively controls their transport and translation during adaptation to BRAF-targeted therapy. UHMK1 inactivation induces cell death by disrupting therapy induced metabolic reprogramming, and importantly, delays resistance to BRAF and MEK combination therapy in multiple in vivo models. We propose selective mRNA processing and translation by UHMK1 constitutes a mechanism of non-genetic resistance to targeted therapy in melanoma by controlling metabolic plasticity induced by therapy.
Publisher: Springer Science and Business Media LLC
Date: 30-10-2020
DOI: 10.1007/S41781-020-00041-Z
Abstract: We describe a method to obtain point and dispersion estimates for the energies of jets arising from b quarks produced in proton–proton collisions at an energy of $$\\sqrt{s}=13\\,\\text {TeV} $$ s = 13 TeV at the CERN LHC. The algorithm is trained on a large s le of simulated b jets and validated on data recorded by the CMS detector in 2017 corresponding to an integrated luminosity of 41 $$\\,\\text {fb}^{-1}$$ fb - 1 . A multivariate regression algorithm based on a deep feed-forward neural network employs jet composition and shape information, and the properties of reconstructed secondary vertices associated with the jet. The results of the algorithm are used to improve the sensitivity of analyses that make use of b jets in the final state, such as the observation of Higgs boson decay to $$\\hbox {b}\\bar{\\hbox {b}}$$ b b ¯ .
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532960.V1
Abstract: Supplementary Figure 7: Characterization of Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl prostate tumors. Representative images of IHC to detect (A) PCNA and (B) Cleaved-caspase 3 (CC3) in Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl prostate tissue 2 weeks post-castration compared to uncastrated, age-matched controls (scale bar: 50 um, n = 3). Mice were castrated when prostate carcinoma was prevalent Pik3ca+/HR = 400 d old, Ptenfl/fl = 200 d old and Pik3ca+/HR Ptenfl/fl =100 d old. Quantitative RT-PCR to detect (C) Nkx3.1 and (D) Pbsn mRNA in Wt prostate and Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl stage-matched prostate carcinomas (n = 5). Error bars: SEM, *P .05 compared to Wt, or as indicated, one-way ANOVA with Tukey's multiple comparison test. (E) Western Blotting of protein lysates isolated from Wt prostate and stage-matched Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl prostate carcinomas to detect total AKT, p-AKT Thr308 and p-AKT Ser473 (n = 3).
Publisher: American Physical Society (APS)
Date: 12-08-2020
Publisher: American Physical Society (APS)
Date: 20-08-2021
Publisher: Elsevier BV
Date: 03-2019
Publisher: Springer Science and Business Media LLC
Date: 05-2021
Abstract: We present the first study of charged-hadron production associated with jets originating from b quarks in proton-proton collisions at a center-of-mass energy of 5.02 TeV. The data s le used in this study was collected with the CMS detector at the CERN LHC and corresponds to an integrated luminosity of 27.4 pb − 1 . To characterize the jet substructure, the differential jet shapes, defined as the normalized transverse momentum distribution of charged hadrons as a function of angular distance from the jet axis, are measured for b jets. In addition to the jet shapes, the per-jet yields of charged particles associated with b jets are also quantified, again as a function of the angular distance with respect to the jet axis. Extracted jet shape and particle yield distributions for b jets are compared with results for inclusive jets, as well as with the predictions from the pythia and herwig++ event generators.
Publisher: American Physical Society (APS)
Date: 23-02-2022
Publisher: Royal Society of Chemistry (RSC)
Date: 1999
DOI: 10.1039/A809571J
Publisher: American Physical Society (APS)
Date: 19-08-2020
Publisher: Springer Science and Business Media LLC
Date: 06-12-2010
DOI: 10.1038/ONC.2010.538
Abstract: Disruption of the breast cancer susceptibility gene Brca1 results in defective lobular-alveolar development in the mammary gland and a predisposition to breast tumourigenesis in humans and in mice. Recent evidence suggests that BRCA1 loss in humans is associated with an expansion of the luminal progenitor cell compartment in the normal breast and tumours with a luminal progenitor-like expression profile. To further investigate the role of BRCA1 in the mammary gland, we examined the consequences of Brca1 loss in mouse mammary epithelial cells in vitro and in vivo. Here, we show that Brca1 loss is associated with defective morphogenesis of SCp2 and HC11 mouse mammary epithelial cell lines and that in the MMTV-Cre Brca1(Co/Co) mouse model of Brca1 loss, there is an accumulation of luminal progenitor (CD61(+)CD29(lo)CD24(+)) cells during pregnancy. By day 1 of lactation, there are marked differences in the expression of 1379 genes, with most significantly altered pathways and networks, including lactation, the immune response and cancer. One of the most differentially expressed genes was the luminal progenitor marker, c-kit. Immunohistochemical analysis revealed that the increase in c-kit levels is associated with an increase in c-kit positivity. Interestingly, an inverse association between Brca1 and c-kit expression was also observed during mammary epithelial differentiation, and small interfering RNA-mediated knockdown of Brca1 resulted in a significant increase in c-kit mRNA levels. We found no evidence that c-kit plays a direct role in regulating differentiation of HC11 cells, suggesting that Brca1-mediated induction of c-kit probably contributes to Brca1-associated tumourigenesis via another cellular process, and that c-kit is likely to be a marker rather than a mediator of defective lobular-alveolar development resulting from Brca1 loss.
Publisher: American Physical Society (APS)
Date: 07-12-2020
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854346.V1
Abstract: The IL-3R dodecamer activates STAT1 to induce cell differentiation.
Publisher: Springer Science and Business Media LLC
Date: 11-2021
Abstract: A search for a heavy Higgs boson H decaying into the observed Higgs boson h with a mass of 125 GeV and another Higgs boson h S is presented. The h and h S bosons are required to decay into a pair of tau leptons and a pair of b quarks, respectively. The search uses a s le of proton-proton collisions collected with the CMS detector at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 137 fb −1 . Mass ranges of 240–3000 GeV for m H and 60–2800 GeV for $$ {m}_{{\\mathrm{h}}_{\\mathrm{S}}} $$ m h S are explored in the search. No signal has been observed. Model independent 95% confidence level upper limits on the product of the production cross section and the branching fractions of the signal process are set with a sensitivity ranging from 125 fb (for m H = 240 GeV) to 2 . 7 fb (for m H = 1000 GeV). These limits are compared to maximally allowed products of the production cross section and the branching fractions of the signal process in the next-to-minimal supersymmetric extension of the standard model.
Publisher: Springer Science and Business Media LLC
Date: 08-04-2022
Abstract: A search for a heavy resonance decaying into a top quark and a W boson in proton-proton collisions at $$ \\sqrt{s} $$ s = 13 TeV is presented. The data analyzed were recorded with the CMS detector at the LHC and correspond to an integrated luminosity of 138 fb − 1 . The top quark is reconstructed as a single jet and the W boson, from its decay into an electron or muon and the corresponding neutrino. A top quark tagging technique based on jet clustering with a variable distance parameter and simultaneous jet grooming is used to identify jets from the collimated top quark decay. The results are interpreted in the context of two benchmark models, where the heavy resonance is either an excited bottom quark b ∗ or a vector-like quark B. A statistical combination with an earlier search by the CMS Collaboration in the all-hadronic final state is performed to place upper cross section limits on these two models. The new analysis extends the lower range of resonance mass probed from 1.4 down to 0.7 TeV. For left-handed, right-handed, and vector-like couplings, b ∗ masses up to 3.0, 3.0, and 3.2 TeV are excluded at 95% confidence level, respectively. The observed upper limits represent the most stringent constraints on the b ∗ model to date.
Publisher: Springer Science and Business Media LLC
Date: 08-04-2022
Abstract: A search is presented for a right-handed W boson (W R ) and a heavy neutrino (N), in a final state consisting of two same-flavor leptons (ee or μμ) and two quarks. The search is performed with the CMS experiment at the CERN LHC using a data s le of proton-proton collisions at a center-of-mass energy of 13 TeV corresponding to an integrated luminosity of 138 fb − 1 . The search covers two regions of phase space, one where the decay products of the heavy neutrino are merged into a single large-area jet, and one where the decay products are well separated. The expected signal is characterized by an excess in the invariant mass distribution of the final-state objects. No significant excess over the standard model background expectations is observed. The observations are interpreted as upper limits on the product of W R production cross sections and branching fractions assuming that couplings are identical to those of the standard model W boson. For N masses m N equal to half the W R mass $$ {m}_{{\\mathrm{W}}_{\\mathrm{R}}} $$ m W R ( m N = 0 . 2 TeV), $$ {m}_{{\\mathrm{W}}_{\\mathrm{R}}} $$ m W R is excluded at 95% confidence level up to 4.7 (4.8) and 5.0 (5.4) TeV for the electron and muon channels, respectively. This analysis provides the most stringent limits on the W R mass to date.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709852
Abstract: Data collection and refinement statistics for the IL-3R ternary complex crystal structure.
Publisher: American Physical Society (APS)
Date: 23-12-2021
Publisher: Elsevier BV
Date: 02-2022
Publisher: American Association for Cancer Research (AACR)
Date: 14-03-2013
DOI: 10.1158/1078-0432.CCR-12-3433
Abstract: Purpose: Ovarian cancer has the highest mortality rate of all the gynecologic malignancies and is responsible for approximately 140,000 deaths annually worldwide. Copy number lification is frequently associated with the activation of oncogenic drivers in this tumor type, but their cytogenetic complexity and heterogeneity has made it difficult to determine which gene(s) within an licon represent(s) the genuine oncogenic driver. We sought to identify licon targets by conducting a comprehensive functional analysis of genes located in the regions of lification in high-grade serous and endometrioid ovarian tumors. Experimental Design: High-throughput siRNA screening technology was used to systematically assess all genes within regions commonly lified in high-grade serous and endometrioid cancer. We describe the results from a boutique siRNA screen of 272 genes in a panel of 18 ovarian cell lines. Hits identified by the functional viability screen were further interrogated in primary tumor cohorts to determine the clinical outcomes associated with lification and gene overexpression. Results: We identified a number of genes as critical for cellular viability when lified, including URI1, PAK4, GAB2, and DYRK1B. Integration of primary tumor gene expression and outcome data provided further evidence for the therapeutic use of such genes, particularly URI1 and GAB2, which were significantly associated with survival in 2 independent tumor cohorts. Conclusion: By taking this integrative approach to target discovery, we have streamlined the translation of high-resolution genomic data into preclinical in vitro studies, resulting in the identification of a number of genes that may be specifically targeted for the treatment of advanced ovarian tumors. Clin Cancer Res 19(6) 1411–21. ©2013 AACR.
Publisher: Elsevier BV
Date: 09-2012
Publisher: Springer Science and Business Media LLC
Date: 04-2022
DOI: 10.1140/EPJC/S10052-022-10127-0
Abstract: A search for low-mass dilepton resonances in Higgs boson decays is conducted in the four-lepton final state. The decay is assumed to proceed via a pair of beyond the standard model particles, or one such particle and a $${\\mathrm{Z}}$$ Z boson. The search uses proton–proton collision data collected with the CMS detector at the CERN LHC, corresponding to an integrated luminosity of 137 $$\\,\\text {fb}^{-1}$$ fb - 1 , at a center-of-mass energy $$\\sqrt{s} = 13\\,\\text {TeV} $$ s = 13 TeV . No significant deviation from the standard model expectation is observed. Upper limits at 95% confidence level are set on model-independent Higgs boson decay branching fractions. Additionally, limits on dark photon and axion-like particle production, based on two specific models, are reported.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709858
Abstract: Increasing IL3Rα/βc ratios lead to hexameric receptor assembly and augmented quiescence.
Publisher: American Society of Hematology
Date: 30-03-2022
DOI: 10.1182/BLOODADVANCES.2021004571
Abstract: Current strategies to target RNA splicing mutant myeloid cancers proposes targeting the remaining splicing apparatus. This approach has only been modestly sensitizing and is also toxic to non-mutant-bearing wild-type cells. To explore potentially exploitable genetic interactions with spliceosome mutations, we combined data mining and functional screening for synthetic lethal interactions with an Srsf2P95H/+ mutation. Analysis of missplicing events in a series of both human and murine SRSF2P95H mutant s les across multiple myeloid diseases (acute myeloid leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia) was performed to identify conserved missplicing events. From this analysis, we identified that the cell-cycle and DNA repair pathways were overrepresented within the conserved misspliced transcript sets. In parallel, to functionally define pathways essential for survival and proliferation of Srsf2P95H/+ cells, we performed a genome-wide Clustered regularly interspaced short palindromic repeat loss-of-function screen using Hoxb8 immortalized R26-CreERki/+Srsf2P95H/+ and R26-CreERki/+Srsf2+/+ cell lines. We assessed loss of single guide RNA representation at 3 timepoints: immediately after Srsf2P95H/+ activation, and at 1 week and 2 weeks after Srsf2P95H/+ mutation. Pathway analysis demonstrated that the cell-cycle and DNA damage response pathways were among the top synthetic lethal pathways with Srsf2P95H/+ mutation. Based on the loss of guide RNAs targeting Cdk6, we identified that palbociclib, a CDK6 inhibitor, showed preferential sensitivity in Srsf2P95H/+ cell lines and in primary nonimmortalized lin−cKIT+Sca-1+ cells compared with wild-type controls. Our data strongly suggest that the cell-cycle and DNA damage response pathways are required for Srsf2P95H/+ cell survival, and that palbociclib could be an alternative therapeutic option for targeting SRSF2 mutant cancers.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22521237.V1
Abstract: Figure S2 shows APR-246 and PX-12 activity correlate in CTRPv2 and their impact on mutant-p53 thermostability.
Publisher: Springer Science and Business Media LLC
Date: 05-2013
Abstract: Differential cross sections for the Drell-Yan process, including Z boson production, using the dimuon decay channel are measured in proton-lead (pPb) collisions at a nucleon-nucleon centre-of-mass energy of 8.16 TeV. A data s le recorded with the CMS detector at the LHC is used, corresponding to an integrated luminosity of 173 nb − 1 . The differential cross section as a function of the dimuon mass is measured in the range 15–600 GeV, for the first time in proton-nucleus collisions. It is also reported as a function of dimuon rapidity over the mass ranges 15–60 GeV and 60–120 GeV, and ratios for the p-going over the Pb-going beam directions are built. In both mass ranges, the differential cross sections as functions of the dimuon transverse momentum p T and of a geometric variable ϕ * are measured, where ϕ * highly correlates with p T but is determined with higher precision. In the Z mass region, the rapidity dependence of the data indicate a modification of the distribution of partons within a lead nucleus as compared to the proton case. The data are more precise than predictions based upon current models of parton distributions.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709855
Abstract: Increasing IL3Rα/βc ratios and enforced hexamer signaling lead to reduced differentiation in in vivo engraftments.
Publisher: IOP Publishing
Date: 07-2021
DOI: 10.1088/1748-0221/16/07/P07001
Abstract: The muon trigger system of the CMS experiment uses a combination of hardware and software to identify events containing a muon. During Run 2 (covering 2015–2018) the LHC achieved instantaneous luminosities as high as 2 × 10 34 while delivering proton-proton collisions at √(s) = 13. The challenge for the trigger system of the CMS experiment is to reduce the registered event rate from about 40MHz to about 1kHz. Significant improvements important for the success of the CMS physics program have been made to the muon trigger system via improved muon reconstruction and identification algorithms since the end of Run 1 and throughout the Run 2 data-taking period. The new algorithms maintain the acceptance of the muon triggers at the same or even lower rate throughout the data-taking period despite the increasing number of additional proton-proton interactions in each LHC bunch crossing. In this paper, the algorithms used in 2015 and 2016 and their improvements throughout 2017 and 2018 are described. Measurements of the CMS muon trigger performance for this data-taking period are presented, including efficiencies, transverse momentum resolution, trigger rates, and the purity of the selected muon s le. This paper focuses on the single- and double-muon triggers with the lowest sustainable transverse momentum thresholds used by CMS. The efficiency is measured in a transverse momentum range from 8 to several hundred.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532972.V1
Abstract: Supplementary Figure 3: Characterization of Pik3ca-mutated and Pten-deleted prostate hyperplasia and carcinoma. (A) IHC to detect the apoptotic marker Cleaved-Caspase-3 (CC3) in Wt, Pik3ca+/HR and Ptenfl/fl mice at 400 d (scale bar: 50 um). (B) Quantitation of CC3-positive nuclei in Wt, Pik3ca+/HR and Ptenfl/fl prostate epithelium (n = 3, *P .05 compared to Wt, or as indicated, one-way ANOVA with Tukey's multiple comparison test, ns = not significant. Error bars: SEM). (C) IHC to detect CK5 and CK8 in Pik3ca+/HR and Ptenfl/fl carcinomas (representative images from 3 prostates per genotype, scale bar: 50 um). (D) Representative IHC images to detect PTEN, mTORC1 signaling components (p-AKT Thr308, p-RPS6 Ser235/236 and p-4E-BP1 Thr37/46) and mTORC2 substrates (p-AKT Ser473 and p-NDRG1 Thr346) in Pik3ca+/HR and Ptenfl/fl hyperplastic lesions (n = 3, scale bar: 50 um). IHC quantitation for (E) p-AKT Thr308, (F) p-RPS6 Ser235/236, (G) p-4E-BP1 Thr37/46, (H) p-AKT Ser473 and (I) p-NDRG1 Thr346 in Pik3ca+/HR and Ptenfl/fl prostate hyperplastic lesions (n = 3, Error bars: SEM, *P 0.05, unpaired, two-tailed t-test).
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709873.V1
Abstract: IL3Rα/βc transcript and protein expression ratio in AML patient s les.
Publisher: Springer Science and Business Media LLC
Date: 15-06-2022
Abstract: Results are presented from a search for charged-lepton flavor violating (CLFV) interactions in top quark production and decay in pp collisions at a center-of-mass energy of 13 TeV. The events are required to contain one oppositely charged electron-muon pair in the final state, along with at least one jet identified as originating from a bottom quark. The data correspond to an integrated luminosity of 138 fb − 1 , collected by the CMS experiment at the LHC. This analysis includes both the production (q → e μ t) and decay (t → e μ q) modes of the top quark through CLFV interactions, with q referring to a u or c quark. These interactions are parametrized using an effective field theory approach. With no significant excess over the standard model expectation, the results are interpreted in terms of vector-, scalar-, and tensor-like CLFV four-fermion effective interactions. Finally, observed exclusion limits are set at 95% confidence levels on the respective branching fractions of a top quark to an e μ pair and an up (charm) quark of 0 . 13 × 10 − 6 (1 . 31 × 10 − 6 ), 0 . 07 × 10 − 6 (0 . 89 × 10 − 6 ), and 0 . 25 × 10 − 6 (2 . 59 × 10 − 6 ) for vector, scalar, and tensor CLFV interactions, respectively.
Publisher: Springer Science and Business Media LLC
Date: 2006
DOI: 10.1038/NATURE04372
Abstract: The existence of mammary stem cells (MaSCs) has been postulated from evidence that the mammary gland can be regenerated by transplantation of epithelial fragments in mice. Interest in MaSCs has been further stimulated by their potential role in breast tumorigenesis. However, the identity and purification of MaSCs has proved elusive owing to the lack of defined markers. We isolated discrete populations of mouse mammary cells on the basis of cell-surface markers and identified a subpopulation (Lin-CD29hiCD24+) that is highly enriched for MaSCs by transplantation. Here we show that a single cell, marked with a LacZ transgene, can reconstitute a complete mammary gland in vivo. The transplanted cell contributed to both the luminal and myoepithelial lineages and generated functional lobuloalveolar units during pregnancy. The self-renewing capacity of these cells was demonstrated by serial transplantation of clonal outgrowths. In support of a potential role for MaSCs in breast cancer, the stem-cell-enriched subpopulation was expanded in premalignant mammary tissue from MMTV-wnt-1 mice and contained a higher number of MaSCs. Our data establish that single cells within the Lin-CD29hiCD24+ population are multipotent and self-renewing, properties that define them as MaSCs.
Publisher: Springer Science and Business Media LLC
Date: 04-2020
Publisher: Springer Science and Business Media LLC
Date: 05-2020
Publisher: Springer Science and Business Media LLC
Date: 05-2020
Publisher: American Physical Society (APS)
Date: 03-09-2020
Publisher: Oxford University Press (OUP)
Date: 16-11-2017
DOI: 10.1093/NAR/GKX1072
Publisher: Springer Science and Business Media LLC
Date: 08-2020
Abstract: A search for a light pseudoscalar Higgs boson (a) decaying from the 125 GeV (or a heavier) scalar Higgs boson (H) is performed using the 2016 LHC proton-proton collision data at $$ \\sqrt{s} $$ s = 13 TeV, corresponding to an integrated luminosity of 35 . 9 fb − 1 , collected by the CMS experiment. The analysis considers gluon fusion and vector boson fusion production of the H, followed by the decay H → aa → μμττ , and considers pseudoscalar masses in the range 3 . 6 m a 21 GeV. Because of the large mass difference between the H and the a bosons and the small masses of the a boson decay products, both the μμ and the ττ pairs have high Lorentz boost and are collimated. The ττ reconstruction efficiency is increased by modifying the standard technique for hadronic τ lepton decay reconstruction to account for a nearby muon. No significant signal is observed. Model-independent limits are set at 95% confidence level, as a function of m a , on the branching fraction (ℬ) for H → aa → μμττ , down to 1 . 5 (2 . 0) × 10 − 4 for m H = 125 (300) GeV. Model-dependent limits on ℬ(H → aa) are set within the context of two Higgs doublets plus singlet models, with the most stringent results obtained for Type-III models. These results extend current LHC searches for heavier a bosons that decay to resolved lepton pairs and provide the first such bounds for an H boson with a mass above 125 GeV.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854352.V1
Abstract: IL3Rα P248 at the IL-3R assembly interface is critical for cell differentiation.
Publisher: Springer Science and Business Media LLC
Date: 12-2020
Abstract: A search for standard model Higgs bosons (H) produced with transverse momentum ( p T ) greater than 450 GeV and decaying to bottom quark-antiquark pairs ( $$ \\mathrm{b}\\overline{\\mathrm{b}} $$ b b ¯ ) is performed using proton-proton collision data collected by the CMS experiment at the LHC at $$ \\sqrt{s} $$ s = 13 TeV. The data s le corresponds to an integrated luminosity of 137 fb − 1 . The search is inclusive in the Higgs boson production mode. Highly Lorentz-boosted Higgs bosons decaying to $$ \\mathrm{b}\\overline{\\mathrm{b}} $$ b b ¯ are reconstructed as single large-radius jets, and are identified using jet substructure and a dedicated b tagging technique based on a deep neural network. The method is validated with Z → $$ \\mathrm{b}\\overline{\\mathrm{b}} $$ b b ¯ decays. For a Higgs boson mass of 125 GeV, an excess of events above the background assuming no Higgs boson production is observed with a local significance of 2.5 standard deviations ( σ ), while the expectation is 0.7. The corresponding signal strength and local significance with respect to the standard model expectation are μ H = 3 . 7 ± 1 . 2(stat) $$ {}_{-0.7}^{+0.8} $$ − 0.7 + 0.8 (syst) $$ {}_{-0.5}^{+0.8} $$ − 0.5 + 0.8 (theo) and 1 . 9 σ . Additionally, an unfolded differential cross section as a function of Higgs boson p T for the gluon fusion production mode is presented, assuming the other production modes occur at the expected rates.
Publisher: Springer Science and Business Media LLC
Date: 09-2018
DOI: 10.1140/EPJC/S10052-018-6242-X
Abstract: A search is presented for physics beyond the standard model, based on measurements of dijet angular distributions in proton–proton collisions at $$\\sqrt{s}=13\\hbox {TeV}$$ s = 13 TeV . The data collected with the CMS detector at the LHC correspond to an integrated luminosity of 35.9 $$\\,\\text {fb}^{-1}$$ fb - 1 . The observed distributions, corrected to particle level, are found to be in agreement with predictions from perturbative quantum chromodynamics that include electroweak corrections. Constraints are placed on models containing quark contact interactions, extra spatial dimensions, quantum black holes, or dark matter, using the detector-level distributions. In a benchmark model where only left-handed quarks participate, contact interactions are excluded at the 95% confidence level up to a scale of 12.8 or 17.5TeV, for destructive or constructive interference, respectively. The most stringent lower limits to date are set on the ultraviolet cutoff in the Arkani–Hamed–Dimopoulos–Dvali model of extra dimensions. In the Giudice–Rattazzi–Wells convention, the cutoff scale is excluded up to 10.1TeV. The production of quantum black holes is excluded for masses below 5.9 and 8.2TeV, depending on the model. For the first time, lower limits between 2.0 and 4.6TeVare set on the mass of a dark matter mediator for (axial-)vector mediators, for the universal quark coupling $$g_{\\mathrm {\\mathrm {q}}} =1.0$$ g q = 1.0 .
Publisher: Springer Science and Business Media LLC
Date: 08-2021
DOI: 10.1140/EPJC/S10052-021-09348-6
Abstract: A search is presented for a heavy vector resonance decaying into a $${\\mathrm{Z}}_{\\mathrm{}}^{\\mathrm{}}$$ Z boson and the standard model Higgs boson, where the $${\\mathrm{Z}}_{\\mathrm{}}^{\\mathrm{}}$$ Z boson is identified through its leptonic decays to electrons, muons, or neutrinos, and the Higgs boson is identified through its hadronic decays. The search is performed in a Lorentz-boosted regime and is based on data collected from 2016 to 2018 at the CERN LHC, corresponding to an integrated luminosity of 137 $$\\,\\text {fb}^{-1}$$ fb - 1 . Upper limits are derived on the production of a narrow heavy resonance $${\\mathrm{{{\\mathrm{Z}}_{\\mathrm{}}^{\\mathrm{}}}}}_{\\mathrm{}}^{\\mathrm{\\prime }}$$ Z ′ , and a mass below 3.5 and 3.7 $$\\,\\text {Te}\\text {V}$$ Te is excluded at 95% confidence level in models where the heavy vector boson couples predominantly to fermions and to bosons, respectively. These are the most stringent limits placed on the Heavy Vector Triplet $${\\mathrm{{{\\mathrm{Z}}_{\\mathrm{}}^{\\mathrm{}}}}}_{\\mathrm{}}^{\\mathrm{\\prime }}$$ Z ′ model to date. If the heavy vector boson couples exclusively to standard model bosons, upper limits on the product of the cross section and branching fraction are set between 23 and 0.3 $$\\,\\text {fb}$$ fb for a $${\\mathrm{{{\\mathrm{Z}}_{\\mathrm{}}^{\\mathrm{}}}}}_{\\mathrm{}}^{\\mathrm{\\prime }}$$ Z ′ mass between 0.8 and 4.6 $$\\,\\text {Te}\\text {V}$$ Te , respectively. This is the first limit set on a heavy vector boson coupling exclusively to standard model bosons in its production and decay.
Publisher: Springer Science and Business Media LLC
Date: 2021
Abstract: Results are reported from a search for the lepton flavor violating decay τ → 3 μ in proton-proton collisions at $$ \\sqrt{\\mathrm{s}} $$ s = 13 TeV. The data s le corresponds to an integrated luminosity of 33.2 fb − 1 recorded by the CMS experiment at the LHC in 2016. The search exploits τ leptons produced in both W boson and heavy-flavor hadron decays. No significant excess above the expected background is observed. An upper limit on the branching fraction ℬ( τ → 3 μ ) of 8 . 0 × 10 − 8 at 90% confidence level is obtained, with an expected upper limit of 6 . 9 × 10 − 8 .
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532966.V1
Abstract: Supplementary Figure 5: Pik3caH1047R mutation and Pten-deletion synergize to promote prostate cancer by increasing mTORC1/2 signaling. Histograms displaying phenotype incidence for anterior (A) and ventral (B) prostate lobes at 56 and 100 days of age. (C) Representative IHC images of Pik3ca+/HR Ptenfl/fl prostate tumors at 100 d stained to detect CK8, CK5 and SMA (n = 3, scale bar: 50 um). (D) Bar chart displaying total prostate weight normalised to body weight for Wt (n = 7), Pik3ca+/HR (n = 8), Ptenfl/fl (n = 8) and Pik3ca+/HR Ptenfl/fl (n = 7) 100 d old mice. Error bars: SEM, *P .05 compared to Wt or as indicated, one-way ANOVA with Tukey's multiple comparison test. (E) Quantitation of the apoptotic marker Cleaved-Caspase-3 (CC3) positive nuclei and (F) representative IHC images of CC3 staining in Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl stage-matched invasive prostate carcinoma (scale bar: 50 um, n = 3, one-way ANOVA with Tukey's multiple comparison test. Error bars: SEM). (G) Representative IHC images of Pik3ca+/HR, Ptenfl/fl and Pik3ca+/HR Ptenfl/fl stage-matched invasive prostate carcinoma stained to detect p-AKT Thr308, p-RPS6 Ser235/236, p-4E-BP1 Thr37/46, p-AKT Ser473 and p-NDRG1 Thr346 (scale bar: 50 um). (H) Representative images of RNA in situ hybridisation (ISH) to detect positive (housekeeping gene PPIB, peptidylprolyl isomerase B) and negative (bacterial gene dapB) control probes to confirm RNA quality and the absence of background signal respectively (scale bar: 50 um, insert scale bar: 5 um).
Publisher: Springer Science and Business Media LLC
Date: 12-2020
Abstract: The dependence of inclusive jet production in proton-proton collisions with a center-of-mass energy of 13 TeV on the distance parameter R of the anti- k T algorithm is studied using data corresponding to integrated luminosities up to 35.9 fb − 1 collected by the CMS experiment in 2016. The ratios of the inclusive cross sections as functions of transverse momentum p T and rapidity y , for R in the range 0.1 to 1.2 to those using R = 0 . 4 are presented in the region 84 p T 1588 GeV and | y | 2 . 0. The results are compared to calculations at leading and next-to-leading order in the strong coupling constant using different parton shower models. The variation of the ratio of cross sections with R is well described by calculations including a parton shower model, but not by a leading-order quantum chromodynamics calculation including nonperturbative effects. The agreement between the data and the theoretical predictions for the ratios of cross sections is significantly improved when next-to-leading order calculations with nonperturbative effects are used.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709849.V1
Abstract: Summary of the key interactions in the IL-3R ternary complex in the IL-3R ternary complex crystal structure.
Publisher: Springer Science and Business Media LLC
Date: 11-04-2022
Abstract: A search for long-lived particles decaying into muon pairs is performed using proton-proton collisions at a center-of-mass energy of 13 TeV, collected by the CMS experiment at the LHC in 2017 and 2018, corresponding to an integrated luminosity of 101 fb − 1 . The data sets used in this search were collected with a dedicated dimuon trigger stream with low transverse momentum thresholds, recorded at high rate by retaining a reduced amount of information, in order to explore otherwise inaccessible phase space at low dimuon mass and nonzero displacement from the primary interaction vertex. No significant excess of events beyond the standard model expectation is found. Upper limits on branching fractions at 95% confidence level are set on a wide range of mass and lifetime hypotheses in beyond the standard model frameworks with the Higgs boson decaying into a pair of long-lived dark photons, or with a long-lived scalar resonance arising from a decay of a b hadron. The limits are the most stringent to date for substantial regions of the parameter space. These results can be also used to constrain models of displaced dimuons that are not explicitly considered in this paper.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854325.V1
Abstract: Summary of the key interactions in the IL-3R ternary complex in the IL-3R ternary complex crystal structure.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709855.V1
Abstract: Increasing IL3Rα/βc ratios and enforced hexamer signaling lead to reduced differentiation in in vivo engraftments.
Publisher: Springer Science and Business Media LLC
Date: 03-2021
Abstract: Measurements of the fiducial inclusive and differential production cross sections of the Higgs boson in proton-proton collisions at $$ \\sqrt{s} $$ s = 13 TeV are performed using events where the Higgs boson decays into a pair of W bosons that subsequently decay into a final state with an electron, a muon, and a pair of neutrinos. The analysis is based on data collected with the CMS detector at the LHC during 2016–2018, corresponding to an integrated luminosity of 137 fb − 1 . Production cross sections are measured as a function of the transverse momentum of the Higgs boson and the associated jet multiplicity. The Higgs boson signal is extracted and simultaneously unfolded to correct for selection efficiency and resolution effects using maximum-likelihood fits to the observed distributions in data. The integrated fiducial cross section is measured to be 86 . 5 ± 9 . 5 fb, consistent with the Standard Model expectation of 82 . 5 ± 4 . 2 fb. No significant deviation from the Standard Model expectations is observed in the differential measurements.
Publisher: IOP Publishing
Date: 28-02-2020
Publisher: American Physical Society (APS)
Date: 25-06-2021
Publisher: American Physical Society (APS)
Date: 25-06-2021
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22522815.V1
Abstract: Supplementary Methods, Figures, and Tables
Publisher: American Association for Cancer Research (AACR)
Date: 31-05-2018
DOI: 10.1158/2159-8290.CD-17-0867
Abstract: Genetic alterations that potentiate PI3K signaling are frequent in prostate cancer, yet how different genetic drivers of the PI3K cascade contribute to prostate cancer is unclear. Here, we report PIK3CA mutation/ lification correlates with poor survival of patients with prostate cancer. To interrogate the requirement of different PI3K genetic drivers in prostate cancer, we employed a genetic approach to mutate Pik3ca in mouse prostate epithelium. We show Pik3caH1047R mutation causes p110α-dependent invasive prostate carcinoma in vivo. Furthermore, we report that PIK3CA mutation and PTEN loss coexist in patients with prostate cancer and can cooperate in vivo to accelerate disease progression via AKT–mTORC1/2 hyperactivation. Contrasting single mutants that slowly acquire castration-resistant prostate cancer (CRPC), concomitant Pik3ca mutation and Pten loss caused de novo CRPC. Thus, Pik3ca mutation and Pten deletion are not functionally redundant. Our findings indicate that PIK3CA mutation is an attractive prognostic indicator for prostate cancer that may cooperate with PTEN loss to facilitate CRPC in patients. Significance: We show PIK3CA mutation correlates with poor prostate cancer prognosis and causes prostate cancer in mice. Moreover, PIK3CA mutation and PTEN loss coexist in prostate cancer and can cooperate in vivo to accelerate tumorigenesis and facilitate CRPC. Delineating this synergistic relationship may present new therapeutic rognostic approaches to overcome castration/PI3K–AKT–mTORC1/2 inhibitor resistance. Cancer Discov 8(6) 764–79. ©2018 AACR. See related commentary by Triscott and Rubin, p. 682. This article is highlighted in the In This Issue feature, p. 663
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709873
Abstract: IL3Rα/βc transcript and protein expression ratio in AML patient s les.
Publisher: American Physical Society (APS)
Date: 23-03-2022
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709870
Abstract: Key interactions between distinct residues in the IL-3R ternary complex crystal structure.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709861.V1
Abstract: Enrichment of the IL-3R hexamer versus dodecamer gene signature in primitive normal and leukemic stem cells.
Publisher: Elsevier BV
Date: 12-2022
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2015
DOI: 10.1158/1078-0432.CCR-14-3026
Abstract: Purpose: Osteosarcoma is the most common cancer of bone occurring mostly in teenagers. Despite rapid advances in our knowledge of the genetics and cell biology of osteosarcoma, significant improvements in patient survival have not been observed. The identification of effective therapeutics has been largely empirically based. The identification of new therapies and therapeutic targets are urgently needed to enable improved outcomes for osteosarcoma patients. Experimental Design: We have used genetically engineered murine models of human osteosarcoma in a systematic, genome-wide screen to identify new candidate therapeutic targets. We performed a genome-wide siRNA screen, with or without doxorubicin. In parallel, a screen of therapeutically relevant small molecules was conducted on primary murine– and primary human osteosarcoma–derived cell cultures. All results were validated across independent cell cultures and across human and mouse osteosarcoma. Results: The results from the genetic and chemical screens significantly overlapped, with a profound enrichment of pathways regulated by PI3K and mTOR pathways. Drugs that concurrently target both PI3K and mTOR were effective at inducing apoptosis in primary osteosarcoma cell cultures in vitro in both human and mouse osteosarcoma, whereas specific PI3K or mTOR inhibitors were not effective. The results were confirmed with siRNA and small molecule approaches. Rationale combinations of specific PI3K and mTOR inhibitors could recapitulate the effect on osteosarcoma cell cultures. Conclusions: The approaches described here have identified dual inhibition of the PI3K–mTOR pathway as a sensitive, druggable target in osteosarcoma, and provide rationale for translational studies with these agents. Clin Cancer Res 21(14) 3216–29. ©2015 AACR.
Publisher: Springer Science and Business Media LLC
Date: 10-2021
Abstract: Double-parton scattering is investigated using events with a Z boson and jets. The Z boson is reconstructed using only the dimuon channel. The measurements are performed with proton-proton collision data recorded by the CMS experiment at the LHC at $$ \sqrt{s} $$ s = 13 TeV, corresponding to an integrated luminosity of 35.9 fb − 1 collected in the year 2016. Differential cross sections of Z+ ≥ 1 jet and Z+ ≥ 2 jets are measured with transverse momentum of the jets above 20 GeV and pseudorapidity |η| 2 . 4. Several distributions with sensitivity to double-parton scattering effects are measured as functions of the angle and the transverse momentum imbalance between the Z boson and the jets. The measured distributions are compared with predictions from several event generators with different hadronization models and different parameter settings for multiparton interactions. The measured distributions show a dependence on the hadronization and multiparton interaction simulation parameters, and are important input for future improvements of the simulations.
Publisher: Springer Science and Business Media LLC
Date: 03-2022
Abstract: A search for long-lived particles (LLPs) produced in association with a Z boson is presented. The study is performed using data from proton-proton collisions with a center-of-mass energy of 13 TeV recorded by the CMS experiment during 2016–2018, corresponding to an integrated luminosity of 117 fb − 1 . The LLPs are assumed to decay to a pair of standard model quarks that are identified as displaced jets within the CMS tracker system. Triggers and selections based on Z boson decays to electron or muon pairs improve the sensitivity to light LLPs (down to 15 GeV). This search provides sensitivity to beyond the standard model scenarios which predict LLPs produced in association with a Z boson. In particular, the results are interpreted in the context of exotic decays of the Higgs boson to a pair of scalar LLPs (H → SS). The Higgs boson decay branching fraction is constrained to values less than 6% for proper decay lengths of 10–100 mm and for LLP masses between 40 and 55 GeV. In the case of low-mass ( ≈ 15 GeV) scalar particles that subsequently decay to a pair of b quarks, the search is sensitive to branching fractions $$ \\mathcal{B} $$ B (H → SS) 20% for proper decay lengths of 10–50 mm. The use of associated production with a Z boson increases the sensitivity to low-mass LLPs of this analysis with respect to gluon fusion searches. In the case of 15 GeV scalar LLPs, the improvement corresponds to a factor of 2 at a proper decay length of 30 mm.
Publisher: Springer Science and Business Media LLC
Date: 10-2021
Abstract: The cross section for W or Z boson production in association with two photons is measured in proton-proton collisions at a centre-of-mass energy of 13 TeV. The data set corresponds to an integrated luminosity of 137 fb − 1 collected by the CMS experiment at the LHC. The W → ℓν and Z → ℓℓ decay modes (where ℓ = e , μ ) are used to extract the W γγ and Z γγ cross sections in a phase space defined by electron (muon) with transverse momentum larger than 30 GeV and photon transverse momentum larger than 20 GeV. All leptons and photons are required to have absolute pseudorapidity smaller than 2.5. The measured cross sections in this phase space are σ (W γγ ) = $$ {13.6}_{-1.9}^{+1.9}{\\left(\\mathrm{stat}\\right)}_{-4.0}^{+4.0} $$ 13.6 − 1.9 + 1.9 stat − 4.0 + 4.0 (syst) ± 0 . 08 (PDF + scale) fb and σ (Z γγ ) = $$ {5.41}_{-0.55}^{+0.58}{\\left(\\mathrm{stat}\\right)}_{-.070}^{+0.64} $$ 5.41 − 0.55 + 0.58 stat − .070 + 0.64 (syst) ± 0 . 06 (PDF + scale) fb. Limits on anomalous quartic gauge couplings are set in the framework of an effective field theory with dimension-8 operators.
Publisher: MDPI AG
Date: 08-06-2023
DOI: 10.3390/BIOM13060965
Abstract: Endometriosis, defined as the growth of hormonally responsive endometrial-like tissue outside of the uterine cavity, is an estrogen-dependent, chronic, pro-inflammatory disease that affects up to 11.4% of women of reproductive age and gender- erse people with a uterus. At present, there is no long-term cure, and the identification of new therapies that provide a high level of efficacy and favourable long-term safety profiles with rapid clinical access are a priority. In this study, quantitative high-throughput compound screens of 3517 clinically approved compounds were performed on patient-derived immortalized human endometrial stromal cell lines. Following assay optimization and compound criteria selection, a high-throughput screening protocol was developed to enable the identification of compounds that interfered with estrogen-stimulated cell growth. From these screens, 23 novel compounds were identified, in addition to their molecular targets and in silico cell-signalling pathways, which included the neuroactive ligand–receptor interaction pathway, metabolic pathways, and cancer-associated pathways. This study demonstrates for the first time the feasibility of performing large compound screens for the identification of new translatable therapeutics and the improved characterization of endometriosis molecular pathophysiology. Further investigation of the molecular targets identified herein will help uncover new mechanisms involved in the establishment, symptomology, and progression of endometriosis.
Publisher: Springer Science and Business Media LLC
Date: 02-05-2012
Abstract: A search for new heavy resonances decaying to a pair of Higgs bosons (HH) in proton-proton collisions at a center-of-mass energy of 13 TeV is presented. Data were collected with the CMS detector at the LHC in 2016–2018, corresponding to an integrated luminosity of 138 fb − 1 . Resonances with a mass between 0.8 and 4.5 TeV are considered using events in which one Higgs boson decays into a bottom quark pair and the other into final states with either one or two charged leptons. Specifically, the single-lepton decay channel $$ \\mathrm{HH}\\to \\mathrm{b}\\overline{\\mathrm{b}}{\\mathrm{WW}}^{\\ast}\\to \\mathrm{b}\\overline{\\mathrm{b}}\\ell v\\mathrm{q}{\\overline{\\mathrm{q}}}^{\\prime } $$ HH → b b ¯ WW ∗ → b b ¯ ℓ v q q ¯ ′ and the dilepton decay channels $$ \\mathrm{HH}\\to \\mathrm{b}\\overline{\\mathrm{b}}{\\mathrm{WW}}^{\\ast}\\to \\mathrm{b}\\overline{\\mathrm{b}}\\ell v\\ell v $$ HH → b b ¯ WW ∗ → b b ¯ ℓ v ℓ v and $$ \\mathrm{HH}\\to \\mathrm{b}\\overline{\\mathrm{b}}\\uptau \\uptau \\to \\mathrm{b}\\overline{\\mathrm{b}}\\ell vv\\ell vv $$ HH → b b ¯ ττ → b b ¯ ℓ vv ℓ vv are examined, where ℓ in the final state corresponds to an electron or muon. The signal is extracted using a two-dimensional maximum likelihood fit of the $$ \\mathrm{H}\\to \\mathrm{b}\\overline{\\mathrm{b}} $$ H → b b ¯ jet mass and HH invariant mass distributions. No significant excess above the standard model expectation is observed in data. Model-independent exclusion limits are placed on the product of the cross section and branching fraction for narrow spin-0 and spin-2 massive bosons decaying to HH. The results are also interpreted in the context of radion and bulk graviton production in models with a warped extra spatial dimension. The results provide the most stringent limits to date for X → HH signatures with final-state leptons and at some masses provide the most sensitive limits of all X → HH searches.
Publisher: Springer Science and Business Media LLC
Date: 05-2021
Abstract: Measurements of the total and differential fiducial cross sections for the Z boson decaying into two neutrinos are presented at the LHC in proton-proton collisions at a center-of-mass energy of 13 TeV. The data were collected by the CMS detector in 2016 and correspond to an integrated luminosity of 35.9 fb − 1 . In these measurements, events are selected containing an imbalance in transverse momentum and one or more energetic jets. The fiducial differential cross section is measured as a function of the Z boson transverse momentum. The results are combined with a previous measurement of charged-lepton decays of the Z boson. The measured total fiducial cross section for events with Z boson transverse momentum greater than 200 GeV is $$ {3000}_{-170}^{+180} $$ 3000 − 170 + 180 fb.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709867.V1
Abstract: IL3Rα P248 at the IL-3R assembly interface is critical for cell differentiation.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.22532978.V1
Abstract: Supplementary Figure 1: PIK3CA mutations are predominantly missense mutations and PTEN mutation/loss predicts for poor prostate cancer patient survival. (A) Pie chart depicting the frequency of missense/nonsense mutations, in-frame deletions and fusion events in PIK3CA identified in the 9 prostate cancer genomic datasets assessed in Fig. 1A (3-10). (B) Kaplan-Meier plot comparing TCGA provisional prostate adenocarcinoma dataset with PTEN homozygous deletion, loss or mutation compared to the general population. PTEN age-adjusted COXPH HR: 0.47, P = 0.0026* (n = 492, s les with sequencing and CNA data only). Data was obtained from the TCGA data portal (tcga-data.nci.nih.gov/). PTEN copy number loss criteria Log R ratio {less than or equal to} -0.48, probe number {greater than or equal to} 10. Silent mutations were excluded.
Publisher: American Physical Society (APS)
Date: 30-07-2021
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709864
Abstract: The IL-3R dodecamer activates STAT1 to induce cell differentiation.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709861
Abstract: Enrichment of the IL-3R hexamer versus dodecamer gene signature in primitive normal and leukemic stem cells.
Publisher: Springer Science and Business Media LLC
Date: 05-2020
Publisher: Springer Science and Business Media LLC
Date: 20-10-2022
DOI: 10.1038/S41567-022-01682-0
Abstract: Since the discovery of the Higgs boson in 2012, detailed studies of its properties have been ongoing. Besides its mass, its width—related to its lifetime—is an important parameter. One way to determine this quantity is to measure its off-shell production, where the Higgs boson mass is far away from its nominal value, and relating it to its on-shell production, where the mass is close to the nominal value. Here we report evidence for such off-shell contributions to the production cross-section of two Z bosons with data from the CMS experiment at the CERN Large Hadron Collider. We constrain the total rate of the off-shell Higgs boson contribution beyond the Z boson pair production threshold, relative to its standard model expectation, to the interval [0.0061, 2.0] at the 95% confidence level. The scenario with no off-shell contribution is excluded at a p -value of 0.0003 (3.6 standard deviations). We measure the width of the Higgs boson as $${{{\\varGamma }}}_{{{{{{\\rm{H}}}}}}}={3.2}_{-1.7}^{+2.4}\\,{{{{{\\rm{MeV}}}}}}$$ Γ H = 3.2 − 1.7 + 2.4 MeV , in agreement with the standard model expectation of 4.1 MeV. In addition, we set constraints on anomalous Higgs boson couplings to W and Z boson pairs.
Publisher: Springer Science and Business Media LLC
Date: 04-2020
Publisher: Public Library of Science (PLoS)
Date: 24-03-2016
Publisher: American Association for Cancer Research (AACR)
Date: 06-2015
DOI: 10.1158/1535-7163.MCT-15-0039
Abstract: Identification of genomic alterations defining ovarian carcinoma subtypes may aid the stratification of patients to receive targeted therapies. We characterized high-grade serous ovarian carcinoma (HGSC) for the association of lified and overexpressed genes with clinical outcome using gene expression data from 499 HGSC patients in the Ovarian Tumor Tissue Analysis cohort for 11 copy number lified genes: ATP13A4, BMP8B, CACNA1C, CCNE1, DYRK1B, GAB2, PAK4, RAD21, TPX2, ZFP36, and URI. The Australian Ovarian Cancer Study and The Cancer Genome Atlas datasets were also used to assess the correlation between gene expression, patient survival, and tumor classification. In a multivariate analysis, high GAB2 expression was associated with improved overall and progression-free survival (P = 0.03 and 0.02), whereas high BMP8B and ATP13A4 were associated with improved progression-free survival (P = 0.004 and P = 0.02). GAB2 overexpression and copy number gain were enriched in the AOCS C4 subgroup. High GAB2 expression correlated with enhanced sensitivity in vitro to the dual PI3K/mTOR inhibitor PF-04691502 and could be used as a genomic marker for identifying patients who will respond to treatments inhibiting PI3K signaling. Mol Cancer Ther 14(6) 1495–503. ©2015 AACR.
Publisher: Springer Science and Business Media LLC
Date: 03-06-2022
Abstract: The first measurement of the CP structure of the Yukawa coupling between the Higgs boson and τ leptons is presented. The measurement is based on data collected in proton-proton collisions at $$ \\sqrt{s} $$ s = 13 TeV by the CMS detector at the LHC, corresponding to an integrated luminosity of 137 fb − 1 . The analysis uses the angular correlation between the decay planes of τ leptons produced in Higgs boson decays. The effective mixing angle between CP -even and CP -odd τ Yukawa couplings is found to be − 1 ± 19°, compared to an expected value of 0 ± 21° at the 68.3% confidence level. The data disfavour the pure CP -odd scenario at 3.0 standard deviations. The results are compatible with predictions for the standard model Higgs boson.
Publisher: Springer Science and Business Media LLC
Date: 10-2021
Abstract: A search for electroweak production of supersymmetric (SUSY) particles in final states with one lepton, a Higgs boson decaying to a pair of bottom quarks, and large missing transverse momentum is presented. The search uses data from proton-proton collisions at a center-of-mass energy of 13 TeV collected using the CMS detector at the LHC, corresponding to an integrated luminosity of 137 fb − 1 . The observed yields are consistent with backgrounds expected from the standard model. The results are interpreted in the context of a simplified SUSY model of chargino-neutralino production, with the chargino decaying to a W boson and the lightest SUSY particle (LSP) and the neutralino decaying to a Higgs boson and the LSP. Charginos and neutralinos with masses up to 820 GeV are excluded at 95% confidence level when the LSP mass is small, and LSPs with mass up to 350 GeV are excluded when the masses of the chargino and neutralino are approximately 700 GeV.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709867
Abstract: IL3Rα P248 at the IL-3R assembly interface is critical for cell differentiation.
Publisher: Springer Science and Business Media LLC
Date: 07-2020
Abstract: The momentum-weighted sum of the electric charges of particles inside a jet, known as jet charge, is sensitive to the electric charge of the particle initiating the parton shower. This paper presents jet charge distributions in $$ \\sqrt{s_{\\mathrm{NN}}} $$ s NN = 5 . 02 TeV lead-lead (PbPb) and proton-proton (pp) collisions recorded with the CMS detector at the LHC. These data correspond to integrated luminosities of 404 μ b − 1 and 27.4 pb − 1 for PbPb and pp collisions, respectively. Leveraging the sensitivity of the jet charge to fundamental differences in the electric charges of quarks and gluons, the jet charge distributions from simulated events are used as templates to extract the quark- and gluon-like jet fractions from data. The modification of these jet fractions is examined by comparing pp and PbPb data as a function of the overlap of the colliding Pb nuclei (centrality). This measurement tests the color charge dependence of jet energy loss due to interactions with the quark-gluon plasma. No significant modification between different centrality classes and with respect to pp results is observed in the extracted quark- and gluon-like jet fractions.
Publisher: Springer Science and Business Media LLC
Date: 07-2020
Abstract: The transverse energy ( $$ {E}_{\mathrm{T}}^{\upgamma} $$ E T γ ) spectra of photons isolated from other particles are measured using proton-proton (pp) and lead-lead (PbPb) collisions at the LHC at $$ \sqrt{s_{\mathrm{NN}}} $$ s NN = 5 . 02 TeV with integrated luminosities of 27.4 pb − 1 and 404 μ b − 1 for pp and PbPb data, respectively. The results are presented for photons with 25 $$ {E}_{\mathrm{T}}^{\upgamma} $$ E T γ 200 GeV in the pseudorapidity range |η| 1 . 44, and for different centrality intervals for PbPb collisions. Photon production in PbPb collisions is consistent with that in pp collisions scaled by the number of binary nucleon-nucleon collisions, demonstrating that photons do not interact with the quark-gluon plasma. Therefore, isolated photons can provide information about the initial energy of the associated parton in photon+jet measurements. The results are compared with predictions from the next-to-leading-order jetphox generator for different parton distribution functions (PDFs) and nuclear PDFs (nPDFs). The comparisons can help to constrain the nPDFs global fits.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22521234.V1
Abstract: Figure S3 shows extended correlation analysis in haematopoietic and lymphoid, breast and lung cancer cell lines
Publisher: Springer Science and Business Media LLC
Date: 14-04-2022
Abstract: A search has been performed for heavy resonances decaying to ZZ or ZW and for axion-like particles (ALPs) mediating nonresonant ZZ or ZH production, in final states with two charged leptons ( ℓ = e , μ) produced by the decay of a Z boson, and two quarks produced by the decay of a Z, W, or Higgs boson H. The analysis is sensitive to resonances with masses in the range 450 to 2000 GeV. Two categories are defined corresponding to the merged or resolved reconstruction of the hadronically decaying boson. The search is based on data collected during 2016–2018 by the CMS experiment at the LHC in proton-proton collisions at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 138 fb − 1 . No significant excess is observed in the data above the standard model background expectation. Upper limits on the production cross section of heavy, narrow spin-2 and spin-1 resonances are derived as functions of the resonance mass, and exclusion limits on the production of bulk graviton particles and W′ bosons are calculated in the framework of the warped extra dimensions and heavy vector triplet models, respectively. In addition, upper limits on the ALP-mediated diboson production cross section and ALP couplings to standard model particles are obtained in the framework of linear and chiral effective field theories. These are the first limits on nonresonant ALP-mediated ZZ and ZH production obtained by the LHC experiments.
Publisher: Springer Science and Business Media LLC
Date: 12-2021
Abstract: A search for a heavy resonance decaying to a top quark and a W boson in the fully hadronic final state is presented. The analysis is performed using data from proton-proton collisions at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 137 fb − 1 recorded by the CMS experiment at the LHC. The search is focused on heavy resonances, where the decay products of each top quark or W boson are expected to be reconstructed as a single, large-radius jet with a distinct substructure. The production of an excited bottom quark, b * , is used as a benchmark when setting limits on the cross section for a heavy resonance decaying to a top quark and a W boson. The hypotheses of b * quarks with left-handed, right-handed, and vector-like chiralities are excluded at 95% confidence level for masses below 2.6, 2.8, and 3.1 TeV, respectively. These are the most stringent limits on the b * quark mass to date, extending the previous best limits by almost a factor of two.
Publisher: Elsevier BV
Date: 12-2020
Publisher: Mary Ann Liebert Inc
Date: 10-2016
DOI: 10.1089/ADT.2016.733
Abstract: Correct subcellular localization of proteins is a requirement for appropriate function. This is especially true in epithelial cells, which rely on the precise localization of a erse array of epithelial polarity and cellular adhesion proteins. Loss of cell polarity and adhesion is a hallmark of cancer, and mislocalization of core polarity proteins, such as Scribble, is observed in a range of human epithelial tumors and is prognostic of poor survival. Despite this, little is known about how Scribble membrane localization is regulated. Here, we describe the development and application of a phenotypic high-content screening assay that is designed to specifically quantify membrane levels of Scribble to identify regulators of its membrane localization. A screening platform that is capable of resolving in idual cells and quantifying membrane protein localization in confluent epithelial monolayers was developed by using the cytoplasm-to-cell-membrane bioapplication integrated with the Cellomics ArrayScan high-content imaging platform. Application of this method to a boutique human epithelial polarity and signaling small interfering RNA (siRNA) library resulted in highly robust coefficient-of-variance and Z' factor values. As proof of concept, we present two candidate genes whose depletion specifically reduces Scribble protein levels at the membrane. Data mining revealed that these proteins interact with components of the Scribble polarity complex, providing support for the utility of the screening approach. This method is broadly applicable to genome-wide and large-scale compound screening of membrane-bound proteins, and when coupled with pathway analysis the dataset becomes even more valuable and can provide predictive mechanistic insight.
Publisher: Elsevier BV
Date: 07-2020
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22521228.V1
Abstract: Figure S5 shows MYC directly regulates SLC7A11 levels and APR-246 sensitivity.
Publisher: Elsevier BV
Date: 07-2000
Publisher: Springer Science and Business Media LLC
Date: 08-2020
Abstract: The combination of measurements of the W boson polarization in top quark decays performed by the ATLAS and CMS collaborations is presented. The measurements are based on proton-proton collision data produced at the LHC at a centre-of-mass energy of 8 TeV, and corresponding to an integrated luminosity of about 20 fb − 1 for each experiment. The measurements used events containing one lepton and having different jet multiplicities in the final state. The results are quoted as fractions of W bosons with longitudinal ( F 0 ), left-handed ( F L ), or right-handed ( F R ) polarizations. The resulting combined measurements of the polarization fractions are F 0 = 0 . 693 ± 0 . 014 and F L = 0 . 315 ± 0 . 011. The fraction F R is calculated from the unitarity constraint to be F R = − 0 . 008 ± 0 . 007. These results are in agreement with the standard model predictions at next-to-next-to-leading order in perturbative quantum chromodynamics and represent an improvement in precision of 25 (29)% for F 0 ( F L ) with respect to the most precise single measurement. A limit on anomalous right-handed vector ( V R ), and left- and right-handed tensor ( g L , g R ) tWb couplings is set while fixing all others to their standard model values. The allowed regions are [ − 0 . 11 , 0 . 16] for V R , [ − 0 . 08 , 0 . 05] for g L , and [ − 0 . 04 , 0 . 02] for g R , at 95% confidence level. Limits on the corresponding Wilson coefficients are also derived.
Publisher: Wiley
Date: 15-09-2020
DOI: 10.1002/PATH.5528
Publisher: Mary Ann Liebert Inc
Date: 09-2016
DOI: 10.1089/ADT.2016.739
Abstract: Hyperactivation of the PI3K/AKT/mTORC1 signaling pathway is a hallmark of the majority of sporadic human cancers. Paradoxically, chronic activation of this pathway in nontransformed cells promotes senescence, which acts as a significant barrier to malignant progression. Understanding how this oncogene-induced senescence is maintained in nontransformed cells and conversely how it is subverted in cancer cells will provide insight into cancer development and potentially identify novel therapeutic targets. High-throughput screening provides a powerful platform for target discovery. Here, we describe an approach to use RNAi transfection of a pre-established AKT-induced senescent cell population and subsequent high-content imaging to screen for senescence regulators. We have incorporated multiparametric readouts, including cell number, proliferation, and senescence-associated beta-galactosidase (SA-βGal) staining. Using machine learning and automated image analysis, we also describe methods to classify distinct phenotypes of cells with SA-βGal staining. These methods can be readily adaptable to high-throughput functional screens interrogating the mechanisms that maintain and prevent senescence in various contexts.
Publisher: Massachusetts Medical Society
Date: 27-07-2000
Publisher: American Physical Society (APS)
Date: 19-01-2022
Publisher: Elsevier BV
Date: 03-2022
Publisher: IOP Publishing
Date: 08-02-2021
Publisher: Springer Science and Business Media LLC
Date: 03-2022
Abstract: The cross sections for inclusive and Mueller-Navelet dijet production are measured as a function of the rapidity separation between the jets in proton-proton collisions at $$ \sqrt{s} $$ s = 2 . 76 TeV for jets with transverse momentum p T 35 GeV and rapidity | y | 4 . 7. Various dijet production cross section ratios are also measured. A veto on additional jets with p T 20 GeV is introduced to improve the sensitivity to the effects of the Balitsky-Fadin-Kuraev-Lipatov (BFKL) evolution. The measurement is compared with the predictions of various Monte Carlo models based on leading-order and next-to-leading-order calculations including the Dokshitzer-Gribov-Lipatov-Altarelli-Parisi leading-logarithm (LL) parton shower as well as the LL BFKL resummation.
Publisher: Elsevier BV
Date: 2021
Publisher: American Physical Society (APS)
Date: 17-09-2021
Publisher: Springer Science and Business Media LLC
Date: 14-04-2022
Abstract: A search for supersymmetry in events with two or three low-momentum leptons and missing transverse momentum is performed. The search uses proton-proton collisions at $$ \\sqrt{s} $$ s = 13 TeV collected in the three-year period 2016–2018 by the CMS experiment at the LHC and corresponding to an integrated luminosity of up to 137 fb − 1 . The data are found to be in agreement with expectations from standard model processes. The results are interpreted in terms of electroweakino and top squark pair production with a small mass difference between the produced supersymmetric particles and the lightest neutralino. For the electroweakino interpretation, two simplified models are used, a wino-bino model and a higgsino model. Exclusion limits at 95% confidence level are set on $$ {\\overset{\\sim }{\\upchi}}_2^0/{\\overset{\\sim }{\\upchi}}_1^{\\pm } $$ χ ~ 2 0 / χ ~ 1 ± masses up to 275 GeV for a mass difference of 10 GeV in the wino-bino case, and up to 205(150) GeV for a mass difference of 7.5 (3) GeV in the higgsino case. The results for the higgsino are further interpreted using a phenomenological minimal supersymmetric standard model, excluding the higgsino mass parameter μ up to 180 GeV with the bino mass parameter M 1 at 800 GeV. In the top squark interpretation, exclusion limits are set at top squark masses up to 540 GeV for four-body top squark decays and up to 480 GeV for chargino-mediated decays with a mass difference of 30 GeV.
Publisher: Springer Science and Business Media LLC
Date: 18-05-2018
DOI: 10.1038/S41598-018-26050-Y
Abstract: Docetaxel and cabazitaxel are taxane chemotherapy treatments for metastatic castration-resistant prostate cancer (CRPC). However, therapeutic resistance remains a major issue. MicroRNAs are short non-coding RNAs that can silence multiple genes, regulating several signalling pathways simultaneously. Therefore, synthetic microRNAs may have therapeutic potential in CRPC by regulating genes involved in taxane response and minimise compensatory mechanisms that cause taxane resistance. To identify microRNAs that can improve the efficacy of taxanes in CRPC, we performed a genome-wide screen of 1280 microRNAs in the CRPC cell lines PC3 and DU145 in combination with docetaxel or cabazitaxel treatment. Mimics of miR-217 and miR-181b-5p enhanced apoptosis significantly in PC3 cells in the presence of these taxanes. These mimics downregulated at least a thousand different transcripts, which were enriched for genes with cell proliferation and focal adhesion functions. In idual knockdown of a selection of 46 genes representing these transcripts resulted in toxic or taxane sensitisation effects, indicating that these genes may be mediating the effects of the microRNA mimics. A range of these genes are expressed in CRPC metastases, suggesting that these microRNA mimics may be functional in CRPC. With further development, these microRNA mimics may have therapeutic potential to improve taxane response in CRPC patients.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22521240
Abstract: Figure S1 shows TP53 mutation alone is not predictive of cancer cell response to PRIMA-1.
Publisher: Springer Science and Business Media LLC
Date: 24-01-2023
DOI: 10.1038/S41388-023-02594-W
Abstract: We have determined that expression of the pseudokinase NRBP1 positively associates with poor prognosis in triple negative breast cancer (TNBC) and is required for efficient migration, invasion and proliferation of TNBC cells in culture as well as growth of TNBC orthotopic xenografts and experimental metastasis. Application of BioID/MS profiling identified P-Rex1, a known guanine nucleotide exchange factor for Rac1, as a NRBP1 binding partner. Importantly, NRBP1 overexpression enhanced levels of GTP-bound Rac1 and Cdc42 in a P-Rex1-dependent manner, while NRBP1 knockdown reduced their activation. In addition, NRBP1 associated with P-Rex1, Rac1 and Cdc42, suggesting a scaffolding function for this pseudokinase. NRBP1-mediated promotion of cell migration and invasion was P-Rex1-dependent, while constitutively-active Rac1 rescued the effect of NRBP1 knockdown on cell proliferation and invasion. Generation of reactive oxygen species via a NRBP1/P-Rex1 pathway was implicated in these oncogenic roles of NRBP1. Overall, these findings define a new function for NRBP1 and a novel oncogenic signalling pathway in TNBC that may be amenable to therapeutic intervention.
Publisher: Springer Science and Business Media LLC
Date: 07-2020
Abstract: A search for charged Higgs bosons (H ± ) decaying into a top and a bottom quark in the all-jet final state is presented. The analysis uses LHC proton-proton collision data recorded with the CMS detector in 2016 at $$ \\sqrt{s} $$ s = 13 TeV, corresponding to an integrated luminosity of 35.9 fb − 1 . No significant excess is observed above the expected background. Model-independent upper limits at 95% confidence level are set on the product of the H ± production cross section and branching fraction in two scenarios. For production in association with a top quark, limits of 21.3 to 0.007 pb are obtained for H ± masses in the range of 0.2 to 3 TeV. Combining this with a search in leptonic final states results in improved limits of 9.25 to 0.005 pb. The complementary s -channel production of an H ± is investigated in the mass range of 0.8 to 3 TeV and the corresponding upper limits are 4.5 to 0.023 pb. These results are interpreted using different minimal supersymmetric extensions of the standard model.
Publisher: Springer Science and Business Media LLC
Date: 07-2020
Abstract: Measurements of the cross section for the production of top quark pairs in association with a pair of jets from bottom quarks $$ \\left({\\sigma}_{\\mathrm{t}\\overline{\\mathrm{t}}\\mathrm{b}\\overline{\\mathrm{b}}}\\right) $$ σ t t ¯ b b ¯ and in association with a pair of jets from quarks of any flavor or gluons $$ \\left({\\sigma}_{\\mathrm{t}\\overline{\\mathrm{t}}\\mathrm{jj}}\\right) $$ σ t t ¯ jj and their ratio are presented. The data were collected in proton-proton collisions at a center-of-mass energy of 13 TeV by the CMS experiment at the LHC in 2016 and correspond to an integrated luminosity of 35.9 fb − 1 . The measurements are performed in a fiducial phase space and extrapolated to the full phase space, separately for the dilepton and lepton+jets channels, where lepton corresponds to either an electron or a muon. The results of the measurements in the fiducial phase space for the dilepton and lepton+jets channels, respectively, are $$ {\\sigma}_{\\mathrm{t}\\overline{\\mathrm{t}}\\mathrm{jj}} $$ σ t t ¯ jj = 2 . 36 ± 0 . 02 (stat) ± 0 . 20 (syst) pb and 31 . 0 ± 0 . 2 (stat) ± 2 . 9 (syst) pb, and for the cross section ratio 0 . 017 ± 0 . 001 (stat) ± 0 . 001 (syst) and 0 . 020 ± 0 . 001 (stat) ± 0 . 001 (syst). The values of $$ {\\sigma}_{\\mathrm{t}\\overline{\\mathrm{t}}\\mathrm{b}\\overline{\\mathrm{b}}} $$ σ t t ¯ b b ¯ are determined from the product of the $$ {\\sigma}_{\\mathrm{t}\\overline{\\mathrm{t}}\\mathrm{jj}} $$ σ t t ¯ jj and the cross section ratio, obtaining, respectively, 0 . 040 ± 0 . 002 (stat) ± 0 . 005 (syst) pb and 0 . 62 ± 0 . 03 (stat) ± 0 . 07 (syst) pb. These measurements are the most precise to date and are consistent, within the uncertainties, with the standard model expectations obtained using a matrix element calculation at next-to-leading order in quantum chromodynamics matched to a parton shower.
Publisher: Springer Science and Business Media LLC
Date: 03-2021
Abstract: A search for nonresonant production of Higgs boson pairs via gluon-gluon and vector boson fusion processes in final states with two bottom quarks and two photons is presented. The search uses data from proton-proton collisions at a center-of-mass energy of $$ \\sqrt{s} $$ s = 13 TeV recorded with the CMS detector at the LHC, corresponding to an integrated luminosity of 137 fb − 1 . No significant deviation from the background-only hypothesis is observed. An upper limit at 95% confidence level is set on the product of the Higgs boson pair production cross section and branching fraction into $$ \\gamma \\gamma \\mathrm{b}\\overline{\\mathrm{b}} $$ γγ b b ¯ . The observed (expected) upper limit is determined to be 0.67 (0 . 45) fb, which corresponds to 7.7 (5.2) times the standard model prediction. This search has the highest sensitivity to Higgs boson pair production to date. Assuming all other Higgs boson couplings are equal to their values in the standard model, the observed coupling modifiers of the trilinear Higgs boson self-coupling κ λ and the coupling between a pair of Higgs bosons and a pair of vector bosons c 2V are constrained within the ranges − 3 . 3 κ λ 8 . 5 and − 1 . 3 c 2V 3 . 5 at 95% confidence level. Constraints on κ λ are also set by combining this analysis with a search for single Higgs bosons decaying to two photons, produced in association with top quark-antiquark pairs, and by performing a simultaneous fit of κ λ and the top quark Yukawa coupling modifier κ t .
Publisher: Elsevier
Date: 2021
Publisher: Springer Science and Business Media LLC
Date: 03-2021
Abstract: A search is presented for a Higgs boson that is produced via vector boson fusion and that decays to an undetected particle and an isolated photon. The search is performed by the CMS collaboration at the LHC, using a data set corresponding to an integrated luminosity of 130 fb − 1 , recorded at a center-of-mass energy of 13 TeV in 2016–2018. No significant excess of events above the expectation from the standard model background is found. The results are interpreted in the context of a theoretical model in which the undetected particle is a massless dark photon. An upper limit is set on the product of the cross section for production via vector boson fusion and the branching fraction for such a Higgs boson decay, as a function of the Higgs boson mass. For a Higgs boson mass of 125 GeV, assuming the standard model production rates, the observed (expected) 95% confidence level upper limit on the branching fraction is 3.5 (2.8)%. This is the first search for such decays in the vector boson fusion channel. Combination with a previous search for Higgs bosons produced in association with a Z boson results in an observed (expected) upper limit on the branching fraction of 2.9 (2.1)% at 95% confidence level.
Publisher: Springer Science and Business Media LLC
Date: 14-05-2020
DOI: 10.1038/S41598-020-64868-7
Abstract: DNA inter-strand crosslinks (ICLs) threaten genomic stability by creating a physical barrier to DNA replication and transcription. ICLs can be caused by endogenous reactive metabolites or from chemotherapeutics. ICL repair in humans depends heavily on the Fanconi Anaemia (FA) pathway. A key signalling step of the FA pathway is the mono-ubiquitination of Fanconi Anaemia Complementation Group D2 (FANCD2), which is achieved by the multi-subunit E3 ligase complex. FANCD2 mono-ubiquitination leads to the recruitment of DNA repair proteins to the site of the ICL. The loss of FANCD2 mono-ubiquitination is a common clinical feature of FA patient cells. Therefore, molecules that restore FANCD2 mono-ubiquitination could lead to a potential drug for the management of FA. On the other hand, in some cancers, FANCD2 mono-ubiquitination has been shown to be essential for cell survival. Therefore, inhibition of FANCD2 mono-ubiquitination represents a possible therapeutic strategy for cancer specific killing. We transferred an 11-protein FANCD2 mono-ubiquitination assay to a high-throughput format. We screened 9,067 compounds for both activation and inhibition of the E3 ligase complex. The use of orthogonal assays revealed that candidate compounds acted via non-specific mechanisms. However, our high-throughput biochemical assays demonstrate the feasibility of using sophisticated and robust biochemistry to screen for small molecules that modulate a key step in the FA pathway. The future identification of FA pathway modulators is anticipated to guide future medicinal chemistry projects with drug leads for human disease.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22521234
Abstract: Figure S3 shows extended correlation analysis in haematopoietic and lymphoid, breast and lung cancer cell lines
Publisher: American Association for Cancer Research (AACR)
Date: 19-08-2021
DOI: 10.1158/1535-7163.MCT-20-0932
Abstract: Monotherapy with PARP inhibitors is effective for the subset of castrate-resistant prostate cancer (CRPC) with defects in homologous recombination (HR) DNA repair. New treatments are required for the remaining tumors, and an emerging strategy is to combine PARP inhibitors with other therapies that induce DNA damage. Here we tested whether PARP inhibitors are effective for HR-proficient CRPC, including androgen receptor (AR)-null tumors, when used in combination with CX-5461, a small molecule that inhibits RNA polymerase I transcription and activates the DNA damage response, and has antitumor activity in early phase I trials. The combination of CX-5461 and talazoparib significantly decreased in vivo growth of patient-derived xenografts of HR-proficient CRPC, including AR-positive, AR-null, and neuroendocrine tumors. CX-5461 and talazoparib synergistically inhibited the growth of organoids and cell lines, and significantly increased the levels of DNA damage. Decreased tumor growth after combination therapy was maintained for 2 weeks without treatment, significantly increasing host survival. Therefore, combination treatment with CX-5461 and talazoparib is effective for HR-proficient tumors that are not suitable for monotherapy with PARP inhibitors, including AR-null CRPC. This expands the spectrum of CRPC that is sensitive to PARP inhibition.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22521237
Abstract: Figure S2 shows APR-246 and PX-12 activity correlate in CTRPv2 and their impact on mutant-p53 thermostability.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22521231
Abstract: Figure S4 shows the effects of p53 overexpression and repression on SLC7A11 mRNA expression.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854331.V1
Abstract: Increasing IL3Rα/βc ratios and enforced hexamer signaling lead to reduced differentiation in in vivo engraftments.
Publisher: American Physical Society (APS)
Date: 10-10-2023
Publisher: American Physical Society (APS)
Date: 28-09-2021
Publisher: Elsevier BV
Date: 06-2022
Publisher: Springer Science and Business Media LLC
Date: 07-2019
Abstract: A search for heavy neutral leptons (HNLs), the right-handed Dirac or Majorana neutrinos, is performed in final states with three charged leptons (electrons or muons) using proton-proton collision data collected by the CMS experiment at $$ \\sqrt{s} $$ s = 13 TeV at the CERN LHC. The data correspond to an integrated luminosity of 138 fb − 1 . The HNLs could be produced through mixing with standard model neutrinos ν . For small values of the HNL mass ( 20 GeV) and the square of the HNL- ν mixing parameter (10 − 7 –10 − 2 ), the decay length of these particles can be large enough so that the secondary vertex of the HNL decay can be resolved with the CMS silicon tracker. The selected final state consists of one lepton emerging from the primary proton-proton collision vertex, and two leptons forming a displaced, secondary vertex. No significant deviations from the standard model expectations are observed, and constraints are obtained on the HNL mass and coupling strength parameters, excluding previously unexplored regions of parameter space in the mass range 1–20 GeV and squared mixing parameter values as low as 10 − 7 .
Publisher: Springer Science and Business Media LLC
Date: 29-06-2022
Abstract: The first collider search for dark matter arising from a strongly coupled hidden sector is presented and uses a data s le corresponding to 138 fb −1 , collected with the CMS detector at the CERN LHC, at $$ \\sqrt{s} $$ s = 13 TeV. The hidden sector is hypothesized to couple to the standard model (SM) via a heavy leptophobic Z′ mediator produced as a resonance in proton-proton collisions. The mediator decay results in two “semivisible” jets, containing both visible matter and invisible dark matter. The final state therefore includes moderate missing energy aligned with one of the jets, a signature ignored by most dark matter searches. No structure in the dijet transverse mass spectra compatible with the signal is observed. Assuming the Z′ boson has a universal coupling of 0.25 to the SM quarks, an inclusive search, relevant to any model that exhibits this kinematic behavior, excludes mediator masses of 1.5–4.0 TeV at 95% confidence level, depending on the other signal model parameters. To enhance the sensitivity of the search for this particular class of hidden sector models, a boosted decision tree (BDT) is trained using jet substructure variables to distinguish between semivisible jets and SM jets from background processes. When the BDT is employed to identify each jet in the dijet system as semivisible, the mediator mass exclusion increases to 5.1 TeV, for wider ranges of the other signal model parameters. These limits exclude a wide range of strongly coupled hidden sector models for the first time.
Location: United States of America
No related grants have been discovered for Sara Fiorendi.