Human Disease-Drug Network Based on Genomic Expression Profiles

BACKGROUND: Drug repositioning offers the possibility of faster development times and reduced risks in drug discovery. With the rapid development of high-throughput technologies and ever-increasing accumulation of whole genome-level datasets, an increasing number of diseases and drugs can be comprehensively characterized by the changes they induce in gene expression, protein, metabolites and phenotypes. METHODOLOGY/PRINCIPAL FINDINGS: We performed a systematic, large-scale analysis of genomic expression profiles of human diseases and drugs to create a disease-drug network. A network of 170,027 significant interactions was extracted from the approximately 24.5 million comparisons between approximately 7,000 publicly available transcriptomic profiles. The network includes 645 disease-disease, 5,008 disease-drug, and 164,374 drug-drug relationships. At least 60% of the disease-disease pairs were in the same disease area as determined by the Medical Subject Headings (MeSH) disease classification tree. The remaining can drive a molecular level nosology by discovering relationships between seemingly unrelated diseases, such as a connection between bipolar disorder and hereditary spastic paraplegia, and a connection between actinic keratosis and cancer. Among the 5,008 disease-drug links, connections with negative scores suggest new indications for existing drugs, such as the use of some antimalaria drugs for Crohn's disease, and a variety of existing drugs for Huntington's disease; while the positive scoring connections can aid in drug side effect identification, such as tamoxifen's undesired carcinogenic property. From the approximately 37K drug-drug relationships, we discover relationships that aid in target and pathway deconvolution, such as 1) KCNMA1 as a potential molecular target of lobeline, and 2) both apoptotic DNA fragmentation and G2/M DNA damage checkpoint regulation as potential pathway targets of daunorubicin. CONCLUSIONS/SIGNIFICANCE: We have automatically generated thousands of disease and drug expression profiles using GEO datasets, and constructed a large scale disease-drug network for effective and efficient drug repositioning as well as drug target/pathway identification

Measurement of the Higgs boson width and evidence of its off-shell contributions to ZZ production

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 $\Gamma$$_H$=3.2$^{+2.4}_{−1.7}$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

Measurement of the Higgs boson width and evidence of its off-shell contributions to ZZ production

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 ΓH=3.2+2.4−1.7MeV, 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

Precision measurement of the W boson decay branching fractions in proton-proton collisions at ? s=13 TeV

The leptonic and inclusive hadronic decay branching fractions of the W boson are measured using proton-proton collision data collected at √ s = 13     TeV by the CMS experiment at the CERN LHC, corresponding to an integrated luminosity of 35.9     fb − 1 . Events characterized by the production of one or two W bosons are selected and categorized based on the multiplicity and flavor of reconstructed leptons, the number of jets, and the number of jets identified as originating from the hadronization of b quarks. A binned maximum likelihood estimate of the W boson branching fractions is performed simultaneously in each event category. The measured branching fractions of the W boson decaying into electron, muon, and tau lepton final states are ( 10.83 ± 0.10 ) % , ( 10.94 ± 0.08 ) % , and ( 10.77 ± 0.21 ) % , respectively, consistent with lepton flavor universality for the weak interaction. The average leptonic and inclusive hadronic decay branching fractions are estimated to be ( 10.89 ± 0.08 ) % and ( 67.32 ± 0.23 ) % , respectively. Based on the hadronic branching fraction, three standard model quantities are subsequently derived: the sum of squared elements in the first two rows of the Cabibbo–Kobayashi–Maskawa (CKM) matrix ∑ i j | V i j | 2 = 1.984 ± 0.021 , the CKM element | V c s | = 0.967 ± 0.011 , and the strong coupling constant at the W boson mass scale, α S ( m 2 W ) = 0.095 ± 0.033

Search for resonances decaying to three W bosons in the hadronic final state in proton-proton collisions at ps=13 TeV

A search for Kaluza-Klein excited vector boson resonances, W KK , decaying in cascade to three W bosons via a scalar radion R , W KK → W R → W W W , in a final state containing two or three massive jets is presented. The search is performed with √ s = 13     TeV proton-proton collision data collected by the CMS experiment at the CERN LHC during 2016–2018, corresponding to an integrated luminosity of 138     fb − 1 . Two final states are simultaneously probed, one where the two W bosons produced by the R decay are reconstructed as separate, large-radius, massive jets, and one where they are merged into a single large-radius jet. The observed data are in agreement with the standard model expectations. Limits are set on the product of the W KK resonance cross section and branching fraction to three W bosons in an extended warped extra-dimensional model and are the first of their kind at the LHC

Measurement of the Inclusive and Differential Higgs Boson Production Cross Sections in the Decay Mode to a Pair of τ Leptons in pp Collisions at s =13 TeV

Copyright © 2022 CERN, for the CMS Collaboration. Measurements of the inclusive and differential fiducial cross sections of the Higgs boson are presented, using the τ lepton decay channel. The differential cross sections are measured as functions of the Higgs boson transverse momentum, jet multiplicity, and transverse momentum of the leading jet in the event, if any. The analysis is performed using proton-proton collision data collected with the CMS detector at the LHC at a center-of-mass energy of 13 TeV and corresponding to an integrated luminosity of 138 fb−1. These are the first differential measurements of the Higgs boson cross section in the final state of two τ leptons. In final states with a large jet multiplicity or with a Lorentz-boosted Higgs boson, these measurements constitute a significant improvement over measurements performed in other final states.SCOAP3

Skin cancer prevention: recent evidence from randomized controlled trials

Despite the billions of health care dollars spent each year on treating skin cancer, there is a dearth of randomized controlled trials (RCTs) that have evaluated skin cancer prevention. RCTs published in the last 3 years that have directly assessed skin cancer prevention as their primary aim suggest that regular use of sunscreen is cost effective, but prolonged use of topical therapies such as tretinoin and 5-fluorouracil may not be. Sirolimus-based immunosuppression for secondary skin cancer prevention in long-term renal transplant recipients appears effective, but benefits may be offset by the adverse effects. Many RCTs using pre-invasive actinic keratoses (AKs) as endpoints are too small and/or too short to provide evidence on skin cancer prevention. Another stumbling block is the difficulty in reproducibly diagnosing and counting AKs in response to preventive agents. Longer term and better surveillance methods are urgently required to improve the quality of evidence from future RCTs

Measurement of the electroweak production of Z gamma and two jets in proton-proton collisions at root s=13 TeV and constraints on anomalous quartic gauge couplings

The first observation of the electroweak (EW) production of a Z boson, a photon, and two forward jets (Z gamma jj) in proton-proton collisions at a center-of-mass energy of 13 TeV is presented. A data set corresponding to an integrated luminosity of 137 fb(-1), collected by the CMS experiment at the LHC in 2016-2018 is used. The measured fiducial cross section for EW Z gamma jj is sigma(Ew )= 5.21 +/- 0.52(stat)+/- 0.56(syst) fb = 5.21 +/- 0.76 fb. Single-differential cross sections in photon, leading lepton, and leading jet transverse momenta, and double-differential cross sections in mjj and vertical bar Delta eta(jj)vertical bar are also measured. Exclusion limits on anomalous quartic gauge couplings are derived at 95% confidence level in terms of the effective field theory operators M-0 to M-5, M-7, T-0 to T-2, and T-5 to T-9.Peer reviewe