Objective

Using electronic health records (EHRs) and biomolecular data, we sought to discover drug pairs with synergistic repurposing potential. EHRs provide real-world treatment and outcome patterns, while complementary biomolecular data, including disease-specific gene expression and drug-protein interactions, provide mechanistic understanding.

Method

We applied Group Lasso INTERaction NETwork (glinternet), an overlap group lasso penalty on a logistic regression model, with pairwise interactions to identify variables and interacting drug pairs associated with reduced 5-year mortality using EHRs of 9945 breast cancer patients. We identified differentially expressed genes from 14 case-control human breast cancer gene expression datasets and integrated them with drug-protein networks. Drugs in the network were scored according to their association with breast cancer individually or in pairs. Lastly, we determined whether synergistic drug pairs found in the EHRs were enriched among synergistic drug pairs from gene-expression data using a method similar to gene set enrichment analysis.

Results

From EHRs, we discovered 3 drug-class pairs associated with lower mortality: anti-inflammatories and hormone antagonists, anti-inflammatories and lipid modifiers, and lipid modifiers and obstructive airway drugs. The first 2 pairs were also enriched among pairs discovered using gene expression data and are supported by molecular interactions in drug-protein networks and preclinical and epidemiologic evidence.

Conclusions

This is a proof-of-concept study demonstrating that a combination of complementary data sources, such as EHRs and gene expression, can corroborate discoveries and provide mechanistic insight into drug synergism for repurposing.

The Tokai to Kamioka (T2K) experiment studies neutrino oscillations using a beam of muon neutrinos produced by an accelerator. The neutrinos travel from J-PARC on the east coast of Japan and are detected 295 kilometers further away in the Super-Kamiokande detector. A complex of near detectors located 280 meters away from the neutrino production target is used to better characterize the neutrino beam and reduce systematic uncertainties. The experiment aims at measuring electronic neutrino appearance (νμ→νe oscillation) to measure the neutrino mixing angle θ13, and muon neutrino disappearance to measure the neutrino mixing angle θ23 and mass splitting |δm322|. We report here electron neutrino appearance results using three years of data, recorded until the 2012 summer, as well as muon neutrino disappearance results based on the data coming from the first two years of the experiment. © 2013 Elsevier B.V.

The T2K Collaboration reports a precision measurement of muon neutrino disappearance with an off-axis neutrino beam with a peak energy of 0.6 GeV. Near detector measurements are used to constrain the neutrino flux and cross section parameters. The Super-Kamiokande far detector, which is 295 km downstream of the neutrino production target, collected data corresponding to 3.01×10(20) protons on target. In the absence of neutrino oscillations, 205±17 (syst) events are expected to be detected while only 58 muon neutrino event candidates are observed. A fit to the neutrino rate and energy spectrum, assuming three neutrino flavors and normal mass hierarchy yields a best-fit mixing angle sin2(θ23)=0.514±0.082 and mass splitting |Δm(32)(2)|=2.44(-0.15)(+0.17)×10(-3) eV2/c4. Our result corresponds to the maximal oscillation disappearance probability.

The T2K Collaboration reports evidence for electron neutrino appearance at the atmospheric mass splitting, |Δm322|≈2.4×10-3 eV2. An excess of electron neutrino interactions over background is observed from a muon neutrino beam with a peak energy of 0.6 GeV at the Super-Kamiokande (SK) detector 295 km from the beam's origin. Signal and background predictions are constrained by data from near detectors located 280 m from the neutrino production target. We observe 11 electron neutrino candidate events at the SK detector when a background of 3.3±0.4(syst) events is expected. The background-only hypothesis is rejected with a p value of 0.0009 (3.1σ), and a fit assuming νμ→νe oscillations with sinâ¡22θ23=1, δCP=0 and |Δm322|=2.4×10-3 eV2 yields sinâ¡22θ13=0.088-0.039+0. 049(stat+syst). © 2013 American Physical Society.

Core-collapse supernovae are among the most magnificent events in the observable universe. They produce many of the chemical elements necessary for life to exist and their remnants -- neutron stars and black holes -- are interesting astrophysical objects in their own right. However, despite millennia of observations and almost a century of astrophysical study, the explosion mechanism of core-collapse supernovae is not yet well understood. Hyper-Kamiokande is a next-generation neutrino detector that will be able to observe the neutrino flux from the next galactic core-collapse supernova in unprecedented detail. We focus on the first 500 ms of the neutrino burst, corresponding to the accretion phase, and use a newly-developed, high-precision supernova event generator to simulate Hyper-Kamiokande's response to five different supernova models. We show that Hyper-Kamiokande will be able to distinguish between these models with high accuracy for a supernova at a distance of up to 100 kpc. Once the next galactic supernova happens, this ability will be a powerful tool for guiding simulations towards a precise reproduction of the explosion mechanism observed in nature.

We report measurements of the flux-integrated and + charged-current cross-sections on water and hydrocarbon targets using the T2K anti-neutrino beam with a mean beam energy of 0.86 GeV. The signal is defined as the (anti-)neutrino charged-current interaction with one induced and no detected charged pion or proton. These measurements are performed using a new WAGASCI module recently added to the T2K setup in combination with the INGRID Proton Module. The phase space of muons is restricted to the high-detection efficiency region, 400 and 30 , in the laboratory frame. An absence of pions and protons in the detectable phase spaces of 200, 70 and 600, 70 is required. In this paper, both the; cross-sections and +; cross-sections on water and hydrocarbon targets and their ratios are provided by using the D'Agostini unfolding method. The results of the integrated ; cross-section measurements over this phase space are ;\sigma{\rm H{2}O}=(1.082\pm0.068(\rm stat.) {+0.145}{-0.128}(\rm syst.)) \times 10 {-39}\,{\rm cm {2} / nucleon};, ;\sigma{\rm CH}=(1.096\pm0.054(\rm stat.) {+0.132}{-0.117}(\rm syst.)) \times 10 {-39}\,{\rm cm {2} / nucleon};, and ;\sigma{\rm H{2}O}/\sigma{\rm CH} = 0.987\pm0.078(\rm stat.) {+0.093}{-0.090}(\rm syst.);. The +; cross-section is ;\sigma{\rm H{2}O} = (1.155\pm0.064(\rm stat.) {+0.148}{-0.129}(\rm syst.)) \times 10 {-39}\,{\rm cm {2} / nucleon};, ;\sigma{\rm CH}=(1.159\pm0.049(\rm stat.) {+0.129}{-0.115}(\rm syst.)) \times 10 {-39}\,{\rm cm {2} / nucleon};, and ;\sigma{\rm H{2}O}/\sigma{\rm CH}=0.996\pm0.069(\rm stat.) {+0.083}{-0.078}(\rm syst.);.