Computational approaches for modeling human intestinal absorption and permeability

Human intestinal absorption (HIA) is an important roadblock in the formulation of new drug substances. Computational models are needed for the rapid estimation of this property. The measurements are determined via in vivo experiments or in vitro permeability studies. We present several computational models that are able to predict the absorption of drugs by the human intestine and the permeability through human Caco-2 cells. The training and prediction sets were derived from literature sources and carefully examined to eliminate compounds that are actively transported. We compare our results to models derived by other methods and find that the statistical quality is similar. We believe that models derived from both sources of experimental data would provide greater consistency in predictions. The performance of several QSPR models that we investigated to predict outside the training set for either experimental property clearly indicates that caution should be exercised while applying any of the models for quantitative predictions. However, we are able to show that the qualitative predictions can be obtained with close to a 70% success rate

A Long Baseline Neutrino Oscillation Experiment Using J-PARC Neutrino Beam and Hyper-Kamiokande

Document submitted to 18th J-PARC PAC meeting in May 2014. 50 pages, 41 figuresDocument submitted to 18th J-PARC PAC meeting in May 2014. 50 pages, 41 figuresDocument submitted to 18th J-PARC PAC meeting in May 2014. 50 pages, 41 figuresHyper-Kamiokande will be a next generation underground water Cherenkov detector with a total (fiducial) mass of 0.99 (0.56) million metric tons, approximately 20 (25) times larger than that of Super-Kamiokande. One of the main goals of Hyper-Kamiokande is the study of $CP$ asymmetry in the lepton sector using accelerator neutrino and anti-neutrino beams. In this document, the physics potential of a long baseline neutrino experiment using the Hyper-Kamiokande detector and a neutrino beam from the J-PARC proton synchrotron is presented. The analysis has been updated from the previous Letter of Intent [K. Abe et al., arXiv:1109.3262 [hep-ex]], based on the experience gained from the ongoing T2K experiment. With a total exposure of 7.5 MW $\times$ 10$^7$ sec integrated proton beam power (corresponding to $1.56\times10^{22}$ protons on target with a 30 GeV proton beam) to a $2.5$-degree off-axis neutrino beam produced by the J-PARC proton synchrotron, it is expected that the $CP$ phase $\delta_{CP}$ can be determined to better than 19 degrees for all possible values of $\delta_{CP}$, and $CP$ violation can be established with a statistical significance of more than $3\,\sigma$ ($5\,\sigma$) for $76$ ($58$) of the $\delta_{CP}$ parameter space

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Photodynamic Therapy of Tumors Can Lead to Development of Systemic Antigen-Specific Immune Response

Background: The mechanism by which the immune system can effectively recognize and destroy tumors is dependent on recognition of tumor antigens. The molecular identity of a number of these antigens has recently been identified and several immunotherapies have explored them as targets. Photodynamic therapy (PDT) is an anti-cancer modality that uses a non-toxic photosensitizer and visible light to produce cytotoxic reactive oxygen species that destroy tumors. PDT has been shown to lead to local destruction of tumors as well as to induction of anti-tumor immune response. Methodology/Principal Findings: We used a pair of equally lethal BALB/c colon adenocarcinomas, CT26 wild-type (CT26WT) and CT26.CL25 that expressed a tumor antigen, β-galactosidase (β-gal), and we treated them with vascular PDT. All mice bearing antigen-positive, but not antigen-negative tumors were cured and resistant to rechallenge. T lymphocytes isolated from cured mice were able to specifically lyse antigen positive cells and recognize the epitope derived from beta-galactosidase antigen. PDT was capable of destroying distant, untreated, established, antigen-expressing tumors in 70% of the mice. The remaining 30% escaped destruction due to loss of expression of tumor antigen. The PDT anti-tumor effects were completely abrogated in the absence of the adaptive immune response. Conclusion: Understanding the role of antigen-expression in PDT immune response may allow application of PDT in metastatic as well as localized disease. To the best of our knowledge, this is the first time that PDT has been shown to lead to systemic, antigen- specific anti-tumor immunity.United States. National Cancer Institute (grant RO1CA/AI838801)United States. National Cancer Institute (grant R01AI050875

Measurement of double-differential muon neutrino charged-current interactions on C8 H8 without pions in the final state using the T2K off-axis beam

We report the measurement of muon neutrino charged-current interactions on carbon without pions in the final state at the T2K beam energy using 5.734×1020 protons on target. For the first time the measurement is reported as a flux-integrated, double-differential cross section in muon kinematic variables (cosθμ, pμ), without correcting for events where a pion is produced and then absorbed by final state interactions. Two analyses are performed with different selections, background evaluations and cross-section extraction methods to demonstrate the robustness of the results against biases due to model-dependent assumptions. The measurements compare favorably with recent models which include nucleon-nucleon correlations but, given the present precision, the measurement does not distinguish among the available models. The data also agree with Monte Carlo simulations which use effective parameters that are tuned to external data to describe the nuclear effects. The total cross section in the full phase space is σ=(0.417±0.047(syst)±0.005(stat))×10-38 cm2 nucleon-1 and the cross section integrated in the region of phase space with largest efficiency and best signal-over-background ratio (cosθμ>0.6 and pμ>200 MeV) is σ=(0.202±0.036(syst)±0.003(stat))×10-38 cm2 nucleon-1

Measurement of the muon neutrino inclusive charged-current cross section in the energy range of 1–3 GeV with the T2K INGRID detector

We report a measurement of the νμ-nucleus inclusive charged-current cross section (¼ σcc) on iron using data from the INGRID detector exposed to the J-PARC neutrino beam. The detector consists of 14 modules in total, which are spread over a range of off-axis angles from 0° to 1.1°. The variation in the neutrino energy spectrum as a function of the off-axis angle, combined with event topology information, is used to calculate this cross section as a function of neutrino energy. The cross section is measured to be σccð1.1 GeVÞ ¼ 1.10 0.15 ð10−38 cm2=nucleonÞ, σccð2.0 GeVÞ ¼ 2.07 0.27 ð10−38 cm2=nucleonÞ, and σccð3.3 GeVÞ ¼ 2.29 0.45 ð10−38 cm2=nucleonÞ, at energies of 1.1, 2.0, and 3.3 GeV, respectively. These results are consistent with the cross section calculated by the neutrino interaction generators currently used by T2K. More importantly, the method described here opens up a new way to determine the energy dependence of neutrino-nucleus cross sections

First measurement of the muon neutrino charged current single pion production cross section on water with the T2K near detector

The T2K off-axis near detector, ND280, is used to make the first differential cross section measurements of muon neutrino charged current single positive pion production on a water target at energies ∼0.8 GeV. The differential measurements are presented as a function of the muon and pion kinematics, in the restricted phase space defined by pπþ > 200 MeV=c, pμ > 200 MeV=c, cosðθπþ Þ > 0.3 and cosðθμÞ > 0.3. The total flux integrated νμ charged current single positive pion production cross section on water in the restricted phase space is measured to be hσiϕ ¼ 4.25 0.48ðstatÞ 1.56ðsystÞ × 10−40 cm2=nucleon. The total cross section is consistent with the NEUT prediction (5.03 × 10−40 cm2=nucleon) and 2σ lower than the GENIE prediction (7.68 × 10−40 cm2=nucleon). The differential cross sections are in good agreement with the NEUT generator. The GENIE simulation reproduces well the shapes of the distributions, but overestimates the overall cross section normalization

Measurement of Muon Antineutrino Oscillations with an Accelerator-Produced Off-Axis Beam.

T2K reports its first measurements of the parameters governing the disappearance of ν[over ¯]_{μ} in an off-axis beam due to flavor change induced by neutrino oscillations. The quasimonochromatic ν[over ¯]_{μ} beam, produced with a peak energy of 0.6 GeV at J-PARC, is observed at the far detector Super-Kamiokande, 295 km away, where the ν[over ¯]_{μ} survival probability is expected to be minimal. Using a data set corresponding to 4.01×10^{20} protons on target, 34 fully contained μ-like events were observed. The best-fit oscillation parameters are sin^{2}(θ[over ¯]_{23})=0.45 and |Δm[over ¯]_{32}^{2}|=2.51×10^{-3}  eV^{2} with 68% confidence intervals of 0.38-0.64 and 2.26-2.80×10^{-3}  eV^{2}, respectively. These results are in agreement with existing antineutrino parameter measurements and also with the ν_{μ} disappearance parameters measured by T2K

Measurement of the nu(mu) charged-current quasielastic cross section on carbon with the ND280 detector at T2K

This paper reports a measurement by the T2K experiment of the νμ charged current quasielastic (CCQE) cross section on a carbon target with the off-axis detector based on the observed distribution of muon momentum (pμ) and angle with respect to the incident neutrino beam (θμ). The flux-integrated CCQE cross section was measured to be ⟨σ⟩=(0.83±0.12)×10−38  cm2. The energy dependence of the CCQE cross section is also reported. The axial mass, MQEA, of the dipole axial form factor was extracted assuming the Smith-Moniz CCQE model with a relativistic Fermi gas nuclear model. Using the absolute (shape-only) pμ−cosθμ distribution, the effective MQEA parameter was measured to be 1.26+0.21−0.18  GeV/c2 (1.43+0.28−0.22  GeV/c2)