DNA double strand breaks as predictor of efficacy of the alpha-particle emitter Ac-225 and the electron emitter Lu-177 for somatostatin receptor targeted radiotherapy

Key biologic effects of the alpha-particle emitter Actinium-225 in comparison to beta-particle emitter Lutetium-177 labeled somatostatin analogue DOTATOC in vitro and in vivo were studied to evaluate the significance of H2AX-foci formation and its downstream effects. To determine relative biological effectiveness (RBE) between the two isotopes somatostatin expressing AR42J cells were incubated with Ac-225-DOTATOC and Lu-177-DOTATOC up to 48 h and viability was analyzed using the MTT assay. DNA double strand breaks were quantified after immunofluorescence staining of H2AX. Cell cycle was analyzed by flow cytometry. In vivo, uptake of both radiolabeled somatostatin-analogues into subcutaneous AR42J tumors and number of cells displaying H2AX-foci were measured. Therapeutic efficacy was assayed by monitoring tumor growth after treatment with activities translated from in vitro cytotoxicity. Ac-225-DOTATOC was synthesized with specific activities between 0.2-0.4 MBq/µg and radiochemical purity of > 90%. ED50 values were 30 kBq/ml after 24 h and 14 kBq/ml after 48 h. Lu-177-DOTATOC displayed radiochemical purity of >95% and ED50 values of 10 MBq/ml after 48 h. Number of DNA double strand breaks increased with increasing concentration of Ac 225 DOTATOC and Lu-177-DOTATOC similarly, if a factor of approximately 700 of Lu-177 activities over Ac-225 activities was applied. Already 24 h after incubation with 2.5, 5, and 10 kBq/ml Ac 225 DOTATOC cell cycle studies showed an increment of the percentage of tumor cells in G2/M phase up to 60%. After 72 h an apoptotic subG1 peak was also detectable. Tumor uptake for both radio peptides at 48 h was identical with 7.5 %ID/g, though overall number of cells with H2AX-foci was higher for tumors treated with 48 kBq Actinium-225-DOTATOC than tumors treated with 30 MBq Lutetium-177-DOTATOC (35% vs. 21%). Tumors with a mean volume of 0.34 ml reached exponential tumor growth after 25 days (44 kBq Ac-225-DOTATOC), after 21 days (34 MBq Lu-177-DOTATOC) and after 5 days (control). Thus H2AX-foci displayed the key parameter after irradiation with similar downstream effects for beta and alpha irradiation.JRC.E.5-Nuclear chemistr

Search for the disappearance of muon antineutrinos in the NuMI neutrino beam

We report constraints on antineutrino oscillation parameters that were obtained by using the two MINOS detectors to measure the 7% muon antineutrino component of the NuMI neutrino beam. In the Far Detector, we select 130 events in the charged-current muon antineutrino sample, compared to a prediction of 136.4 ± 11.7(stat)^(+10.2)_(-8.9)(syst) events under the assumption │Δm^2│ = 2.32 X 10^(-3) eV^2, sin^2(2θ) = 1.0

Improved Search for Muon-Neutrino to Electron-Neutrino Oscillations in MINOS

We report the results of a search for ν_e appearance in a ν_μ beam in the MINOS long-baseline neutrino experiment. With an improved analysis and an increased exposure of 8.2×10^(20) protons on the NuMI target at Fermilab, we find 2sin^2(θ_(23))sin^2(2θ_(13))<0.12(0.20) at 90% confidence level for δ=0 and the normal (inverted) neutrino mass hierarchy, with a best-fit of 2sin^2(θ_(23))sin^2(2θ_(13))=0.041^(+0.047)_(-0.031)(0.079^(+0.071)_(-0.053). The θ_(13)= 0 hypothesis is disfavored by the MINOS data at the 89% confidence level

An improved measurement of muon antineutrino disappearance in MINOS

We report an improved measurement of muon anti-neutrino disappearance over a distance of 735km using the MINOS detectors and the Fermilab Main Injector neutrino beam in a muon anti-neutrino enhanced configuration. From a total exposure of 2.95e20 protons on target, of which 42% have not been previously analyzed, we make the most precise measurement of the anti-neutrino "atmospheric" delta-m squared = 2.62 +0.31/-0.28 (stat.) +/- 0.09 (syst.) and constrain the anti-neutrino atmospheric mixing angle >0.75 (90%CL). These values are in agreement with those measured for muon neutrinos, removing the tension reported previously.Comment: 5 pages, 4 figures. In submission to Phys.Rev.Let

Comparisons of annual modulations in MINOS with the event rate modulation in CoGeNT

The CoGeNT Collaboration has recently published results from a fifteen month data set which indicate an annual modulation in the event rate similar to what is expected from weakly interacting massive particle interactions. It has been suggested that the CoGeNT modulation may actually be caused by other annually modulating phenomena, specifically the flux of atmospheric muons underground or the radon level in the laboratory. We have compared the phase of the CoGeNT data modulation to that of the concurrent atmospheric muon and radon data collected by the MINOS experiment which occupies an adjacent experimental hall in the Soudan Underground Laboratory. The results presented are obtained by performing a shape-free χ^2 data-to-data comparison and from a simultaneous fit of the MINOS and CoGeNT data to phase-shifted sinusoidal functions. Both tests indicate that the phase of the CoGeNT modulation is inconsistent with the phases of the MINOS muon and radon modulations at the 3.0σ level

Combined analysis of νμ disappearance and νμ → νe appearance in MINOS using accelerator and atmospheric neutrinos

We report on a new analysis of neutrino oscillations in MINOS using the complete set of accelerator and atmospheric data. The analysis combines the νμ disappearance and νe appearance data using the three-flavor formalism. We measure |Δm^2 32| = [2.28–2.46] × 10−3 eV^2 (68% C.L.) and sin^2 θ23 = 0.35–0.65 (90% C.L.) in the normal hierarchy, and |Δm^2 32| = [2.32–2.53] × 10−3 eV^2 (68% C.L.) and sin^2 θ23 = 0.34–0.67 (90% C.L.) in the inverted hierarchy. The data also constrain δCP, the θ23 octant degeneracy and the mass hierarchy; we disfavor 36% (11%) of this three-parameter space at 68% (90%) C.L

Precision measurement of the speed of propagation of neutrinos using the MINOS detectors

We report a two-detector measurement of the propagation speed of neutrinos over a baseline of 734 km. The measurement was made with the NuMI beam at Fermilab between the near and far MINOS detectors. The fractional difference between the neutrino speed and the speed of light is determined to be (v/c-1) = (1.0±1.1) × 10^−6, consistent with relativistic neutrinos

Search for Sterile Neutrinos Mixing with Muon Neutrinos in MINOS

We report results of a search for oscillations involving a light sterile neutrino over distances of 1.04 and 735 km in a νμ-dominated beam with a peak energy of 3 GeV. The data, from an exposure of 10.56 × 10^20 protons on target, are analyzed using a phenomenological model with one sterile neutrino. We constrain the mixing parameters θ24 and Δm41^2 and set limits on parameters of the four-dimensional Pontecorvo-Maki- Nakagawa-Sakata matrix, |Uμ4|2 and |Uτ4|2, under the assumption that mixing between νe and νs is negligible (|Ue4|^2 = 0). No evidence for νμ → νs transitions is found and we set a world-leading limit on θ24 for values of Δm41^2 ≲ 1 eV^2