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The CUORE experiment is a ton-scale array of TeO 2 cryogenic bolometers located at the underground Laboratori Nazionali del Gran Sasso of Istituto Nazionale di Fisica Nucleare (INFN), in Italy. The CUORE detector consists of 988 crystals operated as source and detector at a base temperature of ∼ 10 mK. Such cryogenic temperature is reached and maintained by means of a custom built cryogen-free dilution cryostat, designed with the aim of minimizing the vibrational noise and the environmental radioactivity. The primary goal of CUORE is the search for neutrinoless double beta decay of 130 Te , but thanks to its large target mass and ultra-low background it is suitable for the study of other rare processes as well, such as the neutrinoless double beta decay of 128 Te . This tellurium isotope is an attractive candidate for the search of this process, due to its high natural isotopic abundance of 31.75%. The transition energy at (866.7 ± 0.7) keV lies in a highly populated region of the energy spectrum, dominated by the contribution of the two-neutrino double beta decay of 130 Te . As the first ton-scale infrastructure operating cryogenic TeO 2 bolometers in stable conditions, CUORE is able to achieve a factor > 10 higher sensitivity to the neutrinoless double beta decay of this isotope with respect to past direct experiments.

We report the measurement of the two-neutrino double-beta (2νββ) decay of ¹⁰⁰Mo to the ground state of ¹⁰⁰Ru using lithium molybdate (\\crystal) scintillating bolometers. The detectors were developed for the CUPID-Mo program and operated at the EDELWEISS-III low background facility in the Modane underground laboratory. From a total exposure of 42.235 kg×d, the half-life of ¹⁰⁰Mo is determined to be T_(1/2)^(2ν)=[7.12^(+0.18)_(-0.14) \\mathrm{(stat.)}{±}{0}.10 \\mathrm{(syst.)}{]}{×}10¹⁸ years. This is the most accurate determination of the 2νββ half-life of ¹⁰⁰Mo to date. We also confirm, with the statistical significance of >3σ, that the single-state dominance model of the 2νββ decay of ¹⁰⁰Mo is favored over the high-state dominance model.

CUORE is a cryogenic detector consisting of 988 TeO2 crystals, 750 g each, and will be operated at a temperature of ∼10 mK, to search for neutrinoless double beta decay (0νββ) of 130Te. The detector, in the final stages of construction at the Laboratori Nazionali del Gran Sasso (Italy), will start its operations in 2016. CUORE-0, its pilot experiment, has proven the feasibility of CUORE, demonstrating that the target background of 0.01 counts/keV/kg/y and the energy resolution of 5 keV are within reach. CUORE-0 also made the most precise measurement of the 2νββ decay. The expected sensitivity of CUORE to the 0νββ 130Te half-life is 9 ·1025y, for 5 years of data taking. Here, we report the most recent results of CUORE-0, their implications for CUORE, and the current status of the CUORE experiment.

The idea of model-based drug development championed by Lewis Sheiner, in which pharmacostatistical models of drug efficacy and safety are developed from preclinical and available clinical data, offers a quantitative approach to improving drug development and development decision-making. Examples are presented that support this paradigm. The first example describes a preclinical model of behavioral activity to predict potency and time-course of response in humans and assess the potential for differentiation between compounds. This example illustrates how modeling procedures expounded by Lewis Sheiner provided the means to differentiate potency and the lag time between drug exposure and response and allow for rapid decision making and dose selection. The second example involves planning a Phase 2a dose-ranging and proof of concept trial in Alzheimer's disease (AD). The issue was how to proceed with the study and what criteria to use for a go/no go decision. The combined knowledge of AD disease progression, and preclinical and clinical information about the drug were used to simulate various clinical trial scenarios to identify an efficient and effective Phase 2 study. A design was selected and carried out resulting in a number of important learning experiences as well as extensive financial savings. The motivation for this case in point was the \"Learn-Confirm\" paradigm described by Lewis Sheiner. The final example describes the use of Pharmacokinetic and Pharmacodynamic (PK/PD) modeling and simulation to confirm efficacy across doses. In the New Drug Application for gabapentin, data from two adequate and well-controlled clinical trials was submitted to the Food and Drug Administration (FDA) in support of the approval of the indication for the treatment of post-herpetic neuralgia. The clinical trial data was not replicated for each of the sought dose levels in the drug application presenting a regulatory dilemma. Exposure response analysis submitted in the New Drug Application was applied to confirm the evidence of efficacy across these dose levels. Modeling and simulation analyses showed that the two studies corroborate each other with respect to the pain relief profiles. The use of PK/PD information confirmed evidence of efficacy across the three studied doses, eliminating the need for additional clinical trials and thus supporting the approval of the product. It can be speculated that the work by Lewis Sheiner reflected in the FDA document titled \"Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products\" made this scientific approach to the drug approval process possible.