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Mu2e at Fermilab will search for charged lepton flavor violation via thecoherent conversion process mu- N --> e- N with a sensitivity approximatelyfour orders of magnitude better than the current world's best limits for thisprocess. The experiment's sensitivity offers discovery potential over a widearray of new physics models and probes mass scales well beyond the reach of theLHC. We describe herein the conceptual design of the proposed Mu2e experiment.This document was created in partial fulfillment of the requirements necessaryto obtain DOE CD-1 approval, which was granted July 11, 2012.

Deterioration in glucose tolerance occurs rapidly in women with polycystic ovary syndrone (PCOS), suggesting that pancreatic beta-cell dysfunction may supervene early. To determine whether the compensatory insulin secretory response to an increase in insulin resistance induced by the glucocorticoid dexamethasone differs in women with PCOS and control subjects, we studied 10 PCOS and 6 control subjects with normal glucose tolerance. An oral glucose tolerance test (OGTT) and a graded glucose infusion protocol were performed at baseline and after subjects took 2.0 mg of dexamethasone orally. Basal (Phi(b)), static (Phi(s)), dynamic (Phi(d)), and global (Phi) indexes of beta-cell sensitivity to glucose were derived. Insulin sensitivity (S(i)) was calculated using the minimal model; a disposition index (DI) was calculated as the product of S(i) and Phi. PCOS and control subjects had nearly identical fasting and 2-h glucose levels at baseline. Phi(b) was higher, although not significantly so, in the PCOS subjects. The Phi(d), Phi(s), and Phi indexes were 28, 19, and 20% higher, respectively, in PCOS subjects. The DI was significantly lower in PCOS (30.01 +/- 5.33 vs. 59.24 +/- 7.59) at baseline. After dexamethasone, control subjects averaged a 9% increase (to 131 +/- 12 mg/dl) in 2-h glucose levels; women with PCOS had a significantly greater 26% increase to 155 +/- 6 mg/dl. The C-peptide-to-glucose ratios on OGTT increased by 44% in control subjects and by only 15% in PCOS subjects. The accelerated deterioration in glucose tolerance in PCOS may result, in part, from a relative attenuation in the response of the beta-cell to the demand placed on it by factors exacerbating insulin resistance.

Radioimmunotherapy offers an exciting new therapeutic modality for patients with relapsed non-Hodgkin's lymphoma; however, considerable debate exists regarding the optimal dose and administration schedule for radioimmunoconjugates. Myelosuppression has been the dose-limiting toxicity of most clinical trials employing radiolabeled antibodies, and this complication has generated both high-dose and low-dose treatment strategies. 'Low-dose' strategies are nonmyeloablative and rely upon repetitive infusions to effectively eradicate tumor masses. Trials incorporating low-dose radioimmunotherapy have documented high response rates, though the durability of these responses remains unclear. The most encouraging nonmyeloablative studies have documented objective responses in 70%-80% of patients, complete responses in 30%-50% of patients, minimal toxicity, and a median response duration of 12 months. In contrast, high-dose trials performed in conjunction with autologous hematopoietic stem cell transplantation have demonstrated objective responses in 95% of patients, complete responses in 85% of patients, with a progression-free survival of 62% and an overall survival of 93% with a median follow-up of two years. Toxicities are considerably higher than those reported with nonmyeloablative regimens, but are modest compared to conventional marrow transplant conditioning regimens incorporating total body irradiation (TBI). Ongoing trials integrating high-dose radioimmuotherapy with high-dose chemotherapy in an autologous transplantation setting are testing the hypothesis that targeted radiotherapy plus chemotherapy will provide increased efficacy and diminished toxicity as compared to nonspecific external beam TBI-containing regimens.

Radioimmunotherapy offers an exciting new therapeutic modality for patients with recurrent hematologic malignancies and solid tumors resistant to conventional chemotherapy. In this review, a brief overview of tumor radiobiology as well as various obstacles to treatment is presented. Early radiolabeled antibody trials documented myelosuppression as the dose-limiting toxicity. Ongoing trials in solid tumors and hematologic malignancies are testing the hypothesis that myeloablative doses of radiation in conjunction with hematopoietic stem cell rescue will improve long-term survival. For solid tumors, there are many barriers to achieving this goal. The most encouraging trials in metastatic breast cancer have documented significant symptomatic relief and a 50% partial response in patients. In contrast, trials involving hematologic malignancies have produced more impressive results. With a median follow-up of 33 months, 67% of patients with recurrent acute myelogenous leukemia or myelodysplasia treated with radiolabeled antibodies, total-body irradiation, and high-dose chemotherapy remain disease free. Alone, myeloablative doses of radioimmunotherapy have documented a 41% complete response in patients with Hodgkin's disease. Seattle trials with recurrent non-Hodgkin's lymphoma have demonstrated objective responses in 90% of patients, complete responses in 85% of patients, a progression-free survival of 62%, and an overall survival of 93% with a median follow-up of 2 years.