The chemogenetic technology DREADD (designer receptors exclusively activated by designer drugs) is widely used for remote manipulation of neuronal activity in freely moving animals. DREADD technology posits the use of "designer receptors," which are exclusively activated by the "designer drug" clozapine N-oxide (CNO). Nevertheless, the in vivo mechanism of action of CNO at DREADDs has never been confirmed. CNO does not enter the brain after systemic drug injections and shows low affinity for DREADDs. Clozapine, to which CNO rapidly converts in vivo, shows high DREADD affinity and potency. Upon systemic CNO injections, converted clozapine readily enters the brain and occupies central nervous system-expressed DREADDs, whereas systemic subthreshold clozapine injections induce preferential DREADD-mediated behaviors.

Highlights d Gut-to-brain propagation of pathologic a-synuclein via the vagus nerve causes PD d Dopamine neurons degenerate in the pathologic a-synuclein gut-to-brain model of PD d Gut injection of pathologic a-synuclein causes PD-like motor and non-motor symptoms d PD-like pathology and symptoms require endogenous a-synuclein

Autoimmune (lymphocytic) hypophysitis is a rare disease that should be considered in the differential diagnosis of any nonsecreting pituitary mass, especially when occurring during pregnancy or postpartum. We have analyzed 370 articles published from January 1962 to October 2004 and identified a total of 379 patients with primary lymphocytic hypophysitis. The present review synthesizes the clinical and research data reported in this body of scientific literature.

IMPORTANCE Complete metastatic ablation of oligometastatic prostate cancer may provide an alternative to early initiation of androgen deprivation therapy (ADT). OBJECTIVE To determine if stereotactic ablative radiotherapy (SABR) improves oncologic outcomes in men with oligometastatic prostate cancer. DESIGN, SETTING, AND PARTICIPANTS The Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer (ORIOLE) phase 2 randomized study accrued participants from 3 US radiation treatment facilities affiliated with a university hospital from May 2016 to March 2018 with a data cutoff date of May 20, 2019, for analysis. Of 80 men screened, 54 men with recurrent hormone-sensitive prostate cancer and 1 to 3 metastases detectable by conventional imaging who had not received ADT within 6 months of enrollment or 3 or more years total were randomized. INTERVENTIONS Patients were randomized in a 2:1 ratio to receive SABR or observation. MAIN OUTCOMES AND MEASURES The primary outcome was progression at 6 months by prostate-specific antigen level increase, progression detected by conventional imaging, symptomatic progression, ADT initiation for any reason, or death. Predefined secondary outcomes were toxic effects of SABR, local control at 6 months with SABR, progression-free survival, Brief Pain Inventory (Short Form)-measured quality of life, and concordance between conventional imaging and prostate-specific membrane antigen (PSMA)-targeted positron emission tomography in the identification of metastatic disease. RESULTS In the 54 men randomized, the median (range) age was 68 (61-70) years for patients allocated to SABR and 68 (64-76) years for those allocated to observation. Progression at 6 months occurred in 7 of 36 patients (19%) receiving SABR and 11 of 18 patients (61%) undergoing observation (P = .005). Treatment with SABR improved median progression-free survival (not reached vs 5.8 months; hazard ratio, 0.30; 95% CI, 0.11-0.81; P = .002). Total consolidation of PSMA radiotracer-avid disease decreased the risk of new lesions at 6 months (16% vs 63%; P = .006). No toxic effects of grade 3 or greater were observed. T-cell receptor sequencing identified significant increased clonotypic expansion following SABR and correlation between baseline clonality and progression with SABR only (0.082085 vs 0.026051; P = .03). CONCLUSIONS AND RELEVANCE Treatment with SABR for oligometastatic prostate cancer improved outcomes and was enhanced by total consolidation of disease identified by PSMA-targeted positron emission tomography. SABR induced a systemic immune response, and baseline immune phenotype and tumor mutation status may predict the benefit from SABR. These results underline the importance of prospective randomized investigation of the oligometastatic state with integrated imaging and biological correlates.

Amide proton transfer (APT) imaging is a type of chemical exchange-dependent saturation transfer (CEST) magnetic resonance imaging (MRI) in which amide protons of endogenous mobile proteins and peptides in tissue are detected. Initial studies have shown promising results for distinguishing tumor from surrounding brain in patients, but these data were hampered by magnetic field inhomogeneity and a low signal-to-noise ratio (SNR). Here a practical six-offset APT data acquisition scheme is presented that, together with a separately acquired CEST spectrum, can provide B 0 -inhomogeneity corrected human brain APT images of sufficient SNR within a clinically relevant time frame. Data from nine brain tumor patients at 3T shows that APT intensities were significantly higher in the tumor core, as assigned by gadolinium-enhancement, than in contralateral normal-appearing white matter ( Recent progress in the field of proteomics (1-3) has shown that the biological characteristics of human gliomas and other cancers are defined by numerous proteins, and that the pathologic distinctions between normal and malignant tissues can be identified at the level of protein expression. Using in vivo proton MRS, Howe et al. (4) showed that the MRS-detectable mobile macromolecular proton concentration is higher in human brain tumors than in normal white matter (WM), and increases with tumor grade. These advances have prompted much interest in visualizing the protein content of tumors in vivo in MRI.Chemical exchange-dependent saturation transfer (CEST) has recently emerged as a new contrast mechanism for MRI (5-7) in the field of cellular and molecular imaging. This technique, which is a type of magnetization transfer (MT)imaging (8), has now evolved into several different variants as new CEST contrast agents (diamagnetic and paramagnetic) and approaches have been designed (9 -22). In one of these, dubbed amide proton transfer (APT) imaging (9 -13,23-25), endogenous cytosolic proteins and peptides are detected through saturation of the amide protons in the peptide bonds. Similar to the results of Howe et al. (4), this unique amide proton-based MRI contrast mechanism has shown promise for imaging the increase in protein and peptide content in brain tumors in animals (11), as well as in an initial study in human brain tumor patients (23). However, these preliminary human studies were confounded by a low signal-to-noise ratio (SNR; the APT effect is only a few percent of the water signal) and by local field inhomogeneity. The high sensitivity of APT to field inhomogeneity is due to the inherent approach in CEST-type imaging, where water saturation is measured as a function of transmitter frequency, producing the "z-spectra" (26) or CEST spectra (5). Such spectra are dominated by large direct water saturation around the water frequency at about 4.7 ppm in the proton spectrum and other saturation effects, such as conventional MT based on semisolid tissue structures (8). The effects of the saturation transfer of exchangeable protons to water ...