Discovery of High-Affinity Small-Molecule Binders of the Epigenetic Reader YEATS4.

A series of small-molecule YEATS4 binders have been discovered as part of an ongoing research effort to generate high-quality probe molecules for emerging and/or challenging epigenetic targets. Analogues such as 4d and 4e demonstrate excellent potency and selectivity for YEATS4 binding versus YEATS1,2,3 and exhibit good physical properties and in vitro safety profiles. A new X-ray crystal structure confirms direct binding of this chemical series to YEATS4 at the lysine acetylation recognition site of the YEATS domain. Multiple analogues engage YEATS4 with nanomolar potency in a whole-cell nanoluciferase bioluminescent resonance energy transfer assay. Rodent pharmacokinetic studies demonstrate the competency of several analogues as in vivo-capable binders.

Monoamine oxidase binding not expected to significantly affect [18F]flortaucipir PET interpretation.

PURPOSE: [18F]-labeled positron emission tomography (PET) radioligands permit in vivo assessment of Alzheimer's disease biomarkers, including aggregated neurofibrillary tau (NFT) with [18F]flortaucipir. Due to structural similarities of flortaucipir with some monoamine oxidase A (MAO-A) inhibitors, this study aimed to evaluate flortaucipir binding to MAO-A and MAO-B and any potential impact on PET interpretation. METHODS: [18F]Flortaucipir autoradiography was performed on frozen human brain tissue slices, and PET imaging was conducted in rats. Dissociation constants were determined by saturation binding, association and dissociation rates were measured by kinetic binding experiments, and IC50 values were determined by competition binding. RESULTS: Under stringent wash conditions, specific [18F]flortaucipir binding was observed on tau NFT-rich Alzheimer's disease tissue and not control tissue. In vivo PET experiments in rats revealed no evidence of [18F]flortaucipir binding to MAO-A; pre-treatment with MAO inhibitor pargyline did not impact uptake or wash-out of [18F]flortaucipir. [18F]Flortaucipir bound with low nanomolar affinity to human MAO-A in a microsomal preparation in vitro but with a fast dissociation rate relative to MAO-A ligand fluoroethyl-harmol, consistent with no observed in vivo binding in rats of [18F]flortaucipir to MAO-A. Direct binding of flortaucipir to human MAO-B was not detected in a microsomal preparation. A high concentration of flortaucipir (IC50 of 1.3 µM) was found to block binding of the MAO-B ligand safinamide to MAO-B on microsomes suggesting that, at micromolar concentrations, flortaucipir weakly binds to MAO-B in vitro. CONCLUSION: These data suggest neither MAO-A nor MAO-B binding will contribute significantly to the PET signal in cortical target areas relevant to the interpretation of [18F]flortaucipir.

Training dental hygienists to place interim therapeutic restorations in a school-based teledentistry program: Oregon's virtual dental home.

OBJECTIVES: The objectives of this study on Oregon's virtual dental home were to: 1) demonstrate the feasibility of pilot project training of existing Expanded Practice Dental Hygienists (EPDHs) to perform interim therapeutic restorations (ITRs) in the community settings after diagnosis by the supervising dentist via teledentistry and 2) evaluate satisfaction of parents/guardians of children participating in a pilot program that provides school-based/on-site preventive dental care services utilizing expanded scope EPDHs to conduct dental screenings and place ITRs. METHODS: This demonstration project was a 4-years longitudinal cohort study (2016-2019) in the school/community-based settings focusing on children in kindergarten to 3rd grade. EPDHs and dentists from a Dental Care Organization were trained to utilize teledentistry and EPDHs were trained to place ITRs, the latter provided onsite dental care. Data was collected regarding child's demographics and oral health status; and parents reported level of satisfaction from services received by their children. Data analysis included descriptive statistics and logistic regression analysis to assess the relative importance of demographic and clinical factors on caries status. RESULTS: Onsite dental care was provided to 759 children. Of repeat patients (n = 377), 201 (53.3%) children had untreated decay at their first visit. Of these, 13% saw improvements in oral health status at their most recent visit (MRV). There were 162 ITRs planned out of which 50 patients received 99 ITRs. No adverse events were experienced. Of the repeat children receiving ITRs (n = 43), 28% saw improvement in their caries status at their MRV. Parents reported very high levels of satisfaction with the dental care program. CONCLUSION: Oregon's virtual dental home project was successful in training EPDHs to perform ITRs safely in school settings after caries diagnosis by the supervising dentist via teledentistry and in integrating this component into a regular school-based preventive dental program.

Effect and acceptance of silver diamine fluoride treatment on dental caries in primary teeth.

OBJECTIVES: Silver diamine fluoride (SDF) treatment has been identified as a potential solution to address the dental public health issues of untreated dental caries and insufficient access to care. The current study assessed the effectiveness of 38 percent SDF in arresting active dental caries lesions and in reducing or preventing associated dental pain and infections in young, at-risk children. METHODS: We enrolled 32 children aged 2-5 years with 118 active caries lesions in primary teeth from a community dental clinic in Oregon. After baseline examinations, carious lesions were treated with 1-2 applications of 38 percent SDF. Children were re-evaluated at 3-week and 3-month recalls to assess color and consistency changes in lesions (soft/hard). Parents were interviewed regarding symptoms of pain or infection and were surveyed regarding subjective feelings about SDF. RESULTS: Of 102 lesions (16 excluded from analyses), 100 were found to be arrested at first recall and all at second recall. The duration of SDF application was not associated with arrest of decay (P = 0.68). No incidence of pain or infection of an SDF-treated tooth was recorded. Parental impression of ease of application, taste, and esthetics was favorable. CONCLUSIONS: Our results suggested SDF was effective in arresting active caries lesions in primary teeth in young children and was well accepted by parents. SDF offers an easy and highly efficient nonsurgical alternative treatment to traditional restorative dental treatment in young children, and it has great potential to aid the dental public health community to address dental caries in at-risk populations.

Facile Route to 2-Fluoropyridines via 2-Pyridyltrialkylammonium Salts Prepared from Pyridine N-Oxides and Application to (18)F-Labeling.

Among known precursors for 2-[(18)F]fluoropyridines, pyridyltrialkylammonium salts have shown excellent reactivity; however, their broader utility has been limited because synthetic methods for their preparation suffer from poor functional group compatibility. In this paper, we demonstrate the regioselective conversion of readily available pyridine N-oxides into 2-pyridyltrialkylammonium salts under mild and metal-free conditions. These isolable intermediates serve as effective precursors to structurally diverse 2-fluoropyridines, including molecules relevant to PET imaging. In addition to providing access to nonradioactive analogues, this method has been successfully applied to (18)F-labeling in the radiosynthesis of [(18)F]AV-1451 ([(18)F]T807), a PET tracer currently under development for imaging tau.

Modified dermoscopic algorithm for the differentiation between melanocytic and nonmelanocytic skin tumors.

BACKGROUND: The use of dermoscopy (dermatoscopy, epiluminescence microscopy, surface microscopy) improves the clinical diagnostic accuracy of skin tumors by applying different algorithms or scores. The first step in the dermoscopic evaluation is the differentiation between melanocytic and nonmelanocytic skin tumors. OBJECTIVE: To evaluate the diagnostic accuracy of the established dermoscopic algorithm (EDA) and the modified dermoscopic algorithm (MDA) for melanocytic versus nonmelanocytic skin tumors. METHODS: Two hundred forty-nine patients with melanocytic and nonmelanocytic skin lesions were included. Dermoscopic images of the tumors were taken with 10-fold magnification, followed by surgery and histopathology at the departments of Dermatology at the universities of Tuebingen, in Germany, and Naples, in Italy. Each lesion was classified using the EDA and MDA. In the MDA, accessory nipples and dermatofibromas were considered in particular. RESULTS: With the EDA, 225 of 249 (90.4%) skin tumors were correctly classified in one of the six groups. With the MDA, 237 of 249 (95.2%) were correctly classified. Improvement was achieved in 12 (4.8%) better classified skin tumors. In both algorithms, no melanoma was classified as a nonmalignant melanocytic tumor. All melanomas were classified in the group of melanocytic tumors and one melanoma was classified in the group of basal cell carcinomas. CONCLUSION: Both dermoscopic algorithms for the differentiation between melanocytic and nonmelanocytic skin tumors were simple and effective when applied step by step. The MDA is an improvement on the EDA with the classification of accessory nipples and dermatofibromas.