Discovery of the First-in-class G9a/GLP PROTAC Degrader.

Aberrantly expressed lysine methyltransferases G9a and GLP, which catalyze mono- and di-methylation of histone H3 lysine 9 (H3K9), have been implicated in numerous cancers. Recent studies have uncovered both catalytic and non-catalytic oncogenic functions of G9a/GLP. As such, G9a/GLP catalytic inhibitors have displayed limited anticancer activity.

Metabolomic Characteristics of Nontuberculous Mycobacterial Pulmonary Disease.

Background: The therapeutic challenges posed by nontuberculous mycobacterial pulmonary disease (NTM-PD) contribute to an unmet medical need. In this study, we aimed to investigate NTM-PD-specific metabolic pathways using serum metabolomics to understand disease pathogenesis.

Methods: Mass spectrometry-based untargeted metabolomic profiling of serum from patients with NTM-PD (n = 50), patients with bronchiectasis (n = 50), and healthy controls (n = 60) was performed.

Fabrication and Characterization of an Enzyme-Triggered, Therapeutic-Releasing Hydrogel Bandage Contact Lens Material.

Purpose: The purpose of this study was to develop an enzyme-triggered, therapeutic-releasing bandage contact lens material using a unique gelatin methacrylate formulation (GelMA+).

Methods: Two GelMA+ formulations, 20% /, and 30% / concentrations, were prepared through UV polymerization. The physical properties of the material, including porosity, tensile strain, and swelling ratio, were characterized.

Bridged Proteolysis Targeting Chimera (PROTAC) Enables Degradation of Undruggable Targets.

Proteolysis Targeting Chimeras (PROTACs) are attractive therapeutic modalities for degrading disease-causing proteins. While many PROTACs have been developed for numerous protein targets, current small-molecule PROTAC approaches cannot target undruggable proteins that do not have small-molecule binders. Here, we present a novel PROTAC approach, termed bridged PROTAC, which utilizes a small-molecule binder of the target protein's binding partner to recruit the protein complex into close proximity with an E3 ubiquitin ligase to target undruggable proteins.

PT-112 Induces Mitochondrial Stress and Immunogenic Cell Death, Targeting Tumor Cells with Mitochondrial Deficiencies.

PT-112 is a novel pyrophosphate-platinum conjugate, with clinical activity reported in advanced pretreated solid tumors. While PT-112 has been shown to induce robust immunogenic cell death (ICD) in vivo but only minimally bind DNA, the molecular mechanism underlying PT-112 target disruption in cancer cells is still under elucidation. The murine L929 in vitro system was used to test whether differential metabolic status alters PT-112's effects, including cell cytotoxicity.

Discovery of the First-in-Class G9a/GLP Covalent Inhibitors.

The highly homologous protein lysine methyltransferases G9a and GLP, which catalyze mono- and dimethylation of histone H3 lysine 9 (H3K9), have been implicated in various human diseases. To investigate functions of G9a and GLP in human diseases, we and others reported several noncovalent reversible small-molecule inhibitors of G9a and GLP. Here, we report the discovery of the first-in-class G9a/GLP covalent irreversible inhibitors, and (MS8511), by targeting a cysteine residue at the substrate binding site.

Harnessing the E3 Ligase KEAP1 for Targeted Protein Degradation.

Proteolysis targeting chimeras (PROTACs) represent a new class of promising therapeutic modalities. PROTACs hijack E3 ligases and the ubiquitin-proteasome system (UPS), leading to selective degradation of the target proteins. However, only a very limited number of E3 ligases have been leveraged to generate effective PROTACs.

Deep Learning to Determine the Activity of Pulmonary Tuberculosis on Chest Radiographs.

Background Determining the activity of pulmonary tuberculosis on chest radiographs is difficult. Purpose To develop a deep learning model to identify active pulmonary tuberculosis on chest radiographs. Materials and Methods Chest radiographs were retrospectively gathered from a multicenter consecutive cohort with pulmonary tuberculosis who were successfully treated between 2011 and 2017, along with normal radiographs to enrich a negative class.

Normative Data for Myocardial Native T1 and Extracellular Volume Fraction in Children.

Purpose: To establish normative data for myocardial T1, including extracellular volume (ECV) fraction, in healthy children.

Materials And Methods: In this retrospective, single-center study, T1 mapping data were collected from 48 healthy pediatric patients (14 years ± 3 [standard deviation]; range, 9-18 years; 27 of 48 [56%] male) referred for cardiac screening 1.5-T MRI between 2014 and 2017.

Addition of Screening Breast US to Digital Mammography and Digital Breast Tomosynthesis for Breast Cancer Screening in Women at Average Risk.

Background Digital breast tomosynthesis (DBT) with or without digital mammography (DM) is the primary method of breast cancer screening. However, the sufficiency of DBT screening for women at average risk and the need for supplemental whole-breast US needs further investigation. Purpose To evaluate the added value of supplemental US screening following combined DM/DBT.

Potent and Selective Mitogen-Activated Protein Kinase Kinase 1/2 (MEK1/2) Heterobifunctional Small-molecule Degraders.

Previously, we reported a first-in-class von Hippel-Lindau (VHL)-recruiting mitogen-activated protein kinase kinases 1 and 2 (MEK1/2) degrader, MS432. To date, only two MEK1/2 degrader papers have been published and very limited structure-activity relationships (SAR) have been reported. Here, we describe our extensive SAR studies exploring both von Hippel-Lindau (VHL) and cereblon (CRBN) E3 ligase ligands and a variety of linkers, which resulted in two novel, improved VHL-recruiting MEK1/2 degraders, (MS928) and (MS934), and the first CRBN-recruiting MEK1/2 degrader (MS910).

Impact of body mass index on development of nontuberculous mycobacterial pulmonary disease.

The incidence and prevalence of nontuberculous mycobacterial pulmonary disease (NTM-PD) have been increasing worldwide. The risk of NTM-PD may be higher in undernourished populations. In this study, we tried to elucidate the impact of body mass index (BMI) and its change on development of NTM-PD.

Changes in treatment for multidrug-resistant tuberculosis according to national income.

The aim of this study was to analyse temporal changes in treatments for and outcomes of multidrug-resistant (MDR)/rifampin-resistant (RR)-tuberculosis (TB) in the context of national economic status.We analysed data collected by the Collaborative Group for the Meta-Analysis of Individual Patient Data in MDR-TB Treatment on MDR/RR-TB patients from 37 countries. The data were stratified by three national income levels (low-/lower-middle, upper-middle and high) and grouped by time of treatment initiation (2001-2003, 2004-2006, 2007-2009, 2010-2012 and 2013-2015).

The Role of Chest Imaging in Patient Management during the COVID-19 Pandemic: A Multinational Consensus Statement from the Fleischner Society.

With more than 900 000 confirmed cases worldwide and nearly 50 000 deaths during the first 3 months of 2020, the coronavirus disease 2019 (COVID-19) pandemic has emerged as an unprecedented health care crisis. The spread of COVID-19 has been heterogeneous, resulting in some regions having sporadic transmission and relatively few hospitalized patients with COVID-19 and others having community transmission that has led to overwhelming numbers of severe cases. For these regions, health care delivery has been disrupted and compromised by critical resource constraints in diagnostic testing, hospital beds, ventilators, and health care workers who have fallen ill to the virus exacerbated by shortages of personal protective equipment.

pulmonary disease: individual patient data meta-analysis.

Treatment of pulmonary disease (MAB-PD), caused by subsp. , subsp. or subsp.

Anisotropic optical properties in electroluminescent conjugated polymers based on grazing angle photoluminescence measurements.

Grazing angle photoluminescence (GPL) originates from a waveguided light emitted at grazing angle to the substrate due to the total internal reflections, and the light emission is polarized with enhanced intensity at selective mode wavelength. GPL measurements reveal the optical anisotropy of luminescent conjugated polymers, in particular, the alignment of emitting dipoles from which emission occurs, in contrast to spectroscopic ellipsometry measurements that give the anisotropy in the absorption. Based on the GPL emission intensities and spectra, we investigate the anisotropic optical properties in electroluminescent poly(9,9'-di-n-octylfluorene-alt-benzothiadiazole) (F8BT) conjugated polymer thin films of different molecular weights (M(n) = 9-255 kg/mol), both in the pristine and annealed states.