PD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I IFN pathway.

While conventional wisdom initially postulated that PD-L1 serves as the inert ligand for PD-1, an emerging body of literature suggests that PD-L1 has cell-intrinsic functions in immune and cancer cells. In line with these studies, here we show that engagement of PD-L1 via cellular ligands or agonistic antibodies, including those used in the clinic, potently inhibits the type I interferon pathway in cancer cells. Hampered type I interferon responses in PD-L1-expressing cancer cells resulted in enhanced efficacy of oncolytic viruses in vitro and in vivo.

A practical guide for the preparation of C1-labeled α-amino acids using aldehyde catalysis with isotopically labeled CO.

Isotopically carbon-labeled α-amino acids are valuable synthetic targets that are increasingly needed in pharmacology and medical imaging. Existing preparations rely on early stage introduction of the isotopic label, which leads to prohibitive synthetic costs and time-intensive preparations. Here we describe a protocol for the preparation of C1-labeled α-amino acids using simple aldehyde catalysts in conjunction with [*C]CO (* = 14, 13, 11).

Intramolecular Friedel-Crafts Acylation of [C]Isocyanates Enabling the Radiolabeling of [carbonyl-C]DPQ.

α,β-aromatic lactams are highly abundant in biologically active molecules, yet so far they cannot be radiolabeled with short-lived (t=20.3 min), β-decaying carbon-11, which has prevented their application as positron emission tomography tracers. Herein, we developed, optimized, and applied a widely applicable, one-pot, quick, robust and automatable radiolabeling method for α,β-aromatic lactams starting from [C]CO using the reagent POCl⋅AlCl.

Photocatalyzed radiosynthesis of C-phenylacetic acids.

Fast and straightforward incorporation of radionuclides into pharmaceutically relevant molecules is one of the main barriers to preclinical and clinical tracer research. Late-stage direct incorporation of cyclotron-produced [C]CO to afford carbon-11-labeled radiopharmaceuticals has the potential to provide ready-to-inject positron emission tomography agents in less than an hour. The present work describes photocatalyzed carboxylation of alkylbenzene derivatives to afford C-phenylacetic acids.

Pharmacological and metabolic parameters of [F]flubrobenguane in clinical imaging populations.

Background: Cardiac sympathetic nervous system molecular imaging has demonstrated prognostic value. Compared with meta-[C]hydroxyephedrine, [F]flubrobenguane (FBBG) facilitates reliable estimation of SNS innervation using similar analytical methods and possesses a more convenient physical half-life. The aim of this study was to evaluate pharmacokinetic and metabolic properties of FBBG in target clinical cohorts.

Quinazoline-2-Carboxamides as Selective PET Radiotracers for Matrix Metalloproteinase-13 Imaging in Atherosclerosis.

Matrix metalloproteinase-13 (MMP-13) plays a critical role in the progression of unstable atherosclerosis. A series of highly potent and selective MMP-13 inhibitors were synthesized around a quinazoline-2-carboxamide scaffold to facilitate radiolabeling with fluorine-18 or carbon-11 positron-emitting nuclides and visualization of atherosclerotic plaques. enzyme inhibition assays identified three compounds as promising radiotracer candidates.

Synthesis and Evaluation of [C]MCC950 for Imaging NLRP3-Mediated Inflammation in Atherosclerosis.

Overexpression of the NLRP3 inflammasome has been attributed to the progressive worsening of a multitude of cardiovascular inflammatory diseases such as myocardial infarction, pulmonary arterial hypertension, and atherosclerosis. The recently discovered potent and selective NLRP3 inhibitor MCC950 has shown promise in hindering disease progression, but NLRP3-selective cardiovascular positron emission tomography (PET) imaging has not yet been demonstrated. We synthesized [C]MCC950 with no-carrier-added [C]CO fixation chemistry using an iminophosphorane precursor (RCY 45 ± 4%, >99% RCP, 27 ± 2 GBq/μmol, 23 ± 3 min, = 6) and determined its distribution both and in C57BL/6 and atherogenic mice.

Aldehyde-catalysed carboxylate exchange in α-amino acids with isotopically labelled CO.

The isotopic labelling of small molecules is integral to drug development and for understanding biochemical processes. The preparation of carbon-labelled α-amino acids remains difficult and time consuming, with established methods involving label incorporation at an early stage of synthesis. This explains the high cost and scarcity of C-labelled products and presents a major challenge in C applications (C t = 20 min).

The histone H3.1 variant regulates TONSOKU-mediated DNA repair during replication.

The tail of replication-dependent histone H3.1 varies from that of replication-independent H3.3 at the amino acid located at position 31 in plants and animals, but no function has been assigned to this residue to demonstrate a unique and conserved role for H3.

Nanoengineered Sprayable Therapy for Treating Myocardial Infarction.

We report the development, as well as the and testing, of a sprayable nanotherapeutic that uses surface engineered custom-designed multiarmed peptide grafted nanogold for on-the-spot coating of an infarcted myocardial surface. When applied to mouse hearts, 1 week after infarction, the spray-on treatment resulted in an increase in cardiac function (2.4-fold), muscle contractility, and myocardial electrical conductivity.

Cardiac Sympathetic Positron Emission Tomography Imaging with -[F]Fluorobenzylguanidine is Sensitive to Uptake-1 in Rats.

Dysfunction of the cardiac sympathetic nervous system contributes to the development of cardiovascular diseases including ischemia, heart failure, and arrhythmias. Molecular imaging probes such as -[I]iodobenzylguanidine have demonstrated the utility of assessing neuronal integrity by targeting norepinephrine transporter (NET, uptake-1). However, current radiotracers can report only on innervation due to suboptimal kinetics and lack sensitivity to NET in rodents, precluding mechanistic studies in these species.

Evaluation of Therapeutic Collagen-Based Biomaterials in the Infarcted Mouse Heart by Extracellular Matrix Targeted MALDI Imaging Mass Spectrometry.

The goal of this study was to develop strategies to localize human collagen-based hydrogels within an infarcted mouse heart, as well as analyze its impact on endogenous extracellular matrix (ECM) remodeling. Collagen is a natural polymer that is abundantly used in bioengineered hydrogels because of its biocompatibility, cell permeability, and biodegradability. However, without the use of tagging techniques, collagen peptides derived from hydrogels can be difficult to differentiate from the endogenous ECM within tissues.

Does quantification of [C]meta-hydroxyephedrine and [N]ammonia kinetics improve risk stratification in ischemic cardiomyopathy.

Background: In ischemic cardiomyopathy patients, cardiac sympathetic nervous system dysfunction is a predictor of sudden cardiac arrest (SCA). This study compared abnormal innervation and perfusion measured by [C]meta-hydroxyephedrine (HED) vs [N]ammonia (NH), conventional uptake vs parametric tracer analysis, and their SCA risk discrimination.

Methods: This is a sub-study analysis of the prospective PAREPET trial, which followed ischemic cardiomyopathy patients with reduced left ventricular ejection fraction (LVEF ≤ 35%) for events of SCA.

Selective Imaging of Matrix Metalloproteinase-13 to Detect Extracellular Matrix Remodeling in Atherosclerotic Lesions.

Purpose: Overexpression and activation of matrix metalloproteinase-13 (MMP-13) within atheroma increases susceptibility to plaque rupture, a major cause of severe cardiovascular complications. In comparison to pan-MMP targeting [F]BR-351, we evaluated the potential for [F]FMBP, a selective PET radiotracer for MMP-13, to detect extracellular matrix (ECM) remodeling in vascular plaques possessing markers of inflammation.

Procedures: [F]FMBP and [F]BR-351 were initially assessed in vitro by incubation with en face aortae from 8 month-old atherogenic ApoE mice.

Riboflavin Surface Modification of Poly(vinyl chloride) for Light-Triggered Control of Bacterial Biofilm and Virus Inactivation.

Poly(vinyl chloride) (PVC) is the most used biomedical polymer worldwide. PVC is a stable and chemically inert polymer. However, microorganisms can colonize PVC producing biomedical device-associated infections.

Interrupted aza-Wittig reactions using iminophosphoranes to synthesize C-carbonyls.

A direct CO2-fixation methodology couples structurally diverse iminophosphoranes with various nucleophiles to synthesize ureas, carbamates, thiocarbamates, and amides, and is amenable for 11C radiolabeling. This methodology is practical, as demonstrated by the synthesis of >35 products and isolation of the molecular imaging radiopharmaceuticals [11C]URB694 and [11C]glibenclamide.

A low cost and open access system for rapid synthesis of large volumes of gold and silver nanoparticles.

Rapid synthesis of nanomaterials in scalable quantities is critical for accelerating the discovery and commercial translation of nanoscale-based technologies. The synthesis of metal nanogold and silver in volumes larger than 100 mL is not automatized and might require of the use of harsh conditions that in most cases is detrimental for the production of nanoparticles with reproducible size distributions. In this work, we present the development and optimization of an open-access low-cost NanoParticle Flow Synthesis System (NPFloSS) that allows for the rapid preparation of volumes of up to 1 L of gold and silver nanoparticle aqueous solutions.

Fast Carbon Isotope Exchange of Carboxylic Acids Enabled by Organic Photoredox Catalysis.

Carbazole/cyanobenzene photocatalysts promote the direct isotopic carboxylate exchange of C(sp) acids with labeled CO. Substrates that are not compatible with transition-metal-catalyzed degradation-reconstruction approaches or prone to thermally induced reversible decarboxylation undergo isotopic incorporation at room temperature in short reaction times. The radiolabeling of drug molecules and precursors with [C]CO is demonstrated.

Fluorine-18-Labeled Fluorescent Dyes for Dual-Mode Molecular Imaging.

Recent progress realized in the development of optical imaging (OPI) probes and devices has made this technique more and more affordable for imaging studies and fluorescence-guided surgery procedures. However, this imaging modality still suffers from a low depth of penetration, thus limiting its use to shallow tissues or endoscopy-based procedures. In contrast, positron emission tomography (PET) presents a high depth of penetration and the resulting signal is less attenuated, allowing for imaging in-depth tissues.

Regional Distribution of Fluorine-18-Flubrobenguane and Carbon-11-Hydroxyephedrine for Cardiac PET Imaging of Sympathetic Innervation.

Objectives: The aim of this study was to investigate the regional distribution of novel F-labeled positron emission tomographic (PET) tracer flubrobenguane (FBBG) (whose longer half-life could enable more widespread use) to assess myocardial presynaptic sympathetic nerve function in humans in comparison to [C]meta-hydroxyephedrine (HED).

Background: The sympathetic nervous system (SNS) is vitally linked to cardiovascular regulation and disease. SNS imaging has shown prognostic value.

The Future of Cardiac Molecular Imaging.

Molecular imaging with positron emission tomography (PET) and single-photon emission computed tomography (SPECT) serves numerous applications in clinical cardiology and research. Similar to other medical imaging technologies, this area has undergone and continues to experience rapid changes resulting from technological and medical advances. These have immediate impacts on diagnosis, treatment planning, and patient care, as well as supplying innovative tools for fundamental and translational research.

PET and SPECT Tracers for Myocardial Perfusion Imaging.

Coronary artery disease has been the leading cause of death since the 1960s, which has motivated the research and development of myocardial perfusion imaging (MPI) agents for early diagnosis and to guide treatment. MPI with SPECT has been the clinical workhorse for MPI, but over the past two decades PET MPI is experiencing growth due to enhanced image quality that results in superior diagnostic accuracy over SPECT. Furthermore, dynamic PET imaging of the tracer distribution process from time of tracer administration to tracer accumulation in the myocardium has enabled routine quantification of myocardial blood flow (MBF) and myocardial flow reserve (MFR) in absolute units.