ABSTRACT
Statin-associated immune-mediated necrotizing myopathy (IMNM) is a rare presentation of a statin-associated myopathy. Patients usually present with muscle weakness and pain in the setting of statin use with elevated creatine kinase (CK) levels and a positive anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) antibody. Muscle biopsies typically show necrosis, CD68+ macrophages, and minimal lymphocytes. We present a case of a 67-year-old woman who had 2 months of progressive weakness and bilateral lower extremity pain after initiating atorvastatin therapy with symptoms persisting after statin cessation. She was found to have high anti-HMGCR antibody titers, and the biopsy of the rectus femoris muscle showed a prominent endomysial inflammatory cell infiltrate with necrotic and regenerative fibers and an atypical extensive inflammatory infiltrate composed of both CD4+ helper T cells and CD8+ cytotoxic T cells. She showed symptom resolution and normalization of CK levels and inflammatory markers with treatment involving a prolonged prednisone taper and a brief course of azathioprine, which was stopped because of the adverse effects.
ABSTRACT
Bioorthogonal chemistry is bridging the divide between static chemical connectivity and the dynamic physiologic regulation of molecular state, enabling in situ transformations that drive multiple technologies. In spite of maturing mechanistic understanding and new bioorthogonal bond-cleavage reactions, the broader goal of molecular ON/OFF control has been limited by the inability of existing systems to achieve both fast (i.e., seconds to minutes, not hours) and complete (i.e., >99%) cleavage. To attain the stringent performance characteristics needed for high fidelity molecular inactivation, we have designed and synthesized a new C2-symmetric trans-cyclooctene linker (C2TCO) that exhibits excellent biological stability and can be rapidly and completely cleaved with functionalized alkyl-, aryl-, and H-tetrazines, irrespective of click orientation. By incorporation of C2TCO into fluorescent molecular probes, we demonstrate highly efficient extracellular and intracellular bioorthogonal disassembly via omnidirectional tetrazine-triggered cleavage.
Subject(s)
Cyclooctanes/chemistry , Molecular Probes/chemistry , Antibodies/chemistry , Antibodies/metabolism , Carbon/chemistry , Click Chemistry , Fluorescent Dyes/chemistry , IsomerismABSTRACT
We disclose that a predried form of methyliminodiacetic acid (MIDA), MIDA anhydride, acts as both a source of the MIDA ligand and an in situ desiccant to enable a mild and simple MIDA boronate synthesis procedure. This method expands the range of sensitive boronic acids that can be converted into their MIDA boronate counterparts. Further utilizing unique properties of MIDA boronates, we have developed a MIDA Boronate Maker Kit which enables the direct preparation and purification of MIDA boronates from boronic acids using only heating and centrifuge equipment that is widely available in laboratories that do not specialize in organic synthesis.
Subject(s)
Boronic Acids/chemistry , Molecular Structure , StereoisomerismABSTRACT
Fluorine-containing fluorochromes are important validation agents for positron emission tomography imaging compounds, as they can be readily validated in cells by fluorescence imaging. In particular, the (18) F-labeled BODIPY-FL fluorophore has emerged as an important platform, but little is known about alternative (18) F-labeling strategies or labeling on red-shifted fluorophores. In this study we explore acid-catalyzed (18) F/(19) F exchange on a range of commercially available N-hydroxysuccinimidyl ester and maleimide BODIPY fluorophores. We show this method to be a simple and efficient (18) F-labeling strategy for a diverse span of fluorescent compounds, including a BODIPY-modified PARP-1 inhibitor, and amine- and thiol-reactive BODIPY fluorophores.
Subject(s)
Acids/chemistry , Boron Compounds/chemistry , Fluorine/chemistry , Catalysis , Fluorine Radioisotopes/chemistry , Kinetics , Poly(ADP-ribose) Polymerase Inhibitors , Poly(ADP-ribose) Polymerases/metabolism , Positron-Emission Tomography , Sulfhydryl Compounds/chemistryABSTRACT
When resectable, invasive pancreatic ductal adenocarcinoma (PDAC) is most commonly treated with surgery and radiochemotherapy. Given the intricate local anatomy and locoregional mode of dissemination, achieving clean surgical margins can be a significant challenge. On the basis of observations that cathepsin E (CTSE) is overexpressed in PDAC and that an United States Food and Drug Administration (FDA)-approved protease inhibitor has high affinity for CTSE, we have developed a CTSE optical imaging agent [ritonavir tetramethyl-BODIPY (RIT-TMB)] for potential intraoperative use. We show nanomolar affinity [half maximal inhibitory concentration (IC50) of 39.9 ± 1.2 nM] against CTSE of the RIT-TMB in biochemical assays and intracellular accumulation and target-to-background ratios that allow specific delineation of individual cancer cells. This approach should be useful for more refined surgical staging, planning, and resection with curative intent.