High dose acetaminophen inhibits STAT3 and has free radical independent anti-cancer stem cell activity

High-dose acetaminophen (AAP) with delayed rescue using n-acetylcysteine (NAC), the FDA-approved antidote to AAP overdose, has demonstrated promising antitumor efficacy in early phase clinical trials. However, the mechanism of action (MOA) of AAP''s anticancer effects remains elusive. Using clinically relevant AAP concentrations, we evaluated cancer stem cell (CSC) phenotype in vitro and in vivo in lung cancer and melanoma cells with diverse driver mutations. Associated mechanisms were also studied. Our results demonstrated that AAP inhibited 3D spheroid formation, self-renewal, and expression of CSC markers when human cancer cells were grown in serum-free CSC media. Similarly, anti-CSC activity was demonstrated in vivo in xenograft models - tumor formation following in vitro treatment and ex-vivo spheroid formation following in vivo treatment. Intriguingly, NAC, used to mitigate AAP''s liver toxicity, did not rescue cells from AAP''s anti-CSC effects, and AAP failed to reduce glutathione levels in tumor xenograft in contrast to mice liver tissue suggesting nonglutathione-related MOA. In fact, AAP mediates its anti-CSC effect via inhibition of STAT3. AAP directly binds to STAT3 with an affinity in the low micromolar range and a high degree of specificity for STAT3 relative to STAT1. These findings have high immediate translational significance concerning advancing AAP with NAC rescue to selectively rescue hepatotoxicity while inhibiting CSCs. The novel mechanism of selective STAT3 inhibition has implications for developing rational anticancer combinations and better patient selection (predictive biomarkers) for clinical studies and developing novel selective STAT3 inhibitors using AAP''s molecular scaffold.     

Bioadhesive poly(methyl methacrylate) microdevices for controlled drug delivery.

Oral delivery is the preferred route of drug administration. However, the breakdown of molecules and low levels of absorption in the gastrointestinal system render the oral delivery of proteins and peptides ineffective. Bioadhesive delivery devices can be used to circumvent these problems by protecting the drug from gastrointestinal denaturation, localizing and prolonging a drug at a specific target site, and maintaining direct contact with the intestinal cells, thereby increasing the drug concentration gradient. Microfabrication technology may offer some potential advantages over conventional delivery technologies. The benefits of microfabrication include the ability to tailor the size, shape, reservoir volume, and surface characteristics of the drug delivery vehicle. In this study, bioadhesive properties were introduced to microfabricated poly(methyl methacrylate) (PMMA) microdevices by attachment of lectins, a group of proteins capable of specifically targeting cells in the gastrointestinal tract. In this process, the PMMA microdevices were chemically modified by aminolysis to yield amine-terminated surfaces. Avidin molecules were covalently bound to the surface of the particles using a hydroxysuccinimide catalyzed carbodiimide reagent and then incubated in an aqueous solution of biotinylated lectin. The lectin-modified microdevices were examined in vitro in terms of their bioadhesive characteristics.     

Clinical presentation and treatment outcomes of an algorithmic approach to uveal effusion syndrome

Purpose:To describe the clinical features and treatment outcomes in spontaneous uveal effusion syndrome (UES).Methods:A 10-year retrospective chart review of UES patients from a tertiary eye center was carried out. Optical coherence tomography (OCT), fundus fluorescein angiography, and ultrasound biomicroscopy (UBM) scans were performed. UES was managed based on presenting best-corrected visual acuity (BCVA), symptoms, and fundus findings. Patients with secondary causes of uveal effusion were excluded.Results:Twenty-five eyes of 16 patients were included. Of the 16 patients, 14 (88%) were male and 9 (56%) had bilateral disease. Fifteen of 25 affected eyes had nanophthalmos (axial length (AL) <20.5 mm) and 6 had hyperopia with AL >20.5 mm. The presenting mean distance BCVA was 0.74 ± 0.64 logMAR (mean Snellen: 20/100). Eleven eyes had exudative retinal detachment, and 4 also had exudative choroidal detachment (CD). Choroidal thickness (CT) was increased in 11 eyes on B-scan ultrasonography, and the mean CT was 1.74 ± 0.38 mm. Sub-retinal fluid (SRF) and retinal folds were the most common OCT findings. UBM findings included shallow angles, peripheral CD, and supra-ciliary effusion. A combination of local and systemic corticosteroids was used to successfully treat 12 eyes, 6 needed surgery, and 7 were observed. Partial sclerectomy with anterior chamber maintainer-assisted SRF drainage was the favored surgery. The median period of follow-up was 6.5 months (0.1–76 months), and the mean distance BCVA at the last follow-up was 0.58 ± 0.42 logMAR (mean Snellen: 20/80).Conclusion:UES can be suitably managed both medically and surgically based on clinical presentation.