Reversible Covalent Inhibition─Desired Covalent Adduct Formation by Mass Action.

Covalent inhibition has seen a resurgence in the last several years. Although long-plagued by concerns of off-target effects due to nonspecific reactions leading to covalent adducts, there has been success in developing covalent inhibitors, especially within the field of anticancer therapy. Covalent inhibitors can have an advantage over noncovalent inhibitors since the formation of a covalent adduct may serve as an additional mode of selectivity due to the intrinsic reactivity of the target protein that is absent in many other proteins. Unfortunately, many covalent inhibitors form irreversible adducts with off-target proteins, which can lead to considerable side-effects. By designing the inhibitor to form reversible covalent adducts, one can leverage competing on/off kinetics in complex formation by taking advantage of the law of mass action. Although covalent adducts do form with off-target proteins, the reversible nature of inhibition prevents accumulation of the off-target adduct, thus limiting side-effects. In this perspective, we outline important characteristics of reversible covalent inhibitors, including examples and a guide for inhibitor development.

Laryngeal Embryonal Rhabdomyosarcoma: A rare adult neoplasm.

The embryonal subtype of rhabdomyosarcoma is the most frequent, commonly seen in children. However, it is uncommon to discover this subtype in adults, especially in the larynx. We presented a rare case of a 63 years old man who presented with worsening hoarseness, dysphagia for solids, and dyspnea and was later diagnosed with embryonal rhabdomyosarcoma of the larynx.

Preferences for Mobile-Supported e-Cigarette Cessation Interventions Among Young Adults: Qualitative Descriptive Study.

BACKGROUND: Despite the steady rise in electronic cigarette (e-cigarette) uptake among young adults, increasingly more young people want to quit. Given the popularity of smartphones among young adults, mobile-based e-cigarette cessation interventions hold significant promise. Smartphone apps are particularly promising due to their varied and complex capabilities to engage end users. However, evidence around young adults' preferences and expectations from an e-cigarette cessation smartphone app remains unexplored. OBJECTIVE: The purpose of this study was to take an initial step toward understanding young adults' preferences and perceptions on app-based e-cigarette cessation interventions. METHODS: Using a qualitative descriptive approach, we interviewed 12 young adults who used e-cigarettes and wanted to quit. We inductively derived themes using the framework analysis approach and NVivo 12 qualitative data analysis software. RESULTS: All participants agreed that a smartphone app for supporting cessation was desirable. In addition, we found 4 key themes related to their preferences for app components: (1) flexible personalization (being able to enter and modify goals); (2) e-cigarette behavior tracking (progress and benefits of quitting); (3) safely managed social support (moderated and anonymous); and (4) positively framed notifications (encouraging and motivational messages). Some gender-based differences indicate that women were more likely to use e-cigarettes to cope with stress, preferred more aesthetic tailoring in the app, and were less likely to quit cold turkey compared with men. CONCLUSIONS: The findings provide direction for the development and testing of app-based e-cigarette cessation interventions for young adults.

Nanosilver Mitigates Biofilm Formation via FapC Amyloidosis Inhibition.

Multidrug resistance of bacteria is a major challenge due to the wide-spread use of antibiotics. While a range of strategies have been developed in recent years, suppression of bacterial activity and virulence via their network of extracellular amyloid has rarely been explored, especially with nanomaterials. Here, silver nanoparticles and nanoclusters (AgNPs and AgNCs) capped with cationic branched polyethylenimine polymer are synthesized, and their antimicrobial potentials are determined at concentrations safe to mammalian cells. Compared with the ultrasmall AgNCs, AgNPs entail stronger binding to suppress the fibrillization of FapC, a major protein constituent of the extracellular amyloid matrix of Pseudomonas aeruginosa. Both types of nanoparticles exhibit concentration-dependent antibiofilm and antimicrobial properties against P. aeruginosa. At concentrations of 1 × 10-6 m or below, both the bactericidal activity of AgNCs and the antibiofilm capacity of AgNPs are associated with their structure-mediated bio-nano interactions but not ion release. For AgNPs, specifically, their antibiofilm potency correlates with their capacity of FapC fibrillization inhibition, but not with their bactericidal activity. This study demonstrates the antimicrobial potential of safe nanotechnology through the novel route of amyloidosis inhibition.

Polymeric nanocapsules embedded with ultra-small silver nanoclusters for synergistic pharmacology and improved oral delivery of Docetaxel.

Despite of the remarkable cytotoxic and imaging potential of ultra-small metal nanoclusters, their toxicity-free and targeted delivery to cancerous cells remains a substantial challenge that hinders their clinical applications. In this study, a polymeric scaffold was first synthesized by grafting folic acid and thiol groups to chitosan (CS) for cancer cell targeting and improved gastric permeation. Furthermore, silver nanocluster (Ag NCs) were synthesized in situ, within CS scaffold by microwave irradiation and core-shell nanocapsules (NCPs) were prepared with hydrophobic docetaxel (DTX) in the core and Ag NCs embedded CS in the shell. A significant cytotoxicity synergism (~300 folds) was observed for DTX with co-delivery of Ag NCs against breast cancer MDA-MB-231 cells. Following oral administration, the DTX-Ag-NCPs increased bioavailability due to enhanced drug transport across gut (9 times), circulation half-life (~6.8 times) and mean residence time (~6.7 times), as compared to the control DTX suspension. Moreover, 14 days acute oral toxicity of the DTX-Ag-NCPs was performed in mice and evaluated for changes in blood biochemistry parameters, organ to body weight index and histopathology of liver and kidney tissues that revealed no significant evidence of toxicity suggesting the safety and efficiency of the DTX-Ag-NCPs as hybrid nanocarrier for biocompatible delivery of metal nanoclusters.