Response to osimertinib plus trametinib in a heavily treated epidermal growth factor receptor (EGFR)-positive NSCLC harboring a rare, acquired rapidly accelerated fibrosarcoma B-type (BRAF) p.D594N mutation: a case report.

Heterogeneity in the acquired genetic cause of osimertinib resistance leads to difficulties in understanding and addressing molecular mechanisms of resistance in clinical practice. Recent studies and clinical cases established that altered BRAF could drive osimertinib resistance in an EGFR-independent manner. Herein, we present a case in which an EGFR-positive, MET-amplified nonsmall cell lung cancer (NSCLC) patient acquired BRAF p.D594N mutation on third-line osimertinib plus crizotinib and responded to seventh-line treatment with osimertinib plus MEK inhibitor trametinib. Disease control was maintained for 6 months. BRAF p.D594N is a kinase impaired mutation but leads to increased MEK/ERK signaling, which could activate the downstream signaling of EGFR and induce drug resistance. There has been preclinical evidence supporting dual inhibition of MEK and EGFR for overcoming this resistance. To the best of our knowledge, our case is the first to provide clinical evidence that trametinib plus osimertinib was effective for EGFR-mutant NSCLC patients with acquired BRAF p.D594N mutation. More supporting data and systematic validation studies are needed for comprehensive understanding of this therapy strategy and future applications.

Modulating the antibacterial activity of gold nanoparticles by balancing their monodispersity and aggregation.

Aggregation is a key factor influencing the function of nanoparticles. Thioproline-modified gold nanoparticles show potent antibacterial activity, which is compromised by thioproline-mediated particle aggregation. By tuning the balance between the exposure and shielding of thioproline, a maximal antibacterial property of the gold nanoparticles is achieved.

Aminophenol-Decorated Gold Nanoparticles for Curing Bacterial Infections.

Nanomaterials usually kill bacteria via multiple mechanisms which are not explicit to the same degree as those of conventional antibiotics. This situation may hinder the development of novel nanoscale antibiotics. Here, we present aminophenol (AP) to modify gold nanoparticles (AP_Au NPs) which show a broad antibacterial spectrum and potent antibacterial effects against multidrug-resistant (MDR) bacteria with clear antibacterial mechanisms. AP_Au NPs can not only damage bacterial cell walls but also bind to the 16S rRNA to block bacterial protein synthesis. Moreover, AP_Au NPs show excellent performance in curing abdominal bacterial infections in an in vivo model. AP_Au NPs thus have the potential to become a novel antibacterial agent for clinical applications.

Aminophenol-modified gold nanoparticles kill bacteria with minimal ototoxicity.

We report aminophenol (A)-modified gold nanoparticles (AGNPs), which have potent antibacterial effects against multidrug-resistant bacteria with a broad antibacterial spectrum. Moreover, a series of in vitro and in vivo models indicate that AGNPs are much less ototoxic than aminoglycosides. AGNPs thus have the potential to replace aminoglycosides as novel antibacterial agents for clinical applications.

Alteration of immune profiles is associated with pulmonary function and symptoms in patients with chronic obstructive pulmonary disease.

Inflammation serves a key role in chronic obstructive pulmonary disease (COPD). However, changes in the immune profiles of patients with COPD remain unclear. The present prospective observational study aimed to determine the expression profiles of immune cells and inflammatory factors of patients with COPD and healthy controls, and to analyze the relationship between immune profiles and smoking history. A total of 140 subjects were enrolled in the present study between September 2018 and April 2019 at West China Hospital of Sichuan University (Chengdu, China). These included 87 patients with stable COPD and 24 patients with acute exacerbated COPD, as well as 29 healthy controls. Baseline characteristics were recorded during the screening period, and levels of immune cells were examined using flow cytometry. In addition, levels of inflammatory factors were measured using ELISAs. The results revealed increased expression of the CD64+/CD14+ mononuclear phagocyte system (MPS) and CD16+CD66+ neutrophils, and decreased expression of CD3+CD4+ T cells and CD3+ CD8+ T cells (all P<0.05) in the peripheral blood of patients with COPD and smokers relative to non­smoking controls. In addition, significant differences were observed in protein levels of IL­6, IL­1ß, TNF­α, TGF­α, IFN­Î³, IL­8, IL­17A and CRP among the three groups (all P<0.05). Furthermore, the IL­17A, TNF and NF­κB signaling pathways were found to serve a key role in the inflammatory network of COPD. Pearson's correlation analysis revealed a positive correlation between CD3+T lymphocyte counts and pulmonary function, and a negative correlation with smoking and exacerbations. Furthermore, neutrophils and MPS were negatively associated with pulmonary function, and IL­8 was positively associated with cough. There was also a negative association between CRP and IL­17A with pulmonary function but a positive correlation with symptoms and exacerbation. Club cell secretory protein was also negatively associated with emphysema parameters. In conclusion, the present findings revealed significant differences in profiles of immune factors among patients with COPD, smokers and non­smoking controls and their association with clinical characteristics. The clinical trial registration number of the present study is: ChiCTR1800015700 (registered with http://www.chictr.org.cn/index.aspx, 2018/04/16).

Evaluation of the in vivo behavior of antibacterial gold nanoparticles for potential biomedical applications.

The pharmacokinetics is a critical factor determining the clinical applicability of nanomaterials. Systematic study of the pharmacokinetics of functional nanomaterials is thus significant for promoting their applications. Herein, we take aminophenylboronic acid and mercaptophenylboronic acid-co-modified gold nanoparticles (A/M-Au NPs) with potent and tunable antibacterial activity as an example to study their behaviors in vitro and in vivo. The maximum concentration (Cmax, 2 mg L-1), the time to reach the maximum concentration (Tmax, 6 h), and the half-life (T1/2, 12 h) in the plasma of mice reflect appropriate pharmacokinetics of the gold nanoparticles as an ideal nano-antibiotic. Strikingly, the A/M-Au NPs show an extremely high median lethal dose (920 mg kg-1), which is about 100 times their effective dose (7.2 mg kg-1), suggesting their outstanding biosafety. The adequate pharmacokinetic profile and the high biosafety of the gold nanoparticles pave the way for their potential biomedical applications.

Oral Administration of Starting Materials for In Vivo Synthesis of Antibacterial Gold Nanoparticles for Curing Remote Infections.

Oral administration is a facile and safe way for medication. However, most of the reported nanomedicines could not be taken orally, partially due to their unsatisfied stability, poor absorbance, or toxicity in the gastrointestinal tract. Here, we demonstrate that we could robustly synthesize gold nanoparticles (GNPs) in vivo by orally administering two starting materials, tetrachloroauric acid and aminophenyl boronic acid (ABA). The ABA-activated GNPs (A-GNPs) synthesized in vivo could be absorbed by the gastrointestinal tract and reach the remote infection lesions such as peritonitis caused by multidrug resistant (MDR) bacteria in mice. The A-GNPs exhibit excellent antibacterial efficacy (MIC, 3 µg/mL), long half-life (16-17 h), effective clearance (residual concentration is near 0 within 72 h), and high biosafety (safe dose/effective dose, 8 times). Our study is a pioneering attempt for synthesizing and taking nanomedicines orally just like preparing and drinking a cocktail.

The Density of Surface Coating Can Contribute to Different Antibacterial Activities of Gold Nanoparticles.

With the widespread use of antibiotics, the number of complex infection cases caused by unknown pathogens is increasing and novel antibiotics with tunable antibacterial spectra and low toxicity are highly desirable. Herein, we report that, by selecting thiol or amine, two groups with different binding affinities with gold, as anchoring groups, phenylboronic acid can be decorated on gold nanoparticles (AuNPs) with different densities, which contributes to Gram-selective antibacterial activities of the AuNPs. The AuNPs modified with amine- or thiol-tethered phenylboronic acids specifically bind to lipopolysaccharide (LPS, Gram-negative) or lipoteichoic acid (LTA, Gram-positive), respectively. By modifying AuNPs with different ratios of thiol- and amine-tethered phenylboronic acids, the resulting AuNPs show potent and tunable antibacterial activity. The AuNP-based antibacterial agents with optional Gram selectivity are promising for applications in personalized therapy.

Titanium Incorporation into Zr-Porphyrinic Metal-Organic Frameworks with Enhanced Antibacterial Activity against Multidrug-Resistant Pathogens.

This study uses metal-organic frameworks (MOFs) alone without any added antibacterial ingredients as the nonantibiotic agent for photodynamic therapy (PDT) of chronic wounds infected by multidrug-resistant (MDR) bacteria. Nanoparticles (NPs) of MOFs (PCN-224) are incorporated with titanium through a facile cation exchange strategy. The obtained bimetallic PCN-224(Zr/Ti) shows greatly enhanced photocatalytic performance for the generation of reactive oxygen species under visible light, which is responsible for the effective antibacterial activities. The PCN-224(Zr/Ti) NPs are loaded onto lactic-co-glycolic acid nanofibers to prepare a wound dressing, which shows high biocompatibility and minimal cytotoxicity. The wound dressing is efficient for PDT-based in vivo healing of the chronic wound infected by MDR bacteria. Most importantly, this work does not involve any additional antibacterial agents, which is facile, low cost, and in particular, greatly explores the potential of MOFs as a powerful nonantibiotic agent in PDT.

Bacterial Cellulose as a Supersoft Neural Interfacing Substrate.

Biocompatible neural interfaces hold great promise for treating neurological disorders and enhancing the mental and physical ability of human beings. Most of the currently available neural interfaces are made from rigid, dense inorganic materials that cause tissue damage. We present supersoft multichannel electrodes by depositing gold layers on thin bacterial cellulose (BC) (Au-BC electrodes). The Young's modulus of BC ( EBC = 120 kPa) is between those of the brain tissue ( Ebrain = 2.7-3.1 kPa) and the peripheral neural tissues ( Eperipheral nerve = 580-840 kPa). The bending stiffness of the Au-BC electrodes corresponds to 1/5200 of Au-polyimide electrodes with the same layout. Furthermore, the Au-BC electrodes are highly durable (conductivity >95% after 100 cycles of 180° bending). In vivo recording of brain electric activity demonstrates the great potential of the Au-BC electrodes for neural interfacing applications.

Self-powered hydrogels induced by ion transport.

Electroactive hydrogels are needed to enable stretchable electronics because of their flexible mechanical characteristics and electrical conductive properties. We describe a class of viscoelastic, porous, ion-conductive, and self-powered hydrogels that are fabricated based on a PHEMA hydrogel (poly(2-hydroxyethyl methacrylate)) and PPy (polypyrrole). They are capable of creating synchronous ionic current in electrolyte solution when enduring mechanical deformation. The conditions that impact the electric response of the hydrogel, such as stress, strain rate, pH of electrolyte solution, and concentration of ions in the electrolyte solution, have been investigated and reported in this paper. The mechanism of creating ionic current under deformation is elaborated through numerical simulation and experimental tests. Moreover, by embedding the electrically self-powered hydrogel into a movable object, such as a sports shoe, the patterns of mechanical actions (e.g. walking, running, or jumping) can be identified from the generated electrical current without any assistance of external batteries or power sources. It presents the outstanding potential of this hydrogel in building self-powered soft devices including active sensors and artificial skins.

A transparent wound dressing based on bacterial cellulose whisker and poly(2-hydroxyethyl methacrylate).

The current study was aimed to develop a transparent wound dressing comprised of bacterial cellulose (BC) and poly (2-hydroxyethyl methacrylate) (PHEMA) hydrogel coated with silver (Ag) nanoparticles. Briefly, different concentrations of BC whiskers (BCWs) were added into the HEMA solution to form PHEMA/BCWs hydrogel with volume ratio of monomer HEMA and BCWs as 7:3 and 1:1. The addition of BCWs into PHEMA matrix improved its equilibrium water content and light transmittance about 20%-40% and 10%, respectively. The Young's modulus for PHEMA was found to be 0.72MPa, which was improved to 0.57MPa and 0.50MPa for PHEMA/BCWs 7:3 and PHEMA/BCWs 1:1, respectively. Further, immersion of PHEMA/BCWs hydrogel in the AgNO3 and NaBH4 solutions bestowed it with antibacterial property and produced inhibition zones of 0.5±0.15cm and 0.25±0.15cm against Escherichia coli and Staphylococcus aureus, respectively. Similarly, PHEMA/BCWs prepared with 0.001M AgNO3 and 0.001M NaBH4 solutions showed 99% and 90% reduction in colony forming unit (CFU) for E. coli and S. aureus, respectively, after 24h. The PHEMA/BCWs/Ag hydrogel facilitated the growth of NIH3T3 fibroblast, showing their low toxicity. These results demonstrate the suitability of PHEMA/BCWs/Ag hydrogel for its application as potential transparent wound dressing material for skin repair.

Electroconductive natural polymer-based hydrogels.

Hydrogels prepared from natural polymers have received immense considerations over the past decade due to their safe nature, biocompatibility, hydrophilic properties, and biodegradable nature. More recently, when treated with electroactive materials, these hydrogels were endowed with high electrical conductivity, electrochemical redox properties, and electromechanical properties; consequently, forming a smart hydrogel. The biological properties of these smart hydrogels, classified as electroconductive hydrogels, can be combined with electronics. Thus, they are considered as good candidates for some potential uses, which include bioconductors, biosensors, electro-stimulated drug delivery systems, as well as neuron-, muscle-, and skin-tissue engineering. However, there is lacking comprehensive information on the current state of these electroconductive hydrogels which complicates our understanding of this new type of biomaterials as well as their potential applications. Hence, this review provides a summary on the current development of electroconductive natural polymer-based hydrogels (ENPHs). We have introduced various types of ENPHs, with a brief description of their advantages and shortcomings. In addition, emerging technologies regarding their synthesis developed during the past decade are discussed. Finally, two attractive potential applications of ENPHs, cell culture and biomedical devices, are reviewed, along with their current challenges.