Efficacy and Safety of Limertinib (ASK120067) in Patients With Locally Advanced or Metastatic EGFR Thr790Met-Mutated NSCLC: A Multicenter, Single-Arm, Phase 2b Study.

INTRODUCTION: Limertinib (ASK120067) is a newly developed third-generation EGFR tyrosine kinase inhibitor targeting both sensitizing EGFR and EGFR Thr790Met (T790M) mutations. This study aimed to evaluate the efficacy and safety of limertinib in patients with locally advanced or metastatic EGFR T790M-mutated NSCLC. METHODS: This is a single-arm, open-label, phase 2b study conducted at 62 hospitals across the People's Republic of China. Patients with locally advanced or metastatic NSCLC with centrally confirmed EGFR T790M mutations in tumor tissue or blood plasma who progressed after first- or second-generation EGFR tyrosine kinase inhibitors or with primary EGFR T790M mutations were enrolled. Patients received limertinib 160 mg orally twice daily until disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR) assessed by independent review committee per the Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included disease control rate, progression-free survival (PFS), duration of response (DoR), overall survival, and safety. Safety was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. RESULTS: From July 16, 2019, to March 10, 2021, a total of 301 patients were enrolled and started the treatment of limertinib. All patients entered the full analysis set and safety set. By the data cutoff date on September 9, 2021, 76 (25.2%) remained on treatment. The median follow-up time was 10.4 months (range: 0.3-26.3). On the basis of full analysis set, the independent review committee-assessed ORR was 68.8% (95% confidence interval [CI]: 63.2%-74.0%) and disease control rate was 92.4% (95% CI: 88.8%-95.1%). The median PFS was 11.0 months (95% CI: 9.7-12.4), median DoR was 11.1 months (95% CI: 9.6-13.8), and median OS was not reached (95% CI 19.7 months-not evaluable). Objective responses were achieved across all prespecified subgroups. For 99 patients (32.9%) with central nervous system (CNS) metastases, the ORR was 64.6% (95% CI: 54.4%-74.0%), median PFS was 9.7 months (95% CI: 5.9-11.6), and median DoR was 9.6 months (95% CI: 8.1-15.2). For 41 patients who had assessable CNS lesion, the confirmed CNS-ORR was 56.1% (95% CI: 39.7%-71.5%) and median CNS-PFS was 10.6 months (95% CI: 5.6-not evaluable). In safety set, 289 patients (96.0%) experienced at least one treatment-related adverse event (TRAE), with the most common being diarrhea (81.7%), anemia (32.6%), rash (29.9%), and anorexia (28.2%). Grade ≥3 TRAEs occurred in 104 patients (34.6%), with the most common including diarrhea (13.0%), hypokalemia (4.3%), anemia (4.0%), and rash (3.3%). TRAEs leading to dose interruption and dose discontinuation occurred in 24.6% and 2% of patients, respectively. No TRAE leading to death occurred. CONCLUSIONS: Limertinib (ASK120067) was found to have promising efficacy and an acceptable safety profile for the treatment of patients with locally advanced or metastatic EGFR T790M-mutated NSCLC. CLINICAL TRIAL INFORMATION: NCT03502850.

Dihydroartemisinin alleviates hepatic fibrosis through inducing ferroptosis in hepatic stellate cells.

Targeting the elimination of activated hepatic stellate cells (HSCs) and blocking excessive deposition of extracellular matrix are recognized as an effective strategy for the treatment of hepatic fibrosis. As a newly discovered programmed cell death mode, the regulatory mechanism of ferroptosis in the clearance of activated HSCs has not been fully elucidated. In the present study, we reported that the induction of ferroptosis in activated HSCs was required for dihydroartemisinin (DHA) to alleviate hepatic fibrosis. Treatment with DHA could improve the damage of hepatic fibrosis in vivo and inhibit the activation of HSCs in vitro. Interestingly, DHA treatment could trigger ferroptosis to eliminate activated HSCs characterized by iron overload, lipid ROS accumulation, glutathione depletion, and lipid peroxidation. Specific ferroptosis inhibitors ferrostatin-1 and liproxstatin-1 could impair DHA-induced ferroptosis and also damage DHA-mediated the inhibition of activated HSCs. Importantly, autophagy activation may be closely related to DHA-induced ferroptosis. ATG5 siRNA could prevent DHA-mediated autophagy activation and ferroptosis induction, whereas ATG5 plasmid could promote the effect of DHA on autophagy and ferroptosis. Of note, the upregulation of nuclear receptor coactivator 4 (NCOA4) may play a critical role in the molecular mechanism. NCOA4 siRNA could impair DHA-induced ferroptosis, whereas NCOA4 plasmid could enhance the promoting effect of DHA on ferroptosis. Overall, our study revealed the potential mechanism of DHA against hepatic fibrosis and showed that ferroptosis could be a new way to eliminate activated HSCs.

Subtle changes in surface-tethered groups on PEGylated DNA nanoparticles significantly influence gene transfection and cellular uptake.

PEGylation strategy has been widely used to enhance colloidal stability of polycation/DNA nanoparticles (NPs) for gene delivery. To investigate the effect of polyethylene glycol (PEG) terminal groups on the transfection properties of these NPs, we synthesized DNA NPs using PEG-g-linear polyethyleneimine (lPEI) with PEG terminal groups containing alkyl chains of various lengths with or without a hydroxyl terminal group. For both alkyl- and hydroxyalkyl-decorated NPs with PEG grafting densities of 1.5, 3, or 5% on lPEI, the highest levels of transfection and uptake were consistently achieved at intermediate alkyl chain lengths of 3 to 6 carbons, where the transfection efficiency is significantly higher than that of nonfunctionalized lPEI/DNA NPs. Molecular dynamics simulations revealed that both alkyl- and hydroxyalkyl-decorated NPs with intermediate alkyl chain length exhibited more rapid engulfment than NPs with shorter or longer alkyl chains. This study identifies a new parameter for the engineering design of PEGylated DNA NPs.

Efficacy of zinc supplementation for neonatal sepsis: a systematic review and meta-analysis.

Background: Zinc supplementation has some potential in treating neonatal sepsis. We conduct a systematic review and meta-analysis to explore the efficacy of zinc supplementation for neonatal sepsis. Methods: PubMed, Embase, Web of science, EBSCO, and Cochrane Library databases are systematically searched. Randomized controlled trials (RCTs) assessing the efficacy of zinc supplementation in neonatal sepsis are included. Two investigators independently search articles, extract the data, and assessed the quality of included studies. Meta-analysis is performed using the random-effect model. Results: Four RCTs involving 986 patients are included in the meta-analysis. Overall, compared with control intervention in neonatal sepsis, zinc supplementation is able to significantly reduce mortality rate (risk ratio (RR) = 0.48; 95% confidence intervals (CIs) = 0.25-0.94; p = .03) and improve serum zinc (mean difference (MD) = 81.97; 95% CI = 34.57-129.37; p = .0007), but has no remarkable influence on hospital stay (MD = -4.51; 95% CI = -15.08 to 6.05; p = .40) and the number of expired patients (RR = 0.63; 95% CI = 0.24-1.65; p = .35). Conclusions: Zinc supplementation may significantly reduce mortality rate and improve serum zinc in neonatal sepsis, but has no substantial influence on hospital stay and the number of expired patients.

Effect of Surface Modification on Water Adsorption and Interfacial Mechanics of Cellulose Nanocrystals.

With increasing environmental concerns about petrochemical-based materials, the development of high-performance polymer nanocomposites with sustainable filler phases has attracted significant attention. Cellulose nanocrystals (CNCs) are promising nanocomposite reinforcing agents due to their exceptional mechanical properties, low weight, and bioavailability. However, there are still numerous obstacles that prevent these materials from achieving optimal performance, including high water adsorption, poor nanoparticle dispersion, and filler properties that vary in response to moisture. Surface modification is an effective method to mitigate these shortcomings. We use computational approaches to obtain direct insight into the water adsorption and interfacial mechanics of modified CNC surfaces. Atomistic grand-canonical Monte Carlo simulations demonstrate how surface modification of sulfated Na-CNCs impacts water adsorption. We find that methyl(triphenyl)phosphonium (MePh3P+)-exchanged CNCs have lower water uptake than Na-CNCs, supporting experimental dynamic vapor sorption measurements. The adsorbed water molecules show orientational ordering when distributed around the cations. Steered molecular dynamics simulations quantify traction-separation behavior of CNC-CNC interfaces. We find that exchanging sodium for MePh3P+ effectively changes the surface hydrophilicity, which in turn directly impacts interfacial adhesion and traction-separation behavior. Our analysis provides guidelines for controlling moisture effects in cellulose nanocomposites and nanocellulose films through surface modifications.

Optothermally Reversible Carbon Nanotube-DNA Supramolecular Hybrid Hydrogels.

Supramolecular hydrogels (SMHs) are three-dimensional constructs wherein the majority of the volume is occupied by water. Since the bonding forces between the components of SMHs are noncovalent, SMH properties are often tunable, stimuli-responsive, and reversible, which enables applications including triggered drug release, sensing, and tissue engineering. Meanwhile, single-walled carbon nanotubes (SWCNTs) possess superlative electrical and thermal conductivities, high mechanical strength, and strong optical absorption at near-infrared wavelengths that have the potential to add unique functionality to SMHs. However, SWCNT-based SMHs have thus far not realized the potential of the optical properties of SWCNTs to enable reversible response to near-infrared irradiation. Here, we present a novel SMH architecture comprised solely of DNA and SWCNTs, wherein noncovalent interactions provide structural integrity without compromising the intrinsic properties of SWCNTs. The mechanical properties of these SMHs are readily tuned by varying the relative concentrations of DNA and SWCNTs, which varies the cross-linking density as shown by molecular dynamics simulations. Moreover, the SMH gelation transition is fully reversible and can be triggered by a change in temperature or near-infrared irradiation. This work explores a new regime for SMHs with potential utility for a range of applications including sensors, actuators, responsive substrates, and 3D printing.

Self-assembly of electronically abrupt borophene/organic lateral heterostructures.

Two-dimensional boron sheets (that is, borophene) have recently been realized experimentally and found to have promising electronic properties. Because electronic devices and systems require the integration of multiple materials with well-defined interfaces, it is of high interest to identify chemical methods for forming atomically abrupt heterostructures between borophene and electronically distinct materials. Toward this end, we demonstrate the self-assembly of lateral heterostructures between borophene and perylene-3,4,9,10-tetracarboxylic dianhydride (PTCDA). These lateral heterostructures spontaneously form upon deposition of PTCDA onto submonolayer borophene on Ag(111) substrates as a result of the higher adsorption enthalpy of PTCDA on Ag(111) and lateral hydrogen bonding among PTCDA molecules, as demonstrated by molecular dynamics simulations. In situ x-ray photoelectron spectroscopy confirms the weak chemical interaction between borophene and PTCDA, while molecular-resolution ultrahigh-vacuum scanning tunneling microscopy and spectroscopy reveal an electronically abrupt interface at the borophene/PTCDA lateral heterostructure interface. As the first demonstration of a borophene-based heterostructure, this work will inform emerging efforts to integrate borophene into nanoelectronic applications.

Systematic coarse-grained modeling of complexation between small interfering RNA and polycations.

All-atom molecular dynamics simulations can provide insight into the properties of polymeric gene-delivery carriers by elucidating their interactions and detailed binding patterns with nucleic acids. However, to explore nanoparticle formation through complexation of these polymers and nucleic acids and study their behavior at experimentally relevant time and length scales, a reliable coarse-grained model is needed. Here, we systematically develop such a model for the complexation of small interfering RNA (siRNA) and grafted polyethyleneimine copolymers, a promising candidate for siRNA delivery. We compare the predictions of this model with all-atom simulations and demonstrate that it is capable of reproducing detailed binding patterns, charge characteristics, and water release kinetics. Since the coarse-grained model accelerates the simulations by one to two orders of magnitude, it will make it possible to quantitatively investigate nanoparticle formation involving multiple siRNA molecules and cationic copolymers.