Clinical efficacy and identification of factors confer resistance to afatinib(tyrosine kinase inhibitor)in EGFR-overexpressing esophageal squamous cell carcinoma

Epidermal growth factor receptor(EGFR)is reportedly overexpressed in most esophageal squamous cell carcinoma(ESCC)patients,but anti-EGFR treatments offer limited survival benefits.Our preclinical data showed the promising antitumor activity of afatinib in EGFR-overexpressing ESCC.This proof-of-concept,phase II trial assessed the efficacy and safety of afatinib in pretreated metastatic ESCC patients(n=41)with EGFR overexpression(NCT03940976).The study met its primary endpoint,with a confirmed objective response rate(ORR)of 39%in 38 efficacy-evaluable patients and a median overall survival of 7.8 months,with a manageable toxicity profile.Transcriptome analysis of pretreatment tumors revealed that neurotrophic receptor tyrosine kinase 2(NTRK2)was negatively associated with afatinib sensitivity and might serve as a predictive biomarker,irrespective of EGFR expression.Notably,knocking down or inhibiting NTRK2 sensitized ESCC cells to afatinib treatment.Our study provides novel findings on the molecular factors underlying afatinib resistance and indicates that afatinib has the potential to become an important treatment for metastatic ESCC patients.

Molecular Mechanism of the Early Stage of Amyloidogenic Hexapeptides(NFGAIL) Aggregation

Peptides/proteins aggregation can give rise to pathological conditions of many human diseases.Small partially ordered oligomers formed in the early stage of aggregation,rather than mature fibrils,are thought to be the main toxicity agent for the living cell.Thus,understanding the pathway and the underlying physical mechanism in the early stage of aggregation is very important for prevention and treatment of these protein functional diseases.Herein we use all-atom molecular dynamics simulations to study the aggregation of four NFGAIL hexapeptides(NFGAIL peptide is a core segment of human islet amyloid polypeptide and exhibits similar aggregation kinetics as the full-length polypeptide).We observe that the peptide monomers in water mainly adopt non-structural coil configurations;the four peptides which are randomly placed in water aggregate spontaneously to partially ordered oligomer(β-sheets)through dimerization or trimerization,with the dimerization predominated.Both parallel and anti-parallelβ-sheets are observed.The hydrophobic interactions drive the initial peptides associations,and the subsequent conformational fluctuations promote the formation of more hydrogen bonds between the dangling hydrogen sites in the main chains of peptides.

Structure and Dynamics of Ethanol Adsorbed on a Mica Surface

The structural and dynamic properties of nanoscale ethanol film on a mica surface are investigated via molecular dynamics simulations. We observe a dense, almost fiat ethanol bilayer formed in the vicinity of the mica surface, with the hydrophobic alkyl groups pointing outward from the surface. Remarkably, such ethanol bilayer is laterally well-ordered with patterned adsorption sites. Each ethanol molecule in the first layer donates one hydrogen bond to the surface basal oxygen atoms and accepts one hydrogen bond from that in the second layer. The ethanol molecules within the bilayer exhibit constrained lateral mobility and delayed dynamics as compared with bulk ethanol, whereas those on top of the bilayer have bulk-like characteristics.