N-glycosylated GPNMB ligand independently activates mutated EGFR signaling and promotes metastasis in NSCLC.

Lung cancer is the leading cause of cancer-related death worldwide. As well as the identified role of epidermal growth factor receptor (EGFR), its association with driver mutations has improved the therapeutics for patients with lung cancer harboring EGFR mutations. These patients usually display shorter overall survival and a higher tendency to develop distant metastasis compared with those carrying the wild-type EGFR. Nevertheless, the way to control mutated EGFR signaling remains unclear. Here, we performed membrane proteomic analysis to determine potential components that may act with EGFR mutations to promote lung cancer malignancy. Expression of transmembrane glycoprotein non-metastatic melanoma protein B (GPNMB) was positively correlated with the status of mutated EGFR in non-small-cell lung cancer (NSCLC). This protein was not only overexpressed but also highly glycosylated in EGFR-mutated, especially EGFR-L858R mutated, NSCLC cells. Further examination showed that GPNMB could activate mutated EGFR without ligand stimulation and could bind to the C-terminus of EGFR, assist phosphorylation at Y845, turn on downstream STAT3 signaling, and promote cancer metastasis. Moreover, we also found that Asn134 (N134) glycosylation of GPNMB played a crucial role in this ligand-independent regulation. Depleting N134-glycosylation on GPNMB could dramatically inhibit binding of GPNMB to mutated EGFR, blocking its downstream signaling, and ultimately inhibiting cancer metastasis in NSCLC. Clarifying the role of N-glycosylated GPNMB in regulating the ligand-independent activation of mutated EGFR may soon give new insight into the development of novel therapeutics for NSCLC.

Suppression of Drug-Resistant Non-Small-Cell Lung Cancer with Inhibitors Targeting Minichromosomal Maintenance Protein.

Drug resistance has been a major threat in cancer therapies that necessitates the development of new strategies to overcome this problem. We report here a cell-based high-throughput screen of a library containing two-million molecules for the compounds that inhibit the proliferation of non-small-cell lung cancer (NSCLC). Through the process of phenotypic screening, target deconvolution, and structure-activity relationship (SAR) analysis, a compound of furanonaphthoquinone-based small molecule, AS4583, was identified that exhibited potent activity in tyrosine kinase inhibitor (TKI)-sensitive and TKI-resistant NSCLC cells (IC50 = 77 nM) and in xenograft mice. The mechanistic studies revealed that AS4583 inhibited cell-cycle progression and reduced DNA replication by disrupting the formation of the minichromosomal maintenance protein (MCM) complex. Subsequent SAR study of AS4583 gave compound RJ-LC-07-48 which exhibited greater potency in drug-resistant NSCLC cells (IC50 = 17 nM) and in mice with H1975 xenograft tumor.

Sterically modulated silver(I) complexes of coumarin substituted benzimidazol-2-ylidenes: Synthesis, crystal structures and evaluation of their antimicrobial and antilung cancer potentials.

In this contribution, a series of sterically-encumbered coumarin substituted benzimidazole-based N-heterocyclic carbene (NHC) precursors (1-12) and their silver(I)-NHC complexes (13-24) are reported. Molecular structure of NHC precursors 8 and 12 and cationic complexes 15 and 16 was established by single crystal X-ray diffraction method. The silver(I) complexes demonstrated various significant intramolecular agostic-like interactions operating between the metal center and the hydrogen atoms of the substituents alongside a variety of feeble π-π stacking interactions. A distorted linear coordination geometry is documented at the silver(I) center with the anti-arrangement of the ligands. Further, the complexes demonstrated promising antibacterial properties against Gram positive and Gram negative bacterial strains, especially complex 18 displayed a minimum inhibitory concentration (MIC) of 2 and 4 µg/mL against S. aureus and E. coli, and P. aeruginosa, respectively. Furthermore, complexes 14, 15, 16 and 18 were found cytotoxic against the human lung cancer cell lines A549 and H1975 with the IC50 (concentration of the test sample required to kill 50% of the cell population) value under 10 µM, while mono-NHC complex 20 displayed a potential drug window with the IC50 of 13.7 ±â€¯2.70 and 14.5 ±â€¯1.20 µM against the cancer cell lines H1975 and A549, respectively. Notably, these complexes displayed relatively lesser cytotoxic behaviour against the normal skin fibroblast cell line, Hs68. All the NHC precursors displayed significantly lower biological activities compared with their respective complexes, indicating the utility of silver(I) ions in antimicrobial and antilung cancer applications.

Perforation of the right ventricle by a pulmonary artery catheter that continues to measure cardiac output and mixed venous saturation.

During urgent cardiopulmonary bypass for acute myocardial infarction, a pulmonary artery (PA) catheter was inserted in an 81-year-old male patient for monitoring of cardiopulmonary function. The presence of the PA catheter in the right pericardium was noted by the cardiothoracic surgeon during surgery. In retrospect, the malposition of the catheter in the pericardium could be clearly seen in the routine intraoperative transesophageal echocardiogram. The presence of a PA pressure waveform and the ability to measure cardiac output and mixed venous oxygen saturation from the PA catheter does not exclude the possibility that it could still be perforating the right ventricle.

Stress response to hepatectomy in patients with a healthy or a diseased liver.

Partial hepatectomy is a major upper abdominal operation associated with certain stress to the patient. Successful adaptation to such stress is a prerequisite for survival. Donor hepatectomy with maximal safety is a principal concern during living donor liver transplantation. The purpose of the study was to compare the stress response by assessing cytokines and the acute-phase response induced by hepatectomy in patients with a healthy liver and those with a diseased liver. Fourteen patients undergoing partial right hepatectomy were enrolled in this study. Seven of them were donors for living related liver transplantation (group 1, or GI); the other seven were patients with hepatocellular carcinoma due to chronic hepatitis B (Child's class A) (GII). Blood samples for interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFalpha), and C-reactive protein (CRP) assays were collected before the operation, at the beginning and end of the operation, and 24 and 48 hours after the operation. The data were analyzed and compared in the same group using the Friedman test and between groups using the Mann-Whitney U-test. A value of p < 0.05 was regarded as significant. Results showed that resection of the liver in patients with both healthy and disease livers leads to significant increases in IL-6 and CPR but not TNFalpha. Significantly lower levels of IL-6 before and after operation in GI patients compared to those in GII patients suggests that GI patients adapted to surgical stress more easily than did the GII patients.