In non-small-cell lung carcinoma (NSCLC), aberrant activation of mammalian target of rapamycin (mTOR) contributes to tumorigenesis and cancer progression. PQR620 is a novel and highly-potent mTOR kinase inhibitor. We here tested its potential activity in NSCLC cells. In primary human NSCLC cells and established cell lines (A549 and NCI-H1944), PQR620 inhibited cell growth, proliferation, and cell cycle progression, as well as cell migration and invasion, while inducing significant apoptosis activation. PQR620 disrupted assembles of mTOR complex 1 (mTOR-Raptor) and mTOR complex 2 (mTOR-Rictor-Sin1), and blocked Akt, S6K1, and S6 phosphorylations in NSCLC cells. Restoring Akt-mTOR activation by a constitutively-active Akt1 (S473D) only partially inhibited PQR620-induced cytotoxicity in NSCLC cells. PQR620 was yet cytotoxic in Akt1/2-silenced NSCLC cells, supporting the existence of Akt-mTOR-independent mechanisms. Indeed, PQR620 induced sphingosine kinase 1 (SphK1) inhibition, ceramide production and oxidative stress in primary NSCLC cells. In vivo studies demonstrated that daily oral administration of a single dose of PQR620 potently inhibited primary NSCLC xenograft growth in severe combined immune deficient mice. In PQR620-treated xenograft tissues, Akt-mTOR inactivation, apoptosis induction, SphK1 inhibition and oxidative stress were detected. In conclusion, PQR620 exerted potent anti-NSCLC cell activity via mTOR-dependent and -independent mechanisms.

Activation of adenosine monophosphate-activated protein kinase (AMPK) is able to produce significant anti-non-small cell lung cancer (NSCLC) cell activity. ASP4132 is an orally active and highly effective AMPK activator. The current study tested its activity against NSCLC cells. In primary NSCLC cells and established cell lines (A549 and NCI-H1944) ASP4132 potently inhibited cell growth, proliferation and cell cycle progression as well as cell migration and invasion. Robust apoptosis activation was detected in ASP4132-treated NSCLC cells. Furthermore, ASP4132 treatment in NSCLC cells induced programmed necrosis, causing mitochondrial p53-cyclophilin D (CyPD)-adenine nucleotide translocase 1 (ANT1) association, mitochondrial depolarization and medium lactate dehydrogenase release. In NSCLC cells ASP4132 activated AMPK signaling, induced AMPKα1-ACC phosphorylation and increased AMPK activity. Furthermore, AMPK downstream events, including mTORC1 inhibition, receptor tyrosine kinases (PDGFRα and EGFR) degradation, Akt inhibition and autophagy induction, were detected in ASP4132-treated NSCLC cells. Importantly, AMPK inactivation by AMPKα1 shRNA, knockout (using CRISPR/Cas9 strategy) or dominant negative mutation (T172A) almost reversed ASP4132-induced anti-NSCLC cell activity. Conversely, a constitutively active AMPKα1 (T172D) mimicked and abolished ASP4132-induced actions in NSCLC cells. In vivo, oral administration of a single dose of ASP4132 largely inhibited NSCLC xenograft growth in SCID mice. AMPK activation, mTORC1 inhibition and EGFR-PDGFRα degradation as well as Akt inhibition and autophagy induction were detected in ASP4132-treated NSCLC xenograft tumor tissues. Together, activation of AMPK by ASP4132 potently inhibits NSCLC cell growth in vitro and in vivo.

the clinical effect and the value of applying one-stage VATS for BMPNs. Ultimately, the patients had satisfactory surgical results and recovered well. Methods Inclusive and exclusive criteria of patients Inclusive criteria Patients underwent lung-function testing, bronchoscopy, CT scans, complete blood counts and serum biochemistry tests. Positron emission tomography-CT (PET-CT) was not included as a conventional examination for patients. Their

In thoracoscopic segmentectomy, accurate preoperative identification of intersegmental vessels, bronchi, and the surgical safety margin is vital. We applied three dimensional computed tomography bronchography and angiography (3D-CTBA) reconstruction to appropriately plan thoracoscopic segmentectomy for Patients with pulmonary nodules. In this study, we evaluated the effectiveness and accuracy of 3D-CTBA reconstruction for the identification of segmental anatomical structures and variation during thoracoscopic segmentectomy.We retrospectively analyzed data of 30 patients who underwent 3D-CTBA reconstruction before thoracoscopic segmentectomy between January and May 2019 in the Department of Thoracic Surgery, First Affiliated Hospital of Nanchang University. We compared the individual target segment arteries, veins, and bronchi identified during surgery with the preoperative 3D-CTBA model to evaluate its effectiveness and accuracy. The accuracy of the preoperative 3D-CTBA model for the identification of target segmental arteries, veins, and bronchi was 99.08% (108/109), 98.39% (122/124), and 100% (118/118), respectively. Through 3DCTBA modeling, we found mediastinal and interlobar types of lingular segmental arteries in six patients, and central veins were not found in seven patients. In addition, we detected rare anatomical variations in two patients; one patient had the right apical segmental bronchus that stemmed solely from the right primary bronchus (tracheal bronchus), and the other had rare right basal segmental variant bronchi and vessels. The 3D-CTBA model can precisely predict segmental bronchi and vessels and identify anatomical structure variations before operation, which can aid surgeons to avoid incorrect operation and improve surgical efficiency. This has important implications for thoracoscopic segmentectomy.