Whole-exome and targeted gene sequencing of large-cell lung carcinoma reveals recurrent mutations in the PI3K pathway.

BACKGROUND: Large cell lung carcinoma (LCLC) is an exceptionally aggressive disease with a poor prognosis. At present, little is known about the molecular pathology of LCLC. METHODS: Ultra-deep sequencing of cancer-related genes and exome sequencing were used to detect the LCLC mutational in 118 tumor-normal pairs. The cell function test was employed to confirm the potential carcinogenic mutation of PI3K pathway. RESULTS: The mutation pattern is determined by the predominance of A > C mutations. Genes with a significant non-silent mutation frequency (FDR) < 0.05) include TP53 (47.5%), EGFR (13.6%) and PTEN (12.1%). Moreover, PI3K signaling (including EGFR, FGRG4, ITGA1, ITGA5, and ITGA2B) is the most mutated pathway, influencing 61.9% (73/118) of the LCLC samples. The cell function test confirmed that the potential carcinogenic mutation of PI3K pathway had a more malignant cell function phenotype. Multivariate analysis further revealed that patients with the PI3K signaling pathway mutations have a poor prognosis (P = 0.007). CONCLUSIONS: These results initially identified frequent mutation of PI3K signaling pathways in LCLC and indicate potential targets for the treatment of this fatal type of LCLC.

Antitumor effects of a Sb-rich polyoxometalate on non-small-cell lung cancer by inducing ferroptosis and apoptosis.

Polyoxometalates (POMs) are a class of anionic metal-oxygen clusters with versatile biological activities. Over the past decade, an increasing number of POMs, especially Sb-rich POMs, have been proven to exert antitumor activity. However, the antitumor effects and mechanisms of POMs in the treatment of non-small cell lung cancer (NSCLC) remain largely unexplored. This study employed a Sb-rich {Sb21Tb7W56} POM (POM-1) for NSCLC therapy and investigated its mechanism of action. Our results demonstrated that POM-1 exhibited cytotoxicity against H1299 and A549 cells with IC50 values of 3.245 µM and 3.591 µM, respectively. The migration and invasion were also inhibited by 28.05% and 76.18% in H1299 cells, as well as 36.88% and 36.98% in A549 cells at a concentration of 5 µM. In a tumor xenograft mouse model, POM-1 suppressed tumor growth by 76.92% and 84.62% at doses of 25 and 50 mg kg-1, respectively. Transcriptomic analysis indicated the alteration of ferroptosis and apoptosis signaling pathways in POM-treated NSCLC cells. Subsequent experimentation confirmed the induction of ferroptosis, evidenced by 5.6-fold elevated lipid peroxide levels with treatment of 5 µM POM-1, alongside increased expression of ferroptosis-associated proteins. Additionally, the apoptosis induced by POM-1 was also validated by the 19.67% and 30.1% increase in apoptotic cells in H1299 and A549 cells treated with 5 µM POM-1, respectively, as well as the upregulated activation of caspase-3. In summary, this study reveals, for the first time, ferroptosis as the antitumor mechanism of Sb-rich POM, and that synergism with ferroptosis and apoptosis is a highly potent antitumor strategy for POM-based antitumor therapy.

[Changes of cranio-facial hard tissue after orthodontic treatment in bimaxillary protrusive patients].

OBJECTIVE: The aim of this study is to investigate the changes of hard tissue profile in anterior-posterior and vertical direction in bimaxillary protrusion patients after orthodontic treatment. METHODS: A total of 24 bimaxillary protrusion patients (male 8, female 16), aged from 11.2 to 29.0 (average 16.9 years old), were selected to be treated with standard edgewise technique consisted of 4 first premolars extraction. Cephalometrics were taken before and after treatment. The changes of hard tissue profile were studied using the computer-aid X-ray cephalometric analysis. RESULTS: 1. The length of the maxillary and the mandible increased significantly, but the anterior-posterior relationship of the maxillary and the mandible did not change significantly. 2. The anterior and posterior facial height increased significantly, but the ratio of anterior and posterior facial height and the angle of MP-FH which reflected the inclination of the mandible plane did not change significantly. 3. The height of the upper and lower first molar increased significantly along with the increase of the anterior and posterior facial height. 4. The height of the upper incisors increased significantly, but the height of the lower incisors decreased significantly. CONCLUSION: The anchorage in anterior-posterior and vertical direction were controlled preferably, the patients did not manifest disadvantageous vertical growth trend.