Mechanisms of EGFR-TKI-Induced Apoptosis and Strategies Targeting Apoptosis in EGFR-Mutated Non-Small Cell Lung Cancer.

Homeostasis is achieved by balancing cell survival and death. In cancer cells, especially those carrying driver mutations, the processes and signals that promote apoptosis are inhibited, facilitating the survival and proliferation of these dysregulated cells. Apoptosis induction is an important mechanism underlying the therapeutic efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) for EGFR-mutated non-small cell lung cancer (NSCLC). However, the mechanisms by which EGFR-TKIs induce apoptosis have not been fully elucidated. A deeper understanding of the apoptotic pathways induced by EGFR-TKIs is essential for the developing novel strategies to overcome resistance to EGFR-TKIs or to enhance the initial efficacy through therapeutic synergistic combinations. Recently, therapeutic strategies targeting apoptosis have been developed for cancer. Here, we review the state of knowledge on EGFR-TKI-induced apoptotic pathways and discuss the therapeutic strategies for enhancing EGFR-TKI efficiency. We highlight the great progress achieved with third-generation EGFR-TKIs. In particular, combination therapies of EGFR-TKIs with anti-vascular endothelial growth factor/receptor inhibitors or chemotherapy have emerged as promising therapeutic strategies for patients with EGFR-mutated NSCLC. Nevertheless, further breakthroughs are needed to yield an appropriate standard care for patients with EGFR-mutated NSCLC, which requires gaining a deeper understanding of cancer cell dynamics in response to EGFR-TKIs.

Risk Factors Indicating Difficulty During Gastric Endoscopic Submucosal Dissection for Inexperienced Endoscopists: A Retrospective Study.

AIM: Factors that may make endoscopic submucosal dissection (ESD) difficult for operators have been evaluated according to results based on the performance of experienced endoscopists. This study aimed to verify the predictors of difficult gastric ESD for ESD beginners. METHODS: From January 2015 to December 2021, 466 superficial gastric neoplasms were treated with ESD at Showa University Hospital. Excluding 103 lesions that performed ESD by experts who experienced more than 80 ESDs, a total of 363 lesions were included. The lesions were divided into two groups according to the ESD performance experience of the operator: ESD beginner (EB; ESD experience≤30 cases) and ESD intermediate (EI; ESD experience 31-80 cases) groups. Relationships between difficult ESD (having at least one of the following: procedure time>60 min, incomplete resection, change of operator, and occurrence of severe complications) and clinicopathological findings of the lesion were analyzed. RESULTS: The complete resection rates and the difficult ESD rates in the EB and EI groups were 99.3%, 94.8%, and 61.2%, 50.7%, respectively. In the EB group, univariate analysis showed that difficult ESD rate was significantly higher in the non-lower third lesions, the lesser curvature lesions, and cancerous lesions. In the EI group, univariate analysis showed that difficult ESD rate was significantly higher in lesion with ≥20 mm size, lesser curvature lesions, lesions with ulcers, and submucosal cancers. Multivariate analysis showed that the lesser curvature location and cancerous histology in the EB group and ≥20 mm lesion size, the lesser curvature location and submucosal invasion in the EI group were independent predictors of difficult ESD. CONCLUSIONS: The lesser curvature location is recognized as independent ESD difficulty factor for both beginners and intermediates. Cases with lesions located in the lesser curvature should not be selected for gastric ESD training by beginners.

Does supercooled liquid Si have a density maximum?

We have performed precise measurements of the density of supercooled liquid silicon (l-Si) in the temperature range of 1530-1800 K using an electromagnetic levitation (EML) technique with static magnetic fields. We also performed first-principles molecular dynamics simulation (FPMD) of supercooled l-Si. The observed density of the supercooled l-Si and the FPMD results show good agreement in the temperature range of 1530-1800 K. The structure of the supercooled l-Si also showed good agreement between the experimental measurements and FPMD simulations. Based on these results, we discuss nucleation in supercooled l-Si and also the existence of a density maximum in the supercooled l-Si, which is well known in water at 4 degrees C.

Compact electrostatic levitator for diffraction measurements with a two axis diffractometer and a laboratory x-ray source.

A compact electrostatic levitator was developed for the structural analysis of high-temperature liquids by x-ray diffraction methods. The size of the levitator was 200 mm in diameter and 200 mm in height and can be set up on a two axis diffractometer with a laboratory x-ray source, which is very convenient in performing structural measurements of high-temperature liquids. In particular, since the laboratory x-ray source allows a great amount of user time, preliminary or challenging experiments can be performed with trial and error, which prepares and complements synchrotron x-ray experiments. The present small apparatus also provides the advantage of portability and facility of setting. To demonstrate the capability of this electrostatic levitator, the static structure factors of alumina and silicon samples in their liquid phases were successfully measured.