Notch1 binds and induces degradation of Snail in hepatocellular carcinoma

<p>Abstract</p> <p>Background</p> <p>Hepatocellular carcinoma (HCC) is a common, highly invasive malignant tumor associated with a high mortality rate. We previously reported that the aberrant expression of Snail via activation of reactive oxygen species contributes to the invasive property of HCC, in part by downregulation of E-cadherin through both transcriptional repression and epigenetic modification of the E-cadherin promoter. Having demonstrated the ability of Snail to bind and recruit histone deacetylase 1 and DNA methyltransferase 1 in this context, we set out to look for other interactions that could affect its ability to promote oncogenic transformation and cancer cell invasion.</p> <p>Results</p> <p>Using cells that stably expressed Snail, we characterized Snail protein interactors by tandem affinity purification and mass spectrometry. Immunoprecipitation and subcellular colocalization studies were performed to confirm our identification of the Notch1 intracellular domain (NICD) as a novel Snail-binding partner. NICD interaction with Snail was found to induce ubiquitination and MDM2-dependent degradation of Snail. Interestingly, NICD inhibited Snail-dependent invasive properties in both HCC cells and mouse embryonic fibroblasts.</p> <p>Conclusions</p> <p>Our study demonstrates that NICD can oppose Snail-dependent HCC cell invasion by binding and inducing proteolytic degradation of Snail. Although Notch signaling and Snail are both widely considered tumor-promoting factors, our findings indicate that the individual oncogenic contribution of Notch1 and Snail in malignant systems should be interpreted carefully, particularly when they are conjointly expressed.</p

Electrochemical Properties of Chemically Processed SiO

A SiOx coating material for Si anode in lithium-ion battery was processed by using SiCl4 and ethylene glycol. The produced SiOx particles after heat treatment at 725°C for 1 h were porous and irregularly shaped with amorphous structure. Pitch carbon added to SiOx was found to strongly affect solid electrolyte interphase stabilization and cyclic stability. When mixed with an optimal amount of 30 wt% pitch carbon, the SiOx showed a high charge/discharge cyclic stability of about 97% for the 2nd to the 50th cycle. The initial specific capacity of the SiOx was measured to be 1401 mAh/g. On the basis of the evaluation of the SiOx coating material, the process utilized in this study is considered an efficient method to produce SiOx with high performance in an economical way

Complete Atrioventricular Block Secondary to Bortezomib Use in Multiple Myeloma

Bortezomib is an inhibitor of 26S proteasome, which is an effective treatment for multiple myeloma. The common adverse effects of bortezomib are asthenic conditions, gastrointestinal disturbances, and peripheral neuropathy. Here we describe a patient with dyspnea and general weakness because of complete atrioventricular block while receiving bortezomib. We immediately stopped bortezomib, and after inserting a permanent VDD pacemaker, the patients' symptoms disappeared

The First Successful Transapical Aortic Valve Implant in Korea

Transcatheter aortic valve implantation is an alternative to open heart surgery in high risk patients with severe aortic stenosis. High mortality and complications related to cardiopulmonary bypass for conventional open heart surgery can be avoided with this new less invasive technique. In case of concomitant severe arterial disease, the transapical approach is recommended rather than transfemoral access. An 80-yr-old man with symptomatic aortic stenosis and who had very high surgical risk factors such as diabetes mellitus, hypertension, a history of stroke, bronchial asthma including poor pulmonary function and hepatocellular carcinoma was treated with a transapical aortic valve replacement. The expected mortality in this patient was 25.4% by Euroscore if we performed the conventional aortic valve surgery. The patient was discharged and was well at the 45 follow-up days. We report the first case of successful transcatheter transapical aortic valve implantation which is available recently in Korea

Combined inhibition of Bcl-2 family members and YAP induces synthetic lethality in metastatic gastric cancer with RASA1 and NF2 deficiency

Background Targetable molecular drivers of gastric cancer (GC) metastasis remain largely unidentified, leading to limited targeted therapy options for advanced GC. We aimed to identify molecular drivers for metastasis and devise corresponding therapeutic strategies. Methods We performed an unbiased in vivo genome-wide CRISPR/Cas9 knockout (KO) screening in peritoneal dissemination using genetically engineered GC mouse models. Candidate genes were validated through in vivo transplantation assays using KO cells. We analyzed target expression patterns in GC clinical samples using immunohistochemistry. The functional contributions of target genes were studied through knockdown, KO, and overexpression approaches in tumorsphere and organoid assays. Small chemical inhibitors against Bcl-2 members and YAP were tested in vitro and in vivo. Results We identified Nf2 and Rasa1 as metastasis-suppressing genes through the screening. Clinically, RASA1 mutations along with low NF2 expression define a distinct molecular subtype of metastatic GC exhibiting aggressive traits. NF2 and RASA1 deficiency increased in vivo metastasis and in vitro tumorsphere formation by synergistically amplifying Wnt and YAP signaling in cancer stem cells (CSCs). NF2 deficiency enhanced Bcl-2-mediated Wnt signaling, conferring resistance to YAP inhibition in CSCs. This resistance was counteracted via synthetic lethality achieved by simultaneous inhibition of YAP and Bcl-2. RASA1 deficiency amplified the Wnt pathway via Bcl-xL, contributing to cancer stemness. RASA1 mutation created vulnerability to Bcl-xL inhibition, but the additional NF2 deletion conferred resistance to Bcl-xL inhibition due to YAP activation. The combined inhibition of Bcl-xL and YAP synergistically suppressed cancer stemness and in vivo metastasis in RASA1 and NF2 co-deficiency. Conclusion Our research unveils the intricate interplay between YAP and Bcl-2 family members, which can lead to synthetic lethality, offering a potential strategy to overcome drug resistance. Importantly, our findings support a personalized medicine approach where combined therapy targeting YAP and Bcl-2, tailored to NF2 and RASA1 status, could effectively manage metastatic GC.This research was supported by grants of the National Research Foundation (NRF) funded by the Korean government (NRF-RS-2023–00208984, NRF-2021M3H9A1030260, NRF-2021R1F1A1051220, NRF-2016M3A9D5A01952416)

Efficacy of High-dose Chemotherapy and Autologous Stem Cell Transplantation in Patients with Relapsed Medulloblastoma: A Report on The Korean Society for Pediatric Neuro-Oncology (KSPNO)-S-053 Study

The efficacy and toxicity of high-dose chemotherapy and autologous stem cell transplantation (HDCT/ASCT) were investigated for improving the outcomes of patients with relapsed medulloblastoma. A total of 15 patients with relapsed medulloblastoma were enrolled in the KSPNO-S-053 study from May 2005 to May 2007. All patients received approximately 4 cycles of salvage chemotherapy after relapse. Thirteen underwent HDCT/ASCT; CTE and CM regimen were employed for the first HDCT (HDCT1) and second HDCT (HDCT2), respectively, and 7 underwent HDCT2. One transplant related mortality (TRM) due to veno-occlusive disease (VOD) occurred during HDCT1 but HDCT2 was tolerable with no further TRM. The 3-yr overall survival probability and event-free survival rates ±95% confidence intervals (CI) were 33.3±12.2% and 26.7% ±11.4%, respectively. When analysis was confined to only patients who had a complete response (CR) or partial response (PR) prior to HDCT, the probability of 3-yr overall survival rates ±95% CI was 40.0±15.5%. No patients with stable disease (SD) or progressive disease (PD) survived. Survival rates from protocol KSPNO-S-053 are encouraging and show that tumor status prior to HDCT/ASCT is an important factor to consider for improving survival rates of patients with relapsed medulloblastoma