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Introduction: Targeted protein degradation (TPD) has emerged as an innovative therapeutic strategy through selective degradation of specific proteins by harnessing the cellular ubiquitin-proteasome system (UPS), which involves over 600 E3 ubiquitin ligases. Recent proteome profiling reported tumor-specific E3 ligases in human. Development of those tumor-specific E3 ligase ligands would provide a solution for tumor-specific TPD for effective cancer treatment. Areas covered: This review provides a comprehensive list of E3 ligases found only in specific types of tumor from public databases and highlights examples of their ligands discovered through fragment-based approaches. It details their discovery process and potential applications for precise TPD and effective cancer treatments. Expert opinion: Current TPD strategies using proteolysis-targeting chimeras (PROTACs) primarily utilize general E3 ligases, such as CRBN and VHL. Since these E3 ligases demonstrate effective protein degradation activity in most human cell types, CRBN and VHL-based PROTACs can exhibit undesired TPD in off-target tissues, which often leads to the side effects. Therefore, developing tumor-specific E3 ligase ligands can be crucial for effective cancer treatments. Fragment-based ligand discovery (FBLD) approaches would accelerate the identification of these tumor-specific E3 ligase ligands and associated PROTACs, thereby advancing the field of targeted cancer therapies. [ABSTRACT FROM AUTHOR] more...

Background and Objectives: Postclipping cerebral infarction (PCI) remains a major concern after treatment for unruptured intracranial aneurysms (UIAs). However, studies of microsurgical clipping based on diffusion-weighted imaging are limited. We aimed to present the incidence, risk factors, and types of PCI and its radiological and clinical characteristics., Methods: This was a retrospective single-center study in which patients were scheduled to undergo microsurgical clipping for anterior circulation UIAs. The overall incidence and risk factors were calculated. Based on the operation and relevant artery, we categorized PCI on diffusion-weighted imaging into 4 types and presented their radiological and clinical characteristics., Results: We reviewed the radiological and clinical data of 605 patients. The overall incidence of PCI was 16.7% (101/605), of which asymptomatic infarction was 14.9% (90/605) and symptomatic infarction was 1.8% (11/605). Hypertension (adjusted odds ratio [aOR], 2.258; 95% confidence interval [CI]: 1.330-3.833), temporary clipping (aOR, 1.690; 95% CI: 1.034-2.760), multiple aneurysm locations (aOR, 1.832; 95% CI: 1.084-3.095), and aneurysm dome size (aOR, 1.094; 95% CI: 1.006-1.190) were independent risk factors for PCI. Type II (perianeurysmal perforator) infarction was the most common type of PCI (48.6%) and the most common cause of symptomatic infarction (72.7%). Types II and III (distal embolic) infarctions correlated with atherosclerotic changes in the aneurysm wall and temporary clipping (62.4% and 70.6%, respectively). The type IV (unrelated) infarction group had a higher incidence of systemic atherosclerosis (55%)., Conclusion: Microsurgical clipping is a safe and viable option for the treatment of anterior circulation UIAs. However, modification of the surgical technique, preoperative radiological assessment, and patient selection are required to reduce the incidence of PCI., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.) more...

Autophagy plays an important role in the survival of cancer cells under stressful conditions, such as nutrient or oxygen deficiency. Therefore, autophagy inhibition is being considered as a novel therapeutic strategy for cancer. Decursin is a natural compound derived from Angelica gigas ; it has been used in the treatment of various diseases, including cancer. However, the mechanism by which decursin regulates autophagy in gastric cancer and other carcinomas remains unclear. Here, we demonstrated that decursin reduced the growth and induced cell cycle arrest in gastric cancer cells in vitro . Decursin blocked autophagic flux by reducing the expression of lysosomal protein cathepsin C (CTSC) and attenuating its activity, thereby causing autophagic dysregulation (i.e., accumulation of LC3 and SQSTM1). Decursin also inhibited cell proliferation and cell cycle progression by inhibiting CTSC and E2F3, both of which were linked to gastric cancer aggressiveness. The antitumor effects of decursin were confirmed in vivo . We established spheroid and patient-derived organoid models and found that decursin decreased the growth of spheroids and patient-derived gastric organoids, as well as modulated the expression of CTSC and autophagy-related proteins. Hence, our findings uncovered a previously unknown mechanism by which decursin regulates cell growth and autophagy and suggests that decursin may act as a potential therapeutic agent that simultaneously inhibits cell growth and autophagy., Competing Interests: None., (AJCR Copyright © 2021.) more...

CXC chemokine receptor 7 (CXCR7) is highly expressed in various type of cancers and promotes cancer progression and metastasis. However, the biological role and regulation of CXCR7 in gastric cancer remains unclear, and little is known about compounds that modulate CXCR7. Here, we investigated the role of CXCR7 in gastric tumorigenesis, and the effects of decursin, which is derived from Angelica gigas Nakai, on CXCR7. Our results showed that CXCR7 significantly promoted growth of gastric cancer cells and increased migration and invasion, which was mediated by the STAT3/c-Myc pathway. We also confirmed that decursin had an antitumor effect through down-regulating the expression of CXCR7 in gastric cancer. Furthermore, apoptotic cell death was induced through the reduction of anti-apoptotic factors such as Bcl-2 in vitro and in vivo . Our findings show that CXCR7 in gastric cancer promotes cancer progression through the STAT3/c-Myc pathway and that decursin is a natural compound that may target CXCR7 in gastric cancer treatment., Competing Interests: None., (AJCR Copyright © 2019.) more...