Purpose: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, necessitating the identification of novel therapeutic targets. The E3 ubiquitin ligase WW domain-containing E3 ubiquitin protein ligase 2 (WWP2) has been implicated in various cancers, yet its specific role and underlying molecular mechanisms in CRC are poorly understood. This study aimed to investigate the functional role of WWP2 in CRC progression and to elucidate its regulatory mechanisms. Methods: WWP2 expression was evaluated in CRC patient tissues and cell lines using immunohistochemistry, quantitative real-time polymerase chain reaction, and western blotting. The biological functions of WWP2 were assessed using in vitro assays for cell proliferation, migration, and invasion following adenovirus-mediated overexpression. The molecular mechanism was investigated by analyzing the protein expression levels of p53 and its downstream target, p21, via western blot. An in vivo xenograft mouse model was used to confirm the oncogenic role of WWP2. Results: WWP2 expression was significantly upregulated in CRC tissues. Overexpression of WWP2 promoted CRC cell proliferation, migration, and invasion. Mechanistically, increased WWP2 expression led to a marked reduction in the protein levels of the tumor suppressor p53. Consequently, the expression of the p53 downstream target, the cell cycle inhibitor p21, was also suppressed. In the xenograft model, WWP2 overexpression significantly enhanced tumor growth. Conclusion Our findings demonstrate that WWP2 functions as an oncogene in CRC. It promotes cancer progression by destabilizing the tumor suppressor p53 and downregulating p21. This study highlights the WWP2-p53-p21 axis as a potential novel therapeutic target for CRC.

Purpose: This study investigates risk factors for recurrence in patients who underwent laparoscopic primary closure (PC) for pyloroduodenal ulcer perforation (PUP). Methods: We retrospectively analyzed data from patients who underwent laparoscopic PC with or without highly selective vagotomy (HSV) for PUP at a tertiary hospital from 2010 to 2019. Demographics, surgical outcomes, proton pump inhibitor (PPI) use, Helicobacter pylori status, and endoscopic findings were reviewed. Long-term (5 years) endoscopic and clinical outcomes regarding ulcer and perforation recurrence, were collected. Results: A total of 139 patients were included in the analysis. Of these, 109 (78.4%) were male, and 76 (54.7%) were current smokers. Ninety-five patients (68.3%) underwent PC only, while 44 (31.7%) received PC + HSV. During the follow-up period, ulcer recurrence was observed in 19 patients (13.7%) and perforation recurrence in 9 (6.5%). In Cox proportional analysis for ulcer recurrence, smoking (hazard ratio [HR], 6.476; 95% confidence interval [CI], 1.834–22.873; P = 0.004) and older age (HR, 1.049; 95% CI, 1.012–1.088; P = 0.009) were identified as significant factors. For peptic ulcer perforation recurrence, smoking (HR, 19.129; 95% CI, 2.048–178.702; P = 0.010) and older age (HR, 1.062; 95% CI, 1.009–1.118; P = 0.021) were significant. No significant associations were found between sex, duration of PPI therapy, H. pylori eradication success, or surgery type and the risk of either ulcer or perforation recurrence. Conclusion Smoking and age are important factors for recurrence following laparoscopic PC for PUP. These findings emphasize the need for smoking cessation and close postoperative monitoring.

Purpose: Papillary thyroid carcinoma (PTC) is the most prevalent endocrine malignancy, and the global incidence has been steadily increasing over the years. Although PTC generally exhibits favorable prognosis, a subset of patients experiences aggressive progression and increased mortality. Current prognostic approaches, reliant on clinic-pathological factors, have limitations, underscoring the need for innovative biomarkers. MicroRNAs (miRs) have emerged as promising candidates due to their roles in cellular processes and cancer progression. Among them, the present study investigated the role of miR-18b in PTC, exploring its potential as a prognostic biomarker. Methods: Utilizing PTC cell lines (TPC1, K1), we examined miR-18b expression and its regulatory effects. The present study used web-based tools to predict the target of miR-18b and to investigate the prognostic impact of miR-18b on thyroid cancer. Results: Through a series of cell proliferation, invasion assay, gap closure, and colony formation assays, we identified that miR-18b suppresses PTC aggressiveness. Dual-luciferase assays confirmed that miR-18b directly targeted the 3’-untranslated region of CDK2 and suppressed the expression of CDK2. In addition, miR-18b significantly attenuates the interaction between cyclin A or cyclin E with cyclin-dependent kinase 2 according to co-immunoprecipitation assay.Western blotting of cell cycle proteins and flow cytometry revealed miR-18b–induced cell cycle arrest and apoptosis. Conclusion Our findings underscore miR-18b’s potential as a biomarker for predicting the prognosis of PTC and suggest that it functions through direct regulation of CDK2, influencing cell cycle dynamics. This study not only enhances our understanding of miR-18b in thyroid cancer but also highlights its potential in refining prognostic evaluations and therapeutic strategies.

Objective: Chemoresistant-epithelial ovarian cancer (EOC) has a poor prognosis, prompting the search for new therapeutic drugs. The diphenylbutylpiperidine (DPBP) class of antipsychotic drugs used in schizophrenia has shown anticancer effects. This study aimed to investigate the preclinical efficacy of penfluridol, fluspirilene, and pimozide (DPBP) using in vitro and in vivo models of EOC. Methods: Human EOC cell lines A2780, HeyA8, SKOV3ip1, A2780-CP20, HeyA8-MDR, and SKOV3-TR were treated with penfluridol, fluspirilene, and pimozide, and cell proliferation, apoptosis, and migration were assessed. The preclinical efficacy of DPBP was also investigated using in vivo mouse models, including cell lines and patient-derived xenografts (PDX) of EOC. Results: DPBP drugs significantly decreased cell proliferation in chemosensitive (A2780, HeyA8, and SKOV3ip1) and chemoresistant (A2780-CP20, HeyA8-MDR, and SKOV3-TR) cell lines. Among these drugs, penfluridol exerted a relatively stronger cytotoxic effect on all cell lines. Penfluridol significantly increased apoptosis and inhibited migration of EOC cells. In the cell line xenograft mouse model with HeyA8, the penfluridol group showed significantly decreased tumor weight compared with the control group. In the paclitaxel-resistant model with HeyA8-MDR, the penfluridol group had significantly decreased tumor weight compared with the paclitaxel or control groups. Penfluridol exerted anticancer effects on the PDX model. Conclusion Penfluridol exerted significant anticancer effects on EOC cells and xenograft models, including PDX. Thus, penfluridol therapy, as a drug repurposing strategy, might be a potential therapeutic for EOCs.

Background: Bulky or multiple lymph node (LN) metastases are associated with poor prognosis in cervical cancer, and the size or number of LN metastases is not yet reflected in the staging system and therapeutic strategy. Although the therapeutic effects of surgical resection of bulky LNs before standard treatment have been reported in several retrospective studies, wellplanned randomized clinical studies are lacking. Therefore, the aim of the Korean Gynecologic Oncology Group (KGOG) 1047/DEBULK trial is to investigate whether the debulking surgery of bulky or multiple LNs prior to concurrent chemoradiation therapy (CCRT) improves the survival rate of patients with cervical cancer IIICr diagnosed by imaging tests. Methods The KGOG 1047/DEBULK trial is a phase III, multicenter, randomized clinical trial involving patients with bulky or multiple LN metastases in cervical cancer IIICr. This study will include patients with a short-axis diameter of a pelvic or para-aortic LN ≥2 cm or ≥3 LNs with a short-axis diameter ≥1 cm and for whom CCRT is planned. The treatment arms will be randomly allocated in a 1:1 ratio to either receive CCRT (control arm) or undergo surgical debulking of bulky or multiple LNs before CCRT (experimental arm). CCRT consists of extended-field external beam radiotherapy/pelvic radiotherapy, brachytherapy and LN boost, and weekly chemotherapy with cisplatin (40 mg/m 2 ), 4–6 times administered intravenously.The primary endpoint will be 3-year progression-free survival rate. The secondary endpoints will be 3-year overall survival rate, treatment-related complications, and accuracy of radiological diagnosis of bulky or multiple LNs.

Background: The rapid economic development of South Korea provides a unique model to study changes in the clinical characteristics, treatment approaches, and clinical outcomes of patients with rheumatic mitral stenosis (MS) relative to socioeconomic growth. Methods: From the Multicenter mitrAl STEnosis with Rheumatic etiology (MASTER) registry, 2,337 patients diagnosed with moderate or severe rheumatic MS between January 2001 and December 2020 were analyzed. Patients were grouped into consecutive 5-year intervals based on their year of diagnosis. Clinical characteristics, echocardiographic data, and clinical outcomes were assessed. Results: Over 20 years, the severity of mitral stenosis increased from 79.1% to 90.2%; similarly, the average age at diagnosis increased from 54.3 to 63.0 years (all P < 0.001). Comorbidities such as hypertension and atrial fibrillation increased (6.3% to 29.5% and 41.4% to 46.9%, respectively; all P for trend < 0.05). The rate of mitral intervention within five years after diagnosis increased from 31.2% to 47.4% (P for trend < 0.001). However, clinical outcomes of rheumatic mitral stenosis deteriorated over time in the composite outcomes (log-rank test, P < 0.001). Conversely, the incidence of stroke remained stable (60.6–73.7%; P < 0.001), which might be attributed to the increased use of anticoagulation therapy. Conclusion This study observed an increase in patient age, comorbidities, and valve disease severity as the country transitioned from a developing to developed status. Despite a rise in mitral valve interventions, clinical outcomes deteriorated over 20 years, highlighting the need for modified treatment approaches to improve patient outcomes.

Background: Bulky or multiple lymph node (LN) metastases are associated with poor prognosis in cervical cancer, and the size or number of LN metastases is not yet reflected in the staging system and therapeutic strategy. Although the therapeutic effects of surgical resection of bulky LNs before standard treatment have been reported in several retrospective studies, wellplanned randomized clinical studies are lacking. Therefore, the aim of the Korean Gynecologic Oncology Group (KGOG) 1047/DEBULK trial is to investigate whether the debulking surgery of bulky or multiple LNs prior to concurrent chemoradiation therapy (CCRT) improves the survival rate of patients with cervical cancer IIICr diagnosed by imaging tests. Methods The KGOG 1047/DEBULK trial is a phase III, multicenter, randomized clinical trial involving patients with bulky or multiple LN metastases in cervical cancer IIICr. This study will include patients with a short-axis diameter of a pelvic or para-aortic LN ≥2 cm or ≥3 LNs with a short-axis diameter ≥1 cm and for whom CCRT is planned. The treatment arms will be randomly allocated in a 1:1 ratio to either receive CCRT (control arm) or undergo surgical debulking of bulky or multiple LNs before CCRT (experimental arm). CCRT consists of extended-field external beam radiotherapy/pelvic radiotherapy, brachytherapy and LN boost, and weekly chemotherapy with cisplatin (40 mg/m 2 ), 4–6 times administered intravenously.The primary endpoint will be 3-year progression-free survival rate. The secondary endpoints will be 3-year overall survival rate, treatment-related complications, and accuracy of radiological diagnosis of bulky or multiple LNs.

Background: Bulky or multiple lymph node (LN) metastases are associated with poor prognosis in cervical cancer, and the size or number of LN metastases is not yet reflected in the staging system and therapeutic strategy. Although the therapeutic effects of surgical resection of bulky LNs before standard treatment have been reported in several retrospective studies, wellplanned randomized clinical studies are lacking. Therefore, the aim of the Korean Gynecologic Oncology Group (KGOG) 1047/DEBULK trial is to investigate whether the debulking surgery of bulky or multiple LNs prior to concurrent chemoradiation therapy (CCRT) improves the survival rate of patients with cervical cancer IIICr diagnosed by imaging tests. Methods The KGOG 1047/DEBULK trial is a phase III, multicenter, randomized clinical trial involving patients with bulky or multiple LN metastases in cervical cancer IIICr. This study will include patients with a short-axis diameter of a pelvic or para-aortic LN ≥2 cm or ≥3 LNs with a short-axis diameter ≥1 cm and for whom CCRT is planned. The treatment arms will be randomly allocated in a 1:1 ratio to either receive CCRT (control arm) or undergo surgical debulking of bulky or multiple LNs before CCRT (experimental arm). CCRT consists of extended-field external beam radiotherapy/pelvic radiotherapy, brachytherapy and LN boost, and weekly chemotherapy with cisplatin (40 mg/m 2 ), 4–6 times administered intravenously.The primary endpoint will be 3-year progression-free survival rate. The secondary endpoints will be 3-year overall survival rate, treatment-related complications, and accuracy of radiological diagnosis of bulky or multiple LNs.

Purpose: This study aimed to investigate the potential role of copine-1 (CPNE1), a calcium-dependent membrane-binding protein encoded by the CPNE1 gene, in colorectal cancer (CRC). Despite previous research on the involvement of copine family members in various solid tumors, the specific role of CPNE1 in CRC remains poorly understood. Methods: We conducted clinicopathological analysis and functional studies to explore the impact of CPNE1 in human CRC.We examined the expression levels of CPNE1 in CRC patients and correlated it with invasive depth, lymph node metastasis, distant metastasis, lymphatic invasion, and TNM stage. Additionally, we performed experiments to assess the functional consequences of CPNE1 knockdown in CRC cells, including proliferation, colony formation, migration, invasion, and the expression of key regulators involved in the cell cycle and epithelial-mesenchymal transition (EMT). Furthermore, we evaluated the effects of CPNE1 knockdown on tumor growth using a xenograft mouse model. Results: High expression of CPNE1 was significantly associated with advanced tumor features in CRC patients. CPNE1 knockdown in CRC cells led to impaired abilities in proliferation, colony formation, migration, and invasion. Furthermore, CPNE1 silencing resulted in the suppression of protein expression related to the cell cycle and EMT. In the xenograft mouse model, CPNE1 knockdown inhibited tumor growth. Conclusion CPNE1 plays a crucial role in promoting tumorigenesis and metastasis in human CRC. By regulating the cell cycle and EMT, CPNE1 influences critical cellular processes at the membrane-cytoplasm interface. These results provide valuable insights into the potential development of novel therapeutic strategies for CRC targeting CPNE1.

Objective: Fenbendazole (FZ) has potential anti-cancer effects, but its poor water solubility limits its use for cancer therapy. In this study, we investigated the anti-cancer effect of FZ with different drug delivery methods on epithelial ovarian cancer (EOC) in both in vitro and in vivo models. Methods: EOC cell lines were treated with FZ and cell proliferation was assessed. The effect of FZ on tumor growth in cell line xenograft mouse model of EOC was examined according to the delivery route, including oral and intraperitoneal administration. To improve the systemic delivery of FZ by converting fat-soluble drugs to hydrophilic, we prepared FZ-encapsulated poly(D,L-lactide-co-glycolide) acid (PLGA) nanoparticles (FZ-PLGA-NPs). We investigated the preclinical efficacy of FZ-PLGA-NPs by analyzing cell proliferation, apoptosis, and in vivo models including cell lines and patient-derived xenograft (PDX) of EOC. Results: FZ significantly decreased cell proliferation of both chemosensitive and chemoresistant EOC cells. However, in cell line xenograft mouse models, there was no effect of oral FZ treatment on tumor reduction. When administered intraperitoneally, FZ was not absorbed but aggregated in the intraperitoneal space. We synthesized FZ-PLGA-NPs to obtain water solubility and enhance drug absorption. FZ-PLGA-NPs significantly decreased cell proliferation in EOC cell lines. Intravenous injection of FZ-PLGA-NP in xenograft mouse models with HeyA8 and HeyA8-MDR significantly reduced tumor weight compared to the control group. FZ-PLGA-NPs showed anti-cancer effects in PDX model as well. Conclusion FZ-incorporated PLGA nanoparticles exerted significant anti-cancer effects in EOC cells and xenograft models including PDX. These results warrant further investigation in clinical trials.