Cuproptosis, a recently identified form of regulated cell death triggered by excess intracellular copper, has emerged as a promising cytotoxic strategy for cancer therapy. However, the therapeutic efficacy of copper ionophores such as elesclomol (ES) is often hindered by cellular copper homeostasis mechanisms that limit copper influx and cuproptosis induction. To address this challenge, we developed a nanoagent utilizing outer membrane vesicle (OMV) derived from Akkermansia muciniphila (Akk) for co-delivery of antioxidant 1 copper chaperone (Atox1)-targeting siRNA and ES (siAtox1/ES@OMV) to tumors. In vitro, we demonstrated that Atox1 knockdown via siRNA significantly disrupted copper export mechanisms, resulting in elevated intracellular copper levels. Simultaneously, ES facilitated efficient copper influx and mitochondrial transport, leading to Fe-S cluster depletion, increased proteotoxic stress, and robust cuproptosis. In vivo, siAtox1/ES@OMV achieved targeted tumor delivery and induced pronounced cuproptosis. Furthermore, leveraging the immunomodulatory properties of OMVs, siAtox1/ES@OMV promoted T-cell infiltration and the activation of tumor-reactive cytotoxic T cells, enhancing tumor immune responses. The combination of siAtox1/ES-induced cuproptosis and immunogenic cell death synergistically suppressed tumor growth in both subcutaneous breast cancer and orthotopic rectal cancer mouse models. This study highlights the potential of integrating copper homeostasis disruption with a copper ionophore using an immunomodulatory OMV-based vector, offering a promising combinatorial strategy for cancer therapy.

OBJECTIVE: To investigate the long-term outcome of laparoscope-assisted transanal total mesorectal excision (taTME) for rectal cancer. METHODS: Clinicopathological data of 29 patients with mid-low rectal cancer undergoing laparoscope-assisted taTME at Department of Gastrointestinal Surgery, the First Affiliated Hospital of Guangzhou Medical University from May 2010 to December 2015 were collected for the retrospective case-series study. All the operations were performed with transabdominal and transanal procedure simultaneously or sequentially. Perioperative presentations, pathological examinations, and oncologic outcomes were retrospectively analyzed. Long-term recurrence, metastasis and survival were assessed during follow-up. Outpatient clinic and telephone survey were used for follow-up. The follow-up time ended in December 2018. The overall survival (OS) rate and disease-free survival (DFS) rate were calculated by the Kaplan-Meier method. RESULTS: The average intra-operative blood loss was (75.9±9.5) ml (range,20 to 200). The average operating time was (223.6±4.1) minutes (range, 165 to 280). The average number of harvested lymph node was 22.3±2.0. The average length of pathological specimen was (13.1±0.6) cm. The average distal resection margin was (2.9±0.2) cm. 89.7% (26/29) of specimens was complete and 10.3% (3/29) near complete. Two cases (6.9%) had positive cutting circumferential margin. Median follow-up was 56 (range, 22 to 91) months. Local recurrence rate, distant metastasis rate, 3-year OS rate, 3-year DFS rate, 5-year OS rate, 5-year DFS rate were 10.3% (3/29), 20.7%(6/29), 96.6%, 83.2%, 87.6% and 79.6%, respectively. No incisional hernia or adhesive intestinal obstruction was found. CONCLUSION Long-term outcomes of mid-low rectal cancer patients undergoing laparoscope-assisted taTME are satisfactory.
Humans ; Laparoscopes ; Neoplasm Recurrence, Local ; Rectal Neoplasms ; surgery ; Rectum ; Retrospective Studies ; Transanal Endoscopic Surgery

AIM: To obverse the expression and localization of urocortin on ultrathin cryosections of syncytiotrophoblast of human term placenta with immunocytochemistry technique under transmission electron microscope. METHODS: The human term placenta tissue from Cesarean delivery and normal labor were fixed in 4% paraformaldehyde, and then divided into two parts. One part was for regular immunocytochemistry under microscope, and the other part was used to prepare ultrathin cryosections for immunocytochemistry under transmission electron microscope. RESULTS: 1.Uroncortin mainly distributed in cytoplasm of syncytiotrophoblast of human term placenta under microscope. Urocortin also appeared in cytoplasm in some stromal cells. 2. Under transmission electron microscope, the anti-urocortin gold particles were observed in cytoplasm of syncytioptrophoblast ultrathin cryosections and sited on rough-surfaced endoplasmic reticulum. The anti-urocortin gold particles also appeared on nucleus and nuclear membrane of syncytiotrophoblast. CONCLUSION: Syncytiotrophoblast of human term placenta synthesized and secreted urocortin. The internalization of urocortin within syncytiotrophoblast nuclear indicates that urocortin may act as intracrine.