YTHDF1 promotes the osteolytic bone metastasis of breast cancer via inducing EZH2 and CDH11 translation.

Bone metastasis is common in breast cancer and more effective therapies are required, however, its molecular mechanism is poorly understood. Additionally, the role of the m6A reader YTHDF1 in bone metastasis of breast cancer has not been reported. Here, we reveal that the increased expression of YTHDF1 is clinically correlated with breast cancer bone metastases. YTHDF1 promotes migration, invasion, and osteoblast adhesion and induces osteoclast differentiation of cancer cells in vitro and vivo. Mechanically, RNA-seq, MeRIP-seq and RIP-seq analysis, and molecular biology experiments demonstrate that YTHDF1 translationally enhances EZH2 and CDH11 expression by reading m6A-enriched sites of their transcripts. Moreover, adeno-associated virus (AAV) was used to deliver shYTHDF1 (shYTHDF1-AAV) in intratibial injection models, eliciting a significant suppressive effect on breast cancer bone metastatic formation and osteolytic destruction. Overall, we uncovered that YTHDF1 promotes osteolytic bone metastases of breast cancer by inducing EZH2 and CDH11 translation.

Tau Aggregation-Dependent Lipid Peroxide Accumulation Driven by the hsa_circ_0001546/14-3-3/CAMK2D/Tau Complex Inhibits Epithelial Ovarian Cancer Peritoneal Metastasis.

Intraperitoneal dissemination is the main method of epithelial ovarian cancer (EOC) metastasis, which is related to poor prognosis and a high recurrence rate. Circular RNAs (circRNAs) are a novel class of endogenous RNAs with covalently closed loop structures that are implicated in the regulation of tumor development. In this study, hsa_circ_0001546 is downregulated in EOC primary and metastatic tissues vs. control tissues and this phenotype has a favorable effect on EOC OS and DFS. hsa_circ_0001546 can directly bind with 14-3-3 proteins to act as a chaperone molecule and has a limited positive effect on 14-3-3 protein stability. This complex recruits CAMK2D to induce the Ser324 phosphorylation of Tau proteins, changing the phosphorylation status of Tau bound to 14-3-3 and ultimately forming the hsa_circ_0001546/14-3-3/CAMK2D/Tau complex. The existence of this complex stimulates the production of Tau aggregation, which then induces the accumulation of lipid peroxides (LPOs) and causes LPO-dependent ferroptosis. In vivo, treatment with ferrostatin-1 and TRx0237 rescued the inhibitory effect of hsa_circ_0001546 on EOC cell spreading. Therefore, based on this results, ferroptosis caused by Tau aggregation occurs in EOC cells, which is not only in Alzheimer's disease- or Parkinson's disease-related cells and this kind of ferroptosis driven by the hsa_circ_0001546/14-3-3/CAMK2D/Tau complex is LPO-dependent rather than GPX4-dependent is hypothesized.

Efficacy of epidural esketamine on postoperative sleep quality after laparoscopic and robotic lower abdominal surgeries: a study protocol for randomised, double-blind, controlled trial.

INTRODUCTION: Postoperative sleep disturbances significantly impair postoperative recovery. The administration of intravenous esketamine has been shown to potentially improve postoperative sleep quality. However, the effectiveness of epidural esketamine in improving postoperative sleep quality remains to be elucidated. This study aims to explore the impact of both intraoperative and postoperative use of epidural esketamine on the postoperative sleep quality of patients undergoing minimally invasive lower abdominal surgeries. METHODS AND ANALYSIS: This randomised, double-blind, parallel-group, placebo-controlled trial will be conducted at the Fudan University Shanghai Cancer Centre. A total of 128 adults undergoing minimally invasive lower abdominal surgeries will be randomly allocated in a 1:1 ratio to either the esketamine group or the placebo group. In the esketamine group, epidural esketamine will be administered intraoperatively (0.2 mg/kg) and postoperatively (25 mg). Postoperatively, all patients will receive epidural analgesia. The primary outcome of the study is the incidence of poor sleep quality on the third day after surgery. The sleep quality assessment will be conducted using the Pittsburgh Sleep Quality Index and a Numeric Rating Scale of sleep. The main secondary outcomes include postoperative pain and anxiety and depression scores. The postoperative pain, both rest pain and movement pain, will be assessed using a Numerical Rating Scale within 5 days after surgery. Anxiety and depression scores will be evaluated using the Hospital Anxiety and Depression Scale both before and after the surgery. Safety outcomes will include delirium, fidgeting, hallucinations, dizziness and nightmares. The analyses will be performed in accordance with intention-to-treat principle ETHICS AND DISSEMINATION: Ethics approval has been obtained from the Ethics Committee of the Shanghai Cancer Centre (2309281-9). Prior to participation, all patients will provide written informed consent. The results of the trial are intended to be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ChiCTR2300076862.

Single-cell profiling of the microenvironment in human bone metastatic renal cell carcinoma.

Bone metastasis is of common occurrence in renal cell carcinoma with poor prognosis, but no optimal treatment approach has been established for bone metastatic renal cell carcinoma. To explore the potential therapeutic targets for bone metastatic renal cell carcinoma, we profile single cell transcriptomes of 6 primary renal cell carcinoma and 9 bone metastatic renal cell carcinoma. We also include scRNA-seq data of early-stage renal cell carcinoma, late-stage renal cell carcinoma, normal kidneys and healthy bone marrow samples in the study to better understand the bone metastasis niche. The molecular properties and dynamic changes of major cell lineages in bone metastatic environment of renal cell carcinoma are characterized. Bone metastatic renal cell carcinoma is associated with multifaceted immune deficiency together with cancer-associated fibroblasts, specifically appearance of macrophages exhibiting malignant and pro-angiogenic features. We also reveal the dominance of immune inhibitory T cells in the bone metastatic renal cell carcinoma which can be partially restored by the treatment. Trajectory analysis showes that myeloid-derived suppressor cells are progenitors of macrophages in the bone metastatic renal cell carcinoma while monocytes are their progenitors in primary tumors and healthy bone marrows. Additionally, the infiltration of immune inhibitory CD47+ T cells is observed in bone metastatic tumors, which may be a result of reduced phagocytosis by SIRPA-expressing macrophages in the bone microenvironment. Together, our results provide a systematic view of various cell types in bone metastatic renal cell carcinoma and suggest avenues for therapeutic solutions.

Anesthesia-related intervention for long-term survival and cancer recurrence following breast cancer surgery: A systematic review of prospective studies.

OBJECTIVE: Anesthesia is correlated with the prognosis of cancer surgery. However, evidence from prospective studies focusing on breast cancer is currently limited. This systematic review aimed to investigate the effect of anesthesia-related interventions on oncological outcomes following breast cancer surgery in prospective studies. METHODS: Literature searches were performed from inception to June. 2023 in the Pubmed, Web of Science, Embase, and ClinicalTrials databases. The main inclusion criteria comprised a minimum of one-year follow-up duration, with oncological outcomes as endpoints. Anesthesia-related interventions encompassed, but were not limited to, type of anesthesia, anesthetics, and analgesics. The risk of bias was assessed using the Cochrane Risk of Bias Tool. RESULTS: A total of 9 studies were included. Anesthesia-related interventions included paravertebral nerve block (3), pectoral nerve block (1), sevoflurane (2), ketorolac (2), and infiltration of lidocaine (1). Cancer recurrence, metastasis, disease-free survival, or (and) overall survival were assessed. Among all included studies, only infiltration of lidocaine was found to prolong disease-free survival and overall survival. CONCLUSION: Regional anesthesia and propofol did not improve oncological outcomes following breast cancer surgery. The anti-tumorigenic effect of ketorolac warrants future studies with larger sample sizes. Perioperative infiltration of lidocaine around the tumor may be a promising anti-tumorigenic intervention that can prolong overall survival in patients with early breast cancer.