ABSTRACT
Distant metastasis remains the primary cause of morbidity in patients with breast cancer. Hence, the development of more efficacious strategies and the exploration of potential targets for patients with metastatic breast cancer are urgently needed. The data of six patients with breast cancer brain metastases (BCBrM) from two centres were collected, and a comprehensive landscape of the entire tumour ecosystem was generated through the utilisation of single-cell RNA sequencing. We utilised the Monocle2 and CellChat algorithms to investigate the interrelationships among each subcluster. In addition, multiple signatures were collected to evaluate key components of the subclusters through multi-omics methodologies. Finally, we elucidated common expression programs of malignant cells, and experiments were conducted in vitro and in vivo to determine the functions of interleukin enhancer-binding factor 2 (ILF2), which is a key gene in the metastasis module, in BCBrM progression. We found that subclusters in each major cell type exhibited diverse characteristics. Besides, our study indicated that ILF2 was specifically associated with BCBrM, and experimental validations further demonstrated that ILF2 deficiency hindered BCBrM progression. Our study offers novel perspectives on the heterogeneity of BCBrM and suggests that ILF2 could serve as a promising biomarker or therapeutic target for BCBrM.
ABSTRACT
BACKGROUND: The prognostic-related factors of lung invasive mucinous adenocarcinoma(IMA) are unclear because of its rarity. Various inflammation-based biomarkers were reported to predict the survival of malignant diseases. This study aims to explore the prognostic significance of the systemic immune-inflammation index(SII), which is calculated using absolute platelet, neutrophil, and lymphocyte counts, among patients with invasive mucinous adenocarcinoma. METHODS: From January 2015 to December 2019, 106 patients were identified as having IMA accepted radical resection and enrolled in the retrospective study. We analyzed the overall survival and disease-free survival using the Kaplan-Meier method and log-rank test. Receiver operating characteristic curve was used to find the optimal SII cut-off values for survival. A Cox regression model was carried out for multivariable analyses. RESULTS: The study cohort included 53 men and 53 women, with a mean age of 60 years (range 29 to 78 years, median 61 years). The median SII measured before surgery was 378.47 (range: 79.87-1701.97). ROC analyses revealed that the optimal cut-off values of SII was 379.43 for predicting both OS and DFS. An elevated SII (≥379.43) was observed in 52 patients (49.1 %), and was associated with younger age (P = 0.02), advanced T staging (P = 0.042), lymph node metastasis (P = 0.018) and pneumonic-type IMA (P = 0.018). Multivariable analysis showed that SII and pneumonic-type IMA were independent prognostic predictors of OS and DFS in radically resected IMA patients (P < 0.05). CONCLUSION: High SII is correlated with worse outcome and can be a novel prognostic biomarker for IMA patients accepted radical surgery.
ABSTRACT
Cisplatin resistance frequently occurs in esophageal squamous cell carcinoma (ESCC). The underlying mechanism for cisplatin resistance in ESCC remains largely obscure. Here we report that entinostat reversed cisplatin resistance in ESCC both in vitro and in vivo by induction of apoptosis and inhibition of cell proliferation, accompanied by a decrease of multidrug resistance gene 1 (MDR1), P-Src, Mcl-1, Cyclin D1 and an increase of cleaved PARP. MDR1 expression was associated with worsen survival of ESCC patients with cisplatin-based chemotherapy. Dasatinib potentiated entinostat to overcome cisplatin resistance. By inhibiting Src, dasatinib reduced the expression of MDR1 and Mcl-1. Furthermore, Obatoclax, an inhibitor of Mcl-1, obviously decreased the expression of MDR1, suggesting that entinostat might surmount cisplatin resistance in ESCC via a Src-Mcl-1-MDR1 pathway. Interestingly, cisplatin also enhanced the effect of entinostat both in vitro and in vivo. Our data disclose a molecular basis that entinostat reverses cisplatin resistance, and provide a promising strategy with combinatorial drugs to treat cisplatin resistant ESCC patients.
