Prominin 1 Significantly Correlated with Bone Metastasis of Breast Cancer and Influenced the Patient's Prognosis.

Background: This study is aimed at identifying the important biomarkers associated with bone metastasis (BM) in breast cancer (BRCA). Methods: The GSE175692 dataset was used to detect significant differential expressed genes (DEGs) between BRCA samples with or without BM, and DEG-related pathways were then explored. Further, we constructed the protein-protein interaction (PPI) network on GEGs and filtered 5 vital nodes. We then performed the Cox regression, Kaplan-Meier analysis, nomogram, and ROC curve to filter the most significant prognosis genes. The GSE14020 and GSE124647 datasets were used to verify the expression and prognostic value of hub genes, respectively. Finally, the gene set enrichment analysis (GSEA) was performed to reveal the potential mechanism. Results: Totally, 74 DEGs were detected, which mainly correlated with infectious disease, signaling molecules, and interaction. The 5 important DEGs were then filtered, and the Cox regression further showed that 2 genes, including prominin 1 (PROM1) and C-C motif chemokine ligand 2 (CCL2), were related to the prognosis of BRCA metastasis patients. Especially, PROM1 presented a better prognostic performance on the survival probability of patients than CCL2. Verification analysis further confirmed the abnormal expression and significant prognostic influence of PROM1. Finally, GSEA revealed that PROM1 was negatively related to IGF1 and mTOR pathways in BRCA metastasis. Conclusion: PROM1 was an important biomarker associated with BRCA bone metastasis and affected the prognosis of metastatic BRCA patients. It may play a vital role in metastatic BRCA by negatively regulating IGF1 and mTOR pathways.

Prevalence and clinical outcomes of germline mutations in BRCA1/2 and PALB2 genes in 2769 unselected breast cancer patients in China.

To gain more information on the prevalence of germline mutations in BRCA1/2 and PALB2 genes in the Chinese population, and to explore the effects of the mutation status of these genes on clinical outcomes in patients with breast cancer, we performed a screening for BRCA1/2 and PALB2 mutations in a consecutive series of unselected breast cancer patients in the Chinese population. A total of 2,769 cases were enrolled between June 1993 and September 2017. All of the exons and exon-intron boundaries of the BRCA1/2 and PALB2 genes were screened with next-generation sequencing. Of the 2,769 breast cancer patients, BRCA1, BRCA2 and PALB2 mutations accounted for 2.7% (n = 74), 2.7% (n = 76), and 0.9% (n = 24), respectively. The BRCA1 gene had the highest mutation frequency in patients with triple-negative breast cancer (TNBC), which was 9.6% (n = 42), while the BRCA2 gene had the highest mutation frequency in patients with Luminal, which was 3.2% (n = 58). The disease-free survival (DFS) of BRCA1 mutation carriers was significantly lower than that of noncarriers (adjusted HR = 2.20, 95% CI = 1.15-4.18, p = 0.017). The mutation status of the PALB2 gene was significantly associated with the decline in overall survival (OS) (adjusted HR = 8.38, 95% CI = 2.19-32.11, p = 0.002). No significant difference was found between BRCA2 pathogenic mutation carriers and noncarriers. These results demonstrate that BRCA1 mutation status may be associated with a worse disease progression in patients with breast cancer, and women who harbored a PALB2 mutation might be at a higher risk of death due to breast cancer compared to noncarriers.

The relationship between hepatic lipase gene variant and advanced age-related macular degeneration: a meta-analysis.

IMPORTANCE: To date, no consistency exists across studies that have evaluated the relationship between hepatic lipase gene (LIPC) rs10468017 variant and advanced age-related macular degeneration (AMD). OBJECTIVE: To summarize all relevant evidence for a relationship between LIPC variant and advanced AMD. DATA SOURCES: The PubMed and Embase databases were searched for studies potentially eligible in any language published up to September 15, 2013. STUDY SELECTION: Case-control studies of 2 or more comparison groups that included patients with advanced AMD (choroidal neovascularization or geographic atrophy). DATA EXTRACTION AND SYNTHESIS: Allele frequencies and genotype distributions of rs10468017 variant. MAIN OUTCOMES AND MEASURES: Summary odds ratios (ORs) and 95% CIs were estimated under different genetic models using meta-analytic methods. A stratified analysis by advanced AMD subtypes and race/ethnicity was performed, as well as a sensitivity analysis. RESULTS: Data from 10 case-control studies were included in the meta-analysis. The rs10468017 variant (C→T) showed significant summary ORs of 0.81 (95% CI, 0.75-0.88), 0.83 (95% CI, 0.70-0.98), and 0.60 (95% CI, 0.44-0.81) under the allelic (T vs C), heterozygous (TC vs CC), and homozygous (TT vs CC) models, respectively. Carrying at least 1 copy of the T allele decreased the risk of choroidal neovascularization and geographic atrophy by 20% (OR, 0.80; 95% CI, 0.74-0.87) and 29% (OR, 0.71; 95% CI, 0.59-0.86), respectively. The pooled OR for white race/ethnicity under an allelic model was 0.80 (95% CI, 0.74-0.87). The sensitivity analysis indicated the robustness of our findings, and no evidence of publication bias was observed in our meta-analysis. CONCLUSIONS AND RELEVANCE: Our meta-analysis indicates that LIPC rs10468017 variant is associated with a reduced risk of advanced AMD. This finding may lead to insights regarding the pathogenesis, prevention, and treatment of AMD.

Rapamycin interacts synergistically with idarubicin to induce T-leukemia cell apoptosis in vitro and in a mesenchymal stem cell simulated drug-resistant microenvironment via Akt/mammalian target of rapamycin and extracellular signal-related kinase signaling pathways.

T-cell acute lymphoblastic leukemias (T-ALLs) are clonal lymphoid malignancies with a poor prognosis, and still a lack of effective treatment. Here we examined the interactions between the mammalian target of rapamycin (mTOR) inhibitor rapamycin and idarubicin (IDA) in a series of human T-ALL cell lines Molt-4, Jurkat, CCRF-CEM and CEM/C1. Co-exposure of cells to rapamycin and IDA synergistically induced T-ALL cell growth inhibition and apoptosis mediated by caspase activation via the intrinsic mitochondrial pathway and extrinsic pathway. Combined treatment with rapamycin and IDA down-regulated Bcl-2 and Mcl-1, and inhibited the activation of phosphoinositide 3-kinase (PI3K)/mTOR and extracellular signal-related kinase (ERK). They also played synergistic pro-apoptotic roles in the drug-resistant microenvironment simulated by mesenchymal stem cells (MSCs) as a feeder layer. In addition, MSCs protected T-ALL cells from IDA cytotoxicity by up-regulating ERK phosphorylation, while rapamycin efficiently reversed this protective effect. Taken together, we confirm the synergistic antitumor effects of rapamycin and IDA, and provide an insight into the potential future clinical applications of combined rapamycin-IDA regimens for treating T-cell malignancies.