Efficacy of utidelone plus capecitabine versus capecitabine for heavily pretreated, anthracycline- and taxane-refractory metastatic breast cancer: final analysis of overall survival in a phase III randomised controlled trial.

BACKGROUND: Primary analysis of the phase III trial BG01-1323L demonstrated that utidelone plus capecitabine significantly improved progression-free survival (PFS) and overall response rate (ORR) versus capecitabine alone in heavily-pretreated patients with metastatic breast cancer (MBC). Here, we report the final overall survival (OS) analysis and updates of other endpoints. PATIENTS AND METHODS: In total, 405 patients were randomised 2:1 to receive utidelone (30 mg/m2 IV daily, days 1-5, over 90 min) plus capecitabine (1000 mg/m2 orally b.i.d., days 1-14) or capecitabine alone (1250 mg/m2 orally b.i.d., days 1-14) every 21 days. The secondary endpoint, OS, was estimated using the Kaplan-Meier product-limit approach at a two-sided alpha level of 0.05 after the prespecified 310 death events had been reached. Exploratory analyses of the primary endpoint, PFS, and the secondary endpoint, ORR, were also done. Safety was analysed in patients who had at least one dose of study drug. RESULTS: At the final OS analysis, the median duration of follow-up was 19.6 months in the utidelone plus capecitabine group and 15.4 months in the capecitabine alone group. In the intention-to-treat population, 313 deaths had occurred at data cut-off, 203 of 270 patients in the combination group and 110 of 135 in the monotherapy group. Median OS in the combination group was 19.8 months compared with 16.0 months in the monotherapy group [hazard ratio (HR) = 0.75, 95% confidence intervals (CI) 0.59-0.94, P = 0.0142]. The updated analysis of PFS and ORR showed that the combination therapy remained superior to monotherapy. Safety results were similar to those previously reported with respect to incidence, severity and specificity. No late-emerging toxicities or new safety concerns occurred. CONCLUSIONS: For heavily-pretreated, anthracycline- and taxane-resistant MBC patients, utidelone plus capecitabine significantly improved OS versus capecitabine alone. These results support the use of utidelone plus capecitabine as a novel therapeutic regimen for patients with MBC.

Crop milk protein is synthesised following activation of the IRS1/Akt/TOR signalling pathway in the domestic pigeon (Columba livia).

The experiment was conducted to study whether insulin receptor substance 1 (IRS1) / Protein kinase B (Akt)/target of the rapamycin (TOR) signalling pathway activation stimulates crop milk protein synthesis in the domestic pigeon (Columba livia). Crop milk was collected from ten 1-d-old squabs and analysed for nutrient content. During the non-breeding period and the first day of lactation, blood samples were collected from 5 pairs of breeding pigeons and the levels of prolactin and insulin were determined. Crop samples were collected from 5 pairs of breeders at d 14 and 16 of the incubation period and d 1, 3 and 7 of the lactation period. Crop samples were evaluated for changes in crop weight and thickness and changes in the expression patterns of IRS1/Akt/TOR signalling pathway-related proteins. The results demonstrated that prolactin induces a gradual increase in the relative weight and thickness of the crop, with crops reaching a maximum size at the third day of lactation. Pigeon crop milk contains 64.1% crude protein and 29.7% crude fat based on dry weight. Serum prolactin and insulin levels in the lactation period were significantly higher than those in the non-breeding period. Compared with non-breeding pigeons, the expression of the phosphorylated IRS1 phosphorylated Akt, phosphorylated TOR, phosphorylated ribosomal protein S6 kinase, phosphorylated S6, phosphorylated eukaryotic initiation factor 4E binding protein 1 and eukaryotic initiation factor 4E were significantly up-regulated in the crop of pigeons in the lactation period. In conclusion, prolactin might induce changes in crop tissue and form the physiological structure for crop milk synthesis. Furthermore, the synthesis of crop milk protein is regulated by activation of the IRS1/Akt/TOR signalling pathway.

Skin immune response in the zebrafish, Danio rerio (Hamilton), to Aeromonas hydrophila infection: a transcriptional profiling approach.

Skin plays an important role in innate immune responses to bacterial infection, but its molecular mechanism remains unclear in fish. The transcriptional profiling of the skin immune response to Aeromonas hydrophila infection of the zebrafish, Danio rerio (Hamilton), was performed by Affymetrix microarray analysis. The results showed that 538 genes were differentially expressed, of which 388 genes were up-regulated and 150 genes were down-regulated. The expression patterns for 106 representative genes were observed to be up-regulated in zebrafish skin at 24 and 36 h post-infection, and gene expression changes were clearly greater at 36 h. Gene Ontology classification indicated that 222 genes were significantly associated with the skin immunity, including complement activation, acute-phase response, stress response, chemotaxis and apoptosis. Further Kyoto Encyclopedia of Genes and Genomes analysis showed that the significant pathways included MAPK, p53, Wnt, TGF-ß, Notch, ErbB, JAK-STAT, VEGF, mTOR and Calcium signalling in skin immune responses, and several genes (e.g. akt2l, frap1, nras, rac1, xiap) were found to be involved in signalling networks. Moreover, expression changes in nine selected genes were verified by real-time qPCR analysis. This is the first known report on transcriptome analysis in the skin of zebrafish against the pathogen A. hydrophila.

MiR-566 protects the malignant progression of breast cancer by negatively regulating WNT6.

OBJECTIVE: To elucidate the relationship between microRNA-566 (miR-566) and prognosis in breast cancer (BC) and to clarify the influences of miR-566 and WNT6 in its locus region on BC progression. PATIENTS AND METHODS: MiR-566 and WNT6 levels in 44 pairs of BC samples were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The influences of miR-566 on clinical features and prognosis in BC patients were analyzed. According to the differential expressions of miR-566 in the tested BC cell lines, MDA-MB-231 and MCF-7 cells were selected for generating miR-566 knockdown and overexpression models, respectively. Cell counting kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine (EdU) and transwell assays were conducted to explore the role of miR-566 in BC cell functions. Besides, the regulatory interaction between miR-566 and its downstream gene WNT6 was assessed by performing Dual-Luciferase reporter assay. Finally, the co-regulation of miR-566 and WNT6 in BC cell functions was examined. RESULTS: MiR-566 was downregulated in BC tissues. BC patients with a low expression level of miR-566 were prone to suffering a large tumor size, advanced tumor grade, high incidence of lymphatic metastasis and poor prognosis. Overexpression of miR-566 weakened proliferative and migratory abilities in MCF-7 cells, whereas knockdown of miR-566 produced the opposite results in MDA-MB-231 cells. WNT6 was the target gene binding to miR-566, and they displayed a negative expression correlation in BC tissues. Regulatory effects of miR-566 on BC progression could be reversed by WNT6. CONCLUSIONS: MiR-566 is closely related to tumor size, tumor grade, lymphatic metastasis and prognosis in BC. It protects the malignant progression of BC by negatively regulating WNT6.

Norepinephrine attenuates CXCR4 expression and the corresponding invasion of MDA-MB-231 breast cancer cells via ß2-adrenergic receptors.

OBJECTIVE: The growing evidence from laboratory and clinical studies has shown that the stress hormone, norepinephrine, and chronic stress promote tumor progression in a variety of tumor types. Chemokines and chemokine receptors have been shown to play a pivotal role in tumor progression. Recently, norepinephrine was reported to have a significant effect on macrophage migration by altering the expression of the chemokine receptor CCR2. MATERIALS AND METHODS: We investigated whether chemokines and their receptors are involved in the effects of norepinephrine on breast cancer. First, we used microarray analyses to detect the alteration of 128 chemotactically relevant genes after MDA-MB-231 cells were treated for 12 h with 100 µM norepinephrine. The CXCR4 gene demonstrated the greatest response to norepinephrine treatment, with a reduction of transcription of 95.7%, and was the focus of subsequent investigations. Real-time reverse transcription-PCR was used to determine the level of CXCR4 transcription after treatment with norepinephrine at various concentrations and for different durations. RESULTS: The results revealed that norepinephrine reduced CXCR4 transcription in a dose-dependent manner. Norepinephrine was also found to exert a negative effect on CXCR4 translational expression, as evidenced by a 44 ± 1.7% reduction in expression after a 12-h treatment with 10 µM norepinephrine. A Matrigel assay demonstrated a 51.3 ± 9.1% reduction in the number of MDA-MB-231 cells driven to migrate by CXCR4. Finally, we found the specific ß2-adrenergic antagonist, ICI 118,551, eliminated the impact of norepinephrine on CXCR4 expression. CONCLUSIONS: Norepinephrine attenuates CXCR4 expression and the corresponding invasion of MDA-MB-231 tumor cells via the ß2-adrenergic receptor. The complexity of the ß2-adrenergic receptor signaling pathway might contribute to these unexpected observations in our research, and this justifies further investigation into the intricate mechanisms involved.