Here we demonstrate a critical role of protein kinaseD(PKD) and histone deacetylase 5 (HDAC5) in VEGF-induced gene expression and angiogenesis. We found that VEGF stimulated HDAC5 phosphorylation and nuclear export in endothelial cells through a VEGF receptor 2-phospholipase ACY-1215 C gamma-protein kinase C-PKD-dependent pathway. We further showed that the PKD-HDAC5 pathway mediated myocyte enhancer factor-2 transcriptional activation and a specific subset of gene expression in response to VEGF, including NR4A1, an
orphan nuclear receptor involved in angiogenesis. Specifically, inhibition of PKD by overexpression of the PKD kinase-negative mutant prevents VEGF-induced HDAC5 phosphorylation and nuclear export as well as NR4A1 induction. Moreover, a mutant of HDAC5 specifically deficient in PKD-dependent phosphorylation inhibited VEGF-mediated NR4A1 expression, selleck screening library endothelial cell migration, and in vitro angiogenesis. These findings suggest that the PKD-HDAC5 pathway plays an important role in VEGF regulation of gene transcription and angiogenesis.”
“Background: Women treated for Hodgkin’s lymphoma (HL) have an elevated risk of developing second breast cancer (SBC) compared with the general population. We planned this meta-analysis to quantify the long-term risk of SBC and analyze the contributing risk factors among HL survivors.\n\nMethods:
According to predefined selection criteria, literature search identified 34 studies that were included in the analyses.\n\nResults: After eliminating overlapping or duplicate data, 957 incidences of SBC were encountered in 24,505 females with HL over a median follow-up of 14.9 years. The medians: age at the diagnosis of HL, age at diagnosis of SBC, and latency Copanlisib chemical structure since HL treatment to the development of SBC were 23.7, 35.0, and 17.7 years, respectively. The pooled relative risk (RR) of SBC was 8.23 (95% CI, 5.43-12.47, I-2 = 96%), with a median absolute excess rate of 22.9 per 10,000 person-years. The RR was found inversely related to age at diagnosis of HL with the highest rate (68.7; [95%CI, 28.08-168.11], I-2 = 79%), occurred in young patients (<= 15
years old), where the RR in older women (>= 40 years old) was not significant (0.55; [95% CI, 0.09-3.52]). Analysis of RR by 5-year increments since the treatment of HL showed that the risk was highest after 15-19 years of latency (13.87; [95% CI, 7.91-24.30], I-2 = 89%). Analysis of the effect of treatment modalities showed that the RR rates were (4.70; [95% CI, 3.28-6.75], I-2 = 74%), (5.65; [95% CI, 2.94-10.88], I-2 = 91%), and (1.19; [95% CI, 0.50-2.82], I-2 = 65%), for radiotherapy (RT) only, combined RT and chemotherapy (CT), and CT only, respectively. To investigate the demonstrated heterogeneity, meta-regression analysis was performed when feasible. In most such analyses, the natural logarithm of RR was inversely associated with age at HL diagnosis.