8 research outputs found
A long-term "memory" of HIF induction in response to chronic mild decreased oxygen after oxygen normalization
Background
Endothelial dysfunction (ED) is functionally characterized by decreased vasorelaxation, increased thrombosis, increased inflammation, and altered angiogenic potential, has been intimately associated with the progression and severity of cardiovascular disease. Patients with compromised cardiac function oftentimes have a state of chronic mild decreased oxygen at the level of the vasculature and organs, which has been shown to exacerbate ED. Hypoxia inducible factor (HIF) is a transcription factor complex shown to be the master regulator of the cellular response to decreased oxygen levels and many HIF target genes have been shown to be associated with ED.
Methods
Human endothelial and aortic smooth muscle cells were exposed either to A) normoxia (21% O2) for three weeks, or to B) mild decreased oxygen (15% O2) for three weeks to mimic blood oxygen levels in patients with heart failure, or to C) mild decreased oxygen for two weeks followed by one week of normoxia ("memory" treatment). Levels of HIF signaling genes (HIF-1Ī±, HIF-2Ī±, VEGF, BNIP3, GLUT-1, PAI-1 and iNOS) were measured both at the protein and mRNA levels.
Results
It was found that chronic exposure to mild decreased oxygen resulted in significantly increased HIF signaling. There was also a "memory" of HIF-1Ī± and HIF target gene induction when oxygen levels were normalized for one week, and this "memory" could be interrupted by adding a small molecule HIF inhibitor to the last week of normalized oxygen. Finally, levels of ubiquitylated HIF-1Ī± were reduced in response to chronic mild decreased oxygen and were not full restored after oxygen normalization.
Conclusion
These data suggest that HIF signaling may be contributing to the pathogenesis of endothelial dysfunction and that normalization of oxygen levels may not be enough to reduce vascular stress
Synthesis and biological activity of N\u3csup\u3e4\u3c/sup\u3e-phenylsubstituted-6-(2,4-dichloro phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamines as vascular endothelial growth factor receptor-2 inhibitors and antiangiogenic and antitumor agents
A series of eight N4-phenylsubstituted-6-(2,4-dichlorophenylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamines 8-15 were synthesized as vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors with varied substitutions in the phenyl ring of the 4-anilino moiety. In addition, five N4-phenylsubstituted-6-phenylmethylsubstituted-7H-pyrrolo[2,3-d]pyrimidin-4-amines 16-20 were synthesized to evaluate the importance of the 2-NH2 moiety for multiple receptor tyrosine kinase (RTK) inhibition. Cyclocondensation of Ī±-halomethylbenzylketones with 2,6-diamino-4-hydroxypyrimidine afforded 2-amino-6-(2,4-dichlorophenylmethyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 23 and reaction of Ī±-bromomethylbenzylketones with ethylamidinoacetate followed by cyclocondensation with formamide afforded the 6-phenylmethylsubstituted-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-ones, 40-42, respectively. Chlorination of the 4-position and displacement with appropriate anilines afforded the target compounds 8-20. Compounds 8, 10 and 14 were potent VEGFR-2 inhibitors and were 100-fold, 40-fold and 8-fold more potent than the standard semaxanib, respectively. Previously synthesized multiple RTK inhibitor, 5 and the VEGFR-2 inhibitor 8 from this study, were chosen for further evaluation in a mouse orthotopic model of melanoma and showed significant inhibition of tumor growth, angiogenesis and metastasis. Ā© 2010 Elsevier Ltd. All rights reserved
sj-docx-1-tam-10.1177_17588359231200454 ā Supplemental material for Safety and effectiveness of sacituzumab govitecan in patients with metastatic triple-negative breast cancer in real-world settings: first observations from an interdisciplinary breast cancer centre in Germany
Supplemental material, sj-docx-1-tam-10.1177_17588359231200454 for Safety and effectiveness of sacituzumab govitecan in patients with metastatic triple-negative breast cancer in real-world settings: first observations from an interdisciplinary breast cancer centre in Germany by Mattea Reinisch, Simona Bruzas, Jennifer Spoenlein, Satyendra Shenoy, Alexander Traut, Hakima Harrach, Ouafaa Chiari, Efsthatia Cremer, Beyhan Ataseven, Lars Gubelt and Sherko Kuemmel in Therapeutic Advances in Medical Oncology</p
Prognostic and predictive impact of gene expression in nodeāpositive early breast cancer patients receiving doseādense versus standardādose adjuvant chemotherapy
The utility of multigene expression assays in advanced (ā„ā4 positive lymph nodes) early breast cancer (EBC) is limited. We conducted exploratory transcriptomic analysis of 758 genes (Breast Cancer 360 panel, nCounterĀ® platform; NanoString) in primary tumor samples collected during a phase 3 trial comparing adjuvant taxaneācontaining doseādense chemotherapy (ddCTX) versus standardādosed chemotherapy (stCTX) in resected EBC with ā„ā4 positive lymph nodes. Prognostic and predictive associations with diseaseāfree survival (DFS) and overall survival (OS) were evaluated by Cox regression with false discovery rate (FDR) adjustment. Data were available from tumor samples of 141/226 patients (median followāup: 14āyears). Several genes/signatures, including immune markers, showed prognostic relevance in unadjusted analyses. Of these, two remained significant after multiplicity adjustment: a positive effect on DFS of programmed cell death 1 ligandā2 (PDāL2) in the ddCTX arm (univariate HR: 0.53, FDRāadjusted Pā=ā0.036) and a negative effect on OS of HER2āenriched (HER2āE) signature in the stCTX arm (univariate HR: 5.40, FDRāadjusted Pā=ā0.036). Predictive analyses showed greater DFS benefit of ddCTX in tumors with high antigen processing machinery (APM) expression (multivariate interaction Pā=ā0.024). Multigene expression assays have a prognostic and predictive potential in advanced EBC, and further investigation is warranted in order to identify candidates for deāescalated treatment. In addition, intrinsic subtype and immune gene expression have predictive potential