Deguelin exhibits potent apoptotic and antiangiogenic activities in a variety of transformed cells and cancer cells. Deguelin also exhibits potent tumor suppressive effects in xenograft tumor models for many human cancers. Our initial studies confirmed that deguelin disrupts ATP binding to HSP90 and consequently induces destabilization of its client proteins such as HIF-1α. Interestingly, a fluorescence probe assay revealed that deguelin and its analogues do not compete with ATP binding to the N-terminus of HSP90, unlike most HSP90 inhibitors. To determine the key parts of deguelin that contribute to its potent HSP90 inhibition, as well as its antiproliferative and antiangiogenic activities, we have established a structure-activity relationship (SAR) of deguelin. In the course of these studies, we identified a series of novel and potent HSP90 inhibitors. In particular, analogues 54 and 69, the B- and C-ring-truncated compounds, exhibited excellent antiproliferative activities with IC(50) of 140 and 490 nM in the H1299 cell line, respectively, and antiangiogenic activities in zebrafish embryos in a dose dependent manner (0.25-1.25 μM).
When distant metastases are discovered, it is important to determine receptor profiles of these lesions through histologic examination. However, brain metastasis sites are difficult to reach to be routinely biopsied. The purpose of this study was to determine expression profiles of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) in breast cancer brain metastasis (BCBM) and the existence of discordance between primary breast cancer and brain metastasis. A total of 37 patients who underwent craniotomies for metastatic brain tumors arising from breast cancer at National Cancer Center (NCC) of Korea between 2002 and 2014 were retrospectively reviewed. Clinicopathologic data were collected from electronic medical records. Receptor profiles of primary breast cancer and brain metastasis in each patient were identified. Data of ER, PR, and HER2 expression in brain metastasis were available in electronic medical records for 21 (56.8%) of 37 cases. Results of ER, PR, and HER2 expression were positive in 47.6, 42.9, and 38.1% of patients with brain metastasis, respectively. Receptor conversion occurred in 11 (52.4%) of 21 patients (for ER, 9.5%; for PR, 38.1%; for HER2, 23.8%). Overall survival was longer in patients with concordant receptor expression patterns between primary breast cancer and brain lesion compared to that in patients with discordant patterns. However, such difference was not statistically significant (discordant vs. concordant median survival: 19.2 versus 31.1 months, p = 0.181). Receptor conversion in BCBMs was observed in over 50% of Korean patients used in this study. HER2 conversion was observed in 23.8% of patients in this study. Therefore, if resistance to anti-HER2 treatment is suspected in patients with BCBM, biopsy is needed to determine receptor profiles of brain lesion.
The correlation functions of hardsphere chain fluids: Comparison of the Wertheim integral equation theory with the Monte Carlo simulation J. Chem. Phys. 102, 437 (1995); 10.1063/1.469421 Homo-and heterocoordination in nonadditive hard-sphere mixtures and a test of the van der Waals one-fluid model J. Chem. Phys. 100, 528 (1994); 10.1063/1.466967 Fluid-fluid phase separation of nonadditive hardsphere mixtures as predicted by integralequation theories J. Chem. Phys. 95, 4565 (1991);We investigated the phase stability of a system of nonadditive hard sphere ͑NAHS͒ mixtures with equal diameters, d, between like species and an unequal collision diameter, d͑1ϩ␣͒, between unlike species. It is based on an analytic equation of state ͑EOS͒ which refines an earlier expression ͓J. Chem. Phys. 100, 9064 ͑1994͔͒ within the mixed fluid phase range. The new EOS gives a reliable representation of Monte Carlo EOS data over a wide range of density, composition, and nonadditivity parameters ͑␣͒. Comparisons with available computer simulations show that the new EOS predicts satisfactory phase boundaries and the critical density line. It is superior to results derived from integral equations ͑the Percus-Yevick, the Martynov-Sarkisov, and the modified Martynov-Sarkisov͒ and analytic theories ͑the MIX1 model, the van der Waals one-fluid model, and the scaled particle theory͒. The present study shows that, unless ␣ exceeds 0.026, the fluid phase will remain fully miscible up to the freezing point of pure hard spheres. We have also investigated structural aspects of the phase stability by Monte Carlo computations. The radial distribution functions, the local mole fraction, and coordination numbers for like and unlike pairs of hard spheres exhibit significant number dependencies close to the fluid phase boundary. They provide precursory signals to an impending phase change. Finite systems used in the Monte Carlo sampling limit fluctuations in sizes and shapes of heterogeneous clusters. The observed number dependence simply reflects this fact.
The initial BD in pediatric trauma patients except severe brain injury was an independent predictor of mortality and blood transfusion requirement within 24 hours. Mortality and blood transfusion requirement were significantly high when initial BD was less than -8 mEq/L.
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