Hormone antagonist therapy for estrogen receptor positive (ER+) breast cancer patients post radical surgery and radiation therapy has a poor prognosis and also causes bone loss. ...1α,25-dihydroxyvitamin D3 1α,25(OH)2D3 is a potent antitumor agent in pre-clinical studies, but caused hypercalcemia when its effective antitumor doses were used. Therefore, we investigated the effects of a less-calcemic 1α,25(OH)2D3 analog, 19-nor-2α-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D3 (MART-10), on ER+MCF-7 cells. We demonstrate that MART-10 is 500- to 1000-fold more potent than 1α,25(OH)2D3 in inhibiting cell growth in a dose- and time-dependent manner. MART-10 is also much more potent in arresting MCF-7cell cycle progression at G0/G1 phase as compared to 1α,25(OH)2D3, possibly mediated by a greater induction of p21 and p27 expression. Moreover, MART-10 is more active than 1α,25(OH)2D3 in causing cell apoptosis, likely through a higher BAX/Bcl expression ratio and the subsequent cytochrome C release from mitochondria to cytosol. Based on our in vitro findings, MART-10 could be a promising vitamin D analog for the potential treatment of breast cancer, for example, ER+ patients, to decrease the tumor relapse rate and the side effect on bone caused by antihormone regimens. Thus, further in vivo animal study is warranted.
A numerical model based on the second-order fully nonlinear Boussinesq equations of Wei et al. 1995. Journal of Waterway, Port, Coastal and Ocean Engineering 121 (5), 251-263 is developed to simulate ...the Bragg reflection of both regular and irregular surface waves scattered by submerged bars. Particularly for incident regular waves, the computed results are observed to agree very well with the existing experimental data as presented by Davies and Heathershaw 1984. Journal of Fluid Mechanics 144, 419-446 and Kirby and Anton 1990. Proceedings of the 22nd International Conference on Coastal Engineering, ASCE, New York, pp. 757–768). In the case of incident irregular waves, the simulated results reveal that the distribution of Bragg reflection from irregular waves becomes more flat than that of regular waves. Due to lack of experimental data, the numerical results for incident irregular waves are compared with those of the evolution equation of the mild-slope equation Hsu et al., 2002 Proceedings of the 24th Ocean Engineering Conference in Taiwan, pp. 70–77 (in Chinese). In addition, several parameters such as the number of bars, the relative height of bars and the spacing of bars affecting Bragg reflection are also discussed.
Pancreatic neuroendocrine tumors (PanNETs) are usually diagnosed in an advanced stage. Most patients with PanNETs die of metastasis. Vascular endothelial growth factor-A (VEGF-A) is a strong ...stimulator of angiogenesis and tumor metastasis. We aimed to investigate the effect of MART-10 19-nor-2α-(3-hydroxypropyl)-1α,25(OH)
D
, a 1α,25-dihydroxy-vitamin D3 (1α,25(OH)
D
) analog, on PanNET cell metastasis after VEGF-A stimulation.
Migration and invasion assays, western blot, and immunofluorescent staining were applied in this study.
VEGF-A increased PanNET cell migration and invasion, which was attenuated by 1α,25(OH)
D
and MART-10. VEGF-A treatment stimulated epithelial-mesenchymal transition (EMT) of PanNET cells. During this process, expression of snail family transcriptional repressor 1 and 2, and fibronectin was up-regulated. 1α,25(OH)
D
and MART-10 counteracted VEGF-A-induced EMT. In addition, expression of neuropilin 1, a key protein in VEGF-A signaling, was down-regulated by 1α,25(OH)
D
and MART-10. Furthermore, synthesis of F-actin was increased by VEGF-A and reduced by 1α,25(OH)
D
and MART-10.
Our data indicate that MART-10 could be deemed a promising drug for PanNET treatment.
Cholangiocarcinoma (CCA) is a devastating disease without effective treatments. 1α,25(OH)₂D₃, the active form of Vitamin D, has emerged as a new anti-cancer regimen. However, the side effect of ...hypercalcemia impedes its systemic administration. 25(OH)D is biologically inert and needs hydroxylation by CYP27B1 to form 1α,25(OH)₂D₃, which is originally believed to only take place in kidneys. Recently, the extra-renal expression of CYP27B1 has been identified and in vitro conversion of 25(OH)D to 1α,25(OH)₂D₃ has been found in some cancer cells with CYP27B1 expression. In this study, CYP27B1 expression was demonstrated in CCA cells and human CCA specimens. 25(OH)D effectively represses SNU308 cells growth, which was strengthened or attenuated as CYP27B1 overexpression or knockdown. Lipocalcin-2 (LCN2) was also found to be repressed by 25(OH)D. After treatment with 800 ng/mL 25(OH)D, the intracellular 1α,25(OH)₂D₃ concentration was higher in SNU308 cells with CYP27B1 overexpression than wild type SNU308 cells. In a xenograft animal experiment, 25(OH)D, at a dose of 6 μg/kg or 20 μg/kg, significantly inhibited SNU308 cells' growth without inducing obvious side effects. Collectively, our results indicated that SNU308 cells were able to convert 25(OH)D to 1α,25(OH)₂D₃ and 25(OH)D CYP27B1 gene therapy could be deemed as a promising therapeutic direction for CCA.
Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer. Vitamin D, a pro-hormone, is getting popular due to its hormone-like functions after converted to its active form, 1α,25(OH)2D3. Here, ...we show that dietary supplementation with 6 IU/g of vitamin D greatly suppressed ICC initiation and progression without apparent toxicity in a chemically induced rat model. Microarray analysis of rat ICC tissues showed vitamin D supplementation modulated the expressions of several unique genes, including lipocalin 2 (Lcn2), confirmed by RT-qPCR and immunohistochemical (IHC) staining. Further, 53 of 80 human ICC specimens (66%) exhibited high LCN2 expression and LCN2 knockdown in SNU308 cells decreased cell growth and migration, suggesting LCN2 be an oncogene in human ICC. As human ICC SNU1079 cells were treated by 1α,25(OH)2D3, LCN2 expression and cell proliferation were attenuated. The downregulation of LCN2 expression was blunted when vitamin D receptor (VDR) was knocked down, implicating that the in vivo Lcn2 downregulation is a direct consequence of vitamin D supplementation Our results support the prevailing concept that vitamin D status is negatively associated with cancer incidence and mortality and suggest LCN2 may be a potential target against ICC. Further studies of application of vitamin D or its analog against ICC are warranted.
Hormone antagonist therapy for estrogen receptor positive (ER+) breast cancer patients post radical surgery and radiation therapy has a poor prognosis and also causes bone loss. ...1α,25-dihydroxyvitamin D(3) 1α,25(OH)(2)D(3) is a potent antitumor agent in pre-clinical studies, but caused hypercalcemia when its effective antitumor doses were used. Therefore, we investigated the effects of a less-calcemic 1α,25(OH)(2)D(3) analog, 19-nor-2α-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D(3 )(MART-10), on ER+MCF-7 cells. We demonstrate that MART-10 is 500- to 1000-fold more potent than 1α,25(OH)(2)D(3) in inhibiting cell growth in a dose- and time-dependent manner. MART-10 is also much more potent in arresting MCF-7cell cycle progression at G(0)/G(1) phase as compared to 1α,25(OH)(2)D(3), possibly mediated by a greater induction of p21 and p27 expression. Moreover, MART-10 is more active than 1α,25(OH)(2)D(3) in causing cell apoptosis, likely through a higher BAX/Bcl expression ratio and the subsequent cytochrome C release from mitochondria to cytosol. Based on our in vitro findings, MART-10 could be a promising vitamin D analog for the potential treatment of breast cancer, for example, ER+ patients, to decrease the tumor relapse rate and the side effect on bone caused by antihormone regimens. Thus, further in vivo animal study is warranted.
Abstract
Statin therapy can reduce the biosynthesis of both cholesterol and coenzyme Q
10
by blocking the common upstream mevalonate pathway. Coenzyme Q
10
depletion has been speculated to play a ...potential role in statin‐related adverse events, and withdrawal of statin is the choice in patients developing myotoxicity or liver toxicity. However, the effect of statin withdrawal on circulating levels of coenzyme Q
10
remains unknown. Twenty‐six patients with hypercholesterolemia received atorvastatin at 10 mg/day for 3 months. Serum lipid profiles and coenzyme Q
10
were assessed before and immediately after 3 months and were also measured 2 and 3 days after the last day on the statin. After 3 months' atorvastatin therapy, serum levels of total cholesterol (TC), low‐density lipoprotein cholesterol (LDL‐C) and coenzyme Q
10
(0.43 ± 0.23 to 0.16 ± 0.10 μg/mL) were all significantly reduced (all p < 0.001). On day 2 after the last atorvastatin, the coenzyme Q
10
level was significantly elevated (0.37 ± 0.16 μg/mL) and maintained the same levels on day 3 (0.39 ± 0.18 μg/mL) compared with those on month 3 (both p < 0.001), while TC and LDL‐C did not significantly change within the same 3 days. These results suggest that statin inhibition of coenzyme Q
10
synthesis is less strict than inhibition of cholesterol biosynthesis.
Using camera networks to monitor the trajectory of moving vehicles plays important role in many applications, such as video surveillance, intelligent traffic system, and social security management. ...Most of the previous works tried to track the moving vehicle by using either appearance matching or spatial and temporal information. However, we realized that the moving of vehicles should follow some underlying social tendency. By using training data for tendency learning, we proposed a new idea to predict the vehicle trajectory, which is a quite different viewpoint in contrast with previous works. In detail, we regarded trajectory prediction as a recommendation problem. By giving partial and fragmental observations of vehicle locations on the map, the proposed system attempted to predict or recommend the possible vehicle moving trajectory. Three types of algorithms for recommendation were evaluated, including a user-based method, an item-based method, and a latent-based method. The experimental results show the tendency learning could be used as useful prior information for trajectory prediction. Furthermore, the tendency learning could be combined with previous works without conflict.
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