5-alpha-reductase

2013年6月27日星期四

Conserved microRNAs miR-8-5p and miR-2a-3p modulate chitin biosynthesis in response to 20-hydroxyecdysone signaling in the brown planthopper, Nilaparvata lugens.

Conserved microRNAs miR-8-5p and miR-2a-3p modulate chitin biosynthesis in response to 20-hydroxyecdysone signaling in the brown planthopper, Nilaparvata lugens.

Insect Biochem Mol Biol. 2013 Jun 21;

Authors: Chen J, Liang Z, Liang Y, Pang R, Zhang W

Abstract
Molting is an important developmental process in insects, usually along with synthesis and degradation of chitin. 20-hydroxyecdysone (20E), an insect hormone, has been reported to contribute to many processes including molting. However, little is known about the link between the chitin biosynthesis pathway and 20E signaling. Here, we report that conserved miR-8-5p (miR-8-5p) and miR-2a-3p and their new target genes are critical for ecdysone-induced chitin biosynthesis in a hemipteran insect Nilaparvata lugens. We found that membrane-bound trehalase (Tre-2) and phosphoacetylglucosamine mutase (PAGM) in the chitin biosynthesis pathway were targets of miR-8-5p and miR-2a-3p, respectively, through bioinformatic analysis and experimental verification. The levels of miR-8-5p and miR-2a-3p were reduced, whereas the levels of Tre-2 and PAGM were up-regulated in response to 20E. In addition, miR-8-5p and miR-2a-3p were transcriptionally repressed by an early-response gene, the Broad-Complex (BR-C), in the 20E signaling pathway. Moreover, the overexpression of miR-8-5p and miR-2a-3p led to a significant reduction in the survival rate along with a molting obstacles defect phenotype caused by miR-2a-3p mimics feeding, and the chitin content of N. lugens was simultaneously reduced. Thus, miR-8-5p and miR-2a-3p act as molecular link that tune the chitin biosynthesis pathway in response to 20E signaling.

PMID: 23796434 [PubMed - as supplied by publisher]

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Rechallenge with mTOR Inhibitors in Metastatic Renal Cell Carcinoma Patients Who Progressed on Previous mTOR Inhibitor Therapy.

Rechallenge with mTOR Inhibitors in Metastatic Renal Cell Carcinoma Patients Who Progressed on Previous mTOR Inhibitor Therapy.

Oncology. 2013 Jun 21;85(1):8-13

Authors: Maj-Hes A, Medioni J, Scotte F, Schmidinger M, Kramer G, Combe P, Gornadha Y, Elaidi R, Oudard S

Abstract
Objective: To determine if mammalian target of rapamycin (mTOR) inhibitor (everolimus or temsirolimus) rechallenge in the third- or fourth-line setting after sequential use of a vascular endothelial growth factor receptor (VEGF)-targeted agent and an mTOR inhibitor is a feasible and effective treatment strategy in patients with metastatic renal cell carcinoma (mRCC). Methods: Patients who received a VEGF-targeted agent, an mTOR inhibitor and rechallenge with a second mTOR inhibitor at 2 institutions (H�pital Europ�en Georges-Pompidou and Vienna Medical School) between 30 March 2001 and 15 September 2011 were included. Analyses of radiographic images were performed according to the Response Evaluation Criteria in Solid Tumors, version 1.0, to determine the objective response rate and treatment duration (TD). Results: Twelve patients met the inclusion criteria. Following 1 or 2 VEGF receptor-tyrosine kinase inhibitors, 7 patients firstly received everolimus and 5 patients received temsirolimus. Irrespective of treatment sequence, 6 of 12 patients (50%) responded to everolimus and 4 of 12 patients (33%) responded to temsirolimus; 3 patients (25%) did not respond to either. Median TDs (95% confidence interval) for everolimus ? temsirolimus and temsirolimus ? everolimus sequences were 10.3 months (8.8-19.2 months) and 5.8 months (2.9-19.3 months), respectively. Conclusions: Despite the limited number of patients, this highlights the feasibility of utilizing mTOR rechallenge as an integral part of sequential treatment strategies in mRCC.

PMID: 23797151 [PubMed - as supplied by publisher]

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2013年6月26日星期三

Effect of cardiovascular drug classes on all-cause mortality among atrial fibrillation patients treated in primary care in Sweden: a cohort study.

Effect of cardiovascular drug classes on all-cause mortality among atrial fibrillation patients treated in primary care in Sweden: a cohort study.

Eur J Clin Pharmacol. 2013 Feb;69(2):279-87

Authors: W�ndell P, Carlsson AC, Sundquist K, Johansson SE, Sundquist J

Abstract
BACKGROUND: Risk factors for stroke are well known in atrial fibrillation (AF) patients, while less is known on the effect of these factors on total mortality.
OBJECTIVE: Our aim was to study the impact of cardiovascular drug classes on mortality in AF patients treated in primary care.
METHODS: The study population was chosen based on patient data from 75 primary care centres in Sweden compiled in a database. Individuals diagnosed with AF who were older than 45 years were enrolled (n?=?12,302, of whom 6,660 were men). Cox regression analysis with mortality (years to death) as outcome was conducted in the men and women separately, as well in the age categories <80 and ? 80 years, with cardiovascular drugs as independent factors, and age, cardiovascular diagnoses and educational level as covariates.
RESULTS: Lower mortality was shown for anticoagulant treatment among men, both younger (<80 years) [adjusted hazard ratio (HR) 0.43, 95 % confidence interval (CI) 0.31-0.61] and older (? 80 years) (adjusted HR 0.47, 95 % CI 0.32-0.69), and among younger women (adjusted HR 0.46, 95 % CI 0.29-0.74), and for antiplatelet treatment in older men (adjusted HR 0.51, 95 % CI 0.35-0.74). Treatment with thiazides was associated with lower mortality among younger men (adjusted HR 0.68, 95 % CI 0.48-0.96), older men (adjusted HR 0.67, 95 % CI 0.46-0.98) and older women (adjusted HR 0.70, 95 % CI 0.52-0.94). Statins were associated with lower mortality among younger patients, in both men (adjusted HR 0.47, 95 % CI 0.32-0.68) and women (adjusted HR 0.54, 95 % CI 0.35-0.82).
CONCLUSIONS: The differences in age and gender patterns need further exploration.

PMID: 22990327 [PubMed - indexed for MEDLINE]

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[Pharmacodynamic and pharmacokinetic evaluation of respiratory fluoroquinolones. Guideline to selection of the most appropriate fluoroquinolone].

[Pharmacodynamic and pharmacokinetic evaluation of respiratory fluoroquinolones. Guideline to selection of the most appropriate fluoroquinolone].

Rev Esp Quimioter. 2012 Dec;25(4):245-51

Authors: Parra-Ruiz J, Hern�ndez-Quero J

Abstract
Since its approval, fluoroquinolones have become one of the most prescribed antibacterial agents. Because of its widespread use, serious concerns about the emergence of resistance in Streptococcus pneumoniae, Pseudomonas spp, and entrobacteriaceae, has arisen, especially because of cross-resistance between fluoroquinolones. Huge efforts has been done to identify pharmacokinetic (PK) parameters like maximum serum concentration (Cmax), area under the curve of serum concentrations (AUC) and pharmacodynamic (PD) parameters like the minimum inhibitory concentration (MIC) or the mutant prevention concentration (MPC), to optimize the use of the new fluoroquinolones, especially against these difficult to treat microorganisms. The new fluoroquinolones commercially available in Spain, levofloxacin and moxifloxacin, have significant differences in their PK (Cmax, half-life, volume of distribution, etc), PD (MIC, MPC,) and in their PK/PD parameters (AUC/MIC; AUC/MPC) that allow clinicians to establish clear preference for the utilization of one of them. Proper use of these new fluoroquinolones according to these PK/PD parameters will result in better management of respiratory infections with a reduction in the emergence of resistance. Based on data reviewed in this paper moxifloxacin use, with best PK/PD characteristics, should be preferred over levofloxacin. Should levofloxacin be used, alternative dosing strategies would be recommended to avoid selection of resistant variants.

PMID: 23303254 [PubMed - indexed for MEDLINE]

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Conserved microRNAs miR-8-5p and miR-2a-3p modulate chitin biosynthesis in response to 20-hydroxyecdysone signaling in the brown planthopper, Nilaparvata lugens.

Conserved microRNAs miR-8-5p and miR-2a-3p modulate chitin biosynthesis in response to 20-hydroxyecdysone signaling in the brown planthopper, Nilaparvata lugens.

Insect Biochem Mol Biol. 2013 Jun 21;

Authors: Chen J, Liang Z, Liang Y, Pang R, Zhang W

PMID: 23796434 [PubMed - as supplied by publisher]

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Dovitinib preferentially targets endothelial cells rather than cancer cells for the inhibition of hepatocellular carcinoma growth and metastasis.

Dovitinib preferentially targets endothelial cells rather than cancer cells for the inhibition of hepatocellular carcinoma growth and metastasis.

J Transl Med. 2012;10:245

Authors: Chen ZY, Shi M, Peng LX, Wei W, Li XJ, Guo ZX, Li SH, Zhong C, Qian CN, Guo RP

Abstract
BACKGROUND: Dovitinib is a receptor tyrosine kinase (RTK) inhibitor targeting vascular endothelial growth factor receptors, fibroblast growth factor receptors and platelet-derived growth factor receptor ?. Dovitinib is currently in clinical trials for the treatment of hepatocellular carcinoma (HCC).
METHOD: In this study, we used five HCC cell lines and five endothelial cell lines to validate molecular and cellular targets of dovitinib.
RESULTS: Tumor growth and pulmonary metastasis were significantly suppressed in an orthotopic HCC model. Immunoblotting revealed that among known dovitinib targets, only PDGFR-? was expressed in two HCC cell lines, while four of five endothelial lines expressed PDGFR-?, FGFR-1, and VEGFR-2. Dovitinib inhibited endothelial cell proliferation and motility at 0.04 ?mol/L, a pharmacologically relevant concentration; it was unable to inhibit the proliferation or motility of HCC cells at the same concentration. Immunohistochemical analyses showed that dovitinib significantly decreased the microvessel density of xenograft tumors, inhibiting proliferation and inducing apoptosis in HCC cells.
CONCLUSION: Our findings indicate that dovitinib inhibits HCC growth and metastasis preferentially through an antiangiogenic mechanism, not through direct targeting of HCC cells.

PMID: 23228017 [PubMed - indexed for MEDLINE]

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Celecoxib enhances the efficacy of 15-hydroxyprostaglandin dehydrogenase gene therapy in treating murine breast cancer.

Celecoxib enhances the efficacy of 15-hydroxyprostaglandin dehydrogenase gene therapy in treating murine breast cancer.

J Cancer Res Clin Oncol. 2013 May;139(5):797-807

Authors: Zhang B, Ma X, Li Z, Gao X, Wang F, Liu L, Shen G, Sang Y, Li M, Li Y, Zhao J, Wei Y

Abstract
PURPOSE: The overexpression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) has been proved to inhibit tumor growth and metastasis through degradation of prostaglandin E2 (PGE2), which is often overexpressed in various cancers and accelerates tumor progression. Cyclooxygenase-2 (COX-2), a synthase of PGE2, actively produces much PGE2 to counteract the 15-PGDH-induced antitumor efficacy. Here, we investigated the combinational effect by using pcDNA3.1(+) encoding mouse 15-PGDH gene therapy and celecoxib, a COX-2 inhibitor, in mouse breast cancers.
METHODS: Mice bearing 4T1 were treated with short-term administration of the COX-2 inhibitor celecoxib (40 mg/kg/day) plus liposome-encapsulated mouse 15-PGDH in order to determine their synergistic antitumor activity in vivo. And the possible mechanisms were investigated.
RESULTS: We observed that the combination treatment of 15-PGDH and celecoxib significantly inhibited tumor growth and lung metastases than monotherapy or controls. Moreover, the effect of combination treatment was associated with significant reduction of PGE2 in serum, which resulted from increased 15-PDGH and decreased COX-2 in tumor tissues. The tumor tissues in combination treatment presented more apoptotic cells and less microvessel density. Notably, the number of myeloid-derived suppressor cells in the spleen was also significantly decreased in the combination treatment than others.
CONCLUSIONS: Our findings suggested that celecoxib increased the antitumor activity of 15-PGDH by synergistically blocking PGE2 pathway, which might be a new feasible way for cancer therapy.

PMID: 23385883 [PubMed - indexed for MEDLINE]

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