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Viruses usually infect a restricted set of host species, and only in rare cases does productive infection occur outside the natural host range. Infection of a new host species can manifest as a distinct disease. In this respect, the use of non-human viruses in clinical therapy may be a cause for concern. It could provide the opportunity for the viruses to adapt to the new host and be transferred to the recipient's relatives or medical caretakers, or even to the normal host species. Such environmental impact is evidently undesirable. To forecast future clinical use of non-human viruses, a literature study was performed to identify the viruses that are being considered for application as therapeutic agents for use in humans. Twenty-seven non-human virus species were identified that are in (pre)clinical development, mainly as oncolytic agents. For risk management, it is essential that the potential environmental consequences are assessed before initiating clinical use, even if the virus is not formally classified as a genetically modified organism. To aid such assessment, each of these viruses was classified in one of five relative environmental risk categories, ranging from "Negligible" to "Very High". Canary pox virus and the Autographa californica baculovirus were assigned a "Negligible" classification, and Seneca Valley virus, murine leukemia virus, and Maraba virus to the "High" category. A complicating factor in the classification is the scarcity of publicly available information on key aspects of virus biology in some species. In such cases the relative environmental risk score was increased as a precaution.  相似文献   
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This study examined the relationship between negative symptoms and social cognition in individuals with psychosis. Although negative symptoms were associated with social cognition, stereotyped thinking, which is cognitive in nature, emerged as the most significant predictor, suggesting that cognition rather than symptoms may have a greater impact on social cognition.  相似文献   
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The aim of this study is to analyze the impact of various parameters on the course and treatment outcome in patients with laryngotracheal stenosis and recurrent stenosis. Two groups of patients were compared: Group I included 29 patients with primary stenosis, and Group II included 22 patients with recurrent stenosis. The most frequent etiological factor for the development of stenosis was prolonged endotracheal intubation (79.3:77.3%), with subglottic-tracheal (44.8:45.5%) and tracheal (48.3:36.4%) localization being the most affected. Subglottic-tracheal stenosis was more common in men. There were no significant differences between the groups in regard to the grade of lumen obstruction and the length of the resected segment. In male patients, the length of the resected stenotic segment was significantly longer. Subglottic-tracheal stenoses were longer than tracheal ones. Various surgical procedures were performed, with additional management of recurrent laryngeal nerve paralysis, if necessary. Laryngotracheal reconstruction (LTR) with costal cartilage grafting (CCG) was statistically significantly more often performed in Group II, while cricotracheal resection (CTR) was more common in Group I. The incidence of complications in Group I was 24.1%, and in Group II it was 31.8%. Satisfactory airway lumen with undisturbed breathing was achieved in 93.1% of patients in Group I, and in 95.3% in Group II. Since the success rate was similar in both groups of the patients, it could be concluded that treatment outcome depends less on the factors associated with the stenosis, and more on adequate choice of surgical procedure and surgical team know-how.  相似文献   
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We have recently shown that covalent attachment of the nitric oxide (NO) moiety to the HIV protease inhibitor Saquinavir (Saq) produced a qualitatively new chemical entity, named Saquinavir-NO (Saq-NO), with enhanced anticancer properties and reduced toxicity both in?vitro and in?vivo. The aim of this study was to address several unanswered questions both on the pharmacological profile of Saq-NO as well as on the in?vivo role of NO in the oncogenesis of A375 human melanoma cells. To this end, we have evaluated here the impact of single and combined effects of Saq-NO, Saq, the NO-donor DETA NONOate and the iNOS inhibitor L-NAME on the in?vitro as well as in?vivo growth of the iNOS positive A375 cells. Our data confirm clear-cut evidence for a strong and powerful anti-melanoma action of Saq-NO that is not duplicable by the combined use of Saq and DETA NONOate. Surprisingly, but also in agreement with the complex and multifaceted role of endogenous NO in A375 cells, both DETA NONOate and L-NAME significantly suppressed the in?vivo growth of xenotransplants.  相似文献   
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Introduction

Although a high frequency of androgen receptor (AR) expression in human breast cancers has been described, exploiting this knowledge for therapy has been challenging. This is in part because androgens can either inhibit or stimulate cell proliferation in pre-clinical models of breast cancer. In addition, many breast cancers co-express other steroid hormone receptors that can affect AR signaling, further obfuscating the effects of androgens on breast cancer cells.

Methods

To create better-defined models of AR signaling in human breast epithelial cells, we took estrogen receptor (ER)-??-negative and progesterone receptor (PR)-negative human breast epithelial cell lines, both cancerous and non-cancerous, and engineered them to express AR, thus allowing the unambiguous study of AR signaling. We cloned a full-length cDNA of human AR, and expressed this transgene in MCF-10A non-tumorigenic human breast epithelial cells and MDA-MB-231 human breast-cancer cells. We characterized the responses to AR ligand binding using various assays, and used isogenic MCF-10A p21 knock-out cell lines expressing AR to demonstrate the requirement for p21 in mediating the proliferative responses to AR signaling in human breast epithelial cells.

Results

We found that hyperactivation of the mitogen-activated protein kinase (MAPK) pathway from both AR and epidermal growth factor receptor (EGFR) signaling resulted in a growth-inhibitory response, whereas MAPK signaling from either AR or EGFR activation resulted in cellular proliferation. Additionally, p21 gene knock-out studies confirmed that AR signaling/activation of the MAPK pathway is dependent on p21.

Conclusions

These studies present a new model for the analysis of AR signaling in human breast epithelial cells lacking ER??/PR expression, providing an experimental system without the potential confounding effects of ER??/PR crosstalk. Using this system, we provide a mechanistic explanation for previous observations ascribing a dual role for AR signaling in human breast cancer cells. As previous reports have shown that approximately 40% of breast cancers can lack p21 expression, our data also identify potential new caveats for exploiting AR as a target for breast cancer therapy.  相似文献   
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