Candida albicans is a prevalent human fungal pathogen. Rapid genomic change, due to aneuploidy, is a common mechanism that facilitates survival from multiple types of stresses including the few classes of available antifungal drugs. The stress survival of aneuploids occurs despite the fitness costs attributed to most aneuploids growing under idealized lab conditions. Systematic study of the aneuploid state in C. albicans has been hindered by the lack of a comprehensive collection of aneuploid strains. Here, we describe a collection of diploid C. albicans aneuploid strains, each carrying one extra copy of each chromosome, all from the same genetic background. We tested the fitness of this collection under several physiological conditions including shifts in pH, low glucose, oxidative stress, temperature, high osmolarity, membrane stress and cell wall stress. We found that most aneuploids, under most conditions, were less fit than their euploid parent, yet there were specific conditions under which specific aneuploid isolates provided a fitness benefit relative to the euploid parent strain. Importantly, this fitness benefit was attributable to the change in the copy number of specific chromosomes. Thus, C. albicans can tolerate aneuploidy of each chromosome and some aneuploids confer improved growth under conditions that the yeast encounters in its host niches.
Rivaroxaban was more effective than the recommended dose of enoxaparin and had a similar safety profile for thromboprophylaxis after hip and knee arthroplasty.
Among the patients included in the trials analyzed in this meta-analysis, the addition of bevacizumab to cancer therapy treatments significantly increased the risk of significantly raised blood pressure. The risk may be dose-dependent and vary with tumor type.
Candida albicans is the most prevalent fungal pathogen and serious concern for patients with compromised immune systems such as cancer patients, transplant recipients and human immunodeficiency virus (HIV)-infected patients. Compared with bacterial infections, few drugs are available to treat fungal infections.1) This is largely attributable to the eukaryotic nature of fungal cells and the difficulty in identifying unique targets not shared with human hosts. Fluconazole has been shown effective in the treatment of candidaemia and is currently used as first-line drug. However, with the increasing clinical use of fluconazole, fluconazole-resistant isolates are occurring frequently.Attempts have been made to cope with treatment failures by using combination therapy. However, contradictory results of either synergic or antagonistic actions in various antifungal combinations have been reported.2) As for fluconazole-resistant C. albicans, few data are available about the synergism of fluconazole with other antifungal agents.3) Baicalein (BE) is a major component of Scutellaria baicalensis, a Chinese herb described in the Chinese Pharmacopoeia as a medicine (Fig. 1). In addition to its inhibition effect on lipoxygenase, BE was found to have antioxidant, neuroprotective, antibacterial, antiviral, and antifungal activities. [4][5][6][7][8][9][10][11] To seek a novel combination therapy, we investigated the in vitro interaction of fluconazole and baicalein against fluconazole-resistant clinical isolates of C. albicans.
MATERIALS AND METHODS
Strains and AgentsThirty clinical isolates of fluconazole-resistant C. albicans were used in this study, including previously published isolates FH5 and TL3.12-14) BE (Sigma-Aldrich, St. Louis, MO, U.S.A.) was dissolved in dimethyl sulfoxide and fluconazole (Pfizer-Roerig Pharmaceuticals, New York, NY, U.S.A.) in distilled water. Dilutions were made in RPMI 1640 medium (Gibco, U.S.A.) supplemented with L-glutamine and buffered with morpholinepropanesulfonic acid (MOPS). Checkerboard Microdilution Assay Assays were performed on all 30 isolates according to methods of the CLSI (formerly NCCLS) (M27-A2).15) The initial concentration of fungal suspension in RPMI 1640 medium was 10 3 colony forming unit (CFU)/ml, and the final concentrations ranged from 0.125 to 128 mg/ml for fluconazole and from 0.25 to 128 mg/ml for BE. Plates were incubated at 35°C for 24 h. Optical density was measured at 630 nm, and background optical densities were subtracted from that of each well. Each isolate was tested in triplicate. The definition of minimum inhibition concentration (MIC) is the lowest concentration of a drug at which growth of tested strain is not observed. MIC 80 and MIC 50 mean the concentrations at which 80% and 50% of tested strain cannot grow. The fractional inhibitory concentration (FIC) index is defined as the sum of the MIC of each drug when used in combination divided by the MIC of the drug used alone. Synergism and antagonism were defined by FIC indices of Յ0.5 and Ͼ4, respectively. An...
The protein product of hamster islet neogenesis-associated protein (INGAP) cDNA induces new pancreatic islet development. Manipulation of this process provides a new therapeutic strategy for the treatment of diabetes. As regulators of INGAP gene expression are unknown over 6 kb of hamster genomic INGAP has been cloned. Sequence analysis has identified a 3 kb 5-prime region with core promoter elements that is rich in transcription factor binding sites and six exons for the coding region. Analysis of promoter activity reveals stimulus-responsive DNA elements which have been identified though deletion analysis. Comparison of transcription factor binding sites in INGAP to the related gene RegIIIdelta exposes potential sites for differential gene regulation.
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