Antiestrogen use and survival of women with non-small cell lung cancer in Manitoba, Canada.

Lung cancer is the leading cause of cancer death worldwide. Sex differences in lung cancer incidence and survival are known. Female sex is an independent good prognostic factor. Estrogens appear to play a key role in lung cancer outcomes. Accordingly, antiestrogen use may also influence survival in female non-small cell lung cancer (NSCLC) patients. In this study, we compared survival among antiestrogen users and nonusers. We performed a retrospective population-based study. Using the Manitoba Cancer Registry (MCR), we identified all women diagnosed with NSCLC from 2000 to 2007. The population-based Drug Program Information Network was accessed to establish which patients received antiestrogens. Demographic data (e.g., smoking patterns, stage, histology) were gathered from the MCR and by chart review. Survival differences between antiestrogen-exposed and not exposed groups were compared using multivariable Cox regression. Two thousand three hundred twenty women fit our patient criteria, of which 156 had received antiestrogens. Exposure to antiestrogens was associated with a significantly decreased mortality in those exposed both before and after the diagnosis of NSCLC (adjusted hazard ratio, 0.42, p = 0.0006). This association remained consistent across age and stage groups. Antiestrogen use before and after the diagnosis of NSCLC is associated with decreased mortality. This supports previous evidence that estrogens may play a key role in the biology and outcomes of NSCLC and suggests a potential therapeutic use for these agents in this disease.

The Drosophila U1 and U6 gene proximal sequence elements act as important determinants of the RNA polymerase specificity of small nuclear RNA gene promoters in vitro and in vivo.

Transcription of genes coding for metazoan spliceosomal snRNAs by RNA polymerase II (U1, U2, U4, U5) or RNA polymerase III (U6) is dependent upon a unique, positionally conserved regulatory element referred to as the proximal sequence element (PSE). Previous studies in the organism Drosophila melanogaster indicated that as few as three nucleotide differences in the sequences of the U1 and U6 PSEs can play a decisive role in recruiting the different RNA polymerases to transcribe the U1 and U6 snRNA genes in vitro. Those studies utilized constructs that contained only the minimal promoter elements of the U1 and U6 genes in an artificial context. To overcome the limitations of those earlier studies, we have now performed experiments that demonstrate that the Drosophila U1 and U6 PSEs have functionally distinct properties even in the environment of the natural U1 and U6 gene 5'-flanking DNAs. Moreover, assays in cells and in transgenic flies indicate that expression of genes from promoters that contain the "incorrect" PSE is suppressed in vivo. The Drosophila U6 PSE is incapable of recruiting RNA polymerase II to initiate transcription from the U1 promoter region, and the U1 PSE is unable to recruit RNA polymerase III to transcribe the U6 gene.

In vitro kill curves of a new semisynthetic echinocandin, LY-303366, against fluconazole-sensitive and -resistant Candida species.

In vitro killing by a new semisynthetic echinocandin, LY-303366, was characterized using clinical isolates of fluconazole-sensitive (Y58) and -resistant (Y180) Candida albicans as well as Candida glabrata (Y7) and Candida krusei (Y171). The 24-h kill curves for Y58 and Y180 demonstrated dose-independent killing of between 1 and 2 log10 with LY-303366 at concentrations of 0.1, 1, 10, 50, 100, and 1,000 times the MIC. Regrowth did not occur at 24 h with either C. albicans isolate at the aforementioned LY-303366 concentrations. At their MICs, LY-303366 and amphotericin B produced similar killing kinetics in cultures of Y58, Y180, Y7, and Y171, while all cultures exposed to fluconazole at its MIC demonstrated stasis or growth over 24 h.

In vitro activity of a new semisynthetic echinocandin, LY-303366, against systemic isolates of Candida species, Cryptococcus neoformans, Blastomyces dermatitidis, and Aspergillus species.

The in vitro activities of LY-303366, a new semisynthetic echinocandin, and comparators amphotericin B, 5-fluorocytosine, fluconazole, and ketoconazole against 205 systemic isolates of Candida species, Cryptococcus neoformans, Blastomyces dermatitidis, and Aspergillus species were determined. LY-303366 had MICs of < or = 0.32 microg/ml for all Candida albicans (n = 99), Candida glabrata (n = 18), and Candida tropicalis (n = 10) isolates tested. LY-303366 was also active against Aspergillus species (minimum effective concentration at which 90% of the isolates are inhibited, 0.02 microg/ml) (n = 20), was less active against Candida parapsilosis (MIC at which 90% of the isolates are inhibited [MIC90], 5.12 microg/ml) (n = 10), and was inactive against C. neoformans (MIC90, >10.24 microg/ml) (n = 15) and B. dermatitidis (MIC90, 16 microg/ml) (n = 29).

In vitro characterization of aminoglycoside adaptive resistance in Pseudomonas aeruginosa.

Aminoglycoside adaptive resistance was characterized in one reference strain and four clinical isolates of Pseudomonas aeruginosa. Adaptive resistance was initiated with a 2-h gentamicin or tobramycin exposure at the MIC. Each P. aeruginosa strain demonstrated an adaptive-resistance period of between 8 and 12 h when tested with both aminoglycosides. Aminoglycoside adaptive resistance was shown to correlate with a decrease in [3H] gentamicin accumulation and a small (5%) but significant (P < 0.05) reduction in proton motive force. The mean generation time of P. aeruginosa during peak levels of adaptive resistance (i.e., maximum reductions in aminoglycoside killing) was not significantly different from that of control organisms (P < 0.05). No changes in outer membrane protein or lipopolysaccharide sodium dodecyl sulfate-polyacrylamide gel electrophoresis profiles were noted when control, adaptively resistant, and postadaptively resistant cells were compared. Cytoplasmic membrane profiles of adaptively resistant cells, however, demonstrated several band changes when compared with control and postadaptively resistant cells. We conclude that the decrease in aminoglycoside accumulation associated with adaptive resistance in P. aeruginosa may be, in part, a function of reductions in proton motive force and/or cytoplasmic membrane protein changes. However, the importance of these changes requires further investigation.