The transcription factor nuclear factor B (NF-B) regulates the expression of both antiapoptotic and proapoptotic genes. Death receptor 5 (DR5, TRAIL-R2) is a proapoptotic protein considered to be a potential target for cancer therapy, and its expression is mediated by NF-B. The mechanism of NF-B-induced DR5 expression is, however, unknown. Herein, we determined that etoposide-induced DR5 expression requires the first intronic region of the DR5 gene. Mutation of a putative NF-B binding site in this intron eliminates DR5 promoter activity, as do mutations in the p53 binding site in this region. Reduction in p53 expression also blocks p65 binding to the intronic region of the DR5 gene, indicating cooperation between p53 and p65 in DR5 expression. In contrast, the antiapoptotic stimulus, epidermal growth factor (EGF), fails to increase DR5 expression but effectively activates NF-B and induces p65 binding to the DR5 gene. EGF, however, induces the association of histone deacetylase 1 (HDAC1) with the DR5 gene, whereas etoposide treatment fails to induce this association. Indeed, HDAC inhibitors activate NF-B and p53 and upregulate DR5 expression. Blockage of DR5 activation decreased HDAC inhibitor-induced apoptosis, and a combination of HDAC inhibitors and TRAIL increased apoptosis. This provides a mechanism for regulating NF-B-mediated DR5 expression and could explain the differential roles NF-B plays in regulating apoptosis.Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF ligand family. It is capable of inducing apoptosis in transformed cancer cells but not in normal cells (14,53). TRAIL binds to two receptors, death receptor 4 (DR4, TRAIL-R1) and death receptor 5 (DR5, TRAIL-R2) (33,40,41,52,57). Upon binding, an adaptor protein called Fas-associated death domain (FADD) is recruited to the death receptors, forming a death-inducing signaling complex (46). Fas-associated death domain constitutively associates with procaspase 8 and, upon recruitment to death receptors, caspase 8 is activated. This leads to further caspase activation and release of mitochondrial proteins and, ultimately, to apoptosis (3, 38).Chemotherapeutic drugs, including etoposide and doxorubicin in combination with TRAIL, give a synergistic apoptotic response in cancer cells (11,21,43). This synergy is due partially to the ability of chemotherapeutic drugs and TRAIL to induce DR4 and DR5 expression. Up-regulation of DR5 in lung cancer cell lines is p53 dependent, and the p53-responsive element responsible for DR5 expression has been identified in the first intron region of the DR5 gene (47). Indeed, primary chronic lymphocytic leukemia cells lacking functional p53 fail to up-regulate DR5 following genotoxin treatment (20). Besides p53 involvement, blockage of the transcription factor NF-B effectively inhibits etoposide and TRAIL-induced DR5 expression and synergistic apoptotic response (11,42). The mechanism for NF-B up-regulation of DR5 is currently unknown, but a putative NF-B binding site has been i...
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).
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.
Intraabdominal infections are commonly encountered in clinical practice and represent a major cause of morbidity and mortality. The most common etiology is contamination of the peritoneal space by endogenous microflora secondary to loss of integrity of the gastrointestinal tract which results in secondary peritonitis. Primary peritonitis or spontaneous bacterial peritonitis is less common and usually occurs in the presence of ascites without an evident source of infection. Peritonitis associated with chronic ambulatory peritoneal dialysis is not discussed in this review. This review summarizes the significant progress which has been made with regard to primary and secondary peritonitis in the last two decades. The review emphasizes the issues of etiology, pathogenesis, microbiology, diagnosis, medical treatment and prevention.
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.
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