This review summarizes clinical studies in which glutathione was measured in tumor tissue from patients with brain, breast, gastrointestinal, gynecological, head and neck and lung cancer. Glutathione tends to be elevated in breast, ovarian, head and neck and lung cancer and lower in brain and liver tumors compared to disease-free tissue. Cervical, colorectal, gastric and esophageal cancers show both higher and lower levels of tumor glutathione. Some studies show an inverse relationship between patient survival and tumor glutathione. Based on this survey, we recommend approaches that may improve the clinical value of glutathione as a biomarker.

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Currently, our knowledge of how pathogenic fungi grow in mammalian host environments is limited. Using a chemotherapeutic murine model of invasive pulmonary aspergillosis (IPA) and 1H-NMR metabolomics, we detected ethanol in the lungs of mice infected with Aspergillus fumigatus. This result suggests that A. fumigatus is exposed to oxygen depleted microenvironments during infection. To test this hypothesis, we utilized a chemical hypoxia detection agent, pimonidazole hydrochloride, in three immunologically distinct murine models of IPA (chemotherapeutic, X-CGD, and corticosteroid). In all three IPA murine models, hypoxia was observed during the course of infection. We next tested the hypothesis that production of ethanol in vivo by the fungus is involved in hypoxia adaptation and fungal pathogenesis. Ethanol deficient A. fumigatus strains showed no growth defects in hypoxia and were able to cause wild type levels of mortality in all 3 murine models. However, lung immunohistopathology and flow cytometry analyses revealed an increase in the inflammatory response in mice infected with an alcohol dehydrogenase null mutant strain that corresponded with a reduction in fungal burden. Consequently, in this study we present the first in vivo observations that hypoxic microenvironments occur during a pulmonary invasive fungal infection and observe that a fungal alcohol dehydrogenase influences fungal pathogenesis in the lung. Thus, environmental conditions encountered by invading pathogenic fungi may result in substantial fungal metabolism changes that influence subsequent host immune responses.

The fungal secondary metabolite gliotoxin produced by Aspergillus fumigatus has been hypothesized to be important in the development of invasive aspergillosis. In this study, we addressed this hypothesis by disrupting a nonribosomal peptide synthetase (NRPS) (encoded by gliP) predicted to be involved in gliotoxin production. Mutants with a disrupted gliP locus failed to produce gliotoxin, which confirmed the role of the NRPS encoded by gliP in gliotoxin biosynthesis. We found no morphological, developmental, or physiological defects in ⌬gliP mutant strains. In addition, disruption of gliP resulted in down regulation of gene expression in the gliotoxin biosynthesis gene cluster, which was restored with addition of exogenous gliotoxin. This interesting result suggests a role for gliotoxin in regulating its own production. Culture filtrates from the ⌬gliP mutant were unable to inhibit ionomycin-dependent degranulation of mast cells, suggesting a role for gliotoxin in suppressing mast cell degranulation and possibly in disease development. However, the ⌬gliP mutant did not have an impact on survival or tissue burden in a murine inhalational model of invasive aspergillosis. This result suggests that gliotoxin is not required for virulence in an immunosuppressed host with an invasive pulmonary infection.New medical therapies for life-threatening diseases such as solid-organ transplantation, aggressive cancer therapies, and other immunomodulating therapies have resulted in an increase in invasive fungal infections. In particular, the mortality due to invasive aspergillosis (IA) has increased 357% over the last 25 years (19). IA has become one of the leading causes of death in immunocompromised patients, with mortality rates ranging from 60 to 90% (18,19). Although IA can be caused by several members of the genus Aspergillus, Aspergillus fumigatus remains the most prevalent causal organism (13,26).A. fumigatus is a saprophytic, asexually reproducing fungus that is found in soil and compost piles and primarily functions to recycle carbon and nitrogen throughout the environment (35). Yet the high frequency of A. fumigatus infections strongly suggests that this saprophytic fungus has attributes unique among Aspergillus species that make it an effective opportunistic pathogen. Several physiological and morphological characteristics of A. fumigatus have been hypothesized or demonstrated to be involved in fungal pathogenesis. These include thermotolerant growth, fast growth rates, conidial size and morphology, and the production of cell wall-degrading enzymes and proteases (3,6,13,16).Like other Aspergillus species, A. fumigatus is known to produce immunosuppressant secondary metabolites, including the epipolythiodioxopiperazine (ETP) toxin gliotoxin (11). Secondary metabolites are compounds produced by many filamentous fungi that are not required for growth but often have important biological activities. For instance, fungal secondary metabolites often have antimicrobial activity, and it is hypothesized that their production...