Mitochondria-derived reactive intermediate species mediate asbestos-induced genotoxicity and oxidative stress-responsive signaling pathways

Background: The incidence of asbestos-induced human cancers is increasing worldwide, and considerable evidence suggests that reactive oxygen species (ROS) are important mediators of these diseases. Our previous studies suggested that mitochondria might be involved in the initiation of oxidative stress in asbestos-exposed mammalian cells.Objective: We investigated whether mitochondria are a potential cytoplasmic target of asbestos using a mitochondrial DNA–depleted (ρ⁰) human small airway epithelial (SAE) cell model: ρ⁰ SAE cells lack the capacity to produce mitochondrial ROS.Methods: We examined nuclear DNA damage, micronuclei (MN), intracellular ROS production, and the expression of inflammation-related nuclear genes in both parental and ρ⁰ SAE cells in response to asbestos treatment.Results: Asbestos induced a dose-dependent increase in nuclear DNA oxidative damage and MN in SAE cells. Furthermore, there was a significant increase in intracellular oxidant production and activation of genes involved in nuclear factor κB and proinflammatory signaling pathways in SAE cells. In contrast, the effects of asbestos were minimal in ρ⁰ SAE cells.Conclusions: Mitochondria are a major cytoplasmic target of asbestos. Asbestos may initiate mitochondria-associated ROS, which mediate asbestos-induced nuclear mutagenic events and inflammatory signaling pathways in exposed cells. These data provide new insights into the molecular mechanisms of asbestos-induced genotoxicity.     

Clofarabine in leukemia

Clofarabine is a second-generation purine nucleoside analogue that has been synthesized to overcome the limitations and incorporate the best qualities of fludarabine and cladribine. Clofarabine acts by inhibiting ribonucleotide reductase and DNA polymerase, thereby depleting the amount of intracellular deoxynucleoside triphosphates available for DNA replication. Compared with its precursors, clofarabine has an increased resistance to deamination and phosphorolysis, hence better stability, as well as higher affinity to deoxycytidine kinase (dCyd), the rate-limiting step in nucleoside phosphorylation. In 1993, the first Phase I study was initiated in patients with hematologic and solid malignancies. Since then, clofarabine has demonstrated single-agent antitumor activity in pediatric and adult acute leukemia. Owing to its unique properties of biochemical modulation when used in combination with other established antileukemic drugs, mainly cytarabine, combination regimens containing clofarabine are being evaluated. A review of the English literature was performed that included original articles and related reviews from the MEDLINE (PubMed) database and from abstracts based on the publication of meeting materials. This article describes the development, pharmacology and clinical activity of clofarabine, as well as its emerging role in the treatment of acute leukemia, myelodysplastic syndrome and solid tumors.     

Cell mediated immune responses through TLR4 prevents DMBA-induced mammary carcinogenesis in mice

Toll-like receptors (TLRs) activate signals that are critically involved in the initiation of adaptive immune responses and many tumorigenic chemicals have been associated with activation of those pathways. To determine the role of TLR-4 (TLR4) in mammary carcinogenesis, we subjected TLR4 deficient and wild type (WT) mice to oral gavage with carcinogenic polyaromatic hydrocarbon 7,12-dimethylbenz(a)anthracene (DMBA). TLR4 deficient mice developed more tumors relative to the WT mice. T cells of TLR4 deficient mice produced elevated levels of IL-17 and lower levels of IFN-γ relative to WT mice. IL-12 secreted by CD11c(+) cells was higher in WT mice, whereas greater amounts of IL-23 were produced by CD11c(+) cells from TLR4 deficient mice. Moreover, there was higher incidence of regulatory T cells in TLR4 deficient mice than WT mice. Similarly, various markers of angiogenesis [matrix metalloproteinases (MMP)-2 and MMP-9, CD31 and vascular endothelial growth factor] were highly expressed in tumors from TLR4 deficient mice than WT mice. The results of this study indicate that TLR4 plays an important role in the prevention of DMBA induced mouse mammary tumorigenesis and efforts to divert the cell-mediated immune response may, therefore, prove to be beneficial in the prevention of mammary tumors.     

Ameloblastoma: a surgeon's dilemma.

PURPOSE: To investigate whether there were any significant differences in the mode of presentation, treatment, and outcome of patients presenting with a primary diagnosis of ameloblastoma in Glasgow, Scotland and San Francisco, CA. MATERIALS AND METHODS: All cases of ameloblastoma seen in both institutions between January 1, 1980 and December 31, 1999 were included in this study. Mode of presentation, radiographic appearance, histologic appearance, treatment, and follow-up were recorded. RESULTS: There were no significant differences in the clinical features on presentation (swelling, followed by pain, and altered sensation), the radiographic appearance (unilocular approximately 30% and multilocular 70%), or management with either local treatment (enucleation and/or curettage in just over 50% of cases) or radical treatment (a form of resection in under 50%) in the 50 cases included in this study. Primary care by conservative treatment led to a recurrence in approximately 80% of cases and this included cases of unicystic ameloblastoma. CONCLUSION: The mode of presentation, diagnosis, and management of the ameloblastoma was remarkably similar in Glasgow and San Francisco. The recurrence rate following local enucleation and curettage was unacceptably high, and this included the cases of unicystic ameloblastoma, which should be treated more aggressively than has been recommended in the past.