Malignancy is associated with dermatomyositis but not polymyositis in Northern New England, USA.

OBJECTIVE: To retrospectively evaluate the association of idiopathic inflammatory myopathy (IIM) and malignancy in patients seen at 1 academic center over a 23-year period. METHODS: Patients were identified using the International Classification of Diseases, 9th edition (ICD-9) codes and diagnoses, then confirmed by chart review. Population cancer statistics obtained from the US Centers for Disease Control for Vermont and New Hampshire were used for comparison. RESULTS: Chart review confirmed IIM in 198 of 483 patients initially identified by ICD-9 codes. Within 5 years of diagnosis with IIM, malignancy developed in 32 patients (16.2%), 24 of whom (75%) had dermatomyositis (DM). Malignancy and DM developed within 1 year in 75%. The cancer risk associated with DM was much greater than the risk associated with other IIM. The most frequent tumor types were breast, lung, pancreas, and colon. DM patients with cancer were more frequently male and >or= 45 years of age than those without cancer. There were no cases of interstitial lung disease among patients with cancer and any form of IIM. The incidence of cancer was increased in patients with DM compared to age- and sex-matched population controls, both over a 5-year interval surrounding the diagnosis of DM and over the lifetime interval following diagnosis. CONCLUSION: The risk of cancer in IIM is concentrated among patients with DM. The association between DM and cancer was enhanced by its temporal relationship (< 1 year) in 87.5% of these cases. Patients with malignancy-associated DM were more frequently male and over age 45 and less likely to have interstitial lung disease.

The mitochondrial ATP-binding cassette transporter Abcb7 is essential in mice and participates in cytosolic iron-sulfur cluster biogenesis.

Proteins with iron-sulfur (Fe-S) clusters participate in multiple metabolic pathways throughout the cell. The mitochondrial ABC half-transporter Abcb7, which is mutated in X-linked sideroblastic anemia with ataxia in humans, is a functional ortholog of yeast Atm1p and is predicted to export a mitochondrially derived metabolite required for cytosolic Fe-S cluster assembly. Using an inducible Cre/loxP system to delete exons 9 and 10 of the Abcb7 gene, we examined the phenotype of mice deficient in Abcb7. We found that Abcb7 was essential in extra-embryonic tissues early in gestation and that the mutant allele exhibits an X-linked parent-of-origin lethality effect. Furthermore, using X-chromosome inactivation assays and tissue-specific deletions, Abcb7 was found to be essential for the development and function of numerous other cell types and tissues. A notable exception to this was liver, where loss of Abcb7 impaired cytosolic Fe-S cluster assembly but was not lethal. In this situation, control of iron regulatory protein 1, a key cytosolic modulator of iron metabolism, which is responsive to the availability of cytosolic Fe-S clusters, was impaired and contributed to the dysregulation of hepatocyte iron metabolism. Altogether, these studies demonstrate the essential nature of Abcb7 in mammals and further substantiate a central role for mitochondria in the biogenesis of cytosolic Fe-S proteins.

Transplacental genotoxicity of combined antiretroviral nucleoside analogue therapy in Erythrocebus patas monkeys.

Antiretroviral nucleoside analogue drugs are a major constituent of highly active antiretroviral therapy (HAART), the most advanced form of treatment for HIV-1 infection. Currently, HAART combinations that include zidovudine (ZDV) and lamivudine (3TC) are highly effective in preventing HIV-1 vertical transmission; most children are born with no evident adverse clinical effects. However, ZDV is a moderately strong transplacental carcinogen in mice, and potential long-term consequences of fetal exposure to most HAART combinations remain unknown. To model human transplacental ZDV and 3TC exposures, experiments were performed in Erythrocebus patas monkeys given human-equivalent drug exposure protocols. Pregnant monkeys were dosed with either no drug (n = 2), 40.0 mg ZDV/d (about 6 mg/kg body weight/d) for the last 50% (10 weeks) of gestation (n = 3), or with the same regimen of ZDV plus 24.0 mg 3TC/d (about 3.6 mg/kg body weight/d) for the last 20% (4 weeks) of gestation (n = 3). Multiple fetal organs were examined at term for DNA incorporation of ZDV and 3TC using two separate radioimmunoassays (RIAs). Values for ZDV-DNA incorporation were similar in fetuses exposed to ZDV alone and those exposed to ZDV plus 3TC. Values for 3TC-DNA in fetal organs were greater than or equal to values for ZDV-DNA, indicating that the total DNA damage sustained by fetuses exposed to both drugs was at least double that observed in fetuses exposed to ZDV alone. Telomere shortening, determined by Southern blot with a telomeric probe, was observed in most organs of the three animals exposed in utero to ZDV plus 3TC. No telomere shortening was evident in the unexposed fetuses, and occasional telomere shortening was found in fetuses exposed to ZDV alone. Overall, these studies demonstrate that monkey fetuses exposed in utero to the combination ZDV plus 3TC sustain a higher level of drug-DNA incorporation and show evidence of more telomere damage than monkey fetuses exposed to ZDV alone.