Inhibitors of apoptosis proteins in human cervical cancer

BACKGROUND: It has been shown that IAPs, in particular XIAP, survivin and c-IAP1, are overexpressed in several malignancies. In the present study we investigate the expression of c-IAP1, c-IAP2, XIAP and survivin and its isoforms in cervical cancer. METHODS: We used semiquantitative RT-PCR assays to analyze 41 cancer and 6 normal tissues. The study included 8 stage I cases; 16 stage II; 17 stageIII; and a control group of 6 samples of normal cervical squamous epithelial tissue. RESULTS: c-IAP2 and XIAP mRNA levels were similar among the samples, cervical tumors had lower c-IAP1 mRNA levels. Unexpectedly, a clear positive association was found between low levels of XIAP and disease relapse. A log-rank test showed a significant inverse association (p = 0.02) between XIAP expression and tumor aggressiveness, as indicated by disease relapse rates. There were no statistically significant differences in the presence or expression levels of c-IAP1 and c-IAP2 among any of the clinical variables studied. Survivin and its isoforms were undetectable in normal cervical tissues, in contrast with the clear upregulation observed in cancer samples. We found no association between survivin expression and age, clinical stage, histology or menopausal state. Nevertheless, we found that adenocarcinoma tumors expressed higher levels of survivin 2B and DeltaEx3 (p = 0.001 and p = 0.04 respectively, by Kruskal-Wallis). A multivariate Cox's partial likelihood-based analysis showed that only FIGO stage was an independent predictor of outcome. CONCLUSION: There are no differences in the expression of c-IAP2 and XIAP between normal vs. cancer samples, but XIAP expression correlate in cervical cancer with relapse of this disease in the patients. Otherwise, c-IAP1 was downregulated in the cervical cancer samples. The expression of survivin was upregulated in the patients with cervical cancer. We have found that adenocarcinoma presented higher levels of survivin isoforms 2B and DeltaEx3

Independent introductions and sequential founder events shape genetic differentiation and diversity of the invasive green anole (\u3cem\u3eAnolis carolinensis\u3c/em\u3e) on Pacific Islands

Aim: Natural range expansions and human‐mediated colonizations usually involve a small number of individuals that establish new populations in novel habitats. In both cases, founders carry only a fraction of the total genetic variation of the source populations. Here, we used native and non‐native populations of the green anole, Anolis carolinensis, to compare the current distribution of genetic variation in populations shaped by natural range expansion and human‐mediated colonization. Location: North America, Hawaiian Islands, Western Pacific Islands. Methods: We analysed 401 mtDNA haplotypes to infer the colonization history of A. carolinensis on nine islands in the Pacific Ocean. We then genotyped 576 individuals at seven microsatellite loci to assess the levels of genetic diversity and population genetic differentiation for both the native and non‐native ranges. Results: Our findings support two separate introductions to the Hawaiian Islands and several western Pacific islands, with subsequent colonizations within each region following a stepping‐stone model. Genetic diversity at neutral markers was significantly lower in the non‐native range because of founder effects, which also contributed to the increased population genetic differentiation among the non‐native regions. In contrast, a steady reduction in genetic diversity with increasing distance from the ancestral population was observed in the native range following range expansion. Main conclusions: Range expansions cause serial founder events that are the spatial analogue of genetic drift, producing a pattern of isolation‐by‐distance in the native range of the species. In human‐mediated colonizations, after an initial loss of genetic diversity, founder effects appear to persist, resulting in overall high genetic differentiation among non‐native regions but an absence of isolation‐by‐distance. Contrasting the processes influencing the amount and structuring of genetic variability during natural range expansion and human‐mediated biological invasions can shed new light on the fate of natural populations exposed to novel and changing environments

Antibody blockade of IL-15 signaling has the potential to durably reverse vitiligo

Vitiligo is an autoimmune disease of the skin mediated by CD8(+) T cells that kill melanocytes and create white spots. Skin lesions in vitiligo frequently return after discontinuing conventional treatments, supporting the hypothesis that autoimmune memory is formed at these locations. We found that lesional T cells in mice and humans with vitiligo display a resident memory (TRM) phenotype, similar to those that provide rapid, localized protection against reinfection from skin and mucosal-tropic viruses. Interleukin-15 (IL-15)-deficient mice reportedly have impaired TRM formation, and IL-15 promotes TRM function ex vivo. We found that both human and mouse TRM express the CD122 subunit of the IL-15 receptor and that keratinocytes up-regulate CD215, the subunit required to display the cytokine on their surface to promote activation of T cells. Targeting IL-15 signaling with an anti-CD122 antibody reverses disease in mice with established vitiligo. Short-term treatment with anti-CD122 inhibits TRM production of interferon-gamma (IFNgamma), and long-term treatment depletes TRM from skin lesions. Short-term treatment with anti-CD122 can provide durable repigmentation when administered either systemically or locally in the skin. On the basis of these data, we propose that targeting CD122 may be a highly effective and even durable treatment strategy for vitiligo and other tissue-specific autoimmune diseases involving TRM