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Summary Expression of the p16INK4a tumor suppressor sharply increases with age in most mammalian tissues, and contributes to an age-induced functional decline of certain self-renewing compartments. did not independently correlate with gender or bodymass index, but was significantly associated with tobacco use and physical inactivity. In addition, p16 INK4a expression was associated with plasma interleukin-6 concentration, a marker of human frailty. These data suggest that p16 INK4a expression in PBTL is an easily measured, peripheral blood biomarker of molecular age.

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We evaluated a program of payments for ecosystem services in Uganda that offered forest-owning households annual payments of 70,000 Ugandan shillings per hectare if they conserved their forest. The program was implemented as a randomized controlled trial in 121 villages, 60 of which received the program for 2 years. The primary outcome was the change in land area covered by trees, measured by classifying high-resolution satellite imagery. We found that tree cover declined by 4.2% during the study period in treatment villages, compared to 9.1% in control villages. We found no evidence that enrollees shifted their deforestation to nearby land. We valued the delayed carbon dioxide emissions and found that this program benefit is 2.4 times as large as the program costs.

Metastases are the major cause of death from melanoma, a skin cancer which has the fastest rising incidence of any malignancy in the Western world. Molecular pathways that drive melanoblast migration in development are believed to underpin the movement and ultimately the metastasis of melanoma. Here we show that mice lacking P-Rex1, a Rac-specific Rho GTPase guanine nucleotide exchange factor (GEF), have a melanoblast migration defect during development evidenced by a white belly. Moreover, these P-Rex1−/− mice are resistant to metastasis when crossed to a murine model of melanoma. Mechanistically, this is associated with P-Rex1 driving invasion in a Rac-dependent manner. P-Rex1 is elevated in the great majority of human melanoma cell lines as well as tumor tissue. We conclude that P-Rex1 plays an important role in melanoblast migration and cancer progression to metastasis in mice and humans.

BackgroundGenome-wide association studies (GWAS) have linked common single nucleotide polymorphisms (SNPs) on chromosome 9p21 near the INK4/ARF (CDKN2A/B) tumor suppressor locus with risk of atherosclerotic diseases and type 2 diabetes mellitus. To explore the mechanism of this association, we investigated whether expression of proximate transcripts (p16INK4a, p15INK4b, ARF, ANRIL and MTAP) correlate with genotype of representative 9p21 SNPs.Methodology/Principal FindingsWe analyzed expression of 9p21 transcripts in purified peripheral blood T-cells (PBTL) from 170 healthy donors. Samples were genotyped for six selected disease-related SNPs spanning the INK4/ARF locus. Correlations among these variables were determined by univariate and multivariate analysis. Significantly reduced expression of all INK4/ARF transcripts (p15INK4b, p16INK4a, ARF and ANRIL) was found in PBTL of individuals harboring a common SNP (rs10757278) associated with increased risk of coronary artery disease, stroke and aortic aneurysm. Expression of MTAP was not influenced by rs10757278 genotype. No association of any these transcripts was noted with five other tested 9p21 SNPs.Conclusions/SignificanceGenotypes of rs10757278 linked to increased risk of atherosclerotic diseases are also associated with decreased expression in PBTL of the INK4/ARF locus, which encodes three related anti-proliferative transcripts of known importance in tumor suppression and aging.

In this report, we investigated BRAF/NRAS mutations in samples from a case-control study of melanoma and a series of benign melanocytic nevi. We evaluated potential associations between BRAF mutations and histopathologic and pigmentary characteristics of melanoma. Mutations in BRAF and NRAS were detected by sequencing microdissected/laser-captured DNA from 18 in-situ melanomas, 64 primary melanomas, and 51 nevi. Nevi showed the highest frequency of BRAF mutations (82%). BRAF mutations were identified in 29% of invasive melanomas and in only 5.6% of in-situ melanomas. Mutations in NRAS were found in 5.2% of primary melanomas, 5.9% of nevi and no NRAS mutations were seen in in-situ melanomas. A majority of the BRAF mutations observed in primary invasive melanoma were seen in superficial spreading melanoma (15/17), and melanomas with BRAF mutations were also more likely to be found on a body site that was likely to be exposed to intermittent sun exposure compared with chronic or no sun exposure (P=0.02). Tumors with BRAF mutations were also significantly more likely to occur in association with a contiguous nevus (odds ratio 3.49, 95% confidence interval 1.06-11.46), although a contiguous nevus was not found in all melanomas with a BRAF mutation. Our data support the evidence that the mitogen-activated protein kinase pathway is upregulated in a large percentage of melanocytic lesions, but these mutations are not sufficient for malignant transformation. We suggest that BRAF mutations contribute to benign melanocytic hyperplasia, but are likely to contribute to invasive melanoma only in conjunction with other mutations.