Anthropogenic refugia ameliorate the severe climate-related decline of a montane mammal along its trailing edge.

We conducted detailed resurveys of a montane mammal, Urocitellus beldingi, to examine the effects of climate change on persistence along the trailing edge of its range. Of 74 California sites where U. beldingi were historically recorded (1902-1966), 42 per cent were extirpated, with no evidence for colonization of previously unoccupied sites. Increases in both precipitation and temperature predicted site extirpations, potentially owing to snowcover loss. Surprisingly, human land-use change buffered climate change impacts, leading to increased persistence and abundance. Excluding human-modified sites, U. beldingi has shown an upslope range retraction of 255 m. Generalized additive models of past distribution were predictive of modern range contractions (AUC = 0.76) and projected extreme reductions (52% and 99%, respectively) of U. beldingi's southwestern range to 2080 climates (Hadley and CCCMA A2). Our study suggests the strong impacts of climate change on montane species at their trailing edge and how anthropogenic refugia may mitigate these effects.

Inhibiting Histone Deacetylase as a Means to Reverse Resistance to Angiogenesis Inhibitors: Phase I Study of Abexinostat Plus Pazopanib in Advanced Solid Tumor Malignancies.

Purpose This phase I trial evaluated epigenetic modulation of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor by using a histone deacetylase abexinostat in combination with pazopanib to enhance response and reverse resistance. Patients and Methods Pazopanib was administered once a day on days 1 to 28 and abexinostat was administered orally twice a day on days 1 to 5, 8 to 12, and 15 to 19 (schedule A) or on days 1 to 4, 8 to 11, and 15 to 18 (schedule B). Dose escalation (3 + 3 design) in all solid tumors was followed by dose expansion in renal cell carcinoma (RCC). Results Fifty-one patients with RCC (N = 22) were enrolled, including 30 (59%) with one or more lines of prior VEGF-targeting therapy. Five dose-limiting toxicities, including fatigue (n = 2), thrombocytopenia (n = 2), and elevated AST/ALT (n = 1), were observed with schedule A; one dose-limiting toxicity was observed (elevated AST/ALT) was observed with schedule B. Grade ≥ 3 related adverse events included fatigue (16%), thrombocytopenia (16%), and neutropenia (10%). The recommended phase II dose was established as abexinostat 45 mg/m2 twice a day administered per schedule B plus pazopanib 800 mg/d. Objective response rate was 21% overall and 27% in the RCC subset. Median duration of response was 9.1 months (1.2 to > 49 months). Eight patients (16%) had durable control of disease for > 12 months. Durable tumor regressions were observed in seven (70%) of 10 patients with pazopanib-refractory disease, including one patients with RCC with ongoing response > 3.5 years. Peripheral blood histone acetylation and HDAC2 gene expression were associated with durable response to treatment. Conclusion Abexinostat is well tolerated in combination with pazopanib, allowing prolonged exposure and promising durable responses in pazopanib- and other VEGF inhibitor-refractory tumors, which supports epigenetically mediated reversal of treatment resistance.