Keloids mark a chronic inflammatory disease characterized by a fibroproliferative disorder of the skin. A genome-wide association study showed that single-nucleotide polymorphism rs8032158 in the neural precursor cell-expressed NEDD4 gene, which has six protein-coding transcript variants (TVs), is genetically linked to keloids. Here, we show that the high frequency of risk allele C in rs8032158 in keloid patients is associated with a selectively higher expression of TV3 of NEDD4 to activate the NF-kB pathway. Comparisons of keloid scars with normal skin samples that do not have the single-nucleotide polymorphism allele and were derived from different anatomical sites showed stronger expressions of NEDD4 TV3 and activated forms of NF-kB and STAT3 in keloid scars. Forced expression or selective knockdown of NEDD4 TV3 increased or decreased NF-kB activation in vitro. Furthermore, NEDD4 knockdown suppressed NF-kBedependent inflammation development in vivo. Mechanistic analysis showed that NEDD4 TV3 is involved in NF-kB activation through its association with the adaptor protein RIP. These results suggest that NEDD4 TV3 is a potential diagnostic marker and therapeutic target for chronic skin diseases, including keloid.

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The loss of biological diversity within species has the potential to significantly reduce resilience in the face of environmental change. Conservation of genetic variation needs to consider all available sources of diversity within a species, and approaches are required to integrate population management across traditionally separate wild and captive population domains. Here we report on a study that utilises different types of genetic analysis at different taxonomic scales and across an in situ-ex situ transition to support conservation planning for the Japanese golden eagle, a subspecies in serious regional decline. Mitochondrial DNA sequencing and nuclear DNA profiling are used to investigate subspecies differentiation and diversity in the natural population, revealing relatively high levels of variation in Japan. These results are compared with data from a newly established conservation breeding programme that indicates good representation of wild genetic variation in the captive founders. However, subsequent population viability analysis (PVA) to examine the demographic and genetic future of the captive population demonstrates the severe effects of existing reproductive skews, suggesting that this population is not sustainable without intensive genetic management. Lastly, the use of available molecular tools to validate and reconstruct pedigrees in Japanese golden eagle are evaluated and discussed in the context of captive and wild conservation management. The paper highlights the importance of producing and utilising comparative molecular genetic data across the population management spectrum and the benefits of PVA to support the implementation of integrated conservation plans.

Summary Background Taxanes are the current first‐line treatment for advanced cutaneous angiosarcoma (CAS) for patients who are considered difficult to treat with doxorubicin owing to advanced age or comorbidity. However, no effective second‐line therapy for such patients has been established. Methods We designed a single‐arm prospective observational study of eribulin mesylate (ERB) administered at a dose of 1·4 mg m−2 on days 1 and 8 in a 21‐day cycle. Patients with advanced CAS who were previously treated with a taxane and were scheduled to begin ERB treatment were enrolled. The primary endpoint was overall survival (OS) and the secondary endpoints were response rate (RR), progression‐free survival (PFS) and toxicity assessment. Results We enrolled a total of 25 patients. The median OS and PFS were 8·6 months and 3·0 months, respectively. The best overall RR was 20% (five of 25). In total, 16 grade 3/4 severe adverse events (SAEs) occurred; however, all patients recovered. Patients who achieved partial response or stable disease as best response had longer OS than those with progressive disease (median OS not reached and 3·3 months, respectively; P < 0·001). Patients who did not experience SAEs showed longer OS than those who did (median OS 18·8 months and 7·5 months, respectively; P < 0·05). Patients with distant metastasis had shorter median OS than those with locoregional disease, but without statistically significant difference. Conclusions ERB showed a promising RR and is a potential candidate for second‐line treatment for patients with CAS, after treatment with taxanes. However, owing to the occurrence of SAEs in over half of the participants, caution should be exercised regarding ERB use in elderly patients. What is already known about this topic? Taxanes are the current first‐line treatment for patients with advanced cutaneous angiosarcoma (CAS) who are considered difficult to treat with doxorubicin owing to advanced age or comorbidity. No effective therapy for taxane‐resistant CAS has been established thus far. Eribulin suppresses microtubule polymerization and elicits an antitumour effect similar to that of taxanes. What does this study add? In our single‐arm prospective observational study to evaluate the efficacy of eribulin for treating patients with advanced CAS who previously received taxanes, the median overall survival and progression‐free survival were 8·6 and 3·0 months, respectively. Response rates at weeks 7, 13 and 25 were 20%, 17% and 14%, respectively. Although 16 grade 3/4 severe adverse events occurred, all patients recovered. Eribulin showed a promising response rate and is a potential candidate for second‐line treatment in CAS after taxane treatment. Linked Comment: Smrke and Benson. Br J Dermatol 2020; 183:797–798.

Abstract The application of evolutionary genetic research to investigate the potential for endangered species to adapt to changing environments is important for conservation biology. Effective population size (Ne) is informative for understanding adaptive potential as it refers to the genetic variation in breeding individuals who have contributed to contemporary and historic population diversity. We reconstruct fluctuations in Ne in three golden eagle subspecies (Japanese, Scottish, North American) using the pairwise sequential Markovian coalescent (PSMC) model based on whole-genome sequence data. Our results indicate the timing of subspeciation events and suggest significant ongoing demographic reductions since the start of the Last Glacial Period. Importantly, we find evidence for gene flow from continental populations into the ancestral Japanese population resulting in a short, sharp recovery in genetic diversity. Timing agrees with the palaeogeographic estimates of land bridge connections between the Japanese archipelago and Asian continent and matches a similar Ne spike in the Scottish population, but not in the North American population. Given contemporary declines in isolated Japanese and UK island populations, our study highlights a concerning loss of local genetic diversity, but also indicates the likely response of populations to genetic reinforcement from neighbouring subspecies, increasing management options and encouraging a range-wide species conservation approach.