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Editors’ Picks
EDITORS’ PICKS Aging of the microenvironment Older cancer patients typically have a poorer prognosis than younger patients, and while this difference may be attributable to accumulated damage, decreased immunity, or chronic inflammation, Kaur and colleagues investigated the role of the aged tumor microenvironment in tumor progression. In a mouse model of melanoma, tumors grew more slowly in aged mice but were more aggressive and metastatic. The b-catenin antagonist sFRP2 was secreted at increased levels from aged fibroblasts and contributed to phenotype switching in melanoma cells. These studies revealed that sFRP2 increases oxidative stress in melanoma cells via inhibition of b-catenin and subsequent downregulation of the microphthalmia-associated transcription factor (MITF)/APE1 redox pathway. Furthermore, this loss of b-catenin not only promotes invasion of tumor cells but also renders the melanoma cells more sensitive to oxidative stress and therefore more resistant to targeted therapy, such as vemurafenib. These findings suggest potential benefits for use of antioxidant therapy in aged patients. (Nature http://dx.doi.org/ 10.1038/nature17392, 2016) Selected by B. A. Gilchrest
Structural insight CRL4DDB2 is a cullin-RING ubiquitin E3 ligase (CRL) comprised of CUL4, RBX1, DDB1, and DDB2. This complex detects ultraviolet light-induced lesions in the genome, facilitates ubiquitination surrounding these lesions, and leads to nucleotide excision repair. Mutations in DDB2 result in xeroderma pigmentosum, a condition characterized by UV sensitivity and cancer predisposition. This complex remains inactive in the absence of DNA damage and is regulated by the COP9 signalasome complex (CSN), which is essential for efficient nucleotide excision repair. Cavadini and colleagues reported the cryo-electron microscopy structure of human CSN in complex with neddylated (NEDD8) CRL4DDB2 as well as with CRL4A. These structural analyses revealed that an induced-fit mechanism drives CSN activation by neddylated CRLs. CSN, therefore, serves as a primary negative regulatory of CRLs and is a requirement for efficient CRL activity and specificity. (Nature http://dx.doi.org/10.1038/nature 17416, 2016) Selected by E. Lerner
An EGFR-Treg Relationship Regulatory T cells (Tregs) mediate skin immune homeostasis. Nosbaum and colleagues examined the role of these immune cells in wound healing, a vital process mediated by multiple cell types and molecular pathways, including the epidermal growth factor receptor (EGFR) pathway. In a mouse model of skin wounding, Tregs were found to play an important role in facilitating healing early after wounding during the inflammatory phase. In addition, activated Tregs accumulated in the Journal of Investigative Dermatology (2016) 136, 1312. doi:10.1016/ j.jid.2016.05.092
1312 Journal of Investigative Dermatology (2016), Volume 136
skin during this phase, and without these cells, wound closure was inhibited. Specifically, the Treg cells functionally limit the accumulation of interferon-g-producing T cells and proinflammatory macrophages in wounded skin via EGFR expression on the Tregs. Thus, EGFR is important for Treg function. Current strategies to treat chronic skin ulcers by augmentation of EGFR signaling may work via effects on Treg function in the skin, suggesting that modulation of these important immune cells may be a novel means to treat wound-associated inflammation and facilitate healing. ( J Immunol http://dx.doi.org/10.4049/jimmunol.1502139, 2016) Selected by T. Schwarz
Dermatitis in Spades Yasuda and colleagues recently identified a dermatitis animal model in randomly mutagenized mice. These mice spontaneously developed stepwise, progressive atopic dermatitis (“Spade” mice) due to a skin homeostasis defect and a subsequent Th2-biased immune response. Genetic mapping and molecular analysis revealed a single nucleotide gain-offunction mutation in the Jak1 tyrosine kinase near the ATPbinding motif of the kinase domain. This point mutation resulted in hyperactivation of the JAK1/STAT signaling pathway, which is known to affect numerous cytokines, and overexpression of serine proteases in the epidermis, leading to aberrant differentiation, hyperproliferation of keratinocytes, and a skin barrier defect. Emollient treatment delayed the onset of dermatitis in the Spade mice. Thus, the skin is the responsible tissue for dermatitis onset in these animals, although inflammatory responses contribute to disease. Furthermore, hyperphosphorylation of epidermal JAK1 was found in a subset of skin samples from atopic dermatitis patients, lending support to the clinical relevance of this mouse model. (J Clin Invest http://dx.doi.org/10.1172/ JCI82887, 2016) Selected by M. Amagai
Data doping A recent analysis of electrophoretic, microscopic, and flow cytometric data images from 20,621 papers published in 40 different scientific journals from 1995 to 2014 spearheaded by Bik and colleagues revealed that as many as 1 in 25 papers contains inappropriately duplicated images. Due to the nature of the investigation, this figure is likely an underestimation of the extent of problematic data. Interestingly, the prevalence of papers with inappropriate image duplications was higher after 2002 and correlates inversely with journal impact factor. Moreover, other papers by the authors of the originally identified papers that included these duplicated images also often contained duplicated images. These disturbing results ultimately cast doubt on the quality and integrity of the scientific literature and highlight the need for increased scrutiny by authors, reviewers, and editors to identify problematic figures prior to publication. (bioRxlv http://dx.doi.org/10.1101/049452, 2016) Selected by B. A. Gilchrest
ª 2016 The Society for Investigative Dermatology.
Structural insight CRL4DDB2 is a cullin-RING ubiquitin E3 ligase (CRL) comprised of CUL4, RBX1, DDB1, and DDB2. This complex detects ultraviolet light-induced lesions in the genome, facilitates ubiquitination surrounding these lesions, and leads to nucleotide excision repair. Mutations in DDB2 result in xeroderma pigmentosum, a condition characterized by UV sensitivity and cancer predisposition. This complex remains inactive in the absence of DNA damage and is regulated by the COP9 signalasome complex (CSN), which is essential for efficient nucleotide excision repair. Cavadini and colleagues reported the cryo-electron microscopy structure of human CSN in complex with neddylated (NEDD8) CRL4DDB2 as well as with CRL4A. These structural analyses revealed that an induced-fit mechanism drives CSN activation by neddylated CRLs. CSN, therefore, serves as a primary negative regulatory of CRLs and is a requirement for efficient CRL activity and specificity. (Nature http://dx.doi.org/10.1038/nature 17416, 2016) Selected by E. Lerner
An EGFR-Treg Relationship Regulatory T cells (Tregs) mediate skin immune homeostasis. Nosbaum and colleagues examined the role of these immune cells in wound healing, a vital process mediated by multiple cell types and molecular pathways, including the epidermal growth factor receptor (EGFR) pathway. In a mouse model of skin wounding, Tregs were found to play an important role in facilitating healing early after wounding during the inflammatory phase. In addition, activated Tregs accumulated in the Journal of Investigative Dermatology (2016) 136, 1312. doi:10.1016/ j.jid.2016.05.092
1312 Journal of Investigative Dermatology (2016), Volume 136
skin during this phase, and without these cells, wound closure was inhibited. Specifically, the Treg cells functionally limit the accumulation of interferon-g-producing T cells and proinflammatory macrophages in wounded skin via EGFR expression on the Tregs. Thus, EGFR is important for Treg function. Current strategies to treat chronic skin ulcers by augmentation of EGFR signaling may work via effects on Treg function in the skin, suggesting that modulation of these important immune cells may be a novel means to treat wound-associated inflammation and facilitate healing. ( J Immunol http://dx.doi.org/10.4049/jimmunol.1502139, 2016) Selected by T. Schwarz
Dermatitis in Spades Yasuda and colleagues recently identified a dermatitis animal model in randomly mutagenized mice. These mice spontaneously developed stepwise, progressive atopic dermatitis (“Spade” mice) due to a skin homeostasis defect and a subsequent Th2-biased immune response. Genetic mapping and molecular analysis revealed a single nucleotide gain-offunction mutation in the Jak1 tyrosine kinase near the ATPbinding motif of the kinase domain. This point mutation resulted in hyperactivation of the JAK1/STAT signaling pathway, which is known to affect numerous cytokines, and overexpression of serine proteases in the epidermis, leading to aberrant differentiation, hyperproliferation of keratinocytes, and a skin barrier defect. Emollient treatment delayed the onset of dermatitis in the Spade mice. Thus, the skin is the responsible tissue for dermatitis onset in these animals, although inflammatory responses contribute to disease. Furthermore, hyperphosphorylation of epidermal JAK1 was found in a subset of skin samples from atopic dermatitis patients, lending support to the clinical relevance of this mouse model. (J Clin Invest http://dx.doi.org/10.1172/ JCI82887, 2016) Selected by M. Amagai
Data doping A recent analysis of electrophoretic, microscopic, and flow cytometric data images from 20,621 papers published in 40 different scientific journals from 1995 to 2014 spearheaded by Bik and colleagues revealed that as many as 1 in 25 papers contains inappropriately duplicated images. Due to the nature of the investigation, this figure is likely an underestimation of the extent of problematic data. Interestingly, the prevalence of papers with inappropriate image duplications was higher after 2002 and correlates inversely with journal impact factor. Moreover, other papers by the authors of the originally identified papers that included these duplicated images also often contained duplicated images. These disturbing results ultimately cast doubt on the quality and integrity of the scientific literature and highlight the need for increased scrutiny by authors, reviewers, and editors to identify problematic figures prior to publication. (bioRxlv http://dx.doi.org/10.1101/049452, 2016) Selected by B. A. Gilchrest
ª 2016 The Society for Investigative Dermatology.