Showing papers by "William R. Swindell published in 2016"
TL;DR: It is shown that few cutaneous DEGs are psoriasis specific and that the two DEG classes differ in their cell type and cytokine associations, and "cross-disease" transcriptomics is demonstrated as an approach to gain insights into the cutaneous and noncutaneous Psoriasis transcriptomes.
56 citations
TL;DR: It is suggested that loss of visible hair in PP skin may result from abnormal sebaceous gland function, which is inversely correlated with the signature of IL17-stimulated keratinocytes.
40 citations
TL;DR: It is demonstrated that AREG controls G2/M progression and cytokinesis in keratinocytes via activation of a FoxM1-dependent transcriptional program, suggesting new avenues for treatment of epithelial cancer.
Abstract: Epidermal growth factor receptor (EGFR) is central to epithelial cell physiology, and deregulated EGFR signaling has an important role in a variety of human carcinomas. Here we show that silencing of the EGF-related factor amphiregulin (AREG) markedly inhibits the expansion of human keratinocytes through mitotic failure and accumulation of cells with ⩾ 4n DNA content. RNA-sequencing-based transcriptome analysis revealed that tetracycline-mediated AREG silencing significantly altered the expression of 2331 genes, 623 of which were not normalized by treatment with EGF. Interestingly, genes irreversibly upregulated by suppression of AREG overlapped with genes involved in keratinocyte differentiation. Moreover, a significant proportion of the irreversibly downregulated genes featured upstream binding sites recognized by forkhead box protein M1 (FoxM1), a key transcription factor in the control of mitosis that is widely dysregulated in cancer. The downregulation of FoxM1 and its target genes preceded mitotic arrest. Constitutive expression of FoxM1 in AREG knockdown cells normalized cell proliferation, reduced the number of cells with ⩾ 4n DNA content and rescued expression of FoxM1 target genes. These results demonstrate that AREG controls G2/M progression and cytokinesis in keratinocytes via activation of a FoxM1-dependent transcriptional program, suggesting new avenues for treatment of epithelial cancer.
29 citations
TL;DR: The present integrated computational approach provides a systems approach toward identifying cell-defined functional networks that contribute to host defense and immunopathology at the site of human infectious disease.
Abstract: Transcriptome profiles derived from the site of human disease have led to the identification of genes that contribute to pathogenesis, yet the complex mixture of cell types in these lesions has been an obstacle for defining specific mechanisms. Leprosy provides an outstanding model to study host defense and pathogenesis in a human infectious disease, given its clinical spectrum, which interrelates with the host immunologic and pathologic responses. Here, we investigated gene expression profiles derived from skin lesions for each clinical subtype of leprosy, analyzing gene coexpression modules by cell-type deconvolution. In lesions from tuberculoid leprosy patients, those with the self-limited form of the disease, dendritic cells were linked with MMP12 as part of a tissue remodeling network that contributes to granuloma formation. In lesions from lepromatous leprosy patients, those with disseminated disease, macrophages were linked with a gene network that programs phagocytosis. In erythema nodosum leprosum, neutrophil and endothelial cell gene networks were identified as part of the vasculitis that results in tissue injury. The present integrated computational approach provides a systems approach toward identifying cell-defined functional networks that contribute to host defense and immunopathology at the site of human infectious disease.
27 citations
26 citations
TL;DR: In this article, the effect of rapamycin on the survival of mice was analyzed using 29 survival studies of control-and inbred mice, with the goals of estimating summary statistics and identifying factors associated with effect size heterogeneity.
Abstract: Rapamycin has favorable effects on aging in mice and may eventually be applied to encourage "healthy aging" in humans. This study analyzed raw data from 29 survival studies of rapamycin- and control-treated mice, with the goals of estimating summary statistics and identifying factors associated with effect size heterogeneity. Meta-analysis demonstrated significant heterogeneity across studies, with hazard ratio (HR) estimates ranging from 0.22 (95% confidence interval [CI]: 0.06-0.82) to 0.92 (95% CI: 0.65-1.28). Sex was the major factor accounting for effect size variation, and mortality was decreased more in females (HR = 0.41; 95% CI: 0.35-0.48) as compared with males (HR = 0.63; 95% CI: 0.55-0.71). Rapamycin effects were also genotype dependent, however, with stronger survivorship increases in hybrid mice (14.4%; 95% CI: 12.5-16.3%) relative to pure inbred strains (8.8%; 95% CI: 6.2-11.6%). Number needed to treat was applied as an effect size metric, which consistently identified early senescence as the age of peak treatment benefit. These results provide synthesis of existing data to support the potential translation of findings from mouse to primate species. Because rapamycin's effect on survival depends on sex and genotype, further work is justified to understand how these factors shape treatment response.
26 citations
TL;DR: Findings demonstrate a pro-steatosis rather than pro-inflammatory role of calprotectin within the aging liver, which appears to reflect a developmental-metabolic phenotype of Mrp14-KO mice that is manifest at a young age in the absence of pro- inflammatory stimuli.
Abstract: // William R. Swindell 1,2 , Xianying Xing 2 , Yi Fritz 3 , Doina Diaconu 3 , Daniel I. Simon 4 , Nicole L. Ward 3,5,* and Johann E. Gudjonsson 2,* 1 Ohio University Heritage College of Osteopathic Medicine, Athens, OH, USA 2 Department of Dermatology, University of Michigan, Ann Arbor, MI, USA 3 Department of Dermatology, Case Western Reserve University, Cleveland, OH, USA 4 Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA 5 The Murdough Family Center for Psoriasis, Case Western Reserve University, Cleveland, OH, USA * These authors have contributed equally to this manuscript Correspondence to: William R. Swindell, email: // Keywords : B-cell; calgranulin; calprotectin; microarray; S100a8; Gerotarget Received : March 19, 2016 Accepted : May 13, 2016 Published : May 21, 2016 Abstract The Mrp8 and Mrp14 proteins (calprotectin) accumulate within tissues during aging and may contribute to chronic inflammation. To address this possibility, we evaluated female calprotectin-deficient Mrp14-KO and wild-type (WT) mice at 5 and 24 months of age. However, there was no evidence that age-related inflammation is blunted in KO mice. Inflammation markers were in fact elevated in livers from old KO mice, and microarray analysis revealed more consistent elevation of genes specifically expressed by B-cells and T-cells. Adipose-specific genes, however, were less consistently elevated in aged KO mice, suggesting an anti-steatosis effect of Mrp8/14 deficiency. Consistent with this, genes decreased by the anti-steatosis agent SRT1720 were decreased in old KO compared to old WT mice. Expression of lipid metabolism genes was altered in KO mice at 5 months of age, along with genes associated with development, biosynthesis and immunity. These early-age effects of Mrp8/14 deficiency, in the absence of any external stressor, were unexpected. Taken together, our findings demonstrate a pro-steatosis rather than pro-inflammatory role of calprotectin within the aging liver. This appears to reflect a developmental-metabolic phenotype of Mrp14-KO mice that is manifest at a young age in the absence of pro-inflammatory stimuli.
2 citations
1 citations