225 results found
Moorcraft SY, Jones T, Walker BA, et al., 2017, Molecular profiling of colorectal pulmonary metastases and primary tumours: implications for targeted treatment, ONCOTARGET, Vol: 8, Pages: 64999-65008, ISSN: 1949-2553
Anbunathan H, Bowcock AM, 2017, The Molecular Revolution in Cutaneous Biology: The Era of Genome-Wide Association Studies and Statistical, Big Data, and Computational Topics., J Invest Dermatol, Vol: 137, Pages: e113-e118
The investigation of biological systems involving all organs of the body including the skin is in era of big data. This requires heavy-duty computational tools, and novel statistical methods. Microarrays have allowed the interrogation of thousands of common genetic markers in thousands of individuals from the same population (termed genome wide association studies or GWAS) to reveal common variation associated with disease or phenotype. These markers are usually single nucleotide polymorphisms (SNPs) that are relatively common in the population. In the case of dermatological diseases such as alopecia areata, vitiligo, psoriasis and atopic dermatitis, common variants have been identified that are associated with disease, and these provide insights into biological pathways and reveal possible novel drug targets. Other skin phenotypes such as acne, color and skin cancers are also being investigated with GWAS. Analyses of such large GWAS datasets require a consideration of a number of statistical issues including the testing of multiple markers, population substructure, and ultimately a requirement for replication. There are also issues regarding the missing heritability of disease that cannot be entirely explained with current GWAS approaches. Next generation sequencing technologies such as exome and genome sequencing of similar patient cohorts will reveal additional variants contributing to disease susceptibility. However, the data generated with these approaches will be orders of magnitude greater than that those generated with arrays, with concomitant challenges in the identification of disease causing variants.
Gennatas S, Anbunathan H, Bowman A, et al., 2017, Somatic and germline mutations in thymic epithelial tumours and their correlation with histological and clinical phenotypes
Field MG, Durante MA, Decatur CL, et al., 2016, Epigenetic reprogramming and aberrant expression of PRAME are associated with increased metastatic risk in Class 1 and Class 2 uveal melanomas., Oncotarget, Vol: 7, Pages: 59209-59219, ISSN: 1949-2553
BACKGROUND: We previously identified PRAME as a biomarker for metastatic risk in Class 1 uveal melanomas. In this study, we sought to define a threshold value for positive PRAME expression (PRAME+) in a large dataset, identify factors associated with PRAME expression, evaluate the prognostic value of PRAME in Class 2 uveal melanomas, and determine whether PRAME expression is associated with aberrant hypomethylation of the PRAME promoter. RESULTS: Among 678 samples analyzed by qPCR, 498 (73.5%) were PRAME- and 180 (26.5%) were PRAME+. Class 1 tumors were more likely to be PRAME-, whereas Class 2 tumors were more likely to be PRAME+ (P < 0.0001). PRAME expression was associated with shorter time to metastasis and melanoma specific mortality in Class 2 tumors (P = 0.01 and P = 0.02, respectively). In Class 1 tumors, PRAME expression was directly associated with SF3B1 mutations (P < 0.0001) and inversely associated with EIF1AX mutations (P = 0.004). PRAME expression was strongly associated with hypomethylation at 12 CpG sites near the PRAME promoter. MATERIALS AND METHODS: Analyses included PRAME mRNA expression, Class 1 versus Class 2 status, chromosomal copy number, mutation status of BAP1, EIF1AX, GNA11, GNAQ and SF3B1, and genomic DNA methylation status. Analyses were performed on 555 de-identified samples from Castle Biosciences, 123 samples from our center, and 80 samples from the TCGA. CONCLUSIONS: PRAME is aberrantly hypomethylated and activated in Class 1 and Class 2 uveal melanomas and is associated with increased metastatic risk in both classes. Since PRAME has been successfully targeted for immunotherapy, it may prove to be a companion prognostic biomarker.
Decatur CL, Ong E, Garg N, et al., 2016, Driver Mutations in Uveal Melanoma Associations With Gene Expression Profile and Patient Outcomes, JAMA OPHTHALMOLOGY, Vol: 134, Pages: 728-733, ISSN: 2168-6165
Howes A, O'Sullivan PA, Breyer F, et al., 2016, Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-κB activation, Biochemical Journal, Vol: 473, Pages: 1759-1768, ISSN: 1470-8728
Inherited and <em>de novo</em> mutations in the <em>CARD14</em> gene promote the development of psoriasis, an inflammatory disease of the skin. CARD14 is a member of the CARMA protein family that includes the structurally related CARD11 adaptor that mediates NF-κB activation by antigen receptors. We investigated the mechanism by which <em>CARD14 </em>mutation in psoriasis activates NF-κB. In contrast to wild type CARD14, CARD14E138A and CARD14G117S psoriasis mutants interacted constitutively with BCL10 and MALT1, and triggered BCL10 and MALT1 dependent activation of NF-κB in keratinocytes. These alterations disrupted the inhibitory effect of the CARD14 linker region on NF-κB activation by facilitating BCL10 binding. Therefore, psoriasis mutations activated CARD14 by a mechanism analogous to oncogenic CARD11 mutations in non-Hodgkin B cell lymphomas. CARD14E138A also stimulated MALT1 paracaspase activity and activated both ERK1/2 and p38α MAP kinases. Inhibition of MALT1 with mepazine reduced CARD14E138A-induced expression of specific psoriasis-associated transcripts in keratinocytes. Our results establish the mechanism whereby gain-of-function CARD14 variants, which induce psoriatic disease in affected individuals, activate pro-inflammatory signaling.
Gennatas S, Fernandez AM, Bowman A, et al., 2016, Expression of PD-L1, PD-L2 and PD-1 in thymic epithelial tumours (TETs)., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
Moorcraft SY, Ladas G, Bowcock A, et al., 2016, Management of resectable colorectal lung metastases., Clin Exp Metastasis, Vol: 33, Pages: 285-296
Lung metastases occur in 10-20 % of patients with colorectal cancer. The biology of colorectal lung metastases is poorly understood, however lung metastases are more common in patients with rectal cancer and in patients with RAS mutations. Although the majority of patients have extrapulmonary disease, a small proportion of patients with lung metastases are suitable for lung metastasectomy and surgical resection has become a standard of care, based on data from retrospective series demonstrating a 5-year overall survival of 40-68 %. However, there remains uncertainty regarding the optimal management approach for these patients due to the lack of evidence from randomized controlled trials and current practice varies between institutions. For example, the role for neoadjuvant and adjuvant chemotherapy is not yet defined and there are no randomized trials comparing surgery with alternative treatment options such as radiofrequency ablation and stereotactic ablative radiotherapy. Further research is needed to improve the selection of patients for surgery, but favourable prognostic factors include a normal pre-operative CEA, solitary metastasis, complete resection and a long disease-free interval. There is also evidence that patients with resectable liver and lung metastases may benefit from resection of both sites of disease, and that re-resection may be of benefit in selected patients who relapse with resectable lung metastases. This article summarizes the biology of colorectal lung metastases and discusses the management of patients with lung metastases.
Ammar M, Jordan CT, Cao L, et al., 2016, CARD14 alterations in Tunisian patients with psoriasis and further characterization in European cohorts, BRITISH JOURNAL OF DERMATOLOGY, Vol: 174, Pages: 330-337, ISSN: 0007-0963
Ahn RS, Moslehi H, Martin MP, et al., 2016, Inhibitory KIR3DL1 alleles are associated with psoriasis., Br J Dermatol, Vol: 174, Pages: 449-451
Stuart PE, Nair RP, Tsoi LC, et al., 2015, Genome-wide Association Analysis of Psoriatic Arthritis and Cutaneous Psoriasis Reveals Differences in Their Genetic Architecture, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 97, Pages: 816-836, ISSN: 0002-9297
Harden JL, Krueger JG, Bowcock AM, 2015, The immunogenetics of Psoriasis: A comprehensive review., J Autoimmun, Vol: 64, Pages: 66-73
Psoriasis vulgaris is a common, chronic inflammatory skin disease with a complex etiology involving genetic risk factors and environmental triggers. Here we describe the many known genetic predispositions of psoriasis with respect to immune genes and their encoded pathways in psoriasis susceptibility. These genes span an array of functions that involve antigen presentation (HLA-Cw6, ERAP1, ERAP2, MICA), the IL-23 axis (IL12Bp40, IL23Ap19, IL23R, JAK2, TYK2), T-cell development and T-cells polarization (RUNX1, RUNX3, STAT3, TAGAP, IL4, IL13), innate immunity (CARD14, c-REL, TRAF3IP2, DDX58, IFIH1), and negative regulators of immune responses (TNIP1, TNFAIP3, NFKBIA, ZC3H12C, IL36RN, SOCS1). The contribution of some of these gene products to psoriatic disease has also been revealed in recent years through targeting of key immune components, such as the Th17/IL-23 axis which has been highly successful in disease treatment. However, many of the genetic findings involve immune genes with less clear roles in psoriasis pathogenesis. This is particularly the case for those genes involved in innate immunity and negative regulation of immune specific pathways. It is possible that risk alleles of these genes decrease the threshold for the initial activation of the innate immune response. This could then lead to the onslaught of the pathogenic adaptive immune response known to be active in psoriatic skin. However, precisely how these various genes affect immunobiology need to be determined and some are speculated upon in this review. These novel genetic findings also open opportunities to explore novel therapeutic targets and potentially the development of personalized medicine, as well as discover new biology of human skin disease.
Bowcock A, Harbour JW, 2015, COMPOSITIONS AND METHODS FOR DETECTING CANCER METASTASIS, U.S. Patent 9,133,523
Aires DJ, Rockwell G, Menter A, et al., 2015, Reproducible Novel Transcriptional Differences Between Psoriatic Lesional and Non-Lesional Skin Show Increased Inflammation and Metabolism, JOURNAL OF DRUGS IN DERMATOLOGY, Vol: 14, Pages: 794-800, ISSN: 1545-9616
Tagliabue E, Fargnoli MC, Gandini S, et al., 2015, MC1R gene variants and non-melanoma skin cancer: a pooled-analysis from the M-SKIP project., British Journal of Cancer, Vol: 113, Pages: 354-363, ISSN: 1532-1827
BACKGROUND: The melanocortin-1-receptor (MC1R) gene regulates human pigmentation and is highly polymorphic in populations of European origins. The aims of this study were to evaluate the association between MC1R variants and the risk of non-melanoma skin cancer (NMSC), and to investigate whether risk estimates differed by phenotypic characteristics. METHODS: Data on 3527 NMSC cases and 9391 controls were gathered through the M-SKIP Project, an international pooled-analysis on MC1R, skin cancer and phenotypic characteristics. We calculated summary odds ratios (SOR) with random-effect models, and performed stratified analyses. RESULTS: Subjects carrying at least one MC1R variant had an increased risk of NMSC overall, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC): SOR (95%CI) were 1.48 (1.24-1.76), 1.39 (1.15-1.69) and 1.61 (1.35-1.91), respectively. All of the investigated variants showed positive associations with NMSC, with consistent significant results obtained for V60L, D84E, V92M, R151C, R160W, R163Q and D294H: SOR (95%CI) ranged from 1.42 (1.19-1.70) for V60L to 2.66 (1.06-6.65) for D84E variant. In stratified analysis, there was no consistent pattern of association between MC1R and NMSC by skin type, but we consistently observed higher SORs for subjects without red hair. CONCLUSIONS: Our pooled-analysis highlighted a role of MC1R variants in NMSC development and suggested an effect modification by red hair colour phenotype.
Das S, Stuart PE, Ding J, et al., 2015, Fine mapping of eight psoriasis susceptibility loci, EUROPEAN JOURNAL OF HUMAN GENETICS, Vol: 23, Pages: 844-853, ISSN: 1018-4813
Yin X, Low HQ, Wang L, et al., 2015, Genome-wide meta-analysis identifies multiple novel associations and ethnic heterogeneity of psoriasis susceptibility, Nature Communications, Vol: 6, ISSN: 2041-1723
Nititham J, Taylor KE, Gupta R, et al., 2015, Meta-analysis of the TNFAIP3 region in psoriasis reveals a risk haplotype that is distinct from other autoimmune diseases, GENES AND IMMUNITY, Vol: 16, Pages: 120-126, ISSN: 1466-4879
Harden JL, Lewis SM, Pierson KC, et al., 2014, CARD14 Expression in Dermal Endothelial Cells in Psoriasis, PLOS ONE, Vol: 9, ISSN: 1932-6203
Sagoo MS, Harbour JW, Stebbing J, et al., 2014, Combined PKC and MEK inhibition for treating metastatic uveal melanoma, ONCOGENE, Vol: 33, Pages: 4722-4723, ISSN: 0950-9232
Luke JJ, Triozzi PL, McKenna KC, et al., 2014, Biology of advanced uveal melanoma and next steps for clinical therapeutics, Pigment Cell & Melanoma Research, Vol: 28, Pages: 135-147, ISSN: 1755-148X
Uveal melanoma is the most common intraocular malignancy although it is a rare subset of all melanomas. Uveal melanoma has distinct biology relative to cutaneous melanoma, with widely divergent patient outcomes. Patients diagnosed with a primary uveal melanoma can be stratified for risk of metastasis by cytogenetics or gene expression profiling, with approximately half of patients developing metastatic disease, predominately hepatic in location, over a 15-yr period. Historically, no systemic therapy has been associated with a clear clinical benefit for patients with advanced disease, and median survival remains poor. Here, as a joint effort between the Melanoma Research Foundation's ocular melanoma initiative, CURE OM and the National Cancer Institute, the current understanding of the molecular and immunobiology of uveal melanoma is reviewed, and on-going laboratory research into the disease is highlighted. Finally, recent investigations relevant to clinical management via targeted and immunotherpies are reviewed, and next steps in the development of clinical therapeutics are discussed.
Okada Y, Han B, Tsoi LC, et al., 2014, Fine Mapping Major Histocompatibility Complex Associations in Psoriasis and Its Clinical Subtypes, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 95, Pages: 162-172, ISSN: 0002-9297
Rashmi R, DeSelm C, Helms C, et al., 2014, AKT Inhibitors Promote Cell Death in Cervical Cancer through Disruption of mTOR Signaling and Glucose Uptake, PLOS ONE, Vol: 9, ISSN: 1932-6203
Matatall KA, Agapova OA, Onken MD, et al., 2013, BAP1 deficiency causes loss of melanocytic cell identity in uveal melanoma, BMC CANCER, Vol: 13, ISSN: 1471-2407
Ferkol TW, Puffenberger EG, Lie H, et al., 2013, Primary Ciliary Dyskinesia-Causing Mutations in Amish and Mennonite Communities, JOURNAL OF PEDIATRICS, Vol: 163, Pages: 383-387, ISSN: 0022-3476
Jacobs PT, Cao L, Samon JB, et al., 2013, Runx Transcription Factors Repress Human and Murine c-Myc Expression in a DNA-Binding and C-Terminally Dependent Manner, PLOS ONE, Vol: 8, ISSN: 1932-6203
Harden JL, Pierson K, Suarez-Farinas M, et al., 2013, Dermal CARD14 expression in psoriasis, International Investigative Dermatology Meeting, Publisher: NATURE PUBLISHING GROUP, Pages: S25-S25, ISSN: 0022-202X
Chen Y, Liu Y, Huang Y, et al., 2013, Immune activating effects of stimulation of TLR agonists and cytokines on keratinocytes from a patient with a CARD14 mediated pustular psoriasis, 100th Annual Meeting of the American-Association-of-Immunologists, Publisher: AMER ASSOC IMMUNOLOGISTS, ISSN: 0022-1767
Ammar M, Bouchlaka-Souissi C, Helms CA, et al., 2013, Genome-wide linkage scan for psoriasis susceptibility loci in multiplex Tunisian families, BRITISH JOURNAL OF DERMATOLOGY, Vol: 168, Pages: 583-587, ISSN: 0007-0963
Lu Y, Chen H, Nikamo P, et al., 2013, Association of Cardiovascular and Metabolic Disease Genes with Psoriasis, JOURNAL OF INVESTIGATIVE DERMATOLOGY, Vol: 133, Pages: 836-839, ISSN: 0022-202X
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