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Telomere Phenotypes in Females with Heterozygous Mutations in the Dyskeratosis Congenita 1 (DKC1) Gene

Alder, Jonathan K; Parry, Erin M; Yegnasubramanian, Srinivasan; Wagner, Christa L; Lieblich, Lawrence M; Auerbach, Robert; Auerbach, Arleen D; Wheelan, Sarah J; Armanios, Mary
Dyskeratosis congenita (DC) is a telomere-mediated syndrome defined by mucocutaneous features. The X-linked mode of inheritance accounts for half the cases, and is thought to predominantly manifest in childhood as bone marrow failure. We identified two male probands who presented in the fifth decade with idiopathic pulmonary fibrosis and cancer. Their pedigrees displayed consecutively affected generations. Five of six females (83%) manifested mucocutaneous features of DC, and two had wound-healing complications. No mutations in autosomal dominant telomere genes were present, but exome sequencing revealed novel variants in the X-chromosome DKC1 gene that predicted missense mutations in conserved residues, p.Thr49Ser and p.Pro409Arg. Variants segregated with the telomere phenotype, and affected females were heterozygotes, showing skewed X-inactivation. Telomerase RNA levels were compromised in cells from DKC1 mutation carriers, consistent with their pathogenic role. These findings indicate that females with heterozygous DKC1 mutations may be at increased risk for developing penetrant telomere phenotypes that, at times, may be associated with clinical morbidity.
PMCID:3926107
PMID: 23946118
ISSN: 1059-7794
CID: 602732

Methotrexate guidelines 2009? [Letter]

Roenigk, Henry H Jr; Auerbach, Robert; Maibach, Howard I
PMID: 20633805
ISSN: 1097-6787
CID: 133777

Biological and molecular characterization of a canine hemangiosarcoma-derived cell line

Thamm, Douglas H; Dickerson, Erin B; Akhtar, Nasim; Lewis, Rachel; Auerbach, Robert; Helfand, Stuart C; MacEwen, E Gregory
Canine hemangiosarcoma (HSA) is a devastating disease. Investigation of novel therapies has been limited by the limited availability of canine HSA-derived cell lines. We report the development of a canine HSA-derived cell line, DEN-HSA, which recapitulates features of angiogenic endothelium. DEN-HSA cells were derived from a spontaneous HSA arising in the kidney of a dog. DEN-HSA displayed surface molecules distinctive of endothelial histogenesis, including factor VIII-related antigen, ICAM-1 and alpha(v)beta3 integrin. In vitro, DEN-HSA formed microvascular tube-like structures on Matrigel, and proliferated in response to a variety of angiogenic growth factors. The cells expressed mRNA and protein specific for bFGF and its receptors, and VEGF and its receptors, among others. DEN-HSA conditioned medium evoked a marked angiogenic response in a murine corneal pocket assay, indicating potent proangiogenic activity of substances secreted by this cell line. This research confirms the DEN-HSA cell line as endothelial in origin, suggests the presence of angiogenic growth factor autocrine loops, and offers the potential to utilize DEN-HSA cells for the study of novel therapies that modulate endothelial proliferation
PMID: 16256156
ISSN: 0034-5288
CID: 93961

Angiogenesis assays: a critical overview

Auerbach, Robert; Lewis, Rachel; Shinners, Brenda; Kubai, Louis; Akhtar, Nasim
BACKGROUND: Angiogenesis, the formation of new blood vessels, is an integral part of both normal developmental processes and numerous pathologies, ranging from tumor growth and metastasis to inflammation and ocular disease. Angiogenesis assays are used to test efficacy of both pro- and antiangiogenic agents. METHODS: Most studies of angiogenesis inducers and inhibitors rely on various models, both in vitro and in vivo, as indicators of efficacy. In this report we describe the principal methods now in use: the in vivo Matrigel plug and corneal neovascularization assays, the in vivo/in vitro chick chorioallantoic membrane (CAM) assay, and the in vitro cellular (proliferation, migration, tube formation) and organotypic (aortic ring) assays. We include description of two new methods, the chick aortic arch and the Matrigel sponge assays. CONCLUSIONS: In vitro tests are valuable, can be carried out expeditiously, and lend themselves to quantification, but must be interpreted with extreme caution. In vitro tests are best viewed as providing initial information, subject to confirmation by in vivo assays. Multiple tests should be used to obtain maximum benefit from in vitro tests. In vivo tests are more difficult and time-consuming to perform, thereby limiting the number of tests that can run at any one time. Quantification is generally more difficult as well. However, in vivo assays are essential because of the complex nature of vascular responses to test reagents, responses that no in vitro model can fully achieve
PMID: 12507958
ISSN: 0009-9147
CID: 93962

"Erythema multiforme, Stevens-Johnson, toxic epidermal necrolysis"

Chapter by: Auerbach R; Sanchez M
in: Current dermatologic diagnosis & treatment by Freedberg IM; Sanchez MR [Eds]
Philadelphia : Lippincott Williams & Wilkins, 2001
pp. 58-59
ISBN: 0781735319
CID: 3697

Clinical clearing of psoriasis by 6-thioguanine correlates with cutaneous T-cell depletion via apoptosis: evidence for selective effects on activated T lymphocytes

Murphy FP; Coven TR; Burack LH; Gilleaudeau P; Cardinale I; Auerbach R; Krueger JG
BACKGROUND: Psoriasis is a common and persistent disease characterized chiefly by marked epidermal and endothelial cell proliferation and inflammation. These changes are likely a result of activated T lymphocytes infiltrating skin tissue or, in the case of psoriatic arthritis, the joints. OBJECTIVE: To test the hypothesis that the antimetabolite 6-thioguanine (Sigma-Aldrich, St Louis, Mo) might be an effective treatment for psoriasis vulgaris because of its antilymphocytic effects. METHODS: Twenty patients with moderate to severe plaque-type psoriasis were treated with 6-thioguanine for 6 months. The clinical disease was assessed by the psoriasis severity index. Biopsy specimens obtained from lesional skin before treatment and after 1 and 2 months of treatment were examined for disease-related abnormalities using histochemical and computer-assisted image analysis. Antiproliferative effects of 6-thioguanine were compared in human keratinocytes and mitogen-activated lymphocytes over a range of drug concentrations, while viability, cell-cycle, and DNA fragmentation analysis were done using flow cytometry-based assays. RESULTS: After 6 months of treatment, disease severity in 18 of 20 patients showed a significant response to 6-thioguanine: 12 patients were completely cleared of trace disease; 6 showed marked clinical improvement; and 2 did not respond. Patients showed reductions in peripheral blood lymphocytes and total leukocytes, but therapeutic response correlated best with cutaneous T-cell depletion. In vitro assays established that 6-thioguanine has major cytotoxic effects (apparently S-phase specific) on activated T lymphocytes via the induction of apoptosis. Keratinocytes and unactivated T cells, on the other hand, were largely unaffected by incubation with 6-thioguanine. CONCLUSIONS: 6-Thioguanine is effective for the treatment of moderate to severe plaque-type psoriasis, and may be safe when given for defined periods and with careful hematologic monitoring. The mechanism of action of this drug seems to be the induction of apoptosis in activated T lymphocytes
PMID: 10606055
ISSN: 0003-987x
CID: 38332

Methotrexate in psoriasis: consensus conference

Roenigk HH Jr; Auerbach R; Maibach H; Weinstein G; Lebwohl M
PMID: 9520032
ISSN: 0190-9622
CID: 57236

UNTITLED [Letter]

AUERBACH, R
ISI:A1995QY89200031
ISSN: 1076-0512
CID: 87298

Folinic acid to the rescue

Auerbach R
ORIGINAL:0004618
ISSN: 1072-2521
CID: 38479

Psoriasis symposium. Methotrexate

Auerbach R
PMID: 1493099
ISSN: 0278-145x
CID: 38362