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Biomedical subjects

John T Seykora

Publications and source records attributed to John T Seykora.

17 recordsLinked to original sources
PubMed2007

Growth inhibition of Trichophyton species by Pseudomonas aeruginosa.

OBJECTIVE: To assess the ability of Pseudomonas aeruginosa to inhibit the growth of Trichophyton mentagrophytes (TM) and Trichophyton rubrum (TR). DESIGN: Pseudomonas aeruginosa, Escherichia coli, or Staphylococcus epidermidis were grown in co-culture with either TM or TR. SETTING: An academic medical center. MAIN OUTCOME MEASURES: The total fungal units and hyphal-spore ratio were measured at days 1, 5, 10, and 15. RESULTS: There was a 73% and 46% reduction of total fungal units and a final hyphal-spore ratio of 0.16 and 0.04, respectively, when TM and TR were co-cultured with P aeruginosa. The number of fungal units increased when TM and TR were cultured with E coli (28% and 42%, respectively), S epidermidis (13% and 18%, respectively), and control media (44% and 62%, respectively), and the hyphal-spore ratio increased to above 30 in the presence of S epidermidis, E coli, and control media. CONCLUSION: Pseudomonas aeruginosa exhibits growth inhibitory properties against TM and TR.

Coculture Techniques↗
PubMed2006

Methotrexate-associated lymphoproliferative disorder in a patient with rheumatoid arthritis presenting in the skin.

A 91-year-old woman who had been taking methotrexate for approximately 5 years for rheumatoid arthritis developed papules and nodules on her face that enlarged during 6 months. A series of biopsy specimens demonstrated a lymphoplasmacytic infiltrate with increasingly atypical histopathologic features that resembled diffuse large B-cell lymphoma. Epstein-Barr virus was not identified. Withdrawal of methotrexate resulted in complete resolution of all lesions within 8 weeks. This case illustrates the rare occurrence of methotrexate-associated lymphoproliferative disorder with primary presentation in the skin and documents clinical and histopathologic progression from early changes to fully developed lesions.

Aged, 80 and over↗
PubMed2006

Srcasm corrects Fyn-induced epidermal hyperplasia by kinase down-regulation.

Src family tyrosine kinases (SFKs) are important regulators of epithelial cell growth and differentiation. Characterization of cellular mechanisms that regulate SFK activity will provide insights into the pathogenesis of diseases associated with increased SFK activity. Keratin 14-Fyn (K14) transgenic mice were derived to characterize the effect of Fyn on epidermal growth and differentiation in vivo. The epidermis of K14-Fyn mice is thickened, manifests prominent scale, and exhibits features consistent with hyperproliferation. Increased epidermal Fyn levels correlate with activation of p44/42 MAP kinases, STAT-3, and PDK-1, key signaling molecules that promote epithelial cell growth. The Src-activating and signaling molecule (Srcasm) is a substrate of SFKs that becomes tyrosine-phosphorylated downstream of the EGF receptor. In vitro, increased Srcasm levels promote activation of endogenous Fyn and keratinocyte differentiation. To study the in vivo effect of Srcasm upon Fyn, double transgenic lines were derived. K14-Fyn/Srcasm transgenic mice did not manifest the hyperproliferative phenotype. In contrast, K14-Fyn/Srcasm-P transgenic mice, which express a nonphosphorylatable Srcasm mutant, maintained the hyperproliferative phenotype. Resolution of the hyperproliferative phenotype correlated with reduced Fyn levels in vivo in three experimental systems: transgenic mice, primary keratinocytes, and cell lines. Biochemical studies revealed that Srcasm-dependent Fyn down-regulation requires Fyn kinase activity, phosphorylation of Srcasm, and the Srcasm GAT domain. Therefore, Srcasm is a novel regulator of Fyn promoting kinase down-regulation in a phosphorylation-dependent manner. Srcasm may act as a molecular "rheostat" for activated SFKs, and cellular levels of Srcasm may be important for regulating epithelial hyperproliferation associated with increased SFK activity.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed2006

The miRNA-processing enzyme dicer is essential for the morphogenesis and maintenance of hair follicles.

The discovery that microRNAs (miRNAs) play important roles in regulating gene expression via posttranscriptional repression has revealed a previously unsuspected mechanism controlling development and progenitor-cell function (reviewed in ); however, little is known of miRNA functions in mammalian organogenesis. Processing of miRNAs and their assembly into the RNA-induced silencing (RISC) complex requires the essential multifunctional enzyme Dicer . We found that Dicer mRNA and multiple miRNAs are expressed in mouse skin, suggesting roles in skin- and hair-follicle biology. In newborn mice carrying an epidermal-specific Dicer deletion, hair follicles were stunted and hypoproliferative. Hair-shaft and inner-root-sheath differentiation was initiated, but the mutant hair follicles were misoriented and expression of the key signaling molecules Shh and Notch1 was lost by postnatal day 7. At this stage, hair-follicle dermal papillae were observed to evaginate, forming highly unusual structures within the basal epidermis. Normal hair shafts were not produced in the Dicer mutant, and the follicles lacked stem cell markers and degenerated. In contrast to decreased follicular proliferation, the epidermis became hyperproliferative. These results reveal critical roles for Dicer in the skin and implicate miRNAs in key aspects of epidermal and hair-follicle development and function.

Animals↗
PubMed2006

Posttransplantation lymphoproliferative disease with features of lymphomatoid granulomatosis in a lung transplant patient.

A 58-year-old lung transplant patient developed worsening shortness of breath and indurated erythematous plaques on the lower left leg. A skin biopsy specimen revealed a dense angiocentric and angioinvasive infiltrate in the mid to reticular dermis and panniculus containing large, atypical lymphocytes with convoluted nuclei and prominent nucleoli. Immunohistochemical stains showed that the atypical cells were of B-cell origin, and that Epstein-Barr virus was present. Molecular studies demonstrated B-cell clonality. The patient was successfully treated with rituximab. The clinical and pathologic features in this case represent posttransplantation lymphoproliferative disease with features of lymphomatoid granulomatosis. The case also highlights the importance of clinical and pathologic examination of cutaneous lesions in the evaluation of lymphoproliferative disorders for patients undergoing transplantation.

Epstein-Barr Virus Infections↗
PubMed2006

Ossifying fibromyxoid tumor of soft parts presenting as a scalp cyst.

BACKGROUND: Ossifying fibromyxoid tumor of soft parts (OFMT) is a rare mesenchymal neoplasm of intermediate malignant potential. The tumor most commonly occurs on the extremities with a male predominance. We present an unusual case of OFMT occurring as a cystic lesion on the scalp of a female. CASE HISTORY: A 67-year-old woman presented with a 6-year history of a well demarcated cystic scalp mass. Physical examination revealed a slightly movable, multilobular mass of the left parietal scalp which was subsequently excised. Histological evaluation revealed an OFMT comprised of bland, small cells and a thick collagenous capsule containing an incomplete rim of lamellar bone. CONCLUSION: OFMT is an unusual tumor which can usually be considered as having an intermediate risk of malignancy. It generally occurs in the extremities with a male predominance. The clinical differential for a cystic mass on the scalp is broadened by this unusual case of an OFMT.

Aged↗
PubMed2005

Two novel TP63 mutations associated with the ankyloblepharon, ectodermal defects, and cleft lip and palate syndrome: a skin fragility phenotype.

BACKGROUND: Ankyloblepharon, ectodermal defects, and cleft lip and palate (AEC) syndrome is a rare autosomal dominant disorder caused by mutations in the sterile alpha motif region of TP63, a homologue of the tumor suppressor TP53. Recent structure-function studies have identified complexities in the genotype-phenotype correlation of the p63 syndromes. OBSERVATIONS: We report 2 sporadic cases of AEC syndrome in infants. Both patients demonstrated skin erosions with prominent scalp involvement. Histologic studies demonstrated mild basal layer vacuolization and rare dyskeratotic keratinocytes, with evidence of both acantholysis and cytolysis at the blister edge. Immunohistochemistry using anti-p63 monoclonal antibody demonstrated basal epidermal nuclear staining in both healthy control and patient tissue samples. Ultrastructural studies showed focal disruption of anchoring fibrils near the blister edge of one patient and normal desmosomes, hemidesmosomes, and basement membrane zone in the nonblistered skin of the other patient. The DNA analysis of each patient revealed 2 novel missense mutations in the TP63 gene that resulted in L514S and R555P amino acid substitutions within the sterile alpha motif region of the p63 protein. CONCLUSIONS: We report 2 novel TP63 mutations resulting in AEC syndrome. The R555P mutation is the most carboxy-terminal of all the reported AEC missense mutations of p63. The presence of skin fragility, manifested as erosive skin lesions in body areas in addition to the scalp, is postulated to be an important diagnostic feature of AEC syndrome.

Abnormalities, Multiple↗
PubMed2004

Gli proteins up-regulate the expression of basonuclin in Basal cell carcinoma.

Tumorigenesis is frequently accompanied by enhanced rRNA transcription, but the signaling mechanisms responsible for such enhancement remain unclear. Here, we report evidence suggesting a novel link between deregulated Hedgehog signaling and the augmented rRNA transcription in cancer. Aberrant activation of the Hedgehog pathway in keratinocytes is a hallmark of basal cell carcinoma (BCC), the most common cancer in light-skinned individuals. We show that Gli proteins, downstream effectors of the Hedgehog pathway, increase expression of a novel rRNA gene (rDNA) transcription factor, basonuclin, whose expression is markedly elevated in BCCs. The promoter of the human basonuclin gene contains a Gli-binding site, which is required for Gli protein binding and transcriptional activation. We show also that the level of 47S pre-rRNA is much higher in BCCs than in normal epidermis, suggesting an accelerated rRNA transcription in the neoplastic cells. Within BCC, those cells expressing the highest level of basonuclin also exhibit the greatest increase in 47S pre-rRNA, consistent with a role for basonuclin in increasing rRNA transcription in these cells. Our data suggest that Hedgehog-Gli pathway enhances rRNA transcription in BCC by increasing basonuclin gene expression.

Base Sequence↗
PubMed2004

Epithelial Bmpr1a regulates differentiation and proliferation in postnatal hair follicles and is essential for tooth development.

Bone morphogenetic protein (BMP) signaling is thought to perform multiple functions in the regulation of skin appendage morphogenesis and the postnatal growth of hair follicles. However, definitive genetic evidence for these roles has been lacking. Here, we show that Cre-mediated mutation of the gene encoding BMP receptor 1A in the surface epithelium and its derivatives causes arrest of tooth morphogenesis and lack of external hair. The hair shaft and hair follicle inner root sheath (IRS) fail to differentiate, and expression of the known transcriptional regulators of follicular differentiation Msx1, Msx2, Foxn1 and Gata3 is markedly downregulated or absent in mutant follicles. Lef1 expression is maintained, but nuclear beta-catenin is absent from the epithelium of severely affected mutant follicles, indicating that activation of the WNT pathway lies downstream of BMPR1A signaling in postnatal follicles. Mutant hair follicles fail to undergo programmed regression, and instead continue to proliferate, producing follicular cysts and matricomas. These results provide definitive genetic evidence that epithelial Bmpr1a is required for completion of tooth morphogenesis, and regulates terminal differentiation and proliferation in postnatal hair follicles.

Animals↗
PubMed2003

Darier's disease associated with an underlying neoplasm in combination with a nodular fibroproliferative disease.

Darier's disease is an autosomal dominant disease that typically arises during the first or second decades of life. It involves the abnormal keratinization of the epidermis, mucosa, and nails. We describe a 74-year-old man with metastatic carcinoma in whom fibroproliferative disease and an acquired variant of Darier's disease developed, both of which may have been paraneoplastic processes.

Adenocarcinoma↗
PubMed2003

Gene expression profiling of melanocytic lesions.

DNA microarrays, microscopic grids of DNA, can be used to assess gene expression within a particular cell or cell population. Since DNA from thousands of genes can be hybridized and analyzed in one experiment, researchers can globally characterize genes expressed in normal and various pathologic states. To accurately assess the differences between normal and pathologic states, one derives cDNA from control and diseased tissue specimens for genes expression profiling. For these reasons, microarray technology may be of particular interest to dermatopathologists and dermatologists interested in understanding cutaneous disease because these physicians have access to tissue specimens. In addition, microarray technology is an efficient way of identifying molecules expressed in a cell population; therefore, it can be used to search for unique immunohistologic markers. To this end, we have used microarray technology to define differences in the gene expression profile of nevi and melanomas. In this manuscript, we discuss the results of our study, which confirm previously known differences in gene expression between melanoma and nevi. While a few genes appear slightly overexpressed in nevi, a number of genes involved in regulating cell proliferation were upregulated in melanoma, such as cyclin D1, cdc2-related protein kinase, c-Myc binding protein, early growth response protein 1, and pleiotrophin. "Housekeeping" genes such as glyceraldehyde 3-phosphate dehydrogenase were expressed at similar levels in melanoma and nevi. Surprisingly, a majority of genes were expressed at similar levels in both nevi and melanoma. Based on this study, DNA microarray technology appears to be a valuable tool for identifying genes that may be specifically expressed in cutaneous lesions.

Biomarkers, Tumor↗
PubMed2003

Familial basaloid follicular hamartoma: lesional characterization and review of the literature.

Basaloid follicular hamartoma (BFH) is a rare cutaneous lesion associated with the acquisition of small papules that remain stable for many years. Basaloid follicular hamartoma lesions can present sporadically or as part of an inherited syndrome. Occasionally, biopsies of BFH lesions are interpreted as basal cell carcinoma (BCC), which necessitates complete removal of the lesion. In this report, we characterize a case of a familial BFH syndrome and discuss the clinical, histologic, and molecular features of BFH lesions that help to distinguish it from BCC. The BFH lesions in our patients remained stable for many years. Histologically, BFH lesions exhibit fewer mitoses and decreased single cell necrosis when compared with BCC. Immunohistochemical staining for the proliferation markers proliferating cell nuclear antigen and Ki-67 demonstrated less staining in BFH than in BCC. In addition, levels of PTCH (patched) mRNA were increased relative to unremarkable epidermis in familial BFH lesions but to a lesser degree and in a different pattern than that seen in BCC. In summary, familial BFH can be distinguished from BCC based on clinical, histologic, and molecular features and is associated with deregulation of the PTCH pathway. Basaloid follicular hamartoma may represent an indolent lesion within the spectrum of basaloid epithelial neoplasms associated with deregulation of the PTCH signaling pathway. We discuss this case in parallel with a growing body of literature that supports the nosologic designation of BFH.

Adult↗
PubMed2002

Cutaneous adnexal neoplasms.

Cutaneous adnexal tumors are a large and diverse group of tumors that are commonly classified according to their state of appendageal differentiation: eccrine, apocrine, follicular, and sebaceous. These tumors generally behave in a benign manner, but malignant types exist. Most adnexal tumors are not common enough to permit most practitioners to maintain a ready familiarity with them, but they also are not rare. We provide a brief review of the clinical, histopathologic, and other relevant features of some adnexal tumors we believe the practitioner has the greatest likelihood of seeing in daily service. We also enumerate criteria the practitioner can use to distinguish between tumors likely to behave in a benign rather than a malignant manner.

Adolescent↗
PubMed2001

'Srcasm: a novel Src activating and signaling molecule.

The Src family tyrosine kinase, Fyn, can facilitate regulation of cell proliferation and differentiation. Mice with mutations in the fyn gene have defects in the brain, immune system, and epidermal differentiation. To identify molecules that may interact with Fyn in the epidermis, we performed a yeast two-hybrid interaction screen of a murine keratinocyte library. A novel adaptor-like molecule was isolated and termed Srcasm for Src activating and signaling molecule. Murine Srcasm is a 52.7-kDa protein that contains a VHS membrane association domain and a number of tyrosine motifs suggesting that it may be a substrate for Src family kinases and serve as an adaptor protein. Northern blot analysis of murine tissues demonstrates that Srcasm expression is highest in brain and kidney. In situ hybridization analysis reveals that srcasm mRNA is expressed in regions of the epidermis and hair follicle where keratinocyte differentiation occurs. In the brain, srcasm mRNA distribution correlates with that of fyn, with both being highly expressed in the hippocampal and cerebellar Purkinje neurons. Fyn can phosphorylate Srcasm, and association of these molecules relies on cooperative binding between the SH2 and SH3 domains of Fyn and corresponding canonical binding sites in Srcasm. Srcasm is capable of interacting with Grb2 and the regulatory subunit of phosphoinositide 3-kinase, p85, in a phosphorylation-dependent manner. The evidence suggests that Srcasm may help promote Src family kinase signaling in cells.

Adaptor Proteins, Signal Transducing↗