PubMed Health⌕ Search

Biomedical subjects

I Arany

Publications and source records attributed to I Arany.

At least 37 records · Page 2Linked to original sources
PubMed1998

Tissue specific HPV expression and downregulation of local immune responses in condylomas from HIV seropositive individuals.

OBJECTIVE: To study the effect of tissue specific human papillomavirus (HPV) expression and its effect on local immunity in condylomas from HIV positive individuals. METHODS: Biopsy specimens of eight penile and eight perianal condylomas from HIV seropositive individuals were analysed. Expression of viral genes (HIV-tat and HPV E7 and L1) was determined by RT-PCR. The status of local immunity also was determined by RT-PCR by measuring CD4, CD8, CD16, CD1a, HLA-DR, and HLA-B7 mRNA levels in the tissues. Differentiation was determined by measuring involucrin, keratinocyte transglutaminase, as well as cytokeratins 10, 16, and 17. Proliferation markers such as PCNA and c-myc were also determined. RESULTS: The transcription pattern of HPV in perianal condylomas, which preferentially expressed the early (E7) gene, was different from that of penile condylomas, which primarily expressed the late (L1) gene. This transcription pattern is in good correlation with the keratinisation and differentiation patterns of the two epithelia: perianal biopsies preferentially expressed K16 and K17 while penile warts mainly expressed K10, markers of parakeratotic and orthokeratotic epithelia, respectively. Perianal biopsies also showed a higher degree of proliferation (PCNA and c-myc). Interestingly, transcription of HIV-tat was also higher in perianal than in penile biopsies. A high degree of local immunodeficiency was observed in perianal biopsies--that is, levels of CD4, CD16, and CD1a mRNAs were significantly lower. A negative correlation between CD1a (Langerhans cells) levels and HPV E7 levels was established. HPV E7 levels positively correlated with HIV-tat levels. Perianal tissues demonstrated more CD1a depression and tat associated HPV upregulation. CONCLUSION: HIV influences the expression of HPV genes resulting in local immunosuppression that might lead to an inappropriate immune surveillance of viral infection. Also, tissue type is an important factor in controlling viral transcription in a differentiation dependent manner. These findings may explain the higher rate of dysplasia and neoplasia in the perianal area.

Antibody Formation↗
PubMed1998

Status of cytokine and antigen presentation genes in Merkel cell carcinoma of the skin.

BACKGROUND: Merkel carcinoma (MCC) of the skin is an aggressive form of skin cancer, morphologically demonstrating both epithelial and neuroendocrine properties. However, little is known about its molecular characteristics. OBJECTIVE: The aims of the study were to explore growth characteristics and immune responses of MCCs at the molecular level. METHODS: A reverse transcription-polymerase chain reaction (RT-PCR) technique was employed to study those parameters in biopsies of MCCs and their adjacent areas. RESULTS: Analyzing mRNA levels of various epithelial genes (c-myc, cdc2 kinase, E2F, PCNA, p53, and RB, cytokeratins 5 and 10) we concluded that MCCs express markers of epithelial hyperproliferation together with markers of neuroendocrine differentiation (NSE). On the other hand, there is a lack of cytokines (IL-2, IFN-g) typical for a specific, T cell-mediated immune response in MCCs. However, several cytokines (e. g., IL-12) are produced that are required for the initial steps of that type of immune response. CONCLUSION: The epithelial hyperproliferation and impaired local immune responses might contribute to the aggressive behaviour of the tumour.

Antigen Presentation↗
PubMed1998

Systemic immunosuppression by HIV infection influences HPV transcription and thus local immune responses in condyloma acuminatum.

Human immunodeficiency virus (HIV) infection is considered to influence the pathogenesis of human papillomavirus (HPV)-associated diseases. It is not clear whether this occurs directly through molecular interactions between viral genes and/or indirectly through effects on the immune functions. In the present study we compared molecular characteristics of penile condylomas from immunocompetent and HIV-positive individuals. Using polymerase chain reaction (PCR) and reverse transcriptase (RT)-PCR techniques we determined some characteristics of local immune responses and transcriptional activity of both viruses. Our findings revealed that HIV-seropositivity was accompanied by multiple HPV infection and a CD4-count-dependent appearance of oncogenic HPV-types. HIV infection also changed the patterns of HPV transcription favouring transcription of early genes such as E7. Apparently, HIV infection influences local immunity by altering HPV transcription and by systemic immunodeficiency.

Condylomata Acuminata↗
PubMed1997

Lack of mda-6/WAF1/CIP1-mediated inhibition of cyclin-dependent kinases in interferon-alpha resistant murine B16 melanoma cells.

Previously we demonstrated that IFN-alpha augments mda-6/WAF1 and inhibits cyclin-dependent kinases in a p53-independent fashion in B 16 murine melanoma cells. On the other hand, IFN-gamma activates p53 expression without affecting the mda-6/WAF1 system. Combination of the two IFNs is additive. B16 cells acquire IFN-alpha resistant but IFN-gamma sensitive phenotype after long term IFN-alpha treatment (B16alpha cells). Here we demonstrate the absence of mda-6/WAF1-associated repression of cyclin-dependent kinases, but the existence of p53-dependent c-myc inhibition in IFN-gamma-treated B16alpha cells. Clearly, selective desensitization of IFN-alpha related growth regulation does not influence the IFN-gamma associated pathway. Our results further support the coexistence of distinct growth regulatory mechanisms in B16 cells that can be activated by different IFN-types independently of each other.

Animals↗
PubMed1997

Detection and cloning of epidermal zinc-alpha 2-glycoprotein cDNA and expression in normal human skin and in tumors.

Zinc-alpha 2-glycoprotein (Zn alpha 2gp) is almost ubiquitous in body fluids, and its antibody labels the corresponding secretory epithelia. We have found that Zn alpha 2gp is also expressed in human epidermis. We cloned the Zn alpha 2gp cDNA by screening our cDNA library, derived from epidermal keratinocytes, with a probe for prostate Zn alpha 2gp. It had complete nucleic acid sequence homology with that from prostate, including the signal peptide. Just as Zn alpha 2gp expression is higher in more differentiated breast tumors, so in skin tumors the highest mRNA levels occurred in the normal controls, the lowest in basal cell carcinomas (the least differentiated epidermal tumor type), and intermediate levels in squamous cell carcinomas and Merkel cell carcinomas. A similar increase in Zn alpha 2gp gene expression with differentiation was observed when epidermal keratinocytes were cultured in media that varied in cellular maturation potential.

Amino Acid Sequence↗
PubMed1997

Interferon regulates expression of mda-6/WAF1/CIP1 and cyclin-dependent kinases independently from p53 in B16 murine melanoma cells.

Interferons (IFNs) induce growth arrest and terminal differentiation through regulation of proliferative genes in a variety of cell types including tumor cells. Growth of melanoma cells is believed to be controlled by the cyclin-dependent kinase inhibitor, mda-6/WAF1/CIP1 gene. IFNs affect the expression of WAF1 in several cell types, including human melanomas. In our earlier reports we demonstrated the antitumor and anticellular activities of different IFN-types on B16 murine melanoma cells. The present study aimed to demonstrate the involvement of mda-6/WAF1 and related cyclin-dependent kinases in antitumor action of different IFN-types in B16 melanoma cells. IFN-alpha has been proven to be a potent inducer of mda-6/WAF1, also inhibiting cyclin-dependent kinases, such as cdc2- and cdk2-kinase. This induction is p53-independent. However, IFN-gamma affects B16 cells differently, it induces p53 activity without inducing WAF1. The combination of IFN-alpha plus IFN-gamma is additive rather than synergistic. Our data demonstrate differential effects of different IFNs on murine B16 melanoma cells which may have relevance in nonsurgical treatment of melanomas.

Animals↗
PubMed1997

Mastication of verruca vulgaris associated with esophageal papilloma: HPV-45 sequences detected in oral and cutaneous tissues.

Human papillomaviruses (HPVs) are double-stranded, circular, epitheliotropic DNA viruses of which nearly 70 types have been identified. Specific HPV types exhibit a predilection to infect certain sites; however, occurrence is not unique or restricted to these sites. HPV typing may also be helpful in determining the oncogenic potential of HPV lesions. The most common HPV types, 6 and 11, are associated with benign mucosal lesions, whereas types 18, 16, 31, and 33 are thought to confer a high rate of malignant transformation. We describe a patient with both palmar verrucae and esophageal papillomatosis that proved to be HPV type 45 by polymerase chain reaction. HPV 45 has a high homology to HPV 18 and is a member of the relatively new "high-risk" mucosal HPV family in terms of cervical oncogenic potential. To our knowledge, HPV 45 has never been reported in cutaneous warts or esophageal lesions.

DNA, Viral↗
PubMed1996

Induction of iNOS mRNA by interferon-gamma in epithelial cells is associated with growth arrest and differentiation.

Induction of inducible nitric oxide synthase (iNOS) mRNA by interferon-gamma (IFNgamma) is well established in various cell types. We observed earlier that this induction is differentiation-dependent in human keratinocytes. Since IFNgamma-mediated growth arrest and differentiation are separable but interrelated processes in keratinocytes, iNOS might play a role in their regulation. We conducted a series of in vitro experiments on normal and transformed epithelial cells with different tissue origins. We found that immortalization and transformation can influence the IFNgamma-mediated iNOS inducibility, but this process is tissue-specific as the induction correlates with the ability of the cells to differentiate.

Antineoplastic Agents↗
PubMed1996

Regulation of inducible nitric oxide synthase mRNA levels by differentiation and cytokines in human keratinocytes.

Inducible nitric oxide synthase (iNOS) transcription is regulated by cytokines and immune stimuli in various cell types. However, there are few data available on iNOS expression and regulation in keratinocytes, even though it can play a role in keratinocyte proliferation during inflammation following wound healing. Our studies demonstrated a differentiation-dependent regulation of iNOS transcription in human keratinocytes from epidermis but not in buccal mucosal cells, which are less differentiated. Different interferon (IFN) types (alpha and gamma) regulated skin keratinocyte iNOS mRNA levels in different ways, predominantly in a differentiation-dependent manner. TGFbeta1 and IFNalpha can antagonize IFNgamma related iNOS induction. However, the antagonistic effects of IFNalpha on IFNgamma differ from those of TGFbeta1. Our studies demonstrate: (a) the presence of iNOS mRNA in human keratinocytes; (b) inducibility of iNOS mRNA by different cytokines; and (c) antagonism between certain cytokines in induction of iNOS mRNA. Further studies are needed to determine biological and therapeutical relevance of our findings.

Cell Differentiation↗
PubMed1996

Response to interferon treatment decreases with epidermal dedifferentiation in condylomas.

After interferon (IFN) treatment of patients with condyloma acuminatum, groups clinically proven to be responders or nonresponders were selected, and cellular parameters that might influence the clinical response were studied in pretreatment biopsies by reverse transcription polymerase chain reaction (RT-PCR). The nonresponders were found to express higher amounts of cellular proliferative markers, such as proliferating cell nuclear antigen (PCNA), cyclin A, and cdc 2 kinase, but lower levels of growth suppressor genes (TGF-beta 1, TGF-beta 2 and p53) before IFN treatment. The responders retained the epidermal keratinization, except for some signs of hyperproliferation (K6, K16 cytokeratins). In addition, the nonresponders showed a shift in the keratinization pattern to a mucosal or fetal type, as evidenced by high expression of the K18, K6, K16 and K13 cytokeratins but decreased K5, K14 and K10 levels before treatment. The expression of the human papillomavirus (HPV) genes is consistent with these differentiation patterns. The crucial conclusion to be drawn from this study is that those condylomas whose pretreatment phenotype most closely resembles that of normal epidermis respond to IFN treatment, whereas those more akin to nonkeratinizing epithelia fail to respond, i.e. the resistance of condylomas to IFN treatment is correlated with dedifferentiation.

Base Sequence↗
PubMed1996

Activation of local cell-mediated immunity in interferon-responsive patients with human papillomavirus-associated lesions.

Successful immune response to viral infection, such as human papillomavirus (HPV) infection, involves presentation of viral antigens to the immune system, recruitment of T cells and macrophages, and activation of a diverse array of cytokines. Interferons (IFN) are known to exert immunomodulatory functions via activating these pathways. However, the presence of HPV can interact with this process. We employed a reverse transcription-polymerase chain reaction (RT-PCR)-based method to study this phenomenon in biopsies of patients responding well or poorly to IFN treatment. We found that responders show a delayed-type hypersensitivity (DTH) reaction after IFN treatment, in which TH1 cells (interleukin-2, IL-2, IFN-gamma) and macrophages/NK cells (CD16) predominate. Antigen presentation capability (e.g., upregulation of MHC molecules, cytokines) is also enhanced after IFN treatment in responders. The lack of upregulation of MHC molecules (HLA-DR, beta 2-microglobulin) and certain cytokines (IL-1 alpha, IL-2, IFN-gamma) in nonresponders may be due to the overexpression of HPV early (E7) gene in contrast to responders, where HPV late (L1) gene expression predominates. We concluded that differential HPV expression in infected cells can be responsible for an inappropriate IFN-mediated immune response.

Antibody Formation↗
PubMed1995

Gene expression of markers associated with proliferation and differentiation in human keratinocytes cultured from epidermis and from buccal mucosa.

Normal keratinocytes from epidermis and from buccal mucosa underwent dissimilar stages of differentiation in the same culture medium and responded differently to changes in the composition of the medium. Manifestations of these variations were examined in terms of the expression at the mRNA level (as measured by reverse transcriptase-polymerase chain reaction) of three regulatory genes (cdc2, c-myc, and p53) and five that encode structural proteins (keratins K5, K10 and K13, involucrin, and filaggrin), in three growth-medium formulations. The culture conditions enhanced or retarded maturation; the observed alterations in gene expression correlated with these changes. Except for the proliferation genes, the non-keratinizing buccal mucosa generally responded more weakly than the orthokeratotic epidermis to culture-medium supplementation favouring differentiation. Gene expression in cultured keratinocytes reflected their ability to differentiate in vivo; genes were expressed even when the corresponding protein was not seen in vitro. Although keratin K10 is not prevalent in the buccal mucosa nor keratin K13 in the epidermis, the genes for both were found to be expressed in both tissues.

Calcium↗
PubMed1995

Type-specific primer-mediated direct sequencing of consensus primer-generated PCR amplicons of human papilloma viruses: a new approach for the simultaneous detection of multiple viral type infections.

Consensus degenerate primers specific for the L1 and E1 regions were used to amplify anogenital HPV-DNA fragments. The mixture of the viral fragments was then directly sequenced with HPV-6, -11, -16, -18 and -33 type-specific computer-designed oligonucleotides as sequencing primers. The linking of a consensus primer-generated PCR amplification with type-specific primer-mediated direct sequencing and computer data bank analysis provided precise, more objective viral detection in the simultaneous presence of different HPV types. The method was successfully adapted for viral typing in clinical lesions which simultaneously contained different anogenital HPV sequences.

Anus Neoplasms↗
PubMed1995

Induction of apoptotic nuclei by interferon-gamma and by predesquamin in cultured keratinocytes.

Predesquamin is a glycoprotein found in the transition layer and the lower stratum corneum of human epidermis. Interferon-gamma (IFN-gamma) induces the synthesis of predesquamin by keratinocytes in culture. We now show ultrastructurally that exogenous addition of either predesquamin or IFN-gamma to cultured keratinocytes induces apoptotic nuclei with condensed chromatin. Degradation of cellular DNA is also evident as a ladder pattern in an agarose gel. After incubation with both predesquamin and IFN-gamma (but not either alone), the mobility of plasmid DNA in a gel shows retardation specific for guanine residues. This binding to the DNA may impart to it a conformational change that facilitates access by endogenous cellular nucleases. In epidermal cells cultured with IFN-gamma supplementation, we also show by RT-PCR that there is an upregulation of the genes c-myc, p53, gadd45, dsRNA-activated protein kinase, and 2'-5'-oligo(A)-dependent RNase, which have all been implicated in apoptosis in other cell types. These results are pertinent to the mechanism of occurrence of apoptosis in the epidermis in vivo, where predesquamin and IFN-gamma are endogenous. Programmed cell death is an inherent step in the terminal differentiation and desquamation of the epidermis.

Apoptosis↗
PubMed1995

Effect of interferon therapy on human papillomavirus copy number in patients with Condyloma acuminatum.

Interferons exert antiviral, antiproliferative, and immunomodulatory effects on target cells. The effectiveness of interferon treatment can be followed by measuring parameters involved in interferon action. The clinical effectiveness of interferons has been proved in the human papillomavirus (HPV)-associated disease condyloma acuminatum. Because one of the most important goals in the treatment of this condition is the elimination of recurrences, it was asked whether clinically effective interferon therapy was associated with elimination of HPV DNA. The authors used a polymerase chain reaction-based method to detect the HPV from minute amounts of clinical biopsies. Human papillomavirus-transformed cell lines or cloned HPV genomes served as different copy number controls. The intensity ratio of L1 HPV and the human beta-globin (which served as an internal control) fragments was determined and used for estimation of HPV copy number in different biopsies. A direct effect of interferon treatment on HPV viral genome copies was observed in a group of responder patients, but not in the clinically resistant group. With these data, a correlation was found between virologic data and clinical findings. This method also can be used in other lesions to determine the HPV copy number and HPV type and may have value in determining the antiviral activities of other agents used in the treatment of HPV-related lesions.

Cell Line↗
PubMed1995

Skin-associated lymphoid tissue in human immunodeficiency virus-1, human papillomavirus, and herpes simplex virus infections.

The skin-associated lymphoid tissue is composed of keratinocytes, Langerhans cells, skin trophic T cells, and lymphatic endothelial cells of the skin. The epidermis, which is involved in many viral infections, contains all of the components needed for an effective immune response: antigen-presenting Langerhans cells, T cells, and cytokines from leukocytes and keratinocytes. There have been some recent advances in the study of the cutaneous immunology involved in infections with the human immunodeficiency virus (HIV), human papillomavirus (HPV), and herpes simplex virus (HSV). In general, viral diseases with cutaneous manifestations lead to a decline in epidermal Langerhans cell numbers, which probably reflects Langerhans cell emigration out of the epidermis and entry into regional lymph nodes, leading to Langerhans cell activation and antigen presentation to T cells. In HSV, there is a subsequent T-cell infiltration of the epidermis, composed of CD4+ cells that have both immune modulatory action and direct cytotoxic action. In HIV, where there is a systemic depletion of CD4+ cells, the epidermis is left with reduced numbers of T cells. Intradermal injection of interleukin-2, however, leads to an epidermal cellular infiltration in HIV+ individuals. In HPV-induced condyloma, intralesional interferon increases Langerhans cells and CD4+ and CD8+ cells in the skin, as well as transforming growth factor beta 1, tumor necrosis factor-alpha, pRB, and p53. Therefore, viral infections involving the epidermal immune system have certain similar characteristics, whereas other factors are unique to the infecting virus.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Development of human papillomavirus type 16 associated squamous cell carcinoma of the scrotum in a patient with Darier's disease treated with systemic isotretinoin.

In contrast to squamous cell carcinoma of the penis, scrotal carcinoma has historically been associated with exposure to environmental or industrial carcinogens and has only rarely been correlated with human papillomavirus. We report on a patient with squamous cell carcinoma of the scrotum in which human papillomavirus type 16 was integrated into the tumor cell genome, suggesting a causal role of human papillomavirus in the development of squamous cell carcinoma of the scrotum. Other unique features of our case include the presence of Darier's disease, an uncommon genodermatosis, and treatment with oral retinoids, which have prophylactic value in the prevention of cutaneous malignancies.

Amino Acid Sequence↗