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E Tschachler

Publications and source records attributed to E Tschachler.

At least 73 records · Page 4Linked to original sources
PubMed1997

Expression of HHV-8 latency-associated T0.7 RNA in spindle cells and endothelial cells of AIDS-associated, classical and African Kaposi's sarcoma.

Analysis by polymerase chain reaction (PCR) and serological studies have demonstrated a close association between the novel human herpes virus, Kaposi's sarcoma-associated herpes virus (KSHV) or human herpes virus-8 (HHV-8) and the development of Kaposi's sarcoma (KS). To clarify the role of HHV-8 in KS pathogenesis, we investigated at the cellular level by in situ hybridization the expression of a recently described 0.7-kb HHV-8-encoded mRNA (T0.7 mRNA) in KS tissues of different epidemiological origin (AIDS-KS, African endemic KS and classical KS). The T0.7 mRNA likely encodes a small membrane protein, supposedly expressed in latently HHV-8-infected cells. Indeed, we detected T0.7 mRNA in virtually all cells of the cell line BCBL-1 established from a body cavity-based lymphoma (BCBL) and latently infected with HHV-8. In all KS biopsies examined, independent of their epidemiological type, the late-stage (nodular) KS tissues showed a high level of T0.7 mRNA expression in typical KS spindle cells but also in endothelial cells lining blood vessels, indicating latent HHV-8 infection of these cells. The presence of T0.7-expressing cells was restricted to KS tumor tissue and therefore appears to indicate an important role of latent HHV-8 infection in KS pathogenesis.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Characterization of a chemokine receptor-related gene in human herpesvirus 8 and its expression in Kaposi's sarcoma.

Human herpesvirus 8 (HHV-8) is a recently discovered, virus that is highly associated with Kaposi's sarcoma (KS) and AIDS-associated body cavity lymphomas, although it is also found in some normal individuals. HHV-8 is related by nucleotide sequence homology to herpesvirus saimiri (HVS), which causes T cell lymphomas in some New World monkeys, and to Epstein-Barr virus (EBV), a human herpesvirus linked etiologically with Burkitt's lymphoma and nasopharyngeal carcinoma. We report that, like HVS but unlike EBV, HHV-8 contains a gene (ORF74) with significant sequence homology to the high-affinity IL-8 receptor, a member of the alpha (CXC) chemokine receptor family of transmembrane G protein-coupled receptors. We also show by reverse transcription PCR that the chemokine receptor-related HHV-8 gene is detectable in some RNA samples from KS tissue, and that its expression varies independently from that of ORF26, a minor capsid protein. The presence of a potential chemokine receptor in HHV-8 and its expression in KS tissue suggests that it may be important in the regulation of viral gene expression and may play a role in the etiology of KS and AIDS-related body cavity lymphomas.

AIDS-Related Opportunistic Infections↗
PubMed1997

[Microscopic polyangiitis with eosinophilia--an overlap syndrome or separate disease entity? A case report and review of the literature].

Systemic vasculitides are potentially life-threatening diseases. Early and appropriate diagnosis based on case history, clinico-pathological features, and laboratory parameters, such as the presence of anti-neutrophil cytoplasmic antibodies (ANCA), is crucial for starting appropriate and, often, life-saving therapeutic measures. We report a 50-year-old female patient who presented with fever, arthralgias and hemoptysis. Skin signs included disseminated hemorrhagic pustules, ulcerations of oral and genital mucosa, subcutaneous nodules on arms and legs, and a pyoderma gangrenosum-like lesion on the right leg. Laboratory investigations revealed a peripheral eosinophilia and a positive cANCA titer. Histopathologic analysis of various biopsy specimens showed a granulomatous vasculitis in the subcutis, a nongranulomatous vasculitis with massive eosinophil infiltration in the lungs, and a segmental, necrotizing glomerulonephritis in the kidneys. Differential diagnosis included Wegener's granulomatosis, microscopic polyangiitis (MPA) and Churg-Strauss syndrome. MPA was diagnosed based on clinical and histopathological criteria. An interesting feature of this case was marked peripheral and tissue eosinophilia. Therapy consisted of cyclophosphamide and methylprednisolone. The patient went into a long-lasting clinical remission one month after starting therapy.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1997

Differences in tumor microvessel density between squamous cell carcinomas and basal cell carcinomas may relate to their different biologic behavior.

Tumor microvessel density (TMVD) has been recognized as an important indicator for the metastatic risk in certain tumors. The purpose of this study was to analyse whether there is an association of TMVD in epithelial neoplasms of the skin with their clinical behavior. Paraffin sections of keratoacanthomas (KA, n = 10), squamous cell carcinomas (SCC, n = 9), nodular (nod-BCC, n = 13), and sclerosing (scl-BCC, n = 12) basal cell carcinomas were immunohistochemically stained for factor-VIII-related antigen and TMVD was determined. In all SCC, KA and nod-BCC, TMVD significantly exceeded perilesional skin microvessel density (PSMVD) (SCC:TMVD/PSMVD = 20.54:11.25, p < 0.0001; KA:TMVD/PSMVD = 20.90:12.17, p < 0.0001; nod-BCC:TMVD/PSMVD = 16.77:13.34, p = 0.03). In contrast, no significant difference between TMVD and PSMVD was found in scl-BCC (15.44:12.86, p = 0.22). TMVD was significantly higher in SCC and KA compared to nod-BCC (p = 0.036 and 0.006, respectively). Our data demonstrate that SCC and KA are highly vascularized tumors. The fact that TMVD does not differ significantly between SCC and KA (p = 0.80) suggests that MVD is not an indicator for the metastatic risk or aggressive growth behavior of epithelial skin tumors. The finding that MVD in both nod- and scl-BCC is significantly lower than in SCC and KA, might at least in part explain the slow growth of BCC.

Biopsy↗
PubMed1997

Monocytes in Kaposi's sarcoma lesions are productively infected by human herpesvirus 8.

PCR analysis and serological studies demonstrated a close association between Kaposi's sarcoma (KS)-associated herpesvirus, or human herpesvirus 8 (HHV-8), and the development of Kaposi's sarcoma (KS). The majority of the KS cells were shown to be latently infected by the virus. In this study we investigated which type of cell is productively infected in KS lesions. In situ hybridization was performed with strand-specific RNA probes complementary to the sequences coding for the minor capsid protein (VP23) of HHV-8. The VP23 gene is specifically expressed during the lytic or replicative period of the virus life cycle, and therefore it is a useful marker to detect productively infected cells. By in situ hybridization of KS lesions, a strong hybridization signal was detected only in a small subset of the KS cells of the lesions. Simultaneous application of immunohistochemical staining and in situ hybridization identified the virus-replicating cells to be of monocytic origin. Productively infected monocytes may be an important reservoir for transmission of the virus and for the increase and maintenance of the high load of HHV-8 generally observed in nodular KS lesions during late stages of infection.

Biomarkers↗
PubMed1997

Induction of apoptosis in Kaposi's sarcoma spindle cell cultures by the subunits of human chorionic gonadotropin.

OBJECTIVES: Elucidation of the mechanisms of the previously shown growth-inhibitory action of human chorionic gonadotropin (hCG) on Kaposi's sarcoma (KS) cells and the role of the luteinizing hormone/hCG receptor (hCGR). DESIGN AND METHODS: Analysis of KS tissues and cultured spindle-type KS cells for the presence of the hCGR using 125I-hCG binding and reverse transcriptase-polymerase chain reaction; analysis of several hCG preparations (urinary, recombinant, isolated alpha and beta subunits); analysis of apoptosis mechanisms by several assays including using z-Val-Ala-Asp-fluoromethylketone (zVAD-FMK), a known apoptosis-inhibitory drug. RESULTS: First, we found that some urinary preparations of hCG (e.g., CG-10, Steris Profasi) were indeed KS-killing but others (such as Pregnyl, Choragon, Serono Profasi) were not. Secondly, recombinant subunits (alpha as well as beta) of hCG were KS cell-killing but recombinant intact hCG was not. Thirdly, the hCGR message and protein were undetectable in KS. Fourthly, CG10-induced cell death occurred by apoptosis and KS cells could be rescued by preincubation with zVAD-FMK. Finally, we also found that normal peripheral blood lymphocytes (PBL) were killed by CG-10. CONCLUSION: It is proposed that the action of subunits or subunit fragments of hCG, mediated by a putative orphan receptor (as opposed to the hCGR) and executed by interleukin-1-converting enzyme (ICE)-like protease(s), constitutes a novel apoptosis mechanism effective towards KS cells, but PBLs and possibly other cells as well. These results provide a basis for testing in vitro the therapeutic efficacy of hCG preparations which, in turn, should improve current clinical trials with 'hCG' in patients who have KS.

Amino Acid Chloromethyl Ketones↗
PubMed1996

HIV-related skin diseases.

Disorders of the skin and mucous membranes, including various infections, Kaposi's sarcoma, and miscellaneous conditions, occur throughout the course of HIV infection, affecting more than 90% of patients at some time. These lesions are often the first manifestations of symptomatic HIV disease. Clinicians need to be aware of these diagnoses and the order of their appearance since correct interpretation is essential for counselling patients about the progression of their illness and for initiating appropriate therapy.

Adult↗
PubMed1996

Expression of the CD40 antigen on normal endothelial cells and in benign and malignant tumours of vascular origin.

CD40, a member of the nerve growth factor/tumour necrosis factor-receptor family, is expressed on endothelial cells in situ and in tissue culture. It is functionally involved in the regulation of the expression of adhesion molecules in these cells. In the current study we investigated the expression of CD40 on the endothelia of normal fetal and adult human tissues, as well as in the stroma of various neoplasms and in different inflammatory tissue reactions. By immunohistochemistry, endothelia were negative or only weakly positive for CD40 in all normal adult and most fetal organs studied. In contrast, endothelial cells of fetal and embryonic lungs, kidneys and larger vessels consistently expressed the CD40 antigen. Strong expression of CD40 on endothelial cells of blood vessels but not of lymphatic vessels was found in inflammatory reactions. In 65 tumours of vascular origin we found moderate to strong expression of CD40 in all of four juvenile proliferating capillary haemangiomas and 11 lobular capillary haemangiomas of adults. Senile and cavernous haemangiomas as well as lymphangiomas were negative or exhibited only weak CD40 reactivity. Weak to moderate CD40 expression was found in five of eight malignant neoplasms of endothelial origin. Our finding that the CD40 antigen is present on only a minority of normal endothelial cells, whereas strong staining can be detected on the majority of endothelial cells in inflammatory processes, complements previous reports which suggest that this surface receptor plays an important role in tissue inflammation. The heterogeneous pattern of expression in malignant endothelial neoplasms argues against a major role for CD40 in the pathogenesis of these tumours. Its consistent presence in juvenile and lobular capillary haemangiomas suggests rather the involvement of CD40 in the development and/or progression of these benign vascular proliferations.

Adult↗
PubMed1996

Merkel cells and Merkel cell carcinoma express the BCL-2 proto-oncogene.

The bcl-2 proto-oncogene, which is involved in the regulation of apoptosis, is expressed in a wide variety of fetal and adult tissues. We and others have demonstrated recently that in the human skin melanocytes, nervus cells and melanoma cells express bcl-2 constitutively. In the present study, we have analysed the expression of bcl-2 in Merkel cells and in Merkel cell carcinomas. In 2 colour immunofluorescence staining, normal human Merkel cells as identified by the expression of cytokeratins 8, 18 and 20, were also anti-bcl-2 positive. Staining of paraffin sections of Merkel cell carcinomas with an anti-bcl-2 monoclonal antibody revealed strong bcl-2 protein immunoreactivity in all 5 tumors tested. Serial sections of Merkel cell carcinomas stained with the monoclonal antibodies CK 20, CAM 5.2, anti-neuron-specific enolase and anti-bcl-2 showed that the anti-bcl-2 reactive cells were indeed tumor cells. Our data demonstrate for the first time, that normal human Merkel cells and Merkel cell carcinomas express bcl-2 constitutively. Considering the biological function of the bcl-2 proto-oncogene, i.e., its anti-apoptotic effect, it is conceivable that in the near future, modulations of the expression of this protein may offer a new strategy in the therapy of bcl-2 expressing tumors such as Merkel cell carcinoma.

Adult↗
PubMed1996

Merkel cells and Merkel cell carcinoma express the BCL-2 proto-oncogene.

The bel-2 proto-oncogene, which is involved in the regulation of apoptosis, is expressed in a wide variety of fetal and adult tissues. We and others have demonstrated recently that in the human skin melanocytes, nevus cells and melanoma cells express bcl-2 constitutively. In the present study, we have analysed the expression of bcl-2 in Merkel cells and in Merkel cell carcinomas. In 2 colour immunofluorescence staining, normal human Merkel cells as identified by the expression of cytokeratins 8, 18 and 20, were also anti-bcl-2 positive. Staining of paraffin sections of Merkel cell carcinomas with an anti-bcl-2 monoclonal antibody revealed strong bcl-2 protein immunoreactivity in all 5 tumors tested. Serial sections of Merkel cell carcinomas stained with the monoclonal antibodies CK 20, CAM 5.2, anti-neuron-specific enolase and anti-bcl-2 showed that the anti-bcl-2 reactive cells were indeed tumor cells. Our data demonstrate for the first time, that normal human Merkel cells and Merkel cel carcinomas express bcl-2 constitutively. Considering the biological function of the bcl-2 proto-oncogene, i.e., its anti-apoptotic effect, it is conceivable that in the near future, modulations of the expression of this protein may offer a new strategy in the therapy of bcl-2 expressing tumors such as Merkel cell carcinoma.

Adult↗
PubMed1996

The skin immune system in the course of HIV-1 infection.

In human immunodeficiency virus-1 (HIV-1) infection, diseases of the skin and mucous membranes frequently dominate the clinical picture as a consequence of progressive immunodeficiency. Functional impairment of the skin immune system, manifesting as a loss of the skin delayed-type hypersensitivity response is very likely due to the infection of immunocompetent cells of the skin by HIV-1. Besides CD4+ T cells, antigen-presenting Langerhans cells have been established as major targets of HIV-1 infection. The close physical contact of Langerhans with T lymphocytes during immune activation suggests central role of these cells in the dissemination of HIV-1 and the subsequent breakdown of the skin immune system. In addition, there are indications that mucosal Langerhans cells may represent preferred target cells for certain HIV-1 subtypes and thereby facilitate mucocutaneous transmission of HIV-1.

HIV Infections↗
PubMed1996

CD40 antigen is expressed by endothelial cells and tumor cells in Kaposi's sarcoma.

The CD40 antigen is a member of the tumor necrosis factor receptor/nerve growth factor receptor superfamily and is involved in cell proliferation, differentiation, and survival. Using different monoclonal antibodies, we found CD40 expression by immunohistochemistry on CD31- and CD34-positive Kaposi's sarcoma spindle cells in all tumors of 18 HIV-1 seropositive and 4 HIV-1 seronegative patients. Western blot analysis of tumor lysates detected a 48- to 50-kd glycoprotein corresponding to the CD40 antigen expressed by B lymphocytes. CD40 expression was also detectable in one of four cultures of spindle cells derived from Kaposi sarcoma tissue. Treatment of the CD40-positive spindle cells but not of the CD40-negative ones with interferon-gamma up-regulated CD40 surface expression. Besides on Kaposi sarcoma tumor cells, CD40 was distinctly present on vascular endothelial cells in areas within and adjacent to the tumors and in benign inflammatory lesions such as granulation tissue of HIV-1-negative patients. In contrast, CD34-negative endothelia of thin walled vessels, most likely lymphatics, were predominantly CD40 negative. Only faint or no CD40 expression was found on endothelial cells in normal skin. We conclude from our data that expression of the CD40 antigen by endothelial cells is up-regulated during tissue inflammation. As signaling through CD40 is able to increase cell survival, expression of CD40 by Kaposi sarcoma tumor cells might play an important role in the pathogenesis of this neoplasm.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Vascular endothelial growth factor production in normal epidermis and in benign and malignant epithelial skin tumors.

Vascular endothellal growth factor (VEGF) increases vascular permeability and acts as a mitogen for endothelial cells in vivo and in vitro. We and others recently demonstrated that cultured human keratinocytes constitutively secrete VEGF. In the present study, we examined the expression of this growth factor in various epithelial skin tumors and in normal skin. Using in situ hybridization, we detected strong VEGF mRNA expression in all of 10 squamous cell carcinomas, 13 common warts, 11 seborrheic keratoses, and in 7 of 8 keratoacanthomas studied. By contrast, we found no VEGF mRNA in 9 of 14 basal cell carcinomas. VEGF mRNA was readily detectable within the epidermis adjacent to the tumors as well as in tumor cells and in the epidermis of normal human skin. Northern hybridization of RNA derived from normal human epidermis identified VEGF transcripts of 3.7 and 1.8 kb, and reverse transcriptase polymerase chain reaction confirmed that epidermal cells, like keratinocytes in vitro, express the three major splice forms of VEGF. Immunohistochemical staining with monoclonal antibodies confirmed that expression of VEGF mRNA was accompanied by the presence of VEGF protein. Our data demonstrate that VEGF production by tumor cells in situ does not distinguish malignant from benign epithelial tumors of the skin because it is present in both. The constitutive expression of VEGF by normal keratinocytes in situ suggests that this angiotropic cytokine is important for the regulation of vessel function under physiologic conditions.

Blotting, Northern↗
PubMed1996

Vascular endothelial growth factor regulates angiogenesis and vascular permeability in Kaposi's sarcoma.

Abundant vasculature with increased permeability is a prominent histological feature of Kaposi's sarcoma (KS), a multifocal, cytokine-regulated tumor. Here we report on the role of vascular endothelial growth factor (VEGF) in AIDS-KS angiogenesis and vascular permeability. We demonstrate that different cytokines, which were previously shown to be active in KS development, modulate VEGF expression in KS spindle cells and cooperate with VEGF on the functional level. Northern blot analysis as well as studies on single cells using in situ hybridization revealed that VEGF expression in cultivated AIDS-KS spindle cells is up-regulated by platelet-derived growth factor-B and interleukin-1 beta. Western blot and enzyme-linked immunosorbent assay analysis of cell culture supernatants demonstrated that the VEGF protein is secreted by stimulated AIDS-KS spindle cells in sufficiently high amounts to activate proliferation of human dermal microvascular endothelial cells. Basic fibroblast growth factor did not increase VEGF expression but acted synergistically with VEGF in the induction of angiogenic KS-like lesions in a mouse model in vivo. Angiogenesis and cellularity of KS-like lesions were clearly increased when both factors were injected simultaneously into the flanks of mice, compared with separate injection of each factor. A comparable angiogenic reaction as obtained by simultaneous injection of basic fibroblast growth factor and VEGF was observed when cell culture supernatants of AIDS-KS spindle cells were used for these experiments. Finally, analysis of primary human AIDS-KS lesions revealed that high amounts of VEGF mRNA and protein were present in KS spindle cells in vivo. These data provide evidence that VEGF, in concert with platelet-derived growth factor-B, interleukin-1 beta, and basic fibroblast growth factor, is a key mediator of angiogenesis and vascular permeability in KS lesions in vivo.

Animals↗
PubMed1995

Prognostic value of immunohistochemically detected p53 expression in vulvar carcinoma.

BACKGROUND: Overexpression of the p53 protein has been reported to correlate with poor prognosis in several types of tumors. To the authors' knowledge, there are no studies concerning the prognostic value of p53 protein overexpression in squamous cell vulvar carcinoma. METHODS: Twenty-five cases of squamous cell carcinoma of the vulva with International Federation of Gynecology and Obstetrics (FIGO) Stage I-II were examined for p53 protein overexpression using immunohistochemistry. The correlation of p53 protein overexpression with clinical stage, histologic grade, and overall survival was investigated. Follow-up ranged from 36 to 120 months. RESULTS: Clinical stage and histologic grade did not correlate with p53 protein overexpression. p53 protein overexpression was associated with poorer overall survival (log rank: P < 0.05). CONCLUSION: Immunohistochemically detected p53 protein overexpression is significantly correlated with a reduced overall survival rate for patients with vulvar carcinoma.

Adult↗