Biomedical subjects

Mariam Klouche

Publications and source records attributed to Mariam Klouche.

6 recordsLinked to original sources

PubMed2005

Liposomal pegylated doxorubicin versus low-dose recombinant interferon Alfa-2a in the treatment of advanced classic Kaposi's sarcoma; retrospective analysis of three German centers.

BACKGROUND: Classic Kaposi's sarcoma (KS) is a rare neoplasm, predominantly occurring in older subjects of Eastern Europe or Mediterranean descent. While single lesions may be treated by simple excision, laser therapy, cryotherapy, or intralesional therapy, advanced or disseminated disease requires systemic treatment. Several studies reported the effectiveness of pegylated liposomal doxorubicin (PLD) and low-dose recombinant interferon alfa-2a (IFNalpha) in the treatment of AIDS-associated KS. OBJECTIVE: The aim of this retrospective analysis of three German centers was to compare the effectiveness and tolerability of PLD with IFNalpha in patients with advanced classic KS. METHODS: Retrospective analysis of 18 Caucasian patients who had been treated for histologically proven classic KS, with either with PLD or IFNalpha was performed. Twelve patients received 20 mg/m2 of PLD monthly, and the number of cycles was adapted to the clinical response. Dose reduction or increased cycle length was conducted if toxicity intervened. In 6 patients, 3 million U of IFNalpha was injected subcutaneously 3 times a week. IFNalpha -therapy was adapted according to the clinical response. RESULTS: In the 12 KS patients treated with PLD, complete response (CR) was achieved in 8 (67 percent), major response (MR) in 3 (25 percent), and minor response (mR) in 1 (8 percent). Stable disease (SD) or progression of disease (PD) was not observed. An initial response was noted after 4-16 weeks of treatment (mean 8.6 weeks), the mean cumulative dose of PLD was 571.5 mg/m2 (range, 40 to 1496 mg/m2), and the mean follow-up was 13 months. Neutropenia (33 percent) related to PLD was the most common adverse event (4/12). Vomiting occurred in 3 (25 percent) patients; none of these were severe. Six patients were treated with IFNalpha. MR was achieved in 1 (17 percent), mR in 4 (67 percent) and SD in 1 of 6 patients (17 percent), neither had CR or PD. An initial response was observed after 8-17 weeks of treatment (mean 12.7 weeks). Fever occurred in 4 patients (67 percent). Flu-like symptoms in 3 patients (50 percent) related to IFNalpha were the most common adverse events. Mean follow-up was 6.3 months. The differences in response to treatment between PLD and IFNalpha, in general, were significant with p < 0.05 (T-test for independent samples). Comparing weeks to respond and treatment efficiency data were significant with p < 0.001 (Fisher's exact): response to PLD was up to one-third faster than IFNalpha. Calculating different stages of response (MR, CR, etc.), PLD also was clearly superior (p = 0.018) to IFNalpha (Fisher's exact). CONCLUSION: This retrospective analysis of patients with classic KS confirms the efficacy and safety of PLD. The benefits of PLD, including the monthly application, the high response even after previous treatments have failed, and the low rate of side effects even in elderly individuals, outweigh the risks. PLD is superior to IFNalpha and should be considered as an promising option in the treatment of advanced classic KS.

Adult↗

PubMed2005

Plasminogen and matrix metalloproteinase activation by enzymatically modified low density lipoproteins in monocytes and smooth muscle cells.

Protease activity promotes the progression and rupture of atherosclerotic plaques. LDL has been described to become enzymatically modified within the vessel wall yielding an atherogenic moiety (E-LDL). We studied the effect of E-LDL on the activation of plasminogen and matrix metalloproteinases (MMPs) in monocytes and vascular smooth muscle cells (VSMCs) as well as on MMP activation during cellular interactions. Human monocytes, monocytic MonoMac6 cells and human VSMCs were incubated with human native LDL (n-LDL) or E-LDL for 24 hours. E-LDL in contrast to n-LDL induced substantial activation of the plasminogen activation system as well as of the MMP system in monocytic cells, as measured by enhanced cell surface expression of the urokinase receptor (uPAR),the extracellular matrix metalloproteinase Inducer (EMMPRIN) and the membrane type-1 MMPs (MT1-MMP,MMP-14), as well as by secretion of active uPA, and of MMP-9. Consistently, E-LDL-treated monocytes exhibited increased transmigration through "matrigel", which was specifically abrogated by the MMP inhibitor galardin or the plasmin inhibitor aprotinin. In VSMCs, E-LDL induced MMP-1 and MMP-2 secretion. Moreover, monocyte incubation with supernatants of E-LDL-treated (but not n-LDL-treated) VSMCs strongly induced MMP-9 in monoytes, which was inhibited by blocking mAb anti-TNF-alpha. Together, enzymatical modification of LDL allows a direct activation of MMP expression in monocytes and VSMCs, and indirectly promotes the induction of paracrine, cytokine-mediated intercellular activation processes. There by, E-LDL may contribute to atheroprogression, inflammation and plaque rupture.

Arteriosclerosis↗

PubMed2004

Modified atherogenic lipoproteins induce expression of pentraxin-3 by human vascular smooth muscle cells.

Inflammation is a critical contributing factor to the development and the progression of atherosclerosis. Recently, the acute-phase protein pentraxin-3 (PTX3), which has C-terminal sequence homology with the classic pentraxin C-reactive protein (CRP), was described to be increased in patients with myocardial infarction. In this study, we have investigated the capacity of human primary vascular smooth muscle cells (VSMC), derived from arterial specimens of ten different patients, to express PTX3 after incubation with atherogenic lipoproteins. Enzymatically degraded LDL (E-LDL), which is present in human early lesions, mediated a rapid cholesterol loading and foam cell transformation of primary VSMC, which was paralleled by a marked dose- and time-dependent expression of PTX3 mRNA and release of the acute-phase protein. Expression of PTX3 mRNA was delayed and remained almost undetectable for up to 6 h of incubation with E-LDL. However, during extended exposure to E-LDL for more than 24 h, PTX3 mRNA expression increased by more than 15-fold in VSMC foam cells, which was reflected by a concomitant release of up to 211 ng/ml PTX3 protein. We provide evidence for marked expression of PTX3 by VSMC induced by degraded lipoproteins, which may lead to an in situ vascular acute-phase reaction, contributing to the inflammatory pathogenesis of atherosclerosis.

Acute-Phase Reaction↗

PubMed2004

Phagocyte function.

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Calcium Signaling↗

PubMed2004

Virokines in the pathogenesis of cancer: focus on human herpesvirus 8.

During evolution, DNA viruses have captured a broad array of cellular genes involved in immune recognition and growth control that are nonessential for viral replication. The encoded virokines and viroceptors may act as mimetics or antagonists of their cellular homologues, altering signal transduction and cell communication towards survival of virus-infected cells. Human herpesvirus type 8 (HHV8) is the most recently identified human oncogenic herpesvirus. It is associated with Kaposi's sarcoma and lymphoproliferative diseases, such as pleural effusion lymphomas and multicentric Castleman's disease. HHV8 has captured a unique number of cellular regulatory genes, which redirect gene expression and cell growth, prevent apoptosis and immune recognition, and interfere with tumor suppressor gene function. HHV8 encodes a unique virokine, viral interleukin-6, which is particularly relevant for the pathogenesis of HHV8-associated tumors, since it participates in transformation and mediates autocrine and paracrine mitogenic and proinflammatory effects. Viral IL-6 differs fundamentally from human IL-6 in receptor engagement for signal transduction and thus constitutes a singular model to understand the facets of human and viral cytokine biology. We provide an overview of the role of virokines in cancer, with a particular focus on the differences of human and viral IL-6 in the pathophysiology of HHV8-associated tumors.

Animals↗

PubMed2002

Human herpesvirus 8-derived viral IL-6 induces PTX3 expression in Kaposi's sarcoma cells.

OBJECTIVE: To analyse if human herpesvirus 8 (HHV8)-derived viral interleukin-6 (vIL-6) has the capacity to activate Kaposi's sarcoma (KS) cells to elicit a local acute-phase response. DESIGN: Proinflammatory activation of KS cells was compared using vIL-6, human IL-6, as well as the complex of human IL-6 with the soluble IL-6 receptor, and expression of the novel acute-phase protein pentraxin-3 (PTX3) was analysed. METHODS: We established primary KS cell cultures from patients with AIDS-associated and classical KS and expressed recombinant HHV8-derived vIL-6 in COS-7 cells. Expression of PTX3 by vIL-6-stimulated KS cell cultures was analysed by quantitative real-time reverse transcriptase-polymerase chain reaction. Mitogenic effects of vIL-6 on the KS cells of distinct aetiology were compared by [3H]thymidine incorporation. RESULTS: We show that vIL-6 induced a marked and sustained expression of the novel acute-phase protein PTX3 in human primary KS cell cultures. vIL-6 directly activated KS cells, which uniquely expressed gp130, the signal-transducing subunit of the IL-6 receptor, but were negative for the IL-6-binding unit (IL-6R). In contrast, human IL-6 did not stimulate KS cells in the absence of the full IL-6R. Expression of PTX3 messenger RNA increased by more than 25-fold in vIL-6-stimulated KS cells after 24 h. Particularly after extended incubation with the virokine, vIL-6 mediated a pronounced mitogenic effect on KS cells. CONCLUSION: The induction of an extrahepatic acute-phase response by vIL-6-activated KS cells may contribute to local tissue damage and the attraction of inflammatory cells, and add to a more aggressive phenotype.

Acute-Phase Proteins↗