Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fifteen men with HIV-associated Kaposi's sarcoma (KS) and poor risk disease according to the TIS staging were enrolled in a phase II trial of oral 13-cis-retinoic acid. The median CD4 cell count was 95 cells/microl (range 7-260) and 6 had prior AIDS-defining opportunistic infections. One patient was withdrawn on account of cutaneous toxicity. Evaluation was by AIDS Clinical Trials Group (ACTG)1 defined assessment. One patient achieved a partial response and remains on treatment in partial remission. Thus the overall response rate is 7% (95% confidence interval 0-23%). A further 5 patients had stable disease (38%: 95% confidence interval 7-64%). The overall low activity, considerable toxicity and limited cosmetic benefit even in responding patients limits the value of this approach in KS. However, this treatment strategy may be more rewarding in early good risk KS.
Int J STD AIDS 1997 Aug
PMID:Phase II trial of 13-cis-retinoic acid for poor risk HIV-associated Kaposi's sarcoma. 925 1

A retrospective study was performed to assess the efficacy and low mucosal toxicity of intracavitary contact X-ray therapy (ICRT), a proposed treatment of small/medium sized lesions of oral HIV-associated Kaposi's sarcoma (HIV-KS). Twenty-six patients with histologically confirmed oral HIV-KS underwent ICRT in the period 1986-1995. No patient received antiblastic or interferon therapy during the radiotherapy or follow-up periods. ICRT was performed according to the usual technical modalities of contact X-ray therapy, but the end of the source of ionizing radiations was introduced into the oral cavity. The total doses administered ranged from 10 to 50 Gy per field, in one or two weekly fractions of 5 Gy each. The follow-up ranged from 1 to 44 months (mean 7.5 months). Complete remission was obtained in 20 cases (76.92%), partial remission in 6 (23.08%) and relapse in one case (3.84%). Pain was relieved in all cases. Mucosal reaction was mild and did not result in any interruption of treatment. Our data suggest that ICRT is an effective and well tolerated treatment. It can be used in the management of oral HIV-KS instead of external radiotherapy, provided that the size and the location of the lesions and the conformation of the palate are suitable to this technique.
Int J STD AIDS 1997 Sep
PMID:Intracavitary contact X-ray therapy of oral HIV-associated Kaposi's sarcoma. 929 48

Normal human dermis contains mesenchymal cells that are generally referred to as fibroblasts. However the relationships between fibroblasts and endothelial cells with respect to the types of spindle-shaped cells that are present in cultures obtained from tumor bearing-skin is unclear. To explore the potential heterogeneity amongst dermal-derived cells that grow in culture with a spindle-shaped morphology, we compared the immunophenotype and growth characteristics of several types of cells. Besides dermal fibroblasts and microvascular endothelial cells derived from normal adult skin, we also studied large vessel-derived endothelial cells, and spindle-shaped cells derived from three different tumor-bearing dermal-based neoplasms. Kaposi's sarcoma (KS), dermatofibroma (DF), and dermatofibrosarcoma protuberans (DFSP). A broad panel of eight different antibodies were used to immunophenotype the multi-passaged cultured cells. Spindle-shaped cells from all three neoplasms could be distinguished from the normal skin derived fibroblasts by their constitutive expression of factor XIIIa, and the gamma-interferon induced expression of VCAM-1. All seven types of cultured cells stained positive for s-actin and proline-4-hydroxylase, and none of the cells expressed CD34. Both large and small-vessel derived endothelial cells expressed factor VIII, ELAM-1, and VCAM-1. Using two different types of growth media, significant differences were also observed amongst these cultured cell types. Spindle-shaped cells from DFSP did not grow in DMEM containing 10% fetal bovine serum (DMEM-FBS); but they proliferated in KS cell growth medium (KSGM). Spindle-shaped cells from DF grew best in KSGM, but not in DMEM-FBS. KS tumor cells grew well in KSGM, but not in DMEM-FBS. Fibroblasts proliferated in DMEM-FBS, but failed to grow in KSGM; and even when pre-treated with conditioned medium from a transformed KS cell line (i.e. SLK cells), no fibroblast proliferation could be induced in KSGM. These results indicate that KS cell line (i.e. SLK cells), no fibroblast proliferation could be induced in KSGM. These results indicate that even though dermal-derived cells can have an identical spindle-shape by light microscopy, significant heterogeneity can be defined amongst such cells from normal and tumor-bearing human skin. Having established culture conditions to propagate these different cell types and phenotypic criteria to distinguish them from one another, will provide new research opportunities to explore the function and ontogeny of the diverse mesenchymal cells that take on a spindle-shaped morphology in culture.
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PMID:Phenotype and proliferation characteristics of cultured spindle-shaped cells obtained from normal human skin and lesions of dermatofibroma, Kaposi's sarcoma, and dermatofibrosarcoma protuberans: a comparison with fibroblast and endothelial cells of the dermis. 943 8

Kaposi's sarcoma (KS) spindle cell growth and spread have been reported to be modulated by various cytokines as well as the human immunodeficiency virus (HIV) gene product Tat. Recently, HIV-1 Tat has been shown to act like a cytokine and bind to the Flk-1/KDR receptor for the vascular endothelial growth factor A (VEGF-A), which is expressed by KS cells. We have characterized signal transduction pathways stimulated by HIV-1 Tat upon its binding to surface receptors on KS cells. We observed that stimulation in KS 38 spindle cells resulted in tyrosine phosphorylation and activation of the Flk-1/KDR receptor. We also report that HIV-1 Tat treatment enhanced the phosphorylation and association of proteins found in focal adhesions, such as the related adhesion focal tyrosine kinase RAFTK, paxillin, and p130(cas). Further characterization revealed the activation of mitogen-activated protein kinase, c-Jun amino-terminal kinase (JNK), and Src kinase. HIV-1 Tat contains a basic domain which can interact with growth factor tyrosine kinase receptors and a classical RGD sequence which may bind to and activate the surface integrin receptors for fibronectin and vitronectin. We observed that stimulation of KS cells with basic as well as RGD sequence-containing Tat peptides resulted in enhanced phosphorylation of RAFTK and activation of MAP kinase. These studies reveal that Tat stimulation activates a number of signal transduction pathways that are associated with cell growth and migration.
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PMID:Human immunodeficiency virus tat modulates the Flk-1/KDR receptor, mitogen-activated protein kinases, and components of focal adhesion in Kaposi's sarcoma cells. 962 Oct 77

Kaposi's sarcoma (KS) is the most frequent malignancy occurring in HIV-positive individuals. AIDS-KS is a more aggressive disease than the classical form, frequently having a rapid clinical course with numerous serious complications. Current systemic treatments for KS, such as chemotherapy and the administration of biological modifiers, are complicated by both the drug resistance of the tumor and the dose-limiting toxicity of the reagents. The relative accessibility of many KS lesions makes the disease a particularly attractive candidate for in vivo gene therapy protocols. In this regard, we are interested in delivering conditionally toxic suicide and/or antiangiogenic vectors to accomplish targeted cell death selectively in AIDS-KS cells. To this end, we examined both cationic lipid- and adenoviral-mediated DNA transfection methods. Using the firefly luciferase reporter gene, we optimized numerous variables known to be important in lipid-mediated DNA transfection, including lipid formulation, the amount of lipid and DNA, lipid/DNA ratio, and cell concentration. Under optimal transfection conditions, approximately 5-25% of KS cells expressed the introduced DNA sequences. Adenoviral-mediated DNA delivery was more efficient than lipid delivery in 4 of 5 primary KS cell lines. Two of the lines (RW248 and RW376) were transduced by adenovirus at frequencies approaching 100%; two cell lines (CVU-1 and RW80) gave efficiencies of 20-35%. Two immortalized KS cell lines (KS Y-1 and KS SLK) were poorly infected, giving a transduction efficiency of <5%. These findings demonstrate that gene transfer into AIDS-KS cells is feasible, and suggest that vector strategies may be permissive for translating gene therapy approaches for the disease.
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PMID:Lipid- and adenoviral-mediated gene transfer into AIDS-Kaposi's sarcoma cell lines. 962 96

The objectives of this study were to describe the clinical and radiological features at presentation, and the natural history of HIV-related bronchopulmonary Kaposi's sarcoma. A retrospective review of medical records and chest radiographs was performed in 106 HIV-infected homosexual men with bronchopulmonary Kaposi's sarcoma diagnosed at bronchoscopy between September 1988 and November 1994. The majority of patients had evidence of advanced HIV disease at diagnosis (median CD4 cell count was 15 x 10(6)/l, range 0-288), and 93% had had a diagnosis of cutaneous Kaposi's sarcoma for a median duration of 11 months prior to diagnosis of their bronchopulmonary disease. The most frequent symptoms at presentation were cough (92%), dyspnoea (69%), pleuritic pain (20%), haemoptysis (13%) and wheezing (10%). The most common radiological finding in 73% of our series was of poorly defined and confluent opacities, with predominant middle and lower zone involvement. Median survival was 4 months (range 0-37 months) from diagnosis and 9 months (range 1-25) from the onset of symptoms. Treatment with either chemotherapy or radiotherapy was associated with a significantly reduced risk of death (hazards ratio (HR)=0.48, 95% CI=0.26-0.87). Factors associated with a poor survival, after adjustment for treatment effect were older age (HR=1.79, 95% CI=1.22-2.84) for each 10-year increase in age; a history of pleuritic pain (HR=2.97, 95% CI=1.39-6.32); presence of pleural effusion on X-ray (HR=2.01, 95% CI=1.13-3.59) and a prior diagnosis of cutaneous Kaposi's sarcoma (HR=1.8, 95% CI=1.00, 3.24). Bronchopulmonary Kaposi's sarcoma occurs mainly in patients with advanced HIV disease and a prior history of cutaneous disease. Survival is poor, and adverse prognostic factors include older age at diagnosis and the presence of pleural disease.
Int J STD AIDS 1998 Sep
PMID:Bronchopulmonary Kaposi's sarcoma in 106 HIV-1 infected patients. 976 35

The aim of this study was to compare cancer incidence in a cohort of HIV-infected patients with the incidence rates in the population of South East England. Data collected for a retrospective cohort study of 2048 HIV-infected patients were analysed to examine the incidence of cancer. Cases of cancer occurring in South East England from 1985-1995 were obtained from the Thames Cancer Registry. Standardized incidence ratios were calculated by comparison of the observed number of cases for each cancer type in HIV-infected non-Africans with the numbers expected, calculated from the age and sex specific registration rates for the South East England population using person-years of observation. The crude incidence rates of cancer were calculated for HIV-infected Africans. The incidence of non-AIDS defining cancers such as Hodgkin's disease (standardized incidence ratio 22; 95% CI: 3-80) and anal cancer (standardized incidence ratio 125; 95% CI: 3-697) were significantly increased for non-African males with HIV disease. Anal cancer was also significantly increased for non-African females (standardized incidence ratio 1667; 95% CI: 43-9287). Kaposi's sarcoma (KS) was the commonest cancer among HIV-infected Africans and males had an incidence which was nearly 3 times that of females. There is evidence to suggest that the risks for other non-AIDS defining cancers were significantly increased in persons with HIV disease which may have implications for HIV/AIDS surveillance.
Int J STD AIDS 1999 Jan
PMID:Risk of cancer in patients with HIV disease. London African HIV/AIDS Study Group. 1021 28

During physiological stimulation of resting T-cells, at least two activation signals by antigen presenting cells are required. Besides the first antigen-specific signal, the second costimulatory signal involves CD80 and CD86 expressed by the antigen presenting cell. These costimulatory molecules have been suggested to be of clinical relevance in many different autoimmune and malignant disease processes. We previously observed that tumor cells in Kaposi's sarcoma (a common AIDS-related cutaneous neoplasm) completely lack both CD80 and CD86, and these tumor cells fail to stimulate T-cell proliferation. In this study, using a Kaposi's sarcoma tumor cell line designated SLK, various stable transfected cell lines were produced. Tumor cells that were either singly positive for either CD80 or CD86, as well as a double-positive cell line, were examined for their ability to induce T-cell activation, T-cell proliferation, and cytokine production profiles. Compared to the parental double-negative tumor cell line, the CD80-positive cells, but not the CD86-positive tumor cells, induced significant T-cell activation and proliferation. Tumor cells expressing both CD80 and CD86 also induced T-cell activation. After stimulation by the transfected tumor cells, T-cells produced a Th-1 type cytokine production profile with increased IL-2 and IFN-gamma levels. These results demonstrate that Kaposi's sarcoma tumor cells lacking co-stimulatory molecules cannot induce T-cell activation; however, if they express CD80, they can induce peripheral blood T-cell proliferation, and there is a differential response as expression of CD86 did not have the same immunostimulatory effect.
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PMID:Expression of costimulatory molecules CD80 and/or CD86 by a Kaposi's sarcoma tumor cell line induces differential T-cell activation and proliferation. 1037 Mar 81

Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8) encodes a structural and functional homologue of human IL-6 called viral IL-6 (vIL-6). Expression of vIL-6 in KSHV-related lymphoproliferative disorders has been implicated in their pathogenesis. vIL-6 has been shown to mimic a number of IL-6 activities including stimulating the growth of IL-6 dependent cell lines and activating the JAK1 and STAT1/3 pathway in HepG2 cells. However, IL-6 and vIL-6 display differences in receptor usage that may give rise to underlying qualitative and quantitative differences in the signaling pathways utilized. While IL-6 has an absolute requirement for both the IL-6 Ralpha and the gp130 subunits, vIL-6 appears to require only gp130. In addition to JAK1 and STAT1/3 pathways, IL-6 activates multiple other pathways including the direct activation of STAT 5 by JAK1, the Ras-MAP kinase cascade and a novel H7-sensitive pathway. In this study we examined whether vIL-6 is capable of signaling via distinct IL-6 response elements (IL-6 RE) under the control of these different pathways. We show that vIL-6 activates both STAT1/3- and STAT5-dependent Type II IL-6 REs. In addition, vIL-6 induces transcriptional activation via a Type I IL-6 RE that binds C/EBP, indicative of Ras-MAP kinase pathway induction. Furthermore, vIL-6 is capable of activating the IL-6 response element in the c-jun promoter (RE-IL-6). vIL-6 induced activation of JRE-IL-6 requires both the Ets- and Cre-like sites, suggesting that vIL-6 is capable of stimulating the same novel serine/threonine kinase mediated pathway as IL-6. These results demonstrate that vIL-6 can stimulate all of the known IL-6-induced signaling pathways. Therefore, vIL-6 could potentially contribute to KSHV-related disease progression by continued activation of IL-6-stimulated growth and anti-apoptotic pathways even when cells attempt to protect themselves from IL-6 over-stimulation by downmodulating their IL-6Ralpha subunits.
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PMID:KSHV-encoded viral IL-6 activates multiple human IL-6 signaling pathways. 1056 91

Oncostatin M (OSM), a cytokine first identified from activated monocytes and T lymphocytes, is one of the most potent autocrine growth factor for AIDS and Kaposi's sarcoma. Little is known about the effects of OSM on normal vascular cells. We thus exposed human aortic smooth muscle cells (hASMCs) to OSM, examined cell proliferation and morphology, and determined interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2) expression. OSM had a weak antiproliferative effect. After a 4-day incubation with 100 ng/mL OSM, cell count decreased to 69+/-3% of control. However, OSM induced striking changes in hASMC morphology, characterized by a polyclonal shape, in contrast to the spindle morphological feature of control hASMCs. OSM stimulated the release of IL-6 by hASMCs in a dose-dependent way; after a 48-hour exposure, values were 8.5+/-0.7, 29.7+/-3.5, 50.9+/-4.4, and 73.8+/-7.6x10(3) U/mL (n=6) at OSM concentrations of 0, 1, 10, and 100 ng/mL, respectively. OSM induced marked expression of COX-2 protein and mRNA. Leukemia inhibitory factor had no effect on hASMCs, indicating that OSM effects on hASMCs were mediated by the OSM type II receptor and not by the leukemia inhibitory factor receptor. OSM used the JAK/STAT signaling pathway, as demonstrated by rapid phosphorylation of JAK1 and specific activation of STAT1. Interestingly, OSM acted in synergy with IL-1beta on IL-6 production and COX-2 expression. In conclusion, OSM is a novel regulator of human smooth muscle cell functions, acting in concert with IL-1beta, and OSM may play a role in major vascular diseases such as atherosclerosis.
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PMID:Oncostatin M induces interleukin-6 and cyclooxygenase-2 expression in human vascular smooth muscle cells : synergy with interleukin-1beta. 1059 Feb 38


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