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Query: UMLS:C0001175 (AIDS)
 120,706 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Anal intraepithelial lesions (ASILs) are considered as precursors of anal cancer. The incidence of high-grade ASIL (HSIL) and progression of low-grade ASIL (LSIL) to HSIL are high in HIV-positive men. Endogenous cytokines, such as interferons (IFNs) play an important role in the regulation of proliferation and immune responses in epithelial cells, and thus, they might control the above-mentioned progression events. Accordingly, we determined mRNA levels of IFN-gamma and IFN-gamma receptors, levels of IFN-gamma receptor-associated kinases (JAK1 and TYK2) and signalling molecules (signal transducer and activator of transcription-1 [STAT1], STAT3, interferon-responsive-factor-1 [IRF-1] and IRF-2) as well as inhibitors of cytokine signalling (protein inhibitor of activated STAT1 [PIAS1] and suppressor of cytokine signalling 2 [SOCS2]) in biopsies of anal condylomas, LSILs as well as HSILs from HIV-positive individuals by a semi-quantitative reverse transcribed polymerase chain reaction (RT-PCR) method. We found that HSIL significantly differs in expression of these genes from LSIL and condylomas. Expression profile of HSIL samples showed activation of STAT3 signalling, probably accounting for the observed high levels of genes that support cellular proliferation (IRF-2, c-fos and c-myc). Decreases in levels of suppressors (IFN-gamma and IRF-1) and JAK1 kinase, but increases in levels of inhibitors of cytokine signalling (PIAS1 and SOCS2) might also contribute to the altered cytokine signalling in HSIL biopsies. These findings might reveal important molecular events associated with progression of LSIL to HSIL in HIV-infected men.
Int J STD AIDS 2001 Apr
PMID:The endogenous interferon system in anal squamous epithelial lesions with different grades from HIV-positive individuals. 1131 73

Selective serotonin reuptake inhibitors (SSRIs) are the treatment of choice for clinical depression and a range of anxiety-related disorders. They are well tolerated over extended periods with more than 50 million people worldwide benefiting from their use. Here we show that 3 structurally distinct SSRIs--fluoxetine, paroxetine, and citalopram--act directly on Burkitt lymphoma (BL) cells to trigger rapid and extensive programmed cell death. SSRIs unexpectedly stimulated calcium flux, tyrosine phosphorylation, and down-regulation of the c-myc and nm23 genes in Burkitt lymphoma cells remaining faithful to the biopsy phenotype. Resultant SSRI-induced apoptosis was preceded by caspase activation, poly(ADP-ribose) polymerase-1 (PARP-1) cleavage, DNA fragmentation, a loss of mitochondrial membrane potential, and the externalization of phosphatidylserine, and reversed by the overexpression of bcl-2. Normal peripheral blood mononuclear cells and tonsil B cells, whether resting or stimulated into cycle, were largely resistant to SSRI-induced death as were 5 non-BL lymphoid cell lines tested. We discuss these findings within the context of whether the SSRI class of antidepressants could find future application as potential therapeutics for the highly aggressive and-because of its association with AIDS-increasingly more common Burkitt lymphoma.
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PMID:Selective serotonin reuptake inhibitors directly signal for apoptosis in biopsy-like Burkitt lymphoma cells. 1251 26

Epstein-Barr virus (EBV) latently infects and immortalizes B lymphocytes and causes lymphoproliferative malignancies. We show here that the EBV nuclear antigen EBNA2 induces expression of the 2 chains of the interleukin-18 receptor (IL-18R) in Burkitt lymphoma (BL) cell lines and in nontransformed B cells. Activation of IL-18R expression by EBNA2 is independent of its interaction with the transcriptional repressor RBPJ kappa. It occurs in the absence of any other viral protein but requires de novo synthesis of cellular proteins. IL-18R induction is a highly specific function of EBNA2, because neither other EBV latent proteins nor the cellular proteins c-myc or Notch can exert this effect. Using cDNA microarray expression profiling, we find that the IL-18 receptor expressed in EBV-infected BL cells has signaling capacity, because IL-18 significantly modified gene expression. We report that EBNA2 expression is associated with IL-18R expression in vivo in EBV-positive B-lymphomas from AIDS patients.
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PMID:Epstein-Barr virus nuclear antigen 2 induces interleukin-18 receptor expression in B cells. 1549 55

Human monocytes/macrophages (M/M) are the major targets for human immunodeficiency virus type 1 (HIV-1) infection. To characterize the global effects of acute HIV-1 infection on gene expression in M/M, the expression levels of 550 host cell RNA transcripts in U937 human promonocytes at 2-3 days after HIV-1 infection were assessed using cDNA microarray analysis and were compared to those in the infected HUT78, a CD4+ T cell line. Confirmed by semiquantitative RT-PCR, our results showed that 12 genes were up-regulated and 26 genes were down-regulated in the infected U937 cells at 2-3 days post-infection, whereas 8 genes were up-regulated and 20 genes were down-regulated in the infected HUT78 cells at 2-3 days post-infection. These genes encode a host of proteins with divergent functions in a variety of cellular processes including apoptosis (FAS, Fas ligand, PIN, HSP90beta, bcl-2, bcl-x), cell signal transduction (Ras, RGS1, IRF-1, STAT3), receptor-mediated signaling transduction (CD71, CD69, CD3delta), cell cycle and growth (c-myc, cytokines, kinase), transcriptional regulation (EWS, CREB-2), and chemotaxis (beta-chemokines, RANTES), supporting the general effects of HIV-1 infection on cells of different origin. Although most identified genes were regulated similarly in both infected cell lines, differences in gene regulation, such as c-myc, CD71, CD69, and beta-chemokines, between the two infected cell lines were also identified in this study. These differences may further our understanding of the pathogenicity of HIV and enable the discovery of novel therapeutic approach for AIDS.
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PMID:HIV-1 infection initiates changes in the expression of a wide array of genes in U937 promonocytes and HUT78 T cells. 1588 42

Morphologic features of Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) overlap. No single phenotypic marker or molecular abnormality is pathognomonic. We tested a panel of 8 germinal center (GC) and activated B-cell (ABC) markers for their ability to separate BL and DLBCL. We diagnosed 16 BL and 39 DLBCL cases from 21 patients with AIDS and 34 without AIDS based on traditional morphologic criteria, Ki-67 proliferative index, and c-myc rearrangement (fluorescence in situ hybridization). After immunohistochemically staining tissue microarrays of BL and DLBCL for markers of GC (bcl-6, CD10, cyclin H) and ABC (MUM1, CD138, PAK1, CD44, bcl-2), we scored each case for the percentage of positive cells. Hierarchical clustering yielded 2 major clusters significantly associated with morphologic diagnosis (P < .001). For comparison, we plotted the sum of the GC scores and ABC scores for each case as x and y data points. This revealed a high-GC/low-ABC group and a low-GC/high-ABC group that were associated significantly with morphologic diagnosis (P < .001). Protein expression of multiple GC and ABC markers can separate BL and DLBCL.
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PMID:Germinal center and activated b-cell profiles separate Burkitt lymphoma and diffuse large B-cell lymphoma in AIDS and non-AIDS cases. 1620 84

Burkitt lymphoma (BL), a tumor occurring in endemic, sporadic and AIDS-associated forms, is the classic example of a human malignancy whose pathogenesis involves a specific cellular genetic change, namely, a chromosomal translocation deregulating expression of the c-myc oncogene, complemented in many cases by the action of an oncogenic virus, the Epstein-Barr virus (EBV). Here we review recent work in two complementary areas of research: (1) on cellular genetic changes that occur in addition to the c-myc translocation in BL, in particular the capacity of p53/ ARF pathway breakage or of c-myc mutation to decouple the pro-proliferative effects of c-myc deregulation from its pro-apoptotic effects; and (2) on a postulated role for EBV in BL pathogenesis, through adopting restricted forms of virus latent gene expression that remain compatible with the c-myc-driven growth program but offer the tumor additional protection from apoptosis. We stress the many fundamental questions that remain to be resolved and, in that regard, highlight the general lessons that might be learned through understanding how two other infectious agents, malaria and HIV, dramatically enhance BL incidence.
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PMID:Burkitt lymphoma: revisiting the pathogenesis of a virus-associated malignancy. 1802 41

Plasmablastic lymphoma (PBL) is a rare acquired immunodeficiency syndrome-associated non-Hodgkin's lymphoma (AIDS-NHL), with predilection for the mucosa of oral cavity. It usually has a plasmablastic morphology, expressing plasma cell-associated antigens with weak or absent expression of B-cell-associated markers. To further define the immunophenotypic and molecular genetics of these tumors, we investigated two cases of plasmablastic lymphomas of the head and neck for c-myc gene rearrangement and immunoglobulin heavy chain (IgV(H)) hypermutation status. For the first time we report a case of AIDS-related PBL that, by fluorescence in situ hybridization (FISH), shows a c-myc gene rearrangement. Although current literature suggests that most cases of c-myc gene rearranged AIDS-NHL are Burkitt's lymphoma, our case has an immunophenotype characteristic for PBL. In this case, IgV(H) hypermutation analysis showed a somatic hypermutation, indicative of germinal center transit. The concurrent B-cell immunophenotype of BCL-6(-)/CD138(+)/MUM-1(+) also suggests a post-germinal center B-cell origin of this lymphoma. The immunophenotype of our second case (BCL-6(-)/CD138(+)/MUM-1(+)) also suggests a post-germinal center B-cell origin. However, IgV(H) hypermutation analysis was not possible in this case.
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PMID:Plasmablastic lymphoma of head and neck: report of two new cases and correlation with c-myc and IgVH gene mutation status. 2061 67

Plasmablastic lymphoma (PBL) is a rare, highly aggressive subtype of non-Hodgkin lymphoma with plasma-cell differentiation occurring typically in immune-suppressed patients such as those with AIDS. This study reports the establishment and characterization of a new cell line, PBL-1, derived from a patient with AIDS-associated PBL. Morphological assessment of PBL-1 indicated plasma-cell differentiation with a CD20(-) CD38(+) CD138(+) immunophenotype and IgH/c-myc translocation. The cell line harbours Epstein-Barr virus, but a 52.7-kbp length defect was identified in its genome, resulting in no expression of viral microRNAs encoded in the BamHI-A Rightward Transcript region. Importantly, supplementation of culture medium with >5 ng/mL of interleukin-6 (IL-6) was required for PBL-1 growth. Starvation of IL-6 or addition of tocilizumab, an inhibitory antibody for the IL-6 receptor, induced apoptosis of PBL-1. Transduction of IL-6 into PBL-1 by lentivirus vector induced autologous growth without IL-6 supplementation of culture medium. These data indicate the IL-6 dependency of PBL-1 for proliferation and survival. mTOR inhibitors induced cell death effectively, suggesting mTOR in the IL-6 signalling pathway is a potential therapeutic target for PBL. This established PBL cell line will be a useful tool to further understand the pathophysiology of PBL and aid the future development of PBL treatment.
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PMID:Interleukin-6-dependent growth in a newly established plasmablastic lymphoma cell line and its therapeutic targets. 2886 May 65

Kaposi's sarcoma (KS) herpesvirus (KSHV) causes KS, an angiogenic AIDS-associated spindle-cell neoplasm, by activating host oncogenic signaling cascades through autocrine and paracrine mechanisms. Tyrosine kinase receptor (RTK) proteomic arrays, identified PDGF receptor-alpha (PDGFRA) as the predominantly-activated RTK in KSHV-induced mouse KS-tumors. We show that: 1) KSHV lytic replication and the vGPCR can activate PDGFRA through upregulation of its ligands PDGFA/B, which increase c-myc, VEGF and KSHV gene expression in infected cells 2) KSHV infected spindle cells of most AIDS-KS lesions display robust phospho-PDGFRA staining 3) blocking PDGFRA-signaling with N-acetyl-cysteine, RTK-inhibitors Imatinib and Sunitinib, or dominant-negative PDGFRA inhibits tumorigenesis 4) PDGFRA D842V activating-mutation confers resistance to Imatinib in mouse-KS tumorigenesis. Our data show that KSHV usurps sarcomagenic PDGFRA signaling to drive KS. This and the fact that PDGFRA drives non-viral sarcomas highlights the importance for KSHV-induced ligand-mediated activation of PDGFRA in KS sarcomagenesis and shows that this oncogenic axis could be successfully blocked to impede KS tumor growth.
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PMID:KSHV-induced ligand mediated activation of PDGF receptor-alpha drives Kaposi's sarcomagenesis. 2998 58


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