Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The majority of AIDS-related non-Hodgkin's lymphomas are clinically aggressive monoclonal B-cell Burkitt's lymphomas, large cell lymphomas, or immunoblastic lymphomas. In contrast, the lymphoid proliferations arising in solid organ transplant recipients, collectively referred to as posttransplantation lymphoproliferative disorders (PT-LPDs), represent a clinically and histopathologically heterogeneous group of Epstein-Barr virus (EBV)-driven B-cell proliferations of variable clonal composition. During a retrospective histopathologic review of lymphoid proliferations associated with human immunodeficiency virus (HIV) infection we identified 10 cases that morphologically resemble the polymorphic PT-LPDs. They arose in lymph nodes (five), lungs (two), and the parotid gland, perineum, and skin (one each). They exhibit a diffuse growth pattern and are composed of a polymorphic lymphoid cell population exhibiting a variable degree of plasmacytic differentiation, cytologic atypia, and numbers of atypical immunoblasts. A clonal B-cell population was detected by immunoglobulin heavy and light chain gene rearrangement and/or EBV terminal repeat analysis in 8 of the 10 (80%) cases by Southern blotting. The nongermline hybridizing bands were usually faint, however, suggesting that the clonal B-cell population represented only a subpopulation within the polymorphic lesion. Strong clonal rearrangement bands were present in one case in which there was clear morphologic evidence of transformation to diffuse large cell lymphoma. This case exhibited C-MYC, BCL-6, and p53 gene mutations. One other case exhibited a p53 gene mutation. The remaining eight cases lacked C-MYC, BCL-6, RAS, and p53 gene alterations. Clonal EBV infection was detected in 4 of the 10 (40%) lesions. Like EBV-containing PT-LPDs, all four EBV-positive HIV-associated polymorphic lesions were associated with type A EBV. The Kaposi's sarcoma-associated herpesvirus was detectable in two cases by polymerase chain reaction analysis, but not by Southern blotting. In situ hybridization demonstrated Kaposi's sarcoma-associated herpesvirus in some of the cytologically malignant-appearing cells. In conclusion, polymorphic B-cell lymphoproliferative disorders comparable morphologically and molecularly to those arising after solid organ transplantation also occur in association with HIV infection. As in the case of their polymorphic PT-LPD counterparts, their malignant status, biologic significance, and relationship to monomorphic B-cell lymphomas remain to be elucidated.
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PMID:Human immunodeficiency virus (HIV)-associated polymorphic lymphoproliferative disorders. 1260 85

The outcome of acquired immunodeficiency syndrome-related lymphomas (ARLs) has improved since the era of highly active antiretroviral therapy, but median survival remains low. We studied dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) with suspension of antiretroviral therapy in 39 newly diagnosed ARLs and examined protein expression profiles associated with drug resistance and histogenesis, patient immunity, and HIV dynamics and mutations. The expression profiles from a subset of ARL cases were also compared with a matched group of similarly treated HIV-negative cases. Complete remission was achieved in 74% of patients, and at 53 months median follow-up, disease-free and overall survival are 92% and 60%, respectively. Following reinstitution of antiretroviral therapy after chemotherapy, the CD4+ cells recovered by 12 months and the viral loads decreased below baseline by 3 months. Compared with HIV-negative cases, the ARL cases had lower bcl-2 and higher CD10 expression, consistent with a germinal center origin and good prognosis, but were more likely to be highly proliferative and to express p53, adverse features with standard chemotherapy. Unlike HIV-negative cases, p53 overexpression was not associated with a poor outcome, suggesting different pathogenesis. High tumor proliferation did not correlate with poor outcome and may partially explain the high activity of dose-adjusted EPOCH. The results suggest that the improved immune function associated with highly active antiretroviral therapy (HAART) may have led to a shift in pathogenesis away from lymphomas of post-germinal center origin, which have a poor prognosis. These results suggest that tumor pathogenesis is responsible for the improved outcome of ARLs in the era of HAART.
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PMID:Highly effective treatment of acquired immunodeficiency syndrome-related lymphoma with dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology. 1260 27

As part of an extensive multi-institutional DIANAIDS study focused on assessing the risk factors, natural history, diagnosis and follow-up of genital human papillomavirus (HPV) infections in HIV-infected women, the present communication reports a sub-cohort of 142 women (89 HIV+ and 48 HIV-), followed-up for a mean of 14.07 (+/-10.84) months to analyse the factors predicting the persistence and clearance of HPV infections (polymerase chain reaction [PCR] and sequencing) and cervical Papanicolaou (PAP) smear abnormalities, using both univariate (Kaplan-Meier) and multivariate (Cox) survival analysis. The appearance of new HPV infections during the follow-up was significantly more frequent in HIV-positive than in HIV-negative women, odds ratio (OR) 8.800 (95% confidence interval [CI]: 1.199-64.611), and also the clearance rate was significantly less frequent in HIV-positive than in HIV-negative women, 69.2% vs 22.8%, respectively (OR 0.330; 95% CI: 0.163-0.670). These two groups were also markedly different with respect to the clinical course of the cervical lesions, in the frequency of progressive disease (determined by PAP smear) was higher in HIV-positive group (12/89) than in HIV-negative women (2/52) (OR 3.506; 95% CI 0.816-15.055) (P = 0.055), in whom the disease regressed more frequently than in HIV-positive women (13.5% vs 7.9%) (OR 0.584; 95% CI 0.217-1.573). Using (1) HPV-positivity, (2) oncogenic HPV-type and (3) significant PAP smear abnormality at the end of follow-up as outcome measures, (1) was significantly (P < 0.001) predicted by the following variables in univariate analysis: age, mode of contraception, CD4 count, and HIV-positivity. The significant predictors of (2) were age and mode of contraception. The outcome measure (3) was significantly predicted by CD4 count, PAP smear abnormality and PCR status at entry. In the multivariate analysis, the significant independent predictive factors for HPV-positivity proved to be only the HIV status (P < 0.001), and PCR status at entry, p53 polymorphism at aa-72, oncogenic HPV type and significant PAP smear at entry remained independent predictors, with the significance level of P < 0.05. None of the significant predictors of oncogenic HPV type in univariate analysis retained their independent value in multivariate analysis. Oncogenic HPV type at entry proved to be an independent predictor of significant PAP smear (P < 0.05). The present results indicate that HIV-infected women, even on highly active antiretroviral therapy, demonstrate a more aggressive clinical course of cervical HPV infections, and fail to eradicate the disease more frequently than HIV-negative women. This persistence of HPV-positivity, oncogenic HPV type and significant PAP smear abnormality can be predicted by the results of PAP test and HPV typing in univariate analyses, and partly retain their independent predictive value also in multivariate analysis. Clearly, in addition to regular monitoring by PAP smear, HPV testing for the oncogenic HPV types seems to provide additional prognostic information in the management of cervical lesions in HIV-infected women.
Int J STD AIDS 2003 Jun
PMID:Factors predicting the persistence of genital human papillomavirus infections and PAP smear abnormality in HIV-positive and HIV-negative women during prospective follow-up. 1281 71

The incidence of NHL is greatly increased in HIV-infected individuals; malignant lymphoma is the second most common neoplasm that occurs in association with AIDS. The vast majority of neoplasms are clinically aggressive, monoclonal B-cell neoplasms that exhibit Burkitt's, immunoblastic, large cell, or transitional histopathology. Approximately 80% arise systemically (nodal or extranodal) and 20% arise as primary CNS lymphomas. A small proportion of neoplasms are body cavity-based, primary effusion lymphomas that are uniquely associated with KSHV infection. Recently, HIV-associated polymorphic lymphoproliferative disorders have been described as well. AIDS-related NHLs appear to exhibit distinctive clinical characteristics according to their histopathology and anatomic site of origin. Factors that contribute to lymphoma development include HIV-induced immunosuppression, impaired immune surveillance, cytokine release and deregulation, and chronic antigenic stimulation. This environment is associated with the development of oligoclonal B-cell expansions. The appearance of NHL is characterized by the presence of a monoclonal B-cell population that displays a variety of genetic lesions, including, for example, EBV infection, MYC gene rearrangement, BCL6 gene rearrangement, P53 mutations and deletions, and RAS gene mutations. The number and type of genetic lesions vary somewhat among AIDS-related NHLs according to their histopathologic category and anatomic site of origin. These findings suggest that more than one pathogenetic mechanism is operational in the development and progression of AIDS-related NHLs. Further work is necessary to develop a complete understanding of the etiology and pathogenesis of NHL in the setting of HIV infection. AIDS-related NHL is an important biologic model for investigating the development and progression of high-grade NHLs and NHLs that develop in immunedeficient hosts.
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PMID:Etiology and pathogenesis of AIDS-related non-Hodgkin's lymphoma. 1285 56

A number of recent studies have reported the detection of the ubiquitous human polyomavirus, JC virus (JCV), in samples derived from several types of neural as well as non-neural human tumors. The human neurotropic JCV was first identified as the etiologic agent of the fatal demyelinating disease, progressive multifocal leukoencephalopathy, which usually occurs in individuals with defects in cell-mediated immunity, including AIDS. However, upon mounting evidence of the oncogenic potential of the viral regulatory protein, T-antigen, and JCV's oncogenecity in a broad range of animal models, studies were initiated to determine its potential involvement in human carcinogenesis. Initially, the most frequently observed tumors in rodent models, including medulloblastoma, astrocytoma, glioblastoma, and other neural-origin tumors were analysed. These studies were followed by analysis of non-neural tumors such as colorectal carcinomas. In a subset of each tumor type examined, JC viral genomic DNA sequences could be detected by PCR and confirmed by Southern blot hybridization or direct sequencing. In a smaller subset of the tumors, the expression of T-antigen was observed by immunohistochemical analysis. Owing to the established functions of T-antigen including its ability to interact with tumor suppressor proteins such as Rb and p53, and its ability to influence chromosomal stability, potential mechanisms of JCV T-antigen-mediated cellular dysregulation are discussed. Further, as increasing evidence suggests that T-antigen is not required for maintenance of a transformed phenotype, a hit-and-run model for T-antigen-induced transformation is proposed.
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PMID:Human neurotropic polyomavirus, JCV, and its role in carcinogenesis. 1291 Feb 55

Kaposi's sarcoma-associated herpesvirus (KSHV) [or human herpesvirus 8 (HHV-8)] is the most frequent cause of malignancy among AIDS patients. KSHV and related herpesviruses have extensively pirated cellular cDNAs from the host genome, providing a unique opportunity to examine the range of viral mechanisms for controlling cell proliferation. Many of the viral regulatory homologs encode proteins that directly inhibit host adaptive and innate immunity. Other viral proteins target retinoblastoma protein and p53 control of tumor suppressor pathways, which also play key effector roles in intracellular immune responses. The immune evasion strategies employed by KSHV, by targeting tumor suppressor pathways activated during immune system signaling, may lead to inadvertent cell proliferation and tumorigenesis in susceptible hosts.
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PMID:Kaposi's sarcoma-associated herpesvirus immunoevasion and tumorigenesis: two sides of the same coin? 1452 93

Growth hormone (GH) is neuroprotective, presumably through its actions on GH receptor-mediated pathways. Here, we examined the effects of GH using in vitro and in vivo assays of human immunodeficiency virus (HIV)-induced neuronal injury. Neuronal cultures were in assays of neurotoxicity induced by supernatants from HIV-1 tat-transfected monocytoid cells (Tat supernatant). GH treatment reduced neuronal death compared with untreated cultures (p < 0.001), which was blocked by a GH receptor antagonist, B2036. Tat supernatant-induced p53 expression in neurons was also reduced by GH treatment. Expression of both p53 and GH receptor were increased in brain tissue from HIV-infected persons compared with controls (p < 0.05). Mice receiving intrastriatal implants of Tat supernatant and treated with GH showed less neurobehavioral abnormalities together with reduced neuroinflammation and neuronal injury compared with untreated animals (p < 0.01). Three acquired immunodeficiency syndrome-defined patients with neurocognitive impairment were serially evaluated during daily GH treatment showing a sustained improvement in neuropsychological performance (p < 0.01). GH prevents neuronal death through its actions on neurons involving a p53-mediated pathway and also improved in vivo neurological function, indicating that GH may have a role in the treatment of HIV-induced neurodegeneration.
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PMID:Growth hormone prevents human immunodeficiency virus-induced neuronal p53 expression. 1459 50

Association between the p53 codon 72 polymorphism and cervical cancer remains unresolved. We determined the association between the polymorphism and risk of human papillomavirus (HPV) persistence. The polymorphism was detected by restriction enzyme digestion following p53 amplification and HPV detection by the PGMY 09/11 primer set followed by reverse line blot hybridization: 3371 samples were analysed. HPV persistence was assessed on a subset of samples collected at baseline, four and 10 months (n =442). Highly significant differences were observed between ethnic groups (P <0.005). No associations were found between P53 arginine and cytological grade in women infected with any HPV or any oncogenic HPV, despite adjustment for ethnicity. These results were sustained even when HPV-negative women were used as controls. Persistence for any or oncogenic HPV infection was not associated with the polymorphism, irrespective or ethnicity adjustment. Our findings do not support a role for this polymorphism conferring elevated risk for HPV-related disease.
Int J STD AIDS 2003 Dec
PMID:Ethnic variation of the P53 codon 72 polymorphism, HPV persistence, and cervical cancer risk. 1467 86

Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 has been established as the etiological agent of Kaposi's sarcoma and certain AIDS-associated lymphomas. KSHV establishes latent infection in these tumors, invariably expressing high levels of the viral latency-associated nuclear antigen (LANA) protein. LANA is necessary and sufficient to maintain the KSHV episome. It also modulates viral and cellular transcription and has been implicated directly in oncogenesis because of its ability to bind to the p53 and pRb tumor suppressor proteins. Previously, we identified the LANA promoter (LANAp) and showed that it was positively regulated by LANA itself. Here, we present a detailed mutational analysis and define cis-acting elements and trans-acting factors for the core LANAp. We found that a downstream promoter element, TATA box, and GC box/Sp1 site at -29 are all individually required for activity. This architecture places LANAp into the small and unusual group of eukaryotic promoters that contain both the downstream promoter element and TATA element but lack a defined initiation site. Furthermore, we demonstrate that LANA regulates its own promoter via its C-terminal domain and does bind to a defined site within the core promoter.
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PMID:Regulation and autoregulation of the promoter for the latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus. 1474 22

Chloroquine and related anti-malarial drugs appear to promote apoptosis in T-cells by suppressing NF-kappa-B, which enhances the expression of anti-apoptotic proteins (e.g., Bcl-2). Thus, chloroquine has found applications in autoimmune diseases where it apparently facilitates apoptosis of abnormally persistent T-cell clones. The mode of action of chloroquine in prevention of malaria is not known, but it may be to minimize replication of the parasite in the liver cells, which occurs before invasion of the erythrocytes, by facilitating premature apoptosis of the infected host cells. After introduction of chloroquine in the 1950s world-wide for prophylactic use, chloroquine-resistant malaria emerged. Here it is hypothesized that concurrent with emergence of chloroquine-resistant malaria (presumably with enhanced anti-apoptotic capabilities), other intracellular parasites have evolved to enhance their ability to prevent apoptosis in host cells. Two examples of viral diseases that have emerged from areas of high incidence of chloroquine-resistant malaria are AIDS from HIV and SARS from coronavirus. The hypothesis holds that prophylactic exposure to pro-apoptotic chloroquine drugs caused natural selection for strains of viruses and other parasites that have enhanced anti-apoptotic abilities. When transmitted to host organisms that are not under the influence of the pro-apoptotic drug, the new "anti-apoptotic" strains may cause unexpected diseases. In the case of SARS, the coronavirus appears to have accessed a new niche where it proves to be lethal to its host. In the case of AIDS, the HIV (which has had a long-term symbiotic relationship with primates) has run amuck because the infected cells are now substantially more tolerant to the toxins (i.e., resistant to apoptosis) that they secrete than the uninfected bystander cells, which are not unusually resistant to apoptosis. A corollary to the hypothesis is that if the level of resistance to apoptosis in the infected cells were no higher than the level of resistance in the bystander cells, then the infected cells would preferentially kill themselves through apoptosis. It appears that in the case of HIV, the increased resistance to apoptosis is provided by expression of Bcl-2 and suppression of p53. Hence, drugs that suppresses Bcl-2 or restore p53 function might be effective in restoring the parity of resistance to apoptosis between infected and uninfected cells. Currently, an antisense drug targeting Bcl-2 (G3139/Genasense(TM), Genta, Inc.) is in late-stage cancer trials and may be on the market for those indications in months. It would be interesting to try these drugs against various intracellular parasites including HIV. This approach to prevent or eliminate active infections might be particularly attractive against a range of parasites (virus, bacteria, protozoa, fungus) when safe and effective vaccines are not available.
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PMID:Hypothesis links emergence of chloroquine-resistant malaria and other intracellular pathogens and suggests a new strategy for treatment of diseases caused by intracellular parasites. 1497 2


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