Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatitis C virus (HCV) is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Studies of HCV replication and pathogenesis have so far been hampered by the lack of an efficient tissue culture system for propagating HCV in vitro. Although HCV is primarily a hepatotropic virus, an increasing body of evidence suggests that HCV also replicates in extrahepatic tissues in natural infection. In this study, we established a B-cell line (SB) from an HCV-infected non-Hodgkin's B-cell lymphoma. HCV RNA and proteins were detectable by RNase protection assay and immunoblotting. The cell line continuously produces infectious HCV virions in culture. The virus particles produced from the culture had a buoyant density of 1.13 to 1.15 g/ml in sucrose and could infect primary human hepatocytes, peripheral blood mononuclear cells (PBMCs), and an established B-cell line (Raji cells) in vitro. The virus from SB cells belongs to genotype 2b. Single-stranded conformational polymorphism and sequence analysis of the viral RNA quasispecies indicated that the virus present in SB cells most likely originated from the patient's spleen and had an HCV RNA quasispecies pattern distinct from that in the serum. The virus production from the infected primary hepatocytes showed cyclic variations. In addition, we have succeeded in establishing several Epstein-Barr virus-immortalized B-cell lines from PBMCs of HCV-positive patients. Two of these cell lines are positive for HCV RNA as detected by reverse transcriptase PCR and for the nonstructural protein NS3 by immunofluorescence staining. These observations unequivocally establish that HCV infects B cells in vivo and in vitro. HCV-infected cell lines show significantly enhanced apoptosis. These B-cell lines provide a reproducible cell culture system for studying the complete replication cycle and biology of HCV infections.
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PMID:Establishment of B-cell lymphoma cell lines persistently infected with hepatitis C virus in vivo and in vitro: the apoptotic effects of virus infection. 1252 48

Hepatitis C virus (HCV) infection is frequently associated with the development of hepatocellular carcinomas and non-Hodgkin's B-cell lymphomas. Previously, we reported that HCV infection causes cellular DNA damage and mutations, which are mediated by nitric oxide (NO). NO often damages mitochondria, leading to induction of double-stranded DNA breaks (DSBs) and accumulation of oxidative DNA damage. Here we report that HCV infection causes production of reactive oxygen species (ROS) and lowering of mitochondrial transmembrane potential (DeltaPsi(m)) in in vitro HCV-infected cell cultures. The changes in membrane potential could be inhibited by BCL-2. Furthermore, an inhibitor of ROS production, antioxidant N-acetyl-L-cysteine (NAC), or an inhibitor of NO, 1,400W, prevented the alterations of DeltaPsi(m). The HCV-induced DSB was also abolished by a combination of NO and ROS inhibitors. These results indicated that the mitochondrial damage and DSBs in HCV-infected cells were mediated by both NO and ROS. Among the HCV proteins, core, E1, and NS3 are potent ROS inducers: their expression led to DNA damage and activation of STAT3. Correspondingly, core-protein-transgenic mice showed elevated levels of lipid peroxidation and oxidatively damaged DNA. These HCV studies thus identified ROS, along with the previously identified NO, as the primary inducers of DSBs and mitochondrial damage in HCV-infected cells.
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PMID:Hepatitis C virus triggers mitochondrial permeability transition with production of reactive oxygen species, leading to DNA damage and STAT3 activation. 1680 25

Hepatitis C virus (HCV) is a hepatotropic virus causing hepatocellular damage and chronic liver inflammation that progressively can lead to cirrhosis and hepatocellular carcinoma (HCC). HCV is also lymphotropic, as demonstrated by its capacity to replicate in lymphocytes, by the recurrent detection of organ- and non-organ-specific autoantibodies in HCV-infected patients, and by the strong association found between HCV infection and type II mixed cryoglobulinemic syndrome (MC-II). Moreover, accumulating data ascribe an etiopathogenetic role in the development of B cell non-Hodgkin's lymphomas (NHL) to HCV. All these findings account for the profound effect of HCV infection in the host's immune system. The unique virus-host interactions that culminate in the generation and sustained production of autoantibodies and cryoglobulins have not been delineated. It appears that chronic antigenic stimulation could cause the emergence of specific B cell clones that produce cryoglobulins; moreover, B cell activation and/or deregulation could originate as a result of HCV binding to CD81 tetraspanin or as a consequence of its ability to replicate in B cells. In a previous study we demonstrated that, in MC-II HCV-positive patients, cryoprecipitated monoclonal IgMs, and B cell receptors (BCR) of overexpanded B cell clones share the same combinatory region. Moreover, these IgMs were reactive against both the Fc region of human IgG and the HCV-NS3 antigen. NS3 and Fc epitopes have been idengified by epitope excision approach. One of the idengified NS3 epitopes has been used to immunize a mouse and the monoclonal antibody obtained showed the same cross-reactivity as patients' IgMs. The characterization of antigenic specificity of this antibody may be useful to idengify antigens that can stimulate B cell proliferation in HCV-infected individuals.
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PMID:HCV-related immunocytoma and type II mixed cryoglobulinemia-associated autoantigens. 1791 27

Bin3 encodes an evolutionarily conserved and ubiquitously expressed member of the BAR superfamily of curved membrane and GTPase-binding proteins, which includes the BAR, PCH/F-BAR, and I-BAR adapter proteins implicated in signal transduction and vesicular trafficking. In humans, Bin3 maps to chromosome 8p21.3, a region widely implicated in cancer suppression that is often deleted in non-Hodgkin's lymphomas and various epithelial tumors. Yeast studies have suggested roles for this gene in filamentous actin (F-actin) organization and cell division but its physiologic functions in mammals have not been investigated. Here we report that homozygous inactivation of Bin3 in the mouse causes cataracts and an increased susceptibility to lymphomas during aging. The cataract phenotype was marked by multiple morphologic defects in lens fibers, including the development of vacuoles in cortical fibers and a near total loss of F-actin in lens fiber cells but not epithelial cells. Through 1 year of age, no other phenotypes were apparent; however, by 18 months of age, Bin3(-/-) mice exhibited a significantly increased incidence of lymphoma. Bin3 loss did not affect normal cell proliferation, F-actin organization, or susceptibility to oncogenic transformation. In contrast, it increased the proliferation and invasive motility of cells transformed by SV40 large T antigen plus activated ras. Our findings establish functions for Bin3 in lens development and cancer suppression during aging. Further, they define Bin3 as a candidate for an unidentified tumor suppressor that exists at the human chromosome 8p21.3 locus.
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PMID:Bin3 deletion causes cataracts and increased susceptibility to lymphoma during aging. 1833 47

Mutations in the ras family genes (K-ras mainly) represent a common event in lung tumorigenesis which is frequently associated with poor clinical outcome. In order to investigate whether K-ras mutations are detectable in cytological material obtained from patients with lung cancer, 37 cytological specimens (16 fine needle aspiration and 21 bronchoscopy) were assessed for codon 12 point mutations in the H-, K- and N-ras genes by combined polymerase chain reaction-restriction fragment length polymorphism. K-ras codon 12 point mutations were found in 8 out of 37 (22%) specimens while no mutations were found in the H-ras and N-ras genes. Mutations were found in 27% (3 out of 11) of adenocarcinomas while in squamous cell carcinomas the incidence of mutations was 18% (3 out of 17). In addition, a K-ras codon 12 point mutation was found in one (12%) among 8 small cell carcinomas and in the only Hodgkin's lymphoma with metastasis in the lung. Our results are in agreement with previous results that recognise high incidence of K-ras activation in lung carcinomas, and indicate that detection of mutant ras alleles is possible in cytological material.
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PMID:Detection of activating mutations in the ras family genes in cytological specimens from lung-tumors. 2159 13

Elucidation of estrogen carcinogenesis required a few fundamental discoveries made by studying the mechanism of carcinogenesis of polycyclic aromatic hydrocarbons (PAH). The two major mechanisms of metabolic activation of PAH involve formation of radical cations and diol epoxides as ultimate carcinogenic metabolites. These intermediates react with DNA to yield two types of adducts: stable adducts that remain in DNA unless removed by repair and depurinating adducts that are lost from DNA by cleavage of the glycosyl bond between the purine base and deoxyribose. The potent carcinogenic PAH benzo[a]pyrene, dibenzo[a,l]pyrene, 7,12-dimethylbenz[a]anthracene and 3-methylcholanthrene predominantly form depurinating DNA adducts, leaving apurinic sites in the DNA that generate cancer-initiating mutations. This was discovered by correlation between the depurinating adducts formed in mouse skin by treatment with benzo[a]pyrene, dibenzo[a,l]pyrene or 7,12-dimethylbenz[a]anthracene and the site of mutations in the Harvey-ras oncogene in mouse skin papillomas initiated by one of these PAH. By applying some of these fundamental discoveries in PAH studies to estrogen carcinogenesis, the natural estrogens estrone (E1) and estradiol (E2) were found to be mutagenic and carcinogenic through formation of the depurinating estrogen-DNA adducts 4-OHE1(E2)-1-N3Ade and 4-OHE1(E2)-1-N7Gua. These adducts are generated by reaction of catechol estrogen quinones with DNA, analogously to the DNA adducts obtained from the catechol quinones of benzene, naphthalene, and the synthetic estrogens diethylstilbestrol and hexestrol. This is a weak mechanism of cancer initiation. Normally, estrogen metabolism is balanced and few estrogen-DNA adducts are formed. When estrogen metabolism becomes unbalanced, more catechol estrogen quinones are generated, resulting in higher levels of estrogen-DNA adducts, which can be used as biomarkers of unbalanced estrogen metabolism and, thus, cancer risk. The ratio of estrogen-DNA adducts to estrogen metabolites and conjugates has repeatedly been found to be significantly higher in women at high risk for breast cancer, compared to women at normal risk. These results indicate that formation of estrogen-DNA adducts is a critical factor in the etiology of breast cancer. Significantly higher adduct ratios have been observed in women with breast, thyroid or ovarian cancer. In the women with ovarian cancer, single nucleotide polymorphisms in the genes for two enzymes involved in estrogen metabolism indicate risk for ovarian cancer. When polymorphisms produce high activity cytochrome P450 1B1, an activating enzyme, and low activity catechol-O-methyltransferase, a protective enzyme, in the same woman, she is almost six times more likely to have ovarian cancer. These results indicate that formation of estrogen-DNA adducts is a critical factor in the etiology of ovarian cancer. Significantly higher ratios of estrogen-DNA adducts to estrogen metabolites and conjugates have also been observed in men with prostate cancer or non-Hodgkin lymphoma, compared to healthy men without cancer. These results also support a critical role of estrogen-DNA adducts in the initiation of cancer. Starting from the perspective that unbalanced estrogen metabolism can lead to increased formation of catechol estrogen quinones, their reaction with DNA to form adducts, and generation of cancer-initiating mutations, inhibition of estrogen-DNA adduct formation would be an effective approach to preventing a variety of human cancers. The dietary supplements resveratrol and N-acetylcysteine can act as preventing cancer agents by keeping estrogen metabolism balanced. These two compounds can reduce the formation of catechol estrogen quinones and/or their reaction with DNA. Therefore, resveratrol and N-acetylcysteine provide a widely applicable, inexpensive approach to preventing many of the prevalent types of human cancer.
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PMID:The molecular etiology and prevention of estrogen-initiated cancers: Ockham's Razor: Pluralitas non est ponenda sine necessitate. Plurality should not be posited without necessity. 2399 91

Chronic infection with hepatitis C virus (HCV) may lead to B cell activation and transformation into non-Hodgkin lymphoma (NHL). Molecular mechanisms of B cell transformation by HCV are poorly understood. One of the most common lymphoproliferative disorders in HCV-infected patients is splenic marginal zone lymphoma (SMZL). A case of a 42-years old man, affected by HCV-related SMZL, effectively treated with an IFN-free, NS3-NS4A inhibitor-based regimen, is hereby described. The patient was treated for 16 weeks with faldaprevir, deleobuvir, and ribavirin, achieving a very rapid viral eradication without relevant toxicities. A rapid haematologic response was noted as well, with a statistically significant correlation between viral decay and lymphocyte improvement (coefficient r = 0.55, p = 0.042). The viral clearance led to SMZL cure, even without the use of IFN. Thus, the causative role, played by HCV in SMZL development, is once again reinforced, whereby the antiviral, rather than the anti-proliferative activity of IFN is indirectly proven. A regimen including DAAs should be considered when treating a HCV-related extra-hepatic disease.
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PMID:Rapid clearance of HCV-related splenic marginal zone lymphoma under an interferon-free, NS3/NS4A inhibitor-based treatment. A case report. 2528 57


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