Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Background: RNA is extensively degraded by routine formalin fixation to fragments averaging 200 nucleotides (nt). Several methods for the recovery of amplifiable RNA from formalin-fixed, paraffin-embedded tissue have been described; however, a universally accepted approach in a clinical molecular diagnostic laboratory has not yet emerged. Methods and Results: Amplifiable RNA can be recovered with high efficiency from all types of formalin-fixed, paraffin-embedded tissue using proteinase K digestion, either a phenol-chloroform or an acidic guanidinium thiocyanate-phenol chloroform extraction step, and isopropanol precipitation in the presence of glycogen. Designing primers to detect a small target was critical for consistent RNA amplification in the following assays, with the target size indicated: hepatitis C virus, 169nt; morbillivirus, 78 nt; influenza virus, 113 nt; the npm-alk fusion product resulting from t(2;5) translocation, 175 nt; and the bcr-abl fusion product resulting from t(9;22) translocation, 93 or 168 nt. Conclusions: With use of beta-2-microglobulin as the control messenger RNA target for assessing the recovery of amplifiable RNA from human tissue, amplifiable RNA was recovered from 216 of 225 blocks (96%). In a series of veterinary specimens, which were largely postmortem and moderately to severely autolyzed, 158 of 199 blocks (79%) yielded amplifiable RNA using a beta-actin target. Amplifiable influenza RNA has been recovered from archival paraffin blocks as old as 79 years.
Mol Diagn 1997 Sep
PMID:Optimization of the Isolation and Amplification of RNA From Formalin-fixed, Paraffin-embedded Tissue: The Armed Forces Institute of Pathology Experience and Literature Review. 1046 13

Hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide and the leading indication for liver transplantation. The hallmark of the disease is its propensity to evolve into chronicity, probably because viral heterogeneity allows the virus to escape immune-mediated neutralization. Treatment with interferon alpha (IFN-alpha) has been disappointing, but higher and more frequent doses, and combination therapies, including nucleoside analogs, might lead to improved suppression of HCV RNA levels. Molecular analysis of HCV before and during treatment has indicated that high viral RNA levels and the presence of HCV genotype 1 are independent predictors of poor treatment outcome. New antiviral agents in development include inhibitors of HCV replicative enzymes, such as protease, helicase and polymerase, as well as several genetic approaches, such as ribozymes and antisense oligonucleotides. The main hindrance to drug development for hepatitis C is the lack of a small animal model or a productive tissue culture system for assessing drug action.
Mol Med Today 1999 Sep
PMID:Hepatitis C virus: current understanding and prospects for future therapies. 1046 51

Hepatitis C virus (HCV) contains an internal ribosome entry site (IRES) located in the 5' untranslated region of the genomic RNA that drives cap-independent initiation of translation of the viral message. The approximate secondary structure and minimum functional length of the HCV IRES are known, and extensive mutagenesis has established that nearly all secondary structural domains are critical for activity. However, the presence of an IRES RNA tertiary fold and its functional relevance have not been established. Using chemical and enzymatic probes of the HCV IRES RNA in solution, we show that the IRES adopts a unique three-dimensional structure at physiological salt concentrations in the absence of additional cofactors or the translation apparatus. Folding of the IRES involves cooperative uptake of magnesium and is driven primarily by charge neutralization. This tertiary structure contains at least two independently folded regions which closely correspond to putative binding sites for the 40 S ribosomal subunit and initiation factor 3 (eIF3). Point mutations that inhibit IRES folding also inhibit its function, suggesting that the IRES tertiary structure is essential for translation initiation activity. Chemical and enzymatic probing data and small-angle X-ray scattering (SAXS) experiments in solution show that upon folding, the IRES forms an extended structure in which functionally important loops are exposed. These results suggest that the 40 S ribosomal subunit and eIF3 bind an HCV IRES that is prefolded to spatially organize recognition domains.
J Mol Biol 1999 Sep 24
PMID:The hepatitis C virus internal ribosome entry site adopts an ion-dependent tertiary fold. 1049 18

It has been reported that hepatitis C virus (HCV) causes not only liver disease but also disorders of other organs and tissues. Previously, many HCV-related extrahepatic manifestations have been reported. In this study, we report 2 patients in whom tongue cancer was detected during the treatment of HCV-related liver disease. In one patient, tongue cancer was detected during the treatment of HCV-related liver cirrhosis, and articular rheumatism developed thereafter. The duration of HCV-related liver disease was 10 years. In the other patient, tongue cancer was detected during the treatment of HCV-related hepatocellular carcinoma. This patient had a past history of thyroid disease. The duration of HCV-related liver disease was 6 years. In these patients, the possibility that several conditions incidentally and concurrently developed cannot be denied. However, the conditions described above may be regarded as HCV-related extra-hepatic manifestations. In patients with HCV infection, it is important to examine conditions in organs other than the liver. Careful follow-up is needed.
Int J Mol Med 1999 Dec
PMID:Various extrahepatic manifestations caused by hepatitis C virus infection. 1056 73

The regulation of cap-independent translation directed by the internal ribosome entry sites (IRESs) present in some viral and cellular RNAs is poorly understood. Polypyrimidine-tract binding protein (PTB) binds specifically to several viral IRESs. IRES-directed translation may be reduced in cell-free systems that are depleted of PTB and restored by reconstitution of lysates with recombinant PTB. However, there are no data concerning the effects of PTB on IRES-directed translation in vivo. We transfected cells with plasmids expressing dicistronic transcripts in which the upstream cistron encoded PTB or PTB deletion mutants (including a null mutant lacking amino acid residues 87 to 531). The downstream cistron encoded a reporter protein (chloramphenicol acetyltransferase [CAT]) under translational control of the poliovirus IRES which was placed within the intercistronic space. In transfected BS-C-1 cells, transcripts expressing wild-type PTB produced 12-fold more reporter protein than similar transcripts encoding the PTB null mutant. There was a 2.4-fold difference in CAT produced from these transcripts in HeLa cells, which contain a greater natural abundance of PTB. PTB similarly stimulated CAT production from transcripts containing the IRES of hepatitis A virus or hepatitis C virus in BS-C-1 cells and Huh-7 cells (37- to 44-fold increase and 5 to 5.3-fold increase, respectively). Since PTB had no quantitative or qualitative effect on transcription from these plasmids, we conclude that PTB stimulates translation of representative picornaviral and flaviviral RNAs in vivo. This is likely to reflect the stabilization of higher ordered RNA structures within the IRES and was not observed with PTB mutants lacking RNA recognition motifs located in the C-terminal third of the molecule.
Mol Cell Biol 2000 Mar
PMID:Transient expression of cellular polypyrimidine-tract binding protein stimulates cap-independent translation directed by both picornaviral and flaviviral internal ribosome entry sites In vivo. 1066 36

Hepatitis C virus (HCV) of genotype 1 is the most resistant to interferon (IFN) therapy. Here, we have analyzed the response to IFN of the human cell line UHCV-11 engineered to inducibly express the entire HCV genotype 1a polyprotein. IFN-treated, induced UHCV cells were found to better support the growth of encephalomyocarditis virus (EMCV) than IFN-treated, uninduced cells. This showed that expression of the HCV proteins allowed the development of a partial resistance to the antiviral action of IFN. The nonstructural 5A (NS5A) protein of HCV has been reported to inhibit PKR, an IFN-induced kinase involved in the antiviral action of IFN, at the level of control of protein synthesis through the phosphorylation of the initiation factor eIF2alpha (M. Gale, Jr., C. M. Blakely, B. Kwieciszewski, S. L. Tan, M. Dossett, N. M. Tang, M. J. Korth, S. J. Polyak, D. R. Gretch, and M. G. Katze, Mol. Cell. Biol. 18:5208-5218, 1998). Accordingly, cell lines inducibly expressing NS5A were found to rescue EMCV growth (S. J. Polyak, D. M. Paschal, S. McArdle, M. J. Gale, Jr., D. Moradpour, and D. R. Gretch, Hepatology 29:1262-1271, 1999). In the present study we analyzed whether the resistance of UHCV-11 cells to IFN could also be attributed to inhibition of PKR. Confocal laser scanning microscopy showed no colocalization of PKR, which is diffuse throughout the cytoplasm, and the induced HCV proteins, which localize around the nucleus within the endoplasmic reticulum. The effect of expression of HCV proteins on PKR activity was assayed in a reporter assay and by direct analysis of the in vivo phosphorylation of eIF2alpha after treatment of cells with poly(I)-poly(C). We found that neither PKR activity nor eIF2alpha phosphorylation was affected by coexpression of the HCV proteins. In conclusion, expression of HCV proteins in their biological context interferes with the development of the antiviral action of IFN. Although the possibility that some inhibition of PKR (by either NS5A or another viral protein) occurs at a very localized level cannot be excluded, the resistance to IFN, resulting from the expression of the HCV proteins, cannot be explained solely by inhibition of the negative control of translation by PKR.
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PMID:Expression of hepatitis C virus proteins interferes with the antiviral action of interferon independently of PKR-mediated control of protein synthesis. 1082 66

Hepatitis C virus (HCV) genotyping has been shown to predict response to interferon, but is expensive. HCV serotyping is less expensive and simpler, and may be similarly useful. Using data from a large, randomized trial comparing consensus interferon (CIFN) and interferon alfa-2b (IFN alfa-2b) in patients with chronic HCV, we evaluated response rates based on HCV serotypes versus genotypes. Patients included in this analysis received subcutaneous injection of 9 microg CIFN (n = 232) or 3 MU IFN alfa-2b (n = 240) three times weekly for 24 weeks followed by 24 weeks of observation. Serum HCV RNA concentrations were measured regularly during treatment and at the end of both the treatment and post-treatment periods. Response to interferon was similar for HCV antibody types and their corresponding genotypes. The end-of-treatment HCV RNA rate of response (defined as undetectable serum on two consecutive assessments) was 29% for serotype 1 versus 24% for genotype 1 after CIFN; and 14% versus 15%, respectively, after IFN alfa-2b. Independently of treatment, patients infected with serotype or genotype 2 or 3 had a better therapeutic response than those infected with serotype or genotype 1. Similar results were obtained based on HCV antibody typing and genotyping, suggesting the potential of the former for predicting response to interferon.
Cytokines Cell Mol Ther 1999 Dec
PMID:Utility of hepatitis C virus serotypes in predicting response to treatment of chronic hepatitis C. Consensus Interferon Study Group. 1085 Mar 84

Hepatitis C virus (HCV) is an emerging virus of great medical significance. A low drug-response rate and a high frequency of persistent infection have caused HCV to reach pandemic proportions. Many infected individuals go on to develop liver cirrhosis and hepatocellular carcinoma, and HCV is now the leading reason for liver transplants in the United States. Differences in genotype response to interferon therapy suggests that one or more viral genes may participate in evasion of the interferon-mediated cellular antiviral response. This review focuses on the viral genes that interact with the host cell to evade the interferon response and on the insights that these interactions may provide into HCV pathogenesis.
J Mol Med (Berl) 2000
PMID:Hepatitis C virus: evasion of the interferon-induced antiviral response. 1093 80

Among 326 consecutively resected cases of hepatocellular carcinoma (HCC), we studied clinicopathologic features of 13 cases (NBNC-HCC) negative for hepatitis B surface antigen (HBsAg), antibody to HBsAg (HBsAb), antibody to hepatitis B core antigen (HBcAb), hepatitis B envelope antigen (HBeAg), antibody to HBeAg (HBeAb), and antibody to hepatitis C virus (HCVAb). Forty-four HCC cases positive only for HBsAg (B-HCC) and 232 cases positive only for HCVAb (C-HCC) were studied as controls. Clinically, NBNC-HCC cases showed good liver function reserve. None of NBNC-HCC cases had periodic medical check ups and HCC was detected in 12 cases (92.3%) incidentally. Pathologically, the mean tumor diameter was significantly larger and the histologic grade was less differentiated in NBNC-HCC cases than in B-HCC and C-HCC cases. In the background liver, liver cirrhosis was associated in 15.4% of NBNC-HCC cases, 50.0% of B-HCC and 38.2% of C-HCC cases. The degree of inflammation and fibrosis was less in NBNC-HCC cases, and two cases (15.4%) had almost normal liver histology. In NBNC-HCC cases, synchronous and metachronous multicentric occurrence was not observed. In B-HCC cases, synchronous multicentric occurrence was found in 1 case (20.0%), but no metachronous multicentric occurrence. In C-HCC cases, synchronous and metachronous multicentric occurrence was found in 13 (43.3%) and 8 (30.8%) cases, respectively. However, the cumulative recurrence-free rate was not significantly different among the three groups. Accordingly, it was suggested that better prognosis could be expected in NBNC-HCC cases compared with B- and C-HCC cases, if the cancer could be detected in the early stage.
Int J Mol Med 2000 Dec
PMID:Clinicopathologic study on hepatocellular carcinoma negative for hepatitis B surface antigen and antibody to hepatitis C virus. 1107 25

The expression of CD81, a cell receptor for hepatitis C virus, was examined on cancer cells in hepatocellular carcinoma (HCC) C (n=29) to clarify its clinical role. CD81 was expressed on hepatocyte membrane in non-tumor portions in all patients, however, this was not stained on the cancer cell membranes in 6 of 29. Reverse transcriptase-PCR revealed that CD81 gene expression was not detected in the tumorous portions in 3 of 7 samples. The loss of CD81 was prominent in poorly differentiated HCC (5 of 8) and extrahepatic metastasis patients (6 of 8). The loss of CD81 is associated with differentiation and metastasis of HCC.
Int J Mol Med 2001 Jan
PMID:The CD81 expression in liver in hepatocellular carcinoma. 1111 11


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