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)

Infection of human B cells with Epstein-Barr virus (EBV) was seen to result in activation-induced cytidine deaminase (AID) and polymerase-eta (pol-eta) gene expression. AID and pol-eta are cellular gene products that play central roles in the DNA-modifying processes involved in immunoglobulin gene class switch recombination and somatic hypermutation. Errors in these processes can result in oncogene mutation/translocation, thereby contributing to lymphomagenesis. It was seen that EBV infected, AID, and pol-eta expressing B cells accumulated mutations in cellular proto-oncogenes (BCL-6 and p53) that are known to be involved in the genesis of B cell lymphoma. The nature of the mutations seen in these oncogenes was consistent with the known activity of AID and pol-eta. These findings indicate that EBV induced AID and pol-eta expression, and that this was associated with oncogene mutation, providing a novel means by which EBV infection of B cells may contribute to lymphomagenesis.
Mol Immunol 2007 Feb
PMID:Infection of human B cells with Epstein-Barr virus results in the expression of somatic hypermutation-inducing molecules and in the accrual of oncogene mutations. 1673 63

We invented a new method to make microarrays using nuclei extracted from paraffin-embedded tissues or cultured cells. A blank recipient paraffin block with 10 x 10 cores was constructed and sectioned to make the mold for the cell arrays. The sections of paraffin were mounted on poly-L-lysine-coated slides. Prepared nuclei or cells were injected into the cores of the paraffin mold. The slides were dried and dewaxed and nuclei or cell arrays were made. Using this method, we successfully made microarrays of nuclei extracted from diffuse large B-cell lymphoma paraffin-embedded tissues, nasopharyngeal cancer and lymphoma cell lines. This technique resulted in a paraffin-embedded cell preparation that yielded a cell density of approximately 500 to 1000 or 800 cells on average per 0.6-mm-diameter core. The microarrays were successfully used in fluorescence in situ hybridization, mRNA in situ hybridization, and cytohistochemical staining.
Diagn Mol Pathol 2006 Jun
PMID:A new method to make nuclei or cell microarrays. 1677 92

Discovering molecular heterogeneities in phenotypically defined disease is of critical importance both for understanding pathogenic mechanisms of complex diseases and for finding efficient treatments. Recently, it has been recognized that cellular phenotypes are determined by the concerted actions of many functionally related genes in modular fashions. The underlying modular mechanisms should help the understanding of hidden genetic heterogeneities of complex diseases. We defined a putative disease module to be the functional gene groups in terms of both biological process and cellular localization, which are significantly enriched with genes highly variably expressed across the disease samples. As a validation, we used two large cancer datasets to evaluate the ability of the modules for correctly partitioning samples. Then, we sought the subtypes of complex diffuse large B-cell lymphoma (DLBCL) using a public dataset. Finally, the clinical significance of the identified subtypes was verified by survival analysis. In two validation datasets, we achieved highly accurate partitions that best fit the clinical cancer phenotypes. Then, for the notoriously heterogeneous DLBCL, we demonstrated that two partitioned subtypes using an identified module ("cellular response to stress") had very different 5-year overall rates (65% vs. 14%) and were highly significantly (P < 0.007) correlated with the clinical survival rate. Finally, we built a multivariate Cox proportional-hazard prediction model that included 4 genes as risk predictors for survival over DLBCL. The proposed modular approach is a promising computational strategy for peeling off genetic heterogeneities and understanding the modular mechanisms of human diseases such as cancers.
Mol Med
PMID:Peeling off the hidden genetic heterogeneities of cancers based on disease-relevant functional modules. 1683 67

Nitric oxide synthases are isoenzymes that catalyse the synthesis of nitric oxide (NO). NO plays both pathological and physiological roles depending on its rate of synthesis and concentration in cellular source and microenvironment. Apoptosis is an important biological factor in lymphomas. This study evaluates expression of inducible nitric oxide synthase (iNOS) in human lymphomas and its relation with apoptosis. This study comprised 46 cases of B-cell lymphoma. The lymphomas were classified as 3 mantle cell, 5 marginal zone, 4 follicular, 2 Burkitt, 25 diffuse large cell, 2 anaplastic large cell, 3 lymphoblastic, 2 lymphoplasmacytic according to WHO classification of lymphoid neoplasms. Hematoxylin eosin slides of the cases were reviewed and immunoperoxidase technique was performed iNOS and Caspase monoclonal antibodies to selected sections of each case. Antigen staining was carried out with iNOS and Caspase proteins and Ultravision Polyvalent, HRP-AEC kit (Neomarkers-Biogen USA). For the evaluation of iNOS and Caspase, tumor areas with a high density of expression were chosen. Positive stained cells were counted in 5 different areas at a magnification x 40 by an Olympus B x 51 microscope in each case. The iNOS and Caspase expressions were independently recorded by four pathologists and the results were averaged. All of the cases were positive for the iNOS and Caspase. But there is not a statistically important relation between lymphoma grade and iNOS activity. We could not find a correlation between iNOS and patients age. This study reveals the capacity of B-cell neoplasms to express iNOS in situ. In conclusion, our study revealed that there is a positive relation between iNOS expression and apoptosis (p = 0.032 spearman correlation).
Mol Cell Biochem 2006 Oct
PMID:Inducible nitric oxide synthase and apoptosis in human B cell lymphomas. 1692 21

We have recently shown that cannabinoids induce growth inhibition and apoptosis in mantle cell lymphoma (MCL), a malignant B-cell lymphoma that expresses high levels of cannabinoid receptor types 1 and 2 (CB(1) and CB(2)). In the current study, the role of each receptor and the signal transduction triggered by receptor ligation were investigated. Induction of apoptosis after treatment with the synthetic agonists R(+)-methanandamide [R(+)-MA] and Win55,212-2 (Win55; (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo-[1,2,3-d,e]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone) was dependent on both cannabinoid receptors, because pretreatment with N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716A) and N-((1S)-endo-1,3,3-trimethyl bicyclo heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide) (SR144528), specific antagonists to CB(1) and CB(2), respectively, abrogated caspase-3 activity. Preincubation with the inhibitors 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580) and 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole (SB202190) showed that phosphorylation of MAPK p38 was implicated in the signal transduction leading to apoptosis. Treatment with R(+)-MA and Win55 was associated with accumulation of ceramide, and pharmacological inhibition of ceramide synthesis de novo prevented both p38 activation and mitochondria depolarization assessed by binding of 3,3'-dihexyloxacarbocyanine iodide (DiOC(6)). In contrast, the pancaspase inhibitor z-Val-Ala-Asp(Ome)-CH(2)F (z-VAD-FMK) did not protect the mitochondrial integrity. Taken together, these results suggest that concurrent ligation of CB(1) and CB(2) with either R(+)-MA or Win55 induces apoptosis via a sequence of events in MCL cells: accumulation of ceramide, phosphorylation of p38, depolarization of the mitochondrial membrane, and caspase activation. Although induction of apoptosis was observed in both MCL cell lines and primary MCL, normal B cells remained unaffected. The present data suggest that targeting CB(1)/CB(2) may have therapeutic potential for the treatment of mantle cell lymphoma.
Mol Pharmacol 2006 Nov
PMID:Cannabinoid receptor-mediated apoptosis induced by R(+)-methanandamide and Win55,212-2 is associated with ceramide accumulation and p38 activation in mantle cell lymphoma. 1693 28

CD56 (NCAM), a neural adhesion molecule, is normally expressed on natural killer cells and subsets of T cells and is commonly seen on hematolymphoid neoplasms such as plasma cell myeloma and acute myelogenous leukemia. It is uncommon in B-cell lymphoma. From 2001 to 2003 a cohort of 20 cases of CD56 B-cell lymphomas was identified by flow cytometry (<0.5% of all B-cell lymphomas studied) during a 2-year period. Most (90%) expressed CD10 and 5/5 tested cases were BCL6, suggesting a follicular origin. An extranodal disease presentation was seen in 45% and may be related to CD56 expression. These CD56 B-cell lymphomas may represent a new subset of large B-cell lymphoma. The relationship of cells with this antigenic profile to normal B-cell differentiation is explored.
Appl Immunohistochem Mol Morphol 2006 Dec
PMID:CD56-positive large B-cell lymphoma. 1712 31

To determine the usefulness of polymerase chain reaction (PCR) analyses in the diagnosis of lymphoid infiltrate cells in ocular samples, PCR was performed using oligonucleotide primers specific for immunoglobulin heavy chain rearrangement at framework 2, framework 3, and t(14;18) translocation of the bcl-2 gene. These were used to successfully generate amplicons of 220 to 230 bp, 110 to 120 bp, and 175 to 200 bp, respectively. After PCR amplification, primers directed against the t(14;18) detected 10 pg of B-cell lymphoma DNA. PCR against Fr2 and Fr3 IgH rearrangement detected 10 fg and 10 pg in the seminested PCR, respectively. Conventional pathological methods were highly accurate at establishing the correct final diagnosis in formalin-fixed, paraffin-embedded samples but were much less sensitive and predictive in cytological specimens of intraocular fluid. A combination of the three PCR reactions was an equally successful diagnostic approach on paraffin-embedded samples, whereas single PCR reactions did not significantly improve diagnosis over histopathological diagnostic techniques. Thus, a combination of PCR reactions is useful in the detection of B-cell monoclonality, aids the differentiation between lymphomatous and inflammatory infiltrates, and is more powerful as a diagnostic method than single PCR or conventional cytopathology for lymphoid infiltrates in ocular fluid aspirates.
J Mol Diagn 2007 Feb
PMID:Protocol for the use of polymerase chain reaction in the detection of intraocular large B-cell lymphoma in ocular samples. 1725 44

B lymphocyte stimulator (BLyS) is crucial for B-cell survival, and the biological effects of BLyS are mediated by three cell surface receptors designated B cell-activating factor receptor (BAFF-R), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), and B-cell maturation antibody (BCMA). Increased expression of BLyS and its receptors has been identified in numerous B-cell malignancies. We generated a fusion toxin designated rGel/BLyS for receptor-mediated delivery of the recombinant gelonin (rGel) toxin to neoplastic B cells, and we characterized its activity against various B-cell tumor lines. Three mantle cell lymphoma (MCL) cell lines (JeKo-1, Mino, and SP53) and two diffuse large B-cell lymphoma (DLBCL) cell lines (SUDHL-6 and OCI-Ly3) expressing all three distinct BLyS receptors were found to be the most sensitive to the fusion toxin (IC(50) = 2-5 pmol/L and 0.001-5 nmol/L for MCL and DLBCL, respectively). The rGel/BLyS fusion toxin showed specific binding to cells expressing BLyS receptors and rapid internalization of the rGel component into target cells. The cytotoxic effects of rGel/BLyS were inhibited by pretreatment with free BLyS or with soluble BAFF-R, TACI, and BCMA decoy receptors. This suggests that the cytotoxic effects of the fusion toxin are mediated through BLyS receptors. The rGel/BLyS fusion toxin inhibited MCL cell growth through induction of apoptosis associated with caspase-3 activation and poly (ADP-ribose) polymerase cleavage. Our results suggest that BLyS has the potential to serve as an excellent targeting ligand for the specific delivery of cytotoxic molecules to neoplastic B cells expressing the BLyS receptors, and that the rGel/BLyS fusion toxin may be an excellent candidate for the treatment of B-cell malignancies especially MCL and DLBCL.
Mol Cancer Ther 2007 Feb
PMID:The rGel/BLyS fusion toxin specifically targets malignant B cells expressing the BLyS receptors BAFF-R, TACI, and BCMA. 1726 61

Bcl10 (B-cell lymphoma 10) is an adaptor protein comprised of an N-terminal caspase recruitment domain and a C-terminal serine/threonine-rich domain. Bcl10 plays a critical role in antigen receptor-mediated NF-kappaB activation and lymphocyte development and functions. Our current study has discovered that T-cell activation induced monophosphorylation and biphosphorylation of Bcl10 and has identified S138 within Bcl10 as one of the T-cell receptor-induced phosphorylation sites. Alteration of S138 to an alanine residue impaired T-cell activation-induced ubiquitination and subsequent degradation of Bcl10, ultimately resulting in prolongation of TCR-mediated NF-kappaB activation and enhancement of interleukin-2 production. Taken together, our findings demonstrate that phosphorylation of Bcl10 at S138 down-regulates Bcl10 protein levels and thus negatively regulates T-cell receptor-mediated NF-kappaB activation.
Mol Cell Biol 2007 Jul
PMID:Phosphorylation of Bcl10 negatively regulates T-cell receptor-mediated NF-kappaB activation. 1750 53

Comprehensive analysis of gene expression using RNA extracted from frozen lymphoma specimens is becoming increasingly important for understanding disease pathogenesis, disease subclassification, and prognostication. As paraffin tissues are widely available whereas frozen specimens are not, development of gene expression analysis based on RNA extracted from paraffin-embedded tissues would facilitate application of the accumulated knowledge to a sample type that is typical of clinical practice. In the present study, we have developed and optimized methods of RNA extraction from paraffin-embedded lymphoid tissues. In contrast to previously suggested methods of RNA extraction from paraffin, our method uses sodium dodecyl sulfate that better preserves the extracted RNA and is optimized for more complete proteinase K digestion to release RNA from its complexes with protein. These modifications yield long RNA fragments up to 2000 bp enabling amplification of long amplicons. This allows usage of paraffin specimens for molecular rescue of RNA transcripted from rearranged clonal immunoglobulin genes-an advance that may increase the eligibility of lymphoma patients for immunotherapeutic approaches. Furthermore, real-time polymerase chain reaction analysis of expression of genes implicated in determination of prognosis of diffuse large B-cell lymphoma patients demonstrated an extremely high correlation (R>0.90) in normalized gene expression between paired frozen and formalin-fixed, paraffin-embedded specimens. Similarly, good correlation was also observed in gene array studies. These results suggest that the methods of RNA extraction we propose are suitable for giving accurate real-time quantitative reverse transcriptase-polymerase chain reaction results, array gene expression profiling, and molecular rescue of RNA transcripted from rearranged immunoglobulin genes for diagnostic and immunotherapeutic approaches.
Diagn Mol Pathol 2007 Jun
PMID:Optimization of RNA extraction from formalin-fixed, paraffin-embedded lymphoid tissues. 1752 74


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