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)

Polycomb-group (PcG) proteins, such as BMI-1 and EZH2, form multimeric gene-repressing complexes involved in axial patterning, hematopoiesis, and cell cycle regulation. In addition, BMI-1 is involved in experimental lymphomagenesis. Little is known about its role in human lymphomagenesis. Here, BMI-1 and EZH2 expression patterns are analyzed in a variety of B-cell non-Hodgkin lymphomas (B-NHLs), including small lymphocytic lymphoma, follicular lymphoma, large B-cell lymphoma, mantle-cell lymphoma, and Burkitt lymphoma. In contrast to the mutually exclusive pattern of BMI-1 and EZH2 in reactive follicles, the neoplastic cells in B-NHLs of intermediate- and high-grade malignancy showed strong coexpression of BMI-1 and EZH2. This pattern overlapped with the expression of Mib-1/Ki-67, a marker for proliferation. Neoplastic cells in B-NHL of low-grade malignancy were either BMI-1(low)/EZH2(+) (neoplastic centroblasts) or BMI-1(low)EZH2(-) (neoplastic centrocytes). These observations show that low-, intermediate-, and high grade B-NHLs are associated with increased coexpression of the BMI-1 and EZH2 PcG proteins, whose normal expression pattern is mutually exclusive. This expression pattern is probably caused by a failure to down-regulate BMI-1 in dividing neoplastic cells, because BMI-1 expression is absent from normal dividing B cells. These observations are in agreement with findings in studies of Bmi-1 transgenic mice. The extent of BMI-1/EZH2 coexpression correlated with clinical grade and the presence of Mib-1/Ki-67 expression, suggesting that the irregular expression of BMI-1 and EZH2 is an early event in the formation of B-NHL. This points to a role for abnormal PcG expression in human lymphomagenesis. (Blood. 2001;97:3896-3901)
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PMID:Coexpression of BMI-1 and EZH2 polycomb-group proteins is associated with cycling cells and degree of malignancy in B-cell non-Hodgkin lymphoma. 1138 32

We evaluated immunohistochemically the expression of two negative regulators of the cell cycle, namely retinoblastoma gene product (pRb) and WAF1/Cip1 gene product (p21), in paraffin sections from 93 patients with non-Hodgkin's lymphomas (NHL) and related it to clinicopathological parameters, proliferative fraction, p53 expression and survival. Patients were followed until death (n=33) or for an average of 52 months (60-160). Rb labelling index (LI) increased with malignancy grade and proliferative activity but was unrelated to other clinicopathological parameters. In 33% of cases, especially those of the aggressive groups, we observed diminished pRb expression (i.e. low pRb/Ki-67 ratio). p21 expression on the other hand correlated only with histological grade, Rb LI and p53 LI. In multivariate analysis, Rb LI was a negative predictor of disease-free survival but was linked to a higher probability of complete response. However, diminished pRb expression as well as p21 expression were not statistically significant prognostic indicators. Our results suggest that pRb as a cell cycle related molecule may play an important role in determining prognosis and therapeutic response in NHL patients.
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PMID:Retinoblastoma gene product and P21 (WAF1, CIP1) protein expression in non Hodgkin's lymphomas: a multivariate survival analysis. 1142 36

DNA polymerase mu (pol mu) is a novel error-prone DNA repair enzyme bearing significant structural homology with terminal deoxynucleotidyltransferase. Whereas other human error-prone DNA polymerases identified thus far show no preferential lymphoid tissue distribution, the highest levels of pol mu mRNA have been detected in peripheral lymphoid tissues, particularly germinal center B cells. Conceivably, up-regulation of the pol mu gene may be biologically significant in lymphomagenesis, especially in the development of B-cell non-Hodgkin's lymphomas (B-NHLs), because of enhanced error-prone DNA repair activities. To explore this possibility, we generated a digoxigenin-labeled riboprobe to pol mu mRNA and used the probe and in situ hybridization to examine the expression pattern of the pol mu gene in formalin-fixed, paraffin-embedded tissue sections of 37 B-NHLs. This included eight chronic lymphocytic leukemia/small lymphocytic lymphomas, six mantle cell lymphomas, seven follicular lymphomas, nine diffuse large B-cell lymphomas, three splenic marginal zone lymphomas, two Burkitt's lymphomas, and two precursor B-lymphoblastic lymphomas. We also correlated the pol mu mRNA expression levels with the tumor proliferation index, which was assessed in each case by image analysis of Ki-67 immunostained slides. Nineteen of 21 (90%) B-NHLs arising from postgerminal center B cells (follicular lymphomas, diffuse large B-cell lymphomas, splenic marginal zone lymphomas, and Burkitt's lymphomas) exhibited high expression of pol mu mRNA. In contrast, only 2 of 16 (13%) B-NHLs arising from pregerminal center B cells (chronic lymphocytic leukemia/small lymphocytic lymphomas, mantle cell lymphomas, and precursor B-lymphoblastic lymphomas) expressed significant levels of pol mu mRNA. Pol mu gene expression did not seem to correlate with the proliferation index, especially because a significant level of pol mu mRNA was not detected in either case of precursor B-lymphoblastic lymphomas. In conclusion, pol mu gene expression is highly associated with B-NHLs of postgerminal center B-cell derivation. Furthermore, the expression level is independent of the proliferation rate and thus is unrelated to the biological aggressiveness of the tumors. These findings, along with the error-prone nature of the enzyme, suggest that up-regulation of pol mu gene expression may be a contributing factor to the pathogenesis of a subset of B-NHLs through DNA repair-associated genomic instability.
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PMID:DNA polymerase mu gene expression in B-cell non-Hodgkin's lymphomas: an analysis utilizing in situ hybridization. 1236 8

DP-1 is a G1 cell cycle-related protein that forms heterodimers with E2F, a family of transcriptional factors regulating the expression of genes important for G1 to S progression. Although the exact role of DP-1 is not well understood, it has been shown to stabilize DNA binding of E2F proteins. By immunohistochemistry, the authors examined the expression of DP-1 in lymphoid tissues, including 8 cases of reactive follicular hyperplasia and 69 cases of B-cell non-Hodgkin lymphoma. The expression of the cell cycle-related proteins E2F-1 and Ki-67 was also assessed. Scoring was based on the proportion of labeled nuclei (1-10%, 11-25%, 26-50%, and > 50%). In reactive follicular hyperplasia, staining for DP-1, E2F-1, and Ki-67 was largely confined to the germinal centers. All 25 cases of follicular lymphoma, regardless of grade, had a high proportion (> 50%) of DP-1-positive cells but a lower proportion of cells marking for E2F-1 and Ki-67 (P < 0.001). The diffuse large B-cell lymphomas (n = 24) had high DP-1 and Ki-67 scores but low E2F-1 scores (P < 0.001). Small lymphocytic (n = 10), marginal zone (n = 3), and mantle cell lymphomas (n = 5) contained relatively low proportions of cells labeled for all three markers. Precursor B-cell lymphoblastic lymphoma (n = 2) displayed high proportions of cells positive for DP-1, Ki-67, and E2F-1 (> 50% in both cases). Except in follicular center cell lesions, DP-1 expression generally correlated with that of Ki-67. However, the expression of DP-1 was discordant with that of E2F-1 in benign and malignant follicular center cells, suggesting that DP-1 may have functions other than facilitating E2F-1-dependent gene regulation and cell cycle progression in these neoplasms.
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PMID:Immunohistochemical expression of the transcription factor DP-1 and its heterodimeric partner E2F-1 in non-Hodgkin lymphoma. 1260

The nucleoside 5-fluoro-2-deoxyuridine is a pyrimidine analogue accumulating in proliferative cells. We prospectively evaluated biodistribution of the PET tracer [(18)F]5-fluoro-2-deoxyuridine (FdUrd), its value for imaging malignant tumors, and its correlation to both [(18)F]2-fluoro-2-deoxyglucose (FDG)-PET findings and histological proliferation indices. In 11 previously untreated patients (5 lung carcinoma; 3 soft tissue sarcoma; 2 gastrointestinal carcinoma; 1 non-Hodgkin lymphoma [NHL]), mean doses of 290 MBq FdUrd and 390 MBq FDG were administered intravenously on subsequent days. Static PET scans were initiated 50-70 min after administration and the mean standardized uptake values (SUV) were calculated. Dynamic emission FdUrd scans were performed in 8/11 patients. Time-activity curves of blood and tumors as well as SUV of tumor lesions and organs were calculated. Proliferative activity was evaluated by Ki-67 immunohistostaining of biopsies. Tracer accumulated physiologically in liver, kidney, and bladder. SUVs were: kidney, 4.8 +/- 0.66; liver, 4.1 +/- 0.36; vertebrae, 0.70 +/- 0.17; spleen, 0.37 +/- 0.06; lungs, 0.19 +/- 0.05; femora/humeri, 0.14 +/- 0.03. Five patients exhibited significant intratumoral FdUrd-uptake (2 sarcomas; 1 NHL; 2 lung carcinomas) with mean SUVs ranging from 0.7 to 10.5. Metastases were not detected. Time-activity curves showed a rapid initial increase of intratumoral activity followed by activity retention. FDG-PET was positive in 10/11 patients. Correlation between the SUV of FdUrd-PET and FDG-PET or the tissue proliferation index, respectively, was not significant. FdUrd was a suitable tracer for imaging malignant tumors only in exceptional cases: Sarcoma, NHL, and some lung carcinomas were detected. FdUrd-PET was less effective than FDG-PET. In this group of patients, it was not useful in measuring tissue proliferation.
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PMID:[18F]5-fluoro-2-deoxyuridine-PET for imaging of malignant tumors and for measuring tissue proliferation. 1295 20

Polo-like kinases (PLKs) are protein serine/threonine kinases that play important roles in cell division. Expression of PLK1 might, moreover, play a role in the pathogenesis of human neoplasms. The expression of PLK1 mRNA is closely correlated with survival in patients with malignant tumors. We investigated the expression of PLK1 in non-Hodgkin's lymphomas (NHLs) and analyzed the relationships between expression of PLK1, histological grade, and prognosis. We analyzed various types of NHLs from 118 patients using monoclonal antibodies against PLK1 and Ki-67. The levels of expression of PLK1 and Ki-67 were significantly lower in low-grade NHLs than in high-grade and intermediate-grade NHLs (P < 0.001). Moreover, when patients were grouped in terms of 5-year overall survival ( > 70%, group A; 50 - 70%, group B; 30 - 49%, group C; and < 30%, group D), levels of expression of PLK1 and Ki-67 were found to be significantly higher in group D than in group A and they were also significantly higher in group C than in group A (P < 0.001). Conversely, the level of expression, of Ki-67 was significantly lower in group D than in group C (P < 0.05). The labeling indices specific for PLK1 were generally higher than those specific for Ki-67. Once we divided all patients into two groups in terms of the expression levels, high-level expression group of PLK1 (PLK1 index of 70%) and Ki-67 (Ki-67 indices of 60%) and low-level expression, one of these markers (PLK1 index of >/= 70%, Ki-67 indices of >/= 60%) had a similar prognosis, an observation that can be explained by the fact that rapidly proliferating group is more drug-sensitive than the other. Our study demonstrates that expression of PLK1 might reflect the malignant potential of NHLs and that PLK1 might be more useful than Ki-67 for the detection of proliferative cells.
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PMID:Expression of Polo-Like Kinase (PLK1) in non-Hodgkin's lymphomas. 1562 5

We describe successful treatment of a 38-year-old patient with composite lymphoma stage IV(A), who presented with multifocal enlarged lymph nodes. The lymph node histology showed classic morphologic features of Hodgkin's disease, mixed cellularity subtype and follicular B-cell lymphoma. Immunophenotypic analysis showed immunoreactivity for CD20, CD10 and Ki-67 in the malignant small cell population. The areas of Hodgkin's disease demonstrated positive immunoreactivity for CD30 and CD20 in the Hodgkin's cells. Both cell populations were bcl2-oncoprotein positive. Eight courses of dose-escalated BEACOPP were administered. Restaging after chemotherapy showed radiological partial remission, but biopsy confirmed persisting follicular B-cell lymphoma without bone marrow infiltration and no evidence of Hodgkin's disease. He was treated with monoclonal CD 20-antibody (Rituximab) 10 mg/kg weekly for eight consecutive weeks due to marked positivity of CD 20-antigen in follicular lymphoma cells. This treatment was well tolerated and final staging showed complete remission of the composite lymphoma. This patient continues to be in remission 28 months after the end of the treatment. In conclusion, in the very rare case of composite lymphoma a combination of chemotherapy and subsequent immunotherapy might be considered as a promising therapeutic option.
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PMID:Sequential application of chemotherapy and monoclonal CD 20 antibody: successful treatment of advanced composite-lymphoma. 1562 15

This study was undertaken to determine the prognostic relevance of the proliferation rate in neoplastic cells in children and adolescents with Hodgkin's lymphoma. Paraffin-embedded biopsy specimens were immunostained with the proliferation-associated monoclonal antibodies Ki-S5 (Ki-67 antigen) and Ki-S2 (which detects the repp86 protein). Repp86 is a protein of about 100 kDa encoded by a gene located on human chromosome band 20q11.2. In contrast to the Ki-67 antigen, repp86 expression is restricted to the cell cycle phases G(2), S and M. Immunohistochemical results on diagnostic lymph node biopsy specimens from 224 patients included in two pediatric multicenter Hodgkin's trials, GPOH HD-90 and HD-95, were compared with clinical data. High Ki-67 antigen expression was a striking feature of Hodgkin's and Reed-Sternberg cells as well as lymphocytic and histiocytic cells (median: 80%, range: 20-100%), in contrast to low repp86 expression (median: 20%, range: 10-80%; P<0.001). The proliferation rate was independent of histological subtype, stage and presence of B symptoms. The probability of event-free and overall survival (+/-standard error) of all patients at 5 years was 91.6+/-2.0 and 98.1+/-1.0%, respectively. The proliferation rate of tumor cells did not influence the outcome. The difference between Ki-67 and repp86 expression in Hodgkin's and Reed-Sternberg or lymphocytic and histiocytic cells points to a possible cell cycle arrest in the G(1) phase, which may explain the obvious paradox of a highly proliferating but slowly growing paucicellular tumor. High Ki-67 expression does not seem to be an adverse prognostic factor in pediatric and adolescent patients with Hodgkin's lymphoma treated by effective risk-adapted chemo-radiotherapy regimens.
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PMID:Proliferation characteristics in pediatric Hodgkin's lymphoma point to a cell cycle arrest in the G(1) phase. 1605 47

T-cell rich B-cell lymphoma (TCRBCL) is considered a rare variant of aggressive B-cell lymphoma characterized by few neoplastic cells and a large reactive infiltrate with striking similarities to nodular lymphocyte predominant Hodgkin's lymphoma (NLPHL). In childhood, these tumors occur even less frequently. Biopsy specimens at diagnosis from 16 children (13 boys) with a median age of 12 years (range, 7 to 18) were immunophenotyped. The proliferation rate was assessed with monoclonal antibodies against Ki-67 and repp86 antigens and additional clonality analyses were performed. Ten patients had localized disease and only two had B symptoms. All patients showed high Ki-67 expression (median: 80%, range 40% to 90%), but low repp86 expression (median: 25%, range 10% to 50%). PCR-based clonality studies of the hypervariable CDR III region of the immunoglobuline heavy chain and the T-cell receptor gamma-chain genes demonstrated predominant clones in nine and five patients, respectively. Three patients had previous or concomitant NLPHL and two of them received initial treatment for Hodgkin's disease. All patients achieved remission after a brief polychemotherapy regimen. Two patients subsequently relapsed and one was rescued by salvage therapy including autologous stem cell transplantation. At a median follow-up of 23 months, 15 patients (94%) are alive. The striking contrast between the proliferation rates determined by Ki-67 and repp86 expression points to a possible arrest in the G1 cell cycle phase because repp86 expression is restricted to the S, G2 and M cell cycle phases. This G1 arrest may explain the paradoxon of high Ki-67 expression in a paucicellular lymphoma with a favorable prognosis in young patients.
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PMID:Proliferation rate and outcome in children with T-cell rich B-cell lymphoma: a clinicopathologic study from the NHL-BFM-study group. 1610 6

Deregulation of several genes involved in cell cycle control has been reported in classic Hodgkin lymphoma (cHL). This study aimed to investigate the expression of tumor suppressor proteins (P16(INK4A), retinoblastoma protein, and p53) in cHL in relation to the proliferation and apoptosis of Hodgkin/Reed-Sternberg (H/RS) cells, correlating with the status of Epstein-Barr virus (EBV). A total of 66 cHL cases and 10 nonneoplastic reactive lymphoid tissues were retrieved from the archives. Immunohistochemistry technique was used for the detection of protein expression. Presence of EBV infection was detected by EBV early RNA in situ hybridization. p16(INK4A) gene deletion status was assessed by fluorescence in situ hybridization technique. Expression of P16(INK4A) was observed in 49.2% of the cases, whereas positive retinoblastoma protein and p53 expressions in the H/RS cells were detected in 89.1% and 81.5% of the cases, respectively. Epstein-Barr virus positivity was detected in 53.0% of the cases. Proliferation marker, Ki-67 expression, was observed in 86.7% of the cases. There was no significant correlation between the expression of the various tumor suppressor proteins and Ki-67. Retinoblastoma protein and p53 were also not associated with the presence of EBV. An inverse relationship was observed between the expression of P16(INK4A) and the presence of EBV. There were no significant homozygous or hemizygous deletions of the p16(INK4A) gene. However, an aberrant copy number of chromosome 9 with the loss of one or more p16(INK4A) loci was detected in all cases assessable by fluorescence in situ hybridization. Loss of function of one or more tumor suppressor proteins may be involved in defective cell regulation of H/RS cells. Epstein-Barr virus may have a role in inhibiting P16(INK4A) expression, thus resulting in a perturbed p16(INK4A)-Rb cell cycle checkpoint.
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PMID:Expression of retinoblastoma protein and P16 proteins in classic Hodgkin lymphoma: relationship with expression of p53 and presence of Epstein-Barr virus in the regulation of cell growth and death. 1636 Apr 21


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