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

In recent years, substantial experience has been accumulated with tumor-specific immunotherapeutics which seem to be effective against minimal residual disease. The coupling of toxins to monoclonal antibodies has indicated promising results in early clinical trials. Recombinant DNA technology makes it possible to genetically fuse coding regions of V genes or cytokines to modified toxin domains. These recombinant immunotoxins can easily be manipulated to increase the cytotoxic potency or affinity. Binding single-chain variable fragments (scFv) expressed as chimeric fusion proteins on the surface of filamentous bacteriophages were selected on Hodgkin-derived cell lines. This technique was also used to create a new humanized anti-CD30 scFv which exhibits similar binding to the CD30 antigen when compared to its murine predecessor. ScFvs were then inserted into a new bacterial expression vector and thus fused to a deletion mutant of Pseudomonas exotoxin. Anti-CD25(scFv)-ETA' and anti-CD30(scFv)-ETA' were isolated from E. coli periplasm and purified by metal chelate affinity and size exclusion chromatography. All immunotoxins produced showed specific cytotoxicity against Hodgkin lymphoma cell lines as documented by competitive assays. In addition, these constructs were highly efficient in the treatment of disseminated human Hodgkin's disease in SCID mice. These in vivo data indicate a possible clinical impact for patients with relapsed CD25- and/or CD30-positive lymphoma.
Int J Mol Med 2000 Nov
PMID:Recombinant immunotoxins for the treatment of Hodgkin's disease (Review). 1102 15

The BCL6 proto-oncogene, frequently alterated in non-Hodgkin lymphoma, encodes a POZ/zinc finger protein that localizes into discrete nuclear subdomains. Upon prolonged BCL6 overexpression in cells bearing an inducible BCL6 allele (UTA-L cells), these subdomains apparently coincide with sites of DNA synthesis. Here, we explore the relationship between BCL6 and replication by both electron and confocal laser scanning microscopy. First, by electron microscope analyses, we found that endogenous BCL6 is associated with replication foci. Moreover, we show that a relatively low expression level of BCL6 reached after a brief induction in UTA-L cells is sufficient to observe its targeting to mid, late, and at least certain early replication foci visualized by a pulse-labeling with bromodeoxyuridine (BrdU). In addition, when UTA-L cells are simultaneously induced for BCL6 expression and exposed to BrdU for a few hours just after the release from a block in mitosis, a nuclear diffuse BCL6 staining indicates cells in G(1), while cells in S show a more punctate nuclear BCL6 distribution associated with replication foci. Finally, ultrastructural analyses in UTA-L cells exposed to BrdU for various times reveal that replication progresses just around, but not within, BCL6 subdomains. Thus, nascent DNA is localized near, but not colocalized with, BCL6 subdomains, suggesting that they play an architectural role influencing positioning and/or assembly of replication foci. Together with its previously function as transcription repressor recruiting a histone deacetylase complex, BCL6 may therefore contribute to link nuclear organization, replication, and chromatin-mediated regulation.
Mol Cell Biol 2000 Nov
PMID:DNA replication progresses on the periphery of nuclear aggregates formed by the BCL6 transcription factor. 1104 51

Hodgkin's disease is an unusual cancer because the malignant cells constitute only a minority of the total tumour mass and, as a consequence, the study of these cells has been a major challenge. Recently, the application of newer technologies, such as single cell polymerase chain reaction (PCR) and gene expression array analysis, to the study of Hodgkin's disease have yielded new insights into the pathogenesis of this tumour. In addition, the recognition that a proportion of Hodgkin's disease tumours harbour the Epstein-Barr virus (EBV) and that its genome is monoclonal in these tumours suggests that the virus contributes to the development of Hodgkin's disease in some cases. This review summarises current knowledge of the pathogenesis of Hodgkin's disease with particular emphasis on the association with EBV.
Mol Pathol 2000 Oct
PMID:Hodgkin's disease and the Epstein-Barr virus. 1109 50

A new type of shape descriptor is proposed to describe the spatial orientation for non-covalent interactions. It is built from simple, anisotropic Gaussian contributions that are parameterised by 10 adjustable values. The descriptors have been used to fit propensity distributions derived from scatter data stored in the IsoStar database. This database holds composite pictures of possible interaction geometries between a common central group and various interacting moieties, as extracted from small-molecule crystal structures. These distributions can be related to probabilities for the occurrence of certain interaction geometries among different functional groups. A fitting procedure is described that generates the descriptors in a fully automated way. For this purpose, we apply a similarity index that is tailored to the problem, the Split Hodgkin Index. It accounts for the similarity in regions of either high or low propensity in a separate way. Although dependent on the division into these two subregions, the index is robust and performs better than the regular Hodgkin index. The reliability and coverage of the fitted descriptors was assessed using SuperStar. SuperStar usually operates on the raw IsoStar data to calculate propensity distributions, e.g., for a binding site in a protein. For our purpose we modified the code to have it operate on our descriptors instead. This resulted in a substantial reduction in calculation time (factor of five to eight) compared to the original implementation. A validation procedure was performed on a set of 130 protein-ligand complexes, using four representative interacting probes to map the properties of the various binding sites: ammonium nitrogen, alcohol oxygen, carbonyl oxygen, and methyl carbon. The predicted 'hot spots' for the binding of these probes were compared to the actual arrangement of ligand atoms in experimentally determined protein-ligand complexes. Results indicate that the version of SuperStar that applies to our descriptors is capable to predict the above-mentioned atom types in ligands correctly with success rates of 59% and 74%, respectively, for all ligand atoms (regardless of their solvent accessibility), and a subset of solvent-inaccessible ones. If not only exact atom-type matches are counted, but also those that identify ligand atoms of similar physicochemical properties, the prediction rates rise to 75% and 89%. These rates are close to those obtained by the original SuperStar method (being 67% and 82%, respectively, for the prediction of exact matching atom types, and 81% and 91% in the case of predicting similar atom types).
J Comput Aided Mol Des 2000 Nov
PMID:Simple knowledge-based descriptors to predict protein-ligand interactions. methodology and validation. 1113 70

Epstein-Barr virus (EBV) is the causative agent of infectious mononucleosis, and it may also be found in a wide variety of benign and malignant lesions including oral hairy leukoplakia, inflammatory pseudotumor, Hodgkin's disease, non-Hodgkin's lymphoma, nasopharyngeal carcinoma, and gastric carcinoma. Molecular testing is increasingly important in the diagnosis and monitoring of patients affected by these diseases. In biopsy tissues, molecular detection of EBV-encoded RNA transcripts by in situ hybridization remains the gold standard for proving that a histopathological lesion is EBV-related. EBV-encoded RNA hybridization and EBV LMP1 immunostains are used routinely to detect latent EBV in tissues affected by posttransplant lymphoproliferative disorder (PTLD) or in enlarged nodes from patients with infectious mononucleosis. Traditional serology is the best test for evaluating acute versus remote infection in healthy individuals. High serological titers serve as a tumor marker for some EBV-related malignancies, but titers are not a dependable tumor marker in immunocompromised hosts. EBV viral load testing by quantitative DNA amplification of blood samples is a promising new laboratory test that has proven useful for early diagnosis and monitoring patients with PTLD. Recent studies suggest a role for EBV viral load testing in nasopharyngeal carcinoma, Hodgkin's disease, and AIDS patients with brain lymphoma. Further research is needed to define more fully the clinical utility of viral load tests in the full spectrum of EBV-associated diseases. Gene expression profiling is on the horizon as a means to improve subclassification of EBV-related diseases and to predict response to therapy.
J Mol Diagn 2001 Feb
PMID:Molecular diagnosis of Epstein-Barr virus-related diseases. 1122 65

Mitochondrial genes that are overexpressed in human and monkey B-cell non-Hodgkin lymphomas (B-NHLs) were sought via subtraction hybridization, cloning, and differential screening of the resulting cDNA libraries. The cDNAs of mitochondrial genes made an appreciable proportion of all lymphoma-specific cDNAs. Lymphomogenesis was associated with overexpression of a mitochondrial gene set which varied with lymphoma type and always included NADHIV. A possible association between overexpression of certain mitochondrial genes and cell malignant transformation is discussed.
Mol Biol (Mosk)
PMID:[Amplification of transcription of separate mitochondrial genes in human and monkey B-cell non-Hodgkin's lymphoma]. 1123 70

Polymerase chain reaction (PCR)-based analysis for detecting immunoglobulin heavy chain gene (IgH) rearrangements in lymphoproliferative disorders is well established. The presence of one or two discrete bands is interpreted as a monoclonal proliferation, whereas a smear pattern represents a polyclonal population. Prompted by our observation of discrete bands in histologically reactive processes with a relative paucity of B cells, we sought to determine whether low numbers of B cells in biopsy specimens could artifactually produce pseudomonoclonal bands. We performed IgH PCR analysis on serially diluted DNA samples from 5 B cell non-Hodgkin's lymphomas (B-NHLs), 5 reactive lymph nodes, 5 reactive tonsils and 10 microdissected germinal centers from a lymph node with follicular hyperplasia. We also assessed multiple aliquots of DNA samples from small biopsy specimens of reactive lymphocytic processes from the stomach (5 cases). PCR products were evaluated using high resolution agarose or polyacrylamide gels, and DNA sequencing was performed on IgH PCR products from two reactive germinal centers, which yielded monoclonal bands of identical size. All 5 B-NHLs harboring monoclonal B cell populations yielded single discrete bands, which were maintained in all dilutions. By contrast, all of the reactive lesions with polyclonal patterns at 50 ng/microl starting template concentration showed strong pseudomonoclonal bands at dilutions of 1:1,000 to 1:1,500 in placental DNA. Two of the microdissected reactive germinal centers that showed bands of identical size on duplicate reactions were proven to have different IgH sequences by sequencing. We conclude that specimens containing low numbers of polyclonal B cells may produce pseudomonoclonal bands on IgH PCR analysis. IgH PCR analysis should be performed on multiple aliquots of each DNA sample, and only samples that yield reproducible bands of identical size can be reliably interpreted as monoclonal.
J Mol Diagn 2000 May
PMID:PCR analysis of the immunoglobulin heavy chain gene in polyclonal processes can yield pseudoclonal bands as an artifact of low B cell number. 1123 12

The oncoprotein Bcl-2 is a potent survival factor antagonizing p53-dependent and -independent apoptotic cell death. Although many anticancer agents are known to engage apoptotic pathways, the clinical impact of Bcl-2 on treatment outcome remains controversial. Since it might be difficult to assess the contribution of a single gene to treatment response in patient material due to technical considerations, we sought to address Bcl-2's role in a mouse model of primary lymphomas treated at their natural site. Driven by the E(mu)-enhancer controlled c-myc transgene, primary B cell lymphomas arise in this model by several months of age and resemble closely typical clinical and histopathological features of human non-Hodgkin lymphomas. We introduced either bcl-2 or a control construct into identical samples of freshly isolated E(mu)-myc lymphomas by retroviral gene transfer in order to obtain matched pairs of primary lymphomas differing only in their Bcl-2 status. While no Bcl-2-mediated effect was detectable in clonogenic survival assays in vitro, treatment of the genetically modified lymphoma pairs propagated in nontransgenic recipient mice revealed Bcl-2's impact on drug sensitivity in vivo. Bcl-2 efficiently blocked short- and long-term drug-mediated cell death in vivo. In a comparison of 15 matched pairs of primary lymphomas, the bcl-2 transduced sample never achieved longer remission periods than the control counterpart and most of the Bcl-2 overexpressing lymphomas failed to respond at all. We conclude that-when assessed in the physiological environmental context-MBcl-2 contributes to chemoresistance of B cell lymphomas in vivo. This model, able to test any other candidate gene, will be particularly useful to study the implications of specific mutations for drug action in vivo.
Blood Cells Mol Dis
PMID:Bcl-2 mediates chemoresistance in matched pairs of primary E(mu)-myc lymphomas in vivo. 1135 81

Studies of lymphoid neoplasms occurring in normal or genetically engineered mice have revealed parallels and differences to non-Hodgkin lymphomas (NHL) of humans. Some mouse lymphomas have strong histologic similarities to the human NHL subsets including precursor B- and T-cell lymphoblastic, small lymphocytic, splenic marginal zone, and diffuse large-cell B-cell lymphomas (DLCL); whether molecular parallels also exist is under study. Others mouse types such as sIg+ lymphoblastic B-cell lymphoma have no histologic equivalent in human NHL even though they share molecular deregulation of BCL6 with human DLCL. Finally, Burkitt lymphoma does not appear to occur naturally in mice, but it can be induced with appropriately engineered transgenes.
Blood Cells Mol Dis
PMID:Non-Hodgkin lymphomas of mice. 1135 82

Advances in our understanding of the role of cytotoxic T lymphocytes (CTLs) in the control of Epstein-Barr virus (EBV)-associated malignancies and the overall biology of these diseases have led to the development of novel therapeutic strategies designed to specifically target viral antigens expressed in these malignancies. Long-term success of many of these strategies is constrained by the latency phenotypes adopted by different diseases. Adoptive transfer of polyclonal virus-specific CTLs has been used successfully to reverse the outgrowth of malignancies such as post-transplant lymphoproliferative disease (PTLD). On the other hand, limited viral gene expression in other EBV-associated malignancies such as Burkitt's lymphoma, Hodgkin's disease and nasopharyngeal carcinoma limits the efficacy of immunotherapeutic strategies used for PTLD. Preclinical studies based on specific targeting of viral antigens expressed in these malignancies have provided very encouraging results and thus are likely to serve as an important platform for the treatment of human patients.
Trends Mol Med 2001 Jun
PMID:Immunotherapeutic strategies for EBV-associated malignancies. 1137 17


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>