Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Monitoring human antibody recognition of tumor antigens could have potential diagnostic and prognostic significance. Serological analysis of recombinant cDNA expression libraries of human cancer has identified a number of immunogenic tumor antigens. To identify colon cancer antigens associated with a cancer-related serum IgG response, serum samples from 74 patients with colon cancer and 75 normal blood donors were screened for antibody reactivity to 77 serologically defined tumor antigens. The following 13 antigens reacted exclusively with sera from the colon cancer patients and not with sera from normal blood donors: p53, MAGEA3, SSX2, NY-ESO-1, HDAC5, MBD2, TRIP4, NY-CO-45, KNSL6, HIP1R, Seb4D, KIAA1416, and LMNA. Serum samples from 34 of 74 (46%) colon cancer patients detected 1 or more of these 13 antigens. Fifty-three of 74 colon cancer patients were of known clinicopathological stage. Analysis of antibody frequency showed that 5 of 7 (71%) stage I colon cancer patients, 4 of 11 (36%) stage II patients, 2 of 14 (14%) stage III patients, and 11 of 21 (52%) stage IV patients had serum IgG antibody that reacted with 1 or more of the 13 antigens. The mRNA expression patterns of 8 of these 13 antigens were altered in cancer. Three of the 13 antigens were cancer/testis antigens (MAGEA3, SSX2, and NY-ESO-1), which are expressed exclusively in normal gametogenic tissues and aberrantly expressed in a broad range of cancer types. Quantitative real-time reverse transcription-PCR showed that the mRNA expression levels of 2 antigens, HDAC5 and Seb4B, were down-regulated in colon cancer, 2 other antigens, KNSL6 and KIAA1416, were up-regulated, and another antigen, NY-CO-45, showed a variable level of mRNA expression in colon cancer. With regard to KNSL6 mRNA expression, only trace levels were detected in 15 different normal tissues with the exception of testis, which showed a high level of KNSL6 mRNA expression. In contrast, 9 of 9 colon cancer specimens showed overexpression of KNSL6 mRNA, ranging from 5 to 44 times the level detected in normal colon tissue, indicating that this antigen could also be a valuable therapeutic target.
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PMID:Cancer-related serological recognition of human colon cancer: identification of potential diagnostic and immunotherapeutic targets. 1212 39

We utilized SEREX immunoscreening to identify a set of novel tumor antigens that are associated with human serous ovarian cancer and may prove useful for the early detection and treatment of this disease. Extensive screening with a panel of sera from 25 late-stage ovarian cancer patients against 3 independent cDNA libraries identified a set of 9 antigens that were immunogenic in more than 1 patient and not in a panel of 20-45 normal female serum donors. These antigens include p53, NY-ESO-1, UBQLN1, HOXB6, TOP2A, putative helicase-RUVBL (RUVBL), HMBA-inducible (HEXIM1), DDX5 and HDCMA. Ten of 25 ovarian cancer patients (40%) expressed serum IgG to at least 1 of these antigens, while 14% (4/25) had antibodies to 2 or more antigens. Unexpectedly, 4 antigens identified in this screen, DDX5, HEXIM1, TOP2A and HOXB6, are encoded within a region of 17q that also includes the genes for HER2/neu, Homeobox-B7 and BRCA1. Real-time RT-PCR analysis showed that mRNA for HER2/neu and 3 SEREX-defined antigens, TOP2A, HOXB6 and DDX5, was more abundant in ovarian tumors than most normal tissues, including normal and benign ovarian tissues, suggesting that elevated expression of genes encoded within this region of chromosome 17 is a common event in ovarian tumors. Thus, these abnormal expression patterns combined with the endogenous immune response suggests that these antigens represent potential targets for immunotherapy.
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PMID:Serologic analysis of ovarian tumor antigens reveals a bias toward antigens encoded on 17q. 1253 22

The ability of the immune system to recognize structurally altered, amplified or aberrantly expressed proteins can be used to identify molecules of etiologic relevance to cancer and to define targets for cancer immunotherapy. In the current study, ninety-four distinct antigens reactive with serum IgG from breast cancer patients were identified by immunoscreening breast cancer-derived cDNA expression libraries (SEREX). A serological profile was generated for each antigen on the basis of reactivity with allogeneic sera from normal individuals and cancer patients, and mRNA expression profiles for coding sequences were assembled based upon the tissue distribution of expressed sequence tags, Northern blots and real-time RT-PCR. Forty antigens reacted exclusively with sera from cancer patients. These included well-characterized tumor antigens, e.g. MAGE-3, MAGE-6, NY-ESO-1, Her2neu and p53, as well as newly-defined breast cancer antigens, e.g. kinesin 2, TATA element modulatory factor 1, tumor protein D52 and MAGE D, and novel gene products, e.g. NY-BR-62, NY-BR-75, NY-BR-85, and NY-BR-96. With regard to expression profiles, two of the novel gene products, NY-BR-62 and NY-BR-85, were characterized by a high level of testicular mRNA expression, and were overexpressed in 60% and 90% of breast cancers, respectively. In addition, mRNA encoding tumor protein D52 was overexpressed in 60% of breast cancer specimens, while transcripts encoding SNT-1 signal adaptor protein were downregulated in 70% of these cases. This study adds to the growing list of breast cancer antigens defined by SEREX and to the ultimate objective of identifying the complete repertoire of immunogenic gene products in human cancer (the cancer immunome).
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PMID:Humoral immunity to human breast cancer: antigen definition and quantitative analysis of mRNA expression. 1274 65

Cancer-testis (CT) antigens are expressed in a variety of malignant tumors, but in normal adult tissue, they are only expressed in testicular germ cells. Owing to this tumor-associated expression pattern, these antigens are of major interest as potential targets for immunotherapy and possibly for diagnostic purposes. This study was performed to analyze the expression of four CT antigens, NY-ESO-1, MAGE-A3, MAGE-A4, and CT7/MAGE-C1, in endometrial carcinoma using immunohistochemistry, and to correlate expression with histologic subtypes, grade, and expression of WT1 and p53. Formalin-fixed paraffin-embedded tissues of 130 endometrial carcinomas of the following types and grades were analyzed using a tissue microarray: 85 endometrioid carcinomas (FIGO grade 1, 39; grade 2, 11; and grade 3, 35), 18 papillary serous carcinomas, 12 clear cell carcinomas, 13 malignant mixed mullerian tumors, one mucinous adenocarcinoma, and one undifferentiated carcinoma. The following anti-CT monoclonal antibodies/antigens were studied by immunohistochemistry: monoclonal antibody ES121/NY-ESO-1, monoclonal antibody M3H67/MAGE-A3, monoclonal antibody 57B/MAGE-A4, and monoclonal antibody CT7-33/CT7. The CT expression data were compared to WT1 and p53 protein expression as analyzed in a previous study. Positive staining with anti-CT monoclonal antibodies was graded as follows: focal, <5% positive cells; 1+, 5-25% cells; 2+, 26-50% cells; 3+, 51-75%; and 4+, >75% cells. The 3+ and 4+ staining patterns were considered homogeneous patterns of potential clinical significance and were scored positive for statistical analysis. In low-grade tumors, the most immunoreactivity was seen with mAb M3H67 but little labeling was observed with the other monoclonal antibodies. In high-grade tumors, monoclonal antibodies M3H67 (25%), 57B (23%), and CT7-33 (20%) showed the highest reactivity, while ES121 showed the lowest immunoreactivity (6%). The staining pattern was mostly heterogeneous. Statistical significance was found solely for the correlation of monoclonal antibody 57B staining and p53 expression. No correlation was found for any anti-CT monoclonal antibody staining and clinical stage or for anti-CT staining and WT1 expression. CT antigens CT7, MAGE-A3 and MAGE-A4, but not NY-ESO-1, are expressed in high-grade endometrial carcinomas, and expression of MAGE-A4 is correlated with the presence of overexpressed p53.
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PMID:Expression of cancer-testis antigens in endometrial carcinomas using a tissue microarray. 1527 78

Conventional techniques for the detection of biomolecular interactions can be limited by the need for exogenous labels, time- and labor-intensive protocols, as well as by poor sensitivity levels. A refractometer instrument has been reconfigured to detect biomolecular interactions through changes in surface plasmon resonance (SPR). The binding kinetics and affinity values of anti-NY-ESO-1 monoclonal antibody, ES121, to the cancer-testis antigen NY-ESO-1 were determined according to the surface heterogeneity model and resulted in K(D) values of 1.3x10(-9) and 2.1x10(-10) M. The reconfigured instrument was then used to measure the interaction between tumor antigens and serum antibodies against these antigens in preselected cancer patient sera samples. The tumor antigens assayed included NY-ESO-1, SSX2 and p53, all used as recombinant proteins containing polyhistidine tags. These results demonstrated that the instrument is capable of detecting the binding of serum antibodies from cancer patient sera to immobilized tumor antigens, consistent with those observed previously in ELISA-based experiments. These results demonstrate the potential of SPR technology for the rapid diagnosis and monitoring immune responses.
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PMID:Real-Time, label-free monitoring of tumor antigen and serum antibody interactions. 1557 77

Anti-tumor antibodies have potential as cancer biomarkers. There is relatively limited identification of anti-tumor antibodies in response to ovarian cancer, compared with studies for other cancers. There is also very limited information on the prevalence of anti-tumor antibodies among ovarian cancer patients. Although most anti-tumor antibodies react with antigens common to both tumor and normal tissue, the anti-tumor response tends to be confined to individuals with ovarian cancer, similar to other cancers. Antibodies to HOXA7, a differentiation antigen, have the highest reported prevalence in ovarian cancer (67%). Antibodies to other ubiquitous antigens including NY-ESO-1, Ep-CAM (epithelial cell adhesion molecule), HSP-90 (heat shock protein 90), and mutated p53 have been identified in ovarian cancer. Anti-tumor antibody specificity reflects the heterogeneity of antigen expression in tumors. Tests based on panels of a combination of anti-tumor antibodies may be more predictive for ovarian cancer, as no single specificity accounts for ovarian tumors. In addition to characterization of anti-tumor antibodies as diagnostic markers, study of anti-tumor antibodies is likely to provide insights into mechanisms of tumor development. There is evidence of antibodies to tumor antigens and of activated T cells, suggesting immune recognition of tumor antigens occurred. Nonetheless, as tumors are not 'rejected', it is likely that there are alterations in the immune system. The basis for tumor growth in the face of immune activity remains to be determined.
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PMID:Anti-tumor antibodies in ovarian cancer. 1610 96

The use of nonviral gene transfer methods in primary lymphocytes has been hampered by low gene transfer efficiency and high transfection-related toxicity. In this report, high gene transfection efficiency with low transfection-related toxicity was achieved by electroporation using in vitro-transcribed mRNA. Using these methods, >90% transgene expression with >80% viable cells was observed in stimulated primary human and murine T lymphocytes transfected with GFP or mCD62L. Electroporation of unstimulated human PBMCs or murine splenocytes with GFP RNA yielded 95 and 56% GFP+ cells, respectively. Electroporation of mRNA for NY-ESO-1, MART-1, and p53 antigen-specific TCRs into human T lymphocytes redirected these lymphocytes to recognize melanoma cell lines in an MHC-restricted manner. The onset of gene expression was rapid (within 30 min) and durable (up to 7 days postelectroporation) using both GFP and TCR-mediated recognition of target cells. There was no adverse effect observed on the T lymphocytes subjected to RNA electroporation evaluated by cell growth rate, annexin-V staining of apoptotic cells, BrdU incorporation, tumor antigen-specific recognition or antigen-specific TCR affinity. The results of this study indicate that mRNA electroporation provides a powerful tool to introduce genes into both human and murine primary T lymphocytes.
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PMID:High-efficiency transfection of primary human and mouse T lymphocytes using RNA electroporation. 1614 May 84

Carcinoma in situ testis (CIS), also known as intratubular germ cell neoplasia (ITGCN), is a pre-invasive precursor of testicular germ cell tumours, the commonest cancer type of male adolescents and young adults. In this review, evidence supporting the hypothesis of developmental origin of testicular germ cell cancer is summarized, and the current concepts regarding aetiology and pathogenesis of this disease are critically discussed. Comparative studies of cell surface proteins (e.g. PLAP and KIT), some of the germ cell-specific markers (e.g. MAGEA4, VASA, TSPY and NY-ESO-1), supported by studies of regulatory elements of the cell cycle (e.g. p53, CHK2 and p19-INK4d) demonstrated a close similarity of CIS to primordial germ cells and gonocytes, consistent with the pre-meiotic origin of CIS. Recent gene expression profiling studies showed that CIS cells closely resemble embryonic stem cells (ESCs). The abundance of factors associated with pluripotency (NANOG and OCT-3/4) and undifferentiated state (AP-2gamma) may explain the remarkable pluripotency of germ cell neoplasms, which are capable of differentiating to various somatic tissue components of teratomas. Impaired gonadal development resulting in the arrest of gonocyte differentiation and retention of its embryonic features, associated with an increasing genomic instability, is the most probable model for the pathogenesis of CIS. Genomic amplification of certain chromosomal regions, e.g. 12p, may facilitate survival of CIS and further invasive progression. Genetic studies, have so far not identified gene polymorphisms predisposing to the most common non-familial testicular cancer, but this research has only recently begun. Association of CIS with other disorders, such as congenital genital malformations and some forms of impaired spermatogenesis, all rising in incidence in a synchronous manner, led to the hypothesis that CIS might be a manifestation of testicular dysgenesis syndrome (TDS). The aetiology of TDS including testicular cancer remains to be elucidated, but epidemiological trends suggest a primary role for environmental factors, probably combined with genetic susceptibility.
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PMID:Developmental model for the pathogenesis of testicular carcinoma in situ: genetic and environmental aspects. 1654 May 28

Specific p53 binding-induced DNA bending and its underlying responsible forces are crucial for the understanding of selective transcription activation. Diverse p53-response elements exist in the genome; however, it is not known what determines the DNA bending and to what extent. In order to gain knowledge of the forces that govern the DNA bending, molecular dynamics simulations were performed on a series of p53 core domain tetramer-DNA complexes in which each p53 core domain was bound to a DNA quarter site specifically. By varying the sequence of the central 4-base pairs of each half-site, different DNA bending extents were observed. The analysis showed that the dimer-dimer interactions in p53 were similar for the complexes; on the other hand, the specific interactions between the p53 and DNA, including the interactions of Arg280, Lys120, and Arg248 with the DNA, varied more significantly. In particular, the Arg280 interactions were better maintained in the complex with the CATG-containing DNA sequence and were mostly lost in the complex with the CTAG-containing DNA sequence. Structural analysis shows that the base pairings for the CATG sequence were stable throughout the simulation trajectory, whereas those for the CTAG sequence were partially dissociated in part of the trajectory, which affected the stability of the nearby Arg280-Gua base interactions. Thus, DNA bending depends on the balance between the p53 dimer-dimer interactions and p53-DNA interactions, which is in turn related to the DNA sequence and DNA flexibility.
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PMID:p53-Induced DNA bending: the interplay between p53-DNA and p53-p53 interactions. 1846 91

With the identification of tumor antigens, the host immune response to various types of cancers can now be studied with a high degree of specificity in large cohorts of patients, in the hope of correlating immunity with clinical events and defining immunotherapeutic strategies. Several antigens, such as NY-ESO-1, p53, or SOX2, have attracted attention because of their frequent spontaneous immunogenicity in cancer patients, notably in their ability to induce humoral responses. We describe in this chapter a simple implementation of a serological monitoring platform for autoantibody measurement in cancer patients, from production of recombinant antigens to ELISA testing and interpretation.
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PMID:Autoantibodies against cancer antigens. 1938 44


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