Gene/Protein Disease Symptom Drug Enzyme Compound
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The relative affinities of a panel of antibodies submitted to the ISOBM TD-3 PSA Workshop were determined by direct-binding ELISA. The Workshop antibodies were also tested for reactivity with the prostate-specific antigen alpha1-antichymotrypsin complex (PSA-ACT) and cross-reactivity with porcine pancreatic kallikrein. There was a wide range of affinities observed for the panel of antibodies. Twelve antibodies failed to react with the PSA-ACT complex, and 1 antibody was found to recognize an epitope on ACT but not on PSA. Only 2 antibodies were found to react with porcine pancreatic kallikrein, a protein with 64% sequence homology with human glandular kallikrein-2 (hK2).
Tumour Biol 1999
PMID:Relative affinity and specificity of monoclonal antibodies against prostate-specific antigen. 1062 5

Seventy-seven antibodies submitted to the ISOBM TD-3 PSA Workshop (TD-3.1 and TD-3.2) were characterized by measuring their reactivity with isoenzymes of free prostate-specific antigen (PSA), PSA complexed to alpha1-antichymotrypsin (PSA-ACT) and alpha1-proteinase inhibitor (PSA-API). Antibodies were classified into 15 distinct groups according to their reaction profiles with the various isoenzymes. Some antibodies recognizing both free and complexed PSA were inaccurate in measuring total PSA. Eight of the 9 free PSA-specific antibodies cross-reacted more with PSA-API than with PSA-ACT, while 1 antibody reacted less with PSA-API than PSA-ACT. From the panel of antibodies 39 reacted with both free and complexed PSA and were classified as total PSA antibodies.
Tumour Biol 1999
PMID:Reactivity of 77 antibodies to prostate-specific antigen with isoenzymes and complexes of prostate-specific antigen. 1062 6

Eighty-three antibodies submitted to the ISOBM TD-3 Workshop on prostate-specific antigen (PSA) were characterized by cross-inhibition studies, immunometric assay and affinity estimation with free or complexed PSA (PSA-alpha1-antichymotrypsin, PSA-ACT). Nine antibodies did not bind PSA or PSA-ACT when coated onto microtiter plates or in solution. Another 3 antibodies bound the antigens only when in solution and were therefore omitted from the cross-inhibition experiments. Dissociation constants (Kd) were estimated from the concentration of free antibody needed to achieve half-maximal binding of the antigen. Kd values for PSA and PSA-ACT ranged from 2 x 10(-12) to >10(-8) mol/l. Antibodies were classified into 6 main groups according to their reactivity. Group 1 comprised 15 antibodies (#25, 26, 33, 68, 73, 77, 78, 80, 85, 209, 213, 216, 223, 230, and 262) specific for free PSA. These antibodies had >80% cross-inhibition and showed high affinity for PSA with minimal or no affinity for the PSA-ACT complex. Group 2 comprised antibodies that reacted with both free PSA and PSA-ACT. Three subgroups were defined: group 2a (#40), group 2b (#32) and group 2c (#35, 37, 63, 90, 215 and 226). Group 3a antibodies (#31, 36, 37, 57, 64, 66, 72, 82, 84, 212, 224, 229, 257 and 260) were closely related to those of group 2, with two exceptions in group 3b (#88 and 89). Group 4 contains antibodies with binding patterns similar to those represented by groups 3b and 6b. These antibodies could be divided into two subgroups: group 4a (#30, 38, 51, 217, and 220) and group 4b (#74). Group 5 was more heterogeneous, with distinct inhibition patterns: group 5a (#50, 54, 76, 81,207, and 222); group 5b (#41), and group 5c (#28 and 86). Group 6 antibodies bind epitopes on both free PSA and PSA-ACT, but have epitopes unrelated to those represented in groups 1-3: group 6a contains 15 antibodies (#24, 27, 29, 34, 55, 56, 65, 79, 210, 214, 218, 221, 225, 258 and 261), and group 6b 2 antibodies (#67 and 75). These 6 groups represent the major immunodominant regions, one of which is exposed only on free PSA. Our classification could provide a useful guide in choosing antibodies for future PSA assays.
Tumour Biol 1999
PMID:Epitope mapping and affinity estimation of 83 antibodies against prostate-specific antigen. 1062 10

Rat stomach cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) are widely used as a model of differentiated-type human stomach cancers. ACI/N (ACT) rats are susceptible and BUF/Nac (BUF) rats are resistant to MNNG-induced stomach carcinogenesis, and the presence of an autosomal gene with a dominant BUF allele has been suggested. In this study, we performed a carcinogenicity test by giving MNNG in drinking water to 117 male ACI x (ACIxBUF)F1 backcross rats. Each of 100 effective rats was diagnosed for its "carcinoma development" and when it was bearing stomach carcinoma(s), for histological grade, depth of invasion, and size and number of tumors. Carcinoma development was diagnosed based both on the age of the rat and on the presence of stomach carcinoma(s). Linkage analysis was performed with the genotypes of 161 loci, covering 1637 cM of the rat genome. Contrary to our original expectations, the most influential gene was the one on chromosome (chr.) 15, Gastric cancer susceptibility gene 1 (Gcs1), which confers susceptibility to stomach carcinogenesis (LOD, 3.8) with a dominant BUF allele by promoting conversion from adenomas to carcinomas. Two resistance genes on chr. 4 and chr. 3, Gastric cancer resistance gene 1 (Gcr1) and Gcr2, were shown to confer dominant resistance (LOD, 2.7 and 2.6, respectively). Gcs1, Gcr1, and Gcr2 exerted additive effects on the development of stomach carcinomas. A gene on chr. 16, Gcr3, was indicated to reduce the depth of invasion (LOD, 2.2) and sizes of tumors (LOD, 1.9). No linkage was obtained using the number of tumors. These findings show that the coordinate effect of a susceptibility gene, Gcs1, and two resistance genes, Gcr1 and Gcr2, is responsible for the development of MNNG-induced stomach carcinomas and that Gcr3 is responsible for the growth of a stomach carcinoma, reflected in the depth of invasion and in the tumor size.
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PMID:Chromosomal mapping of genes controlling development, histological grade, depth of invasion, and size of rat stomach carcinomas. 1070 29

Gap junctional intercellular communication is often impaired in cancers, and the genes which encode the connexin gap junction proteins are considered to be tumor-suppressor genes. In this study, we analyzed the presence of mutations in the connexin 37 (Cx37) gene in 22 human hepatic angiosarcomas, 6 and 4 of which were associated with exposure to vinyl chloride and Thorotrast, respectively. The other 12 samples were from patients with no history of exposure to these 2 agents. In 9 samples, a proline (ACC) to serine (ACT) amino acid change in codon 319 was detected. However, DNA from non-tumorigenic tissue of the same patients also showed this amino acid change, suggesting that this is a polymorphism rather than a mutation. Subsequent analysis of 84 DNA samples from normal donors revealed the frequencies of Pro/Pro, Pro/Ser and Ser/Ser alleles to be 65.5%, 23.8% and 10.7%, respectively, while among the group of angiosarcoma patients the corresponding figures were 59.1%, 31.8% and 9. 1%, respectively. Thus, there was no correlation between the polymorphism at codon 319 and hepatic angiosarcoma occurrence. However, among the 6 cases of vinyl chloride-associated angiosarcoma, the percentages of the polymorphic alleles were 33.3%, 66.7% and 0%, respectively. While the number of samples was too small to allow us to conclude that the Ser319 allele in Cx37 predisposes to this rare type of human cancer, it may be noted that codon 319 is located at the cytoplasmic tail of Cx37, where most regulatory sequences reside, and that it could be a site of phosphorylation for some protein kinases, which may in turn affect the function of Cx37, including intercellular communication.
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PMID:Human hemangiosarcomas have a common polymorphism but no mutations in the connexin37 gene. 1072 96

Primary bone tumors represent about 7% of paediatric malignancies. Osteosarcoma and Ewing's tumor are the most frequent ones, however they are rare in facial bones. Mandibular localization is slightly more frequent and of better prognosis than maxillary one. Until 1995 there were only about 70 cases reported in the medical literature, mainly in the oncological or dental periodics. Our material consists of two children with Ewing's tumor of the mandible and one patient with osteosarcoma. The diagnosis was based on histopathological or cytological studies. The combined treatment--chemotherapy and radiotherapy--was performed in two patients with Ewing's tumor. The recommended resection of the mandible including the tumor mass has not been performed. No facial asymmetry is seen after termination of the radiotherapy. The boy with osteosarcoma underwent primary mandibular partial resection; a two-year chemotherapy was introduced only when metastases in the regional lymph nodes occurred (BLM, CTX, ACT-D, ADM, CDDP). The mandible was reconstructed surgically in 5 years after termination of radiotherapy and the anatomical relationship in the masticatory organ was restored. All children are now in good condition under our long-term observation. We present these cases of mandibular tumors regarding their rare occurrence and positive results of the introduced treatment.
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PMID:[Malignant tumors of mandible in children]. 1073 62

Resection of the considerable part of the arch of the mandible disturbs breathing, swallowing, speaking and alters the facial symmetry. One-staged reconstruction of the mandible is contraindicated in patients with malignant tumor and serious prognosis. The course of the combined treatment in 9-year-old boy with osteosarcoma of the mandible is presented (May 1987--resection of the anterior part of the body of the mandible and suprahyoid lymphadenectomy); the most severe postoperative functional disorders were treated immediately (tracheostomy, nasogastric tube for 3 weeks). The reconstruction of the mandible and restoration of the anatomical relationship in the masticatory organ were performed after 5 years. Because of the metastatic disease in the nuchal and cervical lymph nodes boy underwent chemotherapy (Jan 5th 1988-Feb 21st 1990) of the primary site of the tumor 7 months after surgery. The following cytostatic drugs were administered; BLM, CTX, ACT-D, ADM, CDDP. The functional rehabilitation, small correctional surgery and improvement in perception in the oral cavity facilitated the restoration of important functions of the masticatory organ (proved by the following studies: gustometric, manometric, logopedic, stereognostic, rentgenotelevision of the swallowing process). In addition, the self-perception and the boy's social status improved significantly after favourable change in patient's appearance.
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PMID:[Functional reconstruction of the masticatory organ after combined therapy in a 9-year-old boy with osteosarcoma of the mandible]. 1073 93

p73 is structurally and functionally related to p53 and is possibly a tumor suppressor gene. Using 15 surgically resected frozen esophageal specimens containing both squamous cell carcinomas (ESCC) and neighboring normal epithelia, we studied p73 gene alterations and mRNA expression. Loss of heterozygosity of the p73 loci was found in nine of 14 informative cases (64%). A polymorphism at codon 173 (Thr) of p73 was identified (eight samples had ACC and seven had ACT), but mutation was not detected in tumor samples. Nine of the 15 ESCC samples (60%) displayed significantly elevated expression of p73 over the neighboring normal epithelium; of these nine samples, four displayed loss of imprinting (LOI) and one switched the expressed allele. Hypermethylation of exon 1 of the p73 gene was not detected, using the bisulfite modification method, in normal or tumor samples. Twelve of the 15 (80%) ESCC samples contained p53 defects, including missense mutation, non-frameshift small deletion or insertion, non-detectable transcripts and protein accumulation. The ESCC samples with p53 defects were significantly correlated with those which had elevated expression of p73 (Fisher's exact test, P < 0.05). The results suggest that increased expression of p73, including that by LOI, could be a partial compensatory mechanism for defective p53.
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PMID:Molecular alterations of p73 in human esophageal squamous cell carcinomas: loss of heterozygosity occurs frequently; loss of imprinting and elevation of p73 expression may be related to defective p53. 1075 4

We describe the human ACT genomic and cDNA sequence which like its murine counterpart contains the defining secondary structure of the FHL (Four-and-a-Half LIM-domain) LIM-protein family. The coding region of the human ACT gene spans five exons. This distribution is very similar to the FHL1 gene and includes the arrangement of split codons across exon boundaries suggesting that these genes share a common ancestor. The human ACT gene was not detected by Northern analysis in the adult testis although this is the only known site of expression found with its murine counterpart. However, the human ACT gene was found to be expressed in a panel of human tumor cell lines derived from squamous cell carcinomas, melanomas, and leukemias. Interestingly, FHL1, FHL2, and FHL3 were also found to be expressed in some of these cell lines and the results suggest an important role for FHLs in tumor biology.
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PMID:The structure of the human LIM protein ACT gene and its expression in tumor cell lines. 1087 80

Molecular forms of prostate-specific antigen (PSA) improve the differentiation between benign prostatic hyperplasia (BPH) and prostate cancer (PCa) in men with total PSA concentrations between 4 and 10 microg/l. To evaluate the diagnostic utility of free PSA (fPSA) and complexed PSA forms for identification of men with PCa in the low PSA range of <4 microg/l, total PSA (tPSA), alpha(1)-antichymotrypsin complexed PSA (PSA-ACT) and fPSA (Roche Elecsys [ES] system) as well as tPSA and complexed PSA (cPSA) (Bayer Immuno 1 system) were measured in archival serum samples from 31 untreated patients with PCa, 66 patients with BPH, and 90 men without prostatic disease. The median ratios of fPSA/tPSA, PSA-ACT/tPSA and cPSA/tPSA were significantly different between patients with BPH and PCa (27.2 vs. 19.4%, 64 vs. 88%, 77.2 vs. 88.2%, p < 0.05). No associations between PSA forms and tumor stage and grade were found. Analysis of the receiver operating characteristic curves showed that these ratios could discriminate better between BPH and PCa patients than determination of the analytes tPSA, fPSA, cPSA and PSA-ACT alone. The use of one of the ratios would have eliminated roughly half of the unnecessary biopsies in this study. The ratios should be considered as potential tools to increase the selectivity of PCa detection at low PSA concentration. The ratios fPSA/tPSA and cPSA/tPSA can be determined using commercially available assays so that one of these ratios could be preferred instead of PSA-ACT determination. The ratios could be useful in assessing the risk of PCa in the individual and therefore in deciding on prostate biopsy for final diagnosis.
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PMID:Molecular forms of prostate-specific antigen in serum with concentrations of total prostate-specific antigen <4 microg/L: are they useful tools for early detection and screening of prostate cancer? 1147 92


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