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Biomedical subjects

S Jothy

Publications and source records attributed to S Jothy.

At least 55 records · Page 3Linked to original sources
PubMed1994

Hereditary nonpolyposis colon cancer: analysis of linkage to 2p15-16 places the COCA1 locus telomeric to D2S123 and reveals genetic heterogeneity in seven Canadian families.

Hereditary nonpolyposis colon cancer (HNPCC) is an autosomal dominant trait responsible for approximately 6% of colorectal cancers. Linkage of the HNPCC trait to the D2S123 locus on 2p15-16 has previously been reported in two families. This HNPCC locus is now designated "COCA1." We have tested seven Canadian HNPCC families, who have a variety of clinical presentations, for linkage to a panel of microsatellite polymorphisms in the vicinity of D2S123. One family was clearly linked to the COCA1 locus (LOD = 4.21), and a second family is likely to be linked (LOD = 0.92). In three families linkage was excluded. In the remaining two families the data were inconclusive. In the linked family, individuals with cancer of the endometrium or ureter share a common haplotype with 12 family members with colorectal cancer. This supports the suspected association between these extracolonic neoplasms and the HNPCC syndrome. In addition, five of the six individuals with adenomatous polyps (but no colorectal cancer) have the same haplotype as the affected individuals, while the sixth carries a recombination. One individual with colorectal cancer carries a recombination that places the COCA1 locus telomeric to D2S123. This study localizes the COCA1 gene to an 8-cM region that is consistent with the location of the hMSH2 gene. We also confirm that families presently classified as HNPCC are genetically heterogeneous.

Adenomatous Polyps↗
PubMed1993

The expression of mouse biliary glycoprotein, a carcinoembryonic antigen-related gene, is down-regulated in malignant mouse tissues.

Mouse biliary glycoprotein (Bgp) is a member of the carcinoembryonic antigen gene family and is highly expressed in the epithelial cells of normal hepatic biliary ducts and intestine. Nine mouse Bgp isoforms have been identified through molecular cloning and shown to be splice and allelic variants of one Bgp gene. These glycoproteins function in vitro as intercellular adhesion molecules and serve as the mouse hepatitis virus receptors. Since human carcinoembryonic antigen is overexpressed in gastrointestinal tumors, we have investigated the expression of mouse Bgp in primary tumors and carcinoma cell lines. Our results demonstrate that the expression of the major mouse Bgp isoforms is down-regulated in tumors at the transcriptional and the posttranscriptional levels. This decrease in expression is corroborated by immunostaining of primary colonic tumors with anti-mouse Bgp antibodies. In addition, Bgp expression is influenced by transcriptional control mechanisms involving DNA methylation of the Bgp gene upstream regulatory region. Our results demonstrate that mouse Bgp protein expression is decreased upon malignant transformation and further suggest that Bgp proteins may be involved in the maintenance of the differentiated cellular phenotype.

3T3 Cells↗
PubMed1993

Prognostic significance of proliferating cell nuclear antigen expression in colorectal cancer.

BACKGROUND: Recognition of a biologic marker in colorectal cancer tissue that correlates with recurrence and poor survival would offer a rationale for planning aggressive adjuvant therapy. This study assessed the prognostic significance of proliferation activity in cancer cells and nonneoplastic epithelial cells in patients with colorectal cancer, using proliferating cell nuclear antigen (PCNA) immunohistochemical analysis. METHODS: A mouse monoclonal antibody that reacted with PCNA was used to measure proliferation indexes in neoplastic and nonneoplastic colonic tissues of two sex-matched and age-matched groups of 40 patients with different clinical outcomes. In one group of 20 patients, there was no evidence of recurrence or residual disease after a median follow-up of 5.3 years. In the other group, all 20 patients had died within 3.6 years of recurrent disease. RESULTS: The proliferation indexes in both cancer cells and epithelial cells of adjacent nonneoplastic crypts were elevated significantly in those who died compared with survivors; this finding was independent of other variables. There was evidence of an upward shift in the proliferation compartment of the normal crypt that occurred to the same extent in both patient groups. No correlation between Dukes stage and any of the proliferation indexes was observed. CONCLUSION: Proliferation indexes in neoplastic and adjacent normal mucosa, as defined by PCNA immunohistochemical analysis, are independent predictors of recurrence and poor survival in patients with colorectal cancer, indicating that they may be helpful as predictors of long-term survival and in planning prophylactic adjuvant therapy.

Aged↗
PubMed1993

Turcot's syndrome of glioma and polyposis occurs in the absence of germ line mutations of exons 5 to 9 of the p53 gene.

The term "Turcot's syndrome" has been used to describe approximatively 55 patients with an association of colonic polyposis and primary neuroepithelial tumors of the central nervous system. The p53 tumor suppressor gene is a possible candidate underlying the syndrome because (a) mutations in the p53 gene are ubiquitous in human cancer, including colon carcinoma and gliomas, and (b) somatic or germ line mutations of the p53 tumor suppressor gene cause the Li-Fraumeni syndrome, which is characterized by the association of breast and soft tissue tumors. We determined the DNA sequence of the conserved regions of the p53 gene (exons 5 to 9) in the tumor tissues and lymphocytes of two patients with glioma-polyposis and found that mutations did occur as independent tumor-specific alterations but did not involve the germ line of these patients, suggesting that p53 may play a role in progression but not initiation of the disease.

Base Sequence↗
PubMed1993

Acute fatty liver of pregnancy after exposure to toluene. A case report.

We describe a patient in whom acute fatty liver of pregnancy developed after long-term toluene exposure. Acute fatty liver of pregnancy was documented by a liver biopsy specimen stained with oil red O and observed under electron microscopy. Although the mother did well, she gave birth to a stillborn whose autopsy showed visceral congestion and placental infarction. This case raises the hypothesis of a possible relationship between toluene exposure and acute fatty liver of pregnancy.

Acute Disease↗
PubMed1993

Carcinoembryonic antigen isotypes in tissue sections and loose cyst fluid cells of ovarian neoplasms.

The aim of this study was to establish whether different subsets of ovarian neoplasms express a restricted isotype of carcinoembryonic antigen (CEA) which can be detected in solid tumors and detached cells. Sixty-one cases of mucinous, serous, endometrioid, and Krukenberg tumors were studied by immunohistochemistry using two monoclonal antibodies (MAbs), commercial anti-CEA and D14 with a higher specificity for colorectal adenocarcinomas. The results with both antibodies showed a considerable degree of heterogeneity between cases of nonserous tumors, with a more restrictive pattern observed with the D14 MAb. The proportion of immunostained cells was comparable in tumors and fluids.

Adenocarcinoma↗
PubMed1993

Localization and measurement of corticostatin-I in nonpregnant and pregnant rabbit tissues during late gestation.

Corticostatin-I (CSI) is the most potent of the corticostatic peptides isolated from rabbit lungs and neutrophils. CSI was localized in cells by immunohistochemistry using highly specific polyclonal antisera raised against the synthetic peptide. Western blot showed a single 4-kilodalton band, indicating that the antibody employed was specific for CSI in spleen, intestine, adrenal, and lung, but no CSI band was observed in liver. CSI was localized to macrophages in spleen, adult lung, placenta, and adult duodenum. CSI was found in epithelial cells of the upper half of the villi of the small intestine, but not in the Paneth cells. In the adrenal, CSI staining was observed only in the zona fasciculata and zona reticularis, and no immunostaining was observed in kidney, liver, heart, or ovary. CSI was measured in the maternal and fetal tissues of the pregnant rabbit on days 24, 27, and 30 of gestation and in nonpregnancy tissues. First, the peptide was extracted using mild acid conditions, purified by HPLC, and then quantitated by RIA. Immunoreactive CSI was highest in lung, spleen, intestine, and adrenal. In the brain, CSI was found in higher amounts in the pituitary, hypothalamus, and thalamus, with peak values observed at 27 days gestation. The largest amounts were found in the pituitary and hypothalamus of the nonpregnant animal. Rabbit lung had large amounts of immunoreactive CSI, with rising values in both maternal and fetal lung with progressing gestation. Again, the highest amounts were found in the lung of the nonpregnant rabbit. The adrenal contained large amounts of immunoreactive CSI, and the fetal adrenal concentrations declined with progressing pregnancy, whereas the maternal adrenal values were much lower and showed a small decline at 27 and 30 days gestation. The placenta had large amounts of immunoreactive CSI, which increased with progressing gestation. In fetal and maternal plasma, there were small amounts of ACTH, which remained constant in the maternal circulation, but increased in the fetal circulation with progressing gestation. Immunoreactive CSI was present in plasma in a much higher concentration, which decreased in the fetal compartment but increased in the maternal compartment with progressing gestation. The data presented indicate that CSI is localized to a large number of tissues in the rabbit, as visualized by immunoperoxidase staining, and that in a number of tissues it is found in macrophages. After HPLC purification from tissues, CSI was measured by RIA and found in all tissues examined except liver, kidney, heart, and ovary.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Transcription of carcinoembryonic antigen in normal colon and colon carcinoma. In situ hybridization study and implication for a new in vivo functional model.

Recently carcinoembryonic antigen (CEA) has been functionally identified in vitro as a cell adhesion protein. Identification of its function in vivo requires knowing how CEA mRNA is transcribed in intact tissues. For this purpose, 16 cases of colon adenocarcinomas and autologous normal colon were studied by quantitative in situ hybridization for the expression of CEA mRNA. Normal colonic crypts displayed an upward gradient of mRNA expression. In colon carcinoma, tumor cells at the deep invading front of the tumor contain 2.6 times more CEA mRNA than tumor cells near the luminal surface. Immunoelectron microscopy showed intercellular CEA. In normal colon and colonic carcinoma, changes in CEA mRNA were paralleled by similar gradients in CEA protein, consistent with a transcriptional regulation of CEA expression. A new in vivo model of CEA function is presented to account for this overexpression of CEA occurring at sites characterized by changes in cell adhesion. The model requires that secreted CEA inhibits cell adhesion mediated by cell-bound CEA.

Aged↗
PubMed1991

Antiserum against tumor necrosis factor-alpha and a protease inhibitor reduce immune glomerular injury.

Previous studies in this laboratory have documented tumor necrosis factor alpha (TNF) release by macrophage laden glomeruli in the accelerated autologous form of nephrotoxic serum nephritis (AA-NTSN). We now report that the administration of anti-TNF antiserum to rats with the AA-NTSN reduces albuminuria in a dose related manner (day 8 postinduction) and limits glomerular necrosis (P less than 0.05) without affecting the endogenous creatinine clearance (CCr). Protease inhibitors block cytolytic activity of TNF in vitro and reduce glomerular necrosis in experimental nephritis in vivo. The combined administration of anti-TNF antiserum and an amidine-type protease inhibitor (BABIM) to rats with the AA-NTSN caused a greater diminution of albuminuria and histopathology than observed in rats treated with either agent alone, and also prevented the fall in CCr otherwise observed in this model system. Since, in our studies, BABIM did not inhibit cytolytic TNF activity in vitro, we conclude that the effects of combined administration of these two agents are mediated by independent mechanisms. Our results highlight the pathogenic significance of local TNF release in immune renal disease accompanied by prominent glomerular macrophage accumulation.

Albuminuria↗
PubMed1990

Interleukin-6 and its receptor are expressed in human intestinal epithelial cells.

Recent studies have suggested that intestinal epithelial cells demonstrate some of the functions associated with immune competent cells. Based on these observations, we investigated whether gastrointestinal epithelial cells express Interleukin-6 (IL-6). The presence of this cytokine was tested in 53 normal and pathological tissue specimens of the human gastrointestinal tract using an immunohistochemical technique with anti-IL-6 monoclonal and polyclonal antibodies. Immunostaining shows that IL-6 is expressed in gastric and small intestinal epithelial cells. The tumor cells from a large subset (11 of 15) of colon cancer specimens were strongly immunostained. IL-6 immunostaining was less conspicuous and less frequent in the epithelial cells of normal colonic mucosa. Northern blot experiments indicated that the expression of IL-6 in colonic mucosa correlates quantitatively with the presence of its m-RNA. Furthermore, IL-6 receptor (IL-6R) m-RNA was also detected and was twice as abundant in colonic carcinoma as in normal colon. It is concluded that mucosal epithelial cells of the gastrointestinal system express IL-6 and that in the case of the colon, malignancy is accompanied by a higher expression. In addition, the presence of IL-6R transcript suggests that normal and neoplastic colonic epithelial cells might be autocrinally regulated by IL-6.

Antibodies, Monoclonal↗
PubMed1990

Isolation and immunohistochemical characterization of a pancreatic carcinoma-associated monoclonal antibody.

The aim of this study was to define a cellular antigen associated with human pancreatic ductal carcinoma, and to study its distribution in a large panel of malignant, benign, and normal tissues. For this purpose, monoclonal antibodies were generated against a postmicrosomal fraction of fresh human pancreatic cancer. One such antibody, LD-B1, reacted strongly with 95% of cases of primary and metastatic pancreatic ductal carcinomas. It also immunostained gallbladder carcinomas and cholangiocarcinomas. By contrast, it exhibited focal or weak reactivity to 10% of other types of common malignant tumors. On normal pancreas, staining was observed in ductal and centriacinar cells, but not in acinar or endocrine cells. In chronic pancreatitis, ductal staining intensity increased proportionally with the degree of cellular atypia. The antigen was also detected in gallbladder epithelium, bile ducts, ductal epithelium of sweat glands and salivary glands, and focally in a few other normal nonpancreatic tissues. These results suggest that LD-B1 MoAb can be used in immunohistochemical studies as a marker of pancreatic adenocarcinoma.

Adenocarcinoma↗
PubMed1990

Biochemical characterization and serological immunoassay of a pancreatic carcinoma-associated antigen defined by monoclonal antibody LD-B1.

Several glycosylated macromolecules associated with normal and malignant pancreatic ductal cells have been described. We have generated a monoclonal antibody, LD-B1, by immunizing Balb/c mice with the postmicrosomal extract of fresh human pancreatic ductal carcinoma tissue and used it in this study to characterize the nature of the target antigen. The antigen detected by LD-B1 antibody was purified to homogeneity by affinity chromatography. Enzymatic and biochemical analysis showed it to be a nonsialylated glycoprotein that on Western blotting and immunoprecipitation analyses had an apparent molecular weight of 300-400 kDa. The mobility on gels was not affected by reducing or denaturing conditions. Competitive inhibition assays with various MoAbs and lectins indicated that the epitope recognized by LD-B1 antibody involves the carbohydrate sequence Gal beta 1----3Gal beta 1----3(or 4)GlcNAc beta 1----3Gal. Using a double determinant sandwich ELISA, elevated antigen levels were detected in the sera of 5 of 6 patients with pancreatic carcinoma, 0 of 3 patients with chronic pancreatitis, and 12 of 137 normal controls. These results suggest that patients with pancreatic carcinoma exhibit altered expression of a heavily glycosylated molecule related to a blood group precursor immunodeterminant.

Animals↗
PubMed1990

Characterization of a monoclonal antibody against a mucin-type glycoprotein in human sweat.

We report the preparation and characterization of an IgG2 monoclonal antibody (MAb), HSMA, prepared against a human pooled sweat extract (HPSE). The major component of HPSE was a mucin-type molecule, as revealed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) stained with periodic acid-Schiff (PAS) reagent. By immunoblotting, HSMA revealed a smear in the high molecular weight range, typical of mucins. In enzyme-linked immunosorbent assay (ELISA), HSMA failed to react with HPSE fractions isolated after anionic exchange gel chromatography. Similarly, radio-immunobinding assays demonstrated no reactivity between HSMA and A, B, H, and Lewis blood group-related structures. The immunohistological labeling on normal skin showed that HSMA reacted with the cells of eccrine sweat glands, and to a lesser extent, with sebaceous glands and epidermal cells. Periodate treatment in situ abolished these reactions, thus suggesting the carbohydrate structure of the HSMA-epitope. In indirect immunofluorescence (IF) studies, HSMA also reacted with other exocrine glands, e.g. mammary glands, sublingual glands, mixed sero-mucous glands of the trachea, and in the pancreas. Sparse positive cells were also observed in the testis, kidney, thyroid and digestive tract.

Animals↗
PubMed1990

Spatiotemporal expression of murine carcinoembryonic antigen (CEA) gene family members during mouse embryogenesis.

Carcinoembryonic antigen is a glycosylated protein used as a human tumor marker to assess recurrences of gastrointestinal, breast and lung cancers. This protein is a member of the immunoglobulin supergene family and has been shown to function as a homophilic and heterophilic cell adhesion molecule. We have studied the spatial and temporal expression of two cloned mouse CEA gene family members during development using Northern analyses and in situ hybridization. Transcripts detected by the mouse CEA probes are expressed from 10.5 days post coitum (p.c.) to birth in mouse embryos and fetuses and are present from 16.5 days p.c. to adulthood in intestine and colon as evaluated by Northern analyses. The RNA is also present in many other tissues including meninges, cartilage and bone, blood vessel walls, placenta, dermis, muscle layers of the stomach and intestine and bronchioles of developing mouse embryos and fetuses. This expression pattern is similar to that of proteins of the Transforming Growth Factor beta gene family. The role of mouse CEA gene family members is unclear; however, the localizations of these CEA family members in the mouse embryo and fetus suggest an important functional role during active morphogenesis, a complex process in which cell adhesion molecules are significantly involved.

Animals↗
PubMed1989

Carcinoembryonic antigen, a human tumor marker, functions as an intercellular adhesion molecule.

Carcinoembryonic antigen (CEA) is a member of a family of cell surface glycoproteins that are produced in excess in essentially all human colon carcinomas and in a high proportion of carcinomas at many other sites. The function of this widely used tumor marker and its relevance to malignant transformation is therefore of considerable interest. We demonstrate here that CEA mediates Ca2+-independent, homotypic aggregation of cultured human colon adenocarcinoma cells (LS-180) and rodent cells transfected with functional CEA cDNA. Furthermore, CEA can effect the homotypic sorting of cells in heterogeneous populations of aggregating cells. CEA can thus be considered a new addition to the family of intercellular adhesion molecules. We also show that, whereas CEA is localized mainly to epithelial cell membranes facing the lumen in normal adult intestine, it is found on adjacent cell membranes in both embryonic intestine and colonic tumors. A model for the role of CEA in the tissue architecture of adult, embryonic, and aberrant tumor intestinal epithelium is presented.

Biomarkers, Tumor↗
PubMed1989

Transient nuclear location of the IL-2 receptor during T cell activation.

Binding of interleukin-2 (IL-2) to its membrane receptor (IL-2R) on target cells is followed by internalization of the IL-2R. The subsequent intracellular fate of IL-2R is not known. This paper describes the intracellular location of the p55 subunit of the IL-2R during IL-2 mediated T cell activation and growth of two mouse T helper clones. IL-2R was visualized by immunohistochemistry using two rat monoclonal antibodies (5A2 and 7D4). Immunostaining shows that the p55 subunit of the IL-2R is transiently present in the nucleus of activated T cells. The intranuclear location of the IL-2R suggests that the p55 subunit, either alone or in conjunction with the IL-2 or the p70 subunit, may be implicated in the regulation of gene expression involved in T cell proliferation.

Animals↗