Biomedical subjects

U Mandel

Publications and source records attributed to U Mandel.

At least 19 recordsLinked to original sources

PubMed1992

Expression of histo-blood-group-A/B-gene-defined glycosyltransferases in normal and malignant epithelia: correlation with A/B-carbohydrate expression.

Malignant transformation of oral and bladder epithelia is often associated with loss of histo-blood-group-A- and -B-carbohydrate antigens, whereas these antigens, which are absent in normal adult distal colon (but present in fetal colon) reappear in malignant distal colon. In order to gain insight into the genetic basis of the biosynthetic regulation for these changes, we have correlated the expression of the A- and B-carbohydrate antigens with that of the A/B-gene-defined glycosyltransferases in colon, bladder and oral carcinomas by immunohistology. A newly developed anti-A/B-transferase monoclonal antibody (MAb) was used to demonstrate the in situ localization of transferase expression at the individual cell level with correlation to carbohydrate antigen expression, and gave the essential information that the transferase is derived from the ABO gene complex. The reappearance of A- and B-carbohydrate antigens in carcinomas of the distal colon was found to be unrelated to the expression of the A/B-transferase proteins, which were expressed throughout normal adult colon in accordance with previous enzymatic studies. In contrast, the loss of A- and B-carbohydrate antigens in malignant bladder and oral epithelia was accompanied by concordant loss of enzymes.

ABO Blood-Group System↗

PubMed1992

The distribution of type-2 chain histo-blood group antigens in normal cycling human endometrium.

The blood group ABO(H) determinants are major allogenic antigens in both erythrocytes and tissue of man. These antigens and related carbohydrates are markers of cellular maturation and differentiation in many epithelial tissues and have recently attracted great interest as tumor-associated antigens. Previous studies of endometrial tissues have indicated that glycosylation in this tissue may be related to hormonal stimulation. We have investigated the immunohistochemical distribution of type-2 chain histo-blood group-related carbohydrates in specimens of normal, cycling endometria obtained from hysterectomies on women with known ABO/Lewis erythrocyte type and saliva secretor status. N-acetyllactosamine and Le(x) were demonstrated to be uninfluenced by the genetic background. A and Ale(y) antigens were exclusively demonstrated in endometria from blood group A individuals, while Le(y) was expressed in endometria from blood group 0 individuals mainly. The precursor N-acetyllactosamine as well as the terminal H, A, and ALe(y) antigens were shown in only a few cells. In contrast, N-acetyllactosamine substituted by sialic acid and/or fucose residues (Le(x), sialosyl-Le(x), Le(y)) were demonstrated in epithelial cells of normal, cycling endometrium, but with both quantitative and qualitative differences in staining relating to the menstrual cycle, indicating that type-2 chain antigens are expressed under both genetic and hormonal influence in human cycling endometrium.

Animals↗

PubMed1992

Altered expression of ABO (H) carbohydrate antigens is seen in pleomorphic adenomas.

Cell surface carbohydrate antigens show changes in relation to differentiation, maturation and malignant transformation. The expression of type 2 chain ABH carbohydrate structures of the ABO histo-blood group system was investigated in 28 pleomorphic adenomas (PA) and normal parotid glands in order to study possible changes in the glycosylation pattern. The distribution of carbohydrate structures was investigated by immunohistological stainings of formalin-fixed paraffin-embedded material using monoclonal antibodies (MAbs) with well-defined specificity. A strong interindividual variation was found in the normal tissue as well as in the tumors. In normal tissue, acinus and duct cells all expressed elongated carbohydrate structures. The yoepithelial cells did not stain with any of the MAbs investigated. In the PAs, staining was seen in the ductular structures and myoepithelial cells. In contrast to normal tissue, the tumors expressed the short precursor molecule sialylated N-acetyllactosamine. Furthermore, the PAs showed loss of H and A antigens, and a reduced expression of Le(y) compared to normal tissue. The ductular structures as well as the modified myoepithelial cells expressed binary N-acetyllactosamine, which in the normal tissue could only be found in the striated and excretory ducts. Thus our study has shown that aberrant glycosylation is not only a feature of malignant neoplasms but also occurs in pleomorphic adenomas.

ABO Blood-Group System↗

PubMed1992

Cancer-associated changes in glycosylation of fibronectin. Immunohistological localization of oncofetal fibronectin defined by monoclonal antibodies.

The extracellular matrix adhesion molecule fibronectin exhibits different isoforms derived by alternative splicing as well as recently demonstrated variation in O-glycosylation. Although fibronectin is widely distributed in normal tissues, the individual isoforms have been found to show restricted tissue distribution and association with malignancies. The monoclonal antibody FDC-6 defines a cancer-associated de novo glycosylation of a specific threonine residue in the C-terminal region of the fibronectin molecule termed oncofetal fibronectin. Here we report an immunohistological study of oral squamous cell carcinomas (n = 33), premalignant lesions (n = 15), and normal oral mucosa (n = 10) using the FDC-6 antibody. A selective expression of the oncofetal fibronectin epitope was demonstrated in close relation to the invading carcinoma, whereas no staining was observed in premalignant lesions without epithelial dysplasia, or in normal epithelium. Furthermore, we attempted to identify additional carbohydrate-related epitopes distinguishing fibronectin of human hepatoma cell line HUH-7 from plasma fibronectin. No novel epitopes were identified, as all generated monoclonal antibodies lacking reactivity with plasma fibronectin showed the same specificity as FDC-6. Previous studies have indicated that the de novo glycosylation is induced by a novel transferase activity only found in fetal and carcinoma cell lines, placenta and hepatoma tissues. Here we provide further evidence that a purified UDP-GalNAc:peptide N-acetylgalactosaminyltransferase from normal bovine thymus and human placentae is incapable of utilizing the hexapeptide VTHPGY as a substrate. The results demonstrate that oncofetal fibronectin is highly associated with malignancy, and appears to be induced by expression of a unique glycosyltransferase or modification of the specificity of the normally expressed transferase.

Aged↗

PubMed1992

Carbohydrates in oral epithelia and secretions: variation with cellular differentiation.

The oral mucosa has been extensively studied in the past, and has thus become a model for demonstration of dynamic changes in cellular glycosylation and many other cell products such as keratins in relation to epithelial differentiation. The extensive knowledge of the glycosylation pattern in normal cells is instrumental in evaluation of the often occurring aberrant glycosylation of carcinoma cells. The emerging developments in antibodies to the glycosyltransferases and probes for their genes will enable us to gain insight into the regulatory mechanisms leading to the apparently well-controlled glycosylation process in epithelia. The first example of such a correlation has been studied in oral epithelia.

Antibodies, Monoclonal↗

PubMed1992

Carbohydrate changes in squamous cell carcinomas.

Cell surface carbohydrates serve as differentiation and development markers characteristic of different cell and tissue types. The expression of these carbohydrate antigens is often significantly altered in tumours, particularly in those arising from epithelial tissues. Analyses of cell surface carbohydrates in stratified epithelium have shown a remarkable variation in glycosylation pattern in relation to terminal differentiation. The carbohydrate expression is altered in squamous cell carcinomas and in premalignant lesions. There is evidence that the expression of certain carbohydrate structures in the deep invasive part of the tumours is correlated with tumour prognosis. The change in carbohydrate expression can at present be explained by the lack of synthesis of specific glycosyltransferases. New evidence suggests that the expression of certain carbohydrate structures may be importance for the formation of metastasies.

Antigens, Tumor-Associated, Carbohydrate↗

PubMed1991

Simple mucin-type carbohydrates in oral stratified squamous and salivary gland epithelia.

Simple mucin-type carbohydrate antigens, T, Tn, and sialosyl-Tn, have been found to be good markers of malignant transformation in several epithelial tissues as a result of incomplete synthesis with precursor accumulation. The T, Tn, and sialosyl-Tn antigens represent the initial, most immature glycosylation of serine and threonine amino acids of proteins. In normal adult cells these structures are generally masked by addition of further saccharides to form more complex structures. We analyzed simple mucin-type carbohydrates in human labial stratified squamous and minor salivary gland epithelia in order to define the glycosylation pattern in normal cells in relation to epithelial differentiation and maturation. A panel of monoclonal antibodies with well-characterized specificity for T, Tn, sialosyl-Tn and the histo-blood group H and A variants hereof were used in immunohistology of sections from 30 individuals with known ABO, Lewis, and secretor status. In stratified epithelium the sialylated T structure was confined to cell membranes of immature basal cells, whereas the H and A variants were observed on cell membranes of more mature parabasal and spinous cell layers. Furthermore, superficial spinous cells produced a fine granular cytoplasmic staining for Tn and sialosyl-Tn antigens. In minor salivary glands mucous cells expressed Tn and sialosyl-Tn as well as the H and A variants in the area of the nucleus, whereas T and the H variant were found in duct cells and unsubstituted T antigen in myoepithelial cells. These results indicate that incomplete synthesis, i.e., deletion of sialyltransferases and/or histo-blood group ABH transferases, may result in accumulation of T, Tn, and sialosyl-Tn antigens in oral epithelia, thus offering a baseline for further studies of changes in premalignant and malignant oral epithelia.

Antibodies, Monoclonal↗

PubMed1991

Lewis blood group antigens in salivary glands and stratified epithelium: lack of regulation of Lewis antigen expression in ductal and buccal mucosal lining epithelia.

The expression of Lewis antigens is thought to be controlled by the Secretor and Lewis genes. While secretor status is known to regulate the expression of ABH antigens in many tissues, few studies have attempted to correlate Lewis antigen expression on erythrocytes and saliva with that of epithelial tissues. We examined the expression of Lewis a and b and related antigens in human epithelium of minor salivary glands and labial nonkeratinized oral mucosae from 16 individuals by immunohistology using monoclonal antibodies. The expression of these antigens, as detected by monoclonal antibodies (MAbs) used, was correlated with erythrocyte phenotype and saliva secretor status. In acinar cells of glands, Leb antigen was expressed only in secretors, and Lea only in nonsecretors. However, in gland ducts and oral mucosae, Leb was found in both secretors and nonsecretors, as well as in 2 cases of Lea-b-, secretors. Thus, antigen expression in acinar cells of minor salivary glands was correlated with the predicted genotypes, whereas inappropriate expression of Leb antigen was found in epithelial cells of gland ducts and oral mucosae. The present data indicate that the Lewis blood group phenotype is regulated differently in duct cells and stratified epithelium than in saliva and erythrocytes.

Carbohydrate Sequence↗

PubMed1991

Expression of mucin type carbohydrates may supplement histologic diagnosis in oral premalignant lesions.

Recent studies have shown that changes within membrane bound carbohydrates may be essential for cellular differentiation and malignant transformation. We have therefore, by means of immunohistochemistry, studied the expression of T/Tn related (Thomsen-Friedenrich) carbohydrates in 13 oral lesions with squamous cell dysplasia. The epithelial grade of dysplasia was graded as mild, moderate or severe. The following carbohydrate structures were studied: Tn, T, mucintype 3 chain H, and the sialylated derivates, sialosyl-Tn and sialosyl-T. In general, short structures were detected on the basal cells and longer structures on the more mature spinous cells. In many cases, this sequential expression was more disturbed with increasing grade of epithelial dysplasia. However, our results also showed that some lesions with the same grade of epithelial dysplasia showed different carbohydrate expression. These findings indicate that expression of carbohydrates may supplement histologic diagnosis in the evaluation of the prognosis of premalignant lesions.

Antigens, Surface↗

PubMed1991

Aberrant glycosylation in oral malignant and premalignant lesions.

Cell surface carbohydrates serve as differentiation and developmental markers characteristic of different cell and tissue types. The expression of these carbohydrate antigens is often significantly altered in tumors, particularly in those arising from epithelial tissues. Analysis of cell surface carbohydrates in oral epithelium have shown that in normal epithelium they are expressed in a way that shorter carbohydrates are found on basal cells and that these carbohydrate structures are elongated parallel to terminal differentiation. The carbohydrate expression is altered in oral carcinomas and in some oral premalignant lesions. The change in carbohydrate expression can at present be explained by the lack of synthesis of specific glycosyltransferases. We have found mosaicism in the expression of carbohydrate antigens in all tumors and have found that the expression of a specific carbohydrate in the deep invasive parts of the tumor correlates with tumor prognosis.

Carbohydrate Metabolism↗

PubMed1991

Cell surface carbohydrates are markers of differentiation in human oral epithelium.

Carbohydrates of the epithelial cell membrane are involved in cell-cell and cell-substrate interaction, and changes are seen in relationship to cell differentiation and neoplastic transformation. The terminal part of carbohydrate structures carried on oral epithelial cells often expresses antigens of the ABO and Lewis blood group systems. The expression of these antigens are in oral mucosa genetically regulated by the A, B, H, Lewis, and secretor genes with subsequent correspondence between the blood group antigens expressed on erythrocytes and on oral epithelial cells. Variation in expression of carbohydrates is also seen in relationship to terminal differentiation in that blood group antigens and their immediate precursor structures are sequentially expressed on cells during their pathway through the epithelium. Various organs and tissues differ in their expression of cell surface carbohydrates. In oral mucosa, a close relationship is seen between the type of tissue differentiation and expression of blood group antigen; keratinized, nonkeratinized, and junctional epithelium all show different patterns of carbohydrate expression.

Antigens, Surface↗

PubMed1991

Distribution of histo-blood group antigens in cervical and uterine endometrium.

Cell surface carbohydrates serve as differentiation and developmental markers characteristic of different cell and tissue types. Expression of these carbohydrate antigens is often significantly altered in tumors particularly in those arising from epithelial tissues. Analysis of the expression of cell surface carbohydrates in normal endometrium has shown that this glycosylation is hormonally influenced. Change in expression of carbohydrates in malignant tissue should therefore be evaluated against this normal fluctuation. In normal cervical uterine epithelium the result shows that the glycosylation of metaplastic squamous cells is different from that of original squamous cells indicating that the regulation and differentiation of the epithelium in the transformation zone is different from that of the original squamous epithelium. This variation in expression of carbohydrates seen in the metaplastic epithelium may be of importance for the development of carcinomas in this area.

Antigens, Surface↗

PubMed1990

Murine monoclonal antibodies directed to the human histo-blood group A transferase (UDP-GalNAc:Fuc alpha 1----2Gal alpha 1----3-N-acetylgalactosaminyltransferase) and the presence therein of N-linked histo-blood group A determinant.

Mouse MAbs (WKH-1 through -3) to the human histo-blood group A glycosyltransferase (Fuc alpha 1----2Gal alpha 1----3 galactosaminyltransferase) were established by immunization with the purified native A transferase protein. Hybridomas were selected on the basis of solid-phase reactivity with the purified native A transferase, cell immunofluorescence and immunoprecipitation of transferase activity, and absence of reactivity with blood group ABH carbohydrate determinants. Three MAbs, thus selected, were found most likely to react with the protein epitopes unrelated to carbohydrate epitopes of purified A transferase. The MAbs reacted with cells having high A transferase activity and immunoprecipitated the A transferase activity as well as the 40,000 MW iodinated transferase protein. The antibodies were shown, however, to immunoprecipitate and partially inhibit not only A1 and A2 but also B transferase activity from plasma and A transferase from human lung, and to react with B cells expressing B transferase, thus indicating a cross-reactivity with B transferase. In contrast, they showed no reactivity with various cells having the O phenotype and did not immunoprecipitate the A transferase from porcine submaxillary glands or the alpha 1----2fucosyltransferase from Colo205 cells. The purified A glycosyltransferase was found to carry blood group A carbohydrate determinants by immunochemical detection with a panel of anti-carbohydrate MAbs. These determinants are believed to be N-linked, since treatment of the purified A transferase with N-glycanase removed activity. Immunohistological studies of three epithelial tissues showed that the antibodies stained the Golgi area of cells in epithelia from A and B, but not O, individuals.

ABO Blood-Group System↗

PubMed1990

Expression of the histo-blood group ABO gene defined glycosyltransferases in epithelial tissues.

The histo-blood group ABO carbohydrate antigens are differentially expressed in epithelia in close correlation with cellular differentiation. In order to gain insight into the biosynthetic regulation of these carbohydrate antigens, we correlated the expression of A carbohydrate antigens with that of the A gene defined glycosyl-transferase by immunohistology of human oral epithelia using monoclonal antibodies. In glandular epithelium the A transferase was found in mucous cells similar to that of the A carbohydrate antigens. In stratified non-keratinized squamous epithelium the A transferase was expressed only in spinous cell layers, which is in accordance with the appearance of the A carbohydrate antigens in these more mature cell layers. This simultaneous acquisition of the primary and secondary gene product of a glycosyltransferase gene, provides evidence that the well-defined sequential expression of histo-blood group carbohydrate antigens in stratified squamous epithelium may be directly regulated at the transcriptional level of the glycosyltransferase. Future studies will address the mechanism behind loss of A antigens in premalignant lesions and carcinomas.

ABO Blood-Group System↗

PubMed1990

Cell surface glycosylation patterns in psoriasis.

Cell surface carbohydrates are excellent markers of cellular differentiation and maturation processes due to their great structural and antigenic diversity as well as their known biosynthetic precursor/product relationships. Using a panel of monoclonal antibodies with well-defined carbohydrate specificities we have studied the expression of biosynthetically related antigens in normal and psoriatic skin. Two "families" of carbohydrate structures were investigated. One series of structures based on N-acetyllactosamine chains (type 2 chain: N-acetyllactosamine and fucosylated derivates hereof of H, Lex, Ley and sialyl-Lex) and another based on the simple mucin type core structures (type 3 chain: Tn, T and sialylated derivates hereof as well as the fucosylated derivative, H). Previously we have found these carbohydrate structures define distinct cell layers in stratified squamous epithelia of mucosa of the cheek, esophagus and uterine cervix. In normal and uninvolved epidermis, N-acetyllactosamine and T carbohydrates were found in the spinous cell layer, whereas the fucosylated derivates, H structures, were found in the granular cell layers above. The fucosylated and sialylated derivate of N-acetyllactosamine, sialylated Lex, had the same distribution as N-acetyllactosamine and T structures. This sequential expression of carbohydrates is similar to our previous findings in mucosa. However, in contrast to mucosa, normal skin basal cells did not label. The glycosylation pattern in psoriatic epithelium was changed in two ways. 1) Some carbohydrates (types 2 and 3 chain H and T) were expressed at an earlier stage of cell maturation. 2) The biosynthetic precursors to T structures, Tn and sialyl-Tn, which are not expressed in normal skin, and are often considered cancer-associated antigens, appeared in psoriatic skin. The Tn-antigen was expressed on basal and lower spinous cells, whereas the sialyl-Tn was only found on basal cells above the dermal papillae. The findings in the present work support previous studies of changes in cell surface glycosylation in psoriatic epidermis and demonstrate the appearance of tumor-associated antigens in highly proliferative, but benign, stratified epithelium.

Adult↗

PubMed1989

A series of disialogangliosides with binary 2----3 sialosyllactosamine structure, defined by monoclonal antibody NUH2, are oncodevelopmentally regulated antigens.

A mouse IgM monoclonal antibody, NUH2, was raised after immunization of mice with the disialoganglioside fraction of human colonic adenocarcinoma. This antibody reacts specifically with disialogangliosides having the Structure 1 shown below. (formula; see text) NUH2 does not react with structures lacking the sialic acid at either the beta 1----3 or beta 1----6 side chain, nor with a binary structure having unequal chain lengths, nor with a binary type 2 chain structure having a trimannosyl core as found in the side chain of N-linked complex type oligosaccharides. (formula; see text) In humans, the disialoganglioside antigens defined by antibody NUH2 are present in low quantity in normal cells (e.g., erythrocytes) and tissues, but are expressed highly in some colonic cancers, placenta, trophoblast, and sperm, and can be regarded as oncodevelopmentally regulated antigens.

Adenocarcinoma↗

PubMed1989

Effect of splinting on the mechanical and histological properties of the healing periodontal ligament in the vervet monkey (Cercopithecus aethiops).

Healing of the periodontal ligament (PDL) after extrusive luxation of two upper central incisors was evaluated when one tooth was splinted and the other left untreated. One millimetre thick, transverse sections of tooth, PDL and alveolar bone were examined in a materials testing machine. Load deformation curves were recorded and a number of mechanical properties were assessed. To eliminate the influence of differences in sizes and fibre arrangements, load values were reduced by the area and deformation values by the width of the PDL, and comparisons between splinted and non-splinted teeth were made at identical root levels 2 weeks after injury. Healing was also evaluated histologically at 1, 2, 3, 4 and 8 weeks after injury. There were no significant differences in mechanical and histological properties between splinted and non-splinted teeth, which suggests that splinting is of doubtful value in treatment of extrusive luxated teeth. The values for the mechanical properties of injured PDL had returned to 50-60% of those of uninjured PDL by 2 weeks after injury, indicating a rapid healing rate.

Animals↗

PubMed1989

Expression of blood group antigen-related carbohydrates by human gingival epithelia.

A panel of monoclonal antibodies was used to examine differentiation-related carbohydrate structures on the surfaces of gingival epithelial cells. The patterns of binding observed indicate distinct differences in the expression of the epitopes examined for three regions of the gingival epithelia corresponding approximately to the regions defined anatomically as the junctional, oral sulcular and oral epithelia. However, epithelium with the staining pattern of oral sulcular epithelium consistently extended beyond the sulcular region to cover the gingival crest and often the uppermost part of the oral aspect of the gingiva. Differential staining of basal and suprabasal cells indicated an unusual pattern of differentiation of the junctional epithelium. The phenotype of this epithelium appears to differ from patterns reported for any other oral epithelium and the possible functional significance of this difference is discussed.

Antibodies, Monoclonal↗