Biomedical subjects

J J Ho

Publications and source records attributed to J J Ho.

At least 37 records · Page 2Linked to original sources

PubMed1999

Expression of MUC1 and MUC2 mucin antigens in intrahepatic bile duct tumors: its relationship with a new morphological classification of cholangiocarcinoma.

Our previous immunohistochemical study on intrahepatic bile duct tumors showed that invasive cholangiocarcinoma (ICC) with a poor outcome expressed MUC1 mucin but was negative for MUC2 mucin, whereas bile duct cystadenocarcinoma (BDCC) with a favorable outcome was MUC1 negative and MUC2 positive. In the present study, ICC was further subdivided into 2 subtypes: intraductal growth type and/or periductal infiltrating type (ICC-IP) and mass forming type (ICC-M). The survival of patients with BDCC or ICC-IP is significantly better than that of patients with ICC-M. We examined these subtypes (ICC-IP and ICC-M) and BDCC for their expression of MUC1 mucins of different glycoforms. ICC-M showed significantly higher MUC1 expression rates (90%, 95%, and 85% positive rates as measured with the DF3, MY.1E12, and MUC1-Glycoprotein antibodies, respectively) than BDCC and ICC-IP (14% and 33%, 58% and 58%, and 0% and 50% positive respectively, as measured by the same antibodies). In contrast, BDCC (86% positive) and ICC-IP (67% positive) showed significantly higher MUC2 expression rates than ICC-M (25% positive) as measured with the anti-MRP antibody. Thus, the immunohistochemical staining pattern of ICC-IP resembled the pattern of BDCC more than they resembled ICC-M. In general, MUC1 expression is associated with poor patient outcome, irrespective of the glycosylation status. In particular, high expression of more sialylated forms of MUC1 mucins was correlated with poor survival. In contrast, expression of non-sialylated MUC2 mucin is a favorable prognostic indicator. These results suggest that ICC-IP is a different entity from ICC-M. This reclassification may have value in determining prognosis and treatment method.

Antigens, Neoplasm↗

PubMed1999

Human immunodeficiency virus prevalence in women at delivery using unlinked anonymous testing of newborns in the Malaysian setting.

OBJECTIVE: To determine the community prevalence of human immunodeficiency virus (HIV) in women at the time of delivery in a Malaysian setting. METHODOLOGY: Cord blood samples from a pilot screening programme for congenital hypothyroidism in 1995 at Ipoh city and surrounding district hospitals were screened anonymously for HIV 1 and 2. HIV status was determined using chemiluminescent technology. Positive samples were retested using the Genelavia Mixt assay. RESULTS: A total of 4927 samples were tested. The ethnic breakdown included 51.7% Malays, 18.9% Chinese, 14.3% Indian, 2.3% Others and 12.9% unknown. The geographical distribution of samples was 73.9% urban, 24.2% rural and 1.9% unknown. The seroprevalence of HIV positivity was 3.25 per 1000 deliveries (95% CI: 1.92-5.16). Seroprevalence was higher for samples from rural and Malay mothers. CONCLUSION: The high seroprevalence in this study suggests that the spread of HIV is far wider than that anticipated by mandatory national reporting. It also supports antenatal screening and the use of antiretroviral therapy as an important strategy to reduce perinatal transmission.

AIDS Serodiagnosis↗

PubMed1999

Neurodevelopmental outcome of very low birth weight babies admitted to a Malaysian nursery.

OBJECTIVE: To examine the prevalence and pattern of neurodevelopmental handicap at 2 years of age in very low birth weight infants (VLBW) admitted in 1993 to a level 3 Malaysian nursery. METHODS: All VLBW babies born in the hospital or referred for neonatal care during 1993 were enrolled prospectively in the study. At 2 years of age development was assessed using the Griffiths mental scales. Neurological, hearing and visual assessments were graded into five groups according to functional handicap. Control infants were randomly selected during attendance at a primary health care clinic. RESULTS: One hundred and fifty VLBW infants were admitted and 82 (54.6%) survived to 2 years, of whom 77 (93.9%) were assessed. The mean General Quotient (GQ) on the Griffiths Scales was 94 (15.7) for the study group and 104 (8.3) for the 60 controls. For GQ, 21 (27.3%) of the study population were 1 or more SD below the mean (18 between 1 and 2 SD and 3 > 2 SD) compared with 1 (1.6%) of the controls who was 1-2 SD below the mean. Visual impairment occurred in 2 study infants and none of the controls. There was no hearing impairment in either group. Cerebral palsy occurred in 3 (1 mild and 2 moderate-severe) of the study group and none of the controls. Functionally 18 (23.3%) of the study group had mild handicap, 1 (1.3%) moderate, 2 (2.5%) severe, 2 (2.5%) multiply severe and 54 (70.2%) were normal. CONCLUSION: Although survival was low, overall rates of functional handicap were similar to those reported in developed countries but the proportion with moderate or severe handicap was low.

Analysis of Variance↗

PubMed1999

Preoperative clinical radioimmunodetection of pancreatic cancer by 111 In-labeled chimeric monoclonal antibody Nd2.

The present study was carried out with the purpose of evaluating the clinical usefulness of radioimmunodetection (RAID) with 111In-labeled murine/human chimeric monoclonal antibody, Nd2 (c-Nd2) in patients with pancreatic cancer. Nineteen patients suspected to have pancreatic cancer were administered intravenously 74 MBq/2 mg 111In-labeled c-Nd2 in 100 ml of saline containing 2% albumin over 30 min. A scintigram was obtained on the 3rd day after infusion by using single photon emission computed tomography (SPECT) imaging. Of the 14 patients finally diagnosed as having pancreatic cancer on the basis of surgical specimens or progress of disease, specific focal uptake at the site of the tumor was detected in 12 (true positive cases), representing a sensitivity of 85.7% (12/14), and liver metastasis was found in one case with metastasis. Of the 5 patients diagnosed with tumor-forming pancreatitis (TFP), 4 patients demonstrated true negative imaging, but one patient whose tumor demonstrated interesting findings in histology and immunostaining, showed false positive imaging. Of patients investigated for human anti-chimeric antibody (HACA) response, none showed HACA response, and no allergic reaction was seen in any of the patients administered c-Nd2. These results suggest that RAID with 11In-labeled c-Nd2 is useful for differential preoperative diagnosis between invasive pancreatic cancer and TFP.

Aged↗

PubMed1999

Mucin gene and antigen expression in biliopancreatic carcinogenesis.

Mucins are high molecular weight glycoproteins which are heavily glycosylated with many carbohydrate side chains. In epithelial cancers such as biliopancreatic cancer, both quantitative and qualitative alterations in carbohydrate and polypeptide moieties of mucin glycoproteins occur. These changes in mucin glycoproteins are one of the most common phenotypic markers of biliopancreatic carcinogenesis and may play an important pathobiological role. The expression of some of the sialylated carbohydrate antigens appears to correlate with a poor prognosis and increased metastatic potential in biliopancreatic cancer. The increased exposure of peptide epitopes of mucin glycoproteins in biliopancreatic cancer appears to be due to either abnormal glycosylation and/or altered levels of mucin gene transcription. In addition, dysregulation of tissue specific mucin gene expression occurs in biliopancreatic cancer. This information is currently being exploited for further elucidation of the molecular mechanisms involved in carcinogenesis, tumor progression and metastasis, and the development of novel methods of diagnosis and therapy of biliopancreatic cancer.

Antigens, Neoplasm↗

PubMed1999

Biliopancreatic malignancy: future prospects for progress.

Several key areas are targeted by novel therapies. Growth factors and their receptors are overexpressed in a high percentage of pancreatic tumors. These factors are critical to tumor cell growth and development. They also promote tumor growth by stimulating angiogenesis. Mutations in other molecules that regulate cell growth, such as the ras protein and the tumor suppressor p53, contribute to a state of continuously stimulated cell proliferation. Other types of molecules such as mucins are also altered or overexpressed in tumors. Mucins are immunosuppressive and are important in tumor cell metastasis. A number of promising new therapeutic strategies are now being tested. Ribozymes or antisense nucleic acids can prevent synthesis of growth factor receptors or ras protein. Monoclonal antibodies block interaction between receptor and its ligand. Newly developed drugs prevent tyrosine phosphorylation of growth factor receptors or farnesylation of ras protein. Gene therapy is another approach that is under investigation. Transduction or transfection of genes for wild-type tumor suppressors could correct defects in growth regulation. Vaccines developed against tumor antigens provide hope for the control of not only the primary tumor, but also of the metastatic lesions as well.

Biliary Tract Neoplasms↗

PubMed1997

MUC3 human intestinal mucin. Analysis of gene structure, the carboxyl terminus, and a novel upstream repetitive region.

MUC3 is a large mucin glycoprotein expressed by the human intestine and gall bladder. In this manuscript, we present details of the deduced protein structure of MUC3. The MUC3 carboxyl-terminal domain is 617 residues in length, including 511 residues of a non-repetitive mucin-like domain (27% Thr, 22% Ser, and 11% Pro) and a 106-residue Cys-rich domain with homology to the epidermal growth factor (EGF) -like structural motifs found in many proteins. The region of MUC3 located upstream of the previously described 51-base pair (bp) tandem repeats, which encode a major Ser and Thr-rich domain, consists of a second type of repetitive structure with an imperfect periodicity of approximately 1125 bp. This domain is also mucin-like and appears to be considerably larger than 2000 residues (6000 bp). The MUC3 gene itself is large and complex. Using pulse field gel electrophoresis and blot analysis, the smallest fragment found that contained all human genomic DNA hybridizing to the 51-bp tandem repeat probe was 200 kilobases with restriction enzyme SwaI. Both PvuII and PstI produced two sets of hybridizing fragments that were hypervariable within the human population with a pattern suggestive of both a variation in the number of tandem repeats (VNTR) and sequence polymorphism. These fragments varied independently of each other, but no genetic recombination was detected in a study of 40 human families. Thus, the MUC3 gene encodes a very large glycoprotein with a structure very different from that of any mucin currently described.

Amino Acid Sequence↗

PubMed1997

Expression of mucin-associated tumor antigens is altered by cell density.

Mucin-associated sialylated Lewis antigens are implicated in tumor cell metastasis and are used in several tests for pancreatic cancer. Despite their clinical importance, little is known about the structures of the oligosaccharides of pancreatic cancer mucins or about the regulation of their synthesis or of the synthesis of their protein cores. In this study, we examined the effects of culture at high cell density on the expression of these antigens in the SW1990 human pancreatic cancer cell line. Mucins from cells that were 2.5 weeks post-confluent had increased expression of sialyl-Lewis(a) and Lewis(x) antigens but reduced expression of the DU-PAN-2 antigen (NeuAc alpha2,3Galbeta1,3GlcNAc-Gal-R) when compared to mucins from 1 day post-confluent cells. Sialyl-Lewis antigens differ from the DU-PAN-2 antigen by the presence of an additional fucose. Mucins from 2.5-week cells also had increased binding to lectins specific for fucose, such as AAL and UEAI, with no apparent change in the binding of lectins specific for sialic acids. Metabolically radiolabeled O-linked oligosaccharides with sialyl-Lewis(a) antigenic reactivity eluted from Bio-Gel P-10 in the region of sialylated and sulfated oligosaccharides. Oligosaccharides eluted from QAE-Sephadex (2 mM Tris base) in a pattern suggesting the presence of 1, 2 and 3 or more negative charges per oligosaccharide. Even after desialylation and desulfation, oligosaccharides eluted from Bio-Gel P-10 with apparent molecular sizes greater than glucose oligomers of 12 units. Culture of SW 1990 cells at high density also increased the steady-state levels of mRNA for mucins MUC1, 2, 4, 5 and 6. In summary, after prolonged culture at high cell density, SW1990 cells have qualitative changes in their oligosaccharides that may be due to up-regulation of fucosyltransferases.

Antigens, Tumor-Associated, Carbohydrate↗

PubMed1997

Radioimmunodetection with 111In-labeled monoclonal antibody Nd2 in patients with pancreatic cancer.

This report summarizes results from an initial clinical evaluation of radioimmunodetection (RAID) in patients with pancreatic cancer using murine monoclonal antibody Nd2, directed against mucins from pancreatic cancer. Nd2 (2 mg) was labeled with 111In (2 mCi) and injected into 19 patients suspected of having pancreatic cancer. Planar scintigrams were taken 3 days post-infusion. As for final diagnoses after surgery, 14 cases were pancreatic cancer, and one case each was chronic pancreatitis, neurilemmoma, islet cell carcinoma, cholangioma, and apparent absence of suspected recurrent lesion of pancreatic cancer. Of 14 patients with pancreatic cancer, RAID was positive in 10 cases (71.4%). Cases other than pancreatic cancer were all negative, so the specificity was 100%. These results demonstrate that RAID using 111In-Nd2 can be useful in differentiating exocrine pancreatic cancer from benign conditions and other types of carcinomas in the pancreatoduodenal regions.

Adenocarcinoma↗

PubMed1996

Radioimmunotherapy for pancreatic carcinoma using (131)I-labeled monoclonal antibody Nd2 in xenografted nude mice.

We investigated the biodistribution, radiolocalization, and radioimmunotherapeutic potential of (131)I-labeled Nd2 in athymic nude mice bearing human pancreatic carcinoma xenografts. (131)I-Nd2 was accumulated at high levels in the tumor, in contrast to blood, liver, spleen, and other normal organs. The tumor was clearly delineated in scintigraphs. The volumes of tumors of mice injected with 7.4 MBq of (131)I-Nd2 were 80% less than those of tumors before injection of radiolabeled Nd2. Fibrous or vacuolar degeneration was seen in histological sections of tumors of 7-week-treated mice. The growth of tumors in mice treated with misonidazole, a hypoxic cell radiosensitizer, and then injected twice with 3.7 MBq of (131)I-Nd2 was suppressed over 7 weeks. Neither leucocytopenia nor thrombocytopenia was severe after injection of radiolabeled Nd2. Thus (131)I-labeled Nd2 may have clinical application in the radioimmunotherapy of pancreatic cancer.

Animals↗

PubMed1995

Association of sialyl-Lewis(a) and sialyl-Lewis(x) with MUC-1 apomucin ina pancreatic cancer cell line.

We have shown previously that the mucins of the human pancreatic cancer cell line, SW1990, have both sialyl-Lewis(a) and sialyl-Lewis(x) carbohydrate ligands that are implicated in tumor cell metastasis. In the present study, we undertook to identify the protein core of these mucins. SW1990 mucins that carry sialyl-Lewis(a) and sialyl-Lewis(x) bound to the MUC1 peptide-specific mAb 139H2. Removal of most of the sialic acids from SW1990 mucins by neuraminidase greatly enhanced binding of two other MUC1 peptide specific antibodies, HMFG-2 and SM-3. After removal of sialic acids, most of the mucins rich in sialyl-Lewis(a) and sialyl-Lewis(x) oligosaccharides no longer bound to a DEAE-cellulose column at pH 8.0. These results indicate that at least part of the sialyl-Lewis(a) and sialyl-Lewis(x) in SW1990 cells is associated with the MUC1 polypeptide. Moreover, sialic acids play an important role in determining the net negative charge of sialyl-Lewis(a) and sialyl-Lewis(x) rich mucins and in obscuring MUC1 peptide regions.

Amino Acid Sequence↗

PubMed1995

Access to peptide regions of a surface mucin (MUC1) is reduced by sialic acids.

Mucinous glycoproteins are present on the surfaces of tumor cells. Knowledge of which parts of the mucin molecule are accessible targets for cells of the immune system is important in the development of successful therapeutic approaches. One breast (ZR-75-1), two colon (Colo 205 and SW1116), and three pancreas (Capan-2, HPAF and SW1990) cancer cell lines were examined. The reactivities of antibodies HMFG-2, specific for the tripeptide (DTR) in the 20 amino acid tandem repeat of MUC1, and SM-3 (PDTRP) were greatly enhanced by pre-treating cells with an inhibitor of O-glycosylation, benzyl-alpha-N-acetylgalactosamide. However, desialylation of cell surfaces with neuraminidase or pre-treatment with an inhibitor of carbohydrate processing, monensin, also greatly enhanced the reactivities of HMFG-2, SM-3 and HMFG-1 (PDTR). Thus, sialic acids on termini of neighboring oligosaccharides significantly limit access to the peptide region recognized by antibodies HMFG-1/2 and SM-3.

Amino Acid Sequence↗

PubMed1995

Intratumoral injection of an adriamycin immunoconjugate against human pancreatic cancer xenografts.

We have evaluated the effect of an adriamycin conjugate of monoclonal antibody Nd2 (ADM-Nd2) on the growth rate of SW1990 xenografts grown subcutaneously in athymic nude mice. Intravenous or intraperitoneal administration of radiolabeled Nd2 resulted in a maximum tumor accumulation of approximately 45% of the initial dose/g of tumor 3-7 days after administration. However, administration into the tumor produced retention of 1200%ID/g 1 day after, with 50% of this high value remaining even at 7 days after administration. In contrast, intratumoral administration of a non-specific immunoglobulin showed a lower initial retention and rapid loss of label. Both intravenously and intratumorally administered ADM-Nd2 reduced the growth rate of SW1990 xenografts. While a single intravenous administration arrested growth for about two weeks, a single intratumoral injection prevented any increase in tumor size even 45 days after administration. Xenografts treated with ADM-Nd2 showed degenerative changes at the histological level. Neither Nd2 alone nor Adriamycin alone inhibited growth when administered at the same dose as the conjugate.

Animals↗

PubMed1994

E-selectin binding by pancreatic tumor cells is inhibited by cancer sera.

Tumor cells interact with endothelial cells during both intra- and extravasation. Understanding how these interactions are modulated could lead to the development of ways to alter the metastatic potential of tumor cells. Three pancreatic cancer cell lines, SW1990, CAPAN-2 and PANC-I, were examined for their ability to bind to the endothelial cell adhesion molecule E-selectin (ELAM-1). SW1990 cells exhibited highest binding, highest surface expression of the carbohydrate antigens sialylated Lewis(a) (sLe(a)) and sialylated Lewis(x) (sLe(x)) and released the most high m.w. sLe(a) and sLe(x) antigens. Expression of sLe(a) and sLe(x) antigens and binding to E-selectin were reduced by pre-treatment of SW1990 cells with the O-linked glycosylation inhibitor benzyl-alpha-GalNAc but not with the N-linked glycosylation inhibitor tunicamycin. Expression of peptide epitopes associated with MUC1 apomucins was increased by benzyl-alpha-GalNAc. Cell binding was greatly reduced by mucins purified from SW1990 xenografts and by an antibody against sLe(a). An antibody against sLe(x) had a much less marked effect. Sera from pancreatic cancer patients reduced SW1990 cell binding to E-selectin but sera from normals did not. The degree of inhibition was related to the sLe(x) level in the sample. When cancer serum was separated by column chromatography on Sephacryl S-400, the void volume fractions contained most of the sLe(a) and sLe(x) antigens and most of the inhibitory activity to E-selectin binding. Differences in the relative availability of sLe(a) and sLe(x) ligands on serum molecules and on the SW1990 cell surface may account for the differences between antibody and serum inhibition results. Thus SW1990 cell adhesion to E-selectin is mediated by ligands on mucinous glycoproteins, and adhesion can be inhibited by mucins, high blood levels of sLe(x) and reduction of cellular O-linked glycosylation.

Acetylgalactosamine↗

PubMed1994

Serological pancreatic tumor markers and the MUC1 apomucin.

Over 80% of adenocarcinomas of the pancreas originate from duct cells, which are the major source of mucins in the pancreas. Pathological conditions produce changes in the composition and structure of the oligosaccharides of colonic and pancreatic mucins, and it has been suggested that mucins may have a role in the detection of pancreatic cancer. Mucins are now the targets of a number of immunodiagnostic assays for cancer, and their possible use in therapy is being studied. This review describes the structure, biosynthesis, and release of mucins, as well as some of their therapeutic applications. The MUC1 type of mucin is emphasized because it is the main type present in both normal and malignant pancreas and because it is associated with several of the serological pancreatic cancer carbohydrate markers, including CA19-9.

Adenocarcinoma↗

PubMed1993

Biphasic effect of cell surface sialic acids on pancreatic cancer cell adhesiveness.

Partial removal of cell surface sialic acids, by enzymatic hydrolysis or by reducing sialylation, increased both adhesion to Matrigel and cellular aggregation in the pancreatic cancer cell line, SW1990. In contrast, a greater reduction in cell surface sialic acids decreased cellular adhesiveness below that of untreated cells. Cellular adhesion and homotypic cellular aggregation were enhanced by reducing O-linked glycosylation. Addition of purified SW1990 mucins reversed the effect of the inhibition of O-glycosylation. Both adhesion to extracellular matrix proteins and cellular aggregation were generally unaffected or decreased by inhibition of N-linked glycosylation. These results suggest that although certain sialic acids are required for the adhesion, sialic acids on oligosaccharides O-linked to surface glycoproteins inhibit SW1990 cellular aggregation and adhesion to the substratum.

Acetylgalactosamine↗

PubMed1993

Monoclonal antibody directed against colon cancer mucin has high specificity for malignancy.

Exposure of core carbohydrate structures such as NeuAc alpha2-6GalNAc-Ser/Thr (sialosyl-Tn) in mucus glycoproteins is often associated with malignant transformation in a number of different tissues. Reagents that specifically identify such structures would be useful in the diagnosis of cancer. Monoclonal antibody JT10e has been produced against mucins from xenografts of LS174T colon cancer cells but also reacts with mucins of pancreatic cancer xenografts. The following data suggest that JT10e reacts with sialosyl-Tn: (I) reactivity with bovine and ovine submaxillary mucins; (2) reactivity sensitive to neuraminidase or mild acid; (3) inhibition of reactivity by NeuAc and NeuAc alpha2-6 lactose; and (4) lack of reactivity with other glycoproteins with related carbohydrate structures but no sialosyl-Tn. JT10e is distinguishable from 2 other antibodies which react with sialosyl-Tn, B72.3 and TKH2 because JT10e: (a) did not react with normal gastric tissue while B72.3 and TKH2 did; (b) was only partially inhibited by TKH2 and not at all by B72.3; (c) did not react with Tn antigen while B72.3 did; and (d) bound more strongly to pancreatic cancer mucins than did either B72.3 or TKH2. JT10e reacted with a high percentage of malignant colonic, pancreatic, gastric and mammary tissues but not with the corresponding normal tissues. A high percentage of patients with colonic, pancreatic, gastric, mammary and lung cancers had elevated blood levels of JT10e antigen. A number of colonic cancer patients had elevated JT10e antigen levels without corresponding elevations in CA19-9 levels. These results suggest that JT10e antibody could be used in conjunction with other mucin markers to improve the identification of malignancy in colon, and to study the structure of oligosaccharides in cancer mucins.

Animals↗

PubMed1993

Immunohistochemical study of mucin carbohydrates and core proteins in human pancreatic tumors.

BACKGROUND: Pancreatic cancer has a poor prognosis, and early diagnosis of carcinoma and discrimination between malignant and benign conditions are difficult. Many pancreatic cancer-associated antigens, such as CA 19-9, DU-PAN-2, YPan-1, and SPan-1, have been studied. However, expression of Tn, sialosyl-Tn, and T antigens in tissues of different types of pancreatic neoplasms has not been investigated systematically. Moreover, little is known about the distribution of different types of apomucins in the pancreas. METHODS: The expression of Tn, sialosyl-Tn, and T antigens and DF3 (mammary type apomucin) and intestinal MRP (intestinal type apomucin) was examined immunohistochemically in 47 pancreatic tumors: 36 invasive ductal carcinomas, 5 intraductal papillary tumors, and 6 adenomas. RESULTS: In normal pancreatic tissues, neither Tn nor sialosyl-Tn antigen was expressed. In contrast, expression of both Tn and sialosyl-Tn antigens was observed in all the invasive ductal carcinomas and intraductal papillary tumors. None of the adenomas expressed both Tn and sialosyl-Tn. DF3 antigen was expressed in all invasive ductal carcinomas but not in intraductal papillary tumors, whereas intestinal MRP was expressed in all the intraductal papillary tumors but not in the invasive ductal carcinomas. CONCLUSIONS: The results from this study suggest that the expression of the mucin core protein and mucin carbohydrate antigens is correlated with the biologic behavior of pancreatic tumors. In particular, the expression of mammary type mucin core protein and intestinal type mucin core protein showed a striking contrast between invasive ductal carcinomas with a poor prognosis and intraductal papillary tumors with a favorable prognosis.

Adenoma↗