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Biomedical subjects

S C Tang

Publications and source records attributed to S C Tang.

At least 37 records · Page 2Linked to original sources
PubMed1999

Differential expression of antiapoptotic gene BAG-1 in human breast normal and cancer cell lines and tissues.

BAG-1 is an antiapoptotic protein that binds to and enhances the antiapoptotic activity of Bcl-2. It binds several growth factor and hormone receptors and modulates their function. BAG-1 was also shown recently to be expressed as four protein isoforms, p50, p46, p33, and p29, through alternative translation initiation. Although many apoptosis-associated genes have been linked to oncogenesis of human breast cancer, the role of BAG-1 has not been fully elucidated. In this study, we examined the expression of BAG-1 RNA or protein isoforms and its interacting antiapoptotic proteins, Bcl-2 and BcI-X(L), in breast normal and tumor cell lines and tissues by Northern or Western blot analysis. We provide convincing evidence that both BAG-1 RNA and protein are overexpressed in human breast cancer cell lines. More importantly, we found that the expression of two isoforms of BAG-1, p46 and p33, was also much higher in breast primary tumors. The expression of Bcl-2 and Bcl-X(L) correlated with that of BAG-1 in breast normal and carcinoma cell lines but not tissues. Our study suggests that BAG-1 isoforms may serve as a molecular marker, independent of Bcl-2 and Bcl-X(L), for human breast cancer.

Adenocarcinoma↗
PubMed1998

Human BAG-1/RAP46 protein is generated as four isoforms by alternative translation initiation and overexpressed in cancer cells.

Previously, a Bcl-2-interacting protein, BAG-1, was cloned from mouse cells and was shown to interact with several other proteins and to be important for inhibition of apoptosis. Human BAG-1 (hBAG-1) cDNA, recently isolated by us and two other groups, has been shown to be identical to a hormone receptor-binding protein, RAP46. However, different molecular masses of hBAG-1 protein products were noted by these three groups. Here we demonstrated that hBAG-1 protein was expressed as four isoforms, designated p50, p46, p33 and p29, with apparent molecular masses of 50 kDa, 46 kDa, 33 kDa and 29 kDa, respectively. Deletion, site-directed mutagenesis and in vitro transcription/translation analysis showed that the four protein products of hBAG-1 were expressed by alternative initiation from four different start codons through a leaky scanning mechanism. Furthermore, we demonstrated that the distinct forms of hBAG-1 have different subcellular localizations, suggesting that they may have distinct functions in the cells. Characterization of hBAG-1 RNA and protein also showed that hBAG-1 was overexpressed in human cervical, breast and lung cancer cell lines. Taken together, these data clarify the conflicting observations reported in the literature and suggest that hBAG-1 is expressed as four forms of protein products, which may play a differential role in apoptosis and oncogenesis of human cells.

Alternative Splicing↗
PubMed1998

Dietary risk factors associated with the transmission of Helicobacter pylori in Lima, Peru.

The factors influencing the risk of acquisition of Helicobacter pylori infection are not well established. One hundred four children (0-17 years of age) requiring an endoscopy for the evaluation of gastrointestinal symptoms had demographic and dietary data collected and biopsy specimens of the gastric antrum stained for the identification of H. pylori. The 52 (50%) infected subjects were significantly older than the uninfected ones with no difference in gender, crowding, source of drinking water, or exposure to domestic animals. Increased prevalence of infection was associated with increased consumption of food from street vendors, and decreased consumption of fruits in the subgroup that denied consuming food from street vendors. No association was found with consumption of fish, chicken, beef, beans, vegetables, rice, cheese, milk, and unboiled water. These findings support the role of food prepared under unhygienic conditions as a probable mechanism of transmission of H. pylori in developing countries.

Adolescent↗
PubMed1998

Enhanced expression of anti-apoptotic proteins in human papillomavirus-immortalized and cigarette smoke condensate-transformed human endocervical cells: correlation with resistance to apoptosis induced by DNA damage.

Apoptosis plays an important role in various biological processes including embryogenesis, differentiation, homeostasis, and oncogenesis. We have developed a system composed of primary human endocervical cells (HEN), HEN immortalized by human papillomavirus (HPV) type 16, and their counterparts subsequently malignantly transformed by cigarette smoke condensate (CSC). To understand the role of apoptosis in the multistep oncogenesis of human cervical cells, we examined the expression of apoptosis-associated proteins in our in vitro model system. The results showed no significant difference in the levels of apoptosis-inducing proteins bak and bax among all the cell types examined. On the other hand, the levels of apoptosis-inhibiting proteins bcl-2, bcl-xL and BAG-1 increased progressively after immortalization and transformation. The p53 protein level decreased in the HPV16-immortalized HEN and increased in one of two lines of the CSC-transformed HEN. Further, the increased levels of apoptosis-inhibiting proteins in the HPV16-immortalized and the CSC-transformed HEN correlated with progressively increased resistance of these cells to apoptosis induced by staurosporine or cisplatin. This study provided the first evidence that overexpression of apoptosis-inhibiting proteins is important for both multistep oncogenesis and resistance of human endocervical cells to apoptosis induced by DNA-damaging reagents.

Antineoplastic Agents↗
PubMed1997

Different HPV16 E6/E7 oncogene expression patterns in epithelia reconstructed from HPV16-immortalized human endocervical cells and genital keratinocytes.

Human papillomavirus type 16 (HPV16) E6/E7 oncogenes immortalize two types of human genital epithelial cells in vitro, endocervical cells and ectocervical or foreskin keratinocytes. Epithelia reconstructed in in vivo nude mouse implants or in vitro organotypic raft cultures from immortalized endocervical cells form higher grade dysplasia than those from keratinocytes. Here, we compared viral E6/E7 mRNA expression in immortalized cell lines of the three cell types using implants, rafts and in situ hybridization assays. Endocervical cells expressed E6/E7 throughout their reconstructed epithelia. In contrast, oncogenes were limited to basal cells for keratinocyte lower grade dysplasias. To study the role of the HPV16 promoter/enhancer in this repression in the upper layers of keratinocyte epithelia, new cell lines were established by immortalization with E6/E7 controlled by the SV40 promoter. The oncogenes were shown to be controlled from the SV40 elements after immortalization. Nevertheless, E6/E7 in the two cell types had the same cell-specific expression pattern as that controlled from the homologous HPV16 promoter. In addition, naturally occurring premalignant lesions having integrated HPV16 DNA expressed E6/E7 extensively in the high-grade dysplastic region of undifferentiated metaplasia. On the other hand, oncogene expression was restricted to lower layers in the lower grade dysplastic region of more mature differentiation. Our data suggest that keratinocytes have an inherent HPV16 promoter-nonspecific mechanism of repression. Apparently this mechanism, which can be acquired during maturation, is initially nonfunctional in in vitro and in vivo epithelia derived from metaplastic endocervical cells.

Animals↗
PubMed1997

Expression of cellular genes in HPV16-immortalized and cigarette smoke condensate-transformed human endocervical cells.

We studied the molecular mechanism of successive multistep cervical carcinogenic progression with our previously established in vitro model system. This system was composed of primary human endocervical cells (HEN), two lines of HEN immortalized by HPV16 and their counterparts subsequently malignantly transformed by cigarette smoke condensate (CSC). The expression was examined of diverse cellular genes associated with oncogenesis and senescence, especially for cervical cancer. Consistent results were seen for the pairs of immortalized and malignantly transformed lines. Immortalization of HEN by HPV16 resulted in enhanced expression of H-ras, c-myc, B-myb, p53, p16INK4 and PCNA mRNA; enhanced expression of p16 and PCNA proteins; decreased expression of WAF1/p21/Cip1/Sid1 and fibronectin mRNA; and decreased p53 protein. On the other hand, the CSC-transformed counterparts of HPV16-immortalized cells had up-regulated levels of B-myb, p53 and WAF1 mRNA and p53 protein. Our results indicate that the differential activation or inactivation of multiple cellular genes is important for the immortalization, as well as the transformation, of human cervical cells. Further, we suggest that our in vitro model system is useful for investigating the molecular mechanism of multistep cervical carcinogenesis.

Actins↗
PubMed1997

Effect of glucocorticoid hormones on viral gene expression, growth, and dysplastic differentiation in HPV16-immortalized ectocervical cells.

Steroid hormones are proposed to act as cofactors with human papillomaviruses (HPVs) in the etiology of cervical cancer. We and others reported that progesterone and glucocorticoid hormones induce the expression of HPV16 via three glucocorticoid response elements (GREs) in the viral regulatory region. Consensus GREs (GREcs) are useful in other systems for examining the effect of hormones after enhancing the response with mutated GREc constructs. Therefore, this study used human ectocervical cells (HEC) and HPV type 16 containing three GREcs to establish immortalized cells (HEC-16GREc). Northern blot assays showed that the level of viral E6-E7 oncogene RNA was increased by hormones substantially more in HEC-16GREc than in wild-type HPV16-immortalized human ectocervical cells (HEC-16). The saturation density and the hormone response of the growth rate were significantly higher for HEC-16GREc and the doubling was faster in the presence of hormone than for HEC-16. Although both were nontumorigenic, only HEC-16GREc showed anchorage-independent growth, which was dependent on hormone. Also, HEC-16GREc were more abnormal in their epithelium differentiation pattern in organotypic (raft) cultures. Furthermore, hormone-treated HEC-16GREc rafts showed more dysplastic features than hormone-treated HEC-16 rafts. These results suggest new features of the role of hormones: that enhanced expression of viral oncogenes in response to hormones apparently confers a greater risk for cervical cells containing HPV16. Further, HEC-16GREc could be ideal for studying hormone-dependent and -independent malignant transformation.

Animals↗
PubMed1997

Induction of p16 during immortalization by HPV 16 and 18 and not during malignant transformation.

The p16 (MTS1) tumour-suppressor gene is a cyclin-dependent kinase (cdk) inhibitor that decelerates the cell cycle by inactivating the cdks that phosphorylate the retinoblastoma tumour-suppressor gene (Rb) protein (pRb). In cervical cancers, pRb is inactivated by the HPV E7 oncoprotein or by mutations. The hypothesis of earlier reports was that the disruption of the p16/cdk-cyclin/Rb cascade is essential for malignant cervical transformation/carcinogenesis. We previously established in vitro model systems of cervical cancer representing four steps of oncogenic progression initiated by the two most common oncogenic HPVs in ectocervical and endocervical epithelial cells. This report used these systems to investigate the role of p16 in cervical cancers. A dramatic enhancement of the p16 RNA level was observed after immortalization by HPV 16 or 18. Furthermore, the p16 protein was newly observed following immortalization. However, no further changes were found for RNA or protein levels after serum selection or malignant transformation. For three cervical carcinoma cell lines, similar high levels of p16 expression were seen. Point mutations or homozygous deletions of p16 were not observed in the in vitro systems or in clinical specimens. These results suggest that the inactivation of the p16/cdk-cyclin/Rb cascade does not occur during malignant transformation but occurs during the immortalization by HPV in HPV-harbouring premalignant lesions, the in situ equivalent of immortalized cells. Also suggested is that p16 has no role in the specific malignant transformation step from immortal premalignant lesions during the carcinogenesis of HPV-initiated cervical cancers.

Adenocarcinoma↗
PubMed1997

Short-term safety of live attenuated Japanese encephalitis vaccine (SA14-14-2): results of a randomized trial with 26,239 subjects.

The short-term safety of an effective and inexpensive new live attenuated Japanese encephalitis vaccine (SA14-14-2) was studied in a randomized trial, using block randomization. Of 26,239 children who were enrolled, half received the vaccine and half served as controls. Subjects were prospectively followed for 30 days for severe adverse events, such as encephalitis, meningitis, and "all-cause" hospitalization. No cases of encephalitis or meningitis occurred in either group. The upper 95% confidence limit for adverse events not occurring among subjects receiving their first dose was 4.1/10,000. Risk ratios and 95% confidence intervals for other adverse events were 0.70 (0.43-1.15) for all-cause hospitalization, 0.91 (0.37-2.22) for seizure, and 0.79 (0.56-1.11) for fever lasting > or = 3 days. These data attest to the short-term safety of the SA14-14-2 virus strain and the hamster kidney cell substrate.

Animals↗
PubMed1997

Helicobacter pylori infection in children with abdominal ailments in a developing country.

Helicobacter pylori commonly infects children in developing countries. To determine the frequency of this infection and its potential role in specific gastrointestinal entities, all patients requiring upper gastrointestinal endoscopy for the evaluation of abdominal ailments in a gastroenterology practice in Lima, Peru, were evaluated during a 1-year period. Gastric biopsies were obtained for each child and were stained with hematoxylin-eosin and Warthin-Starry stains. Of the 107 evaluable patients (mean age 7.4 years, 58% boys), 52 (49%) were infected. The infection rate increased with older patients (P = 0.004). Children with recurrent abdominal pain (P = 0.04), an endoscopic finding of nodular gastritis (P = 0.007), and a histologic finding of chronic active gastritis (P < 0.0001) were infected more commonly.

Abdominal Pain↗
PubMed1996

Characterization of HIV incubation distributions and some comparative studies.

In this paper we use a general stochastic model to characterize the HIV incubation distributions. We generate some Monte Carlo data under different conditions and compare the fitting of HIV incubation distributions by some well known parametric models and some non-parametric methods. The parametric models include most of those that have appeared in the literature. The non-parametric methods include the Kaplan--Meier method, the EMS method, the spline approximation and the Bacchetti method. The comparison criteria are the chi-square statistic, the residual sum of squares, the AIC and the BIC. We show that the non-parametric methods, especially the EMS method, provide excellent fits in almost all cases; for the parametric models, the generalized log-logistic distributions with three and with four parameters fit better than other parametric models.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Glial and muscle embryonal carcinoma cell-specific independent regulation of expression of human JC virus early promoter by cyclic AMP response elements and adjacent nuclear factor 1 binding sites.

The human polyoma JC virus (JCV) is a glial cell-specific virus and is the etiological agent for the terminal AIDS-associated brain disease, progressive multifocal leukoencephalopathy (PML). JCV contains several binding sites for transcriptional factors that are important for activity in glial cells, including cyclic AMP (cAMP) response elements (CREs) which are four nucleotides from nuclear factor 1 (NF1) sites within the two 98 bp repeat regions. We studied the combined role of cAMP and NF1 in regulating the expression of the JCV early promoter-enhancer (JCVE) in differentiating glial and muscle P19 embryonal carcinoma cells. JCVE expression remained several-fold higher in the presence of cAMP in glial cells, irrespective of whether the relatively strong activity of JCVE was greatly reduced by NF1 site mutations. In contrast, cAMP had no effect in muscle cells, independent of whether the modest activity of JCVE was two-fold higher due to NF1 site mutations. The in vivo effects were confirmed with in vitro transcription assays using glial cell extracts, competitors of CRE, and the NF1 site, and single repeat JCVE region with mutations in the NF1 II/ III binding sites as templates. The in vitro results also indicated that the effects were due to the CREs of JCV, rather than to the indirect effects of cAMP. Overall, the results indicated that NF1 and cAMP have independent, different, tissue-specific, and direct effects in the regulation of JCVE. These effects may contribute the neurotropic PML-inducing pattern of expression of JCVE.

Binding Sites↗
PubMed1996

Up-regulation of hormone response of human papillomavirus type 16 expression and increased DNA-protein binding by consensus mutations of viral glucocorticoid response elements.

Human papillomaviruses (HPVs) and steroid hormones are linked to the development of cervical cancer. Studies from our laboratory and others showed that the steroid glucocorticoid and progesterone hormones activated the expression of HPV type 16. This activation was attributed to the specific interaction of the glucocorticoid receptor (GR) with the three glucocorticoid response elements (GREs) in the HPV16 regulatory region. In the present study, we first examined the glucocorticoid response mediated through the GREs, using GRE consensus (GREc) mutations and expression assays from a heterologous basal promoter. Both single and triple HPV16 GREc constructs increased expression in the presence of the dexamethasone glucocorticoid in HeLa cervical carcinoma cells and primary baby rat kidney epithelial cells, in comparison with the triple wild-type GREs. Further, the hormone increased significantly the expression of the viral E6-E7 oncogene mRNA from intact HPV in primary human ectocervical cells in in situ hybridization assays. Three in vitro assays of DNA-protein interaction with oligonucleotides and HeLa cell extracts showed a higher binding of protein to two of the HPV16 GREcs than to the wild-type GREs. This applied especially to the GRE containing an overlapping NF1 half site, that also had a greater differential induction by dexamethasone of expression in vivo. The NF1 site was mutated in the GREc that also was bound by unique, lower-mobility complexes in electrophoretic mobility shift assays. UV-crosslinking assays confirmed the increased binding and showed binding by a 96-kDa protein, probably the GR. Our results show an important role of glucocorticoids in HPV16 expression. The direct action through the HPV16 GREs is suggested to be mediated by the hormone-activated GR in association with other factors.

Animals↗
PubMed1996

Human JC virus nuclear factor 1 binding motifs and large tumor antigen region rquired for transactivation of late promoter.

The nuclear factor 1 (NF-1) motifs, NF-1 II/III, In the two 98-bp repeats of the transcription-regulatory region of JC virus (JCV), have a critical role in brain-specific transcription from the JCV early promoter-enhancer. In this study, the role of these motifs in transactivation of the JCV late promoter-enhancer (JCVL) was examined in differentiating glial P19 embryonal carcinoma cells. The expression of papovaviral large tumor antigen (T-Ag) in the glial cells was shown by double immunofluorescence assays. By using site-directed mutagenesis and in vivo assays, the two wild-type NF-1 II/III sites, but not the third site, were found to be essential for the transactivation of JCVL by JCV T-Ag. In vitro transcription assays confirmed this specific transactivation and the transactivation was abolished by T-Ag antibody. In electrophoretic mobility shift assays, expression of JCV T-Ag increased the binding of a factor(s) to the 98-bp repeat. T-Ag antibody abolished the increase of binding. Binding assays with oligonucleotides of NF-1 11/111 motifs showed that the increased binding specifically required the wild-type NF-1 II/III sequences and confirmed the requirement of T-Ag. To determine the region of T-Ag necessary for transactivation Of JCVL, the coding sequences were mutated. The amino-terminal region of JCV Ag in amino acids 1-437 was essentially required for efficient transactivation. These results indicated that transactivation of JCVL and increased binding require a factor(s) found specifically in glial cells, the JCV NF-1 II/III sites, and the T-Ag amino-terminal region.

Animals↗
PubMed1996

Immunosuppressive toxicity of CAMPATH1H monoclonal antibody in the treatment of patients with recurrent low grade lymphoma.

We have studied, as part of a group of international multicenter phase II clinical trials, the toxicity and effectiveness of CAMPATH1H administered intravenously three times a week in an outpatient setting to patients with recurrent or progressive low grade lymphoma. We report here on the toxicity and therapeutic results of the first seven patients treated before the study was closed prematurely because of unacceptable toxicity. Classical complete or partial responses of treatment were seen in three of seven patients. One complete response lasted 8.5 months and the other complete response is ongoing at 1 year. Responses occurred in nodal sites as well as in skin and peripheral blood. The first three or four antibody infusions in each patient was associated with grade 1 or 2 side-effects including rigor, fever, facial flushing, nausea, vomiting, hives, wheezes, hypotension, and/or diarrhea but these subsequently decreased or disappeared. The most significant toxicity was profound lymphopenia and associated infection, usually viral. Six of seven patients had culture or serologically documented infections and four patients had two or more such episodes. All infections responded to temporary discontinuation of antibody therapy and appropriate antiviral or antibiotic agents. We conclude that CAMPATH1H monoclonal antibody has therapeutic activity against low grade non-Hodgkin's lymphoma but that this activity is limited by marked lymphopenia and an unacceptably high frequency of serious infection at the dose and schedule used in this trial.

Adult↗
PubMed1995

Characterization of HIV infection and seroconversion by a stochastic model of the HIV epidemic.

In this paper we use a stochastic model for the HIV epidemic in homosexual populations to characterize the HIV infection and seroconversion. Using computer generated data, we compare the fitting of infection distributions and of seroconversion distributions by different parametric models as well as by nonparametric methods. The nonparametric methods include the Kaplan-Meier method, EMS method, Bacchetti's method, and the spline approximation. The parametric models include most of the models which have been used in the literature. The comparison criteria are the chi-square statistic, the AIC (Akaike Information Criterion) and the residual sums of squares. The numerical results suggest that for the proportional mixing pattern, the EMS method, the spline method, Bacchetti's method, and the generalized log-logistic distributions with three and with four parameters provide better fitting for the infection and the seroconversion distributions in most cases. For the restricted mixing patterns, the EMS method, the spline method, Bacchetti's method, and some mixtures of distributions provide close fitting to the infection and the seroconversion distributions.

Disease Outbreaks↗
PubMed1994

Clinical significance of bcl-2-MBR gene rearrangement and protein expression in diffuse large-cell non-Hodgkin's lymphoma: an analysis of 83 cases.

PURPOSE: The goal of this study was to assess the prognostic significance of a rearrangement of the major breakpoint region of the bcl-2 gene and/or expression of bcl-2 protein in diffuse large-cell lymphomas of B-cell origin. PATIENTS AND METHODS: All 83 patients diagnosed at the Cross Cancer Institute between 1987 and 1992 with malignant lymphoma (ML), diffuse large-cell ML non-cleaved-cell ML or cleaved-cell ML, or with diffuse large-cell immunoblastic ML were studied. bcl-2 rearrangement was identified by a polymerase chain reaction technique. This technique detects the approximately 60% of rearrangements involving the major breakpoint region bcl-2 gene (bcl-2-MBR). bcl-2 protein expression was studied by immunohistochemistry. RESULTS: More than 66% of the cases expressed bcl-2 protein, whereas 18% had a detectable bcl-2-MBR gene rearrangement. Overall, cases with bcl-2-MBR rearrangement had shorter disease-free periods. Cases with nodal and extranodal presentation had a similar frequencies of bcl-2-MBR rearrangement; however, the disease-free period of patients with extranodal presentation and bcl-2-MBR rearrangement was significantly shorter than that of those without rearrangement. CONCLUSION: bcl-2 protein is frequently expressed in diffuse large-cell lymphomas, but does not influence prognosis. The bcl-2-MBR gene rearrangement may possibly be associated with a shorter disease-free period, particularly in the specific setting of a lymphoma with extranodal presentation.

Adolescent↗