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S Loh

Publications and source records attributed to S Loh.

11 recordsLinked to original sources
PubMed1997

Transfection of the gene for B7-1 but not B7-2 can induce immunity to murine malignant mesothelioma.

Transfection of the genes encoding the co-stimulatory molecules B7-1 and B7-2 has enhanced the development of immunity to a variety of experimental tumors, although most of these were inherently immunogenic. We have determined the effect of expression of these genes on the induction of immunity to 2 non-immunogenic murine malignant mesothelioma (MM) cell lines (AC29 and AB1). We had previously shown that B7-1 transfection into AC29 delayed but did not prevent tumor development by certain of the transfectant clones. Here we demonstrate that over-expression of B7-1 can inhibit tumor development by certain AB1-B7-1 clones, that inhibition of transfectant growth is dependent on CD4+ and CD8+ T cells and that mice that reject some of these transfectant clones are capable of rejecting subsequent inocula of the parental cell line, AB1. The transfectant clones can generate tumor-specific cytotoxic T cells. By contrast, expression of B7-2 in several clones derived from either AB1 or AC29 had no significant effect on the development of tumors in vivo. Our data are consistent with data from other systems that show differences in the effect of modification by B7-1 or B7-2 on the modulation of anti-tumor immune responses. They demonstrate that such modifications can induce protective immunity against an MM cell line but confirm the intra- and inter-tumoral heterogeneity in the effect of genetic modification on the induction of immunity. Our observations are relevant to human MM because these cell lines have been derived from asbestos-induced tumors and share many properties with human cell lines of the same histological type.

Animals↗
PubMed1997

The induction of immune responses to murine malignant mesothelioma by IL-2 gene transfer.

Stable IL-2 transfectant clones have been derived from two non-immunogenic murine malignant mesothelioma (MM) cell lines to investigate the induction of protective antitumor immunity to MM. AC29-IL-2 transfectant clones grew at a slower rate in vivo than the parental cell line or a transfectant control clone but all inoculated mice developed tumours despite the continued ability of the tumour cells to express IL-2. Tumour development after inoculation of AB1-IL-2 transfectants varied, the degree of in vivo inhibition (40-100%) being directly related to the rate of IL-2 secretion of the transfectants. When mice which had rejected the AB1-IL-2 transfectants were challenged with parental AB1 cells, a proportion (16-70%) of mice from each group remained tumour free at least 45 days after challenge (naive mice developed tumours within 26 days). The inhibition of growth of the initial inoculum of AB1-IL-2 transfectants was independent of CD4+ and CD8+ cells, consistent with the demonstration of non-specific cytotoxic activity by splenocytes from mice inoculated with the IL-2 transfectants. These data suggest that IL-2 expression by MM cells is capable of generating in vivo immunity to the tumour. This immunity may be relatively weak or may be subject to down-regulation so that consistent rejection of unmodified tumour cells is not achieved. Genetic modification with combinations of genes, including IL-2 and B7-1, will be necessary for reliable generation of protective immunity to MM.

Animals↗
PubMed1996

The energetics of hydrogen bonds in model systems: implications for enzymatic catalysis.

Low-barrier or short, strong hydrogen bonds have been proposed to contribute 10 to 20 kilocalories per mole to transition-state stabilization in enzymatic catalysis. The proposal invokes a large increase in hydrogen bond energy when the pKa values of the donor and acceptor (where Ka is the acid constant) become matched in the transition state (delta pKa=0). This hypothesis was tested by investigating the energetics of hydrogen bonds as a function of delta pKa for homologous series of compounds under nonaqueous conditions that are conducive to the formation of low-barrier hydrogen bonds. In all cases, there was a linear correlation between the increase in hydrogen-bond energy and the decrease in delta pKa, as expected from simple electrostatic effects. However, no additional energetic contribution to the hydrogen bond was observed at delta pKa=0. These results and those of other model studies suggest alternative mechanisms by which hydrogen bonds can contribute to enzymatic catalysis, in accord with conventional electrostatic considerations.

Catalysis↗
PubMed1995

A phase I and pharmacology study of an oral platinum complex, JM216: dose-dependent pharmacokinetics with single-dose administration.

JM216 [bis-acetato-ammine-dichloro-cyclo-hexylamine-platinum (IV)] is an oral platinum complex with in vivo activity against murine and human tumor models and a lack of nephro- and neurotoxicity in rodents. During a phase I study of a single-dose schedule, JM216 was given in dry-filled hard gelatin capsules by mouth without hydration or diuresis. In all, 37 patients were given a total of 88 courses at doses ranging from 60 to 700 mg/m2. The study was stopped before the MTD was reached because of nonlinear pharmacokinetics. Myelosuppression was manifest by leucopenia or thrombocytopenia and showed marked variability at 420-700 mg/m2. Vomiting was mild and controllable by antiemetics in approximately 50% of courses. The onset of vomiting was delayed to 4 h after during ingestion. There was no nephro-, oto- or neuro-toxicity. A partial response was recorded in a patient with recurrent ovarian cancer, and significant falls in plasma tumour markers (CA125) were seen in two further cases. Plasma pharmacokinetics were linear and showed moderate interpatient variability at dose levels of < or = 120 mg/m2. At dose levels of > or = 200 mg/m2, Cmax and AUC increased less than proportionally to dose. This was associated with greater interpatient pharmacokinetic variability and reduced urinary platinum recovery. A significant sigmoidal relationship existed between ultrafilterable plasma AUC and the percentage of reduction in platelet count (r2 = 0.78). Nonlinear absorption was a limitation to this single-dose schedule of oral NM216; however, little non-haematological toxicity was seen at doses associated with myelosuppression and antitumour activity. Clinical studies of divided dose schedules using doses within the range of pharmacokinetic linearity (< or = 120 mg/m2) are now being investigated.

Administration, Oral↗
PubMed1995

Delivering health information databases on World Wide Web at the National University of Singapore.

The National University of Singapore (NUS) is one of the first medical schools in Asia to exploit the use of the World Wide Web on the Internet for the delivery of health information databases. Its WWW server was established in 1993 by the NUS Biocomputing Research and User Support (BRUS) technology group in collaboration with the Computer Resource Planning committee of the Faculty of Medicine. As a result of the early recognition of the powerful platform on which health information services can be delivered worldwide, the NUS effort has been accredited with a number of Internet firsts in the area of health informatics. The following are some of the NUS achievements: NUS-NCI CancerNet on the Web. The NUS developed and implemented the first WWW version of the popular CancerNet database offered by the National Cancer Institute, NIH, USA. Health Info-Com Network Medical Newsletter. The NUS developed and implemented the first WWW version of the medical newsletter, MEDNEWS which is edited by Dr. David Dodell, USA. It is now mirrored by the University of Pennsylvania in the United States and De Montfort University, U.K. Poisons Information Database. This first WWW implementation of a database on known plant, snake and other animal toxins with directories of antivenoms, toxinologists and poisons control centers around the world is offered by the NUS Venom and Toxin Research Group. HistoNet. This is a large collection of histology specimens from the NUS Department of Anatomy. MEDISTAT. This is the first WWW implementation of a Health and Population Statistical Database which contains information for Singapore, selected Asian countries and aggregate data for world regions. The Singapore Biotechnology Database. This database features companies and organizations involved in biotechnology and related activities in Singapore. Efforts are continuing to offer more value-added health information databases on the NUS WWW server and to link the server with other top-class information centers worldwide. Our mission is to identify the National University of Singapore as a global health information hub on the Internet.

Computer Communication Networks↗
PubMed1989

Nucleotide sequence of the leading region adjacent to the origin of transfer on plasmid F and its conservation among conjugative plasmids.

The leading region of the Escherichia coli K12 F plasmid is the first segment of DNA to be transferred into the recipient cell during conjugal transfer. We report the nucleotide sequence of the 64.20-66.77F portion of the leading region immediately adjacent to the origin of transfer, oriT. The 2582 bp region encodes three open reading frames, ORF95, ORF169 and ORF273; the product of ORF273, is equivalent in size and map location to the 35 kDa protein, 6d, previously described (Cram et al. 1984). S1 nuclease analyses of mRNA transcripts have identified a potential promoter for ORF95 and ORF273 and indicated that these ORFs are transcribed as a single transcript; in contrast, ORF169 appears to be transcribed from two overlapping promoters on the complementary DNA strand. The products of ORF95 and ORF273 are mainly hydrophilic and are probably located in the cytoplasm. ORF273 shares some homology with DNA-binding proteins. There is a signal peptide sequence at the NH2-terminus of ORF169 and the mature form of ORF169 probably resides in the periplasm due to its hydrophilic nature. Both ORF273 and ORF169 are well conserved among conjugative F-like and a few non-F-like plasmids. On the other hand, ORF95 sequences are only present on some of these plasmids. Several primosome and integration host factor recognition sites are present implicating this region in DNA metabolism and/or replication functions.

Amino Acid Sequence↗
PubMedDate not supplied

Induction and maintenance of T-cell response to a nonimmunogenic murine mesothelioma cell line requires expression of B7-1 and the capacity to upregulate class II major histocompatibility complex expression.

Intratumoral expression of the T-cell costimulator B7-1 has been reported to induce tumor-specific immunity against immunogenic, but not nonimmunogenic, tumors. We transfected the B7-1 gene into a nonimmunogenic murine mesothelioma cell line that constitutively expresses high levels of class I major histocompatibility complex (MHC) and transforming growth factor-beta (TGF-beta). Tumor development by two of the four B7-1 transfectant clones was markedly delayed, although all clones eventually formed tumors. Retardation of tumor growth required both CD4+ and CD8+ T cells. Tumor-specific cytotoxic T-lymphocytes (CTLs) were elicited in response to the least (AC29-B7-6), but not the most (AC29-B7-7), tumorigenic transfectant clone. Tumor-specific CTL activity could be detected at early time points but not at the time of tumor outgrowth. This lack of responsiveness was tumor antigen specific. Differences in immunogenicity of transfectant clones did not relate to the level of expression of MHC class I, vascular cell adhesion molecule-1, or transfected B7-1, or to the level of TGF-beta secreted. Class II MHC expression was most readily inducible in those transfectant clones whose growth in vivo was most delayed. An explant cell line derived from a tumor that developed from AC29-B7-6 had a markedly reduced capacity to upregulate MHC class II expression and produced tumors in vivo at a faster rate than did the parental cell line. Thus, B7-1 expression in this nonimmunogenic tumor cell line can promote the generation of tumor-specific CTLs with consequent retardation of tumor development, and coexpression of MHC class II seems likely to play an important role in this process. This work also illustrates that clonal heterogeneity within a single tumor and the development of immunological nonresponsiveness resulting in tumor outgrowth, even in the presence of continued B7-1 expression, are potential difficulties associated with this therapeutic approach.

Animals↗