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Biomedical subjects

K W Hunter

Publications and source records attributed to K W Hunter.

At least 19 recordsLinked to original sources
PubMed2004

Host genetics and tumour metastasis.

Metastasis, the spread and growth of tumours at secondary sites, is an extremely important clinical event, since a majority of cancer mortality is associated with the metastatic tumours, rather than the primary tumour. In spite of the importance of metastasis in the clinical setting, the actual process is extremely inefficient. Millions of tumour cells can be shed into the vasculature daily; yet, few secondary tumours are formed. The classical hypothesis explaining the inefficiency was a series of secondary events occurring in the tumour, resulting in a small subpopulation of cells capable of completing all of the steps required to successfully colonise a distant site. However, recent discoveries demonstrating the ability to predict metastatic propensity from gene expression profiles in bulk tumour tissue are not consistent with only a small subpopulation of cells in the primary tumour acquiring metastatic ability, suggesting that metastatic ability might be pre-programmed in tumours by the initiating oncogenic mutations. Data supporting both of these seemingly incompatible theories exist. Therefore, to reconcile the observed results, additional variables need to be added to the model of metastatic inefficiency. One possible variable that might explain the discrepancies is genetic background effects. Studies have demonstrated that the genetic background on which a tumour arises on can have significant affects on the ability of the tumour to metastasise and on gene expression profiles. Thus, the observations could be reconciled by combining the theories, with genetic background influencing both metastatic efficiency and predictive gene expression profiles, upon which, subsequently, metastasis-promoting mutational and epigenetic events occur. If the genetic background is an important determinant of metastatic efficiency, it would have significant implications for the clinical prediction and treatment of metastatic disease, as well as for the design of potential prevention strategies.

Animals↗
PubMed2002

Preparation of microparticulate beta-glucan from Saccharomyces cerevisiae for use in immune potentiation.

AIMS: To develop a method for the preparation of an immunologically active, homogeneous, nonaggregated, microparticulate beta-glucan-containing material from the budding yeast Saccharomyces cerevisiae. METHODS AND RESULTS: Using a combination of sonication and spray-drying, a homogeneous preparation of 1-2-mu diameter beta-glucan-containing particles was made from alkali- and acid-insoluble yeast cell wall material. This microparticulate beta-glucan remained in suspension longer and, following oral administration at 0.1 mg kg(-1) for 14 d, enhanced phagocytosis of mouse peritoneal macrophages significantly better than did aggregated beta-glucan particles. CONCLUSIONS: A new sonication and spray-drying method can be employed to overcome the problem of aggregation of beta-glucan microparticles in aqueous media. SIGNIFICANCE AND IMPACT OF THE STUDY: A microparticulate form of beta-glucan that remains in suspension longer for pharmaceutical applications and has superior immune potentiation characteristics has been developed.

Adjuvants, Immunologic↗
PubMed2001

Predisposition to efficient mammary tumor metastatic progression is linked to the breast cancer metastasis suppressor gene Brms1.

Tumor metastasis is one of the most important clinical aspects of neoplastic disease because patient mortality is frequently attributable to disseminated rather than primary tumors. However, it still is not possible to definitively distinguish those individuals at high risk for disseminated disease, who would benefit from aggressive adjuvant therapy, from the low-risk patients who might be spared the side effects of additional anticancer therapy. To identify factors that predispose toward metastatic disease, we have used a genetic approach. Using a highly metastatic model of mammary cancer, we identified previously inbred mouse strains (DBA/2J, NZB/B1NJ, and I/LnJ) that harbor genetic factors that significantly suppress metastatic efficiency. In this study, we report the results of four experiments to localize the genetic map locations of the metastasis efficiency modifier genes. One statistically significant locus was identified on proximal Chr 19 designated Mtes1. Secondary candidate intervals were detected on Chrs 6, 9, 13, and 17. Interestingly, Mtes1 colocalizes with the murine orthologue of the human breast cancer metastasis suppressor gene Brms1, suggesting that allelic variants of Brms1 might be responsible for the metastasis suppression observed.

Animals↗
PubMed2001

Three loci modify growth of a transgene-induced mammary tumor: suppression of proliferation associated with decreased microvessel density.

In earlier studies it was observed that the genetic background significantly affected the phenotype of a transgene-induced mammary tumor. Tumors arising in an (I/LnJ x PyMT) F1 hybrid background appeared earlier than in the FVB/N-TgN(MMTV-PyVT)(634Mul) parent, but accumulated less tumor mass, indicating a net decrease in tumor growth. Quantitative genetic mapping in a backcross identified three loci that were associated with the decreased proliferative capacity of the I/LnJ F1 tumors. Molecular analysis of the tumors suggests that these loci may act by restricting the tumor's ability to recruit microvessels. The three loci, designated Mmtg1-3, are unlinked to the angiogenic genes Fgf2, Flt1, Flk4, Flk1, Vegf, and Vegfc, as well as the precursors of the endogenous antiangiogenic molecules angiostatin and endostatin. The Mmtg loci may therefore provide novel targets for antiangiogenic therapeutic strategies.

Animals↗
PubMed1998

Identification of inbred mouse strains harboring genetic modifiers of mammary tumor age of onset and metastatic progression.

Metastasis is one of the most important and complex processes in human neoplastic disease. A large number of both positive and negative events must occur to permit a tumor cell to colonize a distant site successfully. To identify mouse strains that harbor dominant genetic modifiers of this process, a strain survey was initiated utilizing a transgenic mouse mammary tumor model that exhibits a high incidence of pulmonary metastases. The transgenic animal was bred to 27 different inbred strains of mice and scored for the metastatic organ tropism and metastatic density. Thirteen strains were identified that had a statistically significant reduction in the numbers of pulmonary metastases. In addition, 10 strains were identified that altered the kinetics of induction of the primary mammary tumor. These strains will likely provide useful model systems for the analysis of genetic interactions in the initiation and progression of mammary adenocarcinomas.

Age of Onset↗
PubMed1996

Toward the construction of integrated physical and genetic maps of the mouse genome using interspersed repetitive sequence PCR (IRS-PCR) genomics.

Using two recently developed techniques, IRS-PCR YAC walking and IRS-PCR genotyping, a framework-integrated physical and genetic map of the mouse genome was constructed. The map consists of 821 contigs, containing 7746 YAC clones originating from three different YAC libraries. Three hundred eighty of the contigs have been anchored to the genetic map. Approximately 16% of the physical length of the mouse genome is estimated to be represented.

Animals↗
PubMed1994

Rapid and efficient construction of yeast artificial chromosome contigs in the mouse genome with interspersed repetitive sequence PCR (IRS-PCR): generation of a 5-cM, > 5 megabase contig on mouse chromosome 1.

We have developed a new technique for the generation of YAC contigs in the mouse genome that is based on the ability to detect overlapping clones by hybridization of shared IRS-PCR products. As a demonstration of the technique, a 5-cM, > 5 megabase contig was developed on the distal half of mouse Chromosome (Chr) 1, spanning the region from Lamb2 to At3. The contig covers roughly 5% of the genetic distance of the chromosome and is comprised of more than 80 clones; 71 probes were assigned physical order to the chromosome, of which 59 were new markers generated in this study. Eight of the new probes were shown to be polymorphic between C3H/HeJ-gld and M. spretus. Three probes were mapped on a [(C3H/HeJ-gld x M. spretus) x C3H/HeJ-gld] interspecific backcross to integrate the physical map with a high-resolution genetic map of the region.

Animals↗
PubMed1993

Single-strand conformational polymorphism (SSCP) mapping of the mouse genome: integration of the SSCP, microsatellite, and gene maps of mouse chromosome 1.

Interspersed repetitive sequence (IRS) PCR and repetitive element-to-bubble (IRS-bubble) PCR have been utilized to rapidly generate large numbers of mouse-specific, chromosome 1-enriched STSs from mouse-hamster somatic cell hybrids. Single-strand conformational polymorphism (SSCP) has been used to localize 39 new repetitive element-linked STSs to the mouse map: 22 to Chr 1, 10 to Chr. 15, 2 each to Chrs 12 and 14, and three to Chr 7. In addition, we have integrated the SSCP, single-strand length polymorphism, and restriction fragment length polymorphism maps of mouse Chr. 1, resulting in a high-density map of the chromosome, containing over 100 loci, all typed on a single interspecific backcross.

Animals↗
PubMed1990

Reversal of intracellular toxicity of the trichothecene mycotoxin T-2 with monoclonal antibody.

The trichothecene mycotoxin T-2 is a potent inhibitor of intracellular protein synthesis. We have previously shown that a mouse immunoglobulin G1 monoclonal antibody (15H6) specific for T-2 toxin can neutralize the in vitro protein synthesis inhibitory effect of the toxin in human B-lymphoblastoid cultures, and protect rats from lethal toxemia. We now report that these monoclonal antibodies can induce the net efflux of [3H]-T-2 toxin from poisoned human B-lymphoblastoid cells in vitro, and restore protein synthesis. Administration of the monoclonal antibodies (250 mg/kg) 30 min before infusion of a lethal dose (1 mg/kg) of T-2 toxin causes the sequestration of the toxin in the plasma compartment. When administered 35 min after T-2 toxin, a time when the bulk of toxin is in the tissues, the monoclonal antibodies facilitate the migration of toxin back into the plasma compartment. These data demonstrate that monoclonal antibodies can be of therapeutic value against an intracellular toxin.

Animals↗
PubMed1989

Biosensors. A new analytic technology for real-time, on-line biochemical monitoring.

A new technology is evolving that has the potential of improving patient management while substantially reducing the overall cost of health care. This new technology is based on biosensors, analytic microelectronic devices that use biologic detector molecules (e.g., antibodies, enzymes, receptor proteins, lectins, nucleic acids) as the sensing or signal transducing elements. An array of different biosensor configurations are under development, spurred on by recent advances in biotechnology and solid-state electronics. Although not all biosensors can detect their target analytes instantaneously, nor perform continuous measurements, certain biosensors embody both capabilities. Real-time, on-line biochemical monitoring will offer important information heretofore unavailable to the physician. It is also inevitable that biosensor-based instruments will decentralize patient testing, but telemetric systems can maintain the active and necessary involvement of the clinical pathologist.

Biosensing Techniques↗
PubMed1987

Early diagnosis of Schistosoma mansoni in mice using assays directed against cercarial antigens isolated by hydrophobic chromatography.

Two diagnostic assays are described for the early diagnosis of acute schistosomiasis, using a defined cercarial antigen preparation obtained by hydrophobic chromatography. Circulating IgM antibodies against this antigen fraction could be detected by ELISA as early as 1 wk after exposure in experimentally infected mice; IgM levels against other antigens and IgG levels against all the preparations examined were not significantly elevated until approximately 4-5 wk postinfection. Circulating antigen was detected as early as 3 days after exposure by a competitive inhibition ELISA using rabbit serum prepared against the cercarial antigen; antigen levels in the serum of mice with a 100-worm infection were found to exceed 100 ng/ml. Studies using sera from infected humans indicate that the assay can also recognize chronic S. mansoni, S. haematobium or S. japonicum infections. In a very limited field study, the specificity of the circulating antigen assay with regard to other helminthic infections was found to be 85%; sensitivity 100%. Preliminary characterization of the relevant antigen indicates that it is a relatively hydrophobic polypeptide with a molecular weight of approximately 41,000 daltons. The implications of these findings with regard to the treatment of travelers or the conduct of seroepidemiological studies in endemic areas are discussed.

Animals↗
PubMed1987

Technological advances in bedside monitoring: biosensors.

The need to monitor certain key biochemical parameters in hospitalized patients is driving the development of biosensors, a new class of medical device for real-time, on-line quantitative analysis. A biosensor is a microelectronic device that utilizes a biological molecule (eg, antibody, enzyme, or receptor) as the sensing or signal-transducing element. Biosensors can be configured into simple, rapid, and cost-effective laboratory devices that will allow the clinical pathologist to become even more responsive to the primary care physician. In those instances where measurements on discrete samples do not provide the required information, continuous monitoring with implantable biosensors could provide real-time data on levels of critical endogenous or exogenous substances. By hybridizing recent advances in transdermal substance collection with the analytical capabilities of biosensors, devices for continuous noninvasive monitoring at the bedside can be envisioned. The clinical pathologist can and should play a key role in the clinical evaluation and implementation of such technological advances.

Antibodies↗
PubMed1986

Development of circulating antigen assay for rapid detection of acute schistosomiasis.

A circulating antigen assay to detect acute schistosomiasis mansoni in experimentally infected mice has been developed. The competitive-inhibition enzyme-linked immunosorbent assay uses rabbit serum prepared against purified cercarial antigen. The assay detects a 100-worm infection as early as 1 week after exposure; circulating antigen levels in mouse serum exceeded 0.1 microgram/ml. Preliminary characterisation of the cercarial antigen shows that it is a hydrophobic polypeptide of approximate molecular weight 41,000. A rapid and accurate diagnosis of acute schistosomiasis in travellers would facilitate appropriate chemotherapy before the onset of pathology. A circulating antigen assay would also be valuable for seroepidemiological studies in areas where the disease is endemic.

Acute Disease↗
PubMed1986

Secretion of acetylcholinesterase by a mouse hepatocyte X rat liver cell hybrid culture.

A hybrid cell line (E-2) that secretes the enzyme acetylcholinesterase (AChE) has been prepared. The E-2 cell was the product of a fusion between primary mouse hepatocytes and a chemically transformed rat liver cell line (FRL), neither of which expresses AChE activity. The enzyme was determined to be AChE on the basis of its susceptibility to inhibition by BW284c51 but not by iso-OMPA, as well as its substrate specificity. Although the secreted enzyme was salt soluble and its activity not modified by the addition of the nonionic detergent, Triton X-100, the activity of the cellular enzyme (derived from homogenates of E-2 cells) was greatly enhanced in the presence of the detergent.

Acetylcholinesterase↗