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Biomedical subjects

H J Anderson

Publications and source records attributed to H J Anderson.

At least 19 recordsLinked to original sources
PubMed2000

Cell-based screen for antimitotic agents and identification of analogues of rhizoxin, eleutherobin, and paclitaxel in natural extracts.

We describe a cell-based assay for antimitotic compounds that is suitable for drug discovery and for quantitative determination of antimitotic activity. In the assay, cells arrested in mitosis as a result of exposure to antimitotic agents in pure form or in crude natural extracts are detected by ELISA using the monoclonal antibody TG-3. The assay was used to screen >24,000 extracts of marine microorganisms and invertebrates and terrestrial plants and to guide the purification of active compounds from 5 of 119 positive extracts. A new rhizoxin analogue was found in a Pseudomonas species, six new eleutherobin analogues were identified from the octocoral Erythropodium caribaeorum, and two paclitaxel analogues were found in the stem bark of the tree Ilex macrophylla. The assay was also used for quantitative comparison of the antimitotic activity of different analogues. It revealed the importance of the C-11 to C-13 segment of the diterpene core of eleutherobin for its antimitotic activity. The identification of antimitotic compounds in very low abundance and their high (0.5%) occurrence in natural extracts indicates that drug discovery efforts using this cell-based assay may lead to the identification of structurally novel antimitotic agents.

Alkaloids↗
PubMed1999

Phosphorylation-induced rearrangement of the histone H3 NH2-terminal domain during mitotic chromosome condensation.

The NH2-terminal domain (N-tail) of histone H3 has been implicated in chromatin compaction and its phosphorylation at Ser10 is tightly correlated with mitotic chromosome condensation. We have developed one mAb that specifically recognizes histone H3 N-tails phosphorylated at Ser10 (H3P Ab) and another that recognizes phosphorylated and unphosphorylated H3 N-tails equally well (H3 Ab). Immunocytochemistry with the H3P Ab shows that Ser10 phosphorylation begins in early prophase, peaks before metaphase, and decreases during anaphase and telophase. Unexpectedly, the H3 Ab shows stronger immunofluorescence in mitosis than interphase, indicating that the H3 N-tail is more accessible in condensed mitotic chromatin than in decondensed interphase chromatin. In vivo ultraviolet laser cross-linking indicates that the H3 N-tail is bound to DNA in interphase cells and that binding is reduced in mitotic cells. Treatment of mitotic cells with the protein kinase inhibitor staurosporine causes histone H3 dephosphorylation and chromosome decondensation. It also decreases the accessibility of the H3 N-tail to H3 Ab and increases the binding of the N-tail to DNA. These results indicate that a phosphorylation-dependent weakening of the association between the H3 N-tail and DNA plays a role in mitotic chromosome condensation.

Anaphase↗
PubMed1998

High-throughput assay for G2 checkpoint inhibitors and identification of the structurally novel compound isogranulatimide.

Treatment of cancer cells lacking p53 function with G2 checkpoint inhibitors sensitizes them to the toxic effects of DNA damage and has been proposed as a strategy for cancer therapy. However, few inhibitors are known, and they have been found serendipitously. We report the development of a G2 checkpoint inhibition assay that is suitable for high-throughput screening and its application to a screen of 1300 natural extracts. We present the isolation of a new G2 checkpoint inhibitor, the structurally novel compound isogranulatimide. In combination with gamma-irradiation, isogranulatimide selectively kills MCF-7 cells lacking p53 function.

Adenocarcinoma↗
PubMed1998

Flow cytometry of mitotic cells.

We have developed a procedure using flow cytometric measurement of a mitosis-specific antigen that may be used to count mitotic cells and sort them from non-mitotic cells. The procedure may also be used in conjunction with measurement of cellular DNA content and of bromodeoxyuridine incorporation into cellular DNA to assign cells to the G1/G0, S, G2, or M phase of the cell cycle.

Antibodies, Monoclonal↗
PubMed1998

Entry into mitosis without Cdc2 kinase activation.

Mouse FT210 cells at 39 degreesC cannot enter mitosis but arrest in G2 phase, because they lack Cdc2 kinase activity as a result of a temperature-sensitive lesion in the cdc2 gene. Incubation of arrested cells with the protein phosphatase 1 and 2A inhibitor okadaic acid induces morphologically normal chromosome condensation. We now show that okadaic acid also induces two other landmark events of early mitosis, nuclear lamina depolymerization and centrosome separation, in the absence of Cdc2 kinase activity. Okadaic acid-induced entry into mitosis is accompanied by partial activation of Cdc25C and may be prevented by tyrosine phosphatase inhibitors and by the protein kinase inhibitor staurosporine, suggesting that Cdc25C and kinases distinct from Cdc2 are required for these mitotic events. Using in-gel assays, we show that a 45-kDa protein kinase normally activated at mitosis is also activated by okadaic acid independently of Cdc2 kinase. The 45-kDa kinase can utilize GTP, is stimulated by spermine and is inhibited by heparin. These properties are characteristic of the kinase CK2, but immunoprecipitation studies indicate that it is not CK2. The data underline the importance of a tyrosine phosphatase, possibly Cdc25C, and of kinases other than Cdc2 in the structural changes the cell undergoes at mitosis, and indicate that entry into mitosis involves the activation of multiple kinases working in concert with Cdc2 kinase.

Animals↗
PubMed1997

Contrasting effects of mitogenic growth factors on oligodendrocyte precursor cell migration.

We have examined the effects of the mitogenic growth factors platelet derived growth factor (PDGF), basic fibroblast growth factor (bFGF) and glial growth factor-2 (GGF-2) on oligodendrocyte precursor migration. In an agarose drop migration assay PDGF and bFGF stimulated migration while GGF-2 had no effect. The migration-enhancing effect of bFGF cannot be blocked by neutralising antibodies against PDGF, confirming that this effect is direct and not mediated via upregulation of PDGF receptors. Based on our results, we propose a model in which the differing effects of PDGF and GGF-2 ensure appropriate numbers of oligodendrocyte precursor cells in the vicinity of axons to be myelinated during development.

Cell Division↗
PubMed1997

Cytotoxic peptides hemiasterlin, hemiasterlin A and hemiasterlin B induce mitotic arrest and abnormal spindle formation.

PURPOSE: Hemiasterlin, hemiasterlin A and hemiasterlin B are newly isolated cytotoxic tripeptides with potential as antitumor drugs. We wished to determine their mechanism of cytotoxicity. METHODS: We studied their effect on cell survival, cell cycle progression, and microtubule morphology in MCF-7 human mammary carcinoma cells. RESULTS: At the nanomolar concentrations at which they were cytotoxic, the peptides induced arrest in mitotic metaphase. Hemiasterlin A produced abnormal mitotic spindles like those produced by the microtubule inhibitors taxol, nocodazole and vinblastine at low concentrations. At high concentrations hemiasterlin A did not cause microtubule bundling like taxol, but caused microtubule depolymerization like nocodazole and vinblastine. CONCLUSIONS: The hemiasterlins probably exert their cytotoxic effect by inhibiting spindle microtubule dynamics.

Animals↗
PubMed1997

The battle between Unix and Windows NT.

For more than a decade, Unix has been the dominant back-end operating system in health care. But that prominent position is being challenged by Windows NT, touted by its developer, Microsoft Corp., as the operating system of the future. CIOs and others are attempting to figure out which system is the best choice in the long run.

Administrative Personnel↗
PubMed1995

Chromosome condensation induced by fostriecin does not require p34cdc2 kinase activity and histone H1 hyperphosphorylation, but is associated with enhanced histone H2A and H3 phosphorylation.

Chromosome condensation at mitosis correlates with the activation of p34cdc2 kinase, the hyperphosphorylation of histone H1 and the phosphorylation of histone H3. Chromosome condensation can also be induced by treating interphase cells with the protein phosphatase 1 and 2A inhibitors okadaic acid and fostriecin. Mouse mammary tumour FT210 cells grow normally at 32 degrees C, but at 39 degrees C they lose p34cdc2 kinase activity and arrest in G2 because of a temperature-sensitive lesion in the cdc2 gene. The treatment of these G2-arrested FT210 cells with fostriecin or okadaic acid resulted in full chromosome condensation in the absence of p34cdc2 kinase activity or histone H1 hyperphosphorylation. However, phosphorylation of histones H2A and H3 was strongly stimulated, partly through inhibition of histone H2A and H3 phosphatases, and cyclins A and B were degraded. The cells were unable to complete mitosis and divide. In the presence of the protein kinase inhibitor starosporine, the addition of fostriecin did not induce histone phosphorylation and chromosome condensation. The results show that chromosome condensation can take place without either the histone H1 hyperphosphorylation or the p34cdc2 kinase activity normally associated with mitosis, although it requires a staurosporine-sensitive protein kinase activity. The results further suggest that protein phosphatases 1 and 2A may be important in regulating chromosome condensation by restricting the level of histone phosphorylation during interphase, thereby preventing premature chromosome condensation.

Alkaloids↗
PubMed1994

A catalyst for the networking movement.

Charles Jones has a clear vision for how community health information networks can improve health care delivery in West Virginia. He's seen what EDI has done for retailing and manufacturing industries. Now, he's trying to turn his dreams into reality by heading a consortium that's developing a strategy for building several networks in the state. Jones is demonstrating how one hospital executive with strong personal convictions can spark a sweeping effort to change the way a state health care system functions.

Computer Communication Networks↗
PubMed1993

Putting patients first. Hospitals work to define patient-centered care.

Patient-centered care is quickly becoming a reality across the country, as hospitals begin to define and implement the concept. In a series of articles, we examine the phenomenon and present the results of our exclusive new survey. On page 14, what is patient-centered care, and why has its time come? On page 18, what are the human resources implications for administrators? On page 20, the strategic planning and financial considerations. On page 22, a look at the wide range of facilities implications involved in the patient-centered care concept.

Attitude of Health Personnel↗