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M Noble

Publications and source records attributed to M Noble.

At least 55 records · Page 3Linked to original sources
PubMed1996

On the track of cell survival pharmaceuticals in the oligodendrocyte type-2 astrocyte lineage.

The identification of compounds that can protect cells against death induced by exposure to noxious stimuli and against programmed cell death (apoptosis) associated with exposure to inadequate amounts of trophic factors is of great interest in contemporary biology. We have found that N-acetyl-L-cysteine (NAC) is able to promote cell survival in these two distinct experimental paradigms of, respectively, "death by murder" and "death by neglect." In the former case, NAC prevented the death of oligodendrocytes induced by glutamate or tumor necrosis factor-alpha (TNF-alpha), and also prevented TNF-alpha-induced death of L929 cells. NAC also acted in synergy with ciliary neurotrophic factor (CNTF) to prevent killing of oligodendrocytes by TNF-alpha. In analysis of "death by neglect," NAC markedly enhanced the extent of spinal ganglion neuron survival obtained with suboptimal concentrations of nerve growth factor and of oligodendrocyte survival obtained with suboptimal concentrations of CNTF or insulin-like growth factor-1. Surprisingly, significant rescue of oligodendrocytes from apoptosis was also observed with combinations of NAC with progesterone, vitamin C, or Trolox, a water-soluble vitamin E analogue, although not with any of these compounds applied individually. These results demonstrate that cocktails of small molecules such as those we have studied may have beneficial effects not predictable from the action of any individual member of the cocktail. In light of the long clinical history of therapeutic use of NAC and the other compounds identified in our studies, we suggest that it may be of interest to examine use of NAC alone, or combinations of NAC with the other small molecules we have studied, in conditions in which certain toxin-mediated forms of cell death or apoptosis contribute significantly to disease.

Acetylcysteine↗
PubMed1995

Limk1 is predominantly expressed in neural tissues and phosphorylates serine, threonine and tyrosine residues in vitro.

We have isolated the murine Limk1 gene, which is a single copy gene located at the distal end of mouse chromosome 5. Limk1 exhibits a 95% homology to the human homologue, LIMK, which contains two LIM domains and a putative protein kinase domain. Although Limk1 and LIMK contain all motifs found in catalytic kinase domains, amino acids previously described to be diagnostic of either serine/threonine- or tyrosine-kinases are not present. It is demonstrated that GST-Limk1-fusion protein can autophosphorylate on serine, tyrosine and threonine residues in vitro and that mutation of residue D460 within the IHRDL motif abolishes kinase activity. Northern blot showed preferential expression of a 3.5 kb message in adult spinal cord and brain. In situ hybridisation confirmed high expression levels in the nervous system, particularly in the spinal cord and the cranial nerve and dorsal root ganglia. Limk1 also contains two tandem LIM-domains. These zinc-finger like domains can mediate protein-protein interactions and have been described in nuclear and cytoskeletal proteins. The combination of LIM- and kinase domains may provide a novel route by which intracellular signalling can be integrated.

Amino Acid Sequence↗
PubMed1995

From rodent glial precursor cell to human glial neoplasia in the oligodendrocyte-type-2 astrocyte lineage.

With only a few exceptions, the precursor cells representing the normal counterparts of human tumours are unknown. The comparative lack of information about the lineages involved in tissue development, and difficulties in growing many human tumors in a manner suitable for cellular biological analysis, together often make it difficult to study the differences between normal and tumor cells and to develop many of the model systems that would be useful in the study of human cancer. By applying techniques previously utilized to study glial progenitor cells, we have isolated a human glioblastoma multiforme (GBM)-derived population that expresses many properties otherwise uniquely expressed by oligodendrocyte-type-2 astrocyte (O-2A) progenitor cells. Hu-O-2A/Gb1 (for Human O-2A lineage Glioblastoma number 1) cells responded to similar mitogens and differentiation modulators as rodent O-2A progenitors, and generated cells with features of precursor cells, oligodendrocytes and astrocytes. Moreover, 1H-NMR analysis of amino acid composition demonstrated a striking conversation of types and quantities of free amino acids between the human tumour cells and the rodent primary cells. Hu-O-2A/Gb1 cells represent the first human glioma-derived population for which unambiguous lineage assignment has been possible, and our results indicate that the human O-2A lineage can contribute to one of the most malignant of glial tumours. In addition, the highly diagnostic 1H-NMR spectrum expressed by Hu-O-2A/Gb1 cells raises the possibility of eventual non-invasive identification of tumors of this lineage.

Animals↗
PubMed1995

Characteristic metabolic profiles revealed by 1H NMR spectroscopy for three types of human brain and nervous system tumours.

Cell culture techniques, high-resolution in vitro 1H NMR spectroscopy, and chromatographic analyses were used to compare the properties of three types of human brain and nervous system tumours. Cell lines were immunocytochemically characterized at all stages in culture with specific antibodies. Intracellular metabolites present in cell extracts were analysed by 1H NMR spectroscopy and by high performance liquid chromatography (HPLC). The spectra from meningiomas, neuroblastomas, and glioblastomas displayed, in addition to similarities-including the presence of signals from leucine, isoleucine, valine, threonine, lactate, acetate, glutamate, choline-containing compounds and glycine-certain distinguishing metabolic features. Spectra from meningiomas featured relatively high signals from alanine. Intense signals from creatine were present in neuroblastoma spectra, while in spectra from glioblastoma they were not detectable. We found statistically significant differences by 1H NMR spectroscopy in the amounts of alanine, glutamate, creatine, phosphorylcholine and threonine among the types of tumours examined. HPLC determinations confirmed that there were also other metabolites specific to a type of tumour, such as taurine, gamma-aminobutyric acid, and serine. We suggest that these findings have potential relevance for the development of non-invasive diagnosis of tumour lineage by 1H NMR spectroscopy in vivo.

Alanine↗
PubMed1995

The H-2KbtsA58 transgenic mouse: a new tool for the rapid generation of novel cell lines.

The ability to generate expanded populations of individual cell types able to undergo normal differentiation in vitro and in vivo is of critical importance in the investigation of the mechanisms that underly differentiation and in studies on the use of cell transplantation to repair damaged tissues. This review discusses the development of a strain of transgenic mice that allows the direct derivation of conditionally immortal cell lines from a variety of tissues, simply by dissociation of the tissue of interest and growth of cells in appropriate conditions. In these mice the tsA58 mutant of SV40 large T antigen is controlled by the interferon-inducible Class I antigen promoter. Cells can be grown for extended periods in vitro simply by growing them at 33 degrees C in the presence of interferon, while still retaining the capacity to undergo normal differentiation in vivo and in vitro. In addition, it appears that cell lines expressing mutant phenotypes can readily be generated by preparing cultures from appropriate offspring of matings between H-2KbtsA58 transgenic mice and mutant mice of interest.

Animals↗
PubMed1995

Transitional cell carcinoma of the renal pelvis or ureter: patterns of failure.

OBJECTIVES: To identify recurrence patterns and possible indications for adjuvant treatment. METHODS: Ninety-four patients with transitional cell carcinoma of the renal pelvis or ureter were reviewed to determine their pattern of failure. Factors including gender and age, tumor stage and grade, and extent of surgical procedure and adjuvant radiation therapy (RT) were analyzed with respect to local and distant recurrence and survival. RESULTS: Seventy-seven patients had resections without residual. On multivariate analysis, grade (P = 0.01) and adjuvant RT (P = 0.02) had significant effects on local control. Metastases were solely dependent on stage (P = 0.0001). Survival was dependent on stage (P = 0.0059) and age (P = 0.036), with the use of adjuvant RT of borderline significance (P = 0.07). Twenty-seven patients were excluded from local failure and survival analysis; of these, 3 died within 1 month of surgery, 5 had metastasis at presentation, and 19 had local disease that was unresectable. Eleven of these 19 were treated by RT, resulting in 2 long-term disease-free survivors after receiving doses of 45 and 50.4 Gy. CONCLUSIONS: In patients with adverse factors, such as high grade or stage, close margins, or positive nodes, local control can be improved with adjuvant radiation. Improvement in survival is of borderline significance on multivariate analysis, with approximately 50% of high stage or grade patients developing metastasis.

Adult↗
PubMed1994

N-acetyl-L-cysteine is a pluripotent protector against cell death and enhancer of trophic factor-mediated cell survival in vitro.

We have discovered that N-acetyl-L-cysteine (NAC) protects cells against death induced by exposure to noxious stimuli and against programmed cell death (apoptosis) associated with exposure to inadequate amounts of trophic factors. NAC prevented glutamate-induced death of oligodendrocytes and tumor necrosis factor alpha (TNF-alpha)-induced death of oligodendrocytes and L929 fibroblasts. Moreover, suboptimal doses of NAC plus ciliary neurotrophic factor (which also protects oligodendrocytes against TNF-alpha-mediated killing) acted synergistically to protect oligodendrocytes against TNF-alpha-induced death. Protection against death by growth factor deprivation was provided by the combination of (i) NAC, vitamin C, or Trolox (a water-soluble analogue of vitamin E) with suboptimal concentrations of protein trophic factors, (ii) NAC, vitamin C, or Trolox with progesterone, and (iii) NAC with either vitamin C or Trolox; these latter experiments suggest that the addition of tyrosine kinase stimulators is not required to promote cell survival. In all paradigms, NAC was either equally or more effective than the other compounds examined. In light of the long history of therapeutic application of NAC, we suggest that use of this compound may be of interest in conditions where certain toxin-mediated forms of cell death and/or apoptosis contribute significantly to disease.

Acetylcysteine↗
PubMed1994

Measurement of time in oligodendrocyte-type-2 astrocyte (O-2A) progenitors is a cellular process distinct from differentiation or division.

When stimulated by platelet-derived growth factor (PDGF), oligodendrocyte-type-2 astrocyte (O-2A) progenitors derived from perinatal rat optic nerves undergo a limited number of cell divisions before clonally related cells synchronously and symmetrically differentiate into nondividing oligodendrocytes. The duration of this mitotic period is thought to be controlled by a cell-intrinsic biological clock. Thus, in the presence of PDGF, the measurement of time by the biological clock is intimately coupled to the control of division and differentiation. In contrast, O-2A progenitors grown in the presence of PDGF plus basic fibroblast growth factor (bFGF) divide indefinitely in the absence of differentiation and so do not exhibit a limited period of division. We have tested whether growth in PDGF plus bFGF alters the duration of the limited period of division O-2A progenitors exhibit in response to PDGF alone. Accordingly, O-2A progenitors were grown in the presence of PDGF plus bFGF for varying lengths of time, before being switched to conditions that promote timed differentiation (PDGF but not bFGF). Increasing duration of culture in PDGF plus bFGF led to a gradual shortening of the period for which O-2A progenitors were subsequently responsive to PDGF alone, until eventually all cells differentiated without dividing after switching. In contrast, a short exposure to bFGF was not sufficient to cause a similar alteration in the pattern of differentiation. These results indicate that O-2A progenitors prevented from undergoing timed differentiation nevertheless retain the ability to measure elapsed time, implying that the biological clock in this cell type can be uncoupled from differentiation. Furthermore, they demonstrate that the biological clock does not impose an absolute limit on the number of divisions that an O-2A progenitor can undergo. In contrast with existing hypotheses, our observations suggest that the molecular mechanism that controls timed differentiation must consist of at least two components, with the clock itself being in some manner distinct from mechanisms that limit cell division and/or directly regulate differentiation.

Animals↗
PubMed1994

Efficacy of microbial identification system for epidemiologic typing of coagulase-negative staphylococci.

The lack of an adequate typing system hampers our understanding of the epidemiology of infections caused by coagulase-negative staphylococci (CoNS). CoNS have become recognized as important nosocomial pathogens and the principal cause of infections associated with invasive devices. Sensitive, specific, and convenient methods are needed to evaluate whether implementing infection control guidelines reduces the risk of nosocomial infections from CoNS and other pathogens. The Microbial Identification System (MIDI) (Microbial ID Inc., Newark, Del.), a semiautomated system for fatty acid methyl ester analysis, shows considerable promise for clinical and epidemiologic applications. Its predictive accuracy and reliability were tested by using epidemiologically related and replicated CoNS isolates as well as CoNS from epidemiologically unrelated clinical infections, which were obtained from five established hospital culture collections in diverse geographic locations. Two hundred isolates were fully characterized in 5 days by one person using MIDI, and the results were similar to those produced by more expensive and time-consuming conventional typing methods. MIDI appears to be a useful screening tool that could be used before more expensive and labor-intensive molecular methods. It offers important advantages to hospital epidemiologists and clinical microbiologists who must identify and type CoNS isolates.

Bacterial Typing Techniques↗
PubMed1994

Ciliary neurotrophic factor and leukemia inhibitory factor promote the generation, maturation and survival of oligodendrocytes in vitro.

We have found that CNTF and LIF are pleiotropic modulators of development in the O-2A lineage. Both molecules enhanced the generation of oligodendrocytes in cultures of dividing O-2A progenitors. CNTF and LIF also promoted oligodendrocyte maturation, as determined by expression of myelin basic protein, and could promote oligodendrocyte survival to an extent comparable with insulin-like growth factor-1 or insulin. In addition, LIF and CNTF both promoted the differentiation of O-2A progenitors into type-2 astrocytes but only when applied in the presence of extracellular matrix (EnMx) derived from cultures of endothelial cells. The ability of CNTF and LIF to enhance differentiation of O-2A progenitors along either of the alternative pathways of oligodendrocyte and astrocyte differentiation suggests that these proteins are able to enhance the process of differentiation per se, while the actual path of differentiation promoted is determined by the presence or absence of additional molecules in the extracellular environment.

Animals↗
PubMed1994

The effects of the neuN and neuT genes on differentiation and transformation of mammary epithelial cells.

Overexpression of the proto-oncogene product, p185neuN, in a non-tumorigenic mammary epithelial line (31E) facilitates aspects of lactogenic differentiation. Formation of branching cords and induction of beta-casein synthesis by 31E cells normally require co-culture of these cells with fibroblasts, or the presence of collagen or fibronectin. In contrast, 31E cells expressing p185neuN spontaneously form branching cords when grown on tissue culture plastic and can synthesize beta-casein in the absence of exogenous substrates or feeder layers. Under these conditions, the cells deposit laminin and fibronectin, indicating a possible role for p185neuN in the deposition of extracellular matrix proteins. Overexpression of the corresponding oncogene product, p185neuT, has markedly different effects. Expression of p185neuT does not facilitate the formation of branching cords or the synthesis of beta-casein when grown on tissue culture plastic, although these cells do deposit laminin and fibronectin. Confocal microscopy indicates a significant difference in the distribution of laminin and fibronectin in 31E cells expressing p185neuT compared to those expressing p185neuN. The effects of p185neuN and p185neuT expression on cell transformation depend on cell type. Expression of both p185neuN and p185neuT increases anchorage-independent growth of 31E cells, but only p185neuT induces anchorage-independent growth of NIH 3T3 fibroblasts. This lineage specificity in the action of p185neuN may be related to observations that overexpression of p185c-erbB-2 (the human homologue of p185neuN) is only associated with the development of human epithelial cancers. The effects of p185neuN on laminin deposition by 31E cells may be relevant to the transforming ability of p185neuN, since laminin can induce anchorage-independent growth of mouse mammary cells. These results suggest that p185neuN and p185neuT could exert their effects on differentiation and transformation of mammary epithelial cells in part by promoting the deposition of extracellular matrix proteins.

Animals↗
PubMed1993

Repair of demyelinated lesions by transplantation of purified O-2A progenitor cells.

The transplantation of well defined populations of precursor cells offers a means of repairing damaged tissue and of delivering therapeutic compounds to sites of injury or degeneration. For example, a functional immune system can be reconstituted by transplantation of purified haematopoietic stem cells, and transplanted skeletal myoblasts and keratinocytes can participate in the formation of normal tissue in host animals. Cell transplantation in the central nervous system (CNS) has been proposed as a means of correcting neuronal dysfunction in diseases associated with neuronal loss; it might also rectify glial cell dysfunction, with transplanted oligodendrocyte precursor cells eventually allowing repair of demyelinating damage in the CNS. Here we use co-operating growth factors to expand purified populations of oligodendrocyte type-2 astrocyte (O-2A) progenitor cells for several weeks in vitro. When injected into demyelinating lesions in spinal cords of adult rats, created in such a way as to preclude host-mediated remyelination, these expanded populations are capable of producing extensive remyelination. In addition, transplantation of O-2A progenitor cells genetically modified to express the bacterial beta-galactosidase gene gives rise to beta-galactosidase-positive oligodendrocytes which remyelinate demyelinated axons within the lesion. These results offer a viable strategy for the manipulation of neural precursor cells which is compatible with attempts to repair damaged CNS tissue by precursor transplantation.

Animals↗