Biomedical subjects

A C Lloyd

Publications and source records attributed to A C Lloyd.

15 recordsLinked to original sources

PubMed2001

Lack of replicative senescence in cultured rat oligodendrocyte precursor cells.

Most mammalian somatic cells are thought to have a limited proliferative capacity because they permanently stop dividing after a finite number of divisions in culture, a state termed replicative cell senescence. Here we show that most oligodendrocyte precursor cells purified from postnatal rat optic nerve can proliferate indefinitely in serum-free culture if prevented from differentiating; various cell cycle-inhibitory proteins increase, but the cells do not stop dividing. The cells maintain high telomerase activity and p53- and Rb-dependent cell cycle checkpoint responses, and serum or genotoxic drugs induce them to acquire a senescence-like phenotype. Our findings suggest that some normal rodent precursor cells have an unlimited proliferative capacity if cultured in conditions that avoid both differentiation and the activation of checkpoint responses that arrest the cell cycle.

Animals↗

PubMed2001

Lack of replicative senescence in normal rodent glia.

Replicative senescence is thought to be an intrinsic mechanism for limiting the proliferative life-span of normal somatic cells. We show here that rat Schwann cells can be expanded indefinitely in culture while maintaining checkpoints normally lost during the immortalization process. These findings demonstrate that senescence is not an inevitable consequence of extended proliferation in culture.

Animals↗

PubMed2001

Cell senescence and cancer.

Historically, the senescent state has been associated with, and was named after, the cell-cycle arrest that occurs after cells have undergone an intrinsically defined number of divisions in vitro. More recently, however, it has been shown that extrinsic factors, including those encountered in normal tissue-culture environments, can prematurely induce an indistinguishable senescent phenotype. In this review, we discuss the pathways of cell senescence, the mechanisms involved and the role that these pathways have in regulating the initiation and progression of cancer.

Animals↗

PubMed2001

Diesel engines: environmental impact and control.

The diesel engine is the most efficient prime mover commonly available today. Diesel engines move a large portion of the world's goods, power much of the world's equipment, and generate electricity more economically than any other device in their size range. But the diesel is one of the largest contributors to environmental pollution problems worldwide, and will remain so, with large increases expected in vehicle population and vehicle miles traveled (VMT) causing ever-increasing global emissions. Diesel emissions contribute to the development of cancer; cardiovascular and respiratory health effects; pollution of air, water, and soil; soiling; reductions in visibility; and global climate change. Where instituted, control programs have been effective in reducing diesel fleet emissions. Fuel changes, such as reduced sulfur and aromatics content, have resulted in immediate improvements across the entire diesel on- and off-road fleet, and promise more improvements with future control. In the United States, for example, 49-state (non-California) off-road diesel fuel sulfur content is 10 times higher than that of national on-road diesel fuel. Significantly reducing this sulfur content would reduce secondary particulate matter (PM) formation and allow the use of control technologies that have proven effective in the on-road arena. The use of essentially zero-sulfur fuels, such as natural gas, in heavy-duty applications is also expected to continue. Technology changes, such as engine modifications, exhaust gas recirculation, and catalytic aftertreatment, take longer to fully implement, due to slow fleet turnover. However, they eventually result in significant emission reductions and will be continued on an ever-widening basis in the United States and worldwide. New technologies, such as hybrids and fuel cells, show significant promise in reducing emissions from sources currently dominated by diesel use. Lastly, the turnover of trucks and especially off-road equipment is slow; pollution control agencies need to address existing emissions with in-use programs, such as exhaust trap retrofits and smoke inspections. Such a program is underway in California. These and other steps that can be continued and improved will allow the use of the diesel engine, with its superior fuel consumption, to continue to benefit society while greatly reducing its negative environmental and health impacts. The next ten years can and must become the "Decade of Clean Diesel."

Air Pollution↗

PubMed2000

p53: only ARF the story.

Two tumour-suppressor proteins - p16INK4A and p19 ARF - encoded by the same genetic locus both have a role in arresting the cell-division cycle. New results have revealed further complexities in the pathways involved.

Animals↗

PubMed1998

Ras versus cyclin-dependent kinase inhibitors.

In the past year, complex interactions between Ras and the cell cycle have been identified. In primary cells, activated Ras induces a cell-cycle arrest via the induction of cyclin-dependent kinase inhibitors (CDKIs). Oncogenic changes that cooperate with Ras act by neutralising CDKIs by various mechanisms. In the absence of a negative growth signal from Ras, such as in most immortalised cell lines, Ras acts positively on the cell cycle. Insights have been made into the mechanisms by which Ras abrogates remaining cell-cycle controls.

Animals↗

PubMed1997

Cooperating oncogenes converge to regulate cyclin/cdk complexes.

The cooperation of oncogenes in the transformation of primary rat Schwann cells is a strikingly synergistic process. We have explored the molecular mechanisms involved. Activation of an inducible Raf kinase results in morphologically transformed cells that are arrested in G1 via the induction of p21(CiP1) and subsequent inhibition of cyclin/cdk activity. In contrast, coexpression of SV40 large T (LT) or a dominant-negative mutant of p53 abolishes p21(CiP1) induction and alleviates the growth arrest. Moreover in this scenario, Raf activation results in an increase in the specific activity of cyclin/cdk complexes with Raf and LT cooperating to superinduce cyclin A/cdk2 activity and stimulate proliferation in the absence of mitogens. Thus, signaling by Raf and its cooperating partners converges at the regulation of cyclin/cdk complexes, with the cellular responses to Raf modulated by p53.

Animals↗

PubMed1997

High-intensity Raf signal causes cell cycle arrest mediated by p21Cip1.

Activated Raf has been linked to such opposing cellular responses as the induction of DNA synthesis and the inhibition of proliferation. However, it remains unclear how such a switch in signal specificity is regulated. We have addressed this question with a regulatable Raf-androgen receptor fusion protein in murine fibroblasts. We show that Raf can cause a G1-specific cell cycle arrest through induction of p21Cip1. This in turn leads to inhibition of cyclin D- and cyclin E-dependent kinases and an accumulation of hypophosphorylated Rb. Importantly, this behavior can be observed only in response to a strong Raf signal. In contrast, moderate Raf activity induces DNA synthesis and is sufficient to induce cyclin D expression. Therefore, Raf signal specificity can be determined by modulation of signal strength presumably through the induction of distinct protein expression patterns. Similar to induction of Raf, a strong induction of activated Ras via a tetracycline-dependent promoter also causes inhibition of proliferation and p21Cip1 induction at high expression levels. Thus, p21Cip1 plays a key role in determining cellular responses to Ras and Raf signalling. As predicted by this finding we show that Ras and loss of p21 cooperate to confer a proliferative advantage to mouse embryo fibroblasts.

3T3 Cells↗

PubMed1992

Reactivity-based hydrocarbon controls: scientific issues and potential regulatory applications.

The California Air Resources Board and the South Coast Air Quality Management District hosted a conference on April 8-9, 1991 to examine the scientific issues associated with reactivity-based hydrocarbon controls, and to identify the obstacles to potential regulatory applications. Owing to residual uncertainties in the underlying science, and the complex emission measurement capabilities required for enforcement, a general consensus emerged on the need for further research before application of reactivity-based controls. A number of recommendations were made for research on the remaining scientific, enforcement, and policy issues, many of which have led to cooperative efforts initiated since the conference.

Air Pollutants, Occupational↗

PubMed1989

Bombesin stimulation of inositol 1,4,5-trisphosphate generation and intracellular calcium release is amplified in a cell line overexpressing the N-ras proto-oncogene.

Bombesin stimulation of T15 cells in which the inducible N-ras oncogene is overexpressed caused elevated production of inositol phosphates compared to uninduced cells [Wakelam, Davies, Houslay, McKay, Marshall & Hall (1986) Nature (London) 323, 173-176]. This elevated response is shown here to result from increased generation of inositol 1,4,5-trisphosphate leading to an elevated release of intracellular stored Ca2+. Single-cell analysis of Ca2+ release showed that the elevated response is not a consequence of an increased fraction of responding cells. These amplifications are consistent with p21N-ras acting like a guanine nucleotide coupling protein in this cell line.

Bombesin↗

PubMed1989

Signal transduction by p21ras.

Experiments using the physical loading of purified recombinant p21 ras proteins into quiescent normal cells to analyze how the proteins stimulate DNA synthesis and morphological transformation are reviewed. The results indicate that oncogenic p21ras proteins rapidly activate a protein-kinase-C-dependent pathway and a protein-kinase-C-independent pathway. The activation of protein kinase C is absolutely required for p21ras to stimulate DNA synthesis but is not required for morphological transformation.

Animals↗

PubMed1989

p21H-ras-induced morphological transformation and increases in c-myc expression are independent of functional protein kinase C.

It has previously been demonstrated that efficient DNA synthesis by oncogenic p21H-ras only occurs in the presence of insulin and is absolutely dependent on functional protein kinase C. Here we show that morphological transformation induced by oncogenic p21H-ras does not require functional protein kinase C. The early phases of protein kinase C-independent morphological transformation do not require de novo protein synthesis. We have also demonstrated that the introduction of p21H-ras into quiescent Swiss 3T3 cells by scrape-loading leads to increased levels of c-myc mRNA similar to those seen following serum stimulation. The increases in c-myc mRNA levels induced by p21H-ras are also independent of functional protein kinase C. Both morphological transformation and the elevation of c-myc mRNA levels do not require insulin. These results demonstrate that p21H-ras is generating protein kinase C-dependent and -independent signals.

Animals↗

PubMed1989

Scrape-loading of Swiss 3T3 cells with ras protein rapidly activates protein kinase C in the absence of phosphoinositide hydrolysis.

Scrape-loading has been used to analyse the biochemical function of purified p21ras protein. We have shown that scrape-loading oncogenic p21ras into quiescent Swiss 3T3 cells causes morphological transformation of 90% of the cell population within 15 h. Since large numbers of cells can be loaded with p21ras, early induced biochemical changes can be analysed. In this way we have shown that oncogenic p21ras causes rapid activation of protein kinase C five minutes after introduction of protein, but that ras protein fails to stimulate measurable inositol phosphate formation. It appears, therefore, that the stimulation of protein kinase C activity is due to a ras induced increase in diacylglycerol from a source other than inositol phospholipids. Efficient stimulation of DNA synthesis by oncogenic p21ras only occurs in the presence of insulin. This stimulation of DNA synthesis by ras is absolutely dependent on functional protein kinase C activity.

Cycloheximide↗

PubMed1986

Intertissue differences in the hysteretic behaviour of carnitine palmitoyltransferase in the presence of malonyl-CoA.

In the presence of malonyl-CoA, the overt form of carnitine palmitoyltransferase (CPT1) in mitochondria from rat liver, kidney cortex, heart, skeletal muscle and brown adipose tissue shows non-linear time courses, suggesting hysteretic behaviour. The pattern of this hysteresis is similar in heart, skeletal muscle and brown adipose tissue, but the hysteretic behaviour of the enzyme in these three tissues differs markedly from that seen in liver and kidney.

Acyl Coenzyme A↗

PubMedDate not supplied

Economic evaluation of the use of nadroparin in the treatment of deep-vein thrombosis in Switzerland.

OBJECTIVE: To compare the cost implications, from the payer's perspective, of the use of nadroparin instead of unfractionated heparin in the initial treatment of deep-vein thrombosis. DESIGN: Cost-minimization study. SETTING: Switzerland. MATERIAL: Survey of clinical practice in six Swiss hospitals used to model three treatment regimens. MAIN OUTCOME MEASURES: Cost of treatment ($ US) per patient. RESULTS: Treatment with nadroparin instead of unfractionated heparin would reduce costs by $153 per patient. Treatment with nadroparin instead of subcutaneous unfractionated heparin would reduce costs by $109 per patient. CONCLUSIONS: The cost of initial treatment of deep-vein thrombosis is considerably lower with nadroparin than with either of the alternative regimens. Nadroparin reduces costs through greater ease of administration and by reducing the amount of laboratory monitoring. Treatment with nadroparin might also allow patients to be discharged from the hospital more quickly than is possible with intravenous infusion of unfractionated heparin.

Anticoagulants↗