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PubMed2001

The role of fat cell derived peptides in age-related metabolic alterations.

Aging in humans is associated with alterations in body fat distribution and a parallel gradual increase in the prevalence of atherosclerotic cardiovascular disease, as well as mortality of all causes. Because of nutrient cost, availability, and the sedentary life-style, half of the western world population has fat mass in excess of 30% of the body weight that weighs 3-4 times more than the fat mass of lean subjects. Recent discoveries of various hormones, cytokines and complement factors secreted by adipose cells opened a new avenue of research, looking at the role of these fat derived peptides in different conditions. We will focus here on the potential role of fat tissue in different physiological and physiopathological conditions associated with age-related metabolism and risk factors for diseases. We will also exemplify how body fat capacity, distribution and function can be directly linked, and may play a central role in energy metabolism and homeostasis, atherosclerosis, and possibly in the defense against cancer. We hypothesize that biological pathways involved in nutrient regulation in fat tissue may be important in inducing longevity in calorie restricted animals.

Adipocytes↗
PubMed1996

Childhood social circumstances and psychosocial and behavioural factors as determinants of plasma fibrinogen.

BACKGROUND: High plasma fibrinogen concentration is associated with an increased risk of coronary heart disease. We have investigated associations between plasma fibrinogen and factors operating in childhood and in adulthood, including the psychosocial characteristics. METHODS: In a cross-sectional study of Civil Servants in London, UK, 2095 men and 1202 women aged 45-55 years provided blood samples for fibrinogen measurement at the time of the Whitehall II study baseline. The participants completed a questionnaire on demographic characteristics, education, employment grade, parents' occupation, health behaviours, and work characteristics. FINDINGS: Measures of childhood environment (adult height, father's social class, and participant's education) were inversely associated with adult plasma fibrinogen concentration in both sexes. Lower socioeconomic status (as shown by employment grade) was associated with higher fibrinogen concentrations, with differences from top to bottom grade of 0.22 g/L (95% Cl 0.13-0.31) in men and 0.37 g/L (0.18-0.56) in women (p<0.0001, both sexes). This association was not accounted for by measures of childhood circumstances. Control over work, assessed by personnel managers, was inversely related to fibrinogen in both sexes, and a similar relation was seen for self-rated control over work among men but not women. Men in the bottom third of the distribution for self-rated and externally assessed control over work had higher fibrinogen concentrations than those in the top third for both measures (difference 0.16 g//L [0.07-0.26]; p<0.001.) There was no difference between these extremes among women (0.02 g/L [0.16 to 0.19]). Current smokers had higher fibrinogen concentrations than non-smokers, and moderate alcohol consumers had lower concentrations than those who drank occasionally or never. INTERPRETATION: Although our study was cross-sectional, it provides evidence that adult fibrinogen concentration is determined by factors operating throughout life. Fibrinogen may be a marker of the biological pathways that mediate the inverse socioeconomic gradient in coronary disease.

Adult↗
PubMed2001

Stearyl poly(ethylene oxide) grafted surfaces for preferential adsorption of albumin.

An ideal surface for many biomedical applications would resist non-specific protein adsorption while at the same time triggering a specific biological pathway. Based on the approach of selectively binding albumin to free fatty acids, stearyl groups were immobilized onto poly(styrene) backbone via poly(ethylene oxide) side chains. X-ray photoelectron spectroscopy (XPS) analysis indicates substantial surface enrichment of the stearyl poly(ethylene oxide) (SPEO). In an aqueous environment, the surface rearrangement is limited, as proved by dynamic contact angle tests. The comb-like copolymer presents a special hydrophobic surface with high SPEO surface density, which may be due to the 'tail like' SPEO architecture at the copolymer/water interface. Protein adsorption tests confirm that the comb-like surfaces adsorb high levels of albumin and resist fibrinogen adsorption very significantly. The surfaces prepared in this research attract and reversibly bind albumin due to the synergistic action of the PEO chains and the stearyl end groups.

Adsorption↗
PubMed2002

Complex regulation of thyroid hormone action: multiple opportunities for pharmacological intervention.

The thyroid hormone (TH; 3,3',5,5'-tetra-iodothyronine and 3,3',5'-triiodothyronine) regulates growth, development, and critical metabolic functions. Thyroid diseases are among the most prevalent group of metabolic disorders in the Western world. TH exerts effects through complex biological pathways, which offer a wealth of opportunities to pharmacologically intervene in TH signalling at numerous steps. These include biosynthesis, cell-specific uptake or export (involving L-type amino acid transporter, organic anion transporter, organic cation transporter, or multidrug resistance transporter), as well as nuclear targeting and actions (the latter including TH receptor binding and histone acetylation/deacetylation). Such processes represent potentially important pharmacological targets for the design of novel or improved therapies for TH disorders, obesity, and cardiovascular diseases.

Receptors, Thyroid Hormone↗
PubMed2002

Targeted therapy in non-small cell lung cancer.

Cytotoxic chemotherapy for advanced non-small cell lung cancer (NSCLC) offers only modest benefits over best supportive care alone by modestly prolonging survival, reducing symptoms, and improving quality of life. Despite the introduction of a number of new agents over the past decade, we have seen no convincing improvements in efficacy and safety with platinum-based regimens. It appears that a plateau has been reached in the development of traditional cytotoxic chemotherapy and a new paradigm is needed. Novel treatment modalities have emerged from advances in the understanding of tumor cell biology. These sophisticated new agents home in on and neutralize specific targets in the biologic pathway of cancer. This "targeted therapy" represents a new generation of anticancer treatment and a chance to revitalize the moribund state of NSCLC treatment.

Angiogenesis Inhibitors↗
PubMed2003

Understanding the mechanisms of action of EGFR inhibitors in NSCLC: what we know and what we do not know.

The development of rationally designed agents targeting specific biological pathways in tumor development has been heralded as a major paradigm shift in the approach to the treatment of cancer. The application of these agents has lead to promising pre-clinical findings in a variety of human cancer pre-clinical models including lung cancer. Results from initial clinical trials employing targeted agents have shown that in contrast to what was expected, only selected patients may benefit. Determining which patients will benefit remains a major challenge. Findings from the 'Iressa' Dose Evaluation in Lung Cancer and INTACT trials for non-small cell lung cancer (NSCLC) require investigators to return to the laboratory to design relevant pre-clinical studies that improve our ability to predict response to targeted agents in the clinic.

Antineoplastic Agents↗
PubMed2003

Genetics of psoriasis: the potential impact on new therapies.

There is considerable epidemiologic evidence that genes play a key role in the pathogenesis of psoriasis. It is also clear that multiple genes are involved and that the disease is genetically heterogeneous. Important interactions with the environment are also implicated in its development. A number of genetic loci have been identified by genome wide linkage scans and two loci have been replicated: PSORS1 on chromosome 6, within the major histocompatibility complex, and PSORS2 on chromosome 17q. Understanding the genetic basis of psoriasis will represent a major advance in our understanding of the disease and will reveal novel disease-specific biologic pathways. This information will be used to develop more specific diagnostic and prognostic tools and also lead to the development of individualized treatment plans. Benefits of the latter include more effective and safer treatments and potentially major pharmaco-economic gain.

Chromosome Mapping↗
PubMed2001

Hypoglycaemia-induced cell death: features of neuroprotection by the P2 receptor antagonist basilen blue.

Our previous work in neuronal cultures has shown that several antagonists of P2 ATP receptors prevent cell death evoked by hypoglycaemia, chemical hypoxia, mitochondria dysfunction, as well as glutamate-dependent excitotoxicity and low potassium-induced apoptosis. Experiments are now designed to examine which biological pathway contributes to cell death/survival under glucose starvation. We show here that, consequently to hypoglycaemic insults, cerebellar granule neurones undergo a combination of apoptosis and necrosis both inhibited by the P2 receptor antagonist basilen blue. This is demonstrated by morphological and biochemical features, such as TdT-mediated dUTP-biotin nick end-labelling, fluorescent staining of nuclear chromatin using Hoechst 33258, direct counting of intact viable nuclei and extracellular releasing of the cytosolic enzyme LDH. Furthermore, we show that hypoglycaemia induces outflow of cytochrome c from mitochondria and it up-regulates heat-shock proteins HSP70, but not HSP90, glucose-regulated proteins GRP75 and GRP78, as well as expression and activity of the enzyme caspase-2. Basilen blue can modulate only some of these effects. Our data contribute to dissect the role played by P2 receptor antagonism in sustaining neuroprotection against metabolic stresses.

Animals↗
PubMed2002

Molecular biology of lung cancer: clinical implications.

This review summarizes the rapidly expanding knowledge of the molecular pathogenesis of lung cancer. It is clear that respiratory epithelial cells require many genetic alterations to become invasive and metastatic cancer. Much more is to be learned, but with modern technology. Clinicians can detect "field cancerized" regions and preneoplastic and malignant cells, therefore offering the opportunity to intercede with biomarker-monitored prevention and early detection efforts. Such molecular screening and detection efforts will likely be coupled to advances in low-dose computed tomographic imaging, positron emission tomography scans, and other imaging modalities. Although this molecular marker approach has great potential, there is not yet a molecular marker validated in large prospective trials that has major independent predictive prognostic value. There is an urgent need for large, adequately powered, carefully designed prospective studies to identify clinically useful new biomarkers. Finally, new therapeutic strategies with genetic manipulation, small molecules, antibodies, vaccines, and, particularly, new drugs targeting specific biologic pathways found to be abnormal in lung provide for future optimism. Researchers need to define their individual value, especially when integrated with standard therapies.

Biomarkers, Tumor↗
PubMed2004

Cumulative biological risk and socio-economic differences in mortality: MacArthur studies of successful aging.

Previous research has suggested that socio-economic status (SES) differences in mortality are only partially explained by differences in life-style, psychological and social factors. Seven year mortality data (1988-1995) from the MacArthur Study of Successful Aging, a longitudinal study of adults, aged 70-79, from New Haven, CT; East Boston, MA; and Durham, NC; were used to test the hypothesis that a cumulative measure of biological dysregulation ("allostatic load"), reflecting multiple regulatory systems, would serve as a further mediator of SES differences in mortality. Logistic regression analyses revealed that a cumulative index of biological risk explained 35.4% of the difference in mortality risk between those with higher versus lower SES (as measured by less than high school education versus high school or greater educational attainment). Importantly, the cumulative index provided independent explanatory power, over and above a measure of doctor-diagnosed disease, though the latter also contributed to education-related variation in mortality risks. The summary measure of biological risk also accounted for more variance than individual biological parameters, suggesting the potential value of a multi-systems view of biological pathways through which SES ultimately affects morbidity and mortality.

Adaptation, Physiological↗
PubMed1998

Direct selection cloning vectors adapted to the genetic analysis of gram-negative bacteria and their plasmids.

A range of specific and unusual biological pathways are found in Gram-negative bacteria. It is possible to express the genes involved in these processes in Escherichia coli, however, some genes prove lethal when cloned into high copy number vectors in common usage. Conversely, various genetic functions remain silent in E. coli and require to be transferred into their original host for expression and subsequent analysis. To facilitate the cloning and the characterisation of bacterial genes, we have constructed CcdB 'positive-selection' vectors that possess one or more of the following properties: (i) low or medium copy number; (ii) narrow or broad replication host range; (iii) conjugational mobilisation. In this communication, we illustrate the use of these new cloning tools and analyse the CcdB toxicity in different bacterial species.

Bacterial Proteins↗
PubMed2003

Identification of gene expression profiles in rat ears with cDNA microarrays.

The physiological processes of hearing implicate thousands of molecules acting in harmony; however, their identities are only partially understood. We used cDNA microarrays containing 1,176 genes to identify >150 genes expressed in rat middle and inner ear tissue. Expressed genes covered several gene families and biological pathways, many of which have previously not been described. Transcription factor genes that were expressed included inhibitors of DNA binding protein (Id). These were localized to the spiral ganglion, organ of Corti and stria vascularis, and they are possibly involved in neurogenesis and angiogenesis. Transcriptional factors that were highly expressed included Gax (homeobox) and I-kappaB, which inhibit cellular proliferation. Their presence suggests that inhibitory programs for cell proliferation are enforced in the ear. Ion channel genes that were expressed included voltage-dependent L-type calcium channels (LTCC) and proton-gated cation channels (PGCC). Genes involved in neurotransmitter production and release included glutamic acid decarboxylase (GAD1). Genes involved in postsynaptic inhibition included neuropeptide Y5 receptors (NPY5) and GAD1. Due to the existence of receptors and/or enzymes involved in their biochemical synthesis, neurotransmitters associated with these might include serotonin, glutamide, acetylcholine, gamma-aminobutyric acid (GABA), neurotensin, and dopamine.

Animals↗
PubMed2000

Common gene variants, mortality and extreme longevity in humans.

Genetic factors influence variation in human life span. The fast technological advancements in genome research and the methodology for statistical analysis of complex traits provided new tools to unravel these genetic influences. Most of the genetic epidemiology and quantitative genetics is focused on the dissection of the genetic component of specific diseases rather than of human life span. Nevertheless, common variants of 22 genes have been tested for their contribution to mortality in the general population and extreme longevity in one or more studies. These studies provide indications as to the nature of biological pathways that might play a role in human ageing. Perhaps even more important at this time is the fact that they give valuable insights in the strengths and weaknesses of current strategies to identify gene variants affecting human life span and point at more powerful approaches.

Apolipoproteins E↗
PubMed2001

Molecular biology of nervous system tumors.

Many genetic alterations that contribute to CNS tumorigenesis and progression have been identified. One goal of such studies is to identify loci that would serve as diagnostic prognostic markers or both. A significant advance is the observation that chromosome 1p loss identified anaplastic oligodendroglioma and a subset of high-grade glioma patients who responded to chemotherapy and had longer survival times. Combined 1p and 19q loss was a predictor of prolonged survival of patients having pure oligodendrogliomas. Such markers eventually may be used to identify patients upfront who would benefit from treatment, while sparing patients who would not benefit. Although many molecular participants involved in the biologic pathways that promote proliferation, angiogenesis, and invasion have been elucidated, there are still many gaps in clinicians' knowledge. It is expected that the use of the human genome project information and databases such as SAGEmap, in combination with techniques such as cDNA arrays and proteomics, will facilitate greatly the identification of novel genes that contribute to CNS tumors. cDNA arrays and tissue arrays will permit the construction of CNS-specific screening tools that will permit the identification of tumor-specific mutations and alterations so that patient-specific therapies can be designed.

Cell Division↗
PubMed2003

RNA cargoes associating with FMRP reveal deficits in cellular functioning in Fmr1 null mice.

The Fragile X mental retardation-1 (Fmr1) gene encodes a multifunctional protein, FMRP, with intrinsic RNA binding activity. We have developed an approach, antibody-positioned RNA amplification (APRA), to identify the RNA cargoes associated with the in vivo configured FMRP messenger ribonucleoprotein (mRNP) complex. Using APRA as a primary screen, putative FMRP RNA cargoes were assayed for their ability to bind directly to FMRP using traditional methods of assessing RNA-protein interactions, including UV-crosslinking and filter binding assays. Approximately 60% of the APRA-defined mRNAs directly associate with FMRP. By examining a subset of these mRNAs and their encoded proteins in brain tissue from Fmr1 knockout mice, we have observed that some of these cargoes as well as the proteins they encode show discrete changes in abundance and/or differential subcellular distribution. These data are consistent with spatially selective regulation of multiple biological pathways by FMRP.

Animals↗
PubMed2000

The role of apolipoprotein E in Alzheimer's disease: pharmacogenomic target selection.

The association of inheritance of different apolipoprotein E (APOE, gene; apoE, protein) alleles with the risk and rate of onset of Alzheimer's disease (AD) is now well established and widely confirmed. While there are now a collection of hypotheses concerning the specific relationship of APOE polymorphisms to various phenotypic manifestations of AD, no single compelling theory has been tested and universally accepted. The only clear fact emerging during the past 6 years is that differences in APOE genotype affect the average rate of disease onset as a predictable function of the inheritance of this polymorphic gene. Methods now exist to enable experimental designs to study the metabolic effects of inheriting different APOE alleles, addressing what differences that may be present for many years, perhaps over the entire lifetime, can lead to earlier or later manifestations of the disease and are therapeutically tractable. This review summarizes part of an experimental approach to identify biological pathways influenced by the different APOE polymorphisms that are relevant to the pathogenesis of AD.

Alleles↗
PubMed1997

Bioinformatics: from genome data to biological knowledge.

Recently, molecular biologists have sequenced about a dozen bacterial genomes and the first eukaryotic genome. We can now obtain answers to detailed questions about the complete set of genes of an organism. Bioinformatics methods are increasingly used for attaching biological knowledge to long lists of genes, assigning genes to biological pathways, comparing the gene sets of different species, identifying specificity factors, and describing sets of highly conserved proteins common to all domains of life. Substantial progress has recently been made in the availability of primary and added-value databases, in the development of algorithms and of network information services for genome analysis. The pharmaceutical industry has greatly benefited from the accumulation of sequence data through the identification of targets and candidates for the development of drugs, vaccines, diagnostic markers and therapeutic proteins.

Databases, Factual↗
PubMed2002

Effects of combination anti-vascular endothelial growth factor receptor and anti-epidermal growth factor receptor therapies on the growth of gastric cancer in a nude mouse model.

We hypothesised that the combination of anti-angiogenic and anti-epidermal growth factor (EFG)-receptor (R) therapies would more effectively inhibit gastric cancer growth than single-agent therapy. TMK-1 gastric cancer cells were injected into the gastric wall of nude mice to generate tumours. After 4 days, mice were randomly assigned to the following groups: control, DC101 ([vascular endothelial growth factor (VEGF)-receptor (R)-2 antibody], C225 (EGF-R antibody), or a combination of DC101 and C225. The combination therapy significantly inhibited gastric tumour growth compared with the control group, whereas the decrease in tumour growth in mice treated with DC101 or C225 alone did not reach statistical significance. All mice administered DC101 demonstrated decreased tumour vascularity and increased endothelial cell apoptosis. C225 alone did not affect angiogenesis, but inhibited tumour cell proliferation. The combination therapy led to a further decrease in tumour cell proliferation. The combination of anti-VEGF-R and anti-EGF-R therapies was effective in inhibiting gastric cancer growth. These findings support the hypothesis that inhibiting multiple biological pathways that mediate tumour growth may be an effective therapeutic strategy.

Animals↗