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PubMed2006

The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms.

The greatest risk factor for developing carcinoma of the prostate is advanced age. Potential molecular and physiologic contributors to the frequency of cancer occurrence in older individuals include the accumulation of somatic mutations through defects in genome maintenance, epigenetic gene silencing, oxidative stress, loss of immune surveillance, telomere dysfunction, chronic inflammation, and alterations in tissue microenvironment. In this context, the process of prostate carcinogenesis can be influenced through interactions between intrinsic cellular alterations and the extrinsic microenvironment and macroenvironment, both of which change substantially as a consequence of aging. In this study, we sought to characterize the molecular alterations that occur during the process of prostate fibroblast senescence to identify factors in the aged tissue microenvironment capable of promoting the proliferation and potentially the neoplastic progression of prostate epithelium. We evaluated three mechanisms leading to cell senescence: oxidative stress, DNA damage, and replicative exhaustion. We identified a consistent program of gene expression that includes a subset of paracrine factors capable of influencing adjacent prostate epithelial growth. Both direct coculture and conditioned medium from senescent prostate fibroblasts stimulated epithelial cell proliferation, 3-fold and 2-fold, respectively. The paracrine-acting proteins fibroblast growth factor 7, hepatocyte growth factor, and amphiregulin (AREG) were elevated in the extracellular environment of senescent prostate fibroblasts. Exogenous AREG alone stimulated prostate epithelial cell growth, and neutralizing antibodies and small interfering RNA targeting AREG attenuated, but did not completely abrogate the growth-promoting effects of senescent fibroblast conditioned medium. These results support the concept that aging-related changes in the prostate microenvironment may contribute to the progression of prostate neoplasia.

Cell Proliferation↗
PubMed1998

Effects of vitamin E and C supplementation on oxidative stress and viral load in HIV-infected subjects.

OBJECTIVES: The HIV-infected population is known to be oxidatively stressed and deficient in antioxidant micronutrients. Since in vitro replication of HIV is increased with oxidative stress, this study assessed the effect of antioxidant vitamin supplementation on lipid peroxidation, a measure of oxidative stress, and viral load in humans. DESIGN: A randomized placebo-controlled, double-blind study. METHODS: Forty-nine HIV-positive patients were randomized to receive supplements of both DL-alpha-tocopherol acetate (800 IU daily) and vitamin C (1000 mg daily), or matched placebo, for 3 months. Plasma antioxidant micronutrient status, breath pentane output, plasma lipid peroxides, malondialdehyde and viral load were measured at baseline and at 3 months. New or recurrent infections for the 6-month period after study entry were also recorded. RESULTS: The vitamin group (n = 26) had an increase in plasma concentrations of alpha-tocopherol (P < 0.0005) and vitamin C (P < 0.005) and a reduction in lipid peroxidation measured by breath pentane (P < 0.025), plasma lipid peroxides (P < 0.01) and malondialdehyde (P < 0.0005) when compared with controls (n = 23). There was also a trend towards a reduction in viral load (mean +/- SD changes over 3 months, -0.45 +/- 0.39 versus +0.50 +/- 0.40 log10 copies/ml; P = 0.1; 95% confidence interval, -0.21 to -2.14). The number of infections reported was nine in the vitamin group and seven in the placebo group. CONCLUSION: Supplements of vitamin E and C reduce oxidative stress in HIV and produce a trend towards a reduction in viral load. This is worthy of larger clinical trials, especially in HIV-infected persons who cannot afford new combination therapies.

Adult↗
PubMed1990

Inhibition of infant glucocorticoid stress response: specific role of maternal cues.

Previous work from this laboratory has shown that passive contact with an anesthetized lactating dam eliminates the corticosteroid stress response to novelty in 12-, 16-, and 20-day-old rat pups. In the present study, we further examined some of the sensory and developmental aspects of this phenomenon. In two experiments, we asked whether inhibition of the corticosteroid stress response is related exclusively to contact with a maternal stimulus as opposed to other social stimuli. Experiment I compared the effectiveness of contact with an anesthetized dam vs, an anesthetized adult male rat. At 12 and 16 days of age, contact with an adult male was somewhat effective in reducing stress responsiveness, whereas at 20 days, contact with an adult male was entirely ineffective. At all ages, contact with an anesthetized dam was an effective inhibitor of the stress response. Experiment II compared the relative effectiveness of contact with an anesthetized dam vs. an anesthetized sibling pup. At all ages, contact with a dam was very effective, whereas contact with an anesthetized pup was entirely ineffective in inhibiting the glucocorticoid stress response. In Experiment III, the effect of maternal contact was assessed during a period of development when the biological, and presumably social, significance of the lactating-dam stimulus is changing. In this study, 20-, 24-, and 28-day-old rat pups revealed a progressive decrement in the ability of maternal contact to inhibit stress responsiveness. These findings replicate and extend our previous ones by showing that maternal stimuli play a special role in the modulation of pituitary-adrenal activity during development.

Animals↗
PubMed2005

Human DNA topoisomerase I: relaxation, roles, and damage control.

Human DNA topoisomerase I is an essential enzyme involved in resolving the torsional stress associated with DNA replication, transcription, and chromatin condensation. The catalytic cycle of the enzyme consists of DNA cleavage to form a covalent enzyme-DNA intermediate, DNA relaxation, and finally, re-ligation of the phosphate backbone to restore the continuity of the DNA. Structure/function studies have elucidated a flexible enzyme that relaxes DNA through coordinated, controlled movements of distinct enzyme domains. The cellular roles of topoisomerase I are apparent throughout the nucleus, but the concentration of processes acting on ribosomal DNA results in topoisomerase I accumulation in the nucleolus. Although the activity of topoisomerase I is required in these processes, the enzyme can also have a deleterious effect on cells. In the event that the final re-ligation step of the reaction cycle is prevented, the covalent topoisomerase I-DNA intermediate becomes a toxic DNA lesion that must be repaired. The complexities of the relaxation reaction, the cellular roles, and the pathways that must exist to repair topoisomerase I-mediated DNA damage highlight the importance of continued study of this essential enzyme.

DNA Damage↗
PubMed2004

Cell division induced by mechanical stimulation in starved Tetrahymena thermophila: cell cycle without synthesis of macronuclear DNA.

Starved Tetrahymena thermophila cells underwent synchronous cell division 2 h after a mechanical stimulation. The macronucleus showed no obvious increase in DNA content before the cell division in the starvation medium, and the DNA content was decreased after the cell division. On the other hand, when the starved cells were given nutrient-supplied medium immediately after the mechanical stimulation, cell division was delayed for 3 h. This period was almost the same as that for G1 cells in the stationary culture to first division after transfer to fresh nutrient medium. These results suggest that the mechanical stimulation induces an early division of starved cells, skipping the macronuclear S-phase with the starved cells probably becoming trapped in G1. Starved cells that had finished division soon formed mating pairs with cells of the opposite type. These observations lead us to propose that cell division in starvation conditions may be necessary to reduce macronuclear DNA content prior to the mating of T. thermophila.

Animals↗
PubMed2004

The role of life events in depression in primary medical care versus psychiatric settings.

BACKGROUND: The relationship between negative life events and depression is inconsistent. The purpose of the current study is to investigate the hypothesis that depression in the community may be related more to major life events than is depression in psychiatric settings. METHODS: This hypothesis was tested using depressed primary medical care (PC; n=70) and psychiatric patients (n=62). Nondistressed (n=109) and distressed/nondepressed PC patients (n=43) served as comparison-control groups. Life events were rated using the contextual method of Brown and Harris (Brown, G.W., Harris, T.O., 1978. Social origins of depression. Tavistock, London). RESULTS: Depressed PC patients, but not depressed psychiatric patients, were significantly more likely to have recent severe events than the comparison-control groups. Self-reported distress in the absence of depression was not associated with severe life events. LIMITATIONS: History of depression was assessed using a simple count of number of previous episodes, and the assessment of depression history may require more sophisticated assessment. The measure of endogenous depression used in this study was created post-hoc and needs replication. CONCLUSIONS: Diathesis-stress models need to accommodate a lack of universality for severe stress prior to the onset of depression. Clinical strategies may need to reflect patient treatment preferences associated with differences across settings with respect to the perceived role of stress in their depression.

Adult↗
PubMed2002

Structural and biochemical analysis of the Obg GTP binding protein.

The Obg nucleotide binding protein family has been implicated in stress response, chromosome partitioning, replication initiation, mycelium development, and sporulation. Obg proteins are among a large group of GTP binding proteins conserved from bacteria to man. Members of the family contain two equally and highly conserved domains, a C-terminal GTP binding domain and an N-terminal glycine-rich domain. Structural analysis of Bacillus subtilis Obg revealed respective domain architectures and how they are coupled through the putative switch elements of the C-terminal GTPase domain in apo and nucleotide-bound configurations. Biochemical analysis of bacterial and human Obg proteins combined with the structural observation of the ppGpp nucleotide within the Obg active sight suggest a potential role for ppGpp modulation of Obg function in B. subtilis.

Amino Acid Sequence↗
PubMed2005

The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor.

Some stimulatory receptors of the innate immune system, such as the NKG2D receptor (also called KLRK1) expressed by natural killer cells and activated CD8(+)T cells, recognize self-molecules that are upregulated in diseased cells by poorly understood mechanisms. Here we show that mouse and human NKG2D ligands are upregulated in non-tumour cell lines by genotoxic stress and stalled DNA replication, conditions known to activate a major DNA damage checkpoint pathway initiated by ATM (ataxia telangiectasia, mutated) or ATR (ATM- and Rad3-related) protein kinases. Ligand upregulation was prevented by pharmacological or genetic inhibition of ATR, ATM or Chk1 (a downstream transducer kinase in the pathway). Furthermore, constitutive ligand expression by a tumour cell line was inhibited by targeting short interfering RNA to ATM, suggesting that ligand expression in established tumour cells, which often harbour genomic irregularities, may be due to chronic activation of the DNA damage response pathway. Thus, the DNA damage response, previously shown to arrest the cell cycle and enhance DNA repair functions, or to trigger apoptosis, may also participate in alerting the immune system to the presence of potentially dangerous cells.

Animals↗
PubMed2000

An in vitro cell culture system to study the influence of external pneumatic compression on endothelial function.

PURPOSE: External pneumatic compression (EPC) is an effective means of prophylaxis against deep venous thrombosis. However, its mechanism remains poorly understood. Understanding of the biological consequences of EPC is an important goal for optimizing performance of the EPC-generating device and providing guidance for clinical use. We present a new in vitro cell culture system (Venous Flow Simulator) that simulates blood flow and vessel collapse conditions during EPC, and we examine the influence of these factors on endothelial cell (EC) fibrinolytic activity and vasomotor function. METHODS: An in vitro cell culture system was designed to replicate the hemodynamic shear stress and vessel wall strain associated with induced blood flow during different modes of EPC. Human umbilical vein endothelial cells were cultured in the system and subjected to intermittent flow, vessel collapse, or a combination of the two. The biologic response was assessed through changes in EC morphology and the expression of fibrinolytic factors tissue plasminogen activator, plasminogen activator inhibitor type 1, profibrinolytic receptor (annexin II), and vasomotor factors endothelial nitric oxide synthase and endothelin-1. RESULTS: The cells remained attached and viable after being subjected to intermittent pulsatile flow (F) and tube compression (C). In F and F + C, cells aligned in the direction of flow after 6 hours. Northern blot analysis of messenger RNA shows that there is an upregulation of tissue plasminogen activator expression (1.95 +/- 0.19 in F and 2.45 +/- 0.46 in FC) and endothelial nitric oxide synthase expression (2.08 +/- 0.25 in F and 2.11 +/- 0.21 in FC). Plasminogen activator inhibitor type 1, annexin II, and endothelin 1 show no significant change under any experimental conditions. The results also show that pulsatile flow, more than vessel compression, influences EC morphology and function. CONCLUSION: Effects on ECs of intermittent flow and vessel collapse, either individually or simultaneously, were simulated with an in vitro system of new design. Initial results show that intermittent flow associated with EPC upregulates EC fibrinolytic potential and influences factors altering vasomotor tone. The system will facilitate future studies of EC function during EPC.

Blood Flow Velocity↗
PubMedDate not supplied

Drinking water, fluid intake, and bladder cancer in western New York.

Fluid intake and consumption of specific beverages were investigated in a study of 351 white male cases for whom transitional cell carcinoma of the bladder had been confirmed histologically during the time period from 1979 to 1985. A total of 855 white male controls was selected from Erie, Niagara, and Monroe counties of western New York state. Total fluid consumption was composed of alcoholic beverages, bottled beverages, soda, milk, coffee, tea, all juices, and glasses of tap water. Tap water included coffee, tea, juices, and glasses of water taken directly from the tap. Total fluid consumption was found to be a strong risk factor for bladder cancer when a number of potential confounding risk factors were controlled for. Risks were higher among those who were less than 65 y of age (odds ratio [OR] = 6.3, 95% C.I. = 2.8-14.0). The OR was 3.4 (95% C.I. = 1.8-6.2) for the highest quartile of fluid consumption among those 65 y of age and older. The tap water component was associated with increased risk in both age categories, and there was a clear dose-response relationship. Risks associated with tap water consumption were higher among those who never smoked cigarettes. Both biological and nonbiological explanations for these results are evaluated. The findings suggest implications for public health, but the limitations of the present investigation preclude definitive conclusions and stress the urgency for replication.

Adult↗
PubMed1992

Early intervention for first episodes of schizophrenia: a preliminary exploration.

This report describes an uncontrolled study of intensive early intervention with adults who displayed signs and symptoms suggestive of schizophrenic disorders. Case detection rates that were lower than expected offer tentative support for the hypothesis that the initial florid episodes of schizophrenia may be modified when they are detected early and when effective therapeutic strategies are applied with minimal delays. The difficulty of drawing any substantive conclusions from this preliminary study is stressed, but further controlled replications of the approach may be warranted.

Adolescent↗
PubMed2004

Role of peroxisome proliferator-activated receptor-alpha (PPARalpha) in bezafibrate-induced hepatocarcinogenesis and cholestasis.

Prolonged administration of peroxisome proliferators to rodents typically leads to hepatocarcinogenesis. Peroxisome proliferator-activated receptor-alpha (PPARalpha) is required to mediate alterations in PPARalpha target gene expression, repress apoptosis, enhance replicative DNA synthesis, oxidative stress to DNA and hepatocarcinogenesis induced by the relatively specific PPARalpha agonist, Wy-14,643. Interestingly, administration of the less specific PPARalpha agonist, bezafibrate, leads to a modest induction of PPARalpha target genes in the absence of PPARalpha expression. In these studies, the role of PPARalpha in modulating hepatocarcinogenesis induced by long-term feeding of 0.5% bezafibrate was examined in wild-type (+/+) and PPARalpha-null (-/-) mice. The average liver weight was significantly higher in (+/+) and (-/-) mice fed bezafibrate than controls, but this effect was considerably less in (-/-) mice as compared with similarly treated (+/+) mice. Increased levels of mRNA encoding cell cycle regulatory proteins and DNA repair enzymes were found in (+/+) mice fed bezafibrate, and this effect was not found in (-/-) mice. In mice fed bezafibrate for 1 year, preneoplastic foci, adenomas and a hepatocellular carcinoma were found in (+/+) mice, while only a single microscopic adenoma was found in one (-/-) mouse. This effect was observed in both Sv/129 and C57BL/6N strains of mice, although only preneoplastic foci were observed in the latter strain. Interestingly, hepatic cholestasis was observed in 100% of the bezafibrate-fed (-/-) mice, and this was accompanied by significantly elevated hepatic expression of mRNA encoding bile salt export pump and lower expression of mRNA encoding cytochrome P450 7A1, consistent with enhanced activation of the bile acid receptor, farnesoid X receptor. Results from these studies demonstrate that the PPARalpha is required to mediate hepatocarcinogenesis induced by bezafibrate, and that PPARalpha protects against potential cholestasis.

Acyl-CoA Oxidase↗
PubMed2004

Ageing across the life span: time to think again.

Living organisms are subject to ageing. This natural process has gained greater importance in socially and medically affluent societies. For many, ageing connotes unattractive changes in the appearance of the skin. The gross morphological changes of ageing skin are mirrored by a range of more profound age-associated physiological declines. Thus, skin ageing can be put into other perspectives which lie at the interfaces of molecular biology, cellular biology, oncology and cosmetic dermatology. Genetically programmed replicative senescence and stress-induced premature senescence (SIPS) are two processes that are fundamental to skin ageing. Some iteroparous species can be used as animal models for human ageing. Undoubtedly, scientific understanding of skin ageing is firmly rooted in the distinction between intrinsic and extrinsic types of ageing. However, seven major types of skin ageing can be distinguished: genetic, chronological, solar, behavioural, endocrinological, catabolic and gravitational types. Preventative measures can target each of these.

Journal Article↗
PubMed2001

Variation of microbial communities in soil, rhizosphere, and rhizoplane in response to crop species, soil type, and crop development.

We investigated the influence of plant species, soil type, and plant development time on the shaping of microbial communities in soil and in association with roots. The sample group consisted of a total of 32 microcosms in three habitats: soil, rhizosphere, and rhizoplane. Communities were represented by the patterns of a sequence-specific separation of rRNA target sequences. Effects of experimental parameters were classified by a cluster analysis of pattern similarities. The type of plant species (clover, bean, or alfalfa) had the greatest effect in plant-associated habitats and also affected soil patterns. Plant development had a minor habitat-dependent effect that was partly obscured by replicate variation. The results stress the applicability of biased community representations in an analysis of induced variation.

Bacteria↗
PubMed2005

Genomic instability in radial growth phase melanoma cell lines after ultraviolet irradiation.

BACKGROUND/AIMS: Although ultraviolet (UV) irradiation, apoptosis, and genomic instability are all potentially involved in the pathogenesis of melanoma, in vitro studies investigating these changes in the radial growth phase of this neoplasm are still lacking; therefore, this study was designed to investigate these changes. METHOD: An in vitro system consisting of three radial growth phase Wistar melanoma cell lines (WM35, WM3211, and WM1650) was established. Cells were UV irradiated (10 mJ/cm2 for UVB and 6 J/cm2 for UVA), harvested after UV exposure, and evaluated for viability and apoptosis using Trypan blue and terminal deoxynucleotidyl transferase mediated dUTP digoxigenin nick end labelling assays, respectively. Polymerase chain reaction based microsatellite assays were used to examine the cell lines for the presence of microsatellite instability (MSI) using 21 markers at the 1p, 2p, 3p, 4q, 9p, and 17p regions. RESULTS: Exposure to UV initiated progressive cell death associated with pronounced apoptosis, with UVA having a greater effect than UVB. MSI was found in UVB (WM35 and WM3211) and UVA (WM35) irradiated cell lines at 1p, 9p, and 17p, but not in non-irradiated cells. The prevalence of MSI was higher after UVB irradiation (14%) than UVA irradiation (4.7%), and was most frequently found at D1S233. CONCLUSIONS: The ability of erythemogenic UV irradiation to induce both apoptosis and MSI in radial growth phase melanoma cells is suggestive of its role in melanoma pathogenesis. This instability may reflect a hypermutability state, oxidative stress induced DNA damage, replication infidelity, or a combination of these factors.

Apoptosis↗
PubMed2006

The DNA damage response arouses the immune system.

Although there is considerable knowledge of how DNA damage triggers cell cycle arrest, DNA repair, and apoptosis, little was known about its potential role in immune responses. Recently, we showed that genotoxic stress and stalled DNA replication forks induce the expression of ligands for the NKG2D receptor found in natural killer cells and certain T cells, cell types that are able to attack tumor cells. Chronic activation of this response in tumor cells may contribute to immune recognition, but it also imposes a selection mechanism for immune escape and malignant progression. This unique arm of the DNA damage response may have implications for understanding therapeutic responses, many of which induce the DNA damage response, and for designing more effective regimens to treat cancer.

Animals↗
PubMed2006

Protein kinases associated with the yeast phosphoproteome.

BACKGROUND: Protein phosphorylation is an extremely important mechanism of cellular regulation. A large-scale study of phosphoproteins in a whole-cell lysate of Saccharomyces cerevisiae has previously identified 383 phosphorylation sites in 216 peptide sequences. However, the protein kinases responsible for the phosphorylation of the identified proteins have not previously been assigned. RESULTS: We used Predikin in combination with other bioinformatic tools, to predict which of 116 unique protein kinases in yeast phosphorylates each experimentally determined site in the phosphoproteome. The prediction was based on the match between the phosphorylated 7-residue sequence and the predicted substrate specificity of each kinase, with the highest weight applied to the residues or positions that contribute most to the substrate specificity. We estimated the reliability of the predictions by performing a parallel prediction on phosphopeptides for which the kinase has been experimentally determined. CONCLUSION: The results reveal that the functions of the protein kinases and their predicted phosphoprotein substrates are often correlated, for example in endocytosis, cytokinesis, transcription, replication, carbohydrate metabolism and stress response. The predictions link phosphoproteins of unknown function with protein kinases with known functions and vice versa, suggesting functions for the uncharacterized proteins. The study indicates that the phosphoproteins and the associated protein kinases represented in our dataset have housekeeping cellular roles; certain kinases are not represented because they may only be activated during specific cellular responses. Our results demonstrate the utility of our previously reported protein kinase substrate prediction approach (Predikin) as a tool for establishing links between kinases and phosphoproteins that can subsequently be tested experimentally.

Amino Acid Sequence↗
PubMed1999

The effects of heat-shock on nuclear matrix-associated DNA-replication complexes.

To better understand the role of the nuclear matrix in heat-induced cell killing, we have investigated the effects of heat shock on DNA replication complexes. Changes in protein extractability are observed following heat shock, including stabilization of which stabilize DNA replication complexes in association with the nuclear matrix. This situation is accompanied by differential delays in the progress and completion of DNA synthesis and the transition from type I to type II DNA replication patterns. Interestingly, prolonged delays in restarting DNA synthesis produced significant protection from heat-induced cell killing. These results show that nuclear matrix-associated DNA replication complexes may be important targets for heat-induced cell killing.

Animals↗