Molecular biology and biochemistry of brain tumours

ßElucidating some molecular mechanisms and biochemistry of brain tumours is an important step towards the development of adjuvant medical therapies. The present study concentrates on cholecystokinin (CCK), a gut-brain peptide that has been described to be able to induce mitosis of rat gliomas as well as hormone secretion by the anterior pituitary, via the CCK-B receptor. The significance of a polymorphism in the growth hormone releasing hormone (GHRH) receptor (GHRH-R) gene was also determined. Finally, defects in the ß-catenin gene, an important component of the developmental pathway, in a sub-set of craniopharyngiomas were investigated. Reverse transcription-polymerase chain reaction (RT-PCR), restriction digestion analysis and direct sequencing demonstrated expression of CCK peptide itself and its A and B receptors by human gliomas, meningiomas and pituitary tumours. CCK peptides stimulated growth of cultured gliomas and meningiomas as well as in vitro hormone secretion [growth hormone (GH), luteinizing hormone (LH) and follicle stimulating hormone (FSH)] by human pituitary tumours. These biological effects were reduced or abolished by CCK antagonists. In addition, an antibody to CCK reduced mitosis by gliomas and meningiomas, and the same antibody inhibited hormone secretion by cultured human pituitary tumours. CCK peptides stimulated phosphatidylinositol (PI) hydrolysis, indicating coupling of the CCK receptors to phopsholipase C. Cyclic AMP was unaffected. In addition, caspase-3 activity was significantly and markedly increased, whilst proteasome activity was decreased. Taken together, these results may indicate an autocrine/paracrine role of CCK in the control of growth and/or functioning of gliomas, meningiomas and pituitary tumours. Primer induced restriction analysis (PIRA) of a rarer and alternative polymorphism in the GHRH-R receptor, in which Thr replaces Ala at codon 57, in human GH-secreting pituitary tumours was investigated. Whilst the rarer form correlated with an increased response of the pituitary cells to GHRH in vitro, allele distribution studies revealed that it is unlikely that the polymorphism contributes to increased risk of developing GH-secreting tumours and therefore acromegaly. Further findings of this study, using PCR and direct sequencing, were the demonstration of an association between b-catenin gene alterations and craniopharyngiomas of the adamantinomatous type. Since this gene product is involved with development, these results suggest that p-catenin mutations may contribute to the initiation and subsequent growth of congenital adamantinomatous craniopharyngiomas.

Motivation and the gift relationship

This thesis proposes a theory of Motivation to Work, as a particular condition of general motivation, using the Maussian concept of the Gift to explain the operation of Lacanian Desire. Specifically, it argues that de-motivation stems from Gift rejection. However, as the arguments are not paradigmatically commensurable with managerialist theories, it has been necessary to establish the epistemological tradition of which this work is representative, namely, Critical Theory and Post-Structuralism/Post- Modernism. In distinction to the managerialist explanations of motivation, management and work, behaviourist theories of motivation are characterised as more properly a concern with psychological incentives, management in its current socio-historic institutionalised form as a process of social domination and work as a social experience of domination, but also as a forum for social life generally. However, as such a view receives little theoretical or empirical confirmation from managerialist literature, it is argued that it is necessary to broaden the catchment area of relevant writing, and that the literary arts have more insight than orthodox science. This is supported by reference to modern literary theory in terms of the Form/Content distinction. Central to this argument is the ontological concept of Difference and its `political' use in maintaining social domination by privileging certain forms over others. Having established the basis on which to articulate this theory of motivation, the Lacanian concept of Desire is explored, together with its relevance to motivation and management/organisation theory. The theory of the Gift Relationship is then explicated and developed, together with some of its popular sociological conceptualisations, and an argument made for an understanding in terms of its psychological signficance in explaining the operationalisation of Lacanian Desire. This is related to the work situation and to its relevance for organisational management. In conclusion, its utility is considered, as are some potential criticisms of the arguments put forward.

Relationship status and identity construction in heterosexual women:A discourse analytic and personal construct study

This thesis reports the findings of three studies examining relationship status and identity construction in the talk of heterosexual women, from a feminist and social constructionist perspective. Semi-structured interviews were conducted with 12 women in study 1 and 13 women for study 2, between the ages of twenty and eighty-seven, discussing their experiences of relationships. All interviews were transcribed and analysed using discourse analysis, by hand and using the Nudist 6 program. The resulting themes create distinct age-related marital status expectations. Unmarried women were aware they had to marry by a ‘certain age’ or face a ‘lonely spinsterhood’. Through marriage women gained a socially accepted position associated with responsibility for others, self-sacrifice, a home-focused lifestyle and relational identification. Divorce was constructed as the consequence of personal faults and poor relationship care, reassuring the married of their own control over their status. Older unmarried women were constructed as deviant and pitiable, occupying social purgatory as a result of transgressing these valued conventions. Study 3 used repertory grid tasks, with 33 women, analysing transcripts and notes alongside numerical data using Web Grid II internet analysis tool, to produce principle components maps demonstrating the relationships between relationship terms and statuses. This study illuminated the consistency with which women of different ages and status saw marriage as their ideal living situation and outlined the domestic responsibilities associated. Spinsters and single-again women were defined primarily by their lack of marriage and by loneliness. This highlighted the devalued position of older unmarried women. The results of these studies indicated a consistent set of age-related expectations of relationship status, acknowledged by women and reinforced by their families and friends, which render many unmarried women deviant and fail to acknowledge the potential variety of women’s ways of living.

A psychological investigation into the relationship between hemispheric functioning and specific written language difficulties (dyslexia), using pharmaceutical intervention techniques

This thesis attempts a psychological investigation of hemispheric functioning in developmental dyslexia. Previous work using neuropsychological methods with developmental dyslexics is reviewed ,and original work is presented both of a conventional psychometric nature and also utilising a new means of intervention. At the inception of inquiry into dyslexia, comparisons were drawn between developmental dyslexia and acquired alexia, promoting a model of brain damage as the common cause. Subsequent investigators found developmental dyslexics to be neurologically intact, and so an alternative hypothesis was offered, namely that language is abnormally localized (not in the left hemisphere). Research in the last decade, using the advanced techniques of modern neuropsychology, has indicated that developmental dyslexics are probably left hemisphere dominant for language. The development of a new type of pharmaceutical prep~ration (that appears to have a left hemisphere effect) offers an oppertunity to test the experimental hypothesis. This hypothesis propounds that most dyslexics are left hemisphere language dominant, but some of these language related operations are dysfunctioning. The methods utilised are those of psychological assessment of cognitive function, both in a traditional psychometric situation, and with a new form of intervention (Piracetam). The information resulting from intervention will be judged on its therapeutic validity and contribution to the understanding of hemispheric functioning in dyslexics. The experimental studies using conventional psychometric evaluation revealed a dyslexic profile of poor sequencing and name coding ability, with adequate spatial and verbal reasoning skills. Neuropsychological information would tend to suggest that this profile was indicative of adequate right hemsiphere abilities and deficits in some left hemsiphere abilities. When an intervention agent (Piracetam) was used with young adult dyslexics there were improvements in both the rate of acquisition and conservation of verbal learning. An experimental study with dyslexic children revealed that Piracetam appeared to improve reading, writing and sequencing, but did not influence spatial abilities. This would seem to concord with other recent findings, that deve~mental dyslexics may have left hemisphere language localisation, although some of these language related abilities are dysfunctioning.

Down-regulation of central glucocorticoid receptor expression using antisense oligonucleotide technology

Endogenous glucocorticoids and serotonin have been implicated in the pathophysiology of depression, anxiety and schizophrenia. This thesis investigates the potential of downregulating expression of central Type II glucocorticoid receptors (GR) both in vitro and in vivo, with empirically-designed antisense oligodeoxynucleotides (ODN), to characterise GR modulation of 5-HT2A receptor expression using quantitative RT-PCR, Western blot analysis and radioligand binding. The functional consequence of GR downregulation is also determined by measuring 1-(2,5-dimethoxy 4-iodophenyl)-2-amino propane hydrochloride (DOI) mediated 5-HT2A receptor specific headshakes. Using a library of random antisense ODN probes, RNAse H accessibility mapping of T7-primed, in vitro transcribed GR mRNA revealed several potential cleavage sites and identified an optimally effect GR antisense ODN sequence of 21-mer length (GRAS5). In vitro efficacy studies using rat C6 glioma cells showed a 56% downregulation in GR mRNA levels and 80% downregulation in GR protein levels. In the same cells a 29% upregulation in 5-HT2A mRNA levels and 32% upregulation in 5-HT2A protein levels was revealed. This confirmed the optimal nature of the GRAS5 sequence to produce marked inhibition of GR gene expression, and also revealed GR modulation of the 50-HT2A receptor subtype in C6 glioma cells to be a tonic repression of receptor expression. The distribution of a fluorescently-labelled GRAS5 ODN was detected in diverse areas of the rat brain after single ICV administration, although this fluorescence signal was not sustained over a period of 5 days. However, fluorescently-labelled GRAS5 ODN, when formulated in polymer microspheres, showed diverse distribution in the brain which was maintained for 5 days following a single ICV administration. This produced no apparent neurotoxic effects on rat behaviour and hypothalamic-pituitary-adrenal (HPA) axis homeostasis. Furthermore, a single polymer microsphere injection ICV proved to be an effective means of delivering antisense ODNs and this was adopted for the in vivo efficacy studies. In vivo characterisation of GRAS5 revealed marked downregulation of GR mRNA in rat brain regions such as the frontal cortex (26%), hippocampus (35%), and hypothalamus (39%). Downregulation of GR protein was also revealed in frontal cortex (67%), hippocampus (76%), and hypothalamus (80%). In the same animals upregulation of 5-HT2A mRNA levels was shown in frontal cortex (13%), hippocampus (7%), and hypothalamus (5%) while upregulation in 5-HT2A protein levels was shown in frontal cortex (21 %). This upregulation in 5-HT2A receptor density as a result of antisense-mediated inhibition of GR was further confirmed by a 55% increase in DOl-mediated 5-HT2A receptor specific headshakes. These results demonstrate that GR is involved in tonic inhibitory regulation of 5-HT2A receptor expression and function in vivo, thus providing the potential to control 5-HT2A-linked disorders through corticosteroid manipulation. These experiments have therefore established an antisense approach which can be used to investigate pharmacological characteristics of receptors.

The effects of the changing energy situation on demand for industrial heat exchangers

The Project arose during a period in which the World was still coming to terms with the effects and implications of the so called 'energy crisis' of 1973/74. Serck Heat Transfer is a manufacturer of heat exchangers which transfer heat between fluids of various sorts. As such the company felt that past and possible future changes in the energy situation could have an impact upon the demand for its products. The thesis represents the first attempt to examine the impact of changes in the energy situation (a major economic variable) on the long term demand for heat exchangers. The scope of the work was limited to the United Kingdom, this being the largest single market for Serek's products. The thesis analyses industrial heat exchanger markets and identifies those trends which are related to both the changing energy situation and the usage of heat exchangers. These trends have been interpreted In terms of projected values of heat exchanger demand. The projections cover the period 197S to the year 2000. Also examined in the thesis is the future energy situation both internationally and nationally and it is found that in the long term there will be increasing pressure on consumers to conserve energy through rising real prices. The possibility of a connection between energy consumption and heat exchanger demand is investigated and no significant correlation found. This appears to be because there are a number of determinants of demand besides energy related factors and also there is a wide diversity of individual markets for heat exchangers. Conclusions are that in all markets, bar one, the changing energy situation should lead to a higher level of heat exchanger demand than would otherwise be the case had the energy situation not changed. It is also pointed out that it is misleading to look at changes in one influence on the demand for a product and ignore others.

Cues and knowledge structures used by mental-health professionals when making risk assessments

Background: Research into mental-health risks has tended to focus on epidemiological approaches and to consider pieces of evidence in isolation. Less is known about the particular factors and their patterns of occurrence that influence clinicians’ risk judgements in practice. Aims: To identify the cues used by clinicians to make risk judgements and to explore how these combine within clinicians’ psychological representations of suicide, self-harm, self-neglect, and harm to others. Method: Content analysis was applied to semi-structured interviews conducted with 46 practitioners from various mental-health disciplines, using mind maps to represent the hierarchical relationships of data and concepts. Results: Strong consensus between experts meant their knowledge could be integrated into a single hierarchical structure for each risk. This revealed contrasting emphases between data and concepts underpinning risks, including: reflection and forethought for suicide; motivation for self-harm; situation and context for harm to others; and current presentation for self-neglect. Conclusions: Analysis of experts’ risk-assessment knowledge identified influential cues and their relationships to risks. It can inform development of valid risk-screening decision support systems that combine actuarial evidence with clinical expertise.

Disentangle contextual and permanent individual motivations:an application to shopping behavior

Past studies resulted in conflicting definitions of consumer motivation. On the one hand, motivations are seen as the consumer’s characteristics that shape her general behavior (motivational trait). On the other hand, they are seen as contextual variables representing the reason why the individual is behaving specific to today’s context (motivational state). The objective of this research is to stress the difference between these two concepts and to understand the impact of each on consumer behavior. We applied our empirical study to shopping motivations; our results show a strong interaction between motivational trait and motivational state. Problem and Hypothesis On the one hand, Westbrook and Black (1985) consider shopping motivations as individual permanent characteristics. This concept is shared by other researchers (Rohm and Swaminathan 2004), which show that some shoppers are functional (they shop for convenience, information seeking, and time saving) while some others are hedonic (they shop for social interaction, bargain hunting and browsing). On the other hand, Kaltcheva and Weitz (2006) define motivations as a contextual orientation changing over time, depending on the situation, and show that contextual shopping motivations have a strong impact on shopping behavior. From our knowledge, no research specifically examined the respective impact of both these shopping motivation types. To deal with this issue, we used the notions of “traits” and “states” that have been largely used in marketing research to designate respectively a permanent characteristic of the individual and a temporary orientation of the consumer (Mowen 2000). The reversal theory (Apter 2001) suggests that two opposite states exist: the telic and the paratelic states. In the telic state, individuals set goals for themselves, must be disciplined to reach these goals, and do not behave in accordance with their personal trait. In the paratelic state, individuals are seeking arousal and enjoyment, do not set rules, and one could postulate that they act in accordance with their natural tendencies. Based on these considerations, we hypothesize the following process: in situations involving paratelic states, hedonic as well as functional individuals should behave according to their natural traits, whereas in situations involving telic states, hedonic people should inhibit their natural propensity to enjoy shopping and behave similarly to functional people. Hence, we postulate the following: Hypothesis: Compared to shoppers with functional motivational trait, shoppers with hedonic motivational trait will a) significantly display more hedonic shopping behavior intentions in a condition of paratelic motivational state, and b) not display more hedonic shopping behavior intentions in a condition a telic motivational state Empirical Research First, 108 participants were asked to fill a multi-items scale about their shopping habits, which actually measured their shopping motivational traits. This questionnaire allowed us to highlight four different dimensions in shopping motivational traits: social interaction, novelty/utility seeking, bargain hunting, and browsing. According to their scores on different items, participants were classified as functional or as hedonic on each of these four dimensions (a single individual may be hedonic on some dimensions and functional on others). Then, participants were then induced to adopt either a telic or a paratelic shopping motivational state while reading an appropriate scenario. Finally, participants were asked for their shopping behavior intentions in response to the shopping context. Four items were developed, corresponding to the four shopping motivational trait dimensions we found with our factor analysis. Results As we found four dimensions in shopping motivational trait, we set up four quasi-experimental designs to capture the entire phenomenon: for each dimension, a 2 (motivational trait) x 2 (motivational state) design was built, where the dependant variable was the shopping behavior element corresponding to the studied dimension. Four 2 x 2 Anovas were performed to assess the interaction between motivational trait and motivational state. Concerning the three dimensions - browsing, novelty/utility seeking, and bargain hunting- , in the paratelic state scenario participants with hedonic motivational trait displayed significantly more hedonic shopping behavior intentions than participants with a functional motivational trait (resp. F = 9.701, p = .003; F = 4.979, p = .03; F = 5.757, p = .02); and in the telic state scenario, there was no significant difference in behavior intentions between participants with hedonic or functional motivation trait. Each time, the interaction effect between motivational state and motivational trait was significant (resp. F = 4.859, p = .03; F = 3.314, p = .07; F = 2.98, p = .08). Concerning the fourth dimension, social interaction, shopping behavior intentions of participants with hedonic and with functional motivational traits were significantly different in the paratelic state scenario (F = 29.898, p <.000) as well as in the telic state scenario (F = 9.559, p = .003). However, the interaction effect showed that this behavioral difference was significantly stronger in the paratelic scenario. All these results support our research hypothesis. Discussion and Implications Our study provides consistent support for our hypotheses saying that there is an interaction effect between shopping motivational states and shopping motivational traits. The generalization of the results is strengthened by the study of four different shopping traits: social interaction, novelty/utility seeking, bargain hunting and browsing. As we proposed, when shopping in a goal-oriented state (telic state), behaviors of hedonic and functional shoppers do not differ significantly. Conversely, when shopping for a recreational reason (paratelic state), hedonic and functional shoppers behave significantly different. These results could explain why some previous studies concluded that shopping motivational traits had no impact on shopping behavior: they did not take into consideration the interaction between motivational trait and motivational state. Moreover, our study shows that marketing surveys performed by store managers to draw the personal profile of their customers must be crossed with contextual motivations in order to accurately forecast shopper behavior. Future Developments Our results can be explained by the self-control process, which pushes hedonic-trait shoppers to behave in a rather functional way in utilitarian situations. However, to be certain that this is the very process that occurs, we plan to add self-control perception scales to our existing measures. This is obviously the next step of this research.

Genetic modulation of the response bias towards facial displays of anger and happiness

Background: Investigating genetic modulation of emotion processing may contribute to the understanding of heritable mechanisms of emotional disorders. The aim of the present study was to test the effects of catechol- O-methyltransferase (COMT) val158met and serotonin-transporter-linked promoter region (5-HTTLPR) polymorphisms on facial emotion processing in healthy individuals. Methods: Two hundred and seventy five (167 female) participants were asked to complete a computerized facial affect recognition task, which involved four experimental conditions, each containing one type of emotional face (fearful, angry, sad or happy) intermixed with neutral faces. Participants were asked to indicate whether the face displayed an emotion or was neutral. The COMT-val158met and 5-HTTLPR polymorphisms were genotyped. Results: Met homozygotes (COMT) showed a stronger bias to perceive neutral faces as expressions of anger, compared with val homozygotes. However, the S-homozygotes (5-HTTLPR) showed a reduced bias to perceive neutral faces as expressions of happiness, compared to L-homozygotes. No interaction between 5-HTTLPR and COMT was found. Conclusions: These results add to the knowledge of individual differences in social cognition that are modulated via serotonergic and dopaminergic systems. This potentially could contribute to the understanding of the mechanisms of susceptibility to emotional disorders. © 2013 Elsevier Masson SAS.

Bromocriptine:old drug, new formulation and new indication

Bromocriptine is an ergot alkaloid dopamine D receptor agonist that has been used extensively in the past to treat hyperprolactinaemia, galactorrhoea and Parkinsonism. It is known that hypothalamic hypodopaminergic states and disturbed circadian rhythm are associated with the development of insulin resistance, obesity and diabetes in animals and humans. When administered in the early morning at the start of the light phase, a new quick release (QR) formulation of bromocriptine appears to act centrally to reset circadian rhythms of hypothalamic dopamine and serotonin and improve insulin resistance and other metabolic abnormalities. Phase II and III clinical studies show that QR-bromocriptine lowers glycated haemoglobin by 0.6-1.2% (7-13 mmol/mol) either as monotherapy or in combination with other antidiabetes medications. Apart from nausea, the drug is well tolerated. The doses used to treat diabetes (up to 4.8 mg daily) are much lower than those used to treat Parkinson's disease and have not been associated with retroperitoneal fibrosis or heart valve abnormalities. QR-bromocriptine (Cycloset™) has recently been approved in the USA for the treatment of type 2 diabetes mellitus (T2DM). Thus, a QR formulation of bromocriptine timed for peak delivery in the early morning may provide a novel neurally mediated approach to the control of hyperglycaemia in T2DM. © 2010 Blackwell Publishing Ltd.

Managing diversity in organizations:an integrative model and agenda for future research

The literature on policies, procedures, and practices of diversity management in organizations is currently fragmented and often contradictory in highlighting what is effective diversity management, and which organizational and societal factors facilitate or hinder its implementation. In order to provide a comprehensive and cohesive view of diversity management in organizations, we develop a multilevel model informed by the social identity approach that explains, on the basis of a work motivation logic, the processes by, and the conditions under which employee dissimilarity within diverse work groups is related to innovation, effectiveness, and well-being. Building on this new model, we then identify those work group factors (e.g., climate for inclusion and supervisory leadership), organizational factors (e.g., diversity management policies and procedures, and top management's diversity beliefs), and societal factors (e.g., legislation, socioeconomic situation, and culture) that are likely to contribute to the effective management of diversity in organizations. In our discussion of the theoretical implications of the proposed model, we offer a set of propositions to serve as a guide for future research. We conclude with a discussion of possible limitations of the model and practical implications for managing diversity in organizations. © 2014 Taylor & Francis.

Effectiveness and uptake of screening programmes for coronary heart disease and diabetes:a realist review of design components used in interventions

Objective - To evaluate behavioural components and strategies associated with increased uptake and effectiveness of screening for coronary heart disease and diabetes with an implementation science focus. Design - Realist review. Data sources - PubMed, Web of Knowledge, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register and reference chaining. Searches limited to English language studies published since 1990. Eligibility criteria - Eligible studies evaluated interventions designed to increase the uptake of cardiovascular disease (CVD) and diabetes screening and examined behavioural and/or strategic designs. Studies were excluded if they evaluated changes in risk factors or cost-effectiveness only. Results - In 12 eligible studies, several different intervention designs and evidence-based strategies were evaluated. Salient themes were effects of feedback on behaviour change or benefits of health dialogues over simple feedback. Studies provide mixed evidence about the benefits of these intervention constituents, which are suggested to be situation and design specific, broadly supporting their use, but highlighting concerns about the fidelity of intervention delivery, raising implementation science issues. Three studies examined the effects of informed choice or loss versus gain frame invitations, finding no effect on screening uptake but highlighting opportunistic screening as being more successful for recruiting higher CVD and diabetes risk patients than an invitation letter, with no differences in outcomes once recruited. Two studies examined differences between attenders and non-attenders, finding higher risk factors among non-attenders and higher diagnosed CVD and diabetes among those who later dropped out of longitudinal studies. Conclusions - If the risk and prevalence of these diseases are to be reduced, interventions must take into account what we know about effective health behaviour change mechanisms, monitor delivery by trained professionals and examine the possibility of tailoring programmes according to contexts such as risk level to reach those most in need. Further research is needed to determine the best strategies for lifelong approaches to screening.

Cholecystokinin (CCK) receptor and CCK gene expression in human pituitary adenomas and in vitro effects of CCK peptides on GH and gonadotrophin secretion

There is growing evidence that cholecystokinin (CCK) affects growth and differentiation of anterior pituitary cells, via the CCK-B receptor. The possibility of an autocrine / paracrine role for CCK to modulate hormone secretion in human pituitary tumour cells is demonstrated here by RT-PCR and direct sequencing. In support of this conclusion, a neutralising antibody against the CCK peptide exhibited a dose dependent inhibition of hormone secretion by functionless pituitary adenomas. Total RNA was extracted from human pituitary adenomas, reverse transcribed into cDNA and subjected to PCR using primers specific for the gene for CCK, CCK-A and CCK-B receptors. PCR bands of the predicted length were observed in all tumours using human CCK gene and CCK-B receptor primers. Restriction digestion and direct sequence analysis provided further evidence that they represented both the human CCK peptide along with the CCK-A and/B receptor mRNA. CCK-33 and CCK octapeptide sulphate (CCK-8s) both powerfully stimulated phosphatidylinositol hydrolysis, providing evidence for functional activity of the CCK-A and/B receptors. A direct stimulatory effect of CCK peptides on both LH and FSH secretion is reported for the first time, whereas stimulatory effects on GH were blocked by antagonists to CCK. These results may indicate an autocrine role for CCK in the functioning and perhaps development of human pituitary tumours. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart.

Meningiomas expressing and responding to cholecystokinin (CCK)

The effect of cholecystokinin (CCK) on cultured human meningioma derived cells was investigated. Exposure of meningioma cells for 6-12 days to CCK-8s (2-200 nM) resulted in a dose dependent stimulation of cell growth to a maximum of 1.1-fold over basal controls. A time course study showed stimulation of cell growth at day 3 followed by increase throughout day 6. The stimulatory effect of CCK on meningioma cell growth was completely abolished by a CCK-B specific receptor antagonist, L-365,260. Reverse-transcription of meningioma-derived RNA into cDNA followed by amplification by the polymerase chain reaction using specific primers for CCK peptide and its CCK-A and/B receptor revealed 100% presence of CCK peptide and CCK-B receptors mRNA whereas CCK-A receptor was expressed in 66% of the meningiomas. These results provide evidence that human meningioma cells possess CCK peptide and its receptors the activation of which leads to increase of cell growth possibly via an autocrine/paracrine mechanism. © Springer 2005.

Vascular endothelial growth factor promotes physical wound repair and is anti-apoptotic in primary distal lung epithelial and A549 cells

Objective: There is evidence to suggest a beneficial role for growth factors, including vascular endothelial growth factor (VEGF), in tissue repair and proliferation after injury within the lung. Whether this effect is mediated predominantly by actions on endothelial cells or epithelial cells is unknown. This study tested the hypothesis that VEGF acts as an autocrine trophic factor for human adult alveolar epithelial cells and that under situations of pro-apoptotic stress, VEGF reduces cell death. Design: In vitro cell culture study looking at the effects of 0.03% H2O2 on both A549 and primary distal lung epithelial cells.Measurement and Main Results: Primary adult human distal lung epithelial cells express both the soluble and membrane-associated VEGF isoforms and VEGF receptors 1 and 2. At physiologically relevant doses, soluble VEGF isoforms stimulate wound repair and have a proliferative action. Specific receptor ligands confirmed that this effect was mediated by VEGF receptor 1. In addition to proliferation, we demonstrate that VEGF reduces A549 and distal lung epithelial cell apoptosis when administered after 0.03% H2O2 injury. This effect occurs due to reduced caspase-3 activation and is phosphatidylinositol 3′–kinase dependent. Conclusion: In addition to its known effects on endothelial cells, VEGF acts as a growth and anti-apoptotic factor on alveolar epithelial cells. VEGF treatment may have potential as a rescue therapy for diseases associated with alveolar epithelial damage such as acute respiratory distress syndrome.