Therapeutic targets for bone metastases in breast cancer

Breast cancer is prone to metastasize to bone. Once metastatic cells are in the bone marrow, they do not, on their own, destroy bone. Instead, they alter the functions of bone-resorbing (osteoclasts) and bone-forming cells (osteoblasts), resulting in skeletal complications that cause pathological fractures and pain. In this review, we describe promising molecular bone-targeted therapies that have arisen from recent advances in our understanding of the pathogenesis of breast cancer bone metastases. These therapies target osteoclasts (receptor activator of nuclear factor kB ligand, integrin αvβ3, c-Src, cathepsin K), osteoblasts (dickkopf-1, activin A, endothelin A) and the bone marrow microenvironment (transforming growth factor β, bone morphogenetic proteins, chemokine CXCL-12 and its receptor CXCR4). The clinical exploitation of these bone-targeted agents will provide oncologists with novel therapeutic strategies for the treatment of skeletal lesions in breast cancer

Multiplicity Distributions and Charged-neutral Fluctuations

Results from the multiplicity distributions of inclusive photons and charged particles, scaling of particle multiplicities, event-by-event multiplicity fluctuations, and charged-neutral fluctuations in 158$\cdot A$ GeV Pb+Pb collisions are presented and discussed. A scaling of charged particle multiplicity as $N_{part}^{1.07\pm 0.05}$ and photons as $N_{part}^{1.12\pm 0.03}$ have been observed, indicating violation of naive wounded nucleon model. The analysis of localized charged-neutral fluctuation indicates a model-independent demonstration of non-statistical fluctuations in both charged particles and photons in limited azimuthal regions. However, no correlated charged-neutral fluctuations are observed.Comment: Talk given at the International Symposium on Nuclear Physics (ISNP-2000), Mumbai, India, 18-22 Dec 2000, Proceedings to be published in Pramana, Journal of Physic

Assessment of the direct effects of DDAH I on tumour angiogenesis in vivo

Nitric oxide (NO) has been strongly implicated in glioma progression and angiogenesis. The endogenous inhibitors of NO synthesis, asymmetric dimethylarginine (ADMA) and N-monomethyl-l-arginine (l-NMMA), are metabolized by dimethylarginine dimethylaminohydrolase (DDAH), and hence, DDAH is an intracellular factor that regulates NO. However, DDAH may also have an NO-independent action. We aimed to investigate whether DDAH I has any direct role in tumour vascular development and growth independent of its NO-mediated effects, in order to establish the future potential of DDAH inhibition as an anti-angiogenic treatment strategy. A clone of rat C6 glioma cells deficient in NO production expressing a pTet Off regulatable element was identified and engineered to overexpress DDAH I in the absence of doxycycline. Xenografts derived from these cells were propagated in the presence or absence of doxycycline and susceptibility magnetic resonance imaging used to assess functional vasculature in vivo. Pathological correlates of tumour vascular density, maturation and function were also sought. In the absence of doxycycline, tumours exhibited high DDAH I expression and activity, which was suppressed in its presence. However, overexpression of DDAH I had no measurable effect on tumour growth, vessel density, function or maturation. These data suggest that in C6 gliomas DDAH has no NO-independent effects on tumour growth and angiogenesis, and that the therapeutic potential of targeting DDAH in gliomas should only be considered in the context of NO regulation

Trait anxiety predicts disease-specific health status in early-stage breast cancer patients

The objectives of this study were to examine the differences in health status (HS) of women with breast cancer (BC) at different moments in time, and between women scoring high and not high on trait anxiety, and to identify possible predictors of HS 6 and 12 months after surgery. Patients (N = 223) completed a trait anxiety questionnaire before diagnosis. Women who received a diagnosis of BC completed a BC-specific HS questionnaire 1, 3, 6 and 12 months after surgery. ANCOVA for repeated measures and multiple regression analysis were used in the analyses. Women scoring high on trait anxiety had significant (P < .005) lower Body image, worse Future perspective and Sexual functioning, and more Side-effects than women who did not score high on trait anxiety. At 6 and 12 months after surgery, the same aspects of HS were predicted by higher trait anxiety scores. Higher scores on trait anxiety resulted in worse scores on four HS domains, indicating that there should be more attention for this group of patients, even before treatment start

The Rotterdam Scan Study: design and update up to 2012

Neuroimaging plays an important role in etiologic research on neurological diseases in the elderly. The Rotterdam Scan Study was initiated as part of the ongoing Rotterdam Study with the aim to unravel causes of neurological disease by performing neuroimaging in a population-based longitudinal setting. In 1995 and 1999 random subsets of the Rotterdam Study underwent neuroimaging, whereas from 2005 onwards MRI has been implemented into the core protocol of the Rotterdam Study. In this paper, we discuss the background and rationale of the Rotterdam Scan Study. We also describe the imaging protocol and post-processing techniques, and highlight the main findings to date. Finally, we make recommendations for future research, which will also be the main focus of investigation in the Rotterdam Scan Study

Discovery of Novel Hypermethylated Genes in Prostate Cancer Using Genomic CpG Island Microarrays

BACKGROUND: Promoter and 5' end methylation regulation of tumour suppressor genes is a common feature of many cancers. Such occurrences often lead to the silencing of these key genes and thus they may contribute to the development of cancer, including prostate cancer. METHODOLOGY/PRINCIPAL FINDINGS: In order to identify methylation changes in prostate cancer, we performed a genome-wide analysis of DNA methylation using Agilent human CpG island arrays. Using computational and gene-specific validation approaches we have identified a large number of potential epigenetic biomarkers of prostate cancer. Further validation of candidate genes on a separate cohort of low and high grade prostate cancers by quantitative MethyLight analysis has allowed us to confirm DNA hypermethylation of HOXD3 and BMP7, two genes that may play a role in the development of high grade tumours. We also show that promoter hypermethylation is responsible for downregulated expression of these genes in the DU-145 PCa cell line. CONCLUSIONS/SIGNIFICANCE: This study identifies novel epigenetic biomarkers of prostate cancer and prostate cancer progression, and provides a global assessment of DNA methylation in prostate cancer

Quantifying the Evolution of Vascular Barrier Disruption in Advanced Atherosclerosis with Semipermeant Nanoparticle Contrast Agents

Acute atherothrombotic occlusion in heart attack and stroke implies disruption of the vascular endothelial barrier that exposes a highly procoagulant intimal milieu. However, the evolution, severity, and pathophysiological consequences of vascular barrier damage in atherosclerotic plaque remain unknown, in part because quantifiable methods and experimental models are lacking for its in vivo assessment.To develop quantitative nondestructive methodologies and models for detecting vascular barrier disruption in advanced plaques.Sustained hypercholesterolemia in New Zealand White (NZW) rabbits for >7-14 months engendered endothelial barrier disruption that was evident from massive and rapid passive penetration and intimal trapping of perfluorocarbon-core nanoparticles (PFC-NP: ∼250 nm diameter) after in vivo circulation for as little as 1 hour. Only older plaques (>7 mo), but not younger plaques (<3 mo) demonstrated the marked enhancement of endothelial permeability to these particles. Electron microscopy revealed a complex of subintimal spongiform channels associated with endothelial apoptosis, superficial erosions, and surface-penetrating cholesterol crystals. Fluorine ((19)F) magnetic resonance imaging and spectroscopy (MRI/MRS) enabled absolute quantification (in nanoMolar) of the passive permeation of PFC-NP into the disrupted vascular lesions by sensing the unique spectral signatures from the fluorine core of plaque-bound PFC-NP.The application of semipermeant nanoparticles reveals the presence of profound barrier disruption in later stage plaques and focuses attention on the disrupted endothelium as a potential contributor to plaque vulnerability. The response to sustained high cholesterol levels yields a progressive deterioration of the vascular barrier that can be quantified with fluorine MRI/MRS of passively permeable nanostructures. The possibility of plaque classification based on the metric of endothelial permeability to nanoparticles is suggested

Rhythmicity in Mice Selected for Extremes in Stress Reactivity: Behavioural, Endocrine and Sleep Changes Resembling Endophenotypes of Major Depression

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, including hyper- or hypo-activity of the stress hormone system, plays a critical role in the pathophysiology of mood disorders such as major depression (MD). Further biological hallmarks of MD are disturbances in circadian rhythms and sleep architecture. Applying a translational approach, an animal model has recently been developed, focusing on the deviation in sensitivity to stressful encounters. This so-called 'stress reactivity' (SR) mouse model consists of three separate breeding lines selected for either high (HR), intermediate (IR), or low (LR) corticosterone increase in response to stressors.In order to contribute to the validation of the SR mouse model, our study combined the analysis of behavioural and HPA axis rhythmicity with sleep-EEG recordings in the HR/IR/LR mouse lines. We found that hyper-responsiveness to stressors was associated with psychomotor alterations (increased locomotor activity and exploration towards the end of the resting period), resembling symptoms like restlessness, sleep continuity disturbances and early awakenings that are commonly observed in melancholic depression. Additionally, HR mice also showed neuroendocrine abnormalities similar to symptoms of MD patients such as reduced amplitude of the circadian glucocorticoid rhythm and elevated trough levels. The sleep-EEG analyses, furthermore, revealed changes in rapid eye movement (REM) and non-REM sleep as well as slow wave activity, indicative of reduced sleep efficacy and REM sleep disinhibition in HR mice.Thus, we could show that by selectively breeding mice for extremes in stress reactivity, clinically relevant endophenotypes of MD can be modelled. Given the importance of rhythmicity and sleep disturbances as biomarkers of MD, both animal and clinical studies on the interaction of behavioural, neuroendocrine and sleep parameters may reveal molecular pathways that ultimately lead to the discovery of new targets for antidepressant drugs tailored to match specific pathologies within MD

Programa de intervención en representaciones de creatividad y motivación académica de adolescentes

Creativity and its promotion are widespread concerns in education. However, few efforts have been made to implement intervention programs designed to promote creativity and other related aspects (e.g., academic motivation). The Future Problem Solving Program International (FPSPI), aimed for training creativity representations and creative problem solving skills in young people, has been one of the most implemented programs. This intervention’s materials and activities were adapted for Portuguese students, and a longitudinal study was conducted. The program was implemented during four months, in weekly sessions, by thirteen teachers. Teachers received previous training for the program and during the program’s implementation. Intervention participants included 77 Basic and Secondary Education students, and control participants included 78 equivalent students. Pretest-posttest measures of academic motivation and creativity representations were collected. Results suggest a significant increase, in the intervention group, in motivation and the appropriate representations of creativity. Practical implications and future research perspectives are presented.A criatividade e sua promoção geram grande preocupação em educação. Contudo, poucos esforços têm existido para implementar programas destinados a sua promoção e de outros aspetos relacionados (e.g., motivação acadêmica). O Future Problem Solving Program International (FPSPI), criado para melhorar as representações de criatividade e a resolução criativa de problemas em jovens, tem sido um dos mais implementados. Os seus materiais e atividades foram adaptados para estudantes portugueses, efetuando-se um estudo longitudinal. O programa foi implementado durante quatro meses, semanalmente, por treze professores, que receberam formação antes e durante a implementação. O grupo experimental incluiu 77 estudantes do Ensino Básico e Secundário, apresentando o grupo de controlo 78 estudantes com características equivalentes. Os dados sobre a motivação e criatividade foram recolhidos num pré e pós-teste. Os resultados sugerem um aumento significativo na motivação e crenças apropriadas de criatividade no grupo experimental. Implicações práticas e perspectivas para investigações futuras são apresentadas.La creatividad y su promoción generan gran preocupación en educación. Sin embargo, han sido llevados a cabo pocos esfuerzos para implementar programas de promoción de la creatividad y otros aspectos (e.g., motivación académica). El Future Problem Solving Program International (FPSPI), creado para mejorar las representaciones de creatividad y la solución creativa de problemas en jóvenes, ha sido bastante implementado. Se adaptaron sus materiales y actividades para estudiantes portugueses, y se desarrolló un estudio longitudinal. El programa se implementó semanalmente durante cuatro meses por trece profesores, que recibieron formación antes y durante la implementación. El grupo experimental incluyó 77 estudiantes de Educación Primaria y Secundaria y el grupo de control incluyó 78 estudiantes con características semejantes. Los datos de motivación y creatividad fueron recogidos en un pre y post-test, sugiriendo un aumento significativo de motivación y creencias apropiadas sobre la creatividad en el grupo experimental. Se presentan implicaciones prácticas y perspectivas para futuras investigaciones.Fundação para a Ciência e a Tecnologia (FCT) - SFRH/BPD/80825/201