Nerve growth factor overexpression and autocrine loop in breast cancer cells

We show here that nerve growth factor (NGF), the canonical neurotrophic factor, is synthesized and released by breast cancer cells. High levels of NGF transcript and protein were detected in breast cancer cells by reverse transcription-PCR, Western blotting, ELISA assay and immunohistochemistry. Conversely, NGF production could not be detected in normal breast epithelial cells at either the transcriptional or protein level. Confocal analysis indicated the presence of NGF within classical secretion vesicles. Breast cancer cell-produced NGF was biologically active, as demonstrated by its ability to induce the neuronal differentiation of embryonic neural precursor cells. Importantly, the constitutive growth of breast cancer cells was strongly inhibited by either NGF-neutralizing antibodies or K-252a, a pharmacological inhibitor of NGF receptor TrkA, indicating the existence of an NGF autocrine loop. Together, our data demonstrate the physiological relevance of NGF in breast cancer and its potential interest as a marker and therapeutic target.

Computational differentiation of N-terminal signal peptides and transmembrane helices

Signal peptides and transmembrane helices both contain a stretch of hydrophobic amino acids. This common feature makes it difficult for signal peptide and transmembrane helix predictors to correctly assign identity to stretches of hydrophobic residues near the N-terminal methionine of a protein sequence. The inability to reliably distinguish between N-terminal transmembrane helix and signal peptide is an error with serious consequences for the prediction of protein secretory status or transmembrane topology. In this study, we report a new method for differentiating protein N-terminal signal peptides and transmembrane helices. Based on the sequence features extracted from hydrophobic regions (amino acid frequency, hydrophobicity, and the start position), we set up discriminant functions and examined them on non-redundant datasets with jackknife tests. This method can incorporate other signal peptide prediction methods and achieve higher prediction accuracy. For Gram-negative bacterial proteins, 95.7% of N-terminal signal peptides and transmembrane helices can be correctly predicted (coefficient 0.90). Given a sensitivity of 90%, transmembrane helices can be identified from signal peptides with a precision of 99% (coefficient 0.92). For eukaryotic proteins, 94.2% of N-terminal signal peptides and transmembrane helices can be correctly predicted with coefficient 0.83. Given a sensitivity of 90%, transmembrane helices can be identified from signal peptides with a precision of 87% (coefficient 0.85). The method can be used to complement current transmembrane protein prediction and signal peptide prediction methods to improve their prediction accuracies. (C) 2003 Elsevier Inc. All rights reserved.

A review of peer support in the context of cancer

Peer support interventions for people with cancer, their families, and friends have been widely used throughout the world. The present study reviewed the research literature on psychosocial oncology over the past decade to assess the prevalence and contribution of articles on peer support. Using CD-Rom databases, 25 articles were retrieved for review. In each article, patients or their family members were the target group for supportive interventions, which were primarily for the delivery of peer support and included either a qualitative or quantitative evaluation of the program. A definitional taxonomy for peer support interventions, which identified eight discrete settings, was derived from three key dimensions: style of supervision, interpersonal context, and mode of delivery. The studies suggested that peer support programs help by providing emotional and informational support from the perspective of shared personal experience. However, a paucity of research-particularly randomized controlled trials-was noted. The reasons may include inherent difficulties in isolating for study what is essentially a naturalistically occurring interpersonal dynamic from the complex social and community contexts from which it emanates. The authors discuss the gap between practice and theory in this area and recommend a broader and more inclusive view of supportive care for people with cancer. (C) 2003 by The Haworth Press, Inc. All rights reserved.

Immunological changes after cancer treatment and participation in an exercise program

Purpose: The purpose of this investigation was to evaluate the impact of undertaking peripheral blood stem cell transplantation (PBST) on T-cell number and function, and to determine the role of a mixed type, moderate intensity exercise program in facilitating the recovery of T-cell number and function. Methods: Immunological measures of white blood cell, lymphocyte, CD3(+), CD4(+), and CD8(+) counts, and CD3(+) cell function were assessed pretransplant (PI), immediately posttransplant (PII), and 1 month (II), 2 months (12) and 3 months (PIII) posttransplant. After PII, 12 patients were divided equally into a control group (CG) or exercise intervention group (EG). Results: Lower total T-cell, helper T-cell, and suppressor T-cell counts (P < 0.01), as well as lower T-cell function (P < 0.01), when compared with normative data, were found at PI. More specifically, 88% of the group had CD3(+), CD4(+), and CD8(+) counts that were more than 40%, 20%, and 50% below normal at PI, respectively. Undertaking a PBST caused further adverse changes to the total leukocyte, lymphocyte, CD3(+), CD4(+) and CD8(+) count. and the helper/suppressor ratio. Although CD8(+) counts had returned to normal by PIII, CD3(+), CD4(+), and the CD4(+)/CD8(+) ratio remained significantly lower than normative data (P < 0.01), with 66%, 100%, and 100% of the subject group reporting counts and ratios, respectively, below the normal range. Conclusion: The PBST patients were immunocompromised before undertaking the transplant, and the transplant procedure imposed further adverse changes to the leukocyte and lymphocyte counts. The leukocyte and CD8(+) counts returned to normal within 3 months posttransplant; however, the other immunological parameters assessed demonstrated a delayed recovery. Although participation in the exercise program did not facilitate a faster immune cell recovery, neither did the exercise program hinder or delay recovery.

E2F modulates keratinocyte squamous differentiation. Implications for E2F inhibition in squamous cell carcinoma

E2F regulation is essential for normal cell cycle progression. Therefore, it is not surprising that squamous cell carcinoma cell lines (SCC) overexpress E2F1 and exhibit deregulated E2F activity when compared with normal keratinocytes. Indeed, deliberate E2F1 deregulation has been shown to induce hyperplasia and skin tumor formation. In this study, we report on a dual role for E2F as a mediator of keratinocyte proliferation and modulator of squamous differentiation. Overexpression of E2F isoforms in confluent primary keratinocyte cultures resulted in suppression of differentiation-associated markers. Moreover, we found that the DNA binding domain and the trans-activation domain of E2F1 are important in mediating suppression of differentiation. Use of a dominant/negative form of E2F1 ( E2F d/n) found that E2F inhibition alone is sufficient to suppress the activity of proliferation-associated markers but is not capable of inducing differentiation markers. However, if the E2F d/n is expressed in differentiated keratinocytes, differentiation marker activity is further induced, suggesting that E2F may act as a modulator of squamous differentiation. We therefore examined the effects of E2F d/n in a differentiation- insensitive SCC cell line. We found that treatment with the differentiating agent, 12-O-tetradecanoyl- phorbol-13-acetate (TPA), or expression of E2F d/n alone had no effect on differentiation markers. However, a combination of E2F d/n + TPA induced the expression of differentiation markers. Combined, these data indicate that E2F may play a key role in keratinocyte differentiation. These data also illustrate the unique potential of anti-E2F therapies in arresting proliferation and inducing differentiation of SCCs.

Quality of Life and Colorectal Cancer: a Review

Objectives: To describe what is known of quality of life for colorectal cancer patients, to review what has been done in the Australian setting and to identify emerging directions for future research to address current gaps in knowledge. Method: A literature search (using Medline, PsychInfo, CINAHL and Sociological Abstracts) was conducted and 41 articles identified for review. Results: Three key areas relating to quality of life in colorectal cancer patients emerged from the literature review: the definition and measurement of quality of life; predictors of quality of life; and the relationship of quality of life to survival. Results of existing studies are inconsistent in relation to quality of life over time and its relationship to survival. Small sample sizes and methodological limitations make interpretation difficult. Conclusions: There is a need for large-scale, longitudinal, population-based studies describing the quality of life experienced by colorectal cancer patients and its determinants. Measurement and simultaneous adjustment for potential confounding factors would productively advance knowledge in this area, as would an analysis of the economic cost of morbidity to the community and an assessment of the cost effectiveness of proposed interventions. Implications: As the Australian population ages, the prevalence of colorectal cancer within the community will increase. This burden of disease presents as a priority area for public health research. An improved understanding of quality of life and its predictors will inform the development and design of supportive interventions for those affected by the disease.

The AF-1 Domain of the Orphan Nuclear Receptor NOR-1 Mediates Trans-activation, Coactivator Recruitment, and Activation by the Purine Anti-metabolite 6-Mercaptopurine

NOR-1/NR4A3 is an orphan member of the nuclear hormone receptor superfamily. NOR-1 and its close relatives Nurr1 and Nur77 are members of the NR4A subgroup of nuclear receptors. Members of the NR4A subgroup are induced through multiple signal transduction pathways. They have been implicated in cell proliferation, differentiation, T-cell apoptosis, chondrosarcomas, neurological disorders, inflammation, and atherogenesis. However, the mechanism of transcriptional activation, coactivator recruitment, and agonist-mediated activation remain obscure. Hence, we examined the molecular basis of NOR-1-mediated activation. We observed that NOR-1 trans-activates gene expression in a cell- and target-specific manner; moreover, it operates in an activation function (AF)-1-dependent manner. The N-terminal AF-1 domain delimited to between amino acids 1 and 112, preferentially recruits the steroid receptor coactivator (SRC). Furthermore, SRC-2 modulates the activity of the AF-1 domain but not the C-terminal ligand binding domain (LBD). Homology modeling indicated that the NOR-1 LBD was substantially different from that of hRORbeta, a closely related AF-2-dependent receptor. In particular, the hydrophobic cleft characteristic of nuclear receptors was replaced with a very hydrophilic surface with a distinct topology. This observation may account for the inability of this nuclear receptor LBD to efficiently mediate cofactor recruitment and transcriptional activation. In contrast, the N-terminal AF-1 is necessary for cofactor recruitment and can independently conscript coactivators. Finally, we demonstrate that the purine anti-metabolite 6-mercaptopurine, a widely used antineoplastic and anti-inflammatory drug, activates NOR-1 in an AF-1-dependent manner. Additional 6-mercaptopurine analogs all efficiently activated NOR-1, suggesting that the signaling pathways that modulate proliferation via inhibition of de novo purine and/or nucleic acid biosynthesis are involved in the regulation NR4A activity. We hypothesize that the NR4A subgroup mediates the genotoxic stress response and suggest that this subgroup may function as sensors that respond to genotoxicity.

Dietary influences on survival after ovarian cancer

We evaluated the effects of various food groups and micronutrients in the diet on survival among women who originally participated in a population-based case-control study of ovarian cancer conducted across 3 Australian states between 1990 and 1993. This analysis included 609 women with invasive epithelial ovarian cancer, primarily because there was negligible mortality in women with borderline tumors. The women's usual diet was assessed using a validated food frequency questionnaire. Deaths in the cohort were identified using state-based cancer registries and the Australian National Death Index (NDI). Crude 5-year survival probabilities were estimated using the Kaplan-Meier technique, and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were obtained from Cox regression models. After adjusting for important confounding factors, a survival advantage was observed for those who reported higher intake of vegetables in general (HR = 0.75, 95% CI = 0.57-0.99, p-value trend 0.01 for the highest third, compared to the lowest third), and cruciferous vegetables in particular (HR = 0.75, 95% CI = 0.57-0.98, p-value trend 0.03), and among women in the upper third of intake of vitamin E (HR = 0.76, 95% CI = 0.58-1.01, p-value trend 0.04). Inverse associations were also seen with protein (p-value trend 0.09), red meat (p-value trend 0.06) and white meat (p-value trend 0.07), and modest positive trends (maximum 30% excess) with lactose (p-value trend 0.04), calcium and dairy products. Although much remains to be learned about the influence of nutritional factors after a diagnosis of ovarian cancer, our study suggests the possibility that a diet high in vegetable intake may help improve survival. (C) 2003 Wiley-Liss, Inc.

The decentralized social networking systems towards mobilizing actions of citizenship and solidarity against cancer

The goal of the present study is mapping the nature of possible contributions of participatory online platforms in citizen actions that may contribute in the fight against cancer and its associated consequences. These platforms are usually associated with entertainment: in that sense, we intent to test their validity in other domains such as health, as well as contribute to an expanded perception of their potential by their users. The research is based on the analysis of online solidarity networks, namely the ones residing on Facebook, Orkut and the blogosphere, that citizens have been gradually resorting to. The research is also based on the development of newer and more efficient solutions that provide the individual (directly or indirectly affected by issues of oncology) with the means to overcome feelings of impotence and fatality. In this article, we aim at summarizing the processes of usage of these decentralized, freer participatory platforms by citizens and institutions, while attempting to unravel existing hype and stigma; we also provide a first survey of the importance and the role of institutions in this kind of endeavor; lastly, we present a prototype, developed in the context of the present study, that is specifically dedicated to addressing oncology through social media. This prototype is already available online at www.talkingaboutcancer.org, however, still under development and testing. The main objective of this platform is to allow every citizen to freely build their network of contacts and information, according to their own individual and/ or collective needs and desires.

Proportional cancer incidence according to selected sites: comparison between residents in the City of S. Paulo, Brazil: Japanese and Brazilian/Portuguese descent

The percentual distributions of selected sites of cancer cases according to origin, sex and age are compared. Data were obtained from the Registry of Cancer of S. Paulo (School of Public Health of the University of S. Paulo, Brazil). The reference period for inhabitants of Japanese descent was 1969/78 and for those of Brazilian descent, the period was 1969/75. Standardized Proportionate Incidence Ratios (SPIR) with approximate 95% Confidence Intervals (CI) were evaluated using age specific Incidence Ratios of S. Paulo, 1973, as standards. The results agree with findings of previous works on mortality, but show different patterns according to origin. The well known fact that some sub-groups of a population may be different from the overall group is once again brought to the fore. Attention should be drawn to the differences detected for stomach, skin and prostate, in males, and for stomach, skin, cervix and uterus in females.

Acompanhamento da construção do projecto de expansão do terminal de GNL de Sines: PETS

O presente relatório de estágio está inserido no âmbito do Trabalho Final de Mestrado do perfil de Edificações, relativo ao curso de Engenharia Civil do Instituto de Engenharia de Lisboa. Foi realizado um estágio com o período de dezasseis semanas na Somague Engenharia, integrado na obra pública do Projecto de Expansão do Terminal de GNL de Sines. O documento compreende o estudo e o acompanhamento da construção dos elementos principais do terminal, nomeadamente, o novo sistema de água do mar e o tanque de armazenagem de GNL. O Capítulo 2 descreve o funcionamento e apresenta os principais sistemas constituintes do terminal. O objectivo primordial deste trabalho tem como base o estudo dos recursos e da metodologia construtiva envolvida no sistema de adução de água do mar, no tanque de armazenagem e no sistema de rejeição de água do mar, apresentando os Capítulos 3,4 e 5, respectivamente. Os Capítulos 6 e 7 desenvolvem, respectivamente, a evolução construtiva verificada durante o período de estágio e os trabalhos realizados enquanto estagiário. Os Capítulos 3 e 5 são complementados pelos Anexos I e II, assim como pelos Apêndices I e II, respectivamente. Os anexos são utilizados como referência para as peças desenhadas, enquanto os apêndices são utilizados para um complemento ao desenvolvimento pormenorizado de algumas soluções.