Cancer cell differentiation heterogeneity and aggressive behavior in solid tumors

The differentiation stage of tumors is a central aspect in the histopathological classification of solid malignancies. The differentiation stage is strongly associated with tumor behavior, and generally an immature tumor is more aggressive than the more differentiated counterpart. While this is common knowledge in surgical pathology, the contribution of differentiation-related gene expression and functions to tumor behavior is often overlooked in the experimental, tumor biological setting. The mechanisms by which tumor cell differentiation stages are perturbed or affected are poorly explored but have recently come into focus with the introduction.of the tumor stem cell concept. While developmental biologists view the differentiation as a unidirectional event, pathologists and tumor biologists have introduced the concept of dedifferentiation to explain phenotypic changes occurring in solid tumors. In this review we discuss the impact of the tumor cell differentiation stage as used in surgical pathology. We further discuss knowledge gained from exploring the molecular basis of the differentiation and dedifferentiation processes in neuroblastoma and breast cancer, two tumor forms where the tumor cell differentiation concept is used in the clinical diagnostic work and where the tumor stem cell theory has been applied

Planning and Designing Walkable Cities: A Smart Approach

Walking may be considered one of the most sustainable and democratic ways of travelling within a city, thus providing benefits not only to pedestrians but also to the urban environment. Besides, walking is also one of the means of transport most likely subjected to factors outside an individual\u2019s control, like social or physical abilities to walk and the presence of comfortable and safe street infrastructures and services. Therefore, improving urban conditions provided to pedestrians has positive impacts on walkability. At the same time technological solutions and innovations have the power to encourage and support people to walk by overcoming immaterial barriers due to a lack of information or boring travel and they give to decision makers the possibility to gain data to understand how and where people travel. Merging these two dimensions into a unique approach can drastically improve accessibility, attractiveness, safety, comfort and security of urban spaces. In this context, this paper aims to draw a more multifaceted context for walkability, where new technologies assume a key role for introducing new approaches to pedestrian paths planning and design and thus for enhancing this mode of transport. Indeed, by combining more traditional spatial-based and perceptual analysis of the urban environment with technological applications and social media exploitation there will be room to better support the decision on and to enhance satisfaction of walking as well as to easier plan and design more walkable cities

Increased epithelial cell proliferation in the ileal pouch mucosa of patients with familial adenomatous polyposis

To eliminate the risk of colorectal cancer in patients with familial adenomatous polyposis (FAP), reconstructive proctocolectomy is performed. Although most colonic mucosa is resected during the ileal pouch anal anastomosis, adenomas and carcinomas may develop in the pouch. This may be caused by altered cell kinetics due to intraluminal changes in the pouch. In 32 patients with FAP, biopsy specimens from the mucosa of the pouch and also of the afferent ileal loop were taken. Tissue sections were immunohistochemically processed with the monoclonal antibodies M30 and MIB-1 to assess apoptotic and proliferative indices, respectively. Cell proliferation was also assessed by a modified sign test. There were no significant differences in apoptotic rates between the mucosa of the pouch and the mucosa of the afferent ileal loop. However, cell proliferation was significantly higher in the mucosa of the pouch vs afferent ileal loop, both by using the quantitative (68.3% vs 61.6%, p = 0.001) and semiquantitative methods (p < 0.05). Our newly developed semiquantitative approach outperformed previously described methods. The higher cell proliferation in the pouch as compared to the afferent ileal loop may contribute to the increased risk for adenomas and carcinomas in the pouch of patients with FAP and emphasizes the need for regular endoscopic surveillance

Differentiation in Neuroblastoma: Diffusion-Limited Hypoxia Induces Neuro-Endocrine Secretory Protein 55 and Other Markers of a Chromaffin Phenotype

Background: Neuroblastoma is a childhood malignancy of sympathetic embryonal origin. A high potential for differentiation is a hallmark of neuroblastoma cells. We have previously presented data to suggest that in situ differentiation in tumors frequently proceeds along the chromaffin lineage and that decreased oxygen ( hypoxia) plays a role in this. Here we explore the utility of Neuro-Endocrine Secretory Protein 55 ( NESP55), a novel member of the chromogranin family, as a marker for this process.Methodology/Principal Findings: Immunohistochemical analyses and in situ hybridizations were performed on human fetal tissues, mouse xenografts of human neuroblastoma cell lines, and on specimens of human neuroblastoma/ganglioneuroma. Effects of anaerobic exposure on gene expression by cultured neuroblastoma cells was analyzed with quantitative real-time PCR. Fetal sympathetic nervous system expression of NESP55 was shown to be specific for chromaffin cell types. In experimental and clinical neuroblastoma NESP55 immunoreactivity was specific for regions of chronic hypoxia. NESP55 expression also correlated strikingly with morphological evidence of differentiation and with other chromaffin-specific patterns of gene expression, including IGF2 and HIF2 alpha. Anaerobic culture of five neuroblastoma cell lines resulted in an 18.9-fold mean up-regulation of NESP55.Conclusions/Significance: The data confirms that chronic tumor hypoxia is a key microenvironmental factor for neuroblastoma cell differentiation, causing induction of chromaffin features and NESP55 provides a reliable marker for this neuronal to neuroendocrine transition. The hypoxia-induced phenotype is the predominant form of differentiation in stroma-poor tumors, while in stroma-rich tumors the chromaffin phenotype coexists with ganglion cell-like differentiation. The findings provide new insights into the biological diversity which is a striking feature of this group of tumors

Prognostic role of p27Kip1 and apoptosis in human breast cancer

Human breast carcinoma is biologically heterogeneous, and its clinical course may vary from an indolent slowly progressive one to a course associated with rapid progression and metastatic spread. It is important to establish prognostic factors which will define subgroups of patients with low vs high risk of recurrence so as to better define the need for additional therapy. Additional characterization of the molecular make-up of breast cancer phenotypes should provide important insights into the biology of breast cancer. In the present study, we investigated apoptosis, expression of p27Kip1 and p53 retrospectively in 181 human breast cancer specimens. In addition, their relevance to the biological behaviour of breast cancer was examined. Our studies found a significant association among high histological grade, high p53, low apoptosis and low p27. Our results also demonstrated that, in human breast cancer, low levels of p27 and apoptotic index (AI) strongly correlated with the presence of lymph node metastasis and decreased patient survival. In node-negative patients, however, p27 also had prognostic value for relapse-free and overall survival in multivariate analysis. Furthermore p27 and AI had predictive value for the benefits of chemotherapy. These latter observations should prompt prospective randomized studies designed to investigate the predictive role of p27 and AI in determining who should receive chemotherapy in node-negative patients. © 1999 Cancer Research Campaig

Preclinical Models for Neuroblastoma: Establishing a Baseline for Treatment

Preclinical models of pediatric cancers are essential for testing new chemotherapeutic combinations for clinical trials. The most widely used genetic model for preclinical testing of neuroblastoma is the TH-MYCN mouse. This neuroblastoma-prone mouse recapitulates many of the features of human neuroblastoma. Limitations of this model include the low frequency of bone marrow metastasis, the lack of information on whether the gene expression patterns in this system parallels human neuroblastomas, the relatively slow rate of tumor formation and variability in tumor penetrance on different genetic backgrounds. As an alternative, preclinical studies are frequently performed using human cell lines xenografted into immunocompromised mice, either as flank implant or orthtotopically. Drawbacks of this system include the use of cell lines that have been in culture for years, the inappropriate microenvironment of the flank or difficult, time consuming surgery for orthotopic transplants and the absence of an intact immune system.Here we characterize and optimize both systems to increase their utility for preclinical studies. We show that TH-MYCN mice develop tumors in the paraspinal ganglia, but not in the adrenal, with cellular and gene expression patterns similar to human NB. In addition, we present a new ultrasound guided, minimally invasive orthotopic xenograft method. This injection technique is rapid, provides accurate targeting of the injected cells and leads to efficient engraftment. We also demonstrate that tumors can be detected, monitored and quantified prior to visualization using ultrasound, MRI and bioluminescence. Finally we develop and test a "standard of care" chemotherapy regimen. This protocol, which is based on current treatments for neuroblastoma, provides a baseline for comparison of new therapeutic agents.The studies suggest that use of both the TH-NMYC model of neuroblastoma and the orthotopic xenograft model provide the optimal combination for testing new chemotherapies for this devastating childhood cancer

Effects of intervention with sulindac and inulin/VSL#3 on mucosal and luminal factors in the pouch of patients with familial adenomatous polyposis

Contains fulltext : 97862.pdf (publisher's version ) (Open Access)BACKGROUND/AIM: In order to define future chemoprevention strategies for adenomas or carcinomas in the pouch of patients with familial adenomatous polyposis (FAP), a 4-weeks intervention with (1) sulindac, (2) inulin/VSL#3, and (3) sulindac/inulin/VSL#3 was performed on 17 patients with FAP in a single center intervention study. Primary endpoints were the risk parameters cell proliferation and glutathione S-transferase (GST) detoxification capacity in the pouch mucosa; secondary endpoints were the short chain fatty acid (SCFA) contents, pH, and cytotoxicity of fecal water. METHODS: Before the start and at the end of each 4-week intervention period, six biopsies of the pouch were taken and feces was collected during 24 h. Cell proliferation and GST enzyme activity was assessed in the biopsies and pH, SCFA contents, and cytotoxicity were assessed in the fecal water fraction. The three interventions (sulindac, inulin/VSL#3, sulindac/inulin/VSL#3) were compared with the Mann-Whitney U test. RESULTS: Cell proliferation was lower after sulindac or VSL#3/inulin, the combination treatment with sulindac/inulin/VSL#3 showed the opposite. GST enzyme activity was increased after sulindac or VSL#3/inulin, the combination treatment showed the opposite effect. However, no significance was reached in all these measures. Cytotoxicity, pH, and SCFA content of fecal water showed no differences at all among the three treatment groups. CONCLUSION: Our study revealed non-significant decreased cell proliferation and increased detoxification capacity after treatment with sulindac or VSL#3/inulin; however, combining both regimens did not show an additional effect

Fatores associados a atividade fisica, comportamento sedentario e participacao na Educacao Fisica em estudantes do Ensino Medio em Santa Catarina, Brasil

Abstract published in English and Portuguese English title: Factors associated with physical activity, sedentary behavior, and participation in physical education among high school students in Santa Catarina State, BrazilThe objectives of this study were to estimate the prevalence of insufficient physical activity, sedentary behavior, and absence from physical education and associated factors. The Santa Catarina State Adolescents' Questionnaire (COMPAC, in Portuguese) was applied to a sample of 5,028 adolescents (15-19 years of age) attending public high schools in the State of Santa Catarina, Brazil. Information included demographic and socioeconomic indicators. Poisson regression analyses were used to test associations. The proportion of students with insufficient physical activity was 28.5%, associated with low consumption of fruits and vegetables (PR = 1.27; 95%CI: 1.15; 1.40) and enrollment in night classes (PR = 1.44; 95%CI: 1.34; 1.54). Absence from physical education was reported by 48.6%; employment and older age were negatively associated with absence from physical education. Sedentary behavior was reported by 38.4%, but was less frequent in rural areas (PR = 0.52; 95%CI: 0.31; 0.83) and among those enrolled in absence from physical education (RP = 0.73; 95%CI: 0.56; 0.95). The results suggest interventions with specific strategies aimed at ameliorating each contributing factor. = O objetivo deste estudo foi analisar as prevalências e fatores associados à atividade física insuficiente, comportamento sedentário e ausência nas aulas de Educação Física em escolares do Ensino Médio. O questionário COMPAC (Comportamento do Adolescente Catarinense) foi respondido por 5.028 estudantes (15 a 19 anos), de escolas públicas de Santa Catarina, Sul do Brasil. Foram analisados comportamentos de risco, informações demográficas e sócio-econômicas. Utilizou-se regressão de Poisson para análises das associações. A prevalência de atividade física insuficiente foi de 28,5% e associou-se a um menor consumo de frutas/verduras (RP = 1,27; IC95%: 1,15-1,40) e estudo noturno (RP = 1,44; IC95%: 1,34-1,54). A prevalência de ausência nas aulas de Educação Física foi de 48,6% e associou-se negativamente à idade e com estar trabalhando (RP = 1,52; IC95%: 1,18-2,19). A prevalência de comportamento sedentário foi de 38,4%, atingindo menos os residentes de áreas rurais (RP = 0,52; IC95%: 0,31-0,83) e que participavam de uma ausência nas aulas de Educação Física semanal (RP = 0,73; IC95%: 0,56-0,95). Os resultados sugerem intervenções com estratégias específicas para cada comportamento analisado.Kelly Samara da Silva, Markus Vinícius Nahas, Karen Glazer Peres, Adair da Silva Lope