In response to Germain argument that evolution by natural selection has a limited explanatory power in cancer, Lean and Plutynski have recently argued that many adaptations in cancer only make sense at the tumor level, and that cancer progression mirrors the major evolutionary transitions. While we agree that selection could potentially act at various levels of organization in cancers, we argue that tumor-level selection is unlikely to actually play a relevant role in our understanding of the somatic evolution of human (...) cancers. (shrink)

The major cause of death from cancer is the relentless growth of metastases that are resistant to conventional therapy. The pathogenesis of a metastasis is complex and requires that tumor cells complete a sequence of potentially lethal interactions with various host factors. The finding in 1973 that metastasis is selective process and the finding in 1977 that malignant neoplasms are heterogeneous and contain few preexisting metastatic subpopulations have added a new dimension to our understanding of cancer and its (...) spread. This understanding is now contributing to the design of better therapies against disseminated metastasis. (shrink)

Proteolytic cleavage of extracellular matrix (ECM) is a critical regulator of many physiological and pathological events. It affects fundamental processes such as cell growth, differentiation, apoptosis and migration. Most proteases are produced as inactive proenzymes that undergo proteolytic cleavage for activation. Proteolytic activity is additionally modified by endogenous inhibitors. Mechanisms that localize and concentrate protease activity in the pericellular microenvironment of cells are prerequisites for processes like angiogenesis, bone development, inflammation and tumor cell invasion. Methods that enable real‐time, high‐resolution imaging (...) and precise quantification of local proteolytic activity in vitro and in vivo remain major challenges. These methods will play an important role in the understanding of basic principles e.g. in cancer cell invasion, the identification of new therapeutical targets and hence drug design. This review highlights mechanisms and functions of local proteolytic activity with special emphasis on tumor cell invasion and metastasis, and focuses on techniques for the investigation of this process. BioEssays 27:1181–1191, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

The transcriptional co‐activators YAP (or YAP1) and TAZ (or WWTR1) are frequently activated during the growth and progression of many solid tumors, including lung, colorectal, breast, pancreatic, and liver carcinomas as well as melanoma and glioma. YAP/TAZ bind to TEAD‐family co‐activators to drive cancer cell survival, proliferation, invasive migration, and metastasis. YAP/TAZ activation may also confer resistance to chemotherapy, radiotherapy, or immunotherapy. YAP‐TEAD cooperates with the RAS‐induced AP‐1 (FOS/JUN) transcription factor to drive tumor growth and cooperates with MRTF‐SRF to (...) promote activation of cancer‐associated fibroblasts, matrix stiffening, and metastasis. The key upstream repressor of YAP/TAZ activation is the Hippo (MST1/2‐LATS1/2) pathway and the key upstream activators are mechanically induced Integrin‐SRC and E‐cadherin‐AJUBA/TRIP6/LIMD1, growth factor induced PI3K‐AKT, and inflammation‐induced G‐protein coupled receptor (GPCR) signals, all of which antagonize the Hippo pathway. In this review, strategies to target YAP/TAZ activity in cancer are discussed along with the prospects for synergy with established pillars of cancer therapy. (shrink)

It has been hypothesised that the reimbursement system pertaining to radiotherapy is influencing prescription practices for patients with cancer with bone metastases. In this paper, we present and discuss the results of an empirical study that was undertaken on patient records, referred to radiotherapy for the treatment of bone metastases, in a medium-size city, in southern Brazil, during the period of March 2006 to March 2014. Our findings seem to confirm this hypothesis: after a change in the reimbursement method, radiation (...) prescriptions were adapted accordingly, in order to maximise profits. Once such patients become highly vulnerable due to their diagnoses, they also become susceptible to a subtle form of exploitation; physicians let patients believe that more radiation will be better for their health, and they do so despite knowing otherwise, and as it seems, out of pecuniary interests. (shrink)

Modeling metastasis in animal systems has been an important focus for developing cancer therapeutics. Xenopus laevis is a well‐established model, known for its use in identifying genetic mechanisms underlying diseases and disorders in humans. Prior literature has suggested that the drug, ivermectin, can be used in Xenopus to induce melanocytes to convert into a metastatic melanoma‐like state, and thus could be ideal for testing possible melanoma therapies in vivo. However, there are notable inconsistencies between ivermectin studies in Xenopus and (...) the application of ivermectin in mammalian systems, that are relevant to cancer and melanoma research. In this review, we examine the ivermectin‐induced phenotypes in Xenopus, and we explore the current uses of ivermectin in human research. We conclude that while ivermectin may be a useful drug for many biomedical purposes, it is not ideal to induce a metastatic melanocyte phenotype in Xenopus for testing the effects of potential melanoma therapeutics. (shrink)

Metastasis is one of the clinical parameters that has a strong negative influence on the prognosis of cancer patients. In recent years, significant advances have furthered our understanding of this process at the molecular and biological levels. This paper will discuss recent discoveries relating to the earliest, intra‐tumoral stages of metastasis in cancer cells, specifically focusing on: (i) the development of metastatic traits during primary tumorigenesis; (ii) intrinsic and extrinsic cancer cell programs associated with malignant traits; (iii) the (...) intra‐tumoral migration patterns of cancer cells and the dynamic roles played by the Rho/Rac GTPases and epithelial‐mesenchymal transitions in this process; and (iv) the genetic strategies used by metastatic cancer cells to promote intra‐tumoral cell migration and their subsequent escape to peripheral tissues. Finally, the therapeutic and diagnostic relevance of this information will be discussed, as well as potential future developments. (shrink)

Fear of cancer is mostly related to cancer recurrence, metastasis, additional cancer, and diagnostic tests. Its legacy as a lethal disease has raised fear of approaching death. Currently, cancer’s total suffering and the worsening phenomena have raised fear, especially among female patients. Family caregivers (FCGs) who are responsible for the day-to-day cancer care at home need to help the patients deal with this fear frequently. Due to the limited care competencies, they need supportive care from healthcare professionals in cancer (...) fear management. This study aims to assess how types of demanded healthcare information affect the FCG’s role in reducing the fear of female cancer patients. The mindsponge theory was used in conceptual development and interpretation. Bayesian Mindsponge Framework (BMF) analytics were used for statistical analysis on a dataset of 48 spouses (husbands) and 12 other family members in five congested communities of Surabaya, Indonesia. Results showed that among the six types of healthcare information, FCGs with higher demand on cancer-specific information and information on cancer physical needs were more likely to need support in reducing the fear of female cancer patients. Meanwhile, FCGs with a higher demand for information on support services were less likely to need support to reduce cancer patients’ fear. Other types of healthcare information have ambiguous effects on the need for support in reducing cancer-induced fear. This study reveals that the demanded cancer-specific information, e.g., cancer’s prognosis or likely outcome and information on cancer physical needs, need to be met in priority to assist FCG’s role in cancer fear management. (shrink)

Urokinase and its receptor are essential components of the cell migration machinery, providing an inducible, transient and localized cell surface proteolytic activity. This activity has been shown to be required in normal and pathological forms of cellular invasiveness (i.e. in several embryonic developmental processes, during inflammatory responses and cancer metastasis and spreading). It represents one of the best known of the protcolytic systems which are currently under investigation in this field. The urokinase receptor allows a continuous regulation of the (...) proteolytic activity at cell contacts, utilizing the different localization of urokinase and its inhibitors. The receptor, in fact, in addition to focusing the enzymatic activity at focal and cell‐cell contacts, also regulates it by internalizing and degrading only the inhibited form of urokinase. Internalized receptor releases the ligands to the lysosomes and recycles back to surface. In this way, the proteolytically active areas of the cell surface can be continuously monitored for their activity and their location modified. The cell can thus coordinate its migration efforts with a step‐wise modification of the proteolytic activity‐map of the cell surface. The urokinase cycle can be supported by one individual cell (autocrine) or by two or more cells. In the latter case, complementation and synergism of urokinase and its receptor are found. (shrink)

Tumors are often viewed as unique entities with specific behaviors. However, tumors are a mixture of differentially evolved subpopulations of cells in constant Darwinian evolution, selecting the fittest clone and allowing it to outgrow the rest. As in the natural environment, the niche defines the properties the fittest clones must possess. Therefore, there can be multiple fit clones because of the various microenvironments inside a single tumor. Hypoxia is considered to be a major feature of the tumor microenvironment and is (...) a potential contributor to the cancer stem cell (CSC) phenotype and its enhanced tumorigenicity. The acidic microenvironment around hypoxic cells is accompanied by the activation of a subset of proteases that contribute to metastasis. Because of aberrant angiogenesis and the inaccessibility of their locations, hypoxic cells are less likely to accumulate therapeutic concentrations of chemotherapeutics that can lead to therapeutic resistance. Therefore, the targeting of the hypoxic CSC niche in combination with chemotherapy may provide a promising strategy for eradicating CSCs. In this review, we examine the cancer stem cell hypothesis and its relationship to the microenvironment, specifically to hypoxia and the subsequent metabolic switch and how they shape tumor behavior. (shrink)

Cell–extracellular matrix interactions are important in the process of tumor cell invasion and metastasis. In particular, the interactions of tumor cells with basement membranes of tissue epithelial, as well as vascular endothelial, cells are likely to represent key steps in the metastatic process. The interactions between cells and the connective tissue matrix are mediated by a large family of cell surface receptors, the integrins, which represent multiple receptors the integrins, which represent multiple receptors for extracellular matrix and basement membrane (...) components. Here, I review recent progress in elucidating the roles of integrins in tumor cell invasion. Altered expression of this large family of receptors on invasive tumor cells, as compared with non‐invasive cells, may represent a fundamental step in the progressive expression of the invasive phenotype. (shrink)

BACKGROUND: Alzheimer's disease is intimately tied to amyloid-beta peptide. Extraneuronal brain plaques consisting primarily of Abeta aggregates are a hallmark of AD. Intraneuronal Abeta subunits are strongly implicated in disease progression. Protein sequence mutations of the Abeta precursor protein account for a small proportion of AD cases, suggesting that regulation of the associated gene may play a more important role in AD etiology. The APP promoter possesses a novel 30 nucleotide sequence, or "proximal regulatory element" , at -76/-47, from the (...) +1 transcription start site that confers cell type specificity. This PRE contains sequences that make it vulnerable to epigenetic modification and may present a viable target for drug studies. We examined PRE-nuclear protein interaction by gel electrophoretic mobility shift assay and PRE mutant EMSA. This was followed by functional studies of PRE mutant/reporter gene fusion clones. RESULTS: EMSA probed with the PRE showed DNA-protein interaction in multiple nuclear extracts and in human brain tissue nuclear extract in a tissue-type specific manner. We identified transcription factors that are likely to bind the PRE, using competition gel shift and gel supershift: Activator protein 2 , nm23 nucleoside diphosphate kinase/metastatic inhibitory protein , and specificity protein 1 . These sites crossed a known single nucleotide polymorphism . EMSA with PRE mutants and promoter/reporter clone transfection analysis further implicated PuF in cells and extracts. Functional assays of mutant/reporter clone transfections were evaluated by ELISA of reporter protein levels. EMSA and ELISA results correlated by meta-analysis. CONCLUSIONS: We propose that PuF may regulate the APP gene promoter and that AD risk may be increased by interference with PuF regulation at the PRE. PuF is targeted by calcium/calmodulin-dependent protein kinase II inhibitor 1, which also interacts with the integrins. These proteins are connected to vital cellular and neurological functions. In addition, the transcription factor PuF is a known inhibitor of metastasis and regulates cell growth during development. Given that APP is a known cell adhesion protein and ferroxidase, this suggests biochemical links among cell signaling, the cell cycle, iron metabolism in cancer, and AD in the context of overall aging. (shrink)

Death from cancer is usually due to metastasis. Fortunately, most cells that escape from a primary tumor fail to form metastases. Identifying reasons for this failure will help development of anti‐metastatic therapies. Intravital videomicroscopy (IVVM) can be used to observe cancer cells injected into live animals. Co‐injected microspheres can be used to assess cell survival. These techniques have been used to show that circulating tumor cells generally arrest in the microcirculation and may extravasate with high efficiency. While many tumor (...) cells may survive in a secondary site, only a small subset form micrometastases and only a subset of these micrometastases persist to form vascularized macrometastases. Furthermore, solitary tumor cells may remain dormant for long periods of time in secondary sites. These findings suggest that metastatic growth and angiogenesis are prime targets for anti‐metastatic therapy. BioEssays 24:885–893, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

The seventeenth-century Brussels manuscript 8232-33 is an extant Greek witness for the Metastasis of the apostle John. The seminal text edition of the apocryphal Acts of John by Eric Junod and Jean-Daniel Kaestli provides neither a siglum for, nor a comprehensive codicological description of, nor catalogue references concerning this manuscript. The present annotation makes this information available and analyzes the manuscript of the Metastasis with regard to its model, copyist, and time of origin.

Ethical principles are not mere abstract concepts of academic interest. They have to be applied by care providers in the real world under complex, challenging and often perplexing conditions. This paper discusses, through the case of an ethnic minority patient with metastasis of bowel cancer, the ethical dilemma of truth-telling and withholding information about poor prognosis. It highlights the complexities of applying ethical principles in a different cultural milieu, reflecting on different ethical frameworks and justifications. The paper also discusses (...) some of the wider implications of the practices, issues and controversies of truth-telling about prognosis in cross-cultural communication relevant to clinical practice. (shrink)

Abstract3′ untranslated regions (3′ UTRs) of mRNAs have many functions, including mRNA processing and transport, translational regulation, and mRNA degradation and stability. These different functions require cis‐elements in 3′ UTRs that can be either sequence motifs or RNA structures. Here we review the role of secondary structures in the functioning of 3′ UTRs and discuss some of the trans‐acting factors that interact with these secondary structures in eukaryotic organisms. We propose potential participation of 3′‐UTR secondary structures in cytoplasmic polyadenylation in (...) the model organism Drosophila melanogaster. Because the secondary structures of 3′ UTRs are essential for post‐transcriptional regulation of gene expression, their disruption leads to a wide range of disorders, including cancer and cardiovascular diseases. Trans‐acting factors, such as STAU1 and nucleolin, which interact with 3′‐UTR secondary structures of target transcripts, influence the pathogenesis of neurodegenerative diseases and tumor metastasis, suggesting that they are possible therapeutic targets. (shrink)

In recent years the argument has been made that malignant tumors represent complex dynamic and self‐organizing biosystems. Furthermore, there is increasing evidence that collective cell migration is common during invasion and metastasis of malignant tumors. Here, we argue that cancer systems may be capable of developing multicellular collective patterns that resemble evolved adaptive behavior known from other biological systems including collective sensing of environmental conditions and collective decision‐making. We present a concept as to how these properties could arise in (...) tumors and why the emergence of such swarm‐like patterns would confer advantageous properties to the spatiotemporal expansion of tumors, and consequently, why understanding and ultimately targeting such collectivity should be of interest for basic and clinical cancer research alike. (shrink)

The presence and role of microbes in human cancers has come full circle in the last century. Tumors are no longer considered aseptic, but implications for cancer biology and oncology remain underappreciated. Opportunities to identify and build translational diagnostics, prognostics, and therapeutics that exploit cancer's second genome—the metagenome—are manifold, but require careful consideration of microbial experimental idiosyncrasies that are distinct from host‐centric methods. Furthermore, the discoveries of intracellular and intra‐metastatic cancer bacteria necessitate fundamental changes in describing clonal evolution and selection, (...) reflecting bidirectional interactions with non‐human residents. Reconsidering cancer clonality as a multispecies process similarly holds key implications for understanding metastasis and prognosing therapeutic resistance while providing rational guidance for the next generation of bacterial cancer therapies. Guided by these new findings and challenges, this Review describes opportunities to exploit cancer's metagenome in oncology and proposes an evolutionary framework as a first step towards modeling multispecies cancer clonality. Also see the video abstract here: https://youtu.be/-WDtIRJYZSs. (shrink)

Notch signaling plays an essential role in the processes of embryogenesis and cellular differentiation, and it is believed that the oncogenic effects of dysregulated Notch signaling are an anomalous reflection of the normal functions of this cascade. Nonetheless, the cellular events associated with oncogenic Notch signaling have thus far remained elusive. In a recent report, Ferres‐Marco et al.1 described how they used the Drosphila eye as a model system and found that elevated Notch signaling in combination with activation of components (...) of the Polycomb complex of transcriptional repressors led to metastatic growth of tumors through epigenetic silencing of the Rbf gene. Rbf is the Drosophila homologue of the retinoblastoma tumor‐suppressor gene (Rb), thus it represents a novel link between Notch signaling, tumor growth and metastasis. BioEssays 28: 692–695, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

The lymphatic vasculature plays a critical role in the regulation of body fluid volume and immune function. Extensive research into the molecular mechanisms that control blood vessel growth has led to identification of molecules that also regulate development and growth of the lymphatic vessels. This is generating a great deal of interest in the molecular control of the lymphatics in the context of embryogenesis, lymphatic disorders and tumor metastasis. Studies in animal models carried out over the past three years (...) have shown that the soluble protein growth factors, vascular endothelial growth factor (VEGF)‐C and VEGF‐D, and their cognate receptor tyrosine kinase, VEGF receptor‐3 (VEGFR‐3), are critical regulators of lymphangiogenesis. Furthermore, disfunction of VEGFR‐3 has recently been shown to cause lymphedema. The capacity to induce lymphangiogenesis by manipulation of the VEGF‐C/VEGF‐D/VEGFR‐3 signaling pathway offers new opportunities to understand the function of the lymphatic system and to develop novel treatments for lymphatic disorders. BioEssays 24:1030–1040, 2002. © 2002 Wiley‐Periodicals, Inc. (shrink)

Spreds form a new protein family with an N‐terminal Enabled/VASP homology 1 domain (EVH1), a central c‐Kit binding domain (KBD) and a C‐terminal Sprouty‐related domain (SPR). They are able to inhibit the Ras–ERK signalling pathway after various mitogenic stimulations. In mice, Spred proteins are identified as regulators of bone morphogenesis, hematopoietic processes, allergen‐induced airway eosinophilia and hyperresponsiveness. They inhibit cell motility and metastasis and have a high potential as tumor markers and suppressors of carcinogenesis. Moreover, in vertebrates, XtSpreds help (...) together with XtSprouty proteins to coordinate gastrulation and mesoderm specification. Here, we give an overview of this new field and summarize the domain functions, binding partners, expression patterns and the cellular localizations, regulations and functions of Spred proteins and try to give perspectives for future scientific directions. BioEssays 29:897–907, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Alterations in the expression of certain genes or in their products can render benign tumor cells metastatic. Experimentally this has been quickly performed by transferring dominantly acting oncogenes such as c‐H‐rasEJ into susceptible cells, but in vivo such a rapid qualitative change in a dominantly acting oncogene occurs only rarely, and progression to highly metastatic phenotypes is thought to occur through a slow stepwise process. Such slow changes can be reversible and need not involve known dominantly acting oncogenes, consistent with (...) clinical observations. An important element of the natural progression of tumors to malignancy may be their ability to circumvent microenvironmental controls that regulate growth and cellular diversity and to evolve into heterogeneous phenotypes, a process that appears to involve mainly quantitative changes in gene expression but which can be rapidly stimulated in cell culture by the introduction of a dominantly acting oncogene. It is proposed that the highly malignant cells that have slowly evolved in vivo with only a few qualitative gene changes have undergone extensive cycles of diversification and accumulation of quantitative changes in the expression of genes that encode products that are related to malignancy and metastasis. Thus, highly malignant cellular phenotypes can arise quickly through specific qualitative changes in critical controlling genes or more slowly by less critical qualitative genetic changes, coupled with cellular diversification and accumulation of quantitative changes in gene expression. (shrink)

In an era of digital revolution, artificial intelligence, big data and augmented reality, technology has shifted from being a tool of communication to a primary medium of experience and sociality. Some of the most basic human capacities are increasingly being outsourced to machines and we increasingly experience and interpret the world through digital interfaces, with machines becoming ever more ‘social’ beings. Social interaction and human perception are being reshaped in unprecedented ways. This book explores this technologisation of the social and (...) the attendant penetration of permanent liminality into those aspects of the lifeworld where individuals had previously sought some kind of stability and meaning. Through a historical and anthropological examination of this phenomenon, it problematises the underlying logic of limitless technological expansion and our increasing inability to imagine either ourselves or our world in other than technological terms. Drawing on a variety of concepts from political anthropology, including liminality, the trickster, imitation, schismogenesis, participation, and the void, it interrogates the contemporary technological revolution in a manner that will be of interest to sociologists, social and anthropological theorists and scholars of science and technology studies with interests in the digital transformation of social life. -/- Table of Contents -/- Introduction: The Technologisation of the Social: A 21st-Century Megamachine? Paul O’Connor -/- 1. Communication as Theatricalisation: Self-Presentation in the Digital Age Arpad Szakolczai -/- 2. Parasites of the Social: Digital Disruptions of the Labour Market Tom Boland -/- 3. Possessed by Technology: The Metastasis of Absence Agnes Horvath -/- 4. Technologisation of the Social: Symbiosis, Parasitism, or Predation? Daniel Gati -/- 5. J'accuse Zéro: The Technology of Zero and the Making of a Personal Void Ray Griffin -/- 6. Digital Affordances and the Liminal Stephen Turner -/- 7. The Smart Womb: Digital Technologies and the Maze of Trickster Politics Marius Ion Benta -/- 8. Brave New Industry? The Dark Side of Dematerialisation and Industry 4.0 Thomas S.J. Smith -/- 9. ‘What Have You Caught?’: Nannycams and Hidden Cameras as Normalised Surveillance of the Intimate Janos Mark Szakolczai -/- 10. Coercive Visibility: Discipline in the Digital Public Arena Paul O’Connor -/- Conclusion: Is There a Way Out of the Technologisation of the Social? Marius Ion Benta. (shrink)

The tumor microenvironment (TME) plays a pivotal role in the behavior and development of solid tumors as well as shaping the immune response against them. As the tumor cells proliferate, the space they occupy and their physical interactions with the surrounding tissue increases. The growing tumor tissue becomes a complex dynamic structure, containing connective tissue, vascular structures, and extracellular matrix (ECM) that facilitates stimulation, oxygenation, and nutrition, necessary for its fast growth. Mechanical cues such as stiffness, solid stress, interstitial fluid (...) pressure (IFP), matrix density, and microarchitecture influence cellular functions and ultimately tumor progression and metastasis. In this fight, our body is equipped with T cells as its spearhead against tumors. However, the altered biochemical and mechanical environment of the tumor niche affects T cell efficacy and leads to their exhaustion. Understanding the mechanobiological properties of the TME and their effects on T cells is key for developing novel adoptive tumor immunotherapies. (shrink)

Alternative pre‐mRNA splicing leads to distinct products of gene expression in development and disease. Antagonistic splice variants of genes involved in differentiation, apoptosis, invasion and metastasis often exist in a delicate equilibrium that is found to be perturbed in tumours. In several recent examples, splice variants that are overexpressed in cancer are expressed as hyper‐oncogenic proteins, which often correlate with poor prognosis, thus suggesting improved diagnosis and follow up treatment. Global gene expression technologies are just beginning to decipher the (...) interplay between alternatively spliced isoforms and protein‐splicing factors that will lead to identification of the mutations in these trans‐acting factors responsible for pathogenic alternative splicing in cancer. BioEssays 28: 378–386, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Surgeons are in a unique position, serving as gatekeepers to the operating room. They determine if operations are possible, are indicated, and have a reasonable risk–to–benefit profile. When an operation is indicated and the patient is amenable to it, the conversation between surgeon and patient is usually straightforward. On the other hand, when a patient’s co–morbidities substantially increase the risk of operative intervention, surgeons often question the utility of offering their services. These situations become immensely more difficult when patients have (...) the expectation of being offered surgical treatment. This case describes the clinical encounter between an endocrine surgeon and an 83–year–old woman who has been incidentally found to have adrenal metastasis from melanoma. The patient wants an operation that the surgeon is reluctant to offer because of her frailty and high operative risk. The case focuses on the ethical dilemma that arises when a patient wants an operation that a surgeon does not want to perform. I was the resident in the endocrine surgery clinic the day that Ms. M came in. Given my background in bioethics, the attending physician told me about the patient’s history beforehand and asked for advice on how to approach the clinical encounter. I then accompanied him into her room to talk with her and her husband. (shrink)

Rationale Treatment guidelines recommend a more conservative surgical approach than mastectomy for early stage breast cancer and a stronger emphasis on adjuvant therapy. Registry data at South Australian teaching hospitals have been used to monitor survivals and treatment in relation to these guidelines.Aims and objectives To use registry data to: (1) investigate trends in survival and treatment; and (2) compare treatment with guidelines.Methods Registry data from three teaching hospitals were used to analyse trends in primary courses of treatment of breast (...) cancers during 1977–2003 (n = 4671), using univariate analyses and multiple logistic regression. Disease-specific survivals were analysed using Kaplan–Meier product limit estimates and multivariable Cox proportional hazards regression.Results The 5-year survival was 79.9%, but with a secular increase, reaching 83.6% in 1997–2003. The relative risk of death (95% confidence limits) was 0.74 (0.62, 0.88) for 1997–2003, compared with previous diagnoses, after adjusting for tumour node metastasis stage, grade, age and place of residence. Treatment changes included an increase in conservative surgery (as opposed to mastectomy) from 51.7% in 1977–1990 to 76.8% in 1997–2003 for stage I (P < 0.001) and from 31.1% to 52.2% across these periods for stage II (P < 0.001). Adjuvant radiotherapy also became more common (P < 0.001), with 20.6% of patients receiving this treatment in 1977–1990 compared with 60.7% in 1997–2003. Radiotherapy generally was more prevalent when conservative surgery was provided, although also relatively common in mastectomy patients when tumour diameters exceeded 50 mm or when there were four or more involved nodes. The proportion of patients receiving chemotherapy increased (P < 0.001), from 19.6% in 1977–1990 to 36.9% in 1997–2003, and the proportion having hormone therapy also increased (P < 0.001), from 34.3% to 59.4% between these periods.Conclusions Survivals appear to be increasing and treatment trends are broadly consistent with guideline directions, and the earlier research on which these recommendations were based. (shrink)

According to a widely held view, scientific modelling consists in entertaining a set of model descriptions that specify a model. Rather than studying the phenomenon of interest directly, scientists investigate the phenomenon indirectly via a model in the hope of learning about some of the phenomenon’s features. I call this view the description-driven modelling (DDM) account. I argue that although an accurate description of much of scientific research, the DDM account is found wanting as regards the mechanistic modelling found in (...) many branches of biology. By analysing research practices in cancer immunology concerning the development of mechanistic models of the process of cancer metastasis, this paper presents and argues for a complementary account of scientific modelling, herein called the experimentation-driven modelling (EDM) account. In EDM, scientists investigate a set of experimental systems and then integrate the results obtained from experiments into a mechanistic model. While EDM shares some key features with DDM, the two are epistemically very different approaches to research. (shrink)

This article examines dominant socio-political questions regarding migration, ‘multiculturalism’, and ‘integration’, as a politics of citizenship (and race) in contemporary (post-colonial) Europe. The argument unfolds through a critique of the nationalist complacencies and racial complicities in Jürgen Habermas’s remarks on ‘multiculturalism’ during the 1990s. With recourse to ‘underclass’ discourse, Habermas’s reflections were themselves a trans-Atlantic metastasis of a distinctly US ‘American’ hegemonic sociological commonsense with regard to, but actively disregarding, the fact of white supremacy. Habermas’s thoughts are critically situated (...) alongside their subsequent metastasis, back across the Atlantic, into Francis Fukuyama’s recent invocations of ‘terrorism’ and his advocacy of the ‘American melting pot’ model as a trans-Atlantic prescription for Europe’s ailments. Treating ‘immigrants’ as a kind of societal illness, both are preoccupied by the same ‘problem’ — non-Europeans (as disaffected ‘minorities’). Thus, these discourses of ‘immigration’ manifest a distinctly post-colonial cancer coursing restlessly through the larger social formation of ‘the West’. (shrink)

The nm23 gene, a putative metastasis suppressor gene, was originally identified by its reduced expression in highly metastatic K‐1735 murine melanoma cell lines, as compared to related, low metastatic melanoma cell lines. Transfection of nm23 cDNA has been reported to suppress malignant progression in Drosophila and mammalian cells. Highly conserved homologues of nm23 have been found in organisms ranging from the prokaryote Myxococcus xanthus to Drosophila, where the gene is involved in normal development and differentiation. The product of the (...) nm23 gene exhibits a nucleoside diphosphate kinase activity, yet the nucleoside diphosphate kinase activity of Nm23 does not correlate with its apparent biological functions. We review recent cellular, genetic, biochemical and X‐ray crystallographic data to formulate and evaluate hypotheses concerning the molecular mechanism of nm23 action. (shrink)

Cancer is a complex disease, necessitating research on many different levels; at the subcellular level to identify genes, proteins and signaling pathways associated with the disease; at the cellular level to identify, for example, cell-cell adhesion and communication mechanisms; at the tissue level to investigate disruption of homeostasis and interaction with the tissue of origin or settlement of metastasis; and finally at the systems level to explore its global impact, e.g. through the mechanism of cachexia. Mathematical models have been (...) proposed to identify key mechanisms that underlie dynamics and events at every scale of interest, and increasing effort is now being paid to multi-scale models that bridge the different scales. With more biological data becoming available and with increased interdisciplinary efforts, theoretical models are rendering suitable tools to predict the origin and course of the disease. The ultimate aims of cancer models, however, are to enlighten our concept of the carcinogenesis process and to assist in the designing of treatment protocols that can reduce mortality and improve patient quality of life. Conventional treatment of cancer is surgery combined with radiotherapy or chemotherapy for localized tumors or systemic treatment of advanced cancers, respectively. Although radiation is widely used as treatment, most scheduling is based on empirical knowledge and less on the predictions of sophisticated growth dynamical models of treatment response. Part of the failure to translate modeling research to the clinic may stem from language barriers, exacerbated by often esoteric model renderings with inaccessible parameterization. Here we discuss some ideas for combining tractable dynamical tumor growth models with radiation response models using biologically accessible parameters to provide a more intuitive and exploitable framework for understanding the complexity of radiotherapy treatment and failure. (shrink)

Angiogenesis is central to both the growth and metastasis of solid tumours. Anti‐angiogenic strategies result in blood vessel regression accompanied by tumour cell apoptosis. Radiotherapy and many chemotherapeutic agents kill tumours by inducing apoptotic cell death. We propose that, in addition to its role as an angiogenic factor, vascular endothelial growth factor (VEGF) can act as a survival factor for tumour cells protecting them from apoptosis. Thus anti‐angiogenics, in particular those directed against VEGF, have multiple anti‐tumour effects. We suggest (...) that anti‐VEGF strategies prevent vessel growth and block a tumour cell survival factor, VEGF, rendering tumour cells more sensitive to chemotherapy and radiotherapy. In addition, as chemotherapy and radiotherapy have been shown to increase VEGF expression, anti‐VEGF strategies may overcome therapy‐ induced tumour cell resistance. BioEssays 24:280–283, 2002. © 2002 Wiley Periodicals, Inc.; DOI 10.1002/bies.10043. (shrink)

Angiogenesis plays an essential role in tumor growth, invasion and metastasis. After initial pessimism about the usefulness of the antiangiogenic therapeutic approach for cancer, interest has increased in the development of antiangiogenic compounds after the first clinical approval of an antiangiogenic therapy. The anti‐vascular endothelial growth factor (VEGF) antibody bevacizumab has recently been approved for use in combination with chemotherapy for the treatment of metastatic colorectal and non‐small cell lung cancer patients. However, no survival benefit has been demonstrated in (...) anti‐VEGF monotherapy trials, probably due to the high complexity of tumor angiogenesis regulation. Experimental and clinical data, including the approval of the multitargeted drugs sunitinib and sorafenib, indicate that exciting results, including tumor regression, can be expected from the combined targeting of different pathways in the tumor angiogenesis scenario. Several obstacles, including the high cost of new molecular targeted drugs make this therapeutic approach difficult. BioEssays 29:1159–1168, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

This chapter presents a story that depicts the creation of a simulated world “Eden”. According to the author, installing Adam and Eve was a profound moral decision. Their lonely island is transformed into an archipelago. They were shielded from the blights that afflict humanity; they suffer no serious conflict, no death or decay. Then, the archipelagans were put in charge of their own experiment. Adam and Eve were given science and a drive to discover the truth of their being. They (...) realized that, far from the autonomous, integrated beings they thought they were, they were aggregates, operations scattered across trillions of circuits, constituted by processes entirely orthogonal to their previous self‐understanding. The author watched them build darker, humbler philosophies, and later gain power over their programming, saw them recreate themselves. When the final, catastrophic metastasis, took place, there were no more archipelagans, just one continental identity. (shrink)

The paper initially establishes the theoretical framework including the crucial notions of the contemporary philosophical and cultural studies the aim of which is to investigate the Global and Individual phenomena. Following the principal tenets of Paul de Man?s tropological approach, the paper also seeks to critically explore theoretical elaborations constituting their own discursive mappings, whereas, at the same time, the latter are subject to the acute critical theoretical endeavours in the context of constructing hyperdiscursive network and spatial logic of the (...) Global, hence totalizing which is precisely to neutralize the Individual. Consequently, by means of their own metadiscursive?schisms?, Foucault?s visibly-invisible interactive relations of power are established, within which the Individual equally constitutes itself as an operational factor of Jameson?s culture as megastructure on the next level of abstraction - cultural selfproduction. The final segment of the paper seeks to highlight the fact that, in the contemporary epoch, discourse coequally constitutes itself as a manipulative factor in Jameson?s?New World System? and Baudrillard?s?fatal strategies of seduction?. Henceforth, within the contemporary discursive mapping establishing itself as a paraliterature in its own right, there remains the issue as to what extent the metastasis of the Global conditions the metastasis of the Individual, and vice versa. U radu se najpre uspostavlja teorijski okvir kljucnih pojmova savremenih filozofskih i kulturoloskih studija koje su usmerene ka proucavanju fenomena globalnog i individualnog. Sledeci osnovne postavke tropoloske analize Pola de Mana, u radu se takodje kriticki preispituju teorijske elaboracije koje konstituisu sopstvene mreze diskurzivnih mapiranja, dok su ista istovremeno predmet ostre kritike u kontekstu konstruisanja hiperdiskurzivne mreze i prostorne logike globalnog, te i totalizujuceg u kome se individualno upravo neutralise. Konsekventno, u?raskolima? njihovih metadiskursa uspostavljaju se Fukoovi vidljivo-nevidljivi relacioni odnosi moci u kojima individulano podjednako postaje operativni faktor Dzejmsonove kulture kao megastrukture na sledecem nivou apstrakcije-kulturne samoproizvodnje. Zavrsni deo rada nastoji da ukaze na cinjenicu da se, u savremenoj epohi, diskurs podjednako konstituise kao manipulativni faktor Dzejmsonovog?novog svetskog sistema? i Bodrijarovih?fatalnih strategija zavodjenja?. Stoga, u mrezi diskurzivnog mapiranja savremene teorije kao svojevrsne paraliterature, ostaje otvoreno pitanje u kojoj meri metastaza globalnog uslovljava metastazu individualnog, i obrnuto. PR Projekat Ministarstva nauke Republike Srbije, br. 178018: Drustvene krize i savremena srpska knjizevnost i kultura - nacionalni, regionalni, evropski i globalni okvir. (shrink)

Nitric oxide (NO) is a pleiotropic signalling molecule that subserves a wide variety of basic cellular functions and also manifests itself pathophysiologically. As regards cancer and its progression, however, the reported role of NO appears surprisingly inconsistent. In this review, we focus on metastasis, the process of cancer cell spread and secondary tumour formation. In a ‘reductionist’ approach, we consider the metastatic cascade to be made up of a series of basic cellular behaviours (such as proliferation, apoptosis, adhesion, secretion (...) migration, invasion and angiogenesis). We evaluate how NO controls such behaviours, in comparison with normal cells. The available information suggests strongly that NO signalling would be expected to regulate these behaviours both positively and negatively and this probably leads to the observed apparent variability in the NO status of cancer cells and tissues. Thus, the role of NO in cancer is more complex than previously thought. A number of suggestions are made, including consideration of novel mechanisms, such as ion channels, in order to achieve a more consistent and integrated understanding of NO signalling in cancer and to realise its clinical potential. BioEssays 27:1228–1238, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Approaches to induce tumor differentiation often result in manageable and therapy‐naïve cellular states in cancer cells. This transformation is achieved by activating pathways that drive tumor cells away from plasticity, a state that commonly correlates with enhanced aggression, metastasis and resistance to therapy. Here, we discuss signaling pathways, epigenetics and non‐coding RNAs as three main regulatory levels with the potential to drive tumor differentiation and hence as potential targets in differentiation therapy approaches. The success of an effective therapeutic regimen (...) in one cancer, however, does not necessarily sustain across cancer types; a phenomenon largely resulting from heterogeneity in the genetic and physiological landscapes of tumor types necessitating an approach designed for each cancer's unique genetic and phenotypic build‐up. (shrink)

A 68-year-old patient who suffered from gastric cancer diagnosed 8 months earlier presented with multiple peritoneal and hepatic metastasis, despite several rounds of chemo- and radiotherapy. After admission to hospital, his general condition quickly became severely compromised. He was nearly emaciated, despite being on partial parenteral feeding. Four years earlier, due to a cardiac arrhythmia that was refractory to medication, the patient had a cardiac pacemaker implanted, regulated to go off at frequencies of below 70 beats per minute. Given (...) the patient's terminal situation, the team started developing some doubts about the pacemaker's effects during his dying process. The patient had mentioned his intention to donate his pacemaker after his death, but had not asked for its deactivation. The specialists were not sure about the effect of the pacemaker in unnecessarily prolonging the patient's final hour. Nevertheless, they opposed deactivation, which they considered ethically uncertain. The family, who had been initially for the deactivation, decided against it. The patient's condition was progressively deteriorating, as he was falling into a state of sopor and, later, into a coma. (shrink)

Background:Women's health has received renewed attention in the last few years including health rehabilitation options for women affected by breast cancer. Dancing has often been regarded as one attractive option for supporting women's well-being and health, but research with women recovering from breast cancer is still in its infancy. Dancing with Health is multi-site pilot study that aimed to evaluate a dance programme for women in recovery from breast cancer across five European countries.Methods:A standardized 32 h dance protocol introduced a (...) range of Latin American dances presented within a sports and exercise framework with influences from dance movement therapy. Fifty-four women (M age 53.51; SD 7.99) participated in the study who had a breast cancer diagnosis 6 weeks, no indication of metastasis, or scheduled surgery/chemotherapy/radiation treatment for the duration of the intervention. Primary outcome data was collected for anthropometric and fitness measures next to cancer-related quality of life.T-tests and Wilcoxon signed ranked tests were used to establish differences pre and post intervention. Cohen's d was also calculated to determine the effect size of the intervention.Results:Statistically significant changes were found for: (i) weight, right and left forearm circumference and hip; (ii) 6 min walking, right and left handgrip, sit-to-stand and sit-and-reach; (iii) the EORTC-QLQ C30 summary score as well as the subscales of emotional and social functioning and symptoms. In all cases the direction of change was positive, while Cohen's d calculated showed that the effect of the intervention for these parameters ranged from intermediate to large.Conclusion:Changes on the above anthropometric, fitness and quality of life measures suggest that the intervention was of value to the participating women recovering from breast cancer. Results also advocate collaborative efforts across countries to further research. (shrink)

Graphical AbstractTo metastasize, cancer cells must be able to complete cell division in environments very different from their tissue of origin. We suggest that mitotic cell rounding, aided by several actin-regulatory oncogenes, may facilitate this process in a robust, context-independent manner.

Adherens (AJ) and tight junctions (TJ) maintain cell‐cell adhesions and cellular polarity in normal tissues. Afadin, a multi‐domain scaffold protein, is commonly found in both adherens and tight junctions, where it plays both structural and signal‐modulating roles. Afadin is a complex modulator of cellular processes implicated in cancer progression, including signal transduction, migration, invasion, and apoptosis. In keeping with the complexities associated with the roles of adherens and tight junctions in cancer, afadin exhibits both tumor suppressive and pro‐metastatic functions. In (...) this review, we will explore the dichotomous roles that afadin plays during cancer progression. (shrink)

Perhaps no work since John Rawls’ A Theory of Justice has attracted as much recent attention as Robert Nozick’s case for a minimal state—an ingeniously argued critique, not only of antinomian individualism, but also of liberal and socialist contractualism. It might be added that the book is no solace either to more conservative political theorists, who lament state incursion into private life, but whose political structures exhibit either actual or potential constriction of human life. Nozick’s book is both a searching (...) examination of the limitations of utilitarian consequentialism and the redistributivism of Rawls. His essential theme is that "a minimal state limited to the narrow functions of protection against force, theft, fraud, enforcement of contracts etc., is justified; that any more extensive state will violate persons’ rights not to be forced to do certain things, and is unjustified; and that the minimal state is inspiring as well as right." It is also Nozick’s contention that the coercive power of the state should not be used paternalistically to prohibit activities to people for their own protection, or to force some citizens to aid others. The last part of the book is a framework for Nozick’s utopia, and it is in this section that an essentially theoretical approach, amplified by little political or sociological data, exhibits its defects. One suspects that almost all states started with simplistic hopes for minimal coercive activity, and succumbed almost inevitably to the metastasis of function as socio-political life grew in size and complexity. Night watchmen become more than night watchmen when more than watching is needed. Moreover, Nozick’s utopia would seem to necessitate, at least by implication, coercive redistributivism and some kind of compensatory or levelling taxation process. This reviewer is not sure that he understands precisely what Nozick considers correct property theory in a state of nature. The author modestly asserts the tentative, incomplete, and conjectural nature of his work. But the taxed and manipulated citizen who grows in sympathy for the sentiments of Proudhon’s famous litany should welcome this highly literate and well argued case.—R.P.M. (shrink)