In Vivo Evolution of Tumor-Derived Endothelial Cells

The growth of a malignant tumor beyond a certain, limited size requires that it first develop an independent blood supply. In addition to providing metabolic support, this neovasculature also allows tumor cells to access the systemic circulation, thus facilitating metastatic dissemination. The neovasculature may originate either from normal blood vessels in close physical proximity to the tumor and/or from the recruitment of bone marrow-derived endothelial cell (EC) precursors. Recent studies have shown that human tumor vasculature ECs may also arise directly from tumor cells themselves and that the two populations have highly similar or identical karyotypes. We now show that, during the course of serial in vivo passage, these tumor-derived ECs (TDECs) progressively acquire more pronounced EC-like properties. These include higher-level expression of EC-specific genes and proteins, a greater capacity for EC-like behavior in vitro, and a markedly enhanced propensity to incorporate into the tumor vasculature. In addition, both vessel density and size are significantly increased in neoplasms derived from mixtures of tumor cells and serially passaged TDECs. A comparison of early- and late-passage TDECs using whole-genome single nucleotide polymorphism profiling showed the latter cells to have apparently evolved by a process of clonal expansion of a population with a distinct pattern of interstitial chromosomal gains and losses affecting a relatively small number of genes. The majority of these have established roles in vascular development, tumor suppression or epithelial-mesenchymal transition. These studies provide direct evidence that TDECs have a strong evolutionary capacity as a result of their inherent genomic instability. Consequently such cells might be capable of escaping anti-angiogenic cancer therapies by generating resistant populations

Focus on Function – a randomized controlled trial comparing two rehabilitation interventions for young children with cerebral palsy

<p>Abstract</p> <p>Background</p> <p>Children with cerebral palsy receive a variety of long-term physical and occupational therapy interventions to facilitate development and to enhance functional independence in movement, self-care, play, school activities and leisure. Considerable human and financial resources are directed at the "intervention" of the problems of cerebral palsy, although the available evidence supporting current interventions is inconclusive. A considerable degree of uncertainty remains about the appropriate therapeutic approaches to manage the habilitation of children with cerebral palsy. The primary objective of this project is to conduct a multi-site randomized clinical trial to evaluate the efficacy of a task/context-focused approach compared to a child-focused remediation approach in improving performance of functional tasks and mobility, increasing participation in everyday activities, and improving quality of life in children 12 months to 5 years of age who have cerebral palsy.</p> <p>Method/Design</p> <p>A multi-centred randomized controlled trial research design will be used. Children will be recruited from a representative sample of children attending publicly-funded regional children's rehabilitation centers serving children with disabilities in Ontario and Alberta in Canada. Target sample size is 220 children with cerebral palsy aged 12 months to 5 years at recruitment date. Therapists are randomly assigned to deliver either a context-focused approach or a child-focused approach. Children follow their therapist into their treatment arm. Outcomes will be evaluated at baseline, after 6 months of treatment and at a 3-month follow-up period. Outcomes represent the components of the International Classification of Functioning, Disability and Health, including body function and structure (range of motion), activities (performance of functional tasks, motor function), participation (involvement in formal and informal activities), and environment (parent perceptions of care, parental empowerment).</p> <p>Discussion</p> <p>This paper presents the background information, design and protocol for a randomized controlled trial comparing a task/context-focused approach to a child-focused remediation approach in improving functional outcomes for young children with cerebral palsy.</p> <p>Trial registration</p> <p>[clinical trial registration #: NCT00469872]</p

The role of DNA microarrays in Toxoplasma gondii research, the causative agent of ocular toxoplasmosis

Ocular toxoplasmosis, which is caused by the protozoan parasite Toxoplasma gondii, is the leading cause of retinochoroiditis. Toxoplasma is an obligate intracellular pathogen that replicates within a parasitophorous vacuole. Infections are initiated by digestion of parasites deposited in cat feces or in undercooked meat. Parasites then disseminate to target tissues that include the retina where they then develop into long-lived asymptomatic tissue cysts. Occasionally, cysts reactivate and growth of newly emerged parasites must be controlled by the host’s immune system or disease will occur. The mechanisms by which Toxoplasma grows within its host cell, encysts, and interacts with the host’s immune system are important questions. Here, we will discuss how the use of DNA microarrays in transcriptional profiling, genotyping, and epigenetic experiments has impacted our understanding of these processes. Finally, we will discuss how these advances relate to ocular toxoplasmosis and how future research on ocular toxoplasmosis can benefit from DNA microarrays

Pin1 and neurodegeneration: a new player for prion disorders?

Pin1 is a peptidyl-prolyl isomerase that catalyzes the cis/trans conversion of phosphorylated proteins at serine or threonine residues which precede a proline. The peptidyl-prolyl isomerization induces a conformational change of the proteins involved in cell signaling process. Pin1 dysregulation has been associated with some neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease. Proline-directed phosphorylation is a common regulator of these pathologies and a recent work showed that it is also involved in prion disorders. In fact, prion protein phosphorylation at the Ser-43-Pro motif induces prion protein conversion into a disease-associated form. Furthermore, phosphorylation at Ser-43-Pro has been observed to increase in the cerebral spinal fluid of sporadic Creutzfeldt-Jakob Disease patients. These findings provide new insights into the pathogenesis of prion disorders, suggesting Pin1 as a potential new player in the disease. In this paper, we review the mechanisms underlying Pin1 involvement in the aforementioned neurodegenerative pathologies focusing on the potential role of Pin1 in prion disorders