PDGF signaling is required for epicardial function and blood vessel formation in regenerating zebrafish hearts.

A zebrafish heart can fully regenerate after amputation of up to 20% of its ventricle. During this process, newly formed coronary blood vessels revascularize the regenerating tissue. The formation of coronary blood vessels during zebrafish heart regeneration likely recapitulates embryonic coronary vessel development, which involves the activation and proliferation of the epicardium, followed by an epithelial-to-mesenchymal transition.

Platelet-derived growth factor receptor beta is critical for zebrafish intersegmental vessel formation.

Background: Platelet-derived growth factor receptor beta (PDGFRbeta) is a tyrosine kinase receptor known to affect vascular development. The zebrafish is an excellent model to study specific regulators of vascular development, yet the role of PDGF signaling has not been determined in early zebrafish embryos. Furthermore, vascular mural cells, in which PDGFRbeta functions cell autonomously in other systems, have not been identified in zebrafish embryos younger than 72 hours post fertilization.

Interleukin-6 in bone metastasis and cancer progression.

The bone and bone marrow are among the most frequent sites of cancer metastasis. It is estimated that 350,000 patients die with bone metastases annually in the United States. The ability of tumor cells to colonize the bone marrow and invade the bone is the result of close interactions between tumor cells and the bone marrow microenvironment.

Treatment of cyclic vomiting syndrome with co-enzyme Q10 and amitriptyline, a retrospective study.

Background: Cyclic vomiting syndrome (CVS), which is defined by recurrent stereotypical episodes of nausea and vomiting, is a relatively-common disabling condition that is associated with migraine headache and mitochondrial dysfunction. Co-enzyme Q10 (Co-Q) is a nutritional supplement that has demonstrated efficacy in pediatric and adult migraine. It is increasingly used in CVS despite the complete lack of studies to demonstrate its value in treatment

Methods: Using an Internet-based survey filled out by subjects with CVS or their parents, the efficacy, tolerability and subject satisfaction in CVS prophylaxis were queried.

GLI1 is a central mediator of EWS/FLI1 signaling in Ewing tumors.

The Ewing Sarcoma Family Tumors (ESFT) consist of the classical pathologic entities of Ewing Sarcoma and peripheral Primitive Neuroectodermal Tumor. Occurring largely in the childhood through young adult years, these tumors have an unsurpassed propensity for metastasis and have no defined cell of origin. The biology of these aggressive malignancies centers around EWS/FLI1 and related EWS/ETS chimeric transcription factors, which are largely limited to this tumor class.

Transglutaminase 2 regulates the GTPase-activating activity of Bcr.

Transglutaminase 2 (TG2) is a multifunctional protein that has been implicated in numerous pathologies including that of neurodegeneration and celiac disease, but the molecular interactions that mediate its diverse activities are largely unknown. Bcr and the closely related Abr negatively regulate the small G-protein Rac: loss of their combined function in vivo results in increased reactivity of innate immune cells. Bcr and Abr are GTPase-activating proteins that catalyze the hydrolysis of the GTP bound to Rac.

Novel cancer vaccine based on genes of Salmonella pathogenicity island 2.

Although tumors express potentially immunogenic tumor-associated antigens (TAAs), cancer vaccines often fail because of inadequate antigen delivery and/or insufficient activation of innate immunity. Engineering nonpathogenic bacterial vectors to deliver TAAs of choice may provide an efficient way of presenting TAAs in an immunogenic form. In this study, we used genes of Salmonella pathogenicity island 2 (SPI2) to construct a novel cancer vaccine in which a TAA, survivin, was fused to SseF effector protein and placed under control of SsrB, the central regulator of SPI2 gene expression.

Valpha24-invariant NKT cells mediate antitumor activity via killing of tumor-associated macrophages.

Tumor infiltration with Valpha24-invariant NKT cells (NKTs) associates with favorable outcome in neuroblastoma and other cancers. Although NKTs can be directly cytotoxic against CD1d+ cells, the majority of human tumors are CD1d-. Therefore, the role of NKTs in cancer remains largely unknown.

Are pediatric and adult-onset cyclic vomiting syndrome (CVS) biologically different conditions? Relationship of adult-onset CVS with the migraine and pediatric CVS-associated common mtDNA polymorphisms 16519T and 3010A.

Pediatric cyclic vomiting syndrome (CVS) is associated with a high prevalence of co-morbid migraine and other functional disorders, and with two adult migraine-associated mitochondrial DNA (mtDNA) polymorphisms: 16519T and 3010A. These potential associations have not been studied in adult CVS. The objective of this study is to determine the prevalence of 16519T and 3010A mtDNA polymorphisms and other functional disorders in adult CVS patients.

Plasminogen activator inhibitor-1 protects endothelial cells from FasL-mediated apoptosis.

Plasminogen activator inhibitor-1 (PAI-1) paradoxically enhances tumor progression and angiogenesis; however, the mechanism supporting this role is not known. Here we provide evidence that PAI-1 is essential to protect endothelial cells (ECs) from FasL-mediated apoptosis. In the absence of host-derived PAI-1, human neuroblastoma cells implanted in PAI-1-deficient mice form smaller and poorly vascularized tumors containing an increased number of apoptotic ECs.

Identification of galectin-3-binding protein as a factor secreted by tumor cells that stimulates interleukin-6 expression in the bone marrow stroma.

We have previously demonstrated that neuroblastoma cells increase the expression of interleukin-6 by bone marrow stromal cells and that stimulation does not require cell-cell contact. In this study we report the purification and identification of a protein secreted by neuroblastoma cells that stimulates interleukin-6 production by stromal cells. Using a series of chromatographic purification steps including heparin-affinity, ion exchange, and molecular sieve chromatography followed by trypsin digestion and liquid chromatography tandem mass spectrometry, we identified in serum-free conditioned medium of neuroblastoma cells several secreted peptides including galectin-3-binding protein, also known as 90-kDa Mac-2-binding protein.

Symptoms of somatization as a rapid screening tool for mitochondrial dysfunction in depression.

Aims: Somatic symptomatology is common in depression, and is often attributed to the Freudian-inspired concept of "somatization". While the same somatic symptoms and depression are common in mitochondrial disease, in cases with concurrent mood symptoms the diagnosis of a mitochondrial disorder and related therapy are typically delayed for many years. A short screening tool that can identify patients with depression at high risk for having underlying mitochondrial dysfunction is presented.

Reflex sympathetic dystrophy: complex regional pain syndrome type I in children with mitochondrial disease and maternal inheritance.

Objective: Complex regional pain syndrome type I (CRPS-I), previously known as reflex sympathetic dystrophy (RSD), is an idiopathic condition characterised by localised, abnormally intense and prolonged pain, allodynia and autonomic nervous system changes (ie, swelling, skin colour and temperature changes and altered perspiration) that usually appear following a "noxious" trigger such as trauma or surgery. The objective of this report is to demonstrate that children with CRPS-I can have additional dysautonomic conditions secondary to an underlying maternally inherited mitochondrial disease, an association not previously published.

Methods: Medical records of about 500 patients seen by one paediatric metabolic geneticist were reviewed to identify children meeting established CRPS diagnostic criteria.

Development of lentiviral vectors with regulated respiratory epithelial expression in vivo.

Development of gene transfer vectors with regulated, lung-specific expression will be a useful tool for studying lung biology and developing gene therapies. In this study we constructed a series of lentiviral vectors with regulatory elements predicted to produce lung-specific transgene expression: the surfactant protein C promoter (SPC) for alveolar epithelial type II cell (AECII) expression, the Clara cell 10-kD protein (CC10) for Clara cell expression in the airway, and the Jaagskiete sheep retrovirus (JSRV) promoter for expression in both cell types. Transgene expression from the SPC and CC10 vectors was restricted to AECII and Clara cell lines, respectively, while expression from the JSRV vector was observed in multiple respiratory and nonrespiratory cell types.

The cyclin-dependent kinase inhibitors p15INK4B and p21CIP1 are critical regulators of fibrillar collagen-induced tumor cell cycle arrest.

The extracellular matrix is a crucial component in determining cell fate. Fibrillar collagen in its native form inhibits cell proliferation, whereas in its monomeric form it stimulates proliferation. The observation of elevated levels of p27(KIP1) in cells plated in the presence of fibrillar collagen has led to the assumption that this kinase inhibitor was responsible for cell cycle arrest on fibrillar collagen.

Mechanisms of invasion and metastasis in human neuroblastoma.

Neuroblastoma is the second most common solid tumor in children that is metastatic in 70% of patients at the time of diagnosis. The ability of neuroblastoma cells to colonize distant organs like the bone marrow and the bone is the result of close interactions between tumor cells and the microenvironment. Significant progress has been recently made in our understanding of the mechanisms that promote the colonization and invasion of the bone by neuroblastoma cells and these mechanisms are reviewed in this article.

A patient with arginase deficiency and episodic hyperammonemia successfully treated with menses cessation.

Arginase deficiency is an urea cycle disorder that generally presents with mental retardation and spasticity, yet uncommonly with episodes of hyperammonemia. A female adolescent with arginase deficiency developed hyperammonemic episodes temporally related to her menstrual cycle, which ceased upon adequate treatment with depot medroxy progesterone acetate. A similar case was previously reported.

Multimodal imaging analysis of tumor progression and bone resorption in a murine cancer model.

Objective: This study evaluates the use of multimodal imaging to qualitatively and quantitatively measure tumor progression and bone resorption in a xenotransplanted tumor model of human neuroblastoma.

Methods: Human neuroblastoma cells expressing a luciferase reporter gene were injected into the femur of nu/nu mice. Tumor progression with and without zoledronic acid treatment was monitored using radiographs, D-luciferin-induced luminescence, micro-computer tomography (CT) and micro-magnetic resonance imaging (MRI).

Modifying the soil to affect the seed: role of stromal-derived matrix metalloproteinases in cancer progression.

In the 1980's, as the importance of matrix metalloproteinases (MMPs) in cancer progression was discovered, it was recognized that in most tumors these proteases were abundantly and sometimes exclusively expressed not by tumor cells, but by normal host-derived cells like fibroblasts, vascular endothelial cells, myofibroblasts, pericytes or inflammatory cells that contribute to the tumor microenvironment. Later experiments in mice deficient in specific MMPs revealed that host-derived MMPs play a critical role not only in tumor cell invasion, but also in carcinogenesis, angiogenesis, vasculogenesis and metastasis. Tumor cells secrete many factors, cytokines and chemokines that directly or indirectly increase the expression of these MMPs in the tumor microenvironment where they exert extracellular matrix (ECM) degrading and sheddase activities.

Discoidin domain receptor 2 mediates tumor cell cycle arrest induced by fibrillar collagen.

During malignant invasion tumor cells establish contact with extracellular matrix proteins, including fibrillar collagen. In addition to providing a physical barrier against invasion, fibrillar collagen also restricts cell proliferation. It has been assumed that the growth regulatory activity of fibrillar collagen is the result of an indirect restrictive effect on cell spreading and cytoskeletal organization.

Mitochondrial inheritance in depression, dysmotility and migraine?

Background: Several studies have reported a high degree of association of the common conditions of depression, bowel dysmotility and migraine. Mitochondrial dysfunction and mitochondrial DNA (mtDNA) sequence variants have been linked individually to each of these three conditions, providing a plausible hypothesis for the reported association. If this hypothesis is correct, the matrilineal relatives (who all share essentially the same mtDNA sequence) of patients with mitochondrial disease secondary to inherited mtDNA mutations would be expected to have an elevated prevalence of each of these three conditions.

A high predisposition to depression and anxiety in mothers and other matrilineal relatives of children with presumed maternally inherited mitochondrial disorders.

Although mothers of chronically ill children are generally prone to depression and anxiety, clinical observation suggests that these symptoms are relatively increased in mothers of children with maternally inherited mitochondrial disorders (MIMD). In this study, the Beck Depression Inventory II (BDI), the Beck Anxiety Inventory (BAI), and a non-standardized mental health questionnaire were administered to 15 mothers of children with MIMD and 17 mothers of children with autosomal recessive metabolic disorders (ARMD) followed in one clinic. One half of the children in both groups suffer from mental retardation and/or > or = 2 hospitalizations/year related to their genetic disorder, and were labeled as severely affected.

A novel function for the protein tyrosine phosphatase Shp2 during lung branching morphogenesis.

Branching morphogenesis of many organs, including the embryonic lung, is a dynamic process in which growth factor mediated tyrosine kinase receptor activation is required, but must be tightly regulated to direct ramifications of the terminal branches. However, the specific regulators that modulate growth factor signaling downstream of the tyrosine kinase receptor remain to be determined. Herein, we demonstrate for the first time an important function for the intracellular protein tyrosine phosphatase Shp2 in directing embryonic lung epithelial morphogenesis.

The contribution of bone marrow-derived cells to the tumor vasculature in neuroblastoma is matrix metalloproteinase-9 dependent.

The contribution of the tumor stroma to cancer progression has been increasingly recognized. We had previously shown that in human neuroblastoma tumors orthotopically implanted in immunodeficient mice, stromal-derived matrix metalloproteinase-9 (MMP-9) contributes to the formation of a mature vasculature by promoting pericyte recruitment along endothelial cells. Here we show that MMP-9 is predominantly expressed by bone marrow-derived CD45-positive leukocytes.