Fifteen years of shared care for paediatric oncology, haematology and palliative patients across Queensland: The role of Regional Case Managers.

OBJECTIVE: A shared care model was implemented in 2006 in Queensland to facilitate paediatric oncology, haematology and palliative care patients receiving care as close to home as possible. Following initial diagnosis, care planning and treatment at the tertiary children's hospital, appropriate local care was coordinated by Regional Case Managers (RCMs) established at each of 10 Shared Care Units (SCUs). This enabled safe and quality regional care supported by a statewide network providing clinical governance and education. This paper examines learnings from 15 years of this shared care. SETTING: Ten hospitals throughout Queensland facilitated a statewide model of shared care for paediatric oncology, haematology and palliative care patients, supported by a tertiary hub in Brisbane. PARTICIPANTS: Regional Case Managers in Shared Care Units and their supporting staff. DESIGN: Staff from SCUs were surveyed and focus group interviews conducted. RESULTS: The paper reviews the attributes, knowledge and experience required for RCMs. Standards of care were supported through education workshops, clinical placements, chemotherapy credentialing, guidelines and standards. RCMs facilitated communication and information sharing with the tertiary centre, advocated for their cohort of patients locally and streamlined and supported the family's experience of care. CONCLUSION: The RCM role provided invaluable clinical leadership for the care of paediatric oncology, haematology and palliative patients across Queensland. As new treatments evolve, the expertise and coordination provided by the RCMs will be even more critical. Achieving high-quality shared care outcomes is underpinned by the RCMs drive to achieve statewide safety and support for this cohort of children.

Glypicans shield the Wnt lipid moiety to enable signalling at a distance.

A relatively small number of proteins have been suggested to act as morphogens-signalling molecules that spread within tissues to organize tissue repair and the specification of cell fate during development. Among them are Wnt proteins, which carry a palmitoleate moiety that is essential for signalling activity1-3. How a hydrophobic lipoprotein can spread in the aqueous extracellular space is unknown. Several mechanisms, such as those involving lipoprotein particles, exosomes or a specific chaperone, have been proposed to overcome this so-called Wnt solubility problem4-6. Here we provide evidence against these models and show that the Wnt lipid is shielded by the core domain of a subclass of glypicans defined by the Dally-like protein (Dlp). Structural analysis shows that, in the presence of palmitoleoylated peptides, these glypicans change conformation to create a hydrophobic space. Thus, glypicans of the Dlp family protect the lipid of Wnt proteins from the aqueous environment and serve as a reservoir from which Wnt proteins can be handed over to signalling receptors.

Godzilla-dependent transcytosis promotes Wingless signalling in Drosophila wing imaginal discs.

The apical and basolateral membranes of epithelia are insulated from each other, preventing the transfer of extracellular proteins from one side to the other. Thus, a signalling protein produced apically is not expected to reach basolateral receptors. Evidence suggests that Wingless, the main Drosophila Wnt, is secreted apically in the embryonic epidermis. However, in the wing imaginal disc epithelium, Wingless is mostly seen on the basolateral membrane where it spreads from secreting to receiving cells. Here we examine the apico-basal movement of Wingless in Wingless-producing cells of wing imaginal discs. We find that it is presented first on the apical surface before making its way to the basolateral surface, where it is released and allowed to interact with signalling receptors. We show that Wingless transcytosis involves dynamin-dependent endocytosis from the apical surface. Subsequent trafficking from early apical endosomes to the basolateral surface requires Godzilla, a member of the RNF family of membrane-anchored E3 ubiquitin ligases. Without such transport, Wingless signalling is strongly reduced in this tissue.

Drosophila S2 cells secrete wingless on exosome-like vesicles but the wingless gradient forms independently of exosomes.

Wingless acts as a morphogen in Drosophila wing discs, where it specifies cell fates and controls growth several cell diameters away from its site of expression. Thus, despite being acylated and membrane associated, Wingless spreads in the extracellular space. Recent studies have focussed on identifying the route that Wingless follows in the secretory pathway and determining how it is packaged for release. We have found that, in medium conditioned by Wingless-expressing Drosophila S2 cells, Wingless is present on exosome-like vesicles and that this fraction activates signal transduction. Proteomic analysis shows that Wingless-containing exosome-like structures contain many Drosophila proteins that are homologous to mammalian exosome proteins. In addition, Evi, a multipass transmembrane protein, is also present on exosome-like vesicles. Using these exosome markers and a cell-based RNAi assay, we found that the small GTPase Rab11 contributes significantly to exosome production. This finding allows us to conclude from in vivo Rab11 knockdown experiments, that exosomes are unlikely to contribute to Wingless secretion and gradient formation in wing discs. Consistent with this conclusion, extracellularly tagged Evi expressed from a Bacterial Artificial Chromosome is not released from imaginal disc Wingless-expressing cells.

Parcas, a regulator of non-receptor tyrosine kinase signaling, acts during anterior-posterior patterning and somatic muscle development in Drosophila melanogaster.

We have isolated parcas (pcs) in a screen to identify novel regulators of muscle morphogenesis. Pcs is expressed in the ovary and oocyte during oogenesis and again in the embryo, specifically in the developing mesoderm, throughout muscle development. pcs is first required in the ovary during oogenesis for patterning and segmentation of the early Drosophila embryo due primarily to its role in the regulation of Oskar (Osk) levels. In addition to the general patterning defects observed in embryos lacking maternal contribution of pcs, these embryos show defects in Wingless (Wg) expression, causing losses of Wg-dependent cell types within the affected segment. pcs activity is required again later during embryogenesis in the developing mesoderm for muscle development. Loss and gain of function studies demonstrate that pcs is necessary at distinct times for muscle specification and morphogenesis. Pcs is predicted to be a novel regulator of non-receptor tyrosine kinase (NRTK) signaling. We have identified one target of Pcs regulation, the Drosophila Tec kinase Btk29A. While Btk29A appears to be regulated by Pcs during its early role in patterning and segmentation, it does not appear to be a major target of Pcs regulation during muscle development. We propose that Pcs fulfils its distinct roles during development by the regulation of multiple NRTKs.

Delivery of wingless to the ventral mesoderm by the developing central nervous system ensures proper patterning of individual slouch-positive muscle progenitors.

During the development of any organism, care must be given to properly pattern gene expression in temporally and spatially regulated manners. This process becomes more complex when the signals that regulate a target tissue are produced in an adjacent tissue and must travel to the target tissue to affect gene expression. We have used the developing somatic mesoderm in Drosophila as a system in which to examine this problem. Our investigation uncovered a novel mechanism by which Wingless (Wg) can travel from its source in the ectoderm to regulate the expression of the somatic muscle founder identity gene, slouch, in the ventral mesoderm. Delivery of Wg to the mesoderm by the developing Central Nervous System (CNS) exploits the stereotypic formation of this tissue to provide high Wg levels to Slouch founder cell cluster II in a temporally specific manner. Coordinated development of these tissues provides a reliable mechanism for delivering high Wg levels to a subset of mesodermal cells. It also provides a means for one signaling pathway to be used reiteratively throughout development to impart unique positional and character information within a target field.