Balancing the benefits and harms of thyroid cancer surveillance in survivors of Childhood, adolescent and young adult cancer: Recommendations from the international Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium.

Radiation exposure to the thyroid gland during treatment of childhood, adolescent and young adult cancer (CAYAC) may cause differentiated thyroid cancer (DTC). Surveillance recommendations for DTC vary considerably, causing uncertainty about optimum screening practices. The International Late Effects of Childhood Cancer Guideline Harmonization Group, in collaboration with the PanCareSurFup Consortium, developed consensus recommendations for thyroid cancer surveillance in CAYAC survivors. These recommendations were developed by an international multidisciplinary panel that included 33 experts in relevant medical specialties who used a consistent and transparent process. Recommendations were graded according to the strength of underlying evidence and potential benefit gained by early detection and appropriate management. Of the two available surveillance strategies, thyroid ultrasound and neck palpation, neither was shown to be superior. Consequently, a decision aid was formulated to guide the health care provider in counseling the survivor. The recommendations highlight the need for shared decision making regarding whether to undergo surveillance for DTC and in the choice of surveillance modality.

A family of rhomboid-like genes: Drosophila rhomboid-1 and roughoid/rhomboid-3 cooperate to activate EGF receptor signaling.

As in mammals, the Drosophila EGF receptor controls many aspects of growth and development. The rate limiting component of Drosophila Egfr signaling is Rhomboid, a seven transmembrane domain protein, whose expression prefigures Egfr signaling. Little is known about the molecular mechanism of Rhomboid function but genetic evidence suggests that it controls the activation of the ligand Spitz, a TGFalpha-like factor. Spitz/Egfr signaling regulates cell determination in the eye but here there is no apparent function for Rhomboid, an observation that casts doubt on this prevailing model of Rhomboid function. We describe our identification of six new rhomboid-like genes in Drosophila, and a large family of related genes present in organisms as diverse as bacteria and mammals; a human rhomboid homolog has also recently been described. Drosophila rhomboid-3 corresponds to the roughoid mutation; it cooperates with rhomboid-1 to control Egfr signaling in the eye, thereby solving the puzzle of the apparent lack of Rhomboid-1 function there. Rhomboid-1 and Roughoid/Rhomboid-3 act in the signal-emitting not signal-receiving cell, supporting the idea that Spitz activation is regulated by Rhomboid-like molecules.

An autoregulatory cascade of EGF receptor signaling patterns the Drosophila egg.

Intercellular signaling through the EGF receptor (EGFR) patterns the Drosophila egg. The TGF alpha-like ligand Gurken signals from the oocyte to the receptor in the overlying somatic follicle cells. We show that in the dorsal follicle cells this initial paracrine signaling event triggers an autocrine amplification by two other EGFR ligands, Spitz and Vein. Spitz only becomes an effective ligand in the presence of the multitransmembrane domain protein Rhomboid. Consequent high-level EGFR activation leads to localized expression of the diffusible inhibitor Argos, which alters the profile of signaling. This sequential activation, amplification, and local inhibition of the EGFR forms an autoregulatory cascade that leads to the splitting of an initial single peak of signaling into two, thereby patterning the egg.

Multiple functions of the EGF receptor in Drosophila eye development.

BACKGROUND: During animal development, cells need to make spatially and temporally regulated fate decisions. These decisions are largely controlled by intercellular signalling, often through receptor tyrosine kinases. One of these, the epidermal growth factor receptor (EGFR), regulates multiple cell fate decisions. Its importance in the recruitment of photoreceptors in the developing fly eye, a useful model for neural development, has already been reported. Other EGFR functions in the eye have not been characterised. RESULTS: We have examined the consequences of removing or activating the EGFR at different stages of eye development. The earliest stages of assembly occurred normally within EGFR- clones--the morphogenetic furrow was unimpeded and the R8 photoreceptor was specified. All subsequent photoreceptor recruitment was blocked. EGFR- clones had a characteristic shape indicating that they had undergone substantial cell death posterior to the furrow, where the differentiation program is normally activated; consistent with this, excess apoptosis was detected. We found that the receptor also regulates cell proliferation in the disc, has an early function at the disc margin (where the morphogenetic furrow initiates) and contributes to the regulation of spacing of the R8 precursors. Finally, we found that activation of the receptor is sufficient to trigger non-R8 photoreceptor development, even in cells in front of the furrow or in the absence of the proneural gene atonal. CONCLUSION: At least five distinct functions of EGFR signalling need to be integrated during fly eye development. These include roles in cell proliferation, survival and differentiation.

In vivo analysis of Argos structure-function. Sequence requirements for inhibition of the Drosophila epidermal growth factor receptor.

The Drosophila Argos protein is the only known extracellular inhibitor of the epidermal growth factor receptor (EGFR). It is structurally related to the activating ligands, in that it is a secreted protein with a single epidermal growth factor (EGF) domain. To understand the mechanism of Argos inhibition, we have investigated which regions of the protein are essential. A series of deletions were made and tested in vivo; furthermore, by analyzing chimeric proteins between Argos and the activating ligand, Spitz (a transforming growth factor-alpha-like factor), we have examined what makes one inhibitory and the other activating. Our results reveal that Argos has structural requirements that differ from all known EGFR activating ligands; domains flanking the EGF domain are essential for its function. We have also defined the important regions of the atypical Argos EGF domain. The extended B-loop is necessary, whereas the C-loop can be replaced with the equivalent Spitz region without substantially affecting Argos function. Comparison of the argos genes from Drosophila melanogaster and the housefly, Musca domestica, supports our structure-function analysis. These studies are a prerequisite for understanding how Argos inhibits the Drosophila EGFR and provide a basis for designing mammalian EGFR inhibitors.

Control of EGF receptor activation in Drosophila.

Diverse biological and developmental functions are mediated by signalling through the epidermal growth factor (EGF) receptor. In flies, many different mechanisms are used to control and restrict EGF-R signalling, including ligand processing, ligand variety (an inhibitor as well as activators), transcription and perhaps subcellular localization of the receptor. Since the components of EGF-R signalling have been well conserved, understanding these different modes of receptor regulation in flies should lead to general insights into the strategies of receptor activation.

Condensation of plasmid DNA with polylysine improves liposome-mediated gene transfer into established and primary muscle cells.

Cationic liposomes provide a means to introduce genes into cells both ex vivo and in vivo. In the past few years their use has been described in several tissues, e.g. lungs, liver, endothelium, brain. In this study we evaluated a commercially available poly-cationic liposome formulation in delivering a reporter gene into cultured myogenic cell lines from mouse and rat, and primary fetal human myoblasts. We also examined the effect of serum on liposome-mediated transfection and designed a new procedure to enhance transfection efficiency, based on the pre-condensation of plasmid DNA with polylysine. Polylysine pre-condensation was particularly effective when transfecting the cells in the presence of serum, a finding that could be significant for in vivo transfections.