A case study on the design of a modular surgical instrument for removing metastases using engineering design tools

Metastatic cancer is a form of cancer stemming from a primary tumour that propagates to different organs and/or to different sites within the same organ. Studies have indicated that the chances of survival improve upon surgical removal of metastases. The overall goal of this research was to develop a modular surgical instrument that would be easy to use and manipulate and hence facilitate resection of metastases. This research forms part of a final year project carried out by a mechanical engineering student in the four-year bachelors course at the University of Malta. The basic design cycle taught in the third year of the course was employed to systematically generate the design of a novel modular surgical instrument, This was complemented by a number of hospital visits and various meetings with professionals and other stakeholders relevant to the field. Through this case-study, this paper shows how, even at a bachelors level project, the application of design tools and the continuous communication with typical end-users can lead to the development of a high-value added product which can be potentially commercialised. Other benefits of joint supervision are also discussed.peer-reviewe

Interconnected feedback loops among ESRP1, HAS2, and CD44 regulate epithelial-mesenchymal plasticity in cancer

Aberrant activation of epithelial-mesenchymal transition (EMT) in carcinoma cells contributes to increased migration and invasion, metastasis, drug resistance, and tumor-initiating capacity. EMT is not always a binary process; rather, cells may exhibit a hybrid epithelial/mesenchymal (E/M) phenotype. ZEB1—a key transcription factor driving EMT—can both induce and maintain a mesenchymal phenotype. Recent studies have identified two novel autocrine feedback loops utilizing epithelial splicing regulatory protein 1 (ESRP1), hyaluronic acid synthase 2 (HAS2), and CD44 which maintain high levels of ZEB1. However, how the crosstalk between these feedback loops alters the dynamics of epithelial-hybrid-mesenchymal transition remains elusive. Here, using an integrated theoretical-experimental framework, we identify that these feedback loops can enable cells to stably maintain a hybrid E/M phenotype. Moreover, computational analysis identifies the regulation of ESRP1 as a crucial node, a prediction that is validated by experiments showing that knockdown of ESRP1 in stable hybrid E/M H1975 cells drives EMT. Finally, in multiple breast cancer datasets, high levels of ESRP1, ESRP1/HAS2, and ESRP1/ZEB1 correlate with poor prognosis, supporting the relevance of ZEB1/ESRP1 and ZEB1/HAS2 axes in tumor progression. Together, our results unravel how these interconnected feedback loops act in concert to regulate ZEB1 levels and to drive the dynamics of epithelial-hybrid-mesenchymal transition