The muscular dystrophy protein dysferlin plays a key role in the calcium-activated vesicle fusion of membrane repair. This study establishes calpains as upstream regulators of dysferlin in the membrane repair cascade and further demonstrates that similar C-terminal modules are enzymatically released from other ferlin family members.
Circulating tumour cell (CTC) enumeration and profiling has been established as a valuable clinical tool in many solid malignancies. A key challenge in CTC research is the limited number of cells available for study. Ex vivo CTC culture permits expansion of these rare cell populations for detailed characterisation, functional assays including drug sensitivity testing, and investigation of the pathobiology of metastases. We report for the first time the establishment and characterisation of two continuous CTC lines from patients with gastroesophageal cancer. The two cell lines (designated UWG01CTC and UWG02CTC) demonstrated rapid tumorigenic growth in immunodeficient mice and exhibit distinct genotypic and phenotypic profiles which are consistent with the tumours of origin. UWG02CTC exhibits an epcAM+, cytokeratin+, CD44+ phenotype, while UWG01CTC, which was derived from a patient with metastatic neuroendocrine cancer, displays an EpCAM−, weak cytokeratin phenotype, with strong expression of neuroendocrine markers. Further, the two cell lines show distinct differences in drug and radiation sensitivity which match differential cancer-associated gene expression pathways. This is strong evidence implicating EpCAM negative CTCs in metastasis. These novel, well characterised, long-term ctc cell lines from gastroesophageal cancer will facilitate ongoing research into metastasis and the discovery of therapeutic targets.
Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, with surgical resection of the tumor in conjunction with systemic chemotherapy the only potential curative therapy. Up to 80% of diagnosed cases are deemed unresectable, prompting the need for alternative treatment approaches. Herein, coaxial polymeric fibers loaded with two chemotherapeutic agents, gemcitabine (Gem) and paclitaxel (Ptx), are fabricated to investigate the effect of local drug delivery on PDAC cell growth in vitro and in vivo. A wet-spinning fabrication method to form a coaxial fiber with a polycaprolactone shell and alginate core loaded with Ptx and Gem, respectively, is used. In vitro, Gem+Ptx fibers display significant cytotoxicity as well as radiosensitizing properties toward PDAC cell lines greater than the equivalent free drugs, which may be attributed to a radiosensitizing effect of the polymers. In vivo studies assessing Gem+Ptx fiber efficacy found that Gem+Ptx fibers reduce tumor volume in a xenograft mouse model of PDAC. Importantly, no difference in mouse weight, circulating cytokines, or liver function is observed in mice treated with Gem+Ptx fibers compared to the empty fiber controls confirming the safety of the implant approach. With further development, Gem+Ptx fibers can improve the treatment of unresectable PDAC in the future.
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