Identification of lysyl oxidase as an adipocyte-secreted mediator that promotes a partial mesenchymal-to-epithelial transition in MDA-MB-231 cells.

Aim: Breast cancer (BC) is the most common cancer in women worldwide, where adiposity has been linked to BC morbidity. In general, obese premenopausal women diagnosed with triple-negative BC (TNBC) tend to have larger tumours with more metastases, particularly to the bone marrow, and worse prognosis. Previous work using a 3-dimensional (3D) co-culture system consisting of TNBC cells, adipocytes and the laminin-rich extracellular matrix (ECM) trademarked as Matrigel, demonstrated that adipocytes and adipocyte-derived conditioned media (CM) caused a partial mesenchymal-to-epithelial transition (MET). Given that MET has been associated with secondary tumour formation, this study sought to identify molecular mediators responsible for this phenotypic change. Methods: Adipocytes were cultured with and without Matrigel, where semi-quantitative proteomics was used to identify proteins whose presence in the CM was induced or enhanced by Matrigel, which were referred to as adipocyte-secreted ECM-induced proteins (AEPs). The AEPs identified were assessed for association with prognosis in published proteomic datasets and prior literature. Of these, 4 were evaluated by the reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA), followed by a functional and MET marker analysis of 1 AEP on MDA-MB-231 cells grown on Matrigel or as monolayers. Results: The 4 AEPs showed a positive correlation between protein expression and poor prognosis. RT-qPCR analysis reported no significant change in AEPs mRNA expression. However, lysyl oxidase (LOX) was increased in CM of ECM-exposed adipocytes. Recombinant LOX (rLOX) caused the mesenchymal MDA-MB-231 TNBC cells to form less branched 3D structures and reduced the expression of vimentin. Conclusions: The data suggest that adipocyte-secreted LOX changes the mesenchymal phenotype of BC cells in a manner that could promote secondary tumour formation, particularly at sites high in adipocytes such as the bone marrow. Future efforts should focus on determining whether targeting LOX could reduce BC metastasis in obese individuals.

Proteasome Inhibitors and Their Potential Applicability in Osteosarcoma Treatment.

Osteosarcoma (OS) is the most common type of bone cancer, with ~30% of patients developing secondary/metastatic tumors. The molecular complexity of tumor metastasis and the lack of effective therapies for OS has cultivated interest in exploiting the proteasome as a molecular target for anti-cancer therapy. As our understanding towards the behavior of malignant cells expands, it is evident that cancerous cells display a greater reliance on the proteasome to maintain homeostasis and sustain efficient biological activities. This led to the development and approval of first- and second-generation proteasome inhibitors (PIs), which have improved outcomes for patients with multiple myeloma and mantle cell lymphoma. Researchers have since postulated the therapeutic potential of PIs for the treatment of OS. As such, this review aims to summarize the biological effects and latest findings from clinical trials investigating PI-based treatments for OS. Integrating PIs into current treatment regimens may better outcomes for patients diagnosed with OS.

Outcomes of a comprehensive strategy during repeat atrial fibrillation ablation.

BACKGROUND/PURPOSE: Atrial fibrillation (AF) recurs post-ablation in 30-40% of patients. The approach to a repeat ablation, beyond isolation of reconnected pulmonary veins (PVs), is not well established. We sought to prospectively assess outcomes and predictors of recurrence among consecutive patients who underwent repeat AF ablation with a standardized approach. METHODS: This was a single-center prospective study of consecutive patients who underwent repeat AF ablation. Our protocol consisted of six steps: PV re-isolation, ablation of left atrial low-voltage areas (LVAs), ablation of isoproterenol-induced non-PV triggers, electrophysiology study (EPS) and ablation of induced AVNRT/AVRT, ablation of induced clinical atrial flutters, and lastly empiric ablation as per operator discretion if no other ablation was performed. RESULTS: Among 725 AF ablations performed during the study period, 74 were repeat ablations. Of those undergoing repeat ablation, 53 (72%) had PV reconnection, 30 (41%) had LVAs, seven (10%) had non-PV triggers, five (7%) had AVNRT, and 15 (20%) had typical atrial flutter. Following repeat ablation, arrhythmia-free survival was 65% at 1 year. The absence of PV reconnection was the only factor independently associated with recurrence after repeat ablation (recurrence rate 71%, adjusted OR 7.91, 95% CI 2.31-27.16, p = 0.001). CONCLUSIONS: A comprehensive approach to repeat AF ablation including PV re-isolation, LVA ablation, non-PV trigger ablation, EPS, and flutter ablation was associated with a 65% 1-year arrhythmia-free survival. The absence of PV reconnection was the only independent predictor of arrhythmia recurrence. Further research is needed to identify therapies beyond PV isolation for patients undergoing repeat ablation.