Sphingolipid-Based Synergistic Interactions to Enhance Chemosensitivity in Lung Cancer Cells.

Tumor heterogeneity leads to drug resistance in cancer treatment with the crucial role of sphingolipids in cell fate and stress signaling. We analyzed sphingolipid metabolism and autophagic flux to study chemotherapeutic interactions on the A549 lung cancer model. Loaded cells with fluorescent sphingomyelin analog (BODIPY) and mCherry-EGFP-LC3B were used to track autophagic flux and assess cytotoxicity when cells are exposed to chemotherapy (epirubicin, cisplatin, and paclitaxel) together with sphingolipid pathway inhibitors and autophagy modulators. Our cell model approach employed fluorescent sphingolipid biosensors and a Gaussian Mixture Model of cell heterogeneity profiles to map the influence of chemotherapy on the sphingolipid pathway and infer potential synergistic interactions. Results showed significant synergy, especially when combining epirubicin with autophagy inducers (rapamycin and Torin), reducing cell viability. Cisplatin also synergized with a ceramidase inhibitor. However, paclitaxel often led to antagonistic effects. Our mapping model suggests that combining chemotherapies with autophagy inducers increases vesicle formation, possibly linked to ceramide accumulation, triggering cell death. However, the in silico model proposed ceramide accumulation in autophagosomes, and kinetic analysis provided evidence of sphingolipid colocalization in autophagosomes. Further research is needed to identify specific sphingolipids accumulating in autophagosomes. These findings offer insights into potential strategies for overcoming chemotherapy resistance by targeting the sphingolipid pathway.

Journey to chew: a case of maxillary duplication and bony syngnathia.

Tessier no 3 cleft, bony syngnathia, and maxillary duplication are rare as independent anomalies and have never been reported together in a single case. Here we present a patient with congenital bony syngnathia, maxillary duplication, and a Tessier no. 3 nasal cleft. Other abnormalities included situs inversus, dextrocardia, coarctation of the aorta, left choanal stenosis, left coloboma, and hypertelorbitism. Given the unique presentation, we present our early surgical management to this complex problem.