The diversity of skeletal tissues in extant vertebrates includes mineralized and unmineralized structures made of bone, cartilage, or tissues of intermediate nature. This variability, together with the diverse nature of skeletal tissues in fossil species question the origin of skeletonization in early vertebrates. In particular, the study of skeletal tissues in cartilaginous fishes is currently mostly restrained to tessellated cartilage, a derived form of mineralized cartilage that evolved at the origin of this group. In this work, we describe the architectural and histological diversity of neural arch mineralization in cartilaginous fishes. The observed variations in the architecture include tessellated cartilage, with or without more massive sites of mineralization, and continuously mineralized neural arches devoid of tesserae. The histology of these various architectures always includes globular mineralization that takes place in the cartilaginous matrix. In many instances, the mineralized structures also include a fibrous component that seems to emerge from the perichondrium and they may display intermediate features, ranging from partly cartilaginous to mostly fibrous matrix, similar to fibrocartilage. Among these perichondrial mineralized tissues is also found, in few species, a lamellar arrangement of the mineralized extracellular matrix. The evolution of the mineralized tissues in cartilaginous fishes is discussed in light of current knowledge of their phylogenetic relationships.
Chemoresistance, particularly to gemcitabine, is a major challenge in pancreatic cancer. The epidermal growth factor receptor (EGFR) and human epidermal growth factor receptors 2 and 3 (HER2, HER3) are expressed in many tumors, and they are relevant therapeutic targets due to their synergistic interaction to promote tumor aggressiveness and therapeutic resistance. Cocktails of antibodies directed against different targets are a promising strategy to overcome these processes. Here, we found by immunohistochemistry that these three receptors were co-expressed in 11% of patients with pancreatic adenocarcinoma. We then developed gemcitabine-resistant pancreatic cancer cell models (SW-1990-GR and BxPC3-GR) and one patient-derived xenograft (PDX2846-GR) by successive exposure to increasing doses of gemcitabine. We showed that expression of EGFR, HER2 and HER3 was increased in these gemcitabineresistant pancreatic cancer models, and that an antibody mixture against all three receptors inhibited tumor growth in mice and downregulated HER receptors. Finally, we demonstrated that the Pan-HER and gemcitabine combination has an additive effect in vitro and in mice xenografted with the gemcitabinesensitive or resistant pancreatic models. The mixture of anti-EGFR, HER2 and HER3 antibodies is a good candidate therapeutic approach for gemcitabine-sensitive and -resistant pancreatic cancer.
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