Biological Barriers: Transdermal, Oral, Mucosal, Blood Brain Barrier, and the Blood Eye Barrier

© Springer Science+Business Media New York 2013. And Gregor Cevc 2013. All rights reserved. Compartmentalisation is a precondition for the development of life, allowing concentration gradients to be maintained, facilitating selective transport of molecules, functional polarisation, protection of cells and tissues. Consequently, organisms have evolved highly sophisticated structures and mechanisms that allow compartmentalisation to be maintained and controlled in a highly regulated fashion. Under normal conditions these compartmentalising structures are essential building blocks of life, their smooth functioning being central to our health. However, the same effectiveness that is a bonus under physiological conditions means the same structures may become considerable barriers to the pharmacotherapy of diseases, as access of drugs to the sites of disease may be severely restricted. This chapter describes the architecture, organisation, and function of key barriers that therapeutic nanoparticles may encounter for the most important routes of drug administration. The epithelial barriers (skin, mucosa of the airways, and gastrointestinal tract) and endothelial barriers share many commonalities as they all share key design elements that have evolved to support compartmentalisation

Genomic Classification of Cutaneous Melanoma

We describe the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 primary and/or metastatic melanomas from 331 patients. We establish a framework for genomic classification into one of four subtypes based on the pattern of the most prevalent significantly mutated genes: mutant BRAF, mutant RAS, mutant NF1, and Triple-WT (wild-type). Integrative analysis reveals enrichment of KIT mutations and focal amplifications and complex structural rearrangements as a feature of the Triple-WT subtype. We found no significant outcome correlation with genomic classification, but samples assigned a transcriptomic subclass enriched for immune gene expression associated with lymphocyte infiltrate on pathology review and high LCK protein expression, a T cell marker, were associated with improved patient survival. This clinicopathological and multi-dimensional analysis suggests that the prognosis of melanoma patients with regional metastases is influenced by tumor stroma immunobiology, offering insights to further personalize therapeutic decision-making

Genomic Classification of Cutaneous Melanoma

We describe the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 primary and/or metastatic melanomas from 331 patients. We establish a framework for genomic classification into one of four sub-types based on the pattern of the most prevalent significantly mutated genes: mutant BRAF, mutant RAS, mutant NF1, and Triple-WT (wild-type). Integrative analysis reveals enrichment of KIT mutations and focal amplifications and complex structural rearrangements as a feature of the Triple-WT subtype. We found no significant outcome correlation with genomic classification, but samples assigned a transcriptomic subclass enriched for immune gene expression associated with lymphocyte infiltrate on pathology review and high LCK protein expression, a T cell marker, were associated with improved patient survival. This clinicopathological and multidimensional analysis suggests that the prognosis of melanoma patients with regional metastases is influenced by tumor stroma immunobiology, offering insights to further personalize therapeutic decision-makingclose3