Transactions of the American Clinical and Climatological Association

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The journey from in vitro transfer of genes into mammalian cells to approved gene therapy products has spanned decades. This manuscript summarizes hurdles encountered and obstacles overcome in the development of successful adeno-associated viral (AAV) vectors for hemophilia B and for an inherited retinal dystrophy caused by mutations in the RPE65 gene. In the case of hemophilia B, careful analysis of the first unsuccessful attempts led to the realization that the human immune response to AAV vectors was preventing durable expression; elucidation of the response to the recombinant virion led to strategies that enabled successful long-lasting gene transfer...

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Clinical heterogeneity remains a challenge in the practice of medicine and is an underlying motivation for much of biomedical research. Unfortunately, despite an abundance of technologies capable of producing millions of discrete data elements with information about a patient's health status or disease prognosis, our ability to translate those data into meaningful improvements in understanding of clinical heterogeneity is limited. To address this gap, we have applied newer approaches to manifold learning and developed additional and complementary techniques to interrogate and interpret complex, high dimensional omics data...

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Dr. Chi-yuan Hsu describes controversies surrounding the race coefficient ("if African American") in widely used kidney function estimating equations. He outlines recent research results on this topic by himself and others and comments on the relationship between activists and the academic medical community.

I provide a narrative of the path I took to discover the membrane receptors that mediate leukocyte adhesion, now known as β2 integrins or CD11/CD18. We followed this discovery with the first determination of the 3-D structures of integrins. The latter advance provided the foundation for understanding the unique features of integrins as divalent cation-dependent signaling receptors and as mechanosensitive conduits between the extracellular matrix and the intracellular cytoskeleton. Our structural studies are now opening new paths for taming overactive integrins in disease while minimizing the collateral damage associated with the faulty pharmacodynamics of current integrin inhibitory drugs...

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