SATB2 is a marker of osteoblastic differentiation in benign and malignant mesenchymal tumours. Although SATB2 is not specific for osteosarcoma, it has the potential to be a useful adjunct in some settings, particularly in the distinction between hyalinized collagen and osteoid.

The emergence of CRISPR-Cas9 gene-editing technologies and genome-wide CRISPR-Cas9 libraries enables efficient unbiased genetic screening that can accelerate the process of therapeutic discovery for genetic disorders. Here, we demonstrate the utility of a genome-wide CRISPR-Cas9 loss-of-function library to identify therapeutic targets for facioscapulohumeral muscular dystrophy (FSHD), a genetically complex type of muscular dystrophy for which there is currently no treatment. In FSHD, both genetic and epigenetic changes lead to misexpression of DUX4, the FSHD causal gene that encodes the highly cytotoxic DUX4 protein. We performed a genome-wide CRISPR-Cas9 screen to identify genes whose loss-of-function conferred survival when DUX4 was expressed in muscle cells. Genes emerging from our screen illuminated a pathogenic link to the cellular hypoxia response, which was revealed to be the main driver of DUX4-induced cell death. Application of hypoxia signaling inhibitors resulted in increased DUX4 protein turnover and subsequent reduction of the cellular hypoxia response and cell death. In addition, these compounds proved successful in reducing FSHD disease biomarkers in patient myogenic lines, as well as improving structural and functional properties in two zebrafish models of FSHD. Our genome-wide perturbation of pathways affecting DUX4 expression has provided insight into key drivers of DUX4-induced pathogenesis and has identified existing compounds with potential therapeutic benefit for FSHD. Our experimental approach presents an accelerated paradigm toward mechanistic understanding and therapeutic discovery of a complex genetic disease, which may be translatable to other diseases with well-established phenotypic selection assays.

Carcinoma of unknown primary origin (CUP) is one of the 10 most prevalent malignancies. CUP patients in whom a site of origin can be ascribed have better outcomes than those in which the primary tumor remains unidentified. Among the tools available to pathologists in approaching these lesions, immunohistochemistry is a reliable, inexpensive, and widely available resource. New markers continue to emerge, which, in combination with other historically useful antibodies, allow rapid and accurate identification of primary site in an increasing number of cases. This review discusses the approach to the diagnosis of CUP using immunohistochemistry and outlines some of the most useful markers with a particular focus on the utility of lineage-restricted transcription factors, including CDX2, NKX3-1, PAX8, SATB2, TTF-1, and SF1.