Management of extraglandular manifestations of primary Sjögren's syndrome.

Primary Sjögren's syndrome can have multiple extra-glandular manifestations ranging from mild to severe. Treatment for extra-glandular manifestations is organ specific and therapies are targeted based on the primary organs involved. Preferred treatment options used for extra-glandular manifestations of Sjögren's syndrome are usually extrapolated from the physician's experience in treating similar manifestations in other autoimmune conditions such as rheumatoid arthritis and systemic lupus erythematous. The lack of immunomodulating disease modifying drugs in Sjögren's syndrome can be frustrating for patients dealing with extra-glandular manifestations, however recent advances in the field has made the future look promising for new therapeutic options.

Small-molecule inhibitors reveal multiple strategies for Hedgehog pathway blockade.

Inappropriate activation of the Hedgehog (Hh) signaling pathway has been implicated in a diverse spectrum of cancers, and its pharmacological blockade has emerged as an anti-tumor strategy. While nearly all known Hh pathway antagonists target the transmembrane protein Smoothened (Smo), small molecules that suppress downstream effectors could more comprehensively remediate Hh pathway-dependent tumors. We report here four Hh pathway antagonists that are epistatic to the nucleocytoplasmic regulator Suppressor of Fused [Su(fu)], including two that can inhibit Hh target gene expression induced by overexpression of the Gli transcription factors. Each inhibitor has a unique mechanism of action, and their phenotypes reveal that Gli processing, Gli activation, and primary cilia formation are pharmacologically targetable. We further establish the ability of certain compounds to block the proliferation of cerebellar granule neuron precursors expressing an oncogenic form of Smo, and we demonstrate that Hh pathway inhibitors can have tissue-specific activities. These antagonists therefore constitute a valuable set of chemical tools for interrogating downstream Hh signaling mechanisms and for developing chemotherapies against Hh pathway-related cancers.