The past 15 years has seen significant advances in the characterization of myositis-specific autoantibodies (MSAs) and their associated phenotypes in patients with dermatomyositis (DM). As more careful studies are performed, it is clear that unique combinations of clinical and pathological phenotypes are associated with each MSA, despite the fact that there is considerable heterogeneity within antibody classes as well as overlap across the groups. Because risk for interstitial lung disease (ILD), internal malignancy, adverse disease trajectory, and, potentially response to therapy differ by DM MSA group, a deeper understanding of MSAs and validation and standardization of assays used for detection are critical for optimizing diagnosis and treatment. Like any test, the diagnostic sensitivity and specificity of assays for various MSAs is not perfect. Currently tests for MSAs are helpful at minimum for a clinician to assess relative risk or contribute to diagnosis and perhaps counsel the appropriate patient about what to expect.With international standardization and larger studies it is likely that more antibody tests will make their way into formal schemata for diagnosis and actionable risk assessment in DM. In this review, we summarize key considerations for interpreting the clinical and pathologic associations with MSA in DM and identify critical gaps in knowledge and practice that will maximize their clinical utility and utility for understanding disease pathogenesis.
Basosquamous carcinoma (BSC) is an aggressive skin neoplasm with the features of both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). While genetic drivers of BCC and SCC development have been extensively characterized, BSC has not been well studied, and it remains unclear whether these tumors originally derive from BCC or SCC. In addition, it is unknown which molecular pathways mediate the reprogramming of tumor keratinocytes toward basaloid or squamatized phenotypes. We sought to characterize the genomic alterations underlying sporadic BSC to elucidate the derivation of these mixed tumors. We identifed frequent Hedgehog (Hh) pathway mutations in BSCs, implicating Hh deregulation as the primary driving event in BSC. Principal component analysis of BCC and SCC driver genes further demonstrate the genetic similarity between BCC and BSC. In addition, 45% of the BSCs harbor recurrent mutations in the SWI/SNF complex gene, ARID1A, and evolutionary analysis revealed that ARID1A mutations occur after PTCH1 but before SCC driver mutations, indicating that ARID1A mutations may bestow plasticity enabling squamatization. Finally, we demonstrate mitogen-activated protein kinase pathway activation and the loss of Hh signaling associated with the squamatization of BSCs. Overall, these results support the genetic derivation of BSCs from BCCs and highlight potential factors involved in modulating tumor reprogramming between basaloid and squamatized phenotypes.
Abstract. A multi-protein module is a collection of proteins exhibiting modularity in their interactions. Multi-protein modules may perform essential functions and be conserved by purifying selection. Detecting essential multi-protein modules that change infrequently during evolution is a challenging algorithmic task. A new linear-time algorithm named Produles offers significant algorithmic advantages over previous approaches. An algorithmic framework for evaluation is presented that facilitates evaluation of algorithms for detecting conserved modularity with respect to their algorithmic goals.
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