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Human sex‐determination is a poorly understood genetic process, where gonad development depends on a cell fate decision that occurs in a somatic cell to commit to Sertoli (male) or granulosa (female) cells. A lack of testis‐determination in the human results in 46,XY gonadal dysgenesis. A minority of these cases is explained by mutations in genes known to be involved in sex‐determination. Here, we identified a de novo missense mutation, p.Arg235Gln in the highly conserved TALE homeodomain of the transcription factor Pre‐B‐Cell Leukemia Transcription Factor 1 (PBX1) in a child with 46,XY gonadal dysgenesis and radiocubital synostosis. This mutation, within the nuclear localization signal of the protein, modifies the ability of the PBX1 protein to localize to the nucleus. The mutation abolishes the physical interaction of PBX1 with two proteins known to be involved in testis‐determination, CBX2 and EMX2. These results provide a mechanism whereby this mutation results specifically in the absence of testis‐determination. [ABSTRACT FROM AUTHOR]

DMRT transcription factors are deeply conserved regulators of metazoan sexual development. They share the DM DNA-binding domain, a unique intertwined double zinc-binding module followed by a C-terminal recognition helix, which binds a pseudopalindromic target DNA. Here we show that DMRT proteins use a unique binding interaction, inserting two adjacent antiparallel recognition helices into a widened DNA major groove to make base-specific contacts. Versatility in how specific base contacts are made allows human DMRT1 to use multiple DNA binding modes (tetramer, trimer and dimer). Chromatin immunoprecipitation with exonuclease treatment (ChIP-exo) indicates that multiple DNA binding modes also are used in vivo. We show that mutations affecting residues crucial for DNA recognition are associated with an intersex phenotype in flies and with male-to-female sex reversal in humans. Our results illuminate an ancient molecular interaction underlying much of metazoan sexual development. [ABSTRACT FROM AUTHOR]

Introduction: Imatinib is the standard first-line therapy for advanced gastrointestinal stromal tumor. 18F-fluorodeoxyglucose PET computed tomography (FDG PET/CT) shows a faster response than computed tomography in nonpretreated patients. Patients & methods: After disease progression on imatinib 400 mg, 16 patients were exposed to 800 mg. Tumor response was evaluated by FDG PET/CT on days 7 and 37. Primary objective was to correlate early metabolic response (EMR) with progression-free survival (PFS). Results: EMR by FDG PET/CT scan was not predictive of PFS. Median PFS in these patients was 3 months. Overall survival was influenced by gastric primary site (p = 0.05). Conclusion: The assessment of EMR by FDG PET/CT in patients with advanced gastrointestinal stromal tumor exposed to imatinib 800 mg was not predictive of PFS or overall survival. [ABSTRACT FROM AUTHOR]