The DEAD-box helicase DDX56 is a conserved stemness regulator in normal and cancer stem cells.

Across the animal kingdom, adult tissue homeostasis is regulated by adult stem cell activity, which is commonly dysregulated in human cancers. However, identifying key regulators of stem cells in the milieu of thousands of genes dysregulated in a given cancer is challenging. Here, using a comparative genomics approach between planarian adult stem cells and patient-derived glioblastoma stem cells (GSCs), we identify and demonstrate the role of DEAD-box helicase DDX56 in regulating aspects of stemness in four stem cell systems: planarians, mouse neural stem cells, human GSCs, and a fly model of glioblastoma. In a human GSC line, DDX56 localizes to the nucleolus, and using planarians, when DDX56 is lost, stem cells dysregulate expression of ribosomal RNAs and lose nucleolar integrity prior to stem cell death. Together, a comparative genomic approach can be used to uncover conserved stemness regulators that are functional in both normal and cancer stem cells.

Snail coordinately regulates downstream pathways to control multiple aspects of mammalian neural precursor development.

The Snail transcription factor plays a key role in regulating diverse developmental processes but is not thought to play a role in mammalian neural precursors. Here, we have examined radial glial precursor cells of the embryonic murine cortex and demonstrate that Snail regulates their survival, self-renewal, and differentiation into intermediate progenitors and neurons via two distinct and separable target pathways. First, Snail promotes cell survival by antagonizing a p53-dependent death pathway because coincident p53 knockdown rescues survival deficits caused by Snail knockdown. Second, we show that the cell cycle phosphatase Cdc25b is regulated by Snail in radial precursors and that Cdc25b coexpression is sufficient to rescue the decreased radial precursor proliferation and differentiation observed upon Snail knockdown. Thus, Snail acts via p53 and Cdc25b to coordinately regulate multiple aspects of mammalian embryonic neural precursor biology.

An asymmetrically localized Staufen2-dependent RNA complex regulates maintenance of mammalian neural stem cells.

The cellular mechanisms that regulate self-renewal versus differentiation of mammalian somatic tissue stem cells are still largely unknown. Here, we asked whether an RNA complex regulates this process in mammalian neural stem cells. We show that the RNA-binding protein Staufen2 (Stau2) is apically localized in radial glial precursors of the embryonic cortex, where it forms a complex with other RNA granule proteins including Pumilio2 (Pum2) and DDX1, and the mRNAs for ß-actin and mammalian prospero, prox1. Perturbation of this complex by functional knockdown of Stau2, Pum2, or DDX1 causes premature differentiation of radial glial precursors into neurons and mislocalization and misexpression of prox1 mRNA. Thus, a Stau2- and Pum2-dependent RNA complex directly regulates localization and, potentially, expression of target mRNAs like prox1 in mammalian neural stem cells, and in so doing regulates the balance of stem cell maintenance versus differentiation.

Combined clinical and laboratory testing improves diagnostic accuracy for osteomyelitis in the diabetic foot.

UNLABELLED: The purpose of this investigation was to examine the value of using routinely available clinical and laboratory tests in combination to distinguish osteomyelitis from cellulitis in a diabetic population with mild to moderately infected forefoot ulcers. We conducted a case-control study of 54 diabetic patients with 54 locally infected ulcers admitted to a university-affiliated tertiary-care hospital over a 4.5-year period. A total of 30 clinical and laboratory characteristics obtained at admission were tested for their association with pathology-proven osteomyelitis using logistic regression techniques. Ulcer depth greater than 3 mm (univariate odds ratio 10.4, P = .001) and C-reactive protein greater than 3.2 mg/dL (univariate odds ratio 10.8, P < .001) were the most informative individual clinical and laboratory tests for differentiating osteomyelitis from cellulitis. Adding C-reactive protein also significantly improved upon the accuracy of the study's best clinical testing strategy (area under the curve improved from 0.80 to 0.88, P = .040). Strategies that combined ulcer depth with serum inflammatory markers proved most useful in detecting ulcerated patients with concomitant bone infections (sensitivity 100% [95% CI 89.7%-100%] for both ulcer depth greater than 3 mm or C-reactive protein greater than 3.2 mg/dL, and ulcer depth greater than 3 mm or erythrocyte sedimentation rate greater than 60 mm/h). We conclude that considering clinical and laboratory findings together can significantly improve our diagnostic accuracy for osteomyelitis in the diabetic foot. The specific combination of ulcer depth with serum inflammatory markers appears to be a particularly sensitive strategy that may allow for greater detection of early diabetic osteomyelitis. LEVEL OF CLINICAL EVIDENCE: 3.