A model to evaluate Pauwels type III femoral neck fractures.

While many femoral neck fractures can be reliably treated with surgical intervention, Pauwels III femoral neck fractures in the young adult population continue to be a challenging injury, and there is no consensus on optimal treatment. As such, there are past and ongoing biomechanical studies to evaluate the fixation provided by different constructs for this inherently unstable fracture. While many investigations rely on cadavers to evaluate the biomechanical performance of a construct, significant inter-subject variability can confound the analysis. Biomechanical femur analogs are being used more frequently due to more consistent mechanical properties; however, they have not been stringently evaluated for morphology or suitability for instrumentation. This study sought to determine the variability among composite femoral analogs as well as consistently create a Pauwels III injury and instrument the analogs without the need for fluoroscopic guidance. In total, 24 fourth-generation composite femoral analogs were evaluated for femoral height, neck-shaft angle, anteversion, and cortical thickness. A method was developed to simulate a Pauwels III fracture and to prepare three different constructs: an inverted triangle of cannulated screws, a sliding hip screw, and a hybrid inverted triangle with cannulated screws and a sliding hip screw. Radiographs were utilized to evaluate the variation in implant position. All but one of the morphological parameters varied by <1%. The tip-to-apex distance for all sliding hip screw hardware was 18.8 ± 3.3 mm, and all relevant cannulated screw distances were within 5 mm of the adjacent cortex. All screws were parallel, on average, within 1.5° on anterior-posterior and lateral films. Fourth-generation composite femora were found to be morphologically consistent, and it is possible to consistently instrument the analogs without the use of fluoroscopy. This analog and hardware implantation model could serve as a screening model for new fracture repair constructs without the need for cadaveric tissues or radiologic technology.

Genome-wide progesterone receptor binding: cell type-specific and shared mechanisms in T47D breast cancer cells and primary leiomyoma cells.

BACKGROUND: Progesterone, via its nuclear receptor (PR), exerts an overall tumorigenic effect on both uterine fibroid (leiomyoma) and breast cancer tissues, whereas the antiprogestin RU486 inhibits growth of these tissues through an unknown mechanism. Here, we determined the interaction between common or cell-specific genome-wide binding sites of PR and mRNA expression in RU486-treated uterine leiomyoma and breast cancer cells. PRINCIPAL FINDINGS: ChIP-sequencing revealed 31,457 and 7,034 PR-binding sites in breast cancer and uterine leiomyoma cells, respectively; 1,035 sites overlapped in both cell types. Based on the chromatin-PR interaction in both cell types, we statistically refined the consensus progesterone response element to G•ACA• • •TGT•C. We identified two striking differences between uterine leiomyoma and breast cancer cells. First, the cis-regulatory elements for HSF, TEF-1, and C/EBPα and ß were statistically enriched at genomic RU486/PR-targets in uterine leiomyoma, whereas E2F, FOXO1, FOXA1, and FOXF sites were preferentially enriched in breast cancer cells. Second, 51.5% of RU486-regulated genes in breast cancer cells but only 6.6% of RU486-regulated genes in uterine leiomyoma cells contained a PR-binding site within 5 kb from their transcription start sites (TSSs), whereas 75.4% of RU486-regulated genes contained a PR-binding site farther than 50 kb from their TSSs in uterine leiomyoma cells. RU486 regulated only seven mRNAs in both cell types. Among these, adipophilin (PLIN2), a pro-differentiation gene, was induced via RU486 and PR via the same regulatory region in both cell types. CONCLUSIONS: Our studies have identified molecular components in a RU486/PR-controlled gene network involved in the regulation of cell growth, cell migration, and extracellular matrix function. Tissue-specific and common patterns of genome-wide PR binding and gene regulation may determine the therapeutic effects of antiprogestins in uterine fibroids and breast cancer.