Clinicopathologic characterization and assessment of prognostic factors for intraabdominal solitary fibrous tumors involving the gastrointestinal tract and liver.

Solitary fibrous tumors (SFT) are rare mesenchymal neoplasms with a potential to metastasize in 10-30% of cases. Several risk models have been designed to predict tumor behavior at the pleura and extrapleural sites. Intrabdominal SFTs primarily involving the gastrointestinal tract (SFTGI) and liver (SFTL) are rare. We analyzed a series of SFTGI and SFTL to describe the clinicopathologic features and evaluate prognostic factors. The cohort included 33 males and 25 females, with a median age of 58.5 years and a mean tumor size of 15.6 cm. Patients with SFTL were predominantly older females compared to patients with SFTGI. By univariate analysis, high mitotic count (> 4/10 HPF), tumor size, tumor necrosis, and nuclear pleomorphism were associated with both disease-specific survival (DSS) and metastasis-free survival (MFS) (p < 0.05). Tumor location (SFTL vs. SFTGI) also predicted MFS (p = 0.026). Only very high mitotic count (> 9/10 HPF) predicted local recurrence-free survival (LFS, p = 0.001). Further analysis showed that all adverse histologic parameters (necrosis, hypercellularity, pleomorphism) correlated with high mitotic grade (> 4/10 HPF) (p < 0.05). On multivariate analysis, only mitosis predicted DSS (p = 0.023), MFS (p = 0.01), and LFS (p = 0.017). Validation of the 3 risk models (mDemicco, Salas, Pasquali) showed variable associations with DSS, MFS, and LFS, while a simplied 3-tiered risk model based on mitosis (0-4, 5-9, > 9/10 HPF) performed well in predicting all risks. Our results suggest that prognostication of SFTs is mainly associated with mitotic activity, supporting the use of mitosis (> 4 and/or > 9/10 HPF) for tumor grading and risk stratification at specific locations.

Trends and Characteristics of Spine Research From 2006 to 2015: A Review of Spine Articles in a High Impact General Orthopedic Journal.

STUDY DESIGN: Literature review. OBJECTIVE: To determine characteristics and trends in published spine research over a recent decade in a high impact, general orthopedic surgery journal. SUMMARY OF BACKGROUND DATA: Recent trends in published spine research in a high-impact orthopedic surgery journal are unknown. Such knowledge could guide future research in the field. METHODS: A comprehensive literature review of clinical and basic science spine articles published in The Journal of Bone & Joint Surgery from 2006 to 2015 was conducted. Articles were assessed for: title, year of publication, authorship, academic degrees of the authors, number of citations, institution of origin, and spine topic. Clinical articles were evaluated for: sex and race/ethnicity of the human subjects, level of evidence, and inclusion of patient-reported outcome measures (PROMs). Basic science articles were evaluated for: type of study (animal, cadaver, cell-based), sex of the animals, cadavers or cells studied (male, female, or male and female), and presence of sex-based reporting (defined as reporting of results by sex). RESULTS: A total of 203 spine articles were evaluated from the 10-year study period. At least 35 validated or nonvalidated patient-reported outcome measures were utilized in clinical spine research. The most commonly reported PROMs were the Oswestry Disability Index (24.4%), Short Form-36 Health Survey (23.7%), and Visual Analog Scale for Pain (19.3%). The average level of evidence improved from 3.25 in 2006 to 2.60 in 2015. Only 13.2% of clinical spine articles reported the race/ethnicity of the subjects. CONCLUSION: A consensus regarding validated PROMs in spine research would be valuable. From 2006 to 2015, the level of evidence of spine articles in The Journal of Bone & Joint Surgery improved. Accurate and complete reporting of patient demographics is an area for improvement in spine research in light of studies demonstrating sex and race/ethnicity-related differences in clinical outcome after spine surgery. LEVEL OF EVIDENCE: 5.

Author Correction: An atlas of genetic influences on osteoporosis in humans and mice.

In the version of this article initially published, in Fig. 5a, the data in the right column of 'DAAM2 gRNA1' were incorrectly plotted as circles indicating 'untreated' rather than as squares indicating 'treated'. The error has been corrected in the HTML and PDF versions of the article.

An atlas of genetic influences on osteoporosis in humans and mice.

Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR) = 58, P = 1 × 10-75) from cell-specific features, including chromatin conformation and accessible chromatin sites. We next performed rapid-throughput skeletal phenotyping of 126 knockout mice with disruptions in predicted target genes and found an increased abnormal skeletal phenotype frequency compared to 526 unselected lines (P < 0.0001). In-depth analysis of one gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.

Publication rate of podium presentations from the orthopaedic research society annual meeting.

Annual scientific meetings serve as a forum for dissemination of new research findings. Presentations should be of high scientific quality as they have the potential to impact future research projects and current clinical practice. The publication rate of podium presentations at an annual meeting can be used to assess the quality of the research presented. The purpose of this study was to determine the publication rate of podium presentations at the Orthopaedic Research Society (ORS) annual meeting. All podium presentations from the 2012 to 2014 annual ORS meetings were identified. Abstracts were categorized into an orthopaedic topic. A PubMed search was performed to determine if an abstract reached publication in a peer-reviewed journal. The publication rate was determined for each year. Of the 1063 podium presentations identified, 640 (60.2%) reached publication in a peer-reviewed journal. No significant differences were observed in the publication rate between the orthopaedic topics (p = 0.3414). The majority (75.9%) of published abstracts reached publication within 2 years of presentation and the average time to publication was 17.0 months. Abstracts were published in 151 different journals with an average impact factor of 4.46. Time to publication varied significantly by journal (p = 0.025). Journal of Orthopaedic Research, Journal of Biomechanics, PLoS ONE, Osteoarthritis and Cartilage, and Bone were the most common publication journals. This study provides insight into the quality of podium presentations at the ORS annual meeting. The ORS annual meeting compares favorably to other orthopaedic surgery meetings. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:288-292, 2019.

Development and in vitro assessment of enzymatically-responsive poly(ethylene glycol) hydrogels for the delivery of therapeutic peptides.

Despite the recent expansion of peptide drugs, delivery remains a challenge due to poor localization and rapid clearance. Therefore, a hydrogel-based platform technology was developed to control and sustain peptide drug release via matrix metalloproteinase (MMP) activity. Specifically, hydrogels were composed of poly(ethylene glycol) and peptide drugs flanked by MMP substrates and terminal cysteine residues as crosslinkers. First, peptide drug bioactivity was investigated in expected released forms (e.g., with MMP substrate residues) in vitro prior to incorporation into hydrogels. Three peptides (Qk (from Vascular Endothelial Growth Factor), SPARC113, and SPARC118 (from Secreted Protein Acidic and Rich in Cysteine)) retained bioactivity and were used as hydrogel crosslinkers in full MMP degradable forms. Upon treatment with MMP2, hydrogels containing Qk, SPARC113, and SPARC118 degraded in 6.7, 6, and 1 days, and released 5, 8, and, 19% of peptide, respectively. Further investigation revealed peptide drug size controlled hydrogel swelling and degradation rate, while hydrophobicity impacted peptide release. Additionally, Qk, SPARC113, and SPARC118 releasing hydrogels increased endothelial cell tube formation 3.1, 1.7, and 2.8-fold, respectively. While pro-angiogenic peptides were the focus of this study, the design parameters detailed allow for adaptation of hydrogels to control peptide release for a variety of therapeutic applications.

Selective modification of adenovirus replication can be achieved through rational mutagenesis of the adenovirus type 5 DNA polymerase.

Mutations that reduce the efficiency of deoxynucleoside (dN) triphosphate (dNTP) substrate utilization by the HIV-1 DNA polymerase prevent viral replication in resting cells, which contain low dNTP concentrations, but not in rapidly dividing cells such as cancer cells, which contain high levels of dNTPs. We therefore tested whether mutations in regions of the adenovirus type 5 (Ad5) DNA polymerase that interact with the dNTP substrate or DNA template could alter virus replication. The majority of the mutations created, including conservative substitutions, were incompatible with virus replication. Five replication-competent mutants were recovered from 293 cells, but four of these mutants failed to replicate in A549 lung carcinoma cells and Wi38 normal lung cells. Purified polymerase proteins from these viruses exhibited only a 2- to 4-fold reduction in their dNTP utilization efficiency but nonetheless could not be rescued, even when intracellular dNTP concentrations were artificially raised by the addition of exogenous dNs to virus-infected A549 cells. The fifth mutation (I664V) reduced biochemical dNTP utilization by the viral polymerase by 2.5-fold. The corresponding virus replicated to wild-type levels in three different cancer cell lines but was significantly impaired in all normal cell lines in which it was tested. Efficient replication and virus-mediated cell killing were rescued by the addition of exogenous dNs to normal lung fibroblasts (MRC5 cells), confirming the dNTP-dependent nature of the polymerase defect. Collectively, these data provide proof-of-concept support for the notion that conditionally replicating, tumor-selective adenovirus vectors can be created by modifying the efficiency with which the viral DNA polymerase utilizes dNTP substrates.