The Ewing sarcoma family of tumors (EFT) is a group of highly malignant small round blue cell tumors occurring in children and young adults. We report here the largest genomic survey to date of 101 EFT (65 tumors and 36 cell lines). Using a combination of whole genome sequencing and targeted sequencing approaches, we discover that EFT has a very low mutational burden (0.15 mutations/Mb) but frequent deleterious mutations in the cohesin complex subunit STAG2 (21.5% tumors, 44.4% cell lines), homozygous deletion of CDKN2A (13.8% and 50%) and mutations of TP53 (6.2% and 71.9%). We additionally note an increased prevalence of the BRCA2 K3326X polymorphism in EFT patient samples (7.3%) compared to population data (OR 7.1, p = 0.006). Using whole transcriptome sequencing, we find that 11% of tumors pathologically diagnosed as EFT lack a typical EWSR1 fusion oncogene and that these tumors do not have a characteristic Ewing sarcoma gene expression signature. We identify samples harboring novel fusion genes including FUS-NCATc2 and CIC-FOXO4 that may represent distinct small round blue cell tumor variants. In an independent EFT tissue microarray cohort, we show that STAG2 loss as detected by immunohistochemistry may be associated with more advanced disease (p = 0.15) and a modest decrease in overall survival (p = 0.10). These results significantly advance our understanding of the genomic and molecular underpinnings of Ewing sarcoma and provide a foundation towards further efforts to improve diagnosis, prognosis, and precision therapeutics testing.

We report that interferon ␥ (IFN-␥) inhibits transcription of the macrophage scavenger receptor gene by antagonizing the Ras-dependent activities of AP-1 and cooperating ets domain transcription factors, apparently as a result of competition between AP-1͞ets factors and activated STAT1

Purpose-A direct correlation between T 1ρ , T 2 and quantified proteoglycan and collagen contents in human osteoarthritic cartilage has yet to be documented. We aimed to investigate the orientation effect on T 1ρ and T 2 values in human osteoarthritic cartilage; and to quantify the correlation between T 1ρ , T 2 , versus biochemical composition and histology in human osteoarthritic cartilage.Materials and Methods-Thirty-three cartilage specimens were collected from patients who underwent total knee arthroplasty due to severe osteoarthritis, and scanned with a 3T MR scanner for T 1ρ and T 2 quantification. Nine specimens were scanned at three different orientations with respect to the B 0 : 0°, 90°, and 54.7°. Core punches were taken after MRI. Collagen and proteoglycan contents were quantified using biochemical assays. Histology sections were graded using Mankin scores. The correlation between imaging parameters, biochemical contents and histological scores were studied.Results-Both mean T 1ρ and T 2 at 54.7° were significantly higher than those measured at 90°a nd 0°, with T 1ρ showing a less increase compared to T 2 . R 1ρ (1/T 1ρ ) values had a significant, but moderate correlation with proteoglycan contents (R = 0.45, P = 0.002), while R 2 (1/T 2 ) was not correlated with proteoglycan. No significant correlation was found between relaxation times (T 1ρ or T 2 ) and collagen contents. The T 1ρ values of specimen sections with high Mankin scores were significantly higher than those with low Mankin scores (P < 0.05) © 2010 Elsevier Inc. All rights reserved.Corresponding author: Xiaojuan Li, PhD, Department of Radiology and Biomedical Imaging, University of California, San Francisco, 185 Berry Street, Suite 350, San Francisco, CA 94107, xiaojuan.li@radiology.ucsf.edu,. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Competing InterestThe authors declare that they have no competing interests. Conclusions-Quantitative MRI has a great potential to provide non-invasive imaging biomarkers for cartilage degeneration in OA. NIH Public Access

Cellular schwannoma is an uncommon, but well-recognized, benign peripheral nerve sheath tumor, which can be misdiagnosed as malignant peripheral nerve sheath tumor. To develop consensus diagnostic criteria for cellular schwannoma, we reviewed 115 malignant peripheral nerve sheath tumor and 26 cellular schwannoma cases from two institutions. Clinical data were retrieved from the electronic medical records, and morphologic features, maximal mitotic counts, Ki67 labeling indices, and immunohistochemical profiles (SOX10, SOX2, p75NTR, p16, p53, EGFR, and neurofibromin) were assessed. Several features distinguish cellular schwannoma from malignant peripheral nerve sheath tumor. First, in contrast to patients with malignant peripheral nerve sheath tumor, no metastases or disease-specific deaths were found in patients with cellular schwannoma. More specifically, 5-year progression-free survival rates were 100 and 18%, and 5-year disease-specific survival rates were 100 and 32% for cellular schwannoma and malignant peripheral nerve sheath tumor, respectively. Second, the presence of Schwannian whorls, a peritumoral capsule, subcapsular lymphocytes, macrophage-rich infiltrates, and the absence of fascicles favored the diagnosis of cellular schwannoma, while the presence of perivascular hypercellularity, tumor herniation into vascular lumens, and necrosis favor malignant peripheral nerve sheath tumor. Third, complete loss of SOX10, neurofibromin or p16 expression, or the presence of EGFR immunoreactivity was specific for malignant peripheral nerve sheath tumor (Po0.001 for each). Expression of p75NTR was observed in 80% of malignant peripheral nerve sheath tumors compared with 31% of cellular schwannomas (Po0.001). Fourth, Ki-67 labeling indices Z20% were highly predictive of malignant peripheral nerve sheath tumor (87% sensitivity and 96% specificity). Taken together, the combinations of these histopathological and immunohistochemical features provide useful criteria to distinguish between malignant peripheral nerve sheath tumor and cellular schwannoma with high sensitivity and specificity. Additional retrospective and prospective multicenter studies with larger data sets will be required to validate these findings.

Macrophage development is regulated by a complex set of hormone-like molecules and cell adhesion events that control the growth and differentiation of progenitor cells. The macrophage scavenger receptor (SR) gene becomes markedly upregulated during the final stages of monocyte-to-macrophage differentiation and provides a model for the identification and characterization of transcription factors that control this process. In this report, we have identified three genomic regulatory elements that are required for transactivation of the SR gene in the THP-1 monocytic leukemia cell line following induction of macrophage differentiation by tetradecanoyl phorbol acetate. Each of these regulatory elements contains a near-consensus binding site for members of the AP-1 gene family, while the two most quantitatively important elements also contain juxtaposed binding sites for ets domain transcription factors. We demonstrate that tetradecanoyl phorbol acetate treatment results in a marked and prolonged increase in AP-1 binding activity on these elements, which can be accounted for almost entirely by c-jun andjunB. These proteins in turn form ternary complexes with additional factors that bind to the adjacent ets recognition motifs. Several indirect lines of evidence indicate that ets2 represents a component of this ternary complex. The combined expression of c-jun, ets2, and a constitutive form of ras result in synergistic increases in transcription from promoters containing the SR regulatory elements. These observations suggest that SR gene expression is regulated via a signal transduction pathway involving ras, AP-1, and ets domain proteins and imply that at least some of the signalling components involved in ras-dependent growth are also utilized to promote the expression of genes involved in terminal differentiation.Macrophages are derived from circulating monocytes that have traversed the endothelium and migrated into tissues or body cavities. This transition from the circulation is temporally correlated with the unfolding of a program of terminal differentiation that involves the transcriptional activation of a diverse set of immediate/early and late genes. The precise pattern of gene expression that is evoked during this process is dependent on the particular cell-cell interactions and the milieu of cytokines and other regulatory molecules encountered by the nascent macrophage in the postcirculatory environment.The type I and II macrophage scavenger receptors (SRs) represent late gene products that are highly restricted in their patterns of expression to macrophages and related cell types (36). These two forms of the SR are encoded by a single gene that gives rise to an alternatively spliced primary transcript (27,42). Although their normal physiologic roles remain uncertain, biochemical studies have demonstrated that both forms of the SR are capable of binding and internalizing a relatively broad spectrum of polyanionic macromolecules. Ligands for SRs include proteins containing lysine residues that have been acetyl...