The population history of northeastern Siberia since the Pleistocene

FGW – Publications without University Leiden contractDescriptive and Comparative Linguistic

Genome-wide association study identifies two susceptibility loci for osteosarcoma

Osteosarcoma is the most common primary bone malignancy of adolescents and young adults. To better understand the genetic etiology of osteosarcoma, we performed a multistage genome-wide association study consisting of 941 individuals with osteosarcoma (cases) and 3,291 cancer-free adult controls of European ancestry. Two loci achieved genome-wide significance: a locus in the GRM4 gene at 6p21.3 (encoding glutamate receptor metabotropic 4; rs1906953; P = 8.1 × 10⁻⁹) and a locus in the gene desert at 2p25.2 (rs7591996 and rs10208273; P = 1.0 × 10⁻⁸ and 2.9 × 10⁻⁷, respectively). These two loci warrant further exploration to uncover the biological mechanisms underlying susceptibility to osteosarcoma

The Synovial Sarcoma-Associated SS18-SSX2 Fusion Protein Induces Epigenetic Gene (De)Regulation.

Contains fulltext : 35200.pdf (publisher's version ) (Closed access)Fusion of the SS18 and either one of the SSX genes is a hallmark of human synovial sarcoma. The SS18 and SSX genes encode nuclear proteins that exhibit opposite transcriptional activities. The SS18 protein functions as a transcriptional coactivator and is associated with the SWI/SNF complex, whereas the SSX proteins function as transcriptional corepressors and are associated with the polycomb complex. The domains involved in these opposite transcriptional activities are retained in the SS18-SSX fusion proteins. Here, we set out to determine the direct transcriptional consequences of conditional SS18-SSX2 fusion protein expression using complementary DNA microarray-based profiling. By doing so, we identified several clusters of SS18-SSX2-responsive genes, including a group of genes involved in cholesterol synthesis, which is a general characteristic of malignancy. In addition, we identified a group of SS18-SSX2-responsive genes known to be specifically deregulated in primary synovial sarcomas, including IGF2 and CD44. Furthermore, we observed an uncoupling of EGR1, JUNB, and WNT signaling in response to SS18-SSX2 expression, suggesting that the SWI/SNF-associated coactivation functions of the SS18 moiety are impaired. Finally, we found that SS18-SSX2 expression affects histone modifications in the CD44 and IGF2 promoters and DNA methylation levels in the IGF2 imprinting control region. Together, we conclude that the SS18-SSX2 fusion protein may act as a so-called transcriptional "activator-repressor," which induces downstream target gene deregulation through epigenetic mechanisms. Our results may have implications for both the development and clinical management of synovial sarcomas. (Cancer Res 2006; 66(19): 9474-82)

The effect of bacterial biofilms on post-sinus surgical outcomes

BackgroundAlthough the existence of biofilms on the sinus mucosa of patients with chronic rhinosinusitis (CRS) is now well established, the role that these structures play remains unclear. It is thought that biofilms may contribute to the recalcitrant and persistent nature that characterizes CRS, but little research exists documenting the effect that they have on postoperative mucosal outcomes. This article presents a retrospective analysis of sinus surgical patients and correlates the presence of biofilms with mucosal outcomes. This study was performed to evaluate the role that bacterial biofilms have on post-sinus surgical outcomes.MethodsA retrospective analysis of prospectively collected data was performed on 40 patients undergoing endoscopic sinus surgery (ESS) for CRS. Preoperative demographic, clinical, and radiologic data were recorded from each patient and, intraoperatively, sinus culture specimens and mucosal samples were obtained for microbiological and microscopic examination. Biofilm determination was performed using confocal scanning laser microscopy. Postoperatively, patients were followed up for a minimum of 8 months with endoscopic evaluation of their sinonasal mucosa. The presence of ongoing symptoms was recorded also.ResultsBacterial biofilms were found in 20 (50%) of the 40 CRS patients. Patients with biofilms had significantly worse preoperative radiological scores and, postoperatively, had statistically worse postoperative symptoms and mucosal outcomes. The only other factor that was statistically related to an unfavorable outcome was the presence of fungus at the time of surgery. In this study the presence of polyps, eosinophilic mucin, or pus was not related to poor outcomes.ConclusionThis retrospective study showed that bacterial biofilms and fungus were correlated with the persistence of postoperative symptoms and mucosal inflammation after sinus surgery for CRS. This provides evidence that biofilms indeed may play an active role in perpetuating inflammation in CRS patients and may explain the recurrent and resistant nature of this disease. Therapies targeted at removing biofilms may be important in the management of recalcitrant CRS.Alkis J. Psaltis, Erik K. Weitzel, Kien R. Ha, Peter-John Wormald

High frequency of BRAF mutations in nevi

To evaluate the timing of mutations in BRAF (v-raf murine sarcoma viral oncogene homolog B1) during melanocytic neoplasia, we carried out mutation analysis on microdissected melanoma and nevi samples. We observed mutations resulting in the V599E amino-acid substitution in 41 of 60 (68%) melanoma metastases, 4 of 5 (80%) primary melanomas and, unexpectedly, in 63 of 77 (82%) nevi. These data suggest that mutational activation of the RAS/RAF/MAPK pathway in nevi is a critical step in the initiation of melanocytic neoplasia but alone is insufficient for melanoma tumorigenesis