Sarcoma sinovial en el perro : 2 casos clínicos

Dos casos de sarcoma sinovial fueron diagnosticados en dos Rottweiler mediante biopsias sinoviales. Se describen los signos clínicos y radiográficos, así como las características histopatológicas del tumor y del líquido sinovial.Two cases of synovial sarcoma were diagnosed in two Rottweilers on the basis of synovial biopsies. Clinical and radiographic signs are described, along with histopathologic features of the tumour and synovial fluid

The BRD4-NUT Fusion Alone Drives Malignant Transformation of NUT Carcinoma

NUT carcinoma (NC) is an aggressive squamous carcinoma defined by the BRD4-NUT fusion oncoprotein. Routinely effective systemic treatments are unavailable for most NC patients. The lack of an adequate animal model precludes identifying and leveraging cell-extrinsic factors therapeutically in NC. Here, we created a genetically engineered mouse model (GEMM) of NC that forms a Brd4::NUTM1 fusion gene upon tamoxifen induction of Sox2-driven Cre. The model displayed complete disease penetrance, with tumors arising from the squamous epithelium weeks after induction and all mice succumbing to the disease shortly thereafter. Closely resembling human NC (hNC), GEMM tumors (mNC) were poorly differentiated squamous carcinomas with high expression of MYC that metastasized to solid organs and regional lymph nodes. Two GEMM-derived cell lines were developed whose transcriptomic and epigenetic landscapes harbored key features of primary GEMM tumors. Importantly, GEMM tumor and cell line transcriptomes co-classified with those of human NC. BRD4-NUT also blocked differentiation and maintained the growth of mNC as in hNC. Mechanistically, GEMM primary tumors and cell lines formed large histone H3K27ac-enriched domains, termed megadomains, that were invariably associated with the expression of key NC-defining proto-oncogenes, Myc and Trp63. Small-molecule BET bromodomain inhibition (BETi) of mNC induced differentiation and growth arrest and prolonged survival of NC GEMMs, as it does in hNC models. Overall, tumor formation in the NC GEMM is definitive evidence that BRD4-NUT alone can potently drive the malignant transformation of squamous progenitor cells into NC. SIGNIFICANCE: The development of an immunocompetent model of NUT carcinoma that closely mimics the human disease provides a valuable global resource for mechanistic and preclinical studies to improve treatment of this incurable disease

EZH2 Cooperates with BRD4-NUT to Drive NUT Carcinoma Growth by Silencing Key Tumor Suppressor Genes

NUT carcinoma (NC) is an aggressive carcinoma driven by the BRD4-NUT fusion oncoprotein, which activates chromatin to promote expression of pro-growth genes. BET bromodomain inhibitors (BETi) are a promising treatment for NC that can impede BRD4-NUT’s ability to activate genes, but the efficacy of BETi as monotherapy are limited. Here, we demonstrated that EZH2, which silences genes through establishment of repressive chromatin, is a dependency in NC. Inhibition of EZH2 with the clinical compound tazemetostat (taz) potently blocked growth of NC cells. Epigenetic and transcriptomic analysis revealed that taz reversed the EZH2-specific H3K27me3 silencing mark and restored expression of multiple tumor suppressor genes while having no effect on key oncogenic BRD4-NUT-regulated genes. Indeed, H3K27me3 and H3K27ac domains were found to be mutually exclusive in NC cells. CDKN2A was identified as the only gene among all taz-derepressed genes to confer resistance to taz in a CRISPR-Cas9 screen. Combined inhibition of EZH2 and BET synergized to downregulate cell proliferation genes resulting in more pronounced growth arrest and differentiation than either inhibitor alone. In pre-clinical models, combined taz and BETi synergistically blocked tumor growth and prolonged survival of NC-xenografted mice, with complete remission without relapse in one cohort. Identification of EZH2 as a dependency in NC substantiates the reliance of NC tumor cells on epigenetic dysregulation of functionally opposite, yet highly complementary, chromatin regulatory pathways to maintain NC growth

Interlocking Nail Stabilisation of Humeral Fractures. Initial Experience in Seven Clinical Cases

SummarySeven cases of fracture of the humerus were stabilised by interlocking nailing. In six cases fixation was static, and in one dynamic. Healing of the fractures took place within a maximum of 16 weeks and return of functionality was complete within three weeks, with the exception of one case. The complications were: failure to insert the screws in the nail, partial loosening of a screw, and production of a new fracture at the distal end of the nail in the case with dynamic fixation.Seven humeral fractures were stabilised by interlocking nailing. Healing of bone took place in six cases.The complications involved were: failure to insert screws in the nail, loosening of the screws, and production of a fresh fracture at the distal end of the nail.</jats:p

An Experimental Study of Compression of Femoral Fractures by an Interlocking Intramedullary Pin

SummaryReturn of function and callus healing were investigated in a group of ten dogs after osteotomy of the femur treated by application of a pin, perfo-rated by threaded openings, through which a metal bar could be introduced into the trochanteric fossa. A jig, indicating the position of the openings, was attached and the distal fragment fixed with three screws into the pin; the fracture was then compressed by means of a compressor travelling from the base of the jig to rest against the bar inserted into the trochanteric fossa, approximating the proximal fragment to the distal one. Two screws were then inserted into the proximal fragment. The results revealed a full return of limb function between four and 16 days and consolidation of the callus between eight and 16 weeks.Femoral osteotomy was performed in a group of ten mongrel dogs weighing between 16 and 32 kg and stabilised with a pin, fixed with screws, which compressed the fracture. The results revealed return of normal limb function between four and 16 days later; consolidation of the callus was complete between eight and 16 weeks.</jats:p