MicroRNAs at the human 14q32 locus have prognostic significance in osteosarcoma

Molecular tumour pathology - and tumour genetic

The role of KCNQ1 in mouse and human gastrointestinal cancers

Kcnq1, which encodes for the pore-forming alpha subunit of a voltage-gated potassium channel, was identified as a gastrointestinal (GI) tract cancer susceptibility gene in multiple Sleeping Beauty DNA transposon-based forward genetic screens in mice. To confirm that Kcnq1 has a functional role in GI tract cancer we created Apc(Min) mice that carried a targeted deletion mutation in Kcnq1. Results demonstrated that Kcnq1 is a tumor suppressor gene as Kcnq1 mutant mice developed significantly more intestinal tumors, especially in the proximal small intestine and colon, some of these tumors progressed to become aggressive adenocarcinomas. Gross tissue abnormalities were also observed in the rectum, pancreas and stomach. Colon organoid formation was significantly increased in organoids created from Kcnq1 mutant mice compared with wildtype littermate controls, suggesting a role for Kcnq1 in regulation of the intestinal crypt stem cell compartment. To identify gene expression changes due to loss of Kcnq1 we carried out microarray studies in colon and proximal small intestine. We identified altered genes involved in innate immune responses, goblet and Paneth cell function, ion channels, intestinal stem cells, EGFR and other growth regulatory signaling pathways. We also found genes implicated in inflammation and in cellular detoxification. Pathway analysis using Ingenuity Pathway Analysis (IPA) and gene set enrichment analysis (GSEA) confirmed the importance of these gene clusters and further identified significant overlap with genes regulated by MUC2 and CFTR, two important regulators of intestinal homeostasis. To investigate the role of KCNQ1 in human colorectal cancer (CRC) we measured protein levels of KCNQ1 by immunohistochemistry in tissue microarrays containing samples from CRC patients with liver metastases who had undergone hepatic resection. Results showed that low expression of KCNQ1 expression was significantly associated with poor overall survival (OS)

An insertional mutagenesis screen identifies genes that cooperate with Mll-AF9 in a murine leukemogenesis model

Patients with a t(9;11) translocation (MLL-AF9) develop acute myeloid leukemia (AML), and while in mice the expression of this fusion oncogene also results in the development of myeloid leukemia, it is with long latency. To identify mutations that cooperate with Mll-AF9, we infected neonatal wild-type (WT) or Mll- AF9 mice with a murine leukemia virus (MuLV). MuLV-infected Mll-AF9 mice succumbed to disease significantly faster than controls presenting predominantly with myeloid leukemia while infected WT animals developed predominantly lymphoid leukemia. We identified 88 candidate cancer genes near common sites of proviral insertion. Analysis of transcript levels revealed significantly elevated expression of Mn1, and a trend toward increased expression of Bcl11a and Fosb in Mll-AF9 murine leukemia samples with proviral insertions proximal to these genes. Accordingly, FOSB and BCL11A were also overexpressed in human AML harboring MLL gene translocations. FOSB was revealed to be essential for growth in mouse and human myeloid leukemia cells using shRNA lentiviral vectors in vitro. Importantly, MN1 cooperated with Mll-AF9 in leukemogenesis in an in vivo BM viral transduction and transplantation assay. Together, our data identified genes that define transcription factor networks and important genetic pathways acting during progression of leukemia induced by MLL fusion oncogenes

Dispensing Rates of Four Common Hearing Aid Product Features: Associations With Variations in Practice Among Audiologists

The purpose of the study was to develop and examine a list of potential variables that may account for variability in the dispensing rates of four common hearing aid features. A total of 29 potential variables were identified and placed into the following categories: (1) characteristics of the audiologist, (2) characteristics of the hearing aids dispensed by the audiologist, (3) characteristics of the audiologist?s patient population, and (4) evidence-based practice grades of recommendation for each feature. The potentially associative variables then were examined using regression analyses from the responses of 257 audiologists to a dispensing practice survey. There was a direct relation between price and level of hearing aid technology with the frequency of dispensing product features. There was also a direct relation between the belief by the audiologist that a feature might benefit patients and the frequency of dispensing that feature. In general, the results suggested that personal differences among audiologists and the hearing aids audiologists choose to dispense are related more strongly to dispensing rates of product features than to differences in characteristics of the patient population served by audiologists. An additional finding indicated that evidence-based practice recommendations were inversely related to dispensing rates of product features. This finding, however, may not be the result of dispensing trends as much as hearing aid manufacturing trends