Is the beneficial effect of antimuscarinics related to motor or sensory changes in the bladder?

Introduction and hypothesis  

The aim of the study was to assess the sensory and motor effects of antimuscarinic treatment on the bladder in women with overactive bladder, detrusor overactivity demonstrated on urodynamics and a mean bladder wall thickness (BWT) greater than 5 mm.     

Heterogeneity of kinase inhibitor resistance mechanisms in GIST

Most GIST patients develop clinical resistance to KIT/PDGFRA tyrosine kinase inhibitors (TKI). However, it is unclear whether clinical resistance results from single or multiple molecular mechanisms in each patient. KIT and PDGFRA mutations were evaluated in 53 GIST metastases obtained from 14 patients who underwent surgical debulking after progression on imatinib or sunitinib. To interrogate possible resistance mechanisms across a broad biological spectrum of GISTs, inter- and intra-lesional heterogeneity of molecular drug-resistance mechanisms were evaluated in the following: conventional KIT (CD117)-positive GISTs with KIT mutations in exon 9, 11 or 13; KIT-negative GISTs; GISTs with unusual morphology; and KIT/PDGFRA wild-type GISTs. Genomic KIT and PDGFRA mutations were characterized systematically, using complementary techniques including D-HPLC for KIT exons 9, 11-18 and PDGFRA exons 12, 14, 18, and mutation-specific PCR (V654A, D820G, N822K, Y823D). Primary KIT oncogenic mutations were found in 11/14 patients (79%). Of these, 9/11 (83%), had secondary drug-resistant KIT mutations, including six (67%) with two to five different secondary mutations in separate metastases, and three (34%) with two secondary KIT mutations in the same metastasis. The secondary mutations clustered in the KIT ATP binding pocket and kinase catalytic regions. FISH analyses revealed KIT amplicons in 2/10 metastases lacking secondary KIT mutations. This study demonstrates extensive intra- and inter-lesional heterogeneity of resistance mutations and gene amplification in patients with clinically progressing GIST. KIT kinase resistance mutations were not found in KIT/PDGFRA wild-type GISTs or in KIT-mutant GISTs showing unusual morphology and/or loss of KIT expression by IHC, indicating that resistance mechanisms are fundamentally different in these tumours. Our observations underscore the heterogeneity of clinical TKI resistance, and highlight the therapeutic challenges involved in salvaging patients after clinical progression on TKI monotherapies.     

c‐Jun promotes cell migration and drives expression of the motility factor ENPP2 in soft tissue sarcomas

Genomic amplification of the c‐Jun proto‐oncogene has been identified in ～30% of dedifferentiated liposarcomas (DDLPS), but the functional contribution of c‐Jun to the progression of DDLPS remains poorly understood. In previous work we showed that knock‐down of c‐Jun by RNA interference impaired the in vitro proliferation and in vivo growth of a DDLPS cell line (LP6) with genomic amplification of the c‐Jun locus. Here, we used gene expression analysis and functional studies in a broad panel of cell lines to further define the role of c‐Jun in DDLPS and other soft tissue sarcomas. We show that c‐Jun knock‐down impairs transition through the G₁ phase of the cell cycle in multiple DDLPS cell lines. We also found that high levels of c‐Jun expression are both necessary and sufficient to promote DDLPS cell migration and invasion in vitro. Our data suggest that high levels of c‐Jun enhance motility in part by driving the expression of ENPP2/Autotaxin. c‐Jun over‐expression has minimal effects on in vitro proliferation but substantially enhances the in vivo growth of weakly tumourigenic DDLPS cell lines. Finally, we provide evidence that c‐Jun genomic amplification and over‐expression may have similar functional consequences in other types of soft tissue sarcoma. Our data suggest a model in which relatively low levels of c‐Jun are sufficient for in vitro proliferation, but high levels of c‐Jun enhance invasiveness and capacity for in vivo tumour growth. These observations provide an explanation for the selective advantage provided by c‐Jun genomic amplification in vivo and suggest that sarcomas with elevated c‐Jun levels are likely to have a particularly high malignant potential. Data from exon array and RNA‐Seq experiments have been deposited in the GEO database (Accession No. GSE57531). Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd     

Homozygous and compound heterozygous mutations at the Werner syndrome locus

The Werner syndrome (WS) is a rare autosomal recessive progeroid disorder. The Werner syndrome gene (WRN) has recently been identified as a member of the helicase family. Four distinct mutations were previously reported in three Japanese and one Syrian WS pedigrees. The latter mutation was originally described as a 4 bp deletion spanning a spliced junction. It is now shown that this mutation results in a 4 bp deletion at the beginning of an exon. Nine new WRN mutations in 10 additional WS patients, both Japanese and Caucasian, are described. These include three compound heterozygotes (one Japanese and two Caucasian). The new mutations are located all across the coding region.