164,329 research outputs found
Profiling the molecular difference between Patched- and p53-dependent rhabdomyosarcoma
No full textRhabdomyosarcoma (RMS) is a highly malignant tumor that is histologically related to skeletal muscle, yet genetic and molecular lesions underlying its genesis and progression remain largely unknown. In this study we have compared the molecular profiles of two different mouse models of RMS, each associated with a defined primary genetic defect known to play a role in rhabdomyosarco-magenesis in man. We report that RMS of heterozygous Patched1 (Ptch1) mice show less aggressive growth and a greater degree of differentiation than RMS of heterozygous p53 mice. By means of cDNA microarray analysis we demonstrate that RMS in Ptch1 mutants predominantly express a number of myogenic markers, including myogenic differentiation 1, myosin heavy chain, actin, troponin and tropomyosin, as well as genes associated with Hedgehog/Patched signaling like insulin-like growth factor 2, forkhead box gene Foxf1 and the growth arrest and DNA-damage-inducible gene Gadd45a. In sharp contrast, RMS in p53 mutants display higher expression levels of cell cycle-associated genes like cyclin B1, cyclin-dependent kinase 4 and the proliferation marker Ki-67. These results demonstrate that different causative mutations lead to distinct gene expression profiles in RMS, which appear to reflect their different biological characteristics. Our results provide a first step towards a molecular classification of different forms of RMS. If the described differences can be confirmed in human RMS our results will contribute to a new molecular taxonomy of this cancer, which will be critical for gene mutation- and expression-specific therapy
Network Competition and Entry Deterrence
No full textWe develop a model of logit demand that extends the traditional duopoly framework of network competition to a multi-firm industry. First, we show that incumbents establish the reciprocal access charge inefficiently below cost when they compete in prices but they behave efficiently if they compete in utilities. Secondly, we study how incumbents determine the industry-wide access charge under the threat of entry. We show that incumbents may accommodate all possible entrants, only a group of them, or may completely deter entry. When entry deterrence is the preferred option, incumbents distort the access charge upwards. Copyright (C) The Author(s). Journal compilation (C) Royal Economic Society 2008.
Analysis of the PTCH Coding Region in Human Rhabdomyosarcoma.
No full textInherited mutations of the human tumor suppressor gene Patched (PTCH) lead to an autosomal dominant disorder known as Nevoid Basal Cell Carcinoma Syndrome (NBCCS). The syndrome is characterized by a combination of developmental abnormalities and a predisposition to tumor formation. Tumors in patients with NBCCS include basal cell carcinoma, medulloblastoma, fibroma and rhabdomyosarcoma (RMS). RMS are also present in 15 % of mice haplodeficient for Ptch. To investigate whether mutations in PTCH are a general feature in rhabdomyosarcomagenesis we sequenced the protein-coding region in sporadic human cases of these tumors. For this purpose we first determined the distribution and frequency of polymorphisms in 23 exons of PTCH in 48 healthy caucasians. Ten new polymorphisms were identified (IVS11 + 15-17del AAA; IVS14 + 25T>C; 2485G>A; IVS15 + 9G>C; IVS17 + 21A>G; 3033T>C; 3149T>C; 3387T>C; 3617G>A; 4080C>T). Next, the PTCH coding region in 14 RMS was sequenced. Whereas one case with LOH at the PTCH locus was detected, none of the cases showed nonsense or missense mutations in the coding region of PTCH. These data do not support the existence of frequent mutations in the protein-coding region of PTCH in RMS. (C) 2002 Wiley-Liss, Inc.BioFuture-Grant of the German Ministry for Education and Research BMB
Molecular characterization of Patched-associated rhabdomyosarcoma
No full textMutations in the human homologue of Drosophila Patched1 (PTCH1) have been found in several common tumours including basal cell carcinoma, medulloblastoma, and rhabdomyosarcoma (RMS). Medulloblastoma. and RMS are also present in the murine model for Ptch1 deficiency. Tumours in heterozygous Ptch1(neo67/+) mice consistently exhibit elevated transcript levels of the proto-oncogene Gli1, of Ptch1 itself, and of the insulin-like growth factor 2 (Igf2). The present study has investigated additional molecular changes in RMSs of Ptch1 mutant mice by means of microarray analysis find protein expression analysis. The data show activation of the cell survival-promoting Akt/protein kinase B (Pkb). Furthermore, RMSs express increased levels of the anti-apoptotic protein Bcl-2 and of genes and proteins known to inhibit cell proliferation, including Gadd45a and p27(kip1). Taken together, the data suggest that the formation of RMSs in Ptch1 mutants is associated with the ability of tumour cells to resist apoptosis. Copyright (C) 2003 John Wiley Sons, Ltd
Unbalanced overexpression of the mutant allele in murine Patched mutants.
No full textInherited mutations of Patched (PTCH) in the nevoid basal cell carcinoma syndrome (NBCCS) lead to several developmental defects and contribute to tumor formation in a variety of tissues. PTCH mutations have been also identified in sporadic tumors associated with NBCCS including basal cell carcinoma (BCC) and medulloblastoma. Mice heterozygous for Ptch recapitulate the typical developmental symptoms of NBCCS and develop rhabdomyosarcoma (RMS) and medulloblastoma. PTCH is assumed to act as a tumor suppressor gene although inactivation of both alleles has been demonstrated only in a fraction of tumors. We have investigated the status of Ptch in RMS of heterozygous Ptch(neo67/+) mice. Although the wild-type Ptch allele was retained in tumor tissue, the high levels of Ptch mRNA in these tumors result from overexpression of the mutant Ptch transcript. Our results suggest that the wild-type Ptch allele might be selectively silenced in RMS tissue or, alternatively, that haploinsufficiency of Ptch is sufficient to promote RMS formation in mice
[Report to Chief J. E. Curry, by an unknown author #1]
No full textReport to Chief J. E. Curry, by an unknown author. The report contains a list of officers who gave depositions to the United States Attorney
[Report to Chief J. E. Curry, by an unknown author #2]
No full textReport to Chief J. E. Curry, by an unknown author. The report contains a list of officers who gave depositions to the United States Attorney
The very massive X-ray bright binary system Wack 2134 (= WR 21a)
No full textFrom the radial velocities of the N ivλ4058 and He iiλ4686 emission lines, and the N vλ4604-20 absorption lines, determined in digital spectra, we report the discovery that the X-ray bright emission line star Wack 2134 (= WR 21a) is a spectroscopic binary system with an orbital period of 31.673 ± 0.002 d . With this period, the N iv and He ii emission and N v absorption lines, which originate in the atmosphere of the primary component, define a rather eccentric binary orbit (e = 0.64 ± 0.03) . The radial velocity variations of the N v absorptions have a lower amplitude than those of the He ii emission. Such a behaviour of the emission line radial velocities could be due to distortions produced by a superimposed absorption component from the companion. High-resolution echelle spectra observed during the quadrature phases of the binary show H and He ii absorptions of both components with a radial velocity difference of about 541 km s-1. From this difference, we infer quite high values of the minimum masses, of about 87 and 53 M☉ for the primary and secondary components, respectively, if the radial velocity variations of the He ii emission represent the true orbit of the primary. No He i absorption lines are observed in our spectra. Thus, the secondary component in the Wack 2134 binary system appears to be an early O-type star. From the presence of H, He ii and N v absorptions, and N iv and C iv emissions, in the spectrum of the primary component, it most clearly resembles those of Of/WNLha-type stars.<br/
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