668 research outputs found
Downstream and Intermediate Interactions of Synovial Sarcoma-Associated Fusion Oncoproteins and Their Implication for Targeted Therapy
Synovial sarcoma (SS), an aggressive type of soft tissue tumor, occurs mostly in adolescents and young adults. The origin and molecular mechanism of the development of SS remain only partially known. Over 90% of SS cases are characterized by the t(X;18)(p11.2;q11.2) translocation, which results mainly in the formation of
SS18-SSX1 or SS18-SSX2 fusion genes. In recent years, several reports describing direct and indirect interactions of SS18-SSX1/SSX2 oncoproteins have been published. These reports suggest that the fusion proteins particularly affect the cell growth, cell proliferation, TP53 pathway, and chromatin remodeling mechanisms, contributing to SS oncogenesis. Additional research efforts are required to fully explore the protein-protein interactions of SS18-SSX oncoproteins and the pathways that are regulated by these partnerships for the development of effective targeted therapy
Post-Transcriptional Dysregulation by miRNAs Is Implicated in the Pathogenesis of Gastrointestinal Stromal Tumor [GIST]
peer-reviewedIn contrast to adult mutant gastrointestinal stromal tumors [GISTs], pediatric/wild-type GISTs remain poorly understood
overall, given their lack of oncogenic activating tyrosine kinase mutations. These GISTs, with a predilection for gastric origin
in female patients, show limited response to therapy with tyrosine kinase inhibitors and generally pursue a more indolent
course, but still may prove fatal. Defective cellular respiration appears to underpin tumor development in these wild-type
cases, which as a group lack expression of succinate dehydrogenase [SDH] B, a surrogate marker for respiratory chain
metabolism. Yet, only a small subset of the wild-type tumors show mutations in the genes coding for the SDH subunits
[SDHx]. To explore additional pathogenetic mechanisms in these wild-type GISTs, we elected to investigate posttranscriptional
regulation of these tumors by conducting microRNA (miRNA) profiling of a mixed cohort of 73 cases
including 18 gastric pediatric wild-type, 25 (20 gastric, 4 small bowel and 1 retroperitoneal) adult wild-type GISTs and 30
gastric adult mutant GISTs. By this approach we have identified distinct signatures for GIST subtypes which correlate tightly
with clinico-pathological parameters. A cluster of miRNAs on 14q32 show strikingly different expression patterns amongst
GISTs, a finding which appears to be explained at least in part by differential allelic methylation of this imprinted region.
Small bowel and retroperitoneal wild-type GISTs segregate with adult mutant GISTs and express SDHB, while adult wildtype
gastric GISTs are dispersed amongst adult mutant and pediatric wild-type cases, clustering in this situation on the basis
of SDHB expression. Interestingly, global methylation analysis has recently similarly demonstrated that these wild-type,
SDHB-immunonegative tumors show a distinct pattern compared with KIT and PDGFRA mutant tumors, which as a rule do
express SDHB. All cases with Carney triad within our cohort cluster together tightly.Funding was obtained from the Medical Research Charities Group (http://www.mrcg.ie/) and Health Research Board of Ireland (http://www.hrb.ie)
(MO’S), The Children’s Medical and Research Foundation (http://www.cmrf.org) (MO’S), the GIST Cancer Awareness Foundation [GCAF] (http://www.
gistawareness.org/)(MO’S), and research grants from the Life Raft Group (http://www.liferaftgroup.org/)(MD-R) and from the Fonds voor Wetenschappelijk
Onderzoek Vlaanderen (http://www.fwo.be/)(grant # G.0286.05 MD-R)
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p53 Modulation as a Therapeutic Strategy in Gastrointestinal Stromal Tumors
The KIT-inhibitor imatinib mesylate (IM) has greatly improved the treatment of metastatic gastrointestinal stromal tumors (GIST). IM exhibits strong antiproliferative effects but fails to induce sufficient levels of apoptosis resulting in low pathologic complete remission rates and a high rate of secondary progression in the metastatic setting. Upregulation of p53 by MDM2 inhibitors has been shown to induce apoptosis in p53 wildtype tumors. Analyzing a series of 62 mostly untreated, localized and metastatic GIST we detected a low rate (3%) of inactivating p53 mutations, thus providing a rationale for further exploration of p53-directed therapeutic strategies. To this end, we studied nutlin-3, an inhibitor of the p53 antagonist MDM2, and RITA, a putative p53 activator, in GIST cell lines. Nutlin-3 effectively induced p53 at therapeutically relevant levels, which resulted in moderate antiproliferative effects and cell cycle arrest in p53 wildtype GIST cell lines GIST430, GIST48 and GIST48B. P53 reactivation substantially improved the apoptotic response after effective KIT inhibition with sunitinib and 17-AAG in IM-resistant cell lines. The commonly used imatinib-sensitive cell lines GIST882 and GIST-T1 were shown to harbor defective p53 and therefore failed to respond to nutlin-3 treatment. RITA induced p53 in GIST48B, followed by antiproliferative effects and a strong induction of apoptosis. Surprisingly, GIST-T1 was also highly sensitive to RITA despite lacking functional p53. This suggested a more complex, p53-independent mechanism of action for the latter compound. No antagonistic effects from p53-activating drugs were seen with any drug combination. Our data provide first evidence that modulation of the MDM2/p53 pathway may be therapeutically useful to improve the apoptotic response of KIT-inhibitory drugs in the treatment of naïve GIST, with p53 mutation status being a predictive factor of response
Reclassification and subtyping of so-called malignant fibrous histiocytoma of bone: comparison with cytogenetic features
<p>Abstract</p> <p>Background</p> <p>The diagnostic entity malignant fibrous histiocytoma (MFH) of bone is, like its soft tissue counterpart, likely to be a misnomer, encompassing a variety of poorly differentiated sarcomas. When reviewing a series of 57 so-called MFH of bone within the framework of the EuroBoNeT consortium according to up-to-date criteria and ancillary immunohistochemistry, a fourth of all tumors were reclassified and subtyped.</p> <p>Methods</p> <p>In the present study, the cytogenetic data on 11 of these tumors (three myoepithelioma-like sarcomas, two leiomyosarcomas, one undifferentiated pleomorphic sarcoma with incomplete myogenic differentiation, two undifferentiated pleomorphic sarcomas, one osteosarcoma, one spindle cell sarcoma, and one unclassifiable biphasic sarcoma) are presented.</p> <p>Results</p> <p>All tumors were high-grade lesions and showed very complex karyotypes. Neither the overall pattern (ploidy level, degree of complexity) nor specific cytogenetic features distinguished any of the subtypes. The subgroup of myoepithelioma-like sarcomas was further investigated with regard to the status of the <it>EWSR1 </it>and <it>FUS </it>loci; however, no rearrangement was found. Nor was any particular aberration that could differentiate any of the subtypes from osteosarcomas detected.</p> <p>Conclusions</p> <p>chromosome banding analysis is unlikely to reveal potential genotype-phenotype correlations between morphologic subtypes among so-called MFH of bone.</p
Relationship of imatinib-free plasma levels and target genotype with efficacy and tolerability
Imatinib has revolutionised the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumours (GIST). Using a nonlinear mixed effects population model, individual estimates of pharmacokinetic parameters were derived and used to estimate imatinib exposure (area under the curve, AUC) in 58 patients. Plasma-free concentration was deduced from a model incorporating plasma levels of alpha1-acid glycoprotein. Associations between AUC (or clearance) and response or incidence of side effects were explored by logistic regression analysis. Influence of KIT genotype was also assessed in GIST patients. Both total (in GIST) and free drug exposure (in CML and GIST) correlated with the occurrence and number of side effects (e.g. odds ratio 2.7±0.6 for a two-fold free AUC increase in GIST; P<0.001). Higher free AUC also predicted a higher probability of therapeutic response in GIST (odds ratio 2.6±1.1; P=0.026) when taking into account tumour KIT genotype (strongest association in patients harbouring exon 9 mutation or wild-type KIT, known to decrease tumour sensitivity towards imatinib). In CML, no straightforward concentration–response relationships were obtained. Our findings represent additional arguments to further evaluate the usefulness of individualising imatinib prescription based on a therapeutic drug monitoring programme, possibly associated with target genotype profiling of patients
Transverse-momentum-dependent Multiplicities of Charged Hadrons in Muon-Deuteron Deep Inelastic Scattering
A semi-inclusive measurement of charged hadron multiplicities in deep
inelastic muon scattering off an isoscalar target was performed using data
collected by the COMPASS Collaboration at CERN. The following kinematic domain
is covered by the data: photon virtuality (GeV/), invariant
mass of the hadronic system GeV/, Bjorken scaling variable in the
range , fraction of the virtual photon energy carried by the
hadron in the range , square of the hadron transverse momentum
with respect to the virtual photon direction in the range 0.02 (GeV/ (GeV/). The multiplicities are presented as a
function of in three-dimensional bins of , , and
compared to previous semi-inclusive measurements. We explore the
small- region, i.e. (GeV/), where
hadron transverse momenta are expected to arise from non-perturbative effects,
and also the domain of larger , where contributions from
higher-order perturbative QCD are expected to dominate. The multiplicities are
fitted using a single-exponential function at small to study
the dependence of the average transverse momentum on , and . The power-law behaviour of the
multiplicities at large is investigated using various
functional forms. The fits describe the data reasonably well over the full
measured range.Comment: 28 pages, 20 figure
Measurement of the charged-pion polarisability
The COMPASS collaboration at CERN has investigated pion Compton scattering,
, at centre-of-mass energy below 3.5 pion
masses. The process is embedded in the reaction
, which is initiated by
190\,GeV pions impinging on a nickel target. The exchange of quasi-real photons
is selected by isolating the sharp Coulomb peak observed at smallest momentum
transfers, \,(GeV/). From a sample of 63\,000 events the
pion electric polarisability is determined to be $\alpha_\pi\ =\ (\,2.0\ \pm\
0.6_{\mbox{\scriptsize stat}}\ \pm\ 0.7_{\mbox{\scriptsize syst}}\,) \times
10^{-4}\,\mbox{fm}^3\alpha_\pi=-\beta_\pi$, which
relates the electric and magnetic dipole polarisabilities. It is the most
precise measurement of this fundamental low-energy parameter of strong
interaction, that has been addressed since long by various methods with
conflicting outcomes. While this result is in tension with previous dedicated
measurements, it is found in agreement with the expectation from chiral
perturbation theory. An additional measurement replacing pions by muons, for
which the cross-section behavior is unambigiously known, was performed for an
independent estimate of the systematic uncertainty.Comment: Published version: 9 pages, 3 figures, 1 tabl
Longitudinal double spin asymmetries in single hadron quasi-real photoproduction at high
We measured the longitudinal double spin asymmetries for single
hadron muo-production off protons and deuterons at photon virtuality <
1(GeV/) for transverse hadron momenta in the range 0.7
GeV/ to 4 GeV/ . They were determined using COMPASS data taken
with a polarised muon beam of 160 GeV/ or 200 GeV/ impinging on
polarised or targets. The experimental
asymmetries are compared to next-to-leading order pQCD calculations, and are
sensitive to the gluon polarisation inside the nucleon in the range
of the nucleon momentum fraction carried by gluons
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