541 research outputs found
Measurements of the Absolute Branching Ratios for the Dominant KL Decays, the KL Lifetime, and Vus with the KLOE Detector
From a sample of about 10^9 Phi mesons produced at DAFNE, we have selected KL
mesons tagged by observing KS->pi+pi- decays. We present results on the major
KL branching ratios, including those of the semileptonic decays needed for the
determination of Vus. These branching ratio measurements are fully inclusive
with respect to final-state radiation. The KL lifetime has also been measured.Comment: Submitted to Phys. Lett.
Search for supersymmetric particles in scenarios with a gravitino LSP and stau NLSP
Sleptons, neutralinos and charginos were searched for in the context of
scenarios where the lightest supersymmetric particle is the gravitino. It was
assumed that the stau is the next-to-lightest supersymmetric particle. Data
collected with the DELPHI detector at a centre-of-mass energy near 189 GeV were
analysed combining the methods developed in previous searches at lower
energies. No evidence for the production of these supersymmetric particles was
found. Hence, limits were derived at 95% confidence level.Comment: 31 pages, 14 figure
Inhibition of mTOR pathway by everolimus cooperates with EGFR inhibitors in human tumours sensitive and resistant to anti-EGFR drugs
Inhibition of a single transduction pathway is often inefficient due to activation of alternative signalling. The mammalian target of rapamycin (mTOR) is a key intracellular kinase integrating proliferation, survival and angiogenic pathways and has been implicated in the resistance to EGFR inhibitors. Thus, mTOR blockade is pursued to interfere at multiple levels with tumour growth. We used everolimus (RAD001) to inhibit mTOR, alone or in combination with anti-EGFR drugs gefitinib or cetuximab, on human cancer cell lines sensitive and resistant to EGFR inhibitors, both in vitro and in vivo. We demonstrated that everolimus is active against EGFR-resistant cancer cell lines and partially restores the ability of EGFR inhibitors to inhibit growth and survival. Everolimus reduces the expression of EGFR-related signalling effectors and VEGF production, inhibiting proliferation and capillary tube formation of endothelial cells, both alone and in combination with gefitinib. Finally, combination of everolimus and gefitinib inhibits growth of GEO and GEO-GR (gefitinib resistant) colon cancer xenografts, activation of signalling proteins and VEGF secretion. Targeting mTOR pathway with everolimus overcomes resistance to EGFR inhibitors and produces a cooperative effect with EGFR inhibitors, providing a valid therapeutic strategy to be tested in a clinical setting
Detection of human papillomavirus DNA in peri-tumor tissues and pelvic lymph nodes as potential molecular marker of micrometastasis in cervical cancer
Displayed correlation between gene expression profiles and submicroscopic alterations in response to cetuximab, gefitinib and EGF in human colon cancer cell lines
Background: EGFR is frequently overexpressed in colon cancer. We characterized HT-29 and
Caco-2, human colon cancer cell lines, untreated and treated with cetuximab or gefitinib alone and
in combination with EGF.
Methods: Cell growth was determined using a variation on the MTT assay. Cell-cycle analysis was
conducted by flow cytometry. Immunohistochemistry was performed to evaluate EGFR expression
and scanning electron microscopy (SEM) evidenced the ultrastructural morphology. Gene
expression profiling was performed using hybridization of the microarray Ocimum Pan Human 40
K array A.
Results: Caco-2 and HT-29 were respectively 66.25 and 59.24 % in G0/G1. They maintained this
level of cell cycle distribution after treatment, suggesting a predominantly differentiated state.
Treatment of Caco-2 with EGF or the two EGFR inhibitors produced a significant reduction in their
viability. SEM clearly showed morphological cellular transformations in the direction of cellular death in both cell lines treated with EGFR inhibitors. HT-29 and Caco-2 displayed an important
reduction of the microvilli (which also lose their erect position in Caco-2), possibly invalidating
microvilli absorption function. HT-29 treated with cetuximab lost their boundary contacts and
showed filipodi; when treated with gefitinib, they showed some vesicles: generally membrane
reshaping is evident. Both cell lines showed a similar behavior in terms of on/off switched genes
upon treatment with cetuximab. The gefitinib global gene expression pattern was different for the
2 cell lines; gefitinib treatment induced more changes, but directly correlated with EGF treatment.
In cetuximab or gefitinib plus EGF treatments there was possible summation of the morphological
effects: cells seemed more weakly affected by the transformation towards apoptosis. The genes
appeared to be less stimulated than for single drug cases.
Conclusion: This is the first study to have systematically investigated the effect of cetuximab or
gefitinib, alone and in combination with EGF, on human colon cancer cell lines. The EGFR inhibitors
have a weaker effect in the presence of EGF that binds EGFR. Cetuximab treatment showed an
expression pattern that inversely correlates with EGF treatment. We found interesting cytomorphological
features closely relating to gene expression profile. Both drugs have an effect on
differentiation towards cellular death
Differential diagnosis of neurodegenerative dementias with the explainable MRI based machine learning algorithm MUQUBIA
Biomarker-based differential diagnosis of the most common forms of dementia is becoming increasingly important. Machine learning (ML) may be able to address this challenge. The aim of this study was to develop and interpret a ML algorithm capable of differentiating Alzheimer’s dementia, frontotemporal dementia, dementia with Lewy bodies and cognitively normal control subjects based on sociodemographic, clinical, and magnetic resonance imaging (MRI) variables. 506 subjects from 5 databases were included. MRI images were processed with FreeSurfer, LPA, and TRACULA to obtain brain volumes and thicknesses, white matter lesions and diffusion metrics. MRI metrics were used in conjunction with clinical and demographic data to perform differential diagnosis based on a Support Vector Machine model called MUQUBIA (Multimodal Quantification of Brain whIte matter biomArkers). Age, gender, Clinical Dementia Rating (CDR) Dementia Staging Instrument, and 19 imaging features formed the best set of discriminative features. The predictive model performed with an overall Area Under the Curve of 98%, high overall precision (88%), recall (88%), and F1 scores (88%) in the test group, and good Label Ranking Average Precision score (0.95) in a subset of neuropathologically assessed patients. The results of MUQUBIA were explained by the SHapley Additive exPlanations (SHAP) method. The MUQUBIA algorithm successfully classified various dementias with good performance using cost-effective clinical and MRI information, and with independent validation, has the potential to assist physicians in their clinical diagnosis
Search for neutral heavy leptons produced in decays
Weak isosinglet Neutral Heavy Leptons (νm) have been searched for using data collected by the DELPHI detector corresponding to 3.3 × 106 hadronic Z0 decays at LEP1. Four separate searches have been performed, for short-lived νm production giving monojet or acollinear jet topologies, and for long-lived νm giving detectable secondary vertices or calorimeter clusters. No indication of the existence of these particles has been found, leading to an upper limit for the branching ratio BR(Z0 → νmν̄) of about 1.3 × 10-6 at 95% confidence level for νm masses between 3.5 and 50 GeV/c2. Outside this range the limit weakens rapidly with the νm mass. The results are also interpreted in terms of limits for the single production of excited neutrinos. © Springer-Verlag 1997
Measurement of Trilinear Gauge Couplings in Collisions at 161 GeV and 172 GeV
Trilinear gauge boson couplings are measured using data taken by DELPHI at 161~GeV and 172~GeV. Values for couplings () are determined from a study of the reactions \eeWW\ and \eeWev, using differential distributions from the final state in which one decays hadronically and the other leptonically, and total cross-section data from other channels. Limits are also derived on neutral couplings from an analysis of the reaction \eegi
Study of B0_s anti-B0_s oscillations and B0_s lifetimes using hadronic decays of B0_s mesons
Oscillations of B0s mesons have been studied in samples selected from about
3.5 million hadronic Z decays detected by DELPHI between 1992 and 1995. One
analysis uses events in the exclusive decay channels: B0s -> Ds- pi+ or Ds- a1+
and B0s -> anti-D0 K- pi+ or anti-D0 K- a1+, where the D decays are completely
reconstructed. In addition, B0s anti-B0s oscillations have been studied in
events with an exclusively reconstructed Ds accompanied in the same hemisphere
by a high momentum hadron of opposite charge. Combining the two analyses, a
limit on the mass difference between the physical B0s states has been obtained:
Delta(m_B0s) > 4.0 ps^{-1} at the 95% C.L. with a sensitivity of Delta(m_B0s)
= 3.2 ps^{-1}. Using the latter sample of events, the B0s lifetime has been
measured and an upper limit on the decay width difference between the two
physical B0s states has been obtained:
tau(B0s) = 1.53^{+0.16}_{-0.15}(stat.) +/- {0.07}(syst.) ps
\Delta\Gamma(B0s)/\Gamma(B0s) < 0.69 at the 95% C.L.
The combination of these results with those obtained using Ds+- lepton-+
sample gives:
Delta(m_B0s) > 4.9 ps^{-1} at the 95% C.L.
with a sensitivity of Delta(m_B0s) = 8.7 ps^{-1}.
tau(B0s) = 1.46 +/- 0.11 ps and \Delta\Gamma(B0s)/\Gamma(B0s) < 0.45 at the
95% C.L.Comment: 42 pages, 13 figure
Pan-cancer analysis of whole genomes
Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe
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