Tyrosine kinase inhibitors (TKIs) are highly potent cancer therapeutics that have been linked with serious cardiotoxicity, including left ventricular dysfunction, heart failure, and QT prolongation. ...TKI-induced cardiotoxicity is thought to result from interference with tyrosine kinase activity in cardiomyocytes, where these signaling pathways help to control critical processes such as survival signaling, energy homeostasis, and excitation-contraction coupling. However, mechanistic understanding is limited at present due to the complexities of tyrosine kinase signaling, and the wide range of targets inhibited by TKIs. Here, we review the use of TKIs in cancer and the cardiotoxicities that have been reported, discuss potential mechanisms underlying cardiotoxicity, and describe recent progress in achieving a more systematic understanding of cardiotoxicity via the use of mechanistic models. In particular, we argue that future advances are likely to be enabled by studies that combine large-scale experimental measurements with Quantitative Systems Pharmacology (QSP) models describing biological mechanisms and dynamics. As such approaches have proven extremely valuable for understanding and predicting other drug toxicities, it is likely that QSP modeling can be successfully applied to cardiotoxicity induced by TKIs. We conclude by discussing a potential strategy for integrating genome-wide expression measurements with models, illustrate initial advances in applying this approach to cardiotoxicity, and describe challenges that must be overcome to truly develop a mechanistic and systematic understanding of cardiotoxicity caused by TKIs.
This paper describes topological searches for neutral scalar bosons S0 produced in association with a Z0 boson via the Bjorken process \(e^+e^- \to{\rm S}^0{}{\rm Z}^0\) at centre-of-mass energies of ...91 GeV and 183-209 GeV. These searches are based on studies of the recoil mass spectrum of \({\rm Z}^0 \to e^+e^-\) and \(\mu^+ \mu^-\) events and on a search for \({\rm S}^0{\rm Z}^0\) with \({\rm Z}^0 \to \nu\bar{\nu}\) and S\(^0 \to e^+ e^-\) or photons. They cover the decays of the S0 into an arbitrary combination of hadrons, leptons, photons and invisible particles as well as the possibility that it might be stable. No indication for a signal is found in the data and upper limits on the cross section of the Bjorken process are calculated. Cross-section limits are given in terms of a scale factor k with respect to the Standart Model cross section for the Higgs-strahlung process \(e^+ e^-\to{\rm H}_{\rm SM}{\rm Z}^0\). These results can be interpreted in general scenarios independently of the decay modes of the S0. The examples considered here are the production of a single new scalar particle with a decay width smaller than the detector mass resolution, and for the first time, two scenarios with continuous mass distributions, due to a single very broad state or several states close in mass.
Protein structure-based gene expression signatures Rahman, Rayees; Zatorski, Nicole; Hansen, Jens ...
Proceedings of the National Academy of Sciences - PNAS,
05/2021, Volume:
118, Issue:
19
Journal Article
Peer reviewed
Open access
Gene expression signatures (GES) connect phenotypes to differential messenger RNA (mRNA) expression of genes, providing a powerful approach to define cellular identity, function, and the effects of ...perturbations. The use of GES has suffered from vague assessment criteria and limited reproducibility. Because the structure of proteins defines the functional capability of genes, we hypothesized that enrichment of structural features could be a generalizable representation of gene sets. We derive structural gene expression signatures (sGES) using features from multiple levels of protein structure (e.g., domain and fold) encoded by the mRNAs in GES. Comprehensive analyses of data from the Genotype-Tissue Expression Project (GTEx), the all RNA-seq and ChIP-seq sample and signature search (ARCHS4) database, and mRNA expression of drug effects on cardiomyocytes show that sGES are useful for characterizing biological phenomena. sGES enable phenotypic characterization across experimental platforms, facilitates interoperability of expression datasets, and describe drug action on cells.
Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are a promising disease model, even though hiPSC-CMs cultured for extended periods display an undifferentiated transcriptional ...landscape. MiRNA-target gene interactions contribute to fine-tuning the genetic program governing cardiac maturation and may uncover critical pathways to be targeted.
We analyzed a hiPSC-CM public dataset to identify time-regulated miRNA-target gene interactions based on three logical steps of filtering. We validated this process in silico using 14 human and mouse public datasets, and further confirmed the findings by sampling seven time points over a 30-day protocol with a hiPSC-CM clone developed in our laboratory. We then added miRNA mimics from the top eight miRNAs candidates in three cell clones in two different moments of cardiac specification and maturation to assess their impact on differentiation characteristics including proliferation, sarcomere structure, contractility, and calcium handling.
We uncovered 324 interactions among 29 differentially expressed genes and 51 miRNAs from 20,543 transcripts through 120 days of hiPSC-CM differentiation and selected 16 genes and 25 miRNAs based on the inverse pattern of expression (Pearson R-values < - 0.5) and consistency in different datasets. We validated 16 inverse interactions among eight genes and 12 miRNAs (Person R-values < - 0.5) during hiPSC-CMs differentiation and used miRNAs mimics to verify proliferation, structural and functional features related to maturation. We also demonstrated that miR-124 affects Ca
handling altering features associated with hiPSC-CMs maturation.
We uncovered time-regulated transcripts influencing pathways affecting cardiac differentiation/maturation axis and showed that the top-scoring miRNAs indeed affect primarily structural features highlighting their role in the hiPSC-CM maturation.
A study of \(\mathrm{b}\) quark hadronisation is presented using inclusively reconstructed B hadrons in about four million hadronic Z decays recorded in 1992-2000 with the OPAL detector at LEP. The ...data are compared to different theoretical models, and fragmentation function parameters of these models are fitted. The average scaled energy of weakly decaying B hadrons is determined to be \\langle{x}_{ \mathrm{E}}\rangle = 0.7193 \pm 0.0016 (stat)^{+0.0038}_{-0.0033}(syst) \ . \
GridX1: A Canadian computational grid Agarwal, A.; Ahmed, M.; Berman, A. ...
Future generation computer systems,
06/2007, Volume:
23, Issue:
5
Journal Article
Peer reviewed
The present paper discusses the design and application of GridX1, a computational grid project which uses shared resources at several Canadian research institutions. The infrastructure of GridX1 is ...built using off-the-shelf Globus Toolkit 2 middleware, a MyProxy credential server, and a resource broker based on Condor-G to manage the distributed computing environment. The broker-based job scheduling and management functionality are exposed as a Globus GRAM job service. Resource brokering is based on the Condor matchmaking mechanism, whereby job and resource attributes are expressed as ClassAds, with the attributes
Requirements and
Rank being used to define respectively the constraints and preferences that the matched entity must meet. Various strategies for ranking resources are presented, including an Estimated-Waiting-Time (EWT) algorithm, a throttled load balancing strategy, and a novel external ranking strategy based on data location. One of the unique features is a mechanism which transparently presents the GridX1 resources as a single compute element to the LHC Computing Grid (LCG), based at the CERN Laboratory in Geneva. This interface was used during the ATLAS data challenge 2 to federate the Canadian resources into the LCG without the overhead of maintaining separate LCG sites. Further, the BaBar particle physics simulation has been adapted to execute on GridX1 and resulted in a simplified management of the production. The usage of the throttled EWT and load balancing strategies combined with external data ranking was found to be very effective in improving efficiency and reducing the job failure rate.
The branching ratio of the
τ¯→e¯
v¯
e
v
τ decay and the radiative tau decay
τ→
u¯
v¯
u
v
τ
γ have been measured with the OPAL detector at LEP. A branching ratio of 0.1778±0.0010±0.0009 was obtained ...for the
τ¯→e¯
v¯
e
v
τ decay mode and (3.0 ± 0.4 ± 0.5) × 10
−3 for the
τ¯→
u¯
v¯
u
v
τ
γ decay mode for photon energies above 20 MeV in the tau rest frame.
A search was performed for charginos with masses close to the mass of the lightest neutralino in \(\mathrm{e}^{+}\mathrm{e}^{-}\) collisions at centre-of-mass energies of 189-209 GeV recorded by the ...OPAL detector at LEP. Events were selected if they had an observed high-energy photon from initial state radiation, reducing the dominant background from two-photon scattering to a negligible level. No significant excess over Standard Model expectations has been observed in the analysed data set corresponding to an integrated luminosity of 570 pb-1. Upper limits were derived on the chargino pair-production cross-section, and lower limits on the chargino mass were derived in the context of the Minimal Supersymmetric Extension of the Standard Model for the gravity- and anomaly-mediated Supersymmetry breaking scenarios.
A series of data samples was collected with the Belle II detector at the SuperKEKB collider from March 2019 to June 2022. We determine the integrated luminosities of these data samples using three ...distinct methodologies involving Bhabha (\(e^+e^- \to e^+e^-(n\gamma)\)), digamma (\(e^+e^- \to \gamma\gamma(n\gamma)\)), and dimuon (\(e^+e^- \to \mu^+ \mu^- (n\gamma)\)) events. The total integrated luminosity obtained with Bhabha, digamma, and dimuon events is (426.52 \(\pm\) 0.03 \(\pm\) 2.48)~fb\(^{-1}\), (427.32 \(\pm\) 0.03 \(\pm\) 2.56)~fb\(^{-1}\), and (424.84 \(\pm\) 0.04 \(\pm\) 3.88)~fb\(^{-1}\), where the first uncertainties are statistical and the second are systematic. The resulting total integrated luminosity obtained from the combination of the three methods is (426.88 \(\pm\) 1.93)~fb\(^{-1}\).
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