2,452 research outputs found
A phase I, dose-escalation study of volasertib combined with nintedanib in advanced solid tumors
Background: Volasertib is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinases. This study determined the maximum tolerated dose (MTD) and pharmacokinetics of volasertib combined with nintedanib, a potent and orally bioavailable triple angiokinase inhibitor, in patients with advanced solid tumors. Patients and methods: This open-label, dose-escalation trial recruited patients with advanced metastatic solid tumors following failure of conventional treatment (NCT01022853; Study 1230.7). Volasertib was administered by intravenous infusion over 2 h, starting at 100 mg in the first dose cohort. Nintedanib was administered orally at a dose of 200 mg twice daily. The first treatment cycle comprised 28 days (days 1-7 and days 9-28: nintedanib; day 8: volasertib). From cycle 2 onwards, volasertib was administered on day 1 of a 21-day cycle and nintedanib was administered days 2-21. The primary objective was the MTD of volasertib in combination with nintedanib. Results: Thirty patients were treated. The MTD of volasertib plus fixed-dose nintedanib was 300 mg once every 3 weeks, the same as the recommended single-agent dose of volasertib in solid tumors. Two of 12 assessable patients treated with the MTD experienced dose-limiting toxicities [grade 3 increased alanine aminotransferase (ALT); grade 3 ALT increase and grade 3 increased aspartate aminotransferase]. Disease control [stable disease (SD)/partial response (PR)/complete response (CR)] was achieved in 18 patients (60%): 1 CR (breast cancer), 1 PR (nonsmall-cell lung cancer), and 16 patients with SD. Volasertib showed that multiexponential pharmacokinetic behavior and co-administration of nintedanib had no significant effects on its exposure. Conclusions: Volasertib could be combined with fixed-dose nintedanib at the recommended single-agent dose. At this dose, the combination had a manageable safety profile without unexpected or overlapping adverse events, and showed antitumor activity
Stroma Transcriptomic and Proteomic Profile of Prostate Cancer Metastasis Xenograft Models Reveals Prognostic Value of Stroma Signatures.
Resistance acquisition to androgen deprivation treatment and metastasis progression are a major clinical issue associated with prostate cancer (PCa). The role of stroma during disease progression is insufficiently defined. Using transcriptomic and proteomic analyses on differentially aggressive patient-derived xenografts (PDXs), we investigated whether PCa tumors predispose their microenvironment (stroma) to a metastatic gene expression pattern. RNA sequencing was performed on the PCa PDXs BM18 (castration-sensitive) and LAPC9 (castration-resistant), representing different disease stages. Using organism-specific reference databases, the human-specific transcriptome (tumor) was identified and separated from the mouse-specific transcriptome (stroma). To identify proteomic changes in the tumor (human) versus the stroma (mouse), we performed human/mouse cell separation and subjected protein lysates to quantitative Tandem Mass Tag labeling and mass spectrometry. Tenascin C (TNC) was among the most abundant stromal genes, modulated by androgen levels in vivo and highly expressed in castration-resistant LAPC9 PDX. The tissue microarray of primary PCa samples (n = 210) showed that TNC is a negative prognostic marker of the clinical progression to recurrence or metastasis. Stroma markers of osteoblastic PCa bone metastases seven-up signature were induced in the stroma by the host organism in metastatic xenografts, indicating conserved mechanisms of tumor cells to induce a stromal premetastatic signature. A 50-gene list stroma signature was identified based on androgen-dependent responses, which shows a linear association with the Gleason score, metastasis progression and progression-free survival. Our data show that metastatic PCa PDXs, which differ in androgen sensitivity, trigger differential stroma responses, which show the metastasis risk stratification and prognostic biomarker potential
Quantizing the damped harmonic oscillator
We consider the Fermi quantization of the classical damped harmonic
oscillator (dho). In past work on the subject, authors double the phase space
of the dho in order to close the system at each moment in time. For an
infinite-dimensional phase space, this method requires one to construct a
representation of the CAR algebra for each time. We show that unitary dilation
of the contraction semigroup governing the dynamics of the system is a logical
extension of the doubling procedure, and it allows one to avoid the
mathematical difficulties encountered with the previous method.Comment: 4 pages, no figure
Projected Quasi-particle Perturbation theory
The BCS and/or HFB theories are extended by treating the effect of four
quasi-particle states perturbatively. The approach is tested on the pairing
hamiltonian, showing that it combines the advantage of standard perturbation
theory valid at low pairing strength and of non-perturbative approaches
breaking particle number valid at higher pairing strength. Including the
restoration of particle number, further improves the description of pairing
correlation. In the presented test, the agreement between the exact solution
and the combined perturbative + projection is almost perfect. The proposed
method scales friendly when the number of particles increases and provides a
simple alternative to other more complicated approaches
Freeze-out configuration properties in the 197Au + 197Au reaction at 23 AMeV
Data from the experiment on the 197Au + 197Au reaction at 23 AMeV are
analyzed with an aim to find signatures of exotic nuclear configurations such
as toroid-shaped objects. The experimental data are compared with predictions
of the ETNA code dedicated to look for such configurations and with the QMD
model. A novel criterion of selecting events possibly resulting from the
formation of exotic freeze-out configurations, "the efficiency factor", is
tested. Comparison between experimental data and model predictions may indicate
for the formation of flat/toroidal nuclear systems
Constructing Qubits in Physical Systems
The notion of a qubit is ubiquitous in quantum information processing. In
spite of the simple abstract definition of qubits as two-state quantum systems,
identifying qubits in physical systems is often unexpectedly difficult. There
are an astonishing variety of ways in which qubits can emerge from devices.
What essential features are required for an implementation to properly
instantiate a qubit? We give three typical examples and propose an operational
characterization of qubits based on quantum observables and subsystems.Comment: 16 pages, no figures; IoP LaTeX2e style. Submitted to J. Phys. A:
Math. Ge
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