745 research outputs found
Generation of pralatrexate resistant T-cell lymphoma lines reveals two patterns of acquired drug resistance that is overcome with epigenetic modifiers
While pralatrexate (PDX) has been successfully developed for the treatment of T-cell lymphoma, the mechanistic basis for its T-cell selectivity and acquired resistance remains elusive. In an effort to potentially identify synergistic combinations that might circumnavigate or delay acquired PDX resistance, we generated resistant cells lines over a broad concentration range. PDX-resistant cell lines H9-12 and H9-200 were developed, each exhibiting an IC50 of 35 and over 1000 nM, respectively. These lines were established in vitro from parental H9 cells. Expression analysis of the proteins known to be important determinants of antifolate pharmacology revealed increase expression of dihydrofolate reductase (DHFR) due to gene amplification, and reduced folate carrier1 downregulation, as the putative mechanisms of resistance in H9-12 and H9-200 cells. Cross resistance was only seen with methotrexate but not with romidepsin, azacitidine (AZA), decitabine, gemcitabine, doxorubicin, or bortezomib. Resistance to PDX was reversed by pretreatment with hypomethylating agents in a concentration-dependent fashion. Comparison of gene expression profiles of parental and resistant cell lines confirmed markedly different patterns of gene expression, and identified the dual specificity phosphatase four (DUSP4) as one of the molecular target of PDX activity. Reduced STAT5 phosphorylation following exposure to PDX was observed in the H9 but not in the H9-12 and H9-200 cells. These data suggest that combination with hypomethylating agents could be potent, and that DUSP4 and STAT5 could represent putative biomarkers of PDX activity
Multi-photon, multi-mode polarization entanglement in parametric down-conversion
We study the quantum properties of the polarization of the light produced in
type II spontaneous parametric down-conversion in the framework of a multi-mode
model valid in any gain regime. We show that the the microscopic polarization
entanglement of photon pairs survives in the high gain regime (multi-photon
regime), in the form of nonclassical correlation of all the Stokes operators
describing polarization degrees of freedom
EUROnu-WP6 2010 Report
This is a summary of the work done by the Working Package 6 (Physics) of the
EU project "EUROnu" during the second year of activity of the project.Comment: 82 pages, 51 eps figure
Serum KL-6 could represent a reliable indicator of unfavourable outcome in patients with COVID-19 pneumonia
KL-6 is a sialoglycoprotein antigen which proved elevated in the serum of patients with different interstitial lung diseases, especially in those with a poorer outcome. Given that interstitial pneumonia is the most common presentation of SARS-CoV2 infection, we evaluated the prognostic role of KL-6 in patients with COVID-19 pneumonia. Patients with COVID-19 pneumonia were prospectively enrolled. Blood samples were collected at the time of enrolment (TOE) and on day 7 (T1). Serum KL-6 concentrations were measured by chemiluminescence enzyme immunoassay using a KL-6 antibody kit (LUMIPULSE G1200, Fujirebio) and the cut-off value was set at > 1000 U/mL. Fifteen out of 34 enrolled patients (44.1%) died. Patients with unfavourable outcome showed significantly lower P/F ratio and higher IL-6 values and plasmatic concentrations of KL-6 at TOE compared with those who survived (median KL-6: 1188 U/mL vs. 260 U/mL, p 1000 U/mL resulted independently associated with death (aOR: 11.29, p 1000 U/mL resulted independently associated with death and showed good accuracy in predicting a poorer outcome. KL-6 may thus represent a quick, inexpensive, and sensitive parameter to stratify the risk of severe respiratory failure and death
Study of the eightfold degeneracy with a standard -Beam and a Super-Beam facility
The study of the eightfold degeneracy at a neutrino complex that includes a
standard -Beam and a Super-Beam facility is presented for the first time
in this paper. The scenario where the neutrinos are sent toward a Megaton water
Cerenkov detector located at the Fr\'{e}jus laboratory (baseline 130 Km) is
exploited. The performance in terms of sensitivity for measuring the continuous
( and ) and discrete ( and
) oscillation parameters for the -Beam
and Super-Beam alone, and for their combination has been studied. A brief
review of the present uncertainties on the neutrino and antineutrino
cross-sections is also reported and their impact on the discovery potential
discussed
The ArDM experiment
The aim of the ArDM project is the development and operation of a one ton
double-phase liquid argon detector for direct Dark Matter searches. The
detector measures both the scintillation light and the ionization charge from
ionizing radiation using two independent readout systems. This paper briefly
describes the detector concept and presents preliminary results from the ArDM
R&D program, including a 3 l prototype developed to test the charge readout
system.Comment: Proceedings of the Epiphany 2010 Conference, to be published in Acta
Physica Polonica
On dynamic network entropy in cancer
The cellular phenotype is described by a complex network of molecular
interactions. Elucidating network properties that distinguish disease from the
healthy cellular state is therefore of critical importance for gaining
systems-level insights into disease mechanisms and ultimately for developing
improved therapies. By integrating gene expression data with a protein
interaction network to induce a stochastic dynamics on the network, we here
demonstrate that cancer cells are characterised by an increase in the dynamic
network entropy, compared to cells of normal physiology. Using a fundamental
relation between the macroscopic resilience of a dynamical system and the
uncertainty (entropy) in the underlying microscopic processes, we argue that
cancer cells will be more robust to random gene perturbations. In addition, we
formally demonstrate that gene expression differences between normal and cancer
tissue are anticorrelated with local dynamic entropy changes, thus providing a
systemic link between gene expression changes at the nodes and their local
network dynamics. In particular, we also find that genes which drive
cell-proliferation in cancer cells and which often encode oncogenes are
associated with reductions in the dynamic network entropy. In summary, our
results support the view that the observed increased robustness of cancer cells
to perturbation and therapy may be due to an increase in the dynamic network
entropy that allows cells to adapt to the new cellular stresses. Conversely,
genes that exhibit local flux entropy decreases in cancer may render cancer
cells more susceptible to targeted intervention and may therefore represent
promising drug targets.Comment: 10 pages, 3 figures, 4 tables. Submitte
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