Proteasome inhibitor (PI) carfilzomib (CFZ) has activity superior to bortezomib (BTZ) and is increasingly incorporated in multiple myeloma (MM) frontline therapy and relapsed settings. Most MM ...patients ultimately experience PI-refractory disease, an unmet medical need with poorly understood biology and dismal outcome. Pharmacologic targeting of ABCB1 improved patient outcomes, including MM, but suffered from adverse drug effects and insufficient plasma concentrations. Proteomics analysis identified ABCB1 overexpression as the most significant change in CFZ-resistant MM cells. We addressed the functional role of ABCB1 overexpression in MM and observed significantly upregulated ABCB1 in peripheral blood malignant plasma cells (PCs) vs untreated patients' bone marrow PC. ABCB1 overexpression reduces the proteasome-inhibiting activity of CFZ due to drug efflux, in contrast to BTZ. Likewise, the cytotoxicity of established anti-MM drugs was significantly reduced in ABCB1-expressing MM cells. In search for potential drugs targeting ABCB1 in clinical trials, we identified the HIV protease inhibitors nelfinavir (NFV) and lopinavir (LPV) as potent functional modulators of ABCB1-mediated drug export, most likely via modulation of mitochondria permeability transition pore. NFV and LPV restored CFZ activity at therapeutically relevant drug levels and thus represent ready-to-use drugs to be tested in clinical trials to target ABCB1 and to re-sensitize PC to established myeloma drugs, in particular CFZ.
Estimates of the past location of the auroral zone can aid archaeologists in the interpretation of documented light phenomena in the night sky; in particular, during periods without written records ...and in regions where aurorae are scarce today. Aurora occurrence largely depends on solar activity as well as the tilt and strength of the geomagnetic field. Here, we introduce a tool (AUREST) that visually combines the time‐dependent variations of these parameters to provide relative estimates of aurora occurrence in mid‐latitude regions of the Northern Hemisphere over the past 10 000 years. Tests against historical aurora observations show good compatibility with AUREST.
The spectroscopic quadrupole moment of the first 2+ state of 12C has been measured employing the Coulomb-excitation re-orientation technique. Our result of Qs(21+)=+9.3−3.8+3.5efm2 suggests a larger ...oblate deformation than previously reported. Combining this with the consistently re-analyzed adopted value, we present the most precise value to date of Qs(21+)=+9.5(18)efm2, which is consistent with a geometrical rotor description. This simple outcome is compared to state-of-the-art shell-model, mean-field, ab initio calculations, cluster-based and geometrical-like theories, which show varying degrees of emergent quadrupole collectivity.
The electromagnetic character of the ΔI=1 transitions connecting the 1- to 0-phonon and the 2- to 1-phonon wobbling bands should be dominated by an E2 component, due to the collective motion of the ...entire nuclear charge. In the present work it is shown, based on combined angular correlation and linear polarization measurements, that the mixing ratios of all analyzed connecting transitions between low-lying bands in 135Pr interpreted as 0-, 1-, and 2-phonon wobbling bands, have absolute values smaller than one. This indicates predominant M1 magnetic character, which is incompatible with the proposed wobbling nature. All experimental observables are instead in good agreement with quasiparticle-plus-triaxial-rotor model calculations, which describe the bands as resulting from a rapid re-alignment of the total angular momentum from the short to the intermediate nuclear axis.
Abstract
The electromagnetic transition probabilities of the yrast
$$2^+$$
2
+
states in the midshell Te isotopes, two protons above the closed shell at Sn, are of great importance for the ...understanding of nuclear collectivity in these isotopes and the role played by the neutron-proton interactions and cross-shell excitations. However, the large uncertainty of the experimental data for the midshell nucleus
118
Te and the missing data for
116
Te make it difficult to pin down the general trend of the evolution of transition probabilities as a function of the neutron number. In this work, the lifetime of the yrast
$$2^+$$
2
+
state in
118
Te was measured, with the aim of reducing the uncertainty of the previous measurement. The result is
$$\tau _{2+}=7.46(19)$$
τ
2
+
=
7.46
(
19
)
ps. In addition, the lifetime of the
$$4^+$$
4
+
state was measured to be
$$\tau _{4+} = 4.25(23)$$
τ
4
+
=
4.25
(
23
)
ps. The experimental transition rates are extracted from the measured lifetimes and compared with systematic large-scale shell-model calculations. The trend of the
$$B(\textrm{E2};0^+\rightarrow 2^+)$$
B
(
E2
;
0
+
→
2
+
)
values in the midshell area is in good agreement with the calculations and the calculated
$$B_{4/2}$$
B
4
/
2
ratio provide evidence for
118
Te as a near perfect harmonic vibrator.
Prompt and delayed γ-ray spectroscopy of the neutron-deficient, semi-magic isotope 187Pb has been performed using the recoil-decay and isomer-decay tagging techniques at the Argonne Gas-Filled ...Analyzer. A new 5.15(15)-μs isomeric state at only 308 keV above the spherical 3/2− ground state is identified and classified as a shape isomer. A strongly-coupled band is observed on top of the isomer, which is nearly identical to the one built on the prolate 7/2−514 Nilsson state in the isotone 185Hg. Based on this similarity and on the result of the potential-energy surface calculations, the new isomer in 187Pb is proposed to originate from the same configuration. The retarded character of the 308-keV (7/2−)→3/2gs− transition with a deduced B(E2)=5.6(2)×10−4 W.u. can be well explained by the significant difference between the prolate parent and spherical daughter configurations, leading to the shape isomerism. The excitation energy of the isomer is surprisingly low, being roughly half of the excitation energies of the known 0+ intruder bandheads in the neighboring 186,188Pb isotopes. The combined results of the present work and the previous α-decay and laser spectroscopy studies present evidence for triple shape coexistence at low energy in the negative-parity configurations of 187Pb, which is well reproduced by the potential-energy surface calculations.
Lifetimes of low-lying excited states in the νi13/2+ bands of the neutron-deficient osmium isotopes 169,171,173Os have been measured for the first time using the recoil-distance Doppler shift and ...recoil-isomer tagging techniques. An unusually low value is observed for the ratio B(E2;21/2+→17/2+)/B(E2;17/2+→13/2+) in 169Os, similar to the “anomalously” low values of the ratio B(E2;41+→21+)/B(E2;21+→0gs+) previously observed in several transitional rare-earth nuclides with even numbers of neutrons and protons, including the neighbouring 168,170Os. Furthermore, the evolution of B(E2;21/2+→17/2+)/B(E2;17/2+→13/2+) with increasing neutron number in the odd-mass isotopic chain 169,171,173Os is observed to follow the same trend as observed previously in the even-even Os isotopes. These findings indicate that the possible quantum phase transition from a seniority conserving structure to a collective regime as a function of neutron number suggested for the even-even systems is maintained in these odd-mass osmium nuclei, with the odd valence neutron merely acting as a “spectator”. As for the even-even nuclei, the phenomenon is highly unexpected for nuclei that are not situated near closed shells.
The discovery of presolar grains in primitive meteorites has initiated a new era of research in the study of stellar nucleosynthesis. However, the accurate classification of presolar grains as being ...of specific stellar origins is particularly challenging. Recently, it has been suggested that sulfur isotopic abundances may hold the key to definitively identifying presolar grains with being of nova origins and, in this regard, the astrophysical 33Cl ( p , γ ) 34Ar reaction is expected to play a decisive role. As such, we have performed a detailed γ -ray spectroscopy study of 34Ar . Excitation energies have been measured with high precision and spin-parity assignments for resonant states, located above the proton threshold in 34Ar , have been made for the first time. Uncertainties in the 33Cl (p , γ) reaction have been dramatically reduced and the results indicate that a newly identified ℓ = 0 resonance at Er = 396.9 ( 13 ) keV dominates the entire rate for T = 0.25 – 0.40 GK . Furthermore, nova hydrodynamic simulations based on the present work indicate an ejected 32S /33S abundance ratio distinctive from type-II supernovae and potentially compatible with recent measurements of a presolar grain.
PDF
