1,351 research outputs found
Proteasome inhibition, the pursuit of new cancer therapeutics, and the adaptor molecule p130Cas
Current interest in proteasome inhibitors for cancer therapy has stimulated considerable research efforts to identify the molecular pathway to their cytotoxicity with a view to identifying the mechanisms of sensitivity and resistance as well as informing the development of new drugs. Zhao and Vuori describe this month in BMC Biology experiments indicating a novel role of the adaptor protein p130Cas in sensitivity to apoptosis induced not only by proteasome inhibitors but also by the unrelated drug doxorubicin
The Laser Astrometric Test of Relativity Mission
This paper discusses new fundamental physics experiment to test relativistic
gravity at the accuracy better than the effects of the 2nd order in the
gravitational field strength. The Laser Astrometric Test Of Relativity (LATOR)
mission uses laser interferometry between two micro-spacecraft whose lines of
sight pass close by the Sun to accurately measure deflection of light in the
solar gravity. The key element of the experimental design is a redundant
geometry optical truss provided by a long-baseline (100 m) multi-channel
stellar optical interferometer placed on the International Space Station. The
geometric redundancy enables LATOR to measure the departure from Euclidean
geometry caused by the solar gravity field to a very high accuracy. LATOR will
not only improve the value of the parameterized post-Newtonian (PPN) parameter
gamma to unprecedented levels of accuracy of 1 part in 1e8, it will also reach
ability to measure effects of the next post-Newtonian order (1/c^4) of light
deflection resulting from gravity's intrinsic non-linearity. The solar
quadrupole moment parameter, J2, will be measured with high precision, as well
as a variety of other relativistic. LATOR will lead to very robust advances in
the tests of fundamental physics: this mission could discover a violation or
extension of general relativity, or reveal the presence of an additional long
range interaction in the physical law. There are no analogs to the LATOR
experiment; it is unique and is a natural culmination of solar system gravity
experiments.Comment: 8 pages, 2 figures, invited talk given at the Second International
Conference on Particle and Fundamental Physics in Space (SpacePart'03), 10-12
December 2003, Washington, D
Interpreting clinical trial data in multiple myeloma: translating findings to the real-world setting
Substantial improvements in survival have been seen in multiple myeloma (MM) over recent years, associated with the
introduction and widespread use of multiple novel agents and regimens, as well as the emerging treatment paradigm
of continuous or long-term therapy. However, these therapies and approaches may have limitations in the community
setting, associated with toxicity burden, patient burden, and other factors including cost. Consequently, despite
improvements in efficacy in the rigorously controlled clinical trials setting, the same results are not always achieved in
real-world practice. Furthermore, the large number of different treatment options and regimens under investigation in
various MM settings precludes the feasibility of obtaining head-to-head clinical trial data, and there is a temptation to
use cross-trial comparisons to evaluate data across regimens. However, multiple aspects, including patient-related,
disease-related, and treatment-related factors, can influence clinical trial outcomes and lead to differences between
studies that may confound direct comparisons between data. In this review, we explore the various factors requiring
attention when evaluating clinical trial data across available agents/regimens, as well as other considerations that may
impact the translation of these findings into everyday MM management. We also investigate discrepancies between
clinical trial efficacy and real-world effectiveness through a literature review of non-clinical trial data in relapsed/
refractory MM on novel agent−based regimens and evaluate these data in the context of phase 3 trial results for
recently approved and commonly used regimens. We thereby demonstrate the complexity of interpreting data across
clinical studies in MM, as well as between clinical studies and routine-care analyses, with the aim to help clinicians
consider all the necessary issues when tailoring individual patients’ treatment approaches
Search for CP Violation in D^0--> K_S^0 pi^+pi^-
We report on a search for CP violation in the decay of D0 and D0B to Kshort
pi+pi-. The data come from an integrated luminosity of 9.0 1/fb of e+e-
collisions at sqrt(s) ~ 10 GeV recorded with the CLEO II.V detector. The
resonance substructure of this decay is well described by ten quasi-two-body
decay channels (K*-pi+, K*0(1430)-pi+, K*2(1430)-pi+, K*(1680)-pi+, Kshort rho,
Kshort omega, Kshort f0(980), Kshort f2(1270), Kshort f0(1370), and the ``wrong
sign'' K*+ pi-) plus a small non-resonant component. We observe no evidence for
CP violation in the amplitudes and phases that describe the decay D0 to K_S^0
pi+pi-.Comment: 10 pages, 3 figures, also available at
http://w4.lns.cornell.edu/public/CLNS/, submitted to PR
Loss of GABARAP mediates resistance to immunogenic chemotherapy in multiple myeloma
: Immunogenic cell death (ICD) is a form of cell death by which cancer treatments can induce a clinically relevant anti-tumor immune response in a broad range of cancers. In multiple myeloma (MM), the proteasome inhibitor bortezomib is an ICD inducer and creates durable therapeutic responses in patients. However, eventual relapse and resistance to bortezomib appear inevitable. Here, by integrating patient transcriptomic data with an analysis of calreticulin (CRT) protein interactors, we found that GABARAP is a key player whose loss prevented tumor cell death from being perceived as immunogenic after bortezomib treatment. GABARAP is located on chromosome 17p, which is commonly deleted in high-risk MM patients. GABARAP deletion impaired the exposure of the eat-me signal CRT on the surface of dying MM cells in vitro and in vivo, thus reducing tumor cell phagocytosis by dendritic cells and the subsequent anti-tumor T cell response. Low GABARAP was independently associated with shorter MM patient survival and reduced tumor immune infiltration. Mechanistically, we found that GABARAP deletion blocked ICD signaling by decreasing autophagy and altering Golgi apparatus morphology, with consequent defects in the downstream vesicular transport of CRT. Conversely, upregulating autophagy using rapamycin restored Golgi morphology, CRT exposure and ICD signaling in GABARAPKO cells undergoing bortezomib treatment. Therefore, coupling an ICD inducer, like bortezomib, with an autophagy inducer, like rapamycin, may improve patient outcomes in MM, where low GABARAP in the form of del(17p) is common and leads to worse outcomes
Study of the q^2-Dependence of B --> pi ell nu and B --> rho(omega)ell nu Decay and Extraction of |V_ub|
We report on determinations of |Vub| resulting from studies of the branching
fraction and q^2 distributions in exclusive semileptonic B decays that proceed
via the b->u transition. Our data set consists of the 9.7x10^6 BBbar meson
pairs collected at the Y(4S) resonance with the CLEO II detector. We measure
B(B0 -> pi- l+ nu) = (1.33 +- 0.18 +- 0.11 +- 0.01 +- 0.07)x10^{-4} and B(B0 ->
rho- l+ nu) = (2.17 +- 0.34 +0.47/-0.54 +- 0.41 +- 0.01)x10^{-4}, where the
errors are statistical, experimental systematic, systematic due to residual
form-factor uncertainties in the signal, and systematic due to residual
form-factor uncertainties in the cross-feed modes, respectively. We also find
B(B+ -> eta l+ nu) = (0.84 +- 0.31 +- 0.16 +- 0.09)x10^{-4}, consistent with
what is expected from the B -> pi l nu mode and quark model symmetries. We
extract |Vub| using Light-Cone Sum Rules (LCSR) for 0<= q^2<16 GeV^2 and
Lattice QCD (LQCD) for 16 GeV^2 <= q^2 < q^2_max. Combining both intervals
yields |Vub| = (3.24 +- 0.22 +- 0.13 +0.55/-0.39 +- 0.09)x10^{-3}$ for pi l nu,
and |Vub| = (3.00 +- 0.21 +0.29/-0.35 +0.49/-0.38 +-0.28)x10^{-3} for rho l nu,
where the errors are statistical, experimental systematic, theoretical, and
signal form-factor shape, respectively. Our combined value from both decay
modes is |Vub| = (3.17 +- 0.17 +0.16/-0.17 +0.53/-0.39 +-0.03)x10^{-3}.Comment: 45 pages postscript, also available through
http://w4.lns.cornell.edu/public/CLNS, submitted to PR
Topology by Design in Magnetic nano-Materials: Artificial Spin Ice
Artificial Spin Ices are two dimensional arrays of magnetic, interacting
nano-structures whose geometry can be chosen at will, and whose elementary
degrees of freedom can be characterized directly. They were introduced at first
to study frustration in a controllable setting, to mimic the behavior of spin
ice rare earth pyrochlores, but at more useful temperature and field ranges and
with direct characterization, and to provide practical implementation to
celebrated, exactly solvable models of statistical mechanics previously devised
to gain an understanding of degenerate ensembles with residual entropy. With
the evolution of nano--fabrication and of experimental protocols it is now
possible to characterize the material in real-time, real-space, and to realize
virtually any geometry, for direct control over the collective dynamics. This
has recently opened a path toward the deliberate design of novel, exotic
states, not found in natural materials, and often characterized by topological
properties. Without any pretense of exhaustiveness, we will provide an
introduction to the material, the early works, and then, by reporting on more
recent results, we will proceed to describe the new direction, which includes
the design of desired topological states and their implications to kinetics.Comment: 29 pages, 13 figures, 116 references, Book Chapte
Measurement of Lepton Momentum Moments in the Decay bar{B} \to X \ell \bar{\nu} and Determination of Heavy Quark Expansion Parameters and |V_cb|
We measure the primary lepton momentum spectrum in B-bar to X l nu decays,
for p_l > 1.5 GeV/c in the B rest frame. From this, we calculate various
moments of the spectrum. In particular, we find R_0 = [int(E_l>1.7)
(dGam/dE_sl)*dE_l] / [int(E_l>1.5) (dGam/dE_sl)*dE_l] = 0.6187 +/- 0.0014_stat
+/- 0.0016_sys and R_1 = [int(E_l>1.5) E_l(dGam/dE_sl)*dE_l] / [int(E_l>1.5)
(dGam/dE_sl)*dE_l] = (1.7810 +/- 0.0007_stat +/- 0.0009_sys) GeV. We use these
moments to determine non-perturbative parameters governing the semileptonic
width. In particular, we extract the Heavy Quark Expansion parameters
Lambda-bar = (0.39 +/- 0.03_stat +/- 0.06_sys +/- 0.12_th) GeV and lambda_1 =
(-0.25 +/- 0.02_stat +/- 0.05_sys +/- 0.14_th) GeV^2. The theoretical
constraints used are evaluated through order 1/M_B^3 in the non-perturbative
expansion and beta_0*alpha__s^2 in the perturbative expansion. We use these
parameters to extract |V_cb| from the world average of the semileptonic width
and find |V_cb| = (40.8 +/- 0.5_Gam-sl +/- 0.4_(lambda_1,Lambda-bar)-exp +/-
0.9_th) x 10^-3. In addition, we extract the short range b-quark mass m_b^1S =
(4.82 +/- 0.07_exp +/- 0.11_th) GeV/c^2. Finally, we discuss the implications
of our measurements for the theoretical understanding of inclusive semileptonic
processes.Comment: 21 pages postscript, also available through
http://w4.lns.cornell.edu/public/CLNS, submitted to PR
Regular use of aspirin and pancreatic cancer risk
BACKGROUND: Regular use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been consistently associated with reduced risk of colorectal cancer and adenoma, and there is some evidence for a protective effect for other types of cancer. As experimental studies reveal a possible role for NSAIDs is reducing the risk of pancreatic cancer, epidemiological studies examining similar associations in human populations become more important. METHODS: In this hospital-based case-control study, 194 patients with pancreatic cancer were compared to 582 age and sex-matched patients with non-neoplastic conditions to examine the association between aspirin use and risk of pancreatic cancer. All participants received medical services at the Roswell Park Cancer Institute in Buffalo, NY and completed a comprehensive epidemiologic questionnaire that included information on demographics, lifestyle factors and medical history as well as frequency and duration of aspirin use. Patients using at least one tablet per week for at least six months were classified as regular aspirin users. Unconditional logistic regression was used to compute crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Pancreatic cancer risk in aspirin users was not changed relative to non-users (adjusted OR = 1.00; 95% CI 0.72–1.39). No significant change in risk was found in relation to greater frequency or prolonged duration of use, in the total sample or in either gender. CONCLUSIONS: These data suggest that regular aspirin use may not be associated with lower risk of pancreatic cancer
Measurement of the Charge Asymmetry in
We report on a search for a CP-violating asymmetry in the charmless hadronic
decay B -> K*(892)+- pi-+, using 9.12 fb^-1 of integrated luminosity produced
at \sqrt{s}=10.58 GeV and collected with the CLEO detector. We find A_{CP}(B ->
K*(892)+- pi-+) = 0.26+0.33-0.34(stat.)+0.10-0.08(syst.), giving an allowed
interval of [-0.31,0.78] at the 90% confidence level.Comment: 7 pages postscript, also available through
http://w4.lns.cornell.edu/public/CLNS, submitted to PR
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