516 research outputs found
B640: An Evaluation of the Distribution of Trucked Pulpwood in East-Central Maine
The movement of pulpwood from forest to market can be a critical and costly activity. Many factors influence this movement and contribute to its complexity. In 1963, a study was undertaken to quantitatively describe the distribution patterns of trucked pulpwood for a representative area of the state of Maine.https://digitalcommons.library.umaine.edu/aes_bulletin/1074/thumbnail.jp
Novel pyrrolobenzodiazepine benzofused hybrid molecules inhibit NF-κB activity and synergise with bortezomib and ibrutinib in hematological cancers
Chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) are incurable hematological malignancies that are pathologically linked with aberrant NF-κB activation. In this study, we identified a group of novel C8-linked benzofused Pyrrolo[2,1-c][1,4]benzodiazepines (PBD) monomeric hybrids capable of sequence-selective inhibition of NF-κB with low nanomolar LD50 values in CLL (n=46) and MM cell lines (n=5). The lead compound, DC-1-192, significantly inhibited NF-κB DNA binding after just 4h exposure and demonstrating inhibitory effects on both canonical and non-canonical NF-κB subunits. In primary CLL cells, sensitivity to DC-1-192 was inversely correlated with RelA subunit expression (r2=0.2) and samples with BIRC3 or NOTCH1 mutations showed increased sensitivity (P=0.001). RNA-sequencing and gene set enrichment analysis confirmed the over-representation of NF-κB regulated genes in the down-regulated gene list. Furthermore, In vivo efficacy studies in NOD/SCID mice, using a systemic RPMI 8226 human multiple myeloma xenograft model, showed that DC-1-192 significantly prolonged survival (P=0.017). In addition, DC1-192 showed synergy with bortezomib and ibrutinib; synergy with ibrutinib was enhanced when CLL cells were co-cultured on CD40L-expressing fibroblasts in order to mimic the cytoprotective lymph node microenvironment (P = 0.01). Given that NF-κB plays a role in both bortezomib and ibrutinib resistance mechanisms, these data provide a strong rationale for the use of DC-1-192 in the treatment of NF-κB-driven cancers, particularly in the context of relapsed/refractory disease
Effects of systematic shortening of noncovalent C8 side chain on the cytotoxicity and NF-κB inhibitory capacity of pyrrolobenzodiazepines (PBDs)
The systematic shortening of the noncovalent element of a C8-linked pyrrolobenzodiazepine (PBD) conjugate (13) led to the synthesis of a 19-member library of C8-PBD monomers. The critical elements of 13, which were required to render the molecule cytotoxic, were elucidated by an annexin V assay. The effects of shortening the noncovalent element of the molecule on transcription factor inhibitory capacity were also explored through an enzyme-linked immunosorbent assay-based measurement of nuclear NF-κB upon exposure of JJN-3 cells to the synthesized molecules. Although shortening the noncovalent interactive element of 13 had a less than expected effect upon compound cytotoxicity due to reduced DNA interaction, the transcription factor inhibitory capacity of the molecule was notably altered. This study suggests that a relatively short noncovalent side chain at the C8 position of PBD is sufficient to confer cytotoxicity. The shortened PBD monomers provide a new ADC payload scaffold because of their potent cytotoxicity and druglike properties
A dozen colliding wind X-ray binaries in the star cluster R136 in the 30Doradus region
We analyzed archival Chandra X-ray observations of the central portion of the
30 Doradus region in the Large Magellanic Cloud. The image contains 20 X-ray
point sources with luminosities between and erg s (0.2 -- 3.5 keV). A dozen sources have bright WN
Wolf-Rayet or spectral type O stars as optical counterparts. Nine of these are
within pc of R136, the central star cluster of NGC2070. We derive an
empirical relation between the X-ray luminosity and the parameters for the
stellar wind of the optical counterpart. The relation gives good agreement for
known colliding wind binaries in the Milky Way Galaxy and for the identified
X-ray sources in NGC2070. We conclude that probably all identified X-ray
sources in NGC2070 are colliding wind binaries and that they are not associated
with compact objects. This conclusion contradicts Wang (1995) who argued, using
ROSAT data, that two earlier discovered X-ray sources are accreting black-hole
binaries. Five of the eighteen brightest stars in R136 are not visible in our
X-ray observations. These stars are either single, have low mass companions or
very wide orbits. The resulting binary fraction among early type stars is then
unusually high (at least 70%).Comment: 23 pages, To appear in August in Ap
Molecular heterogeneity and receptor coamplification drive resistance to targeted therapy in MET-Amplified esophagogastric cancer
Theoretical X-ray Line Profiles from Colliding Wind Binaries
We present theoretical X-ray line profiles from a range of model colliding
wind systems. In particular, we investigate the effects of varying the stellar
mass-loss rates, the wind speeds, and the viewing orientation. We find that a
wide range of theoretical line profile shapes is possible, varying with orbital
inclination and phase. At or near conjunction, the lines have approximately
Gaussian profiles, with small widths (HWHM ~ 0.1 v_\infty) and definite blue-
or redshifts (depending on whether the star with the weaker wind is in front or
behind). When the system is viewed at quadrature, the lines are generally much
broader (HWHM ~ v_\infty), flat-topped and unshifted. Local absorption can have
a major effect on the observed profiles - in systems with mass-loss rates of a
few times 10^{-6} Msol/yr the lower energy lines (E <~ 1 kev) are particularly
affected. This generally results in blueward-skewed profiles, especially when
the system is viewed through the dense wind of the primary. The orbital
variation of the line widths and shifts is reduced in a low inclination binary.
The extreme case is a binary with i = 0 degrees, for which we would expect no
line profile variation.Comment: 15 pages, 15 figures. To appear in MNRA
First Observation of the decay KL -> pi0 e e gamma
We report on the first observation of the decay KL -> pi0 ee gamma by the
KTeV E799 experiment at Fermilab. Based upon a sample of 48 events with an
estimated background of 3.6 +/- 1.1 events, we measure the KL -> pi0 ee gamma
branching ratio to be (2.34 +/- 0.35 +/- 0.13)x10^{-8}. Our data agree with
recent O(p^6) calculations in chiral perturbation theory that include
contributions from vector meson exchange through the parameter a_V. A fit was
made to the KL -> pi0 ee gamma data for a_V with the result -0.67 +/- 0.21 +/-
0.12, which is consistent with previous results from KTeV.Comment: Submitted to Physical Review Letters, 5 pages, 5 figure
A New Measurement of the Radiative Ke3 Branching Ratio and Photon Spectrum
We present a preliminary report on a new measurement of the radiative neutral
Ke3 branching ratio and the first study of the photon spectrum in this decay.
We find BR(Ke3g, E*_g>30 GeV, Th*_eg>20 deg)/BR(Ke3) =
0.911+-0.009(stat)+0.021-0.010(syst)%. Our measurement of the spectrum is
consistent with inner bremsstrahlung only as the source of photons at the 2
sigma level.Comment: 5 pages, 4 figures, proceedings paper from Meson 2000, Cracow,
Poland, May 200
A Measurement of the Branching Ratio of
We report on a study of the decay carried out as
a part of the KTeV/E799 experiment at Fermilab. The 1997 data yielded a sample
of 1543 events, including an expected background of events. An
effective form factor was determined from the observed distribution of the
invariant mass. Using this form factor in the calculation of the
detector acceptance, the branching ratio was measured to be .Comment: 5 pages, 4 figure
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