143 research outputs found
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
Organochlorine Pesticides in Chlorioallantoic Membranes of Morelet\u27s Crocodile Eggs from Belize
Recent studies examined the utility of the chorioallantoic membrane (CAM) as a nonlethal, noninvasive indicator of environmental contaminant exposure in oviparous wildlife. The CAM is a highly vascularized extraembryonic membrane that functions as a site for respiration, nutrient transport, and waste storage during embryonic development. After hatching, the CAM is usually discarded with the eggshell and can be used for chemical residue analysis. Chorioallantoic membranes have been used successfully to examine contaminant exposure and predict chemical concentrations in multiple species of birds and reptiles. In this study, we examined organochlorine (OC) pesticide concentrations in CAMs from eggs of Morelet\u27s crocodiles (Crocodylus moreletii) from northern Belize. Multiple OCs were detected in crocodile CAMs, including aldrin, dieldrin, endrin, dichlorodiphenyltrichloroethane, dichlorodiphenyldichloroethane, dichlorodiphenyldichloroethylene (DDE), heptachlor, lindane, and methoxychlor. Number and concentrations of OC compounds in CAMs were variable. The most prevalent contaminant detected was DDE, which occurred in 69% of CAMs, with concentrations ranging from 0.3 parts per billion (ppb) to 17.0 ppb. The OC burdens in crocodile CAMs confirm contamination of eggs and suggest exposure in embryos and maternal females. These results further support the use of CAMs as qualitative indicators of OC exposure in oviparous wildlife. The efficacy of this sampling technique in the field will depend on the logistics and cost associated with CAM collection and the specific life history traits of the wildlife species
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
KELT-11b: A Highly Inflated Sub-Saturn Exoplanet Transiting the V=8 Subgiant HD 93396
We report the discovery of a transiting exoplanet, KELT-11b, orbiting the
bright () subgiant HD 93396. A global analysis of the system shows that
the host star is an evolved subgiant star with K,
, , log , and [Fe/H].
The planet is a low-mass gas giant in a day orbit,
with , , g cm, surface gravity log , and equilibrium temperature K. KELT-11 is the brightest known transiting exoplanet host
in the southern hemisphere by more than a magnitude, and is the 6th brightest
transit host to date. The planet is one of the most inflated planets known,
with an exceptionally large atmospheric scale height (2763 km), and an
associated size of the expected atmospheric transmission signal of 5.6%. These
attributes make the KELT-11 system a valuable target for follow-up and
atmospheric characterization, and it promises to become one of the benchmark
systems for the study of inflated exoplanets.Comment: 15 pages, Submitted to AAS Journal
Planetary Candidates Observed by Kepler IV: Planet Sample From Q1-Q8 (22 Months)
We provide updates to the Kepler planet candidate sample based upon nearly
two years of high-precision photometry (i.e., Q1-Q8). From an initial list of
nearly 13,400 Threshold Crossing Events (TCEs), 480 new host stars are
identified from their flux time series as consistent with hosting transiting
planets. Potential transit signals are subjected to further analysis using the
pixel-level data, which allows background eclipsing binaries to be identified
through small image position shifts during transit. We also re-evaluate Kepler
Objects of Interest (KOI) 1-1609, which were identified early in the mission,
using substantially more data to test for background false positives and to
find additional multiple systems. Combining the new and previous KOI samples,
we provide updated parameters for 2,738 Kepler planet candidates distributed
across 2,017 host stars. From the combined Kepler planet candidates, 472 are
new from the Q1-Q8 data examined in this study. The new Kepler planet
candidates represent ~40% of the sample with Rp~1 Rearth and represent ~40% of
the low equilibrium temperature (Teq<300 K) sample. We review the known biases
in the current sample of Kepler planet candidates relevant to evaluating planet
population statistics with the current Kepler planet candidate sample.Comment: 12 pages, 8 figures, Accepted ApJ Supplemen
Securing the Legacy of TESS through the Care and Maintenance of TESS Planet Ephemerides
Much of the science from the exoplanets detected by the Transiting Exoplanet Survey Satellite (TESS) mission relies on precisely predicted transit times that are needed for many follow-up characterization studies. We investigate ephemeris deterioration for simulated TESS planets and find that the ephemerides of 81% of those will have expired (i.e., 1σ mid-transit time uncertainties greater than 30 minutes) 1 yr after their TESS observations. We verify these results using a sample of TESS planet candidates as well. In particular, of the simulated planets that would be recommended as James Webb Space Telescope (JWST) targets by Kempton et al., ~80% will have mid-transit time uncertainties >30 minutes by the earliest time JWST would observe them. This rapid deterioration is driven primarily by the relatively short time baseline of TESS observations. We describe strategies for maintaining TESS ephemerides fresh through follow-up transit observations. We find that the longer the baseline between the TESS and the follow-up observations, the longer the ephemerides stay fresh, and that 51% of simulated primary mission TESS planets will require space-based observations. The recently approved extension to the TESS mission will rescue the ephemerides of most (though not all) primary mission planets, but the benefits of these new observations can only be reaped 2 yr after the primary mission observations. Moreover, the ephemerides of most primary mission TESS planets (as well as those newly discovered during the extended mission) will again have expired by the time future facilities such as the ELTs, Ariel, and the possible LUVOIR/Origins Space Telescope missions come online, unless maintenance follow-up observations are obtained
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