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

Species Identification of Golden and Bald Eagle Talons Using Morphometrics

The Golden Eagle (Aquila chrysaetos) and Bald Eagle (Haliaeetus leucocephalus) are the largest avian predators in North America, and are thus species of great ecological importance and cultural significance. There is a long history of human use of eagle body parts, and this use continues today: Bald and Golden eagles are among the North American birds most affected by the illegal wildlife trade. Detached eagle talons are often recovered in both law enforcement and archaeological contexts, but data to allow morphological identification of these talons have been lacking. This study documents measureable differences in the morphology of Bald Eagle and North American Golden Eagle talons, which can be used to identify the detached talons of these two species. We measured talon samples of both species from the U.S. Fish and Wildlife Service’s National Fish and Wildlife Forensics Laboratory and other collections and categorized them according to species, sex, age, and digit number (Digits I–IV). We then conducted ANOVA and principal components analysis to test for statistical differences in the talon measurements of these two species. Although species identification was not always possible, due to overlap in the morphology of the talons of the two eagles, our results demonstrated that measurements allow identification of many talons, especially the large talons of Digits I and II, which are most commonly recovered in law enforcement cases. These results will be valuable for researchers studying North American eagle remains in the contexts of law enforcement, archaeology, and anthropology

Survey for Transiting Extrasolar Planets in Stellar Systems IV: Variables in the Field of NGC 1245

The Survey for Transiting Extrasolar Planets in Stellar Systems (STEPSS) project is a search for planetary transits in open clusters. In this paper, we analyze the STEPSS observations of the open cluster NGC 1245 to determine the variable star content of the cluster. Out of 6787 stars observed with V < 22, of which ~870 are cluster members, we find 14 stars with clear intrinsic variability that are potential cluster members, and 29 clear variables that are not cluster members. None of these variables have been previously identified. We present light curves, finding charts, and stellar/photometric data on these variable objects. Several of the interacting binaries have estimated distances consistent with the cluster distance determined from isochrone fits to the color magnitude diagram. Four stars at the main sequence turnoff of the cluster have light curves consistent with gamma Doradus variability. If these gamma Doradus candidates are confirmed, they represent the oldest and coolest members of this class of variable discovered to date.Comment: 20 pages, 15 figures. Submitted to AJ. PDF version with full-resolution figures at http://www.astronomy.ohio-state.edu/~pepper/ms.pd

The TESS Mission Target Selection Procedure

We describe the target selection procedure by which stars are selected for 2 minute and 20 s observations by TESS. We first list the technical requirements of the TESS instrument and ground systems processing that limit the total number of target slots. We then describe algorithms used by the TESS Payload Operation Center (POC) to merge candidate targets requested by the various TESS mission elements (the Target Selection Working Group, TESS Asteroseismic Science Consortium, and Guest Investigator office). Lastly, we summarize the properties of the observed TESS targets over the two-year primary TESS mission. We find that the POC target selection algorithm results in 2.1-3.4 times as many observed targets as target slots allocated for each mission element. We also find that the sky distribution of observed targets is different from the sky distributions of candidate targets due to technical constraints that require a relatively even distribution of targets across the TESS fields of view. We caution researchers exploring statistical analyses of TESS planet-host stars that the population of observed targets cannot be characterized by any simple set of criteria applied to the properties of the input Candidate Target Lists

Koinonia

Best Practice FeaturesLife on Life Learning: Steps Towards Authentic Mentoring, Brian Jensen The Heart of the Honor Code: I am My Brother\u27s Keeper, Emily J. Darnell Spotlight FeaturesOld People are Whole Persons, Too: Why Understanding Heritage is a Foundational Component of College Student Development, Philip Byers Ministry and Learning in Residence Life, Josh Arnold Shepherding in an Age of Edupunks, Drew Moser The Gap in the Curtain: Seeing Pieces of a Residential Community\u27s Future, David Johnstone InterviewsA Conversation with Juana Bordas, conducted by Rob Pepper Looking Into the Future: Two Educators\u27 Perspectives on Christian Higher Education, by Kim Stave and Ken Heffner (edited by Kirstin Vander Giessen-Reitsma) Book ReviewsThe Unlikely Disciple (by Kevin Roose), reviewed by Christopher Bohle ReflectionsSeven Greek Words that Mean the World to Me, Bob Crow FeaturesThe President\u27s Corner Editor\u27s Deskhttps://pillars.taylor.edu/acsd_koinonia/1013/thumbnail.jp

Neutrophil gelatinase-associated lipocalin prior to cardiac surgery predicts acute kidney injury and mortality.

OBJECTIVE: We aimed to investigate whether preoperative serum neutrophil gelatinase-associated lipocalin (sNGALpre-op) predicted postoperative acute kidney injury (AKI) during hospitalisation and 1-year cardiovascular and all-cause mortality following adult cardiac surgery. METHODS: This study was a post hoc analysis of the Effect of Remote Ischemic Preconditioning on Clinical Outcomes in Patient Undergoing Coronary Artery Bypass Graft Surgery trial involving adult patients undergoing coronary artery bypass graft. Postoperative AKI within 72 hours was defined using the International Kidney Disease: Improving Global Outcomes classification. RESULTS: 1371 out of 1612 patients had data on sNGALpre-op. The overall 1-year cardiovascular and all-cause mortality was 5.2% (71/1371) and 7.7% (105/1371), respectively. There was an observed increase in the incidence of AKI from the first to the third tertile of sNGALpre-op (30.5%, 41.5% and 45.9%, respectively, p220 ng/L) had an estimated twofold increase risk of cardiovascular and all-cause mortality at 1 year. CLINICAL TRIAL REGISTRATION: NCT101247545; Post-results

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

Transit Detection in the MEarth Survey of Nearby M Dwarfs: Bridging the Clean-First, Search-Later Divide

In the effort to characterize the masses, radii, and atmospheres of potentially habitable exoplanets, there is an urgent need to find examples of such planets transiting nearby M dwarfs. The MEarth Project is an ongoing effort to do so, as a ground-based photometric survey designed to detect exoplanets as small as 2 Earth radii transiting mid-to-late M dwarfs within 33 pc of the Sun. Unfortunately, identifying transits of such planets in photometric monitoring is complicated both by the intrinsic stellar variability that is common among these stars and by the nocturnal cadence, atmospheric variations, and instrumental systematics that often plague Earth-bound observatories. Here we summarize the properties of MEarth data gathered so far, and we present a new framework to detect shallow exoplanet transits in wiggly and irregularly-spaced light curves. In contrast to previous methods that clean trends from light curves before searching for transits, this framework assesses the significance of individual transits simultaneously while modeling variability, systematics, and the photometric quality of individual nights. Our Method for Including Starspots and Systematics in the Marginalized Probability of a Lone Eclipse (MISS MarPLE) uses a computationally efficient semi-Bayesian approach to explore the vast probability space spanned by the many parameters of this model, naturally incorporating the uncertainties in these parameters into its evaluation of candidate events. We show how to combine individual transits processed by MISS MarPLE into periodic transiting planet candidates and compare our results to the popular Box-fitting Least Squares (BLS) method with simulations. By applying MISS MarPLE to observations from the MEarth Project, we demonstrate the utility of this framework for robustly assessing the false alarm probability of transit signals in real data. [slightly abridged]Comment: accepted to the Astronomical Journal, 21 pages, 12 figure