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

Towards wave extraction in numerical relativity: the quasi-Kinnersley frame

The Newman-Penrose formalism may be used in numerical relativity to extract coordinate-invariant information about gravitational radiation emitted in strong-field dynamical scenarios. The main challenge in doing so is to identify a null tetrad appropriately adapted to the simulated geometry such that Newman-Penrose quantities computed relative to it have an invariant physical meaning. In black hole perturbation theory, the Teukolsky formalism uses such adapted tetrads, those which differ only perturbatively from the background Kinnersley tetrad. At late times, numerical simulations of astrophysical processes producing isolated black holes ought to admit descriptions in the Teukolsky formalism. However, adapted tetrads in this context must be identified using only the numerically computed metric, since no background Kerr geometry is known a priori. To do this, this paper introduces the notion of a quasi-Kinnersley frame. This frame, when space-time is perturbatively close to Kerr, approximates the background Kinnersley frame. However, it remains calculable much more generally, in space-times non-perturbatively different from Kerr. We give an explicit solution for the tetrad transformation which is required in order to find this frame in a general space-time.Comment: 13 pages, 3 figure

Boston Hospitality Review: Fall 2016

The Heart of Successful Hotels: Going Beyond the Monopoly Game Strategy By Joseph Khairallah and Andrea Foster -- Fragments of the Past By Peter Szende and Annie Holcombe -- Hospitality Branding in the Age of the Millennial By Allen Adamson and Chekitan S. Dev -- In 2017 What Will a Restaurant Actually Be? A New Taxonomy By Christopher Muller -- The Unreal Thing: Faux Heritage at Disney By Bradford Hudson -- An Insider’s Look at the 2016 Philadelphia Democratic National Convention: Hospitality and Inclusion at Work By Erin Tucker, Leora Halpern Lanz, and Juan Lesme

Detection of SHV β-lactamases in Gram-negative bacilli using fluorescein-labeled antibodies

<p>Abstract</p> <p>Background</p> <p>β-lactam resistance in Gram-negative bacteria is a significant clinical problem in the community, long-term care facilities, and hospitals. In these organisms, β-lactam resistance most commonly results from the production of β-lactamases. In Gram-negative bacilli, TEM-, SHV-, and CTX-M-type β-lactamases predominate. Therefore, new and accurate detection methods for these β-lactamase producing isolates are needed.</p> <p>Results</p> <p><it>E. coli </it>DH10B cells producing SHV-1 β-lactamase and a clinical isolate of <it>K. pneumoniae </it>producing SHV-5 β-lactamase were rendered membrane permeable, fixed and adhered to poly-L-lysine coated slides, and stained with purified polyclonal anti-SHV antibodies that were fluorescein labeled. <it>E. coli </it>DH10B cells without a <it>bla</it>_SHVgene were used as a negative control. The procedure generated a fluorescence signal from those slides containing cells expressing SHV β-lactamase that was sufficient for direct imaging.</p> <p>Conclusion</p> <p>We developed a rapid and accurate method of visualizing the SHV family of enzymes in clinical samples containing Gram-negative bacilli using a fluorescein-labeled polyclonal antibody.</p

Testing the bottleneck account for post-error slowing beyond the post-error response

The bottleneck account for post-error slowing assumes that cognitive resources are depleted after errors and thus the processing of subsequent events is delayed. To test this, we used a novel speeded-choice task and recorded behavioral measures and ERP (event-related potential) components on five trials following either an erroneous or correct response. We found that participants were slower and less accurate immediately after making an error and that this reduction of performance decayed on the following trials. Moreover, post-correct versus post-error differences in both the visual N1 and the P3 component were found. However, the difference in the P3 component rapidly diminished over time, whereas the differences in the N1 component were still evident in the fourth trial following the erroneous response. The results lay further support to the bottleneck account for post-error slowing and show a combination of early attentional and higher-order processing changes that occur after erroneous responses

A new acquisition model for the next disaster: overcoming disaster federalism issues through effective utilization of the Strategic National Stockpile

Using primary data collected from interviews with federal and state government officials and secondary data related to PPE distribution and state healthcare statistics, we discovered evidence that the use of the Strategic National Stockpile (SNS) to distribute personal protective equipment to state and local agencies in need during the height of COVID-19 was indeed poorly designed to cope with the COVID-19 emergency, leaving many states with shortages of badly needed medical supplies. As a result, many states struggled to organize an uncoordinated procurement response – which we suggest is due to federalism issues. To overcome federalism challenges and increase future disaster preparedness, we recommend four necessary reforms to the SNS that include 1) the incorporation of uncompensated industry experts into SNS administration, 2) the provision of an emergency production board for times of crisis, 3) elevated political leadership for the SNS, 4) improvement of federal-state supply chain governance

The Role of Forgetting in Undermining Good Intentions

Evaluating others is a fundamental feature of human social interaction–we like those who help more than those who hinder. In the present research, we examined social evaluation of those who not only intentionally performed good and bad actions but also those to whom good things have happened (the lucky) and those to whom bad things have happened (the unlucky). In Experiment 1a, subjects demonstrated a sympathetic preference for the unlucky. However, under cognitive load (Experiment 1b), no such preference was expressed. Further, in Experiments 2a and 2b, when a time delay between impression formation (learning) and evaluation (memory test) was introduced, results showed that younger (Experiment 2a) and older adults (Experiment 2b) showed a significant preference for the lucky. Together these experiments show that a consciously motivated sympathetic preference for those who are unlucky dissolves when memory is disrupted. The observed dissociation provides evidence for the presence of conscious good intentions (favoring the unlucky) and the cognitive compromising of such intentions when memory fails