The CXCL12/CXCR4 signaling axis retains neutrophils at inflammatory sites in zebrafish

The inappropriate retention of neutrophils at inflammatory sites is a major driver of the excessive tissue damage characteristic of respiratory inflammatory diseases including COPD, ARDS, and cystic fibrosis. The molecular programmes which orchestrate neutrophil recruitment to inflammatory sites through chemotactic guidance have been well-studied. However, how neutrophil sensitivity to these cues is modulated during inflammation resolution is not understood. The identification of neutrophil reverse migration as a mechanism of inflammation resolution and the ability to modulate this therapeutically has identified a new target to treat inflammatory disease. Here we investigate the role of the CXCL12/CXCR4 signaling axis in modulating neutrophil retention at inflammatory sites. We used an in vivo tissue injury model to study neutrophilic inflammation using transgenic zebrafish larvae. Expression of cxcl12a and cxcr4b during the tissue damage response was assessed using in situ hybridization and analysis of RNA sequencing data. CRISPR/Cas9 was used to knockdown cxcl12a and cxcr4b in zebrafish larvae. The CXCR4 antagonist AMD3100 was used to block the Cxcl12/Cxcr4 signaling axis pharmacologically. We identified that cxcr4b and cxcl12a are expressed at the wound site in zebrafish larvae during the inflammatory response. Following tail-fin transection, removal of neutrophils from inflammatory sites is significantly increased in cxcr4b and cxcl12a CRISPR knockdown larvae. Pharmacological inhibition of the Cxcl12/Cxcr4 signaling axis accelerated resolution of the neutrophil component of inflammation, an effect caused by an increase in neutrophil reverse migration. The findings of this study suggest that CXCR4/CXCL12 signaling may play an important role in neutrophil retention at inflammatory sites, identifying a potential new target for the therapeutic removal of neutrophils from the lung in chronic inflammatory disease

Efficacy and safety of weekly carfilzomib (70 mg/m2), dexamethasone, and daratumumab (KdD70) is comparable to twice-weekly KdD56 while being a more convenient dosing option : a cross-study comparison of the CANDOR and EQUULEUS studies

The regimen of carfilzomib, daratumumab, and dexamethasone (KdD) shows activity in patients with relapsed/refractory multiple myeloma. KdD at the twice-weekly 56 mg/m carfilzomib dose (KdD56) was used in the randomized phase 3 CANDOR study (NCT03158688), whereas KdD at the once-weekly 70 mg/m carfilzomib dose (KdD70) was used in the phase 1 b EQUULEUS study (NCT01998971). We analyzed efficacy data from comparable CANDOR and EQUULEUS patients using inverse probability of treatment weighting (IPTW)-adjusted models. These weights were calculated from propensity scores derived to balance prespecified baseline covariates. The side-by-side and adjusted comparisons showed similar efficacy for overall response rates and progression-free survival in the two groups, with a series of sensitivity analyses showing consistent findings. Safety data were generally consistent with the known safety profiles of each individual drug. Once-weekly KdD70 is comparable to twice-weekly KdD56 in terms of efficacy and safety while being a more convenient dosing option

Governing culture: legislators, interpreters and accountants

Cultural policy has become dominated by questions of how to account for the intangible value of government investments. This is as a result of longstanding developments within government’s approaches to policy making, most notably those influenced by practices of audit and accounting. This paper will outline these developments with reference to Peter Miller’s concept of calculative practices, and will argue two central points: first, that there are practical solutions to the problem of measuring the value of culture that connect central government discourses with the discourses of the cultural sector; and second, the paper will demonstrate how academic work has been central to this area of policy making. As a result of the centrality of accounting academics in cultural policy, for example in providing advice on the appropriate measurement tools and techniques, questions are raised about the role academia might take vis-à-vis public policy. Accounting professionals and academics not only provide technical expertise that informs state calculative practices, but also play a surveillance role through the audit and evaluation of government programmes, and act as interpreters in defining terms of performance measurement, success and failure. The paper therefore concludes by reflecting on recent work by Phillip Schlesinger to preserve academic integrity whilst allowing accounting scholars and academics influence and partnership in policy

"Older Adults with ASD: The Consequences of Aging." Insights from a series of special interest group meetings held at the International Society for Autism Research 2016-2017

A special interest group (SIG) entitled "Older Adults with ASD: The Consequences of Aging" was held at the International Society for Autism Research (INSAR) annual meetings in 2016 and 2017. The SIG and subsequent meetings brought together, for the first time, international delegates who were members of the autistic community, researchers, practitioners and service providers. Based on aging autism research that is already underway in UK, Europe, Australia and North America, discussions focussed on conceptualising the parameters of aging when referring to autism, and the measures that are appropriate to use with older adults when considering diagnostic assessment, cognitive factors and quality of life in older age. Thus, the aim of this SIG was to progress the research agenda on current and future directions for autism research in the context of aging. A global issue on how to define 'aging' when referring to ASD was at the forefront of discussions. The ‘aging’ concept can in principle refer to all developmental transitions. However, in this paper we focus on the cognitive and physical changes that take place from mid-life onwards. Accordingly, it was agreed that aging and ASD research should focus on adults over the age of 50 years, given the high rates of co-occurring physical and mental health concerns and increased risk of premature death in some individuals. Moreover, very little is known about the cognitive change, care needs and outcomes of autistic adults beyond this age. Discussions on the topics of diagnostic and cognitive assessments, and of quality of life and well-being were explored through shared knowledge about which measures are currently being used and which background questions should be asked to obtain comprehensive and informative developmental and medical histories. Accordingly, a survey was completed by SIG delegates who were representatives of international research groups across four continents, and who are currently conducting studies with older autistic adults. Considerable overlap was identified across different research groups in measures of both autism and quality of life, which pointed to combining data and shared learnings as the logical next step. Regarding the background questions that were asked, the different research groups covered similar topics but the groups differed in the way these questions were formulated when working with autistic adults across a range of cognitive abilities. It became clear that continued input from individuals on the autism spectrum is important to ensure that questionnaires used in ongoing and future are accessible and understandable for people across the whole autistic spectrum, including those with limited verbal abilities

Daratumumab, lenalidomide, and dexamethasone in relapsed/refractory myeloma: a cytogenetic subgroup analysis of POLLUX

High cytogenetic risk abnormalities confer poor outcomes in multiple myeloma patients. In POLLUX, daratumumab/lenalidomide/dexamethasone (D-Rd) demonstrated significant clinical benefit versus lenalidomide/dexamethasone (Rd) in relapsed/refractory multiple myeloma (RRMM) patients. We report an updated subgroup analysis of POLLUX based on cytogenetic risk. The cytogenetic risk was determined using fluorescence in situ hybridization/karyotyping; patients with high cytogenetic risk had t(4;14), t(14;16), or del17p abnormalities. Minimal residual disease (MRD; 10–5) was assessed via the clonoSEQ® assay V2.0. 569 patients were randomized (D-Rd, n = 286; Rd, n = 283); 35 (12%) patients per group had high cytogenetic risk. After a median follow-up of 44.3 months, D-Rd prolonged progression-free survival (PFS) versus Rd in standard cytogenetic risk (median: not estimable vs 18.6 months; hazard ratio [HR], 0.43; P < 0.0001) and high cytogenetic risk (median: 26.8 vs 8.3 months; HR, 0.34; P = 0.0035) patients. Responses with D-Rd were deep, including higher MRD negativity and sustained MRD-negativity rates versus Rd, regardless of cytogenetic risk. PFS on subsequent line of therapy was improved with D-Rd versus Rd in both cytogenetic risk subgroups. The safety profile of D-Rd by cytogenetic risk was consistent with the overall population. These findings demonstrate the improved efficacy of daratumumab plus standard of care versus standard of care in RRMM, regardless of cytogenetic risk

Designing a broad-spectrum integrative approach for cancer prevention and treatment

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notablesuccesses in some cancers; however, significant problems remain with this approach. Many targetedtherapies are highly toxic, costs are extremely high, and most patients experience relapse after a fewdisease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistantimmortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are notreliant upon the same mechanisms as those which have been targeted). To address these limitations, aninternational task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspectsof relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a widerange of high-priority targets (74 in total) that could be modified to improve patient outcomes. For thesetargets, corresponding low-toxicity therapeutic approaches were then suggested, many of which werephytochemicals. Proposed actions on each target and all of the approaches were further reviewed forknown effects on other hallmark areas and the tumor microenvironment. Potential contrary or procar-cinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixedevidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of therelationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. Thisnovel approach has potential to be relatively inexpensive, it should help us address stages and types ofcancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for futureresearch is offered

Measurement of the View the tt production cross-section using eμ events with b-tagged jets in pp collisions at √s = 13 TeV with the ATLAS detector

This paper describes a measurement of the inclusive top quark pair production cross-section (σtt¯) with a data sample of 3.2 fb−1 of proton–proton collisions at a centre-of-mass energy of √s = 13 TeV, collected in 2015 by the ATLAS detector at the LHC. This measurement uses events with an opposite-charge electron–muon pair in the final state. Jets containing b-quarks are tagged using an algorithm based on track impact parameters and reconstructed secondary vertices. The numbers of events with exactly one and exactly two b-tagged jets are counted and used to determine simultaneously σtt¯ and the efficiency to reconstruct and b-tag a jet from a top quark decay, thereby minimising the associated systematic uncertainties. The cross-section is measured to be: σtt¯ = 818 ± 8 (stat) ± 27 (syst) ± 19 (lumi) ± 12 (beam) pb, where the four uncertainties arise from data statistics, experimental and theoretical systematic effects, the integrated luminosity and the LHC beam energy, giving a total relative uncertainty of 4.4%. The result is consistent with theoretical QCD calculations at next-to-next-to-leading order. A fiducial measurement corresponding to the experimental acceptance of the leptons is also presented

Search for TeV-scale gravity signatures in high-mass final states with leptons and jets with the ATLAS detector at sqrt [ s ] = 13TeV

A search for physics beyond the Standard Model, in final states with at least one high transverse momentum charged lepton (electron or muon) and two additional high transverse momentum leptons or jets, is performed using 3.2 fb−1 of proton–proton collision data recorded by the ATLAS detector at the Large Hadron Collider in 2015 at √s = 13 TeV. The upper end of the distribution of the scalar sum of the transverse momenta of leptons and jets is sensitive to the production of high-mass objects. No excess of events beyond Standard Model predictions is observed. Exclusion limits are set for models of microscopic black holes with two to six extra dimensions

Search for strong gravity in multijet final states produced in pp collisions at √s=13 TeV using the ATLAS detector at the LHC

A search is conducted for new physics in multijet final states using 3.6 inverse femtobarns of data from proton-proton collisions at √s = 13TeV taken at the CERN Large Hadron Collider with the ATLAS detector. Events are selected containing at least three jets with scalar sum of jet transverse momenta (HT) greater than 1TeV. No excess is seen at large HT and limits are presented on new physics: models which produce final states containing at least three jets and having cross sections larger than 1.6 fb with HT > 5.8 TeV are excluded. Limits are also given in terms of new physics models of strong gravity that hypothesize additional space-time dimensions

The performance of the jet trigger for the ATLAS detector during 2011 data taking

The performance of the jet trigger for the ATLAS detector at the LHC during the 2011 data taking period is described. During 2011 the LHC provided proton–proton collisions with a centre-of-mass energy of 7 TeV and heavy ion collisions with a 2.76 TeV per nucleon–nucleon collision energy. The ATLAS trigger is a three level system designed to reduce the rate of events from the 40 MHz nominal maximum bunch crossing rate to the approximate 400 Hz which can be written to offline storage. The ATLAS jet trigger is the primary means for the online selection of events containing jets. Events are accepted by the trigger if they contain one or more jets above some transverse energy threshold. During 2011 data taking the jet trigger was fully efficient for jets with transverse energy above 25 GeV for triggers seeded randomly at Level 1. For triggers which require a jet to be identified at each of the three trigger levels, full efficiency is reached for offline jets with transverse energy above 60 GeV. Jets reconstructed in the final trigger level and corresponding to offline jets with transverse energy greater than 60 GeV, are reconstructed with a resolution in transverse energy with respect to offline jets, of better than 4 % in the central region and better than 2.5 % in the forward direction