Research approvals iceberg: how a 'low-key' study in England needed 89 professionals to approve it and how we can do better.

BACKGROUND: The red tape and delays around research ethics and governance approvals frequently frustrate researchers yet, as the lesser of two evils, are largely accepted as unavoidable. Here we quantify aspects of the research ethics and governance approvals for one interview- and questionnaire-based study conducted in England which used the National Health Service (NHS) procedures and the electronic Integrated Research Application System (IRAS). We demonstrate the enormous impact of existing approvals processes on costs of studies, including opportunity costs to focus on the substantive research, and suggest directions for radical system change. MAIN TEXT: We have recorded 491 exchanges with 89 individuals involved in research ethics and governance approvals, generating 193 pages of email text excluding attachments. These are conservative estimates (e.g. only records of the research associate were used). The exchanges were conducted outside IRAS, expected to be the platform where all necessary documents are provided and questions addressed. Importantly, the figures exclude the actual work of preparing the ethics documentation (such as the ethics application, information sheets and consent forms). We propose six areas of work to enable system change: 1. Support the development of a broad range of customised research ethics and governance templates to complement generic, typically clinical trials orientated, ones; 2. Develop more sophisticated and flexible frameworks for study classification; 3. Link with associated processes for assessment, feedback, monitoring and reporting, such as ones involving funders and patient and public involvement groups; 4. Invest in a new generation IT infrastructure; 5. Enhance system capacity through increasing online reviewer participation and training; and 6. Encourage researchers to quantify the approvals processes for their studies. CONCLUSION: Ethics and governance approvals are burdensome for historical reasons and not because of the nature of the task. There are many opportunities to improve their efficiency and analytic depth in an age of innovation, increased connectivity and distributed working. If we continue to work under current systems, we are perpetuating, paradoxically, an unethical system of research approvals by virtue of its wastefulness and impoverished ethical debate

Targeting murine heart and brain: visualisation conditions for multi-pinhole SPECT with 99mTc- and 123I-labelled probes

The study serves to optimise conditions for multi-pinhole SPECT small animal imaging of (123)I- and (99m)Tc-labelled radiopharmaceuticals with different distributions in murine heart and brain and to investigate detection and dose range thresholds for verification of differences in tracer uptake.A Triad 88/Trionix system with three 6-pinhole collimators was used for investigation of dose requirements for imaging of the dopamine D(2) receptor ligand [(123)I]IBZM and the cerebral perfusion tracer [(99m)Tc]HMPAO (1.2-0.4 MBq/g body weight) in healthy mice. The fatty acid [(123)I]IPPA (0.94 +/- 0.05 MBq/g body weight) and the perfusion tracer [(99m)Tc]sestamibi (3.8 +/- 0.45 MBq/g body weight) were applied to cardiomyopathic mice overexpressing the prostaglandin EP(3) receptor.In vivo imaging and in vitro data revealed 45 kBq total cerebral uptake and 201 kBq cardiac uptake as thresholds for visualisation of striatal [(123)I]IBZM and of cardiac [(99m)Tc]sestamibi using 100 and 150 s acquisition time, respectively. Alterations of maximal cerebral uptake of [(123)I]IBZM by >20% (116 kBq) were verified with the prerequisite of 50% striatal of total uptake. The labelling with [(99m)Tc]sestamibi revealed a 30% lower uptake in cardiomyopathic hearts compared to wild types. [(123)I]IPPA uptake could be visualised at activity doses of 0.8 MBq/g body weight.Multi-pinhole SPECT enables detection of alterations of the cerebral uptake of (123)I- and (99m)Tc-labelled tracers in an appropriate dose range in murine models targeting physiological processes in brain and heart. The thresholds of detection for differences in the tracer uptake determined under the conditions of our experiments well reflect distinctions in molar activity and uptake characteristics of the tracers

Small molecule compounds targeting the p53 pathway: are we finally making progress?

Loss of function of p53, either through mutations in the gene or through mutations to other members of the pathway that inactivate wild-type p53, remains a critically important aspect of human cancer development. As such, p53 remains the most commonly mutated gene in human cancer. For these reasons, pharmacologic activation of the p53 pathway has been a highly sought after, yet unachieved goal in developmental therapeutics. Recently progress has been made not only in the discovery of small molecules that target wild-type and mutant p53, but also in the initiation and completion of the first in-human clinical trials for several of these drugs. Here, we review the current literature of drugs that target wild-type and mutant p53 with a focus on small-molecule type compounds. We discuss common means of drug discovery and group them according to their common mechanisms of action. Lastly, we review the current status of the various drugs in the development process and identify newer areas of p53 tumor biology that may prove therapeutically useful

Class II Transactivator (CIITA) Enhances Cytoplasmic Processing of HIV-1 Pr55Gag

The Pr55(gag) (Gag) polyprotein of HIV serves as a scaffold for virion assembly and is thus essential for progeny virion budding and maturation. Gag localizes to the plasma membrane (PM) and membranes of late endosomes, allowing for release of infectious virus directly from the cell membrane and/or upon exocytosis. The host factors involved in Gag trafficking to these sites are largely unknown. Upon activation, CD4+ T cells, the primary target of HIV infection, express the class II transcriptional activator (CIITA) and therefore the MHC class II isotype, HLA-DR. Similar to Gag, HLA-DR localizes to the PM and at the membranes of endosomes and specialized vesicular MHC class II compartments (MIICs). In HIV producer cells, transient HLA-DR expression induces intracellular Gag accumulation and impairs virus release.Here we demonstrate that both stable and transient expression of CIITA in HIV producer cells does not induce HLA-DR-associated intracellular retention of Gag, but does increase the infectivity of virions. However, neither of these phenomena is due to recapitulation of the class II antigen presentation pathway or CIITA-mediated transcriptional activation of virus genes. Interestingly, we demonstrate that CIITA, apart from its transcriptional effects, acts cytoplasmically to enhance Pr160(gag-pol) (Gag-Pol) levels and thereby the viral protease and Gag processing, accounting for the increased infectivity of virions from CIITA-expressing cells.This study demonstrates that CIITA enhances HIV Gag processing, and provides the first evidence of a novel, post-transcriptional, cytoplasmic function for a well-known transactivator

Rab7A Is Required for Efficient Production of Infectious HIV-1

Retroviruses take advantage of cellular trafficking machineries to assemble and release new infectious particles. Rab proteins regulate specific steps in intracellular membrane trafficking by recruiting tethering, docking and fusion factors, as well as the actin- and microtubule-based motor proteins that facilitate vesicle traffic. Using virological tests and RNA interference targeting Rab proteins, we demonstrate that the late endosome-associated Rab7A is required for HIV-1 propagation. Analysis of the late steps of the HIV infection cycle shows that Rab7A regulates Env processing, the incorporation of mature Env glycoproteins into viral particles and HIV-1 infectivity. We also show that siRNA-mediated Rab7A depletion induces a BST2/Tetherin phenotype on HIV-1 release. BST2/Tetherin is a restriction factor that impedes HIV-1 release by tethering mature virus particles to the plasma membrane. Our results suggest that Rab7A contributes to the mechanism by which Vpu counteracts the restriction factor BST2/Tetherin and rescues HIV-1 release. Altogether, our results highlight new roles for a major regulator of the late endocytic pathway, Rab7A, in the late stages of the HIV-1 replication cycle

Search for dark matter produced in association with a single top quark or a top quark pair in proton-proton collisions at s=13 TeV

A search has been performed for heavy resonances decaying to ZZ or ZW in 2l2q final states, with two charged leptons (l = e, mu) produced by the decay of a Z boson, and two quarks produced by the decay of a W or Z boson. The analysis is sensitive to resonances with masses in the range from 400 to 4500 GeV. Two categories are defined based on the merged or resolved reconstruction of the hadronically decaying vector boson, optimized for high- and low-mass resonances, respectively. The search is based on data collected during 2016 by the CMS experiment at the LHC in proton-proton collisions with a center-of-mass energy of root s = 13 TeV, corresponding to an integrated luminosity of 35.9 fb(-1). No excess is observed in the data above the standard model background expectation. Upper limits on the production cross section of heavy, narrow spin-1 and spin-2 resonances are derived as a function of the resonance mass, and exclusion limits on the production of W' bosons and bulk graviton particles are calculated in the framework of the heavy vector triplet model and warped extra dimensions, respectively.A search has been performed for heavy resonances decaying to ZZ or ZW in 2l2q final states, with two charged leptons (l = e, mu) produced by the decay of a Z boson, and two quarks produced by the decay of a W or Z boson. The analysis is sensitive to resonances with masses in the range from 400 to 4500 GeV. Two categories are defined based on the merged or resolved reconstruction of the hadronically decaying vector boson, optimized for high- and low-mass resonances, respectively. The search is based on data collected during 2016 by the CMS experiment at the LHC in proton-proton collisions with a center-of-mass energy of root s = 13 TeV, corresponding to an integrated luminosity of 35.9 fb(-1). No excess is observed in the data above the standard model background expectation. Upper limits on the production cross section of heavy, narrow spin-1 and spin-2 resonances are derived as a function of the resonance mass, and exclusion limits on the production of W' bosons and bulk graviton particles are calculated in the framework of the heavy vector triplet model and warped extra dimensions, respectively.A search for dark matter produced in association with top quarks in proton-proton collisions at a center-of-mass energy of 13 TeV is presented. The data set used corresponds to an integrated luminosity of 35.9 fb(-1) recorded with the CMS detector at the LHC. Whereas previous searches for neutral scalar or pseudoscalar mediators considered dark matter production in association with a top quark pair only, this analysis also includes production modes with a single top quark. The results are derived from the combination of multiple selection categories that are defined to target either the single top quark or the top quark pair signature. No significant deviations with respect to the standard model predictions are observed. The results are interpreted in the context of a simplified model in which a scalar or pseudoscalar mediator particle couples to a top quark and subsequently decays into dark matter particles. Scalar and pseudoscalar mediator particles with masses below 290 and 300 GeV, respectively, are excluded at 95% confidence level, assuming a dark matter particle mass of 1 GeV and mediator couplings to fermions and dark matter particles equal to unity.Peer reviewe

Search for the pair production of light top squarks in the e(+/-)mu(-/+) final state in proton-proton collisions at root s=13 TeV

A search for the production of a pair of top squarks at the LHC is presented. This search targets a region of parameter space where the kinematics of top squark pair production and top quark pair production are very similar, because of the mass difference between the top squark and the neutralino being close to the top quark mass. The search is performed with 35.9 fb(-1) of proton-proton collisions at a centre-of-mass energy of root s = 13 TeV, collected by the CMS detector in 2016, using events containing one electron-muon pair with opposite charge. The search is based on a precise estimate of the top quark pair background, and the use of the M-T2 variable, which combines the transverse mass of each lepton and the missing transverse momentum. No excess of events is found over the standard model predictions. Exclusion limits are placed at 95% confidence level on the production of top squarks up to masses of 208 GeV for models with a mass difference between the top squark and the lightest neutralino close to that of the top quark.Peer reviewe

Search for strongly interacting massive particles generating trackless jets in proton-proton collisions at s = 13 TeV

A search for dark matter in the form of strongly interacting massive particles (SIMPs) using the CMS detector at the LHC is presented. The SIMPs would be produced in pairs that manifest themselves as pairs of jets without tracks. The energy fraction of jets carried by charged particles is used as a key discriminator to suppress efficiently the large multijet background, and the remaining background is estimated directly from data. The search is performed using proton-proton collision data corresponding to an integrated luminosity of 16.1 fb - 1 , collected with the CMS detector in 2016. No significant excess of events is observed above the expected background. For the simplified dark matter model under consideration, SIMPs with masses up to 100 GeV are excluded and further sensitivity is explored towards higher masses