Estimating the Probability of Human Error by Incorporating Component Failure Data from User-Induced Defects in the Development of Complex Electrical Systems.

This article proposes a methodology for incorporating electrical component failure data into the human error assessment and reduction technique (HEART) for estimating human error probabilities (HEPs). The existing HEART method contains factors known as error-producing conditions (EPCs) that adjust a generic HEP to a more specific situation being assessed. The selection and proportioning of these EPCs are at the discretion of an assessor, and are therefore subject to the assessor's experience and potential bias. This dependence on expert opinion is prevalent in similar HEP assessment techniques used in numerous industrial areas. The proposed method incorporates factors based on observed trends in electrical component failures to produce a revised HEP that can trigger risk mitigation actions more effectively based on the presence of component categories or other hazardous conditions that have a history of failure due to human error. The data used for the additional factors are a result of an analysis of failures of electronic components experienced during system integration and testing at NASA Goddard Space Flight Center. The analysis includes the determination of root failure mechanisms and trend analysis. The major causes of these defects were attributed to electrostatic damage, electrical overstress, mechanical overstress, or thermal overstress. These factors representing user-induced defects are quantified and incorporated into specific hardware factors based on the system's electrical parts list. This proposed methodology is demonstrated with an example comparing the original HEART method and the proposed modified technique.

Ionizing Radiation in Craniofacial Surgery: A Primer on Dose and Risks.

An understanding of radiation dose and the anticipated risk to the patient is an important aspect of ordering radiological imaging studies responsibly. It is especially true for the pediatric practitioner because children are more vulnerable to the biological effects of radiation, such as radiosensitivity, longer lifetime years, and higher cellular mitotic activity. The use of fluoroscopy and computed tomography is commonplace in the practice of craniofacial surgery, but often dose reports from varied investigations are not directly comparable, and the risk of patient harm from the investigation is unclear. This article presents the fundamentals of radiation, dose, and risk as it applies to radiological imaging and also introduces our low dose craniofacial computed tomography protocol.

Parallel Optimization of Potency and Pharmacokinetics Leading to the Discovery of a Pyrrole Carboxamide ERK5 Kinase Domain Inhibitor.

The nonclassical extracellular signal-related kinase 5 (ERK5) mitogen-activated protein kinase pathway has been implicated in increased cellular proliferation, migration, survival, and angiogenesis; hence, ERK5 inhibition may be an attractive approach for cancer treatment. However, the development of selective ERK5 inhibitors has been challenging. Previously, we described the development of a pyrrole carboxamide high-throughput screening hit into a selective, submicromolar inhibitor of ERK5 kinase activity. Improvement in the ERK5 potency was necessary for the identification of a tool ERK5 inhibitor for target validation studies. Herein, we describe the optimization of this series to identify nanomolar pyrrole carboxamide inhibitors of ERK5 incorporating a basic center, which suffered from poor oral bioavailability. Parallel optimization of potency and in vitro pharmacokinetic parameters led to the identification of a nonbasic pyrazole analogue with an optimal balance of ERK5 inhibition and oral exposure.

Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-p53 Protein-Protein Interaction.

Inhibition of murine double minute 2 (MDM2)-p53 protein-protein interaction with small molecules has been shown to reactivate p53 and inhibit tumor growth. Here, we describe rational, structure-guided, design of novel isoindolinone-based MDM2 inhibitors. MDM2 X-ray crystallography, quantum mechanics ligand-based design, and metabolite identification all contributed toward the discovery of potent in vitro and in vivo inhibitors of the MDM2-p53 interaction with representative compounds inducing cytostasis in an SJSA-1 osteosarcoma xenograft model following once-daily oral administration.

Is There a Difference in the Diagnostic Outcomes of Calcifications Initially Identified on Synthetic Tomosynthesis Versus Full-Field Digital Mammography Screening?

PURPOSE: To compare the outcomes of microcalcifications recalled on full-field digital (FFDM) and FFDM and combined tomosynthesis (Combo) to synthetic (SM) screening mammograms. METHOD: We reviewed medical records, radiology, and pathology reports of all patients found to have abnormal calcifications requiring further evaluation on mammography screening at our institution between 11/1/2016-11/1/2018 and collected patient demographics, calcification morphology and distribution, and mammography technique (SM, FFDM, or Combo). We used biopsy pathology or at least 1-year imaging follow-up to establish overall diagnostic outcome (benign or malignant). Fisher's exact test was used to compare validation rates at diagnostic work-up, BI-RADS category, and final outcome of calcifications identified on each screening technique. T-test was used for continuous variables. RESULTS: Of 699 calcifications in 596 women recalled, 176 (30%) of 596 were from SM and 420 (70%) FFDM/Combo. There was a significantly higher rate of calcifications unvalidated at diagnostic work-up for SM compared to FFDM/Combo (0.8% vs. 10%, p < 0.0001). SM calcifications were more likely to receive BI-RADS 2/3 at diagnostic work-up compared to FFDM/Combo ones (55% vs. 42%, p = 0.003). Of 346 (49%) calcifications that underwent biopsy, 88 (25%) were malignant (36% of SM vs. 22% of FFDM/Combo, OR:0.5 [95% CI: 0.3, 0.8] p = 0.01). Of 622 lesions with established diagnostic outcome, there was no difference between having an overall benign or malignant outcome between SM and FFDM/Combo (17% vs. 13%, OR: 0.8 [95% Cl: 0.5, 1.2] p = 0.27). CONCLUSIONS: Synthetic tomosynthesis screening results in a higher rate of false positive and unvalidated calcification recalls compared to FFDM/Combo.

Identification of a novel orally bioavailable ERK5 inhibitor with selectivity over p38α and BRD4.

Extracellular regulated kinase 5 (ERK5) signalling has been implicated in driving a number of cellular phenotypes including endothelial cell angiogenesis and tumour cell motility. Novel ERK5 inhibitors were identified using high throughput screening, with a series of pyrrole-2-carboxamides substituted at the 4-position with an aroyl group being found to exhibit IC50 values in the micromolar range, but having no selectivity against p38α MAP kinase. Truncation of the N-substituent marginally enhanced potency (∼3-fold) against ERK5, but importantly attenuated inhibition of p38α. Systematic variation of the substituents on the aroyl group led to the selective inhibitor 4-(2-bromo-6-fluorobenzoyl)-N-(pyridin-3-yl)-1H-pyrrole-2-carboxamide (IC50 0.82 µM for ERK5; IC50 > 120 µM for p38α). The crystal structure (PDB 5O7I) of this compound in complex with ERK5 has been solved. This compound was orally bioavailable and inhibited bFGF-driven Matrigel plug angiogenesis and tumour xenograft growth. The selective ERK5 inhibitor described herein provides a lead for further development into a tool compound for more extensive studies seeking to examine the role of ERK5 signalling in cancer and other diseases.

Validating and enabling phosphoglycerate dehydrogenase (PHGDH) as a target for fragment-based drug discovery in PHGDH-amplified breast cancer.

3-Phosphoglycerate dehydrogenase (PHGDH) has recently been identified as an attractive target in cancer therapy as it links upregulated glycolytic flux to increased biomass production in cancer cells. PHGDH catalyses the first step in the serine synthesis pathway and thus diverts glycolytic flux into serine synthesis. We have used siRNA-mediated suppression of PHGDH expression to show that PHGDH is a potential therapeutic target in PHGDH-amplified breast cancer. Knockdown caused reduced proliferation in the PHGDH-amplified cell line MDA-MB-468, whereas breast cancer cells with low PHGDH expression or with elevated PHGDH expression in the absence of genomic amplification were not affected. As a first step towards design of a chemical probe for PHGDH, we report a fragment-based drug discovery approach for the identification of PHGDH inhibitors. We designed a truncated PHGDH construct that gave crystals which diffracted to high resolution, and could be used for fragment soaking. 15 fragments stabilising PHGDH were identified using a thermal shift assay and validated by X-ray crystallography and ITC competition experiments to exhibit 1.5-26.2 mM affinity for PHGDH. A structure-guided fragment growing approach was applied to the PHGDH binders from the initial screen, yielding greater understanding of the binding site and suggesting routes to achieve higher affinity NAD-competitive inhibitors.

A pyridazine series of alpha2/alpha3 subtype selective GABA A agonists for the treatment of anxiety.

The development of a series of GABA(A) alpha2/alpha3 subtype selective pyridazine based benzodiazepine site agonists as anxiolytic agents with reduced sedative/ataxic potential is described, including the discovery of 16, a remarkably alpha3-selective compound ideal for in vivo study. These ligands are antagonists at the alpha1 subtype, with good CNS penetration and receptor occupancy, and excellent oral bioavailability.

High-Throughput Screening and Hit Validation of Extracellular-Related Kinase 5 (ERK5) Inhibitors.

The extracellular-related kinase 5 (ERK5) is a promising target for cancer therapy. A high-throughput screen was developed for ERK5, based on the IMAP FP progressive binding system, and used to identify hits from a library of 57 617 compounds. Four distinct chemical series were evident within the screening hits. Resynthesis and reassay of the hits demonstrated that one series did not return active compounds, whereas three series returned active hits. Structure-activity studies demonstrated that the 4-benzoylpyrrole-2-carboxamide pharmacophore had excellent potential for further development. The minimum kinase binding pharmacophore was identified, and key examples demonstrated good selectivity for ERK5 over p38α kinase.

Radiation exposure and safety practices during pediatric central line placement.

PURPOSE: Pediatric surgeons routinely use fluoroscopy for central venous line (CVL) placement. We examined radiation safety practices and patient/surgeon exposure during fluoroscopic CVL. METHODS: Fluoroscopic CVL procedures performed by 11 pediatric surgeons in 2012 were reviewed. Fluoroscopic time (FT), patient exposure (mGy), and procedural data were collected. Anthropomorphic phantom simulations were used to calculate scatter and dose (mSv). Surgeons were surveyed regarding safety practices. RESULTS: 386 procedures were reviewed. Median FT was 12.8 seconds. Median patient estimated effective dose was 0.13 mSv. Median annual FT per surgeon was 15.4 minutes. Simulations showed no significant difference (p=0.14) between reported exposures (median 3.5 mGy/minute) and the modeled regression exposures from the C-arm default mode (median 3.4 mGy/minute). Median calculated surgeon exposure was 1.5 mGy/year. Eight of 11 surgeons responded to the survey. Only three reported 100% lead protection and frequent dosimeter use. CONCLUSION: We found nonstandard radiation training, safety practices, and dose monitoring for the 11 surgeons. Based on simulations, the C-arm default setting was typically used instead of low dose. While most CVL procedures have low patient/surgeon doses, every effort should be used to minimize patient and occupational exposure, suggesting the need for formal hands-on training for nonradiologist providers using fluoroscopy.

Characterisation of a Tip60 specific inhibitor, NU9056, in prostate cancer.

Tip60 (KAT5) is a histone acetyltransferase (HAT enzyme) involved in multiple cellular processes including transcriptional regulation, DNA damage repair and cell signalling. In prostate cancer, aggressive cases over-express Tip60 which functions as an androgen receptor co-activator via direct acetylation of lysine residues within the KLKK motif of the receptor hinge region. The purpose of this study was to identify and characterise a Tip60 acetylase inhibitor. High-throughput screening revealed an isothiazole that inhibited both Tip60 and p300 HAT activity. This substance (initially identified as 4-methyl-5-bromoisothiazole) and other isothiazoles were synthesised and assayed against Tip60. Although an authentic sample of 4-methyl-5-bromoisothiazole was inactive against Tip60, in an in vitro HAT assay, 1,2-bis(isothiazol-5-yl)disulfane (NU9056) was identified as a relatively potent inhibitor (IC(50) 2 µM). Cellular activity was confirmed by analysis of acetylation of histone and non-histone proteins in a prostate cancer cell line model. NU9056 treatment inhibited cellular proliferation in a panel of prostate cancer cell lines (50% growth inhibition, 8-27 µM) and induced apoptosis via activation of caspase 3 and caspase 9 in a concentration- and time-dependent manner. Also, decreased androgen receptor, prostate specific antigen, p53 and p21 protein levels were demonstrated in response to treatment with NU9056. Furthermore, pre-treatment with NU9056 inhibited both ATM phosphorylation and Tip60 stabilization in response to ionising radiation. Based on the activity of NU9056 and the specificity of the compound towards Tip60 relative to other HAT enzymes, these chemical biology studies have identified Tip60 as a potential therapeutic target for the treatment of prostate cancer.

Isoindolinone inhibitors of the murine double minute 2 (MDM2)-p53 protein-protein interaction: structure-activity studies leading to improved potency.

Inhibition of the MDM2-p53 interaction has been shown to produce an antitumor effect, especially in MDM2 amplified tumors. The isoindolinone scaffold has proved to be versatile for the discovery of MDM2-p53 antagonists. Optimization of previously reported inhibitors, for example, NU8231 (7) and NU8165 (49), was guided by MDM2 NMR titrations, which indicated key areas of the binding interaction to be explored. Variation of the 2-N-benzyl and 3-alkoxy substituents resulted in the identification of 3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(4-nitrobenzyl)isoindolin-1-one (74) as a potent MDM2-p53 inhibitor (IC(50) = 0.23 ± 0.01 µM). Resolution of the enantiomers of 74 showed that potent MDM2-p53 activity primarily resided with the (+)-R-enantiomer (74a; IC(50) = 0.17 ± 0.02 µM). The cellular activity of key compounds has been examined in cell lines with defined p53 and MDM2 status. Compound 74a activates p53, MDM2, and p21 transcription in MDM2 amplified cells and shows moderate selectivity for wild-type p53 cell lines in growth inhibition assays.

How will you need me, how will you read me, when I'm 64 (or more!)?: volume computed tomographic scanning and information overload in the emergency department.

Computed tomographic (CT) scanning technology now employs up to 320 detector rows of 0.5-mm width and allows rapid acquisition of isotropic volume datasets over the entire body. Data from a single CT acquisition can be reconstructed into image series that would formerly have required multiple acquisitions. Small isotropic voxels permit scan parameters to be general while reconstruction algorithms remain specific to anatomy. While this results in more efficient operation in the Emergency Department, it necessitates new ways of displaying, interpreting, and archiving the information. Critical decisions include how much of the patient to scan and how to time contrast injections when imaging multiple organs. These choices must be made in light of dose considerations to the patient and the general population of patients. The technical basis of high-density CT scanning is discussed, including detector configurations and reconstruction techniques. Volumetric scanning in the Emergency Department can improve patient care but requires a change of technical habits.