Molecular mechanisms that underpin EML4-ALK driven cancers and their response to targeted drugs

fusion between the EML4 (echinoderm microtubule-associated protein-like) and ALK (anaplastic lymphoma kinase) genes was identified in non-small cell lung cancer (NSCLC) in 2007 and there has been rapid progress in applying this knowledge to the benefit of patients. However, we have a poor understanding of EML4 and ALK biology and there are many challenges to devising the optimal strategy for treating EML4-ALK NSCLC patients. In this review, we describe the biology of EML4 and ALK, explain the main features of EML4-ALK fusion proteins and outline the therapies that target EML4-ALK. In particular, we highlight the recent advances in our understanding of the structures of EML proteins, describe the molecular mechanisms of resistance to ALK inhibitors and assess current thinking about combinations of ALK drugs with inhibitors that target other kinases or Hsp90

Variant signal peptides of vaccine antigen, FHbp, impair processing affecting surface localization and antibody-mediated killing in most meningococcal isolates

© Copyright © 2019 da Silva, Karlyshev, Oldfield, Wooldridge, Bayliss, Ryan and Griffin. Meningococcal lipoprotein, Factor H binding protein (FHbp), is the sole antigen of the Trumenba vaccine (Pfizer) and one of four antigens of the Bexsero vaccine (GSK) targeting Neisseria meningitidis serogroup B isolates. Lipidation of FHbp is assumed to occur for all isolates. We show in the majority of a collection of United Kingdom isolates (1742/1895) non-synonymous single nucleotide polymorphisms (SNPs) in the signal peptide (SP) of FHbp. A single SNP, common to all, alters a polar amino acid that abolishes processing: lipidation and SP cleavage. Whilst some of the FHbp precursor is retained in the cytoplasm due to reduced binding to SecA, remarkably some is translocated and further surface-localized by Slam. Thus we show Slam is not lipoprotein-specific. In a panel of isolates tested, the overall reduced surface localization of the precursor FHbp, compared to isolates with an intact SP, corresponded with decreased susceptibility to antibody-mediated killing. Our findings shed new light on the canonical pathway for lipoprotein processing and translocation of important relevance for lipoprotein-based vaccines in development and in particular for Trumenba

Quality Improvement Project to Evaluate Discharge Prescriptions in Children With Cystic Fibrosis

Introduction: Cystic Fibrosis (CF) requires multiple pharmaceutical treatments, elevating the risk of medication errors (ME), which may compromise patient safety. This study aimed to improve the quality of discharge prescriptions (DPs) using indicators following admissions for IV antibiotics in pediatric CF patients. Methods: This project involved a longitudinal observational retrospective descriptive study followed by a longitudinal quasi-experimental prospective phase between January 2013 and December 2016 in CF patients admitted to a London Children's Hospital. The CF pharmacist reviewed DPs. Six rights of medication administration were defined (6R): dose, drug, frequency, duration of treatment, pharmaceutical form, and route of administration. We classified ME according to 6R, including subtype of error: committed/omitted. We calculated quality indicators by dividing the number of each correct parameter defined by 6R by number of DPs. Retrospective results were used prospectively to describe and implement improvement strategies and safety actions. Results: The retrospective study phase included 42 CF children (100 hospital admissions and 1,343 drugs). The prospective phase included thirty-five children (55 admissions and 822 drugs). The total number of ME identified was 148 (78 committed; 70 omitted) in retrospective phase and 135 (19 committed; 116 omitted) in prospective phase. Quality indicators for drug and dose showed significant improvement after implementing safety strategies. The global quality indicator increased from 22% (retrospective) to 41.82% (prospective), but we did not achieve the previously defined quality standard value (50%). Conclusions: A retrospective review of DP by a CF Pharmacist identified failures in DP quality. Implementing improvement strategies improved prescribing. Integrating pharmacist within multidisciplinary team improves DP reducing errors

No Conclusive Evidence for Transits of Proxima b in MOST photometry

The analysis of Proxima Centauri's radial velocities recently led Anglada-Escud\'e et al. (2016) to claim the presence of a low mass planet orbiting the Sun's nearest star once every 11.2 days. Although the a-priori probability that Proxima b transits its parent star is just 1.5%, the potential impact of such a discovery would be considerable. Independent of recent radial velocity efforts, we observed Proxima Centauri for 12.5 days in 2014 and 31 days in 2015 with the MOST space telescope. We report here that we cannot make a compelling case that Proxima b transits in our precise photometric time series. Imposing an informative prior on the period and phase, we do detect a candidate signal with the expected depth. However, perturbing the phase prior across 100 evenly spaced intervals reveals one strong false-positive and one weaker instance. We estimate a false-positive rate of at least a few percent and a much higher false-negative rate of 20-40%, likely caused by the very high flare rate of Proxima Centauri. Comparing our candidate signal to HATSouth ground-based photometry reveals that the signal is somewhat, but not conclusively, disfavored (1-2 sigmas) leading us to argue that the signal is most likely spurious. We expect that infrared photometric follow-up could more conclusively test the existence of this candidate signal, owing to the suppression of flare activity and the impressive infrared brightness of the parent star.Comment: Accepted to ApJ. Posterior samples, MOST photometry and HATSouth photometry are all available at https://github.com/CoolWorlds/Proxim

Validation of the disease burden morbidity assessment by self-report in a French-speaking population

<p>Abstract</p> <p>Background</p> <p>The Disease Burden Morbidity Assessment (DBMA) is a self-report questionnaire used to estimate the disease burden experienced by patients. The aim of this study was to test and to measure the properties of the French translation of the DBMA (DBMA-Fv).</p> <p>Methods</p> <p>The original version of the DBMA was translated into French (Canadian) and first assessed during cognitive interviews. In the validation study, patients recruited during consecutive consultation periods completed the DBMA-Fv questionnaire while they were in the waiting room of a primary care setting (T1). Participants completed the same questionnaire mailed to their home two weeks later (T2). Concomitant validity of the DBMA-Fv was assessed using the Cumulative Illness Rating Scale (CIRS). Patient medical records were reviewed to verify chronic diseases and past medical history.</p> <p>Results</p> <p>Ninety-seven patients were recruited and 85 (88%) returned the mailed questionnaires; 5 (5.9%) were incomplete. DBMA-Fv scores of the 80 participants with a complete questionnaire at T2 ranged from 0 to 30 (median 5.5, mean 7.7, SD = 7.0). Test-retest reliability of the DBMA-Fv was high (ICC: 0.86, 95% CI: 0.79-0.92). The DBMA-Fv and the CIRS correlated moderately at T1 (r = 0.46, 95% CI: 0.26 - 0.62, <it>p </it>< 0.01) and T2 (r = 0.56, 95% CI: 0.38 - 0.70, <it>p </it>< 0.01). The mean (SD) sensitivity of patient reports of a condition in relation to chart review at T2 was 73.9 (8.4) (range 62.5% to 90%). The overall mean (SD) specificity was 92.2 (6.7) (range 77.6% to 98.6%).</p> <p>Conclusions</p> <p>The DBMA-Fv's properties are similar to its English counterpart as to its median sensitivity and specificity compared to chart reviews. It correlated moderately with an established index of multimorbidity. A high percentage of patients were able to complete the test correctly as a mail questionnaire and it showed high test-retest reliability.</p

Gaze following in multiagent contexts: Evidence for a quorum-like principle

Research shows that humans spontaneously follow another individual’s gaze. However, little remains known on how they respond when multiple gaze cues diverge across members of a social group. To address this question, we presented participants with displays depicting three (Experiment 1) or five (Experiment 2) agents showing diverging social cues. In a three-person group, one individual looking at the target (33% of the group) was sufficient to elicit gaze-facilitated target responses. With a five-person group, however, three individuals looking at the target (60% of the group) were necessary to produce the same effect. Gaze following in small groups therefore appears to be based on a quorum-like principle, whereby the critical level of social information needed for gaze following is determined by a proportion of consistent social cues scaled as a function of group size. As group size grows, greater agreement is needed to evoke joint attention

The selectivity, voltage-dependence and acid sensitivity of the tandem pore potassium channel TASK-1 : contributions of the pore domains

We have investigated the contribution to ionic selectivity of residues in the selectivity filter and pore helices of the P1 and P2 domains in the acid sensitive potassium channel TASK-1. We used site directed mutagenesis and electrophysiological studies, assisted by structural models built through computational methods. We have measured selectivity in channels expressed in Xenopus oocytes, using voltage clamp to measure shifts in reversal potential and current amplitudes when Rb+ or Na+ replaced extracellular K+. Both P1 and P2 contribute to selectivity, and most mutations, including mutation of residues in the triplets GYG and GFG in P1 and P2, made channels nonselective. We interpret the effects of these—and of other mutations—in terms of the way the pore is likely to be stabilised structurally. We show also that residues in the outer pore mouth contribute to selectivity in TASK-1. Mutations resulting in loss of selectivity (e.g. I94S, G95A) were associated with slowing of the response of channels to depolarisation. More important physiologically, pH sensitivity is also lost or altered by such mutations. Mutations that retained selectivity (e.g. I94L, I94V) also retained their response to acidification. It is likely that responses both to voltage and pH changes involve gating at the selectivity filter

Prevalence and phase variable expression status of two autotransporters, NalP and MspA, in carriage and disease isolates of Neisseria meningitidis.

Neisseria meningitidis is a human nasopharyngeal commensal capable of causing life-threatening septicemia and meningitis. Many meningococcal surface structures, including the autotransporter proteins NalP and MspA, are subject to phase variation (PV) due to the presence of homopolymeric tracts within their coding sequences. The functions of MspA are unknown. NalP proteolytically cleaves several surface-located virulence factors including the 4CMenB antigen NhbA. Therefore, NalP is a phase-variable regulator of the meningococcal outer membrane and secretome whose expression may reduce isolate susceptibility to 4CMenB-induced immune responses. To improve our understanding of the contributions of MspA and NalP to meningococcal-host interactions, their distribution and phase-variable expression status was studied in epidemiologically relevant samples, including 127 carriage and 514 invasive isolates representative of multiple clonal complexes and serogroups. Prevalence estimates of >98% and >88% were obtained for mspA and nalP, respectively, with no significant differences in their frequencies in disease versus carriage isolates. 16% of serogroup B (MenB) invasive isolates, predominately from clonal complexes ST-269 and ST-461, lacked nalP. Deletion of nalP often resulted from recombination events between flanking repetitive elements. PolyC tract lengths ranged from 6-15 bp in nalP and 6-14 bp in mspA. In an examination of PV status, 58.8% of carriage, and 40.1% of invasive nalP-positive MenB isolates were nalP phase ON. The frequency of this phenotype was not significantly different in serogroup Y (MenY) carriage strains, but was significantly higher in invasive MenY strains (86.3%; p<0.0001). Approximately 90% of MenB carriage and invasive isolates were mspA phase ON; significantly more than MenY carriage (32.7%) or invasive (13.7%) isolates. This differential expression resulted from different mode mspA tract lengths between the serogroups. Our data indicates a differential requirement for NalP and MspA expression in MenB and MenY strains and is a step towards understanding the contributions of phase-variable loci to meningococcal biology