Structural pharmacological studies on EGFR T790M/C797S.

Biochem Biophys Res Commun. 2017 Apr 26;:

Authors: Kong LL, Ma R, Yao MY, Yan XE, Zhu SJ, Zhao P, Yun CH

Abstract
Drug-resistance is a major challenge in targeted therapy of EGFR mutated non-small cell lung cancers (NSCLCs). The third-generation irreversible inhibitors such as AZD9291, CO-1686 and WZ4002 can overcome EGFR T790M drug-resistance mutant through covalent binding through Cys 797, but ultimately lose their efficacy upon emergence of the new mutation C797S. To develop new reversible inhibitors not relying on covalent binding through Cys 797 is therefore urgently demanded. Gö6976 is a staurosporine-like reversible inhibitor targeting T790M while sparing the wild-type EGFR. In the present work, we reported the complex crystal structures of EGFR T790M/C797S + Gö6976 and T790M + Gö6976, along with enzyme kinetic data of EGFR wild-type, T790M and T790M/C797S. These data showed that the C797S mutation does not significantly alter the structure and function of the EGFR kinase, but increases the local hydrophilicity around residue 797. The complex crystal structures also elucidated the detailed binding mode of Gö6976 to EGFR and explained why this compound prefers binding to T790M mutant. These structural pharmacological data would facilitate future drug development studies.

PMID: 28456628 [PubMed - as supplied by publisher]

Inference in the age of big data: Future perspectives on neuroscience.

Neuroimage. 2017 Apr 26;:

Authors: Bzdok D, Yeo BTT

Abstract
Neuroscience is undergoing faster changes than ever before. Over 100 years our field qualitatively described and invasively manipulated single or few organisms to gain anatomical, physiological, and pharmacological insights. In the last 10 years neuroscience spawned quantitative datasets of unprecedented breadth (e.g., microanatomy, synaptic connections, and optogenetic brain-behavior assays) and size (e.g., cognition, brain imaging, and genetics). While growing data availability and information granularity have been amply discussed, we direct attention to a less explored question: How will the unprecedented data richness shape data analysis practices? Statistical reasoning is becoming more important to distill neurobiological knowledge from healthy and pathological brain measurements. We argue that large-scale data analysis will use more statistical models that are non-parametric, generative, and mixing frequentist and Bayesian aspects, while supplementing classical hypothesis testing with out-of-sample predictions.

PMID: 28456584 [PubMed - as supplied by publisher]

Degradation of indoor limonene by outdoor ozone: A cascade of secondary organic aerosols.

Environ Pollut. 2017 Apr 26;:

Authors: Rösch C, Wissenbach DK, Franck U, Wendisch M, Schlink U

Abstract
In indoor air, terpene-ozone reactions can form secondary organic aerosols (SOA) in a transient process. 'Real world' measurements conducted in a furnished room without air conditioning were modelled involving the indoor background of airborne particulate matter, outdoor ozone infiltrated by natural ventilation, repeated transient limonene evaporations, and different subsequent ventilation regimes. For the given setup, we disentangled the development of nucleated, coagulated, and condensed SOA fractions in the indoor air and calculated the time dependence of the aerosol mass fraction (AMF) by means of a process model. The AMF varied significantly between 0.3 and 5.0 and was influenced by the ozone limonene ratio and the background particles which existed prior to SOA formation. Both influencing factors determine whether nucleation or adsorption processes are preferred; condensation is strongly intensified by particulate background. The results provide evidence that SOA levels in natural indoor environments can surpass those known from chamber measurements. An indicator for the SOA forming potential of limonene was found to be limona ketone. Multiplying its concentration (in μg/m(3)) by 450(±100) provides an estimate of the concentration of the reacted limonene. This can be used to detect a high particle formation potential due to limonene pollution, e.g. in epidemiological studies considering adverse health effects of indoor air pollutants.

PMID: 28456415 [PubMed - as supplied by publisher]

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

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pharmacogenomics

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(exome OR "exome sequencing") AND disease

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29 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2017/04/30

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24 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2017/04/30

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Lmx1b-targeted cis-regulatory modules involved in limb dorsalization.

Development. 2017 Apr 28;:

Authors: Haro E, Watson BA, Feenstra JM, Tegeler L, Pira CU, Mohan S, Oberg KC

Abstract
Lmx1b is a homeodomain transcription factor responsible for limb dorsalization. Despite striking double-ventral (loss-of-function) and double-dorsal (gain-of-function) limb phenotypes, no direct gene targets in the limb have been confirmed. To determine direct targets, we performed a chromatin immunoprecipitation against Lmx1b at E12.5 followed by next generation sequencing (ChIP-seq). Nearly 84% (n=617) of the Lmx1b-bound genomic intervals (LBIs) identified overlap with chromatin regulatory marks indicative of potential cis-regulatory modules (PCRMs). In addition, 73 LBIs mapped to known CRMs active during limb development. We compared Lmx1b-bound PCRMs to genes differentially expressed by Lmx1b and found 292 PCRMs within 1 Mb of 254 Lmx1b-regulated genes. Gene ontologic analysis suggests that Lmx1b targets extracellular matrix production, bone/joint formation, axonal guidance, vascular development, cell proliferation and cell movement. We validated the functional activity of a PCRM associated with joint-related Gdf5 that provides a mechanism for Lmx1b-mediated joint modification and a PCRM associated with Lmx1b that suggests a role in autoregulation. This is the first report to describe genome-wide Lmx1b binding during limb development, directly linking Lmx1b to targets that accomplish limb dorsalization.

PMID: 28455377 [PubMed - as supplied by publisher]

Novel mutation in CNTNAP1 results in congenital hypomyelinating neuropathy.

Muscle Nerve. 2017 May;55(5):761-765

Authors: Mehta P, Küspert M, Bale T, Brownstein CA, Towne MC, De Girolami U, Shi J, Beggs AH, Darras BT, Wegner M, Piao X, Agrawal PB

Abstract
INTRODUCTION: Congenital hypomyelinating neuropathy (CHN) is a rare congenital neuropathy that presents in the neonatal period and has been linked previously to mutations in several genes associated with myelination. A recent study has linked 4 homozygous frameshift mutations in the contactin-associated protein 1 (CNTNAP1) gene with this condition.
METHODS: We report a neonate with CHN who was found to have absent sensory nerve and compound muscle action potentials and hypomyelination on nerve biopsy.
RESULTS: On whole exome sequencing, we identified a novel CNTNAP1 homozygous missense mutation (p.Arg388Pro) in the proband, and both parents were carriers. Molecular modeling suggests that this variant disrupts a β-strand to cause an unstable structure and likely significant changes in protein function.
CONCLUSIONS: This report links a missense CNTNAP1 variant to the disease phenotype previously associated only with frameshift mutations. Muscle Nerve 55: 761-765, 2017.

PMID: 27668699 [PubMed - indexed for MEDLINE]

Genetic variation among 82 pharmacogenes: The PGRNseq data from the eMERGE network.

Clin Pharmacol Ther. 2016 Aug;100(2):160-9

Authors: Bush WS, Crosslin DR, Owusu-Obeng A, Wallace J, Almoguera B, Basford MA, Bielinski SJ, Carrell DS, Connolly JJ, Crawford D, Doheny KF, Gallego CJ, Gordon AS, Keating B, Kirby J, Kitchner T, Manzi S, Mejia AR, Pan V, Perry CL, Peterson JF, Prows CA, Ralston J, Scott SA, Scrol A, Smith M, Stallings SC, Veldhuizen T, Wolf W, Volpi S, Wiley K, Li R, Manolio T, Bottinger E, Brilliant MH, Carey D, Chisholm RL, Chute CG, Haines JL, Hakonarson H, Harley JB, Holm IA, Kullo IJ, Jarvik GP, Larson EB, McCarty CA, Williams MS, Denny JC, Rasmussen-Torvik LJ, Roden DM, Ritchie MD

Abstract
Genetic variation can affect drug response in multiple ways, although it remains unclear how rare genetic variants affect drug response. The electronic Medical Records and Genomics (eMERGE) Network, collaborating with the Pharmacogenomics Research Network, began eMERGE-PGx, a targeted sequencing study to assess genetic variation in 82 pharmacogenes critical for implementation of "precision medicine." The February 2015 eMERGE-PGx data release includes sequence-derived data from ∼5,000 clinical subjects. We present the variant frequency spectrum categorized by variant type, ancestry, and predicted function. We found 95.12% of genes have variants with a scaled Combined Annotation-Dependent Depletion score above 20, and 96.19% of all samples had one or more Clinical Pharmacogenetics Implementation Consortium Level A actionable variants. These data highlight the distribution and scope of genetic variation in relevant pharmacogenes, identifying challenges associated with implementing clinical sequencing for drug treatment at a broader level, underscoring the importance for multifaceted research in the execution of precision medicine.

PMID: 26857349 [PubMed - indexed for MEDLINE]

Hypertonic Saline as a Useful Tool for Sputum Induction and Pathogen Detection in Cystic Fibrosis.

Lung. 2017 Apr 28;:

Authors: Ferreira ACM, Marson FAL, Cohen MA, Bertuzzo CS, Levy CE, Ribeiro AF, Ribeiro JD

Abstract
PURPOSE: The aim of this study was to compare the qualitative and semi-quantitative detection of pathogens in the airway secretions of patients with cystic fibrosis (CF) and the sputum induction capacity before and after inhalation of 7% hypertonic saline solution (HSS).
METHODS: The study enrolled 64 patients with CF. Airway secretions were collected from all enrolled patients with CF before and after inhalation of 7% HSS, and the samples were screened for pathogens.
RESULTS: Inhalation of 7% HSS increased the probability of producing sputum from 36 to 52% (p = 0.002) in children with CF. The effect was most in children under 11 years. Inhalation of 7% HSS improved qualitative pathogen identification (p = 0.008). Inhalation of 7% HSS increased the mucoid Pseudomonas aeruginosa (p = 0.002) and non-mucoid P. aeruginosa in the semi-quantitative analysis (p = 0.035). Four new pathogens (Aspergillus fumigatus, Achromobacter xylosoxidans, Ochrobactrum anthropi, and Elizabethkingia meningoseptica) were identified in the sputum samples collected from the airways of patients with CF following 7% HSS.
CONCLUSIONS: Inhalation of 7% HSS increased sputum production and pathogen identification in children with CF. The inhalation of 7% HSS was feasible and should be implemented for routine pathogen detection in the airways of patients with CF, particularly in those patients who do not produce sputum.

PMID: 28455785 [PubMed - as supplied by publisher]

Macrophage Dysfunction in Respiratory Disease.

Results Probl Cell Differ. 2017;62:299-313

Authors: Belchamber KBR, Donnelly LE

Abstract
In the healthy lung, macrophages maintain homeostasis by clearing inhaled particles, bacteria, and removing apoptotic cells from the local pulmonary environment. However, in respiratory diseases including chronic obstructive pulmonary disease (COPD), asthma, and cystic fibrosis, macrophages appear to be dysfunctional and may contribute to disease pathogenesis. In COPD, phagocytosis of bacterial species and apoptotic cells by both alveolar macrophages and monocyte-derived macrophages is significantly reduced, leading to colonization of the lung with pathogenic bacteria. COPD macrophages also release high levels of pro-inflammatory cytokines and chemokines, including CXCL8, TGFβ, and CCL2, driving recruitment of other inflammatory cells including neutrophils and monocytes to the lungs and promoting disease progression.In asthma, defective phagocytosis and efferocytosis have also been reported, and macrophages appear to have altered cell surface receptor expression; however, it is as yet unclear how this contributes to disease progression but may be important in driving Th2-mediated inflammation. In cystic fibrosis, macrophages also display defective phagocytosis, and reduced bacterial killing, which may be driven by the pro-inflammatory environment present in the lungs of these patients.The mechanisms behind defective macrophage function in lung diseases are not currently understood, but potential mechanisms include alterations in phagocytic receptor expression levels, oxidative stress, but also the possibility that specific diseases are associated with a specific, altered, macrophage phenotype that displays reduced function. Identification of the mechanisms responsible may present novel therapeutic opportunities for treatment.

PMID: 28455714 [PubMed - in process]

Protocol of a Pilot Study of Technology-Enabled Coproduction in Pediatric Chronic Illness Care.

JMIR Res Protoc. 2017 Apr 28;6(4):e71

Authors: Kaplan HC, Thakkar SN, Burns L, Chini B, Dykes DM, McPhail GL, Moore E, Saeed SA, Eslick I, Margolis PA, Opipari-Arrigan L

Abstract
BACKGROUND: Pediatric chronic illness care models are traditionally organized around acute episodes of care and may not meet the needs of patients and their families. Interventions that extend the patient-clinician interaction beyond the health care visit, allow for asynchronous and bidirectional feedback loops that span visits and daily life, and facilitate seamless sharing of information are needed to support a care delivery system that is more collaborative, continuous, and data-driven. Orchestra is a mobile health technology platform and intervention designed to transform the management of chronic diseases by optimizing patient-clinician coproduction of care.
OBJECTIVE: The aim of this study is to assess the feasibility, acceptability, and preliminary impact of the Orchestra technology and intervention in the context of pediatric chronic illness care.
METHODS: This study will be conducted in the cystic fibrosis and inflammatory bowel disease clinics at Cincinnati Children's Hospital Medical Center. We will enroll interested patients and their caregivers to work with clinicians to use the Orchestra technology platform and care model over a 6-month period. In parallel, we will use quality improvement methods to improve processes for integrating Orchestra into clinic workflows and patient/family lifestyles. We will use surveys, interviews, technology use data, and measures of clinical outcomes to assess the feasibility, acceptability, and preliminary impact of Orchestra. Outcome measures will include assessments of: (1) enrollment and dropout rates; (2) duration of engagement/sustained use; (3) symptom and patient-reported outcome tracker completion rates; (4) perceived impact on treatment plan, communication with the clinical team, visit preparation, and overall care; (5) changes in disease self-efficacy and engagement in care; and (6) clinical outcomes and health care utilization.
RESULTS: Participant recruitment began in mid-2015, with results expected in 2017.
CONCLUSIONS: Chronic disease management needs a dramatic transformation to support more collaborative, effective, and patient-centered care. This study is unique in that it is testing not only the impact of technology, but also the necessary processes that facilitate patient and clinician collaboration. This pilot study is designed to examine how technology-enabled coproduction can be implemented in real-life clinical contexts. Once the Orchestra technology and intervention are optimized to ensure feasibility and acceptability, future studies can test the effectiveness of this approach to improve patient outcomes and health care value.

PMID: 28455274 [PubMed - in process]

Bronchoprotective mechanisms for specialized pro-resolving mediators in the resolution of lung inflammation.

Mol Aspects Med. 2017 Apr 25;:

Authors: Duvall MG, Bruggemann TR, Levy BD

Abstract
Bronchi are exposed daily to irritants, microbes and allergens as well as extremes of temperature and acid. The airway mucosal epithelium plays a pivotal role as a sentinel, releasing alarmins when danger is encountered. To maintain homeostasis, an elaborate counter-regulatory network of signals and cellular effector mechanisms are needed. Specialized pro-resolving mediators (SPMs) are chemical mediators that enact resolution programs in response to injury, infection or allergy. SPMs are enzymatically derived from essential polyunsaturated fatty acids with potent cell-type specific immunoresolvent properties. SPMs signal by engaging cell-based receptors to turn off acute inflammatory responses and restore tissue homeostasis. Several common lung diseases involving the airways, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF), are characterized by unresolved bronchial inflammation. In preclinical murine models of lung disease, SPMs carry potent bronchoprotective actions. Here, we review cellular and molecular effects for SPM-initiated catabasis in the lung and their human translation.

PMID: 28455109 [PubMed - as supplied by publisher]

Optimization of the French cystic fibrosis newborn screening programme by a centralized tracking process.

J Med Screen. 2017 Jan 01;:969141317692611

Authors: Munck A, Delmas D, Audrézet MP, Lemonnier L, Cheillan D, Roussey M

Abstract
Objectives To evaluate the French cystic fibrosis newborn screening algorithm, based on data tracked by a centralized monitoring process, from 2002 to 2014. The programme aimed to attain European Standards in terms of positive predictive value, sensitivity, the ratio of screen positive patients diagnosed with cystic fibrosis to infants who screen positive but with inconclusive diagnosis (CFSPID), and time to diagnosis. Methods Retrospective analysis of programme performance, compliance with the algorithm, and changes in screening strategy. Results Modifications in the flow chart protocol improved the positive predictive value to 0.31 while maintaining the sensitivity at 0.95. Among infants diagnosed with cystic fibrosis, or identified as CFSPID, sweat test results were obtained for 94%, and two mutations were identified after exhaustive screening for the gene, when applicable, in 99.6%. The rate of pending diagnosis was very low (0.5%). The ratio of infants with cystic fibrosis:CFSPID was 6.3:1. Age at initial visit at the CF centre was ≤ 35 days, respectively, in 53%/26%. Conclusion Performances were in agreement with European standards, but timeliness of initial visit needed improvement. Our data complement an accumulating body of evidence demonstrating that attention must be paid to such ethical considerations as limiting carrier detection and inconclusive diagnosis. Newborn screening programmes should have a rigorous centralized monitoring process to warrant adjustments for improving performance to attain consensus guidelines.

PMID: 28454512 [PubMed - as supplied by publisher]

Does a checklist reduce the number of errors made in nurse-assembled discharge prescriptions?

Br J Nurs. 2017 Apr 27;26(8):464-467

Authors: Byrne C, Sierra H, Tolhurst R

Abstract
BACKGROUND: The safe supply of medicines is an integral part of being discharged from hospital. Locally, nurses are responsible for assembling medication for discharge prescriptions. Over a 2-year period 15 serious medication errors relating to discharge were reported on the health and ageing unit. This project was designed to evaluate whether a discharge medication checklist could reduce errors on nurse-assembled discharge prescriptions.
METHODS AND RESULTS: A baseline audit was conducted to identify the number of medication errors on nurse-assembled discharge prescriptions. After the audit period the discharge medication checklist was introduced and education and training was provided to nursing staff. There was a statistically significant reduction in the number of assembled discharge prescriptions with one or more errors (28/56 vs. 9/44; p=0.0478) when re-audited.
CONCLUSION: The introduction of a discharge medication checklist demonstrated a significant reduction in errors. The authors recommend that the discharge medication checklist and training programme be rolled out across medical wards to facilitate safe discharge.

PMID: 28453319 [PubMed - in process]