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1.
Biochem J ; 480(15): 1183-1197, 2023 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-37401534

RESUMEN

The development and optimisation of a photoaffinity labelling (PAL) displacement assay is presented, where a highly efficient PAL probe was used to report on the relative binding affinities of compounds to specific binding sites in multiple recombinant protein domains in tandem. The N- and C-terminal bromodomains of BRD4 were used as example target proteins. A test set of 264 compounds annotated with activity against the bromodomain and extra-terminal domain (BET) family in ChEMBL were used to benchmark the assay. The pIC50 values obtained from the assay correlated well with orthogonal TR-FRET data, highlighting the potential of this highly accessible PAL biochemical screening platform.

2.
J Emerg Nurs ; 49(5): 654-660, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37648367

RESUMEN

As multidisciplinary emergency care becomes increasingly complex, all team members must be aware of their respective roles and responsibilities. In the emergency department, nurse practitioners are integral members of the team. They possess a wide range of clinical and leadership competencies that allow them to perform specific and differentiated tasks within the emergency department. A well-defined competency not only contributes to the promotion of a positive work culture but also clarifies performance expectations, identifies skill gaps, and supports team development. Furthermore, it allows the nurse practitioner to adapt to changing conditions while maintaining patient safety. The competencies of emergency nurse practitioners have evolved over the past 2 decades. The authors discuss the importance of establishing clear expectations for emergency nurse practitioner practice in this article and the alignment of competencies with organizational culture and objectives.


Asunto(s)
Servicios Médicos de Urgencia , Enfermeras Practicantes , Humanos , Tratamiento de Urgencia , Servicio de Urgencia en Hospital , Liderazgo
4.
Nat Chem Biol ; 14(11): 1032-1042, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30297875

RESUMEN

α-Ketoglutarate (αKG) is a key node in many important metabolic pathways. The αKG analog N-oxalylglycine (NOG) and its cell-permeable prodrug dimethyloxalylglycine (DMOG) are extensively used to inhibit αKG-dependent dioxygenases. However, whether NOG interference with other αKG-dependent processes contributes to its mode of action remains poorly understood. Here we show that, in aqueous solutions, DMOG is rapidly hydrolyzed, yielding methyloxalylglycine (MOG). MOG elicits cytotoxicity in a manner that depends on its transport by monocarboxylate transporter 2 (MCT2) and is associated with decreased glutamine-derived tricarboxylic acid-cycle flux, suppressed mitochondrial respiration and decreased ATP production. MCT2-facilitated entry of MOG into cells leads to sufficiently high concentrations of NOG to inhibit multiple enzymes in glutamine metabolism, including glutamate dehydrogenase. These findings reveal that MCT2 dictates the mode of action of NOG by determining its intracellular concentration and have important implications for the use of (D)MOG in studying αKG-dependent signaling and metabolism.


Asunto(s)
Aminoácidos Dicarboxílicos/química , Ácidos Cetoglutáricos/química , Transportadores de Ácidos Monocarboxílicos/metabolismo , Adenosina Trifosfato/química , Animales , Fenómenos Bioquímicos , Bovinos , Línea Celular Tumoral , Ciclo del Ácido Cítrico , Perfilación de la Expresión Génica , Glutamina/metabolismo , Humanos , Hidrólisis , Concentración 50 Inhibidora , Células MCF-7 , Metabolómica , Ratones , Mitocondrias/metabolismo , Oxígeno/química , Puromicina/química , Transducción de Señal , Ácidos Tricarboxílicos/química
5.
Angew Chem Int Ed Engl ; 59(47): 21096-21105, 2020 11 16.
Artículo en Inglés | MEDLINE | ID: mdl-32745361

RESUMEN

Advances in genomic analyses enable the identification of new proteins that are associated with disease. To validate these targets, tool molecules are required to demonstrate that a ligand can have a disease-modifying effect. Currently, as tools are reported for only a fraction of the proteome, platforms for ligand discovery are essential to leverage insights from genomic analyses. Fragment screening offers an efficient approach to explore chemical space. Presented here is a fragment-screening platform, termed PhABits (PhotoAffinity Bits), which utilizes a library of photoreactive fragments to covalently capture fragment-protein interactions. Hits can be profiled to determine potency and the site of crosslinking, and subsequently developed as reporters in a competitive displacement assay to identify novel hit matter. The PhABit platform is envisioned to be widely applicable to novel protein targets, identifying starting points in the development of therapeutics.


Asunto(s)
Antineoplásicos/análisis , Compuestos Bicíclicos Heterocíclicos con Puentes/análisis , Reactivos de Enlaces Cruzados/química , Etiquetas de Fotoafinidad/química , Pirazoles/análisis , Quinoxalinas/análisis , Sulfonamidas/análisis , Vemurafenib/análisis , Antineoplásicos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Humanos , Ligandos , Estructura Molecular , Proteínas/antagonistas & inhibidores , Proteínas/química , Pirazoles/farmacología , Quinoxalinas/farmacología , Sulfonamidas/farmacología , Vemurafenib/farmacología
6.
J Am Chem Soc ; 141(6): 2703-2712, 2019 02 13.
Artículo en Inglés | MEDLINE | ID: mdl-30657686

RESUMEN

Modification of proteins with polyubiquitin chains is a key regulatory mechanism to control cellular behavior and alterations in the ubiquitin system are linked to many diseases. Linear (M1-linked) polyubiquitin chains play pivotal roles in several cellular signaling pathways mediating immune and inflammatory responses and apoptotic cell death. These chains are formed by the linear ubiquitin chain assembly complex (LUBAC), a multiprotein E3 ligase that consists of 3 subunits, HOIP, HOIL-1L, and SHARPIN. Herein, we describe the discovery of inhibitors targeting the active site cysteine of the catalytic subunit HOIP using fragment-based covalent ligand screening. We report the synthesis of a diverse library of electrophilic fragments and demonstrate an integrated use of protein LC-MS, biochemical ubiquitination assays, chemical synthesis, and protein crystallography to enable the first structure-based development of covalent inhibitors for an RBR E3 ligase. Furthermore, using cell-based assays and chemoproteomics, we demonstrate that these compounds effectively penetrate mammalian cells to label and inhibit HOIP and NF-κB activation, making them suitable hits for the development of selective probes to study LUBAC biology. Our results illustrate the power of fragment-based covalent ligand screening to discover lead compounds for challenging targets, which holds promise to be a general approach for the development of cell-permeable inhibitors of thioester-forming E3 ubiquitin ligases.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Ubiquitina-Proteína Ligasas/metabolismo , Secuencia de Aminoácidos , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/metabolismo , Células HEK293 , Humanos , Ligandos , Células MCF-7 , Modelos Moleculares , Estructura Secundaria de Proteína , Bibliotecas de Moléculas Pequeñas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Ubiquitina-Proteína Ligasas/química
7.
Biochem J ; 475(1): 329-340, 2018 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-29229763

RESUMEN

The MKK1/2 kinase tumour progression locus 2 (TPL-2) is critical for the production of tumour necrosis factor alpha (TNFα) in innate immune responses and a potential anti-inflammatory drug target. Several earlier pharmaceutical company screens with the isolated TPL-2 kinase domain have identified small-molecule inhibitors that specifically block TPL-2 signalling in cells, but none of these have progressed to clinical development. We have previously shown that TPL-2 catalytic activity regulates TNF production by macrophages while associated with NF-κB1 p105 and ABIN-2, independently of MKK1/2 phosphorylation via an unknown downstream substrate. In the present study, we used a positional scanning peptide library to determine the optimal substrate specificity of a complex of TPL-2, NF-κB1 p105 and ABIN-2. Using an optimal peptide substrate based on this screen and a high-throughput mass spectrometry assay to monitor kinase activity, we found that the TPL-2 complex has significantly altered sensitivities versus existing ATP-competitive TPL-2 inhibitors than the isolated TPL-2 kinase domain. These results imply that screens with the more physiologically relevant TPL-2/NF-κB1 p105/ABIN-2 complex have the potential to deliver novel TPL-2 chemical series; both ATP-competitive and allosteric inhibitors could emerge with significantly improved prospects for development as anti-inflammatory drugs.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Antiinflamatorios/farmacología , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Subunidad p50 de NF-kappa B/antagonistas & inhibidores , Péptidos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Secuencia de Aminoácidos , Antiinflamatorios/síntesis química , Expresión Génica , Células HEK293 , Ensayos Analíticos de Alto Rendimiento , Humanos , Quinasas Quinasa Quinasa PAM/genética , Quinasas Quinasa Quinasa PAM/metabolismo , Subunidad p50 de NF-kappa B/genética , Subunidad p50 de NF-kappa B/metabolismo , Biblioteca de Péptidos , Péptidos/síntesis química , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad , Especificidad por Sustrato
8.
Langmuir ; 33(42): 11246-11256, 2017 10 24.
Artículo en Inglés | MEDLINE | ID: mdl-28826215

RESUMEN

More than half of all pharmaceuticals are chiral compounds. Although the enantiomers of chiral compounds have the same chemical structure, they can exhibit marked differences in physiological activity; therefore, it is important to remove the undesirable enantiomer. Chromatographic separation of chiral enantiomers is one of the best available methods to get enantio-pure substances, but the optimization of the experimental conditions can be very time-consuming. One of the most widely used chiral stationary phases, amylose tris(3,5-dimethylphenyl carbamate) (ADMPC), has been extensively investigated using both experimental and computational methods; however, the dynamic nature of the interaction between enantiomers and ADMPC, as well as the solvent effects on the ADMPC-enantiomer interaction, are currently absent from models of the chiral recognition mechanism. Here we use QM/MM and molecular dynamics (MD) simulations to model the enantiomers of flavanone on ADMPC in either methanol or heptane/2-propanol (IPA) (90/10) to elucidate the chiral recognition mechanism from a new dynamic perspective. In atomistic MD simulations, the 12-mer model of ADMPC is found to hold the 4/3 left-handed helical structure in both methanol and heptane/IPA (90/10); however, the ADMPC polymer is found to have a more extended average structure in heptane/IPA (90/10) than in methanol. This results from the differences in the distribution of solvent molecules close to the backbone of ADMPC leads to changes in the distribution of the (φ, ψ) dihedral angles of the glycoside bond (between adjacent monomers) that define the structure of the polymer. Our simulations have shown that the lifetime of hydrogen bonds formed between ADMPC and flavanone enantiomers in the MD simulations are able to reproduce the elution order observed in experiments for both the methanol and the heptane/IPA solvent systems. Furthermore, the ratios of hydrogen-bonding-lifetime-related properties also capture the solvent effects, in that heptane/IPA (90/10) is found to make the separation between the two enantiomers of flavanone less effective than methanol, which agrees with the experimental separation factors of 0.9 versus 0.4 for R/S, respectively.

9.
Am J Respir Crit Care Med ; 194(8): 961-973, 2016 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-27064380

RESUMEN

RATIONALE: Acute respiratory distress syndrome is refractory to pharmacological intervention. Inappropriate activation of alveolar neutrophils is believed to underpin this disease's complex pathophysiology, yet these cells have been little studied. OBJECTIVES: To examine the functional and transcriptional profiles of patient blood and alveolar neutrophils compared with healthy volunteer cells, and to define their sensitivity to phosphoinositide 3-kinase inhibition. METHODS: Twenty-three ventilated patients underwent bronchoalveolar lavage. Alveolar and blood neutrophil apoptosis, phagocytosis, and adhesion molecules were quantified by flow cytometry, and oxidase responses were quantified by chemiluminescence. Cytokine and transcriptional profiling were used in multiplex and GeneChip arrays. MEASUREMENTS AND MAIN RESULTS: Patient blood and alveolar neutrophils were distinct from healthy circulating cells, with increased CD11b and reduced CD62L expression, delayed constitutive apoptosis, and primed oxidase responses. Incubating control cells with disease bronchoalveolar lavage recapitulated the aberrant functional phenotype, and this could be reversed by phosphoinositide 3-kinase inhibitors. In contrast, the prosurvival phenotype of patient cells was resistant to phosphoinositide 3-kinase inhibition. RNA transcriptomic analysis revealed modified immune, cytoskeletal, and cell death pathways in patient cells, aligning closely to sepsis and burns datasets but not to phosphoinositide 3-kinase signatures. CONCLUSIONS: Acute respiratory distress syndrome blood and alveolar neutrophils display a distinct primed prosurvival profile and transcriptional signature. The enhanced respiratory burst was phosphoinositide 3-kinase-dependent but delayed apoptosis and the altered transcriptional profile were not. These unexpected findings cast doubt over the utility of phosphoinositide 3-kinase inhibition in acute respiratory distress syndrome and highlight the importance of evaluating novel therapeutic strategies in patient-derived cells.


Asunto(s)
Neutrófilos/efectos de los fármacos , Inhibidores de las Quinasa Fosfoinosítidos-3 , Síndrome de Dificultad Respiratoria/inmunología , Líquido del Lavado Bronquioalveolar/citología , Antígeno CD11b/metabolismo , Citocinas/metabolismo , Femenino , Citometría de Flujo , Perfilación de la Expresión Génica , Humanos , Selectina L/metabolismo , Masculino , Persona de Mediana Edad , Neutrófilos/metabolismo , Neutrófilos/fisiología , Análisis de Secuencia por Matrices de Oligonucleótidos , Fenotipo , Síndrome de Dificultad Respiratoria/tratamiento farmacológico
12.
Lancet ; 385 Suppl 1: S55, 2015 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-26312877

RESUMEN

BACKGROUND: Acute respiratory distress syndrome (ARDS) is characterised by diffuse neutrophil-mediated alveolar inflammation. Recently, we demonstrated that blood polymorphonuclear leucocytes (PMNs) in ARDS are basally activated, and exhibit aberrant oxidative burst and survival responses. The molecular mechanisms governing ARDS PMN function and longevity are incompletely understood. We aimed to use genome-wide transcriptional profiling of ARDS blood PMNs to explore underlying disease mechanisms and identify therapeutic targets aimed at manipulating PMN function and longevity. METHODS: GeneChip Affymetrix oligonucleotide arrays were used to assess global transcriptional profiles in highly pure PMNs from ventilated patients fulfilling the Berlin ARDS definition (n=10), in freshly isolated PMNs from age-matched and sex-matched healthy volunteers (n=10), and in healthy volunteer PMNs exposed in vitro to recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) (1 ng/mL for 6 h). Ingenuity Pathway Analysis software was used to map probes identified as important onto specific pathways. FINDINGS: Transcriptomic analysis showed that 1319 genes were altered in ARDS PMNs relative to healthy volunteer PMNs. Compared with well established reference databases, the gene expression profile in ARDS PMNs showed near-complete correlation to datasets derived from patients with sepsis and burns. Transcripts enriched in ARDS PMNs were differentially expressed in known functional network pathways associated with cancer, cellular compromise, apoptotic mechanisms, and chemotaxis. Of the observed gene changes, only 292 (22%) were seen in healthy volunteer PMNs after exposure to rhGM-CSF, of which 216 showed the same directional change as ARDS PMNs. INTERPRETATION: Existing genome-wide studies in ARDS use total blood leucocytes; our study is the first, to our knowledge, to use unbiased global genomic profiling of highly pure ARDS blood PMNs in parallel with age-matched and gender-matched healthy volunteer PMNs treated with rhGM-CSF. Collectively our results show that ARDS PMNs display important de-novo transcriptional activity. The global transcriptomic changes were consistent with the observed aberrant ARDS PMN survival and functional phenotype that we have previously reported, and show near-complete correlation to existing sepsis and burns datasets, but only limited transcriptomic overlap with healthy volunteer PMNs treated with rhGM-CSF. FUNDING: National Institute for Health Research, GlaxoSmithKline.

13.
Org Biomol Chem ; 13(3): 859-65, 2015 Jan 21.
Artículo en Inglés | MEDLINE | ID: mdl-25408068

RESUMEN

Controlling the properties of lead molecules is critical in drug discovery, but sourcing large numbers of lead-like compounds for screening collections is a major challenge. A unified synthetic approach is described that enabled the synthesis of 52 diverse lead-like molecular scaffolds from a minimal set of 13 precursors. The divergent approach exploited a suite of robust, functional group-tolerant transformations. Crucially, after derivatisation, these scaffolds would target significant lead-like chemical space, and complement commercially-available compounds.


Asunto(s)
Aminas/química , Carbonatos/química , Descubrimiento de Drogas , Bibliotecas de Moléculas Pequeñas/síntesis química , Técnicas de Química Sintética , Ciclización , Diseño de Fármacos , Ensayos Analíticos de Alto Rendimiento , Estructura Molecular
14.
J Acoust Soc Am ; 137(6): 3422-35, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26093431

RESUMEN

This investigation explores perceptual and acoustic characteristics of children's successful and unsuccessful productions of /t/ and /k/, with a specific aim of exploring perceptual sensitivity to phonetic detail, and the extent to which this sensitivity is reflected in the acoustic domain. Recordings were collected from 4- to 8-year-old children with a speech sound disorder (SSD) who misarticulated one of the target plosives, and compared to productions recorded from peers with typical speech development (TD). Perceptual responses were registered with regards to a visual-analog scale, ranging from "clear [t]" to "clear [k]." Statistical models of prototypical productions were built, based on spectral moments and discrete cosine transform features, and used in the scoring of SSD productions. In the perceptual evaluation, "clear substitutions" were rated as less prototypical than correct productions. Moreover, target-appropriate productions of /t/ and /k/ produced by children with SSD were rated as less prototypical than those produced by TD peers. The acoustical modeling could to a large extent discriminate between the gross categories /t/ and /k/, and scored the SSD utterances on a continuous scale that was largely consistent with the category of production. However, none of the methods exhibited the same sensitivity to phonetic detail as the human listeners.


Asunto(s)
Acústica , Fonética , Acústica del Lenguaje , Inteligibilidad del Habla , Percepción del Habla , Medición de la Producción del Habla/métodos , Trastorno Fonológico/psicología , Calidad de la Voz , Factores de Edad , Análisis de Varianza , Estudios de Casos y Controles , Niño , Preescolar , Humanos , Juicio , Modelos Teóricos , Procesamiento de Señales Asistido por Computador , Espectrografía del Sonido , Trastorno Fonológico/diagnóstico
15.
Clin Sci (Lond) ; 126(3): 223-32, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23905758

RESUMEN

There are increased numbers of pulmonary CD8 lymphocytes in COPD (chronic obstructive pulmonary disease). CRAC (calcium release-activation calcium) channels play a central role in lymphocyte activation though the regulation of the transcription factor NFAT (nuclear factor of activated T-cells). We studied the expression of NFAT in lungs from COPD patients compared with controls, and evaluated the effects of CRAC channel inhibition compared with corticosteroids on NFAT activation and cytokine production in CD8 cells from COPD patients. The effects of the corticosteroid dexamethasone, the calcineurin inhibitor cyclosporin and the CRAC channel inhibitor Synta 66 were studied on cytokine production and NFAT activation using peripheral blood and isolated pulmonary CD8 cells. NFAT1 and CD8 co-expression in the lungs was compared in COPD patients and controls using combined immunohistochemistry and immunofluorescence. NFAT inhibition with either cyclosporin or Synta 66 resulted in significantly greater maximal inhibition of cytokines than dexamethasone in both peripheral blood and pulmonary CD8 cells [e.g. >95% inhibition of IFNγ (interferon γ) production from pulmonary CD8 cells using cyclosporin and Synta 66 compared with <50% using dexamethasone]. The absolute number of pulmonary CD8 cells co-expressing NFAT1 was significantly raised in lungs from COPD patients compared with controls, but the percentage of CD8 cells co-expressing NFAT1 was similar between COPD patients and controls (80.7% compared with 78.5% respectively, P=0.3). Inhibition of NFAT using the CRAC channel Synta 66 produces greater anti-inflammatory effects on CD8 cells from COPD patients than corticosteroids. NFAT is expressed at a high level in pulmonary CD8 cells in COPD.


Asunto(s)
Antiinflamatorios/farmacología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/patología , Bloqueadores de los Canales de Calcio/farmacología , Factores de Transcripción NFATC/antagonistas & inhibidores , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Bloqueadores de los Canales de Calcio/uso terapéutico , Estudios de Casos y Controles , Células Cultivadas , Ciclosporina/farmacología , Ciclosporina/uso terapéutico , Citocinas/metabolismo , Dexametasona/farmacología , Dexametasona/uso terapéutico , Evaluación Preclínica de Medicamentos , Femenino , Glucocorticoides/farmacología , Glucocorticoides/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Factores de Transcripción NFATC/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/patología
16.
Clin Linguist Phon ; 28(6): 373-95, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24405224

RESUMEN

We explore children's perception of their own speech - in its online form, in its recorded form, and in synthetically modified forms. Children with phonological disorder (PD) and children with typical speech and language development (TD) performed tasks of evaluating accuracy of the different types of speech stimuli, either immediately after having produced the utterance or after a delay. In addition, they performed a task designed to assess their ability to detect synthetic modification. Both groups showed high performance in tasks involving evaluation of other children's speech, whereas in tasks of evaluating one's own speech, the children with PD were less accurate than their TD peers. The children with PD were less sensitive to misproductions in immediate conjunction with their production of an utterance, and more accurate after a delay. Within-category modification often passed undetected, indicating a satisfactory quality of the generated speech. Potential clinical benefits of using corrective re-synthesis are discussed.


Asunto(s)
Trastornos de la Articulación/terapia , Retroalimentación Sensorial , Percepción del Habla , Medición de la Producción del Habla , Logopedia/métodos , Trastornos de la Articulación/psicología , Atención , Niño , Preescolar , Equipos de Comunicación para Personas con Discapacidad , Femenino , Humanos , Masculino , Fonación , Habla
17.
Cancer Discov ; 14(8): 1457-1475, 2024 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-38587317

RESUMEN

Microsatellite-unstable (MSI) cancers require WRN helicase to resolve replication stress due to expanded DNA (TA)n dinucleotide repeats. WRN is a promising synthetic lethal target for MSI tumors, and WRN inhibitors are in development. In this study, we used CRISPR-Cas9 base editing to map WRN residues critical for MSI cells, validating the helicase domain as the primary drug target. Fragment-based screening led to the development of potent and highly selective WRN helicase covalent inhibitors. These compounds selectively suppressed MSI model growth in vitro and in vivo by mimicking WRN loss, inducing DNA double-strand breaks at expanded TA repeats and DNA damage. Assessment of biomarkers in preclinical models linked TA-repeat expansions and mismatch repair alterations to compound activity. Efficacy was confirmed in immunotherapy-resistant organoids and patient-derived xenograft models. The discovery of potent, selective covalent WRN inhibitors provides proof of concept for synthetic lethal targeting of WRN in MSI cancer and tools to dissect WRN biology. Significance: We report the discovery and characterization of potent, selective WRN helicase inhibitors for MSI cancer treatment, with biomarker analysis and evaluation of efficacy in vivo and in immunotherapy-refractory preclinical models. These findings pave the way to translate WRN inhibition into MSI cancer therapies and provide tools to investigate WRN biology. See related commentary by Wainberg, p. 1369.


Asunto(s)
Helicasa del Síndrome de Werner , Humanos , Helicasa del Síndrome de Werner/genética , Ratones , Animales , Inestabilidad de Microsatélites , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Línea Celular Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico
18.
J Prof Nurs ; 44: 26-32, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36746597

RESUMEN

BACKGROUND: Building capacity for teamwork, communication, role clarification and recognition of shared values is essential for interprofessional healthcare workforce development. Requirements to demonstrate interprofessional practice competencies have coincided with pivots to online delivery. Comparison of in-person and online delivery models for interprofessional education is important for future curriculum design. PURPOSE: This article presents an evaluation of in-person and online delivery modes for interprofessional team-based education and compares learner experiences across different health professions. METHODS: Students from 13 health professions (n = 2236) participated between Spring 2020 and Fall 2021. In-person and online delivery models were compared, assessing learner perceptions of efficacy for interprofessional practice, using reflective pre-post responses to the Interprofessional Collaborative Competency Attainment Scale (ICCAS). RESULTS: Mean ICCAS scores improved for in-person and online delivery (0.79 vs 0.66), with strong effect (Cohen's D 2.03 and 1.31 respectively; p < 0.001). Statistically significant differences were observed across professions, although all experienced ICCAS score improvements. Logistical benefits were evident for online delivery. CONCLUSION: In-person and online interprofessional team-based education can provide valuable learner experiences for large student cohorts from multiple professions. ICCAS score differences should be weighed against potential logistical benefits of online delivery. Timing of delivery and determinants of differences in student response across professions warrant evaluation for future curriculum design.


Asunto(s)
Educación Interprofesional , Estudiantes del Área de la Salud , Humanos , Relaciones Interprofesionales , Empleos en Salud , Curriculum
19.
Clin Nurse Spec ; 37(2): 64-77, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36799702

RESUMEN

PURPOSE/AIMS: The aim of this study was to investigate the current practice of clinical nurse specialists working in US emergency care settings to (1) explicate the application of the Emergency Nurses Association core competencies and define the specialized clinical nurse specialist role in emergency care and (2) align current clinical nurse specialist practice in emergency settings with the National Association of Clinical Nurse Specialists core competencies and the identified substantive areas of clinical nurse specialist practice. DESIGN: This study used a quantitative exploratory descriptive approach using survey data. METHODS: A purposive convenience sample was recruited from the Emergency Nurses Association and the National Association of Clinical Nurse Specialists. Participants completed a 39-item survey based on a consensus process to develop competencies for emergency department (ED)-situated clinical nurse specialists. RESULTS: Respondents (n = 285) reported spending more than 50% of their work time in a primary clinical nurse specialist role. Significant differences in practice were found between geographic location, setting, educational preparation, title protection status, and type of institution. CONCLUSIONS: Our findings suggest that that the competencies ascribed to ED-situated clinical nurse specialists are valid in both frequency and importance. However, ED-situated clinical nurse specialists are not fully credentialed or practicing to the full extent of their education and licenses, because of professional, legislative, and environmental limitations.


Asunto(s)
Servicios Médicos de Urgencia , Enfermeras Clínicas , Humanos , Encuestas y Cuestionarios , Competencia Clínica , Proyectos de Investigación
20.
ACS Chem Biol ; 18(2): 285-295, 2023 02 17.
Artículo en Inglés | MEDLINE | ID: mdl-36649130

RESUMEN

Here, we report a comprehensive profiling of sulfur(VI) fluorides (SVI-Fs) as reactive groups for chemical biology applications. SVI-Fs are reactive functionalities that modify lysine, tyrosine, histidine, and serine sidechains. A panel of SVI-Fs were studied with respect to hydrolytic stability and reactivity with nucleophilic amino acid sidechains. The use of SVI-Fs to covalently modify carbonic anhydrase II (CAII) and a range of kinases was then investigated. Finally, the SVI-F panel was used in live cell chemoproteomic workflows, identifying novel protein targets based on the type of SVI-F used. This work highlights how SVI-F reactivity can be used as a tool to expand the liganded proteome.


Asunto(s)
Fluoruros , Proteoma , Proteoma/metabolismo , Fluoruros/química , Azufre/química , Aminoácidos/química , Biología
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