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1.
Emergencias (Sant Vicenç dels Horts) ; 32(1): 9-18, feb. 2020. graf, tab
Artigo em Espanhol | IBECS-Express | ID: ibc-ET2-3431

RESUMO

Objetivos. Analizar qué características clínicas y del ECG de la primera valoración de pacientes con dolor torácico no traumático (DNT) se asocian con una clasificación inicial de sospecha de síndrome coronario agudo (SCA) y con el diagnóstico final de SCA, e identificar cuáles resultan sobre o infravaloradas durante la clasificación inicial. Método. Se incluyeron las consultas consecutivas por DTNT en una unidad de dolor torácico durante 10 años (2008-2017) en las que se disponía de los diagnósticos inicial de sospecha (SCA/no SCA) y final de alta de urgencias (SCA/no SCA). Se incluyeron 33 variables independientes (2 demográficas, 5 comorbilidad cardiovascular, 22 dolor torácico, 4 datos ECG). Se calcularon las odds ratio (OR) para la clasificación (inicial y final) como SCA para cada variable independiente, crudas y ajustadas en modelos globales que incluían todas ellas. En estos modelos ajustados se comparó si las OR para la clasificación inicial y final como SCA eran significativamente diferentes. Resultados. Se incluyeron 34.552 visitas. Las 33 variables analizadas mostraron asociación significativa para la clasificación inicial y final del DTNT como SCA, y en muchos casos esta asociación se mantuvo en el modelo ajustado. Diecinueve variables mostraron OR significativamente diferentes para la sospecha inicial de SCA que para el diagnóstico final de SCA: 10 sobrestimaban la asociación final y 9 la subestimaban. Conclusión. Los datos clínicos iniciales clásicamente utilizados para sospechar SCA pacientes con DTNT en urgencias identifican todos ellos individualmente a pacientes con riesgo incrementado de ser clasificado inicial y finalmente como SCA; sin embargo, algunos de ellos sobreestiman y otros subestiman inicialmente el riesgo final. Los urgenciólogos debieran sensibilizarse más con estos datos subestimados


Objectives. To analyze clinical data and electrocardiographic (ECG) findings obtained during the initial evaluation of patients with nontraumatic chest pain (NTCP). To explore associations between these findings and the initial and final diagnoses of acute coronary syndrome (ACS). To assess which variables initially over- or underestimate risk ACS. Methods. Consecutive patients with NTCP attended in a chest pain unit during the 10-year period of 2008–2017 were included if the suspected and discharge diagnoses of interest (ACS or non-ACS) had been recorded. Thirtythree independent variables (demographic, 2; cardiovascular, 5; chest pain, 22; ECG, 4). We included all variables in models to calculate crude and adjusted odds ratios (ORs) between each independent variable and the initial and final diagnoses. The adjusted ORs were compared to determine whether the initial and final diagnoses of ACS differed significantly in relation to the variables. Results. A total of 34 552 patient visits were attended. The ORs for the 33 variables were significantly associated with initial and final NTCP classification as ACS or non-ACS, and in many cases the association was confirmed by the adjusted ORs. The adjusted ORs for 19 variables were significantly different in their relation to the initial and final diagnoses of ACS: 10 overpredicted the probability of the diagnosis and 9 underpredicted it. Conclusions. The variables traditionally used to warn of ACS in emergency patients with NTCP identify individuals likely to be initially and finally diagnosed with ACS. However, some of these variables overestimate or underestimate the risk of a final ACS diagnosis. Emergency medicine physicians should be aware of variables associated with underestimation of risk

2.
Emergencias ; 32(1): 9-18, 2020 Feb.
Artigo em Espanhol, Inglês | MEDLINE | ID: mdl-31909907

RESUMO

OBJECTIVES: To analyze clinical data and electrocardiographic (ECG) findings obtained during the initial evaluation of patients with nontraumatic chest pain (NTCP). To explore associations between these findings and the initial and final diagnoses of acute coronary syndrome (ACS). To assess which variables initially over- or underestimate risk ACS. MATERIAL AND METHODS: Consecutive patients with NTCP attended in a chest pain unit during the 10-year period of 2008-2017 were included if the suspected and discharge diagnoses of interest (ACS or non-ACS) had been recorded. Thirtythree independent variables (demographic, 2; cardiovascular, 5; chest pain, 22; ECG, 4). We included all variables in models to calculate crude and adjusted odds ratios (ORs) between each independent variable and the initial and final diagnoses. The adjusted ORs were compared to determine whether the initial and final diagnoses of ACS differed significantly in relation to the variables. RESULTS: A total of 34 552 patient visits were attended. The ORs for the 33 variables were significantly associated with initial and final NTCP classification as ACS or non-ACS, and in many cases the association was confirmed by the adjusted ORs. The adjusted ORs for 19 variables were significantly different in their relation to the initial and final diagnoses of ACS: 10 overpredicted the probability of the diagnosis and 9 underpredicted it. CONCLUSION: The variables traditionally used to warn of ACS in emergency patients with NTCP identify individuals likely to be initially and finally diagnosed with ACS. However, some of these variables overestimate or underestimate the risk of a final ACS diagnosis. Emergency medicine physicians should be aware of variables associated with underestimation of risk.

3.
Emergencias (Sant Vicenç dels Horts) ; 31(6): 377-384, dic. 2019. graf, tab
Artigo em Espanhol | IBECS | ID: ibc-ET2-3122

RESUMO

Objetivo. Analizar la evolución de las características epidemiológicas de las visitas atendidas de forma consecutiva en una unidad de dolor torácico (UDT) de un servicio de urgencias hospitalario (SUH) durante un periodo de 10 años. Método. Se incluyeron todas las visitas por dolor torácico no traumático (DTNT), analizándose la evolución temporal de las características epidemiológicas, de la clasificación diagnóstica inicial (evaluación clínica inicial y electrocardiograma) y final (al alta de la UDT), y los tiempos necesarios para alcanzar las mismas. Resultados. Se incluyeron 34.552 pacientes consecutivos con una edad media 59 (DE: 13) años, el 42% mujeres. Se observó un incrementó en el número anual de visitas a la UDT (p < 0,001), menor afluencia los meses de verano (p < 0,001), y mayor los días laborables (p < 0,001) y de 8-16 horas (p < 0,001). Se comprobó que progresivamente más pacientes eran mujeres (+0,29% anual, p < 0,05), menores de 50 años (+0,92%, p < 0,001), con más factores de riesgo cardiovascular, menos antecedentes de cardiopatía isquémica y con DTNT menos sugestivo de síndrome coronario agudo (SCA). La clasificación diagnóstica inicial y final descartó SCA en un 52,2% y un 80,4% de pacientes, respectivamente, hecho que aumentó progresivamente durante el periodo evaluado (+1,86%, p < 0,001; y +0,56%, p = 0,04; respectivamente). El tiempo de clasificación inicial no se modificó, pero se incrementó el necesario para la clasificación final (p < 0,001), que resultó superior en pacientes con diagnostico final de SCA (p < 0,001). Conclusión. Se observa un mayor uso de la UDT tras su creación, causado por un incremento de pacientes con DTNT de características no típicamente coronarias, disminuyendo el porcentaje de clasificados inicial y finalmente como debidos a SCA


Objective. To analyze changes in the characteristics of consecutively treated patients attended in the chest pain unit of a hospital emergency department over a 10-year period. Methods. All patients presenting with nontraumatic chest pain (NTCP) were included. We analyzed changes over time in epidemiologic characteristics, initial diagnostic classification (on clinical and electrocardiographic evaluation), final diagnosis (on discharge), and time until these diagnoses. Results. A total of 34 552 consecutive patients with a mean (SD) age of 59 (13) years were included; 42% were women. The annual number of visits rose over time. Visits were fewer in summer and more numerous on workdays and between the hours of 8 AM and 4 PM (P<.001, both comparisons). The number of women increased over time (up 0.29% annually, P<.05) as did the number of patients under the age of 50 years (up 0.92% annually, P<.001). With time, patients had fewer cardiovascular risk factors and less often had a history of ischemic heart disease. Fewer cases of NTCP had signs suggestive of acute coronary syndrome (ACS). ACS was ruled out at the time of initial and final diagnoses in 52.2% and 80.4%, respectively, and these percentages which rose over the 10-year period by 1.86% (P<.001) and 0.56% (P=.04). Time to initial diagnosis did not change. However, time to final diagnosis did increase (P<.001), and the delay was longer in patients diagnosed with ACS (P<.001). Conclusions. The chest pain unit was more active at the end of the period, in keeping with the increase in patients with NTCP whose characteristics were not typical of coronary disease. The percentages of patients initially and finally diagnosed with ACS decreased with time


Assuntos
Humanos , Feminino , Pessoa de Meia-Idade , Dor no Peito/epidemiologia , Serviços Médicos de Emergência , Síndrome Coronariana Aguda/epidemiologia , Métodos Epidemiológicos , Assistência Ambulatorial/organização & administração , Assistência Ambulatorial/estatística & dados numéricos , Infarto do Miocárdio sem Supradesnível do Segmento ST , Infarto do Miocárdio com Supradesnível do Segmento ST , Estudos Retrospectivos , Fatores de Risco , Análise de Variância
4.
Emergencias ; 31(6): 377-384, 2019.
Artigo em Espanhol, Inglês | MEDLINE | ID: mdl-31777208

RESUMO

OBJECTIVES: To analyze changes in the characteristics of consecutively treated patients attended in the chest pain unit of a hospital emergency department over a 10-year period. MATERIAL AND METHODS: All patients presenting with nontraumatic chest pain (NTCP) were included. We analyzed changes over time in epidemiologic characteristics, initial diagnostic classification (on clinical and electrocardiographic evaluation), final diagnosis (on discharge), and time until these diagnoses. RESULTS: A total of 34 552 consecutive patients with a mean (SD) age of 59 (13) years were included; 42% were women. The annual number of visits rose over time. Visits were fewer in summer and more numerous on workdays and between the hours of 8 AM and 4 PM (P<.001, both comparisons). The number of women increased over time (up 0.29% annually, P<.05) as did the number of patients under the age of 50 years (up 0.92% annually, P<.001). With time, patients had fewer cardiovascular risk factors and less often had a history of ischemic heart disease. Fewer cases of NTCP had signs suggestive of acute coronary syndrome (ACS). ACS was ruled out at the time of initial and final diagnoses in 52.2% and 80.4%, respectively, and these percentages which rose over the 10-year period by 1.86% (P<.001) and 0.56% (P=.04). Time to initial diagnosis did not change. However, time to final diagnosis did increase (P<.001), and the delay was longer in patients diagnosed with ACS (P<.001). CONCLUSION: The chest pain unit was more active at the end of the period, in keeping with the increase in patients with NTCP whose characteristics were not typical of coronary disease. The percentages of patients initially and finally diagnosed with ACS decreased with time.

5.
Future Med Chem ; 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31778323

RESUMO

High-quality small molecule chemical probes are extremely valuable for biological research and target validation. However, frequent use of flawed small-molecule inhibitors produces misleading results and diminishes the robustness of biomedical research. Several public resources are available to facilitate assessment and selection of better chemical probes for specific protein targets. Here, we review chemical probe resources, discuss their current strengths and limitations, and make recommendations for further improvements. Expert review resources provide in-depth analysis but currently cover only a limited portion of the liganded proteome. Computational resources encompass more proteins and are regularly updated, but have limitations in data availability and curation. We show how biomedical scientists may use these resources to choose the best available chemical probes for their research.

8.
Nucleic Acids Res ; 47(D1): D917-D922, 2019 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-30496479

RESUMO

canSAR (http://cansar.icr.ac.uk) is a public, freely available, integrative translational research and drug discovery knowlegebase. canSAR informs researchers to help solve key bottlenecks in cancer translation and drug discovery. It integrates genomic, protein, pharmacological, drug and chemical data with structural biology, protein networks and unique, comprehensive and orthogonal 'druggability' assessments. canSAR is widely used internationally by academia and industry. Here we describe major enhancements to canSAR including new and expanded data. We also describe the first components of canSARblack-an advanced, responsive, multi-device compatible redesign of canSAR with a question-led interface.

9.
ACS Omega ; 3(10): 12707-12712, 2018 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-30411017

RESUMO

Recent network and system biology analyses suggest that most complex diseases are regulated by robust and highly interconnected pathways that could be better modulated by small molecules binding to multiple biological targets. These pieces of evidence recently led to devote efforts on identifying single chemical entities that bind to two different disease-relevant targets. Here, we first predicted in silico and later confirmed in vitro that UPF 1069, a known bioactive poly(ADP-ribose) polymerase-1/2 (PARP1/2) molecule, and hydroxyfasudil, a known bioactive Rho-associated protein kinase-1/2 (ROCK1/2) molecule, have low-micromolar cross-affinity for ROCK1/2 and PARP1/2, respectively. These molecules can now be regarded as chemical seeds from which pharmacological tools could be generated to study the impact of dual inhibition of PARPs and ROCKs in preclinical models of a variety of complex diseases where both targets are involved.

10.
J Comp Eff Res ; 7(4): 319-330, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29570366

RESUMO

AIM: To analyze treatment at discharge/follow-up of patients diagnosed with venous thromboembolism (VTE) in the emergency department (ED). MATERIALS & METHODS: Ambispective study (50 Spanish centers) of consecutive patients (October-December 2014) with VTE diagnosed in ED. RESULTS: VTE was diagnosed in 775 patients (295 pulmonary embolism [PE] without deep vein thrombosis [DVT], 389 DVT without PE and 91 PE + DVT); 95.5% received anticoagulants (90.7% low-molecular-weight heparin [LMWH], 4% LMWH + vitamin K antagonists and <1% direct oral anticoagulants). Overall, 23.3% were discharged from ED and 74.5% hospitalized (98.6% with PE and 50.4% with DVT). After discharge/90/180 days, 43.6/21.0/13.5% were taking LMWH, with similar rates in nononcologic patients. CONCLUSION: There is a poor adherence to international guidelines in management of VTE patients in Spain.


Assuntos
Serviço Hospitalar de Emergência , Tromboembolia Venosa/tratamento farmacológico , Idoso , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Protocolos Clínicos , Feminino , Heparina de Baixo Peso Molecular/administração & dosagem , Heparina de Baixo Peso Molecular/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar , Espanha , Trombose Venosa
11.
Cell Chem Biol ; 25(2): 194-205.e5, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29249694

RESUMO

Chemical probes are essential tools for understanding biological systems and for target validation, yet selecting probes for biomedical research is rarely based on objective assessment of all potential compounds. Here, we describe the Probe Miner: Chemical Probes Objective Assessment resource, capitalizing on the plethora of public medicinal chemistry data to empower quantitative, objective, data-driven evaluation of chemical probes. We assess >1.8 million compounds for their suitability as chemical tools against 2,220 human targets and dissect the biases and limitations encountered. Probe Miner represents a valuable resource to aid the identification of potential chemical probes, particularly when used alongside expert curation.


Assuntos
Sondas Moleculares/química , Bibliotecas de Moléculas Pequenas/química , Química Farmacêutica , Humanos
12.
Medicine (Baltimore) ; 96(48): e8796, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29310357

RESUMO

The objective of this study was to determine the clinical profile of and diagnostic and therapeutic approach to patients with venous thromboembolism (VTE) in Spanish Emergency Departments (EDs). Risk factors, adherence to clinical practice guidelines, and outcomes were also evaluated.Patients with VTE diagnosed in 53 Spanish EDs were prospectively and consecutively included. Demographic data, comorbidities, risk factors for VTE, index event characteristics, hemorrhagic risk, and mortality were evaluated. Adherence to clinical practice guidelines was assessed based on clinical probability scales, requests for determination of D-dimer, use of anticoagulant treatment before confirmation of diagnosis, and assessment of bleeding and prognostic risk. Recurrence, bleeding, and death during admission and at 30, 90, and 180 days after diagnosis in the EDs were recorded.From 549,840 ED visits made over a mean period of 40 days, 905 patients were diagnosed with VTE (incidence 1.6 diagnoses per 1000 visits). The final analysis included 801 patients, of whom 49.8% had pulmonary embolism. The most frequent risk factors for VTE were age (≥70 years), obesity, and new immobility. Clinical probability, prognosis, and bleeding risk scales were recorded in only 7.6%, 7.5%, and 1% of cases, respectively. D-dimer was determined in 87.2% of patients with a high clinical probability of VTE, and treatment was initiated before confirmation in only 35.9% of these patients. In patients with pulmonary embolism, 31.3% had a low risk of VTE. Overall, 98.7% of patients with pulmonary embolism and 50.2% of patients with deep venous thrombosis were admitted. During follow-up, total bleeding was more frequent than recurrences: the rates of any bleeding event were 4.4%, 3.9%, 5.3%, and 3.5% at admission and at 30 and 90, and 180 days, respectively; the rates of VTE recurrence were 2.3%, 1.3%, 1.7%, and 0.6%, respectively. Mortality rates were 3.4%, 3.1%, 4.1%, and 2.6% during hospitalization and at 30, 90, and 180 days, respectively.VTE had a substantial impact on Spanish EDs. The clinical presentation and risk profile for the development of VTE in patients diagnosed in the EDs was similar to that recorded in previous studies. During follow-up, bleeding (overall) was more frequent than recurrences. Adherence to clinical practice guidelines could improve significantly.


Assuntos
Serviço Hospitalar de Emergência , Tromboembolia Venosa/terapia , Fatores Etários , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Prognóstico , Estudos Prospectivos , Sistema de Registros , Medição de Risco , Fatores de Risco , Espanha/epidemiologia , Resultado do Tratamento , Tromboembolia Venosa/epidemiologia
13.
Curr Pharm Des ; 22(46): 6935-6945, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27669965

RESUMO

Over the past decade, a more comprehensive, large-scale approach to studying cancer genetics and biology has revealed the challenges of tumor heterogeneity, adaption, evolution and drug resistance, while systems-based pharmacology and chemical biology strategies have uncovered a much more complex interaction between drugs and the human proteome than was previously anticipated. In this mini-review we assess the progress and potential of drug polypharmacology in biomarker-driven precision oncology. Polypharmacology not only provides great opportunities for drug repurposing to exploit off-target effects in a new single-target indication but through simultaneous blockade of multiple targets or pathways offers exciting opportunities to slow, overcome or even prevent inherent or adaptive drug resistance. We highlight the many challenges associated with exploiting known or desired polypharmacology in drug design and development, and assess computational and experimental methods to uncover unknown polypharmacology. A comprehensive understanding of the intricate links between polypharmacology, efficacy and safety is urgently needed if we are to tackle the enduring challenge of cancer drug resistance and to fully exploit polypharmacology for the ultimate benefit of cancer patients.


Assuntos
Antineoplásicos/farmacologia , Oncologia , Neoplasias/tratamento farmacológico , Polifarmacologia , Reposicionamento de Medicamentos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos
14.
Nucleic Acids Res ; 44(D1): D938-43, 2016 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-26673713

RESUMO

canSAR (http://cansar.icr.ac.uk) is a publicly available, multidisciplinary, cancer-focused knowledgebase developed to support cancer translational research and drug discovery. canSAR integrates genomic, protein, pharmacological, drug and chemical data with structural biology, protein networks and druggability data. canSAR is widely used to rapidly access information and help interpret experimental data in a translational and drug discovery context. Here we describe major enhancements to canSAR including new data, improved search and browsing capabilities, new disease and cancer cell line summaries and new and enhanced batch analysis tools.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Bases de Conhecimento , Neoplasias/metabolismo , Animais , Linhagem Celular Tumoral , Ensaios Clínicos como Assunto , Expressão Gênica , Humanos , Proteínas de Neoplasias/química , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/genética
15.
Cancer Cell ; 27(3): 382-96, 2015 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-25759023

RESUMO

Large efforts dedicated to detect somatic alterations across tumor genomes/exomes are expected to produce significant improvements in precision cancer medicine. However, high inter-tumor heterogeneity is a major obstacle to developing and applying therapeutic targeted agents to treat most cancer patients. Here, we offer a comprehensive assessment of the scope of targeted therapeutic agents in a large pan-cancer cohort. We developed an in silico prescription strategy based on identification of the driver alterations in each tumor and their druggability options. Although relatively few tumors are tractable by approved agents following clinical guidelines (5.9%), up to 40.2% could benefit from different repurposing options, and up to 73.3% considering treatments currently under clinical investigation. We also identified 80 therapeutically targetable cancer genes.


Assuntos
Carcinogênese/genética , Tomada de Decisões Assistida por Computador , Neoplasias/genética , Medicina de Precisão/métodos , Antineoplásicos , Protocolos Clínicos , Ensaios Clínicos como Assunto , Estudos de Coortes , Biologia Computacional , Análise Mutacional de DNA , Reposicionamento de Medicamentos , Humanos , Neoplasias/tratamento farmacológico
16.
ACS Chem Biol ; 10(2): 395-400, 2015 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-25365788

RESUMO

Small molecules are essential tool compounds to probe the role of proteins in biology and advance toward more efficient therapeutics. However, they are used without a complete knowledge of their selectivity across the entire proteome, at risk of confounding their effects due to unknown off-target interactions. Current state-of-the-art computational approaches to predicting the affinity profile of small molecules offer a means to anticipate potential nonobvious selectivity liabilities of chemical probes. The application of in silico target profiling on the full set of chemical probes from the NIH Molecular Libraries Program (MLP) resulted in the identification of biologically relevant in vitro affinities for proteins distantly related to the primary targets of ML006, ML123, ML141, and ML204, helping to lower the risk of their further use in chemical biology.


Assuntos
Interações de Medicamentos , Inibidores Enzimáticos/farmacologia , Sondas Moleculares/química , Polifarmacologia , Inibidores Enzimáticos/química , Estrutura Molecular , Proteínas/química , Proteínas/metabolismo
17.
Oncotarget ; 5(10): 3023-8, 2014 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-24632590

RESUMO

PARP inhibitors hold promise as a novel class of targeted anticancer drugs. However, their true mechanism of action is still not well understood following recent reports that show marked differences in cellular effects. Here, we demonstrate that three PARP drug candidates, namely, rucaparib, veliparib, and olaparib, have a clearly different in vitro affinity profile across a panel of diverse kinases selected using a computational approach that relates proteins by ligand similarity. In this respect, rucaparib inhibits nine kinases with micromolar affinity, including PIM1, PIM2, PRKD2, DYRK1A, CDK1, CDK9, HIPK2, CK2, and ALK. In contrast, olaparib does not inhibit any of the sixteen kinases tested. In between, veliparib inhibits only two, namely, PIM1 and CDK9. The differential kinase pharmacology observed among PARP inhibitors provides a plausible explanation to their different cellular effects and offers unexplored opportunities for this drug class, but alerts also on the risk associated to transferring directly both preclinical and clinical outcomes from one PARP drug candidate to another.


Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Simulação por Computador , Indóis/farmacologia , Ftalazinas/farmacologia , Piperazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases , Antineoplásicos/química , Benzimidazóis/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Indóis/química , Ftalazinas/química , Piperazinas/química
18.
J Mol Graph Model ; 45: 192-201, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24056306

RESUMO

Poly(ADP-ribose)polymerase-1 (PARP-1) is an enzyme belonging to the ADP-ribosyltransferase family. A large body of works has validated PARP-1 as an attractive drug target for different therapeutic areas, including cancers and ischemia. Accordingly, sampling the conformational space of the enzyme is pivotal to understand its functions and improve structure-based drug discovery approaches. In the first part of this study we apply replica exchange molecular dynamic (REMD) simulations to sample the conformational space of the catalytic domain of PARP-1 in the ligand-bound and unbound forms. In the second part, we assess how and to what extend the emerging enzyme flexibility affects the performance of docking experiments of a library of PARP-1 inhibitors. This study pinpoints a putative key role of conformational shifts of Leu324, Tyr325 and Lys242 in opening an additional binding site pocket that affects the binding of ligands to the catalytic cleft of PARP-1. Furthermore, it highlights the improvement of the enrichment factor of active ligands obtained in docking experiments when using conformations generated with REMD simulations of ligand-bound PARP-1.


Assuntos
Modelos Moleculares , Poli(ADP-Ribose) Polimerases/química , Conformação Proteica , Sítios de Ligação , Domínio Catalítico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Humanos , Ligações de Hidrogênio , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/metabolismo , Ligação Proteica , Solventes , Temperatura Ambiente
19.
ACS Chem Biol ; 7(12): 1962-7, 2012 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-23025350

RESUMO

Small molecules are widely used in chemical biology without complete knowledge of their target profile, at risk of deriving conclusions that ignore potential confounding effects from unknown off-target interactions. The prediction and further experimental confirmation of novel affinities for PJ34 on Pim1 (IC(50) = 3.7 µM) and Pim2 (IC(50) = 16 µM) serine/threonine kinases, together with their involvement in many of the processes relevant to PARP biology, questions the appropriateness of using PJ34 as a chemical tool to probe the biological role of PARP1 and PARP2 at the high micromolar concentrations applied in most studies.


Assuntos
Inibidores Enzimáticos/farmacologia , Fenantrenos/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Humanos , Concentração Inibidora 50 , Modelos Moleculares
20.
Med. clín (Ed. impr.) ; 137(13): 587-590, nov. 2011.
Artigo em Espanhol | IBECS | ID: ibc-92062

RESUMO

Fundamento y objetivo: Comparar la calidad técnica, los resultados de salud y el grado de satisfacción de los pacientes ingresados en una Unidad de Hospitalización a Domicilio (UHDOM) desde urgencias de los que lo hicieron desde una sala de hospitalización convencional. Pacientes y métodos: Estudio comparativo y descriptivo, con recogida de datos efectuada mediante revisión del informe de alta de los pacientes ingresados en la UHDOM y entrevista telefónica posterior. Se analizaron aspectos clínicos y de comorbilidad, resultados de salud, indicadores de calidad técnica y calidad percibida por pacientes y cuidadores.Resultados: Se incluyeron 111 pacientes (65 de urgencias y 46 de salas convencionales). Se realizó entrevista telefónica a 76 pacientes y 57 cuidadores. No se observaron diferencias en relación a los resultados de salud, indicadores de calidad técnica o calidad percibida de los pacientes. El tiempo de estancia hospitalaria fue inferior en los pacientes procedentes de urgencias (media [DE] de 1,02 [0,44] frente a 2,23 [0,94] días, p<0,0005).Conclusiones: Podría obviarse el período de hospitalización convencional y todos los pacientes candidatos, tras un período de observación en urgencias, podrían ingresar directamente en hospitalización domiciliaria (AU)


Background and objective: To compare technical quality, patient health outcomes, and satisfaction degree of patients admitted to hospital at home (HAH) from the emergency department (ED) with those with standard hospitalization (SH). Patients and methods: Comparative prospective study. Medical records of patients admitted to the HAH were reviewed and then they were also called and surveyed. The following variables were recorded: demographic and clinical aspects, patient health status at the time of phone survey, technical and perceived quality. Results: Patients included: 111 (65 from the ED and 46 from the SH). Phone survey was performed to 76 patients and 57 carers. Length of stay was significantly shorter in patients from the ED compared with those from SH (1.02±0.44 vs 2.23±0.94 days, P<.0005). No other differences were observed in patients’ demographics, clinical aspects and health status, in technical quality, and in perceived quality between both groups.Conclusion: When HAH is an option, these results seem to indicate that patient hospital stay can be shortened if HAH admittance is obvious, after a period of patient treatment and stabilization, from the ED instead from HAH (AU)


Assuntos
Humanos , Serviços Hospitalares de Assistência Domiciliar/tendências , Serviços Médicos de Emergência/organização & administração , Hospitalização/tendências , Satisfação do Paciente
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