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1.
Medicine (Baltimore) ; 100(5): e24194, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33592864

RESUMO

BACKGROUND: The relationship between p53 expression and chemosensitivity of non-small cell lung cancer (NSCLC) is unclear. This study aims to explore the correlation between p53 expression and sensitivity to platinum-based chemotherapy in patients with NSCLC. METHODS: Pubmed, Web of Science, EMBASE, CNKI, China Wanfang databases were searched for studies on the relationship between the p53 expression and the chemosensitivity to platinum drugs in patients with NSCLC. The last search time was May 2020. Stata 15.0 software was used for statistical analysis. RESULTS: A total of 21 studies were included, covering 1387 patients in total. The results showed that the pooled OR = 1.55 (95%CI: 1.05∼2.29, P < .05), for Asian population, the pooled OR = 1.67 (95%CI: 0.95∼3.09, P > .05), for Caucasian population, the pooled OR = 1.34 (95%CI: 0.74∼2.43), there was no significant difference between Asian and Caucasian. The results of subgroup analysis of publication year showed that, the pooled OR = 2.07 (95%CI: 1.39∼3.07, P < .01), the heterogeneity among the studies decreased remarkably after 2005. The subgroup analysis of advanced patients showed that the pooled OR = 1.93 (95%CI: 1.27∼2.93), the difference was statistically significant. CONCLUSION: Patients with p53 negative expression is more sensitive to platinum-based chemotherapy than those with p53 positive expression in NSCLC, especially in advanced NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Compostos de Platina/farmacologia , Proteína Supressora de Tumor p53/genética , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Testes Farmacogenômicos , Resultado do Tratamento
2.
BMC Palliat Care ; 20(1): 15, 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33435936

RESUMO

BACKGROUND: Effective communication in support of clinical decision-making is central to the pediatric cancer care experience for families. A new laboratory derived pharmacogenetic test (LDT) that can diagnose difficult-to-treat brain cancers has been developed to stratify children based on their ability to respond to available treatment; however, the potential implementation of the LDT may make effective communication challenging since it can potentially remove the option for curative treatment in those children identified as non-responders, i.e. those with a catastrophic diagnosis. OBJECTIVE: We solicited the perspectives of parents of children with difficult-to-treat brain cancer on communication preferences surrounding the potential implementation of the LDT in standard care using deliberative stakeholder consultations. METHODS: Eight bereaved parents of children who succumbed to difficult-to-treat brain cancer, and four parents of children currently undergoing treatment for similar cancers attended separate small-group deliberative consultations - a stakeholder engagement method that enables the co-creation of recommendations following the consideration of competing arguments and diverse opinions of parents with different experiences. In the small-group consultations (Phase I), parents discussed four questions about potential communication issues that may arise with the LDT in practice. In Phase II, a total of five parents from both stakeholder groups (4 bereaved and 1 in current treatment) attended a consultation, known as the 'mixed' consultation, with the purpose of co-developing concrete recommendations for implementation of the LDT. RESULTS: Explaining the risks, benefits, and accuracy of the LDT were considered essential to parents. Once an LDT-based diagnosis/prognosis can be made, parents valued honesty, empathy, and clarity in communication. Parents also requested that all results and treatment options be presented to them in measured doses, and in an unbiased manner over the course of several meetings. This communication strategy allowed sufficient time to understand and accept the diagnosis/prognosis, particularly if it was catastrophic. Continuous access to the appropriate psychological and social support or counselling at and post-diagnosis was also strongly recommended. CONCLUSIONS: Deliberants co-created family-centered recommendations surrounding communication issues of the LDT, providing guidance to pediatric oncologists that could implement the test in practice.


Assuntos
Neoplasias Encefálicas/terapia , Comunicação , Oncologia , Cuidados Paliativos , Pais , Testes Farmacogenômicos , Relações Profissional-Família , Revelação da Verdade , Luto , Neoplasias Encefálicas/genética , Empatia , Humanos , Pediatria , Participação dos Interessados
3.
JAMA Netw Open ; 3(12): e2029411, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33315113

RESUMO

Importance: Genotype-guided prescribing in pediatrics could prevent adverse drug reactions and improve therapeutic response. Clinical pharmacogenetic implementation guidelines are available for many medications commonly prescribed to children. Frequencies of medication prescription and actionable genotypes (genotypes where a prescribing change may be indicated) inform the potential value of pharmacogenetic implementation. Objective: To assess potential opportunities for genotype-guided prescribing in pediatric populations among multiple health systems by examining the prevalence of prescriptions for each drug with the highest level of evidence (Clinical Pharmacogenetics Implementation Consortium level A) and estimating the prevalence of potential actionable prescribing decisions. Design, Setting, and Participants: This serial cross-sectional study of prescribing prevalences in 16 health systems included electronic health records data from pediatric inpatient and outpatient encounters from January 1, 2011, to December 31, 2017. The health systems included academic medical centers with free-standing children's hospitals and community hospitals that were part of an adult health care system. Participants included approximately 2.9 million patients younger than 21 years observed per year. Data were analyzed from June 5, 2018, to April 14, 2020. Exposures: Prescription of 38 level A medications based on electronic health records. Main Outcomes and Measures: Annual prevalence of level A medication prescribing and estimated actionable exposures, calculated by combining estimated site-year prevalences across sites with each site weighted equally. Results: Data from approximately 2.9 million pediatric patients (median age, 8 [interquartile range, 2-16] years; 50.7% female, 62.3% White) were analyzed for a typical calendar year. The annual prescribing prevalence of at least 1 level A drug ranged from 7987 to 10 629 per 100 000 patients with increasing trends from 2011 to 2014. The most prescribed level A drug was the antiemetic ondansetron (annual prevalence of exposure, 8107 [95% CI, 8077-8137] per 100 000 children). Among commonly prescribed opioids, annual prevalence per 100 000 patients was 295 (95% CI, 273-317) for tramadol, 571 (95% CI, 557-586) for codeine, and 2116 (95% CI, 2097-2135) for oxycodone. The antidepressants citalopram, escitalopram, and amitriptyline were also commonly prescribed (annual prevalence, approximately 250 per 100 000 patients for each). Estimated prevalences of actionable exposures were highest for oxycodone and ondansetron (>300 per 100 000 patients annually). CYP2D6 and CYP2C19 substrates were more frequently prescribed than medications influenced by other genes. Conclusions and Relevance: These findings suggest that opportunities for pharmacogenetic implementation among pediatric patients in the US are abundant. As expected, the greatest opportunity exists with implementing CYP2D6 and CYP2C19 pharmacogenetic guidance for commonly prescribed antiemetics, analgesics, and antidepressants.


Assuntos
Serviços de Saúde da Criança , Cálculos da Dosagem de Medicamento , Testes Farmacogenômicos , Padrões de Prática Médica , Medicamentos sob Prescrição , Criança , Serviços de Saúde da Criança/normas , Serviços de Saúde da Criança/estatística & dados numéricos , Estudos Transversais , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Registros Eletrônicos de Saúde/estatística & dados numéricos , Feminino , Perfil Genético , Humanos , Masculino , Pediatria/métodos , Pediatria/normas , Testes Farmacogenômicos/métodos , Testes Farmacogenômicos/estatística & dados numéricos , Padrões de Prática Médica/normas , Padrões de Prática Médica/estatística & dados numéricos , Medicina de Precisão/métodos , Medicamentos sob Prescrição/classificação , Medicamentos sob Prescrição/uso terapêutico , Estados Unidos
4.
Farm. hosp ; 44(6): 243-253, nov.-dic. 2020. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-197693

RESUMO

La rápida implantación clínica de las técnicas de secuenciación masiva en paralelo se debe a su capacidad para secuenciar un gran número de regiones genéticas con un coste menor a las técnicas convencionales. Sin embargo, su uso en el ámbito de la farmacogenética es, todavía, muy escaso. OBJETIVO: Diseño, desarrollo, implementación y validación de un panel de secuenciación masiva en paralelo de farmacogenética orientado a la práctica clínica. MÉTODO: Se desarrolló un panel de sondas de captura híbrida (Sure-Select(R)) para el análisis de las regiones genéticas de interés clínico recopiladas mediante búsqueda bibliográfica. Se empleó la plataforma de secuenciación Illumina HiSeq 1500(R). Se desarrolló un algoritmo de análisis bioinformático para la anotación de variantes puntuales, inferencia de haplotipos y determinación de variantes estructurales en los genes de interés. Los resultados obtenidos se validaron con materiales de referencia Coriell(R) de los repositorios de farmacogenética. RESULTADOS: El panel desarrollado permite el estudio de un total de 12.794 regiones comprendidas en 389 genes. Los resultados de validación mostraron una sensibilidad superior al 99% para variantes puntuales e inserciones y deleciones pequeñas. La imputación de haplotipos fue coherente con los resultados consenso de los materiales de referencia caracterizados. Además, la herramienta desarrollada pudo identificar correctamente diferentes tipos de variaciones de número de copias de CYP2D6, así como una gran variedad de alelos de HLA-B. CONCLUSIONES: Esta tecnología representa una alternativa adecuada para su empleo asistencial con ventajas frente a las técnicas convencionales en su rendimiento de producción y sus capacidades de estudio de genes complejos (CYP2D6, HLA-B)


The rapid clinical implementation of next generation sequencing techniques is due to its ability to sequence a large number of genetic regions at lower costs than conventional techniques. However, its use in the field of pharmacogenetics is still very limited. OBJECTIVE: Design, development, implementation and validation of a clinical pharmacogenetics next-generation sequencing panel. METHOD: We developed a panel of hybrid capture probes (SureSelect(R)) for the analysis of the genetic regions of clinical interest collected by literature search and using Illumina HiSeq 1500(R) sequencing platform. We developed a bioinformatic algorithm for variant annotation, haplotype inference and determination of structural variants in the genes of interest. The results obtained were validated with Coriell(R) reference material from the pharmacogenetic repositories. RESULTS: The developed panel allows the study of a total of 12,794 regions comprised in 389 genes. Validation results showed a sensitivity greater than 99% for single nucleotide variants and small INDELs. Haplotype imputation was consistent with the consensus results in the characterized reference materials. Furthermore, the developed tool was able to correctly identify different types of CYP2D6 copy number variations as well as a wide variety of HLA-B alleles. CONCLUSIONS: This technology represents an appropriate alternative for its clinical use with advantages over conventional techniques in its through-put and complex gene study capabilities (CYP2D6, HLA-B)


Assuntos
Humanos , Farmacogenética/métodos , Testes Farmacogenômicos/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Medicina de Precisão/métodos , Algoritmos , Biologia Computacional , Citocromo P-450 CYP2D6/análise , Análise de Dados , Variantes Farmacogenômicos/genética
5.
Genes (Basel) ; 12(1)2020 12 25.
Artigo em Inglês | MEDLINE | ID: mdl-33375616

RESUMO

The human serine protease serine 2 TMPRSS2 is involved in the priming of proteins of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and represents a possible target for COVID-19 therapy. The TMPRSS2 gene may be co-expressed with SARS-CoV-2 cell receptor genes angiotensin-converting enzyme 2 (ACE2) and Basigin (BSG), but only TMPRSS2 demonstrates tissue-specific expression in alveolar cells according to single-cell RNA sequencing data. Our analysis of the structural variability of the TMPRSS2 gene based on genome-wide data from 76 human populations demonstrates that a functionally significant missense mutation in exon 6/7 in the TMPRSS2 gene is found in many human populations at relatively high frequencies, with region-specific distribution patterns. The frequency of the missense mutation encoded by rs12329760, which has previously been found to be associated with prostate cancer, ranged between 10% and 63% and was significantly higher in populations of Asian origin compared with European populations. In addition to single-nucleotide polymorphisms, two copy number variants were detected in the TMPRSS2 gene. A number of microRNAs have been predicted to regulate TMPRSS2 and BSG expression levels, but none of them is enriched in lung or respiratory tract cells. Several well-studied drugs can downregulate the expression of TMPRSS2 in human cells, including acetaminophen (paracetamol) and curcumin. Thus, the interactions of TMPRSS2 with SARS-CoV-2, together with its structural variability, gene-gene interactions, expression regulation profiles, and pharmacogenomic properties, characterize this gene as a potential target for COVID-19 therapy.


Assuntos
/tratamento farmacológico , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Terapia de Alvo Molecular , Serina Endopeptidases/genética , Acetaminofen/farmacologia , Acetaminofen/uso terapêutico , /biossíntese , Ásia/epidemiologia , Basigina/biossíntese , Basigina/genética , Basigina/fisiologia , /genética , Curcumina/farmacologia , Curcumina/uso terapêutico , Europa (Continente)/epidemiologia , Éxons/genética , Frequência do Gene , Predisposição Genética para Doença , Variação Genética , Humanos , MicroRNAs/genética , Mutação de Sentido Incorreto , Testes Farmacogenômicos , Mapeamento de Interação de Proteínas , Receptores Virais/antagonistas & inibidores , Receptores Virais/biossíntese , Receptores Virais/genética , Serina Endopeptidases/biossíntese , Serina Endopeptidases/fisiologia , Análise de Célula Única , Glicoproteína da Espícula de Coronavírus/metabolismo
6.
Mutat Res ; 786: 108324, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33339576

RESUMO

Severe gastrointestinal (GI) toxicity is a common side effect after platinum-based chemotherapy. The incidence and severity of GI toxicity vary among patients with the same chemotherapy. Genetic factors involved in platinum transport, metabolism, detoxification, DNA repair, cell cycle control, and apoptosis pathways may account for the interindividual difference in GI toxicity. The influence of gene polymorphisms in the platinum pathway on GI toxicity has been extensively analyzed. Variations in study sample size, ethnicity, design, treatment schedule, dosing, endpoint definition, and assessment of toxicity make it difficult to precisely interpret the results. Hence, we conducted a review to summarize the most recent pharmacogenomics studies of GI toxicity in platinum-based chemotherapy and identify the most promising avenues for further research.


Assuntos
Antineoplásicos/toxicidade , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Trato Gastrointestinal/efeitos dos fármacos , Farmacogenética , Platina/toxicidade , Polimorfismo Genético , Reparo do DNA , Tratamento Farmacológico , Genótipo , Humanos , Testes Farmacogenômicos , Fenótipo
8.
PLoS Med ; 17(9): e1003344, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32956352

RESUMO

BACKGROUND: Large sample sizes are often required to detect statistically significant associations between pharmacogenetic markers and treatment response. Meta-analysis may be performed to synthesize data from several studies, increasing sample size and, consequently, power to detect significant genetic effects. However, performing robust synthesis of data from pharmacogenetic studies is often challenging because of poor reporting of key data in study reports. There is currently no guideline for the reporting of pharmacogenetic studies that has been developed using a widely accepted robust methodology. The objective of this project was to develop the STrengthening the Reporting Of Pharmacogenetic Studies (STROPS) guideline. METHODS AND FINDINGS: We established a preliminary checklist of reporting items to be considered for inclusion in the guideline. We invited representatives of key stakeholder groups to participate in a 2-round Delphi survey. A total of 52 individuals participated in both rounds of the survey, scoring items with regards to their importance for inclusion in the STROPS guideline. We then held a consensus meeting, at which 8 individuals considered the results of the Delphi survey and voted on whether each item ought to be included in the final guideline. The STROPS guideline consists of 54 items and is accompanied by an explanation and elaboration document. The guideline contains items that are particularly important in the field of pharmacogenetics, such as the drug regimen of interest and whether adherence to treatment was accounted for in the conducted analyses. The guideline also requires that outcomes be clearly defined and justified, because in pharmacogenetic studies, there may be a greater number of possible outcomes than in other types of study (for example, disease-gene association studies). A limitation of this project is that our consensus meeting involved a small number of individuals, the majority of whom are based in the United Kingdom. CONCLUSIONS: Our aim is for the STROPS guideline to improve the transparency of reporting of pharmacogenetic studies and also to facilitate the conduct of high-quality systematic reviews and meta-analyses. We encourage authors to adhere to the STROPS guideline when publishing pharmacogenetic studies.


Assuntos
Farmacogenética/métodos , Testes Farmacogenômicos/normas , Testes Farmacogenômicos/tendências , Adulto , Lista de Checagem , Consenso , Técnica Delfos , Feminino , Estudos de Associação Genética , Objetivos , Humanos , Masculino , Pessoa de Meia-Idade , Farmacogenética/normas , Política , Editoração/normas , Projetos de Pesquisa/normas , Participação dos Interessados , Inquéritos e Questionários , Reino Unido
9.
Pharm. pract. (Granada, Internet) ; 18(3): 0-0, jul.-sept. 2020. tab, graf
Artigo em Inglês | IBECS | ID: ibc-194197

RESUMO

BACKGROUND: While pharmacists are well positioned to implement pharmacogenomic testing in healthcare systems, uptake has been limited. OBJECTIVE: The primary objective of this survey was to determine how post-graduate education and training influences pharmacist's knowledge and attitudes of pharmacogenomic testing. METHODS: Survey questions were developed by the study team, and responses were collected electronically using REDCapTM. The electronic survey was sent to all pharmacists (n=161) within a large, multi-state healthcare system by email. RESULTS: A total of 75 (47%) respondents completed all aspects of the survey. The majority of respondents were female (60%), worked in acute care settings (57%), were full-time employees (80%), and worked in an urban area (85%), with many graduating in or after 2010 (43%). For post-graduate education, 36% of respondents completed a Post-Graduate Year One Residency (PGY-1), and 27% had a board certification. Those that completed a PGY-1 residency were significantly more likely to have received formal training or education on pharmacogenomics than those who had not. They also assessed their own knowledge of pharmacogenomic resources and guidelines higher than those without PGY-1 training. More recent graduates were also significantly more likely to have received formal training or education on pharmacogenomics. Additionally, pharmacists who completed a PGY-1 residency were more likely to respond favorably to pharmacogenomics being offered through pharmacy services. Pharmacists with board certification were more comfortable interpreting results of a pharmacogenomic test than those without board certification. CONCLUSIONS: Pharmacists who have completed a PGY-1 residency or received board certification appear more comfortable with interpretation and implementation of pharmacogenomic testing


No disponible


Assuntos
Humanos , Masculino , Feminino , Testes Farmacogenômicos/tendências , Conhecimentos, Atitudes e Prática em Saúde , Farmacogenética/educação , Assistência Farmacêutica/normas , Atitude do Pessoal de Saúde , Assistência Farmacêutica/organização & administração , Inquéritos e Questionários , Análise de Dados
11.
Ned Tijdschr Geneeskd ; 1642020 06 04.
Artigo em Holandês | MEDLINE | ID: mdl-32608920

RESUMO

With the exception of a few medical specialties, the implementation of pharmacogenetic tests in daily practice has thus far been limited. The Royal Dutch Pharmacists Association (KNMP) has developed pharmacogenetics-based therapeutic doserecommendations for 80 medicinal product combinations on the basis of a systematic literature review. Genotyping of patients can take place on a reactive or pre-emptive basis; the advantage of pre-emptive genotyping is that it provides genetic information the moment a medicinal product is prescribed. Clinical decision support software is crucial to implement pharmacogenetics into daily practice.


Assuntos
Sistemas de Apoio a Decisões Clínicas , Prescrições de Medicamentos/normas , Farmacogenética/normas , Testes Farmacogenômicos/normas , Cálculos da Dosagem de Medicamento , Técnicas de Genotipagem , Humanos , Países Baixos , Farmacêuticos/organização & administração , Farmacogenética/métodos , Testes Farmacogenômicos/métodos , Revisões Sistemáticas como Assunto
12.
Bone Joint J ; 102-B(6_Supple_A): 73-78, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32475277

RESUMO

AIMS: The purpose of this study was to use pharmacogenetics to determine the frequency of genetic variants in our total knee arthroplasty (TKA) patients that could affect postoperative pain medications. Pharmacogenetic testing evaluates patient DNA to determine if a drug is expected to have a normal clinical effect, heightened effect, or no effect at all on the patient. It also predicts whether patients are likely to experience side effects from medicine. We further sought to determine if changing the multimodal programme based on these results would improve pain control or reduce side effects. METHODS: In this pilot study, buccal samples were collected from 31 primary TKA patients. Pharmacogenetics testing examined genetic variants in genes OPRM1, CYP1A2, CYP2B6, CYP2C19, CYP3A4, CYP2C9, and CYP2D6. These genes affect the pharmacodynamics and pharmacokinetics of non-steroidal anti-inflammatory drugs and opioids. We examined the frequency of genetic variants to any of the medications we prescribed including celecoxib, hydrocodone, and tramadol. Patients were randomized to one of two groups: the control group received the standard postoperative pain regimen, and the study group received a customized regimen based on the pharmacogenetic results. For the first ten postoperative days, patients recorded pain scores, medication, and side effects. RESULTS: Genetic variants involving one or more medications in the multimodal pain protocol occurred in 13 of the 31 patients (42%). In total, eight patients (26%) had variants affecting more than one of the medications. For the 25 patients who recorded pain and medication logs, the mean pain levels and morphine equivalents (MEQs) consumed in the first ten days were higher in the control group than in the custom-guided group (p = 0.019 for pain and p = 0.655 for MEQ). CONCLUSION: Overall, 42% of patients had a variant involving one of the pain medications prescribed in our perioperative pain program for TKA. Ongoing research will help determine if using these data to modify a patient's medication will improve outcomes. Cite this article: Bone Joint J 2020;102-B(6 Supple A):73-78.


Assuntos
Analgésicos Opioides/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Artroplastia do Joelho , Manejo da Dor/métodos , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Farmacogenômicos , Projetos Piloto , Estudos Prospectivos , Método Simples-Cego
13.
Stud Health Technol Inform ; 270: 618-622, 2020 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-32570457

RESUMO

Pharmacogenetic testing can prevent adverse drug events but has rarely found its way into clinical routine. One reason is the lack of tools for smooth and automatable integration of pharmacogenetic knowledge into existing processes. Especially, electronic medical records (EMR) represent a suitable environment for such tools. We developed a modular service-oriented prototype of a pharmacogenetic decision support system within an EMR system of the Bern University Hospital. Here, we present the component architecture of our system and discuss issues required for generalizing our results.


Assuntos
Testes Farmacogenômicos , Sistemas de Apoio a Decisões Clínicas , Registros Eletrônicos de Saúde , Farmacogenética , Software
14.
Pharmacogenomics ; 21(10): 695-703, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32501190

RESUMO

COVID-19 utilizes the ACE2 pathway as a means of infection. Early data on COVID-19 suggest heterogeneity in the severity of symptoms during transmission and infection ranging from no symptoms to death. The source of this heterogeneity is likely multifaceted and may have a genetic component. Demographic and clinical comorbidities associated with the severity of infection suggest that possible variants known to influence the renin-angiotensin-aldosterone (RAAS) system pathway (particularly those that influence ACE2) may contribute to the heterogenous infection response. ACE2 and Ang(1-7) (the product of ACE2) seem to have a protective effect on the pulmonary and cardiac systems. Hypertension medication modulation, may alter ACE2 and Ang(1-7), particularly in variants that have been shown to influence RAAS system function, which could be clinically useful in patients with COVID-19.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/genética , Peptidil Dipeptidase A/efeitos dos fármacos , Peptidil Dipeptidase A/genética , Farmacogenética , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/genética , Humanos , Pandemias , Testes Farmacogenômicos , Sistema Renina-Angiotensina/efeitos dos fármacos
16.
Psychopharmacology (Berl) ; 237(7): 2151-2159, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32382784

RESUMO

INTRODUCTION: We explore the transcription factors involved in the molecular mechanism of antipsychotic (AP)-induced acute extrapyramidalsymptoms (EPS) in order to identify new candidate genes for pharmacogenetic studies. METHODS: Protein-protein interaction (PPI) networks previously created from three pharmacogenomic models (in vitro, animal, and peripheral blood inhumans) were used to, by means of several bioinformatic tools; identify key transcription factors (TFs) that regulate each network. Once the TFs wereidentified, SNPs disrupting the binding sites (TFBS) of these TFs in the genes of each network were selected for genotyping. Finally, SNP-basedassociations with EPS were analyzed in a sample of 356 psychiatric patients receiving AP. RESULTS: Our analysis identified 33 TFs expressed in the striatum, and 125 SNPs disrupting TFBS in 50 genes of our initial networks. Two SNPs (rs938112,rs2987902) in two genes (LSMAP and ABL1) were significantly associated with AP induced EPS (p < 0.001). These SNPs disrupt TFBS regulated byPOU2F1. CONCLUSION: Our results highlight the possible role of the disruption of TFBS by SNPs in the pharmacological response to AP.


Assuntos
Antipsicóticos/efeitos adversos , Doenças dos Gânglios da Base/induzido quimicamente , Doenças dos Gânglios da Base/genética , Farmacogenética/métodos , Testes Farmacogenômicos/métodos , Fatores de Transcrição/genética , Animais , Doenças dos Gânglios da Base/metabolismo , Biologia Computacional/métodos , Seguimentos , Humanos , Estudos Longitudinais , Camundongos , Polimorfismo de Nucleotídeo Único/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único/fisiologia , Estudos Prospectivos , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Fatores de Transcrição/biossíntese
17.
Aliment Pharmacol Ther ; 51(11): 1105-1115, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32363635

RESUMO

BACKGROUND: High inter-individual variability in therapeutic response to drugs used in the management of Inflammatory Bowel Disease (IBD) leads to high morbidity and high costs. Genetic variants predictive of thiopurine-induced myelosuppression, thiopurine-induced pancreatitis and immunogenicity of Tumour Necrosis Factor alpha (TNFα) antagonists have been identified, but uptake of pre-treatment pharmacogenetic testing into clinical guidelines has been slow. AIM: To explore the efficacy of a pharmacogenetic passport for IBD that includes multiple pharmacogenetic predictors of response. METHODS: Patients with IBD exposed to thiopurines and/or TNFα antagonists were retrospectively evaluated for the presence of thiopurine toxicity and/or immunogenicity of TNFα antagonists. All patients were genotyped using both whole-exome sequencing and the Illumina Global Screening Array. An in-house-developed computational pipeline translated genetic data into an IBD pharmacogenetic passport that predicted risks for thiopurine toxicity and immunogenicity of TNFα antagonists per patient. Using pharmacogenetic-guided treatment guidelines, we calculated clinical efficacy estimates for pharmacogenetic testing for IBD. RESULTS: Among 710 patients with IBD exposed to thiopurines and/or TNFα antagonists, 150 adverse drug responses occurred and our pharmacogenetic passport would have predicted 54 (36%) of these. Using a pharmacogenetic passport for IBD that includes genetic variants predictive of thiopurine-induced myelosuppression, thiopurine-induced pancreatitis, and immunogenicity of TNFα antagonists, 24 patients need to be genotyped to prevent one of these adverse drug responses. CONCLUSIONS: This study highlights the clinical efficacy of a pharmacogenetic passport for IBD. Implementation of such a pharmacogenetic passport into clinical management of IBD may contribute to a reduction in adverse drug responses.


Assuntos
Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/genética , Variantes Farmacogenômicos/genética , Transcriptoma , Adolescente , Adulto , Idoso , Biomarcadores Farmacológicos/análise , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Testes Farmacogenômicos/métodos , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Estudos Retrospectivos , Transcriptoma/efeitos dos fármacos , Resultado do Tratamento , Adulto Jovem
18.
Nucleic Acids Res ; 48(W1): W494-W501, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32442307

RESUMO

Drug-combination data portals have recently been introduced to mine huge amounts of pharmacological data with the aim of improving current chemotherapy strategies. However, these portals have only been investigated for isolated datasets, and molecular profiles of cancer cell lines are lacking. Here we developed a cloud-based pharmacogenomics portal called SYNERGxDB (http://SYNERGxDB.ca/) that integrates multiple high-throughput drug-combination studies with molecular and pharmacological profiles of a large panel of cancer cell lines. This portal enables the identification of synergistic drug combinations through harmonization and unified computational analysis. We integrated nine of the largest drug combination datasets from both academic groups and pharmaceutical companies, resulting in 22 507 unique drug combinations (1977 unique compounds) screened against 151 cancer cell lines. This data compendium includes metabolomics, gene expression, copy number and mutation profiles of the cancer cell lines. In addition, SYNERGxDB provides analytical tools to discover effective therapeutic combinations and predictive biomarkers across cancer, including specific types. Combining molecular and pharmacological profiles, we systematically explored the large space of univariate predictors of drug synergism. SYNERGxDB constitutes a comprehensive resource that opens new avenues of research for exploring the mechanism of action for drug synergy with the potential of identifying new treatment strategies for cancer patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Testes Farmacogenômicos , Software , Linhagem Celular Tumoral , Sinergismo Farmacológico , Dosagem de Genes , Variação Genética , Humanos , Metabolômica
20.
Thorac Surg Clin ; 30(2): 127-136, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32327171

RESUMO

Up to 20% of lung adenocarcinomas in the United States and Europe and 50% in Asia have activating mutations of the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). The identification and subsequent targeting of mutations with EGFR-tyrosine kinase inhibitors (TKIs) led to significant advances in treatment of EGFR-mutant lung cancer. Newer-generation EGFR-TKIs resulted in improvement in outcomes, with less toxic side effects and better tolerability. Resistance to EGFR-TKIs remains a significant barrier, and better understanding of resistance mechanisms is needed. Efforts are ongoing to incorporate targeted therapy into treatment of patients with earlier-stage disease.


Assuntos
Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Carcinoma Pulmonar de Células não Pequenas , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Testes Farmacogenômicos , Inibidores de Proteínas Quinases/farmacologia
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