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1.
Sci Rep ; 11(1): 21126, 2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34702867

RESUMO

Rapid identification of SARS-CoV-2-infected individuals is a cornerstone for the control of virus spread. The sensitivity of SARS-CoV-2 RNA detection by RT-PCR is similar in saliva and nasopharyngeal swabs. Rapid molecular point-of-care tests in saliva could facilitate, broaden and speed up the diagnosis. We conducted a prospective study in two community COVID-19 screening centers to evaluate the performances of a CE-marked RT-LAMP assay (EasyCoV) designed for the detection of SARS-CoV2 RNA from fresh saliva samples, compared to nasopharyngeal RT-PCR, to saliva RT-PCR and to nasopharyngeal antigen testing. Overall, 117 of the 1718 participants (7%) tested positive with nasopharyngeal RT-PCR. Compared to nasopharyngeal RT-PCR, the sensitivity and specificity of the RT-LAMP assay in saliva were 34% and 97%, respectively. The Ct values of nasopharyngeal RT-PCR were significantly lower in the 40 true positive subjects with saliva RT-LAMP (Ct 25.9) than in the 48 false negative subjects with saliva RT-LAMP (Ct 28.4) (p = 0.028). Considering six alternate criteria for reference tests, including saliva RT-PCR and nasopharyngeal antigen, the sensitivity of saliva RT-LAMP ranged between 27 and 44%. The detection of SARS-CoV-2 in crude saliva samples with an RT-LAMP assay had a lower sensitivity than nasopharyngeal RT-PCR, saliva RT-PCR and nasopharyngeal antigen testing.Registration number: NCT04578509.


Assuntos
Assistência Ambulatorial/métodos , Teste de Ácido Nucleico para COVID-19/métodos , COVID-19/diagnóstico , COVID-19/metabolismo , SARS-CoV-2 , Saliva/metabolismo , Adulto , Testes Diagnósticos de Rotina , Reações Falso-Negativas , Reações Falso-Positivas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Medicina Molecular , Nasofaringe/virologia , Técnicas de Amplificação de Ácido Nucleico , Sistemas Automatizados de Assistência Junto ao Leito , Testes Imediatos , Estudos Prospectivos , RNA Viral/genética , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
2.
Sci Rep ; 11(1): 20864, 2021 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-34675303

RESUMO

Following SARS-CoV-2 infection, some COVID-19 patients experience severe host driven adverse events. To treat these complications, their underlying etiology and drug treatments must be identified. Thus, a novel AI methodology MOATAI-VIR, which predicts disease-protein-pathway relationships and repurposed FDA-approved drugs to treat COVID-19's clinical manifestations was developed. SARS-CoV-2 interacting human proteins and GWAS identified respiratory failure genes provide the input from which the mode-of-action (MOA) proteins/pathways of the resulting disease comorbidities are predicted. These comorbidities are then mapped to their clinical manifestations. To assess each manifestation's molecular basis, their prioritized shared proteins were subject to global pathway analysis. Next, the molecular features associated with hallmark COVID-19 phenotypes, e.g. unusual neurological symptoms, cytokine storms, and blood clots were explored. In practice, 24/26 of the major clinical manifestations are successfully predicted. Three major uncharacterized manifestation categories including neoplasms are also found. The prevalence of neoplasms suggests that SARS-CoV-2 might be an oncovirus due to shared molecular mechanisms between oncogenesis and viral replication. Then, repurposed FDA-approved drugs that might treat COVID-19's clinical manifestations are predicted by virtual ligand screening of the most frequent comorbid protein targets. These drugs might help treat both COVID-19's severe adverse events and lesser ones such as loss of taste/smell.


Assuntos
COVID-19/complicações , COVID-19/diagnóstico , COVID-19/tratamento farmacológico , Biologia Computacional/métodos , Neoplasias/complicações , Doenças do Sistema Nervoso/complicações , Trombose/complicações , Replicação Viral , Benchmarking , Comorbidade , Simulação por Computador , Síndrome da Liberação de Citocina , Descoberta de Drogas , Humanos , Aprendizado de Máquina , Medicina Molecular , Fenótipo , SARS-CoV-2 , Resultado do Tratamento
3.
Nat Commun ; 12(1): 3346, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099720

RESUMO

Characterizing the human leukocyte antigen (HLA) bound ligandome by mass spectrometry (MS) holds great promise for developing vaccines and drugs for immune-oncology. Still, the identification of non-tryptic peptides presents substantial computational challenges. To address these, we synthesized and analyzed >300,000 peptides by multi-modal LC-MS/MS within the ProteomeTools project representing HLA class I & II ligands and products of the proteases AspN and LysN. The resulting data enabled training of a single model using the deep learning framework Prosit, allowing the accurate prediction of fragment ion spectra for tryptic and non-tryptic peptides. Applying Prosit demonstrates that the identification of HLA peptides can be improved up to 7-fold, that 87% of the proposed proteasomally spliced HLA peptides may be incorrect and that dozens of additional immunogenic neo-epitopes can be identified from patient tumors in published data. Together, the provided peptides, spectra and computational tools substantially expand the analytical depth of immunopeptidomics workflows.


Assuntos
Aprendizado Profundo , Peptídeos/imunologia , Espectrometria de Massas em Tandem/métodos , Linhagem Celular , Epitopos , Proteínas da Matriz Extracelular/metabolismo , Antígenos HLA/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Ligantes , Espectrometria de Massas , Medicina Molecular , Peptídeos/metabolismo , Proteômica
4.
Sci Rep ; 11(1): 7389, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33795764

RESUMO

To assess the predictive and prognostic aim of interim and end-treatment 18F-fluorocholine PET/CT (FCH-PET/CT) and 99mTc-methilen diphosphonate bone scintigraphy (BS) in patients with castration-resistant prostate cancer and bone metastases (CRPC-BM) treated with Radium 223 dichloride (223Ra). Prospective and multicentre ChoPET-Rad study including 82 patients with CRPC-BM. Baseline, after 3 (interim) and 6 doses (end-treatment) BS and FCH PET/CT were performed in patients who meet the study criteria. Clinical variables, imaging and clinical progression were obtained and their association with progression free survival (PFS), and overall survival (OS) was studied. Agreement between BS and FCH PET/CT response was assessed using Kappa (K) analysis. Median of PFS and OS was 3 and 16 months, respectively. Agreement between interim BS and FCH PET/CT was weak (K: 0.28; p = 0.004). No agreement was observed between end-treatment diagnostic studies. Interim and end-treatment FCH PET/CT were related to PFS (p = 0.011 and p < 0.001, respectively). Therapeutic failure and interim BS and FCH PET/CT showed association with OS (p < 0.001, p = 0.037 and p = 0.008, respectively). Interim and end-treatment FCH PET/CT were good predictors of biochemical progression in patients treated with 223Ra. Therapeutic failure and progression in interim BS or FCH PET/CT were adverse factors for OS.


Assuntos
Neoplasias Ósseas/diagnóstico por imagem , Osso e Ossos/diagnóstico por imagem , Colina/análogos & derivados , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Neoplasias da Próstata/diagnóstico por imagem , Rádio (Elemento)/química , Idoso , Neoplasias Ósseas/secundário , Colina/química , Progressão da Doença , Intervalo Livre de Doença , Humanos , Masculino , Pessoa de Meia-Idade , Medicina Molecular , Análise Multivariada , Modelos de Riscos Proporcionais , Estudos Prospectivos , Radioisótopos/química , Reprodutibilidade dos Testes , Resultado do Tratamento
6.
Nat Commun ; 11(1): 6371, 2020 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-33311470

RESUMO

Genetic mutations predispose the serine protease inhibitor α1-antitrypsin to misfolding and polymerisation within hepatocytes, causing liver disease and chronic obstructive pulmonary disease. This misfolding occurs via a transiently populated intermediate state, but our structural understanding of this process is limited by the instability of recombinant α1-antitrypsin variants in solution. Here we apply NMR spectroscopy to patient-derived samples of α1-antitrypsin at natural isotopic abundance to investigate the consequences of disease-causing mutations, and observe widespread chemical shift perturbations for methyl groups in Z AAT (E342K). By comparison with perturbations induced by binding of a small-molecule inhibitor of misfolding we conclude that they arise from rapid exchange between the native conformation and a well-populated intermediate state. The observation that this intermediate is stabilised by inhibitor binding suggests a paradoxical approach to the targeted treatment of protein misfolding disorders, wherein the stabilisation of disease-associated states provides selectivity while inhibiting further transitions along misfolding pathways.


Assuntos
Espectroscopia de Ressonância Magnética/métodos , Deficiência de alfa 1-Antitripsina/genética , Deficiência de alfa 1-Antitripsina/metabolismo , alfa 1-Antitripsina/química , alfa 1-Antitripsina/genética , alfa 1-Antitripsina/metabolismo , Predisposição Genética para Doença/genética , Glicoproteínas , Humanos , Modelos Moleculares , Medicina Molecular , Mutação , Agregação Patológica de Proteínas , Conformação Proteica , Proteínas Recombinantes , Inibidores de Serino Proteinase/química
7.
Nat Commun ; 11(1): 5666, 2020 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-33168815

RESUMO

Aquaporin 3 (AQP3) is a transporter of water, glycerol and hydrogen peroxide (H2O2) that is expressed in various epithelial cells and in macrophages. Here, we developed an anti-AQP3 monoclonal antibody (mAb) that inhibited AQP3-facilitated H2O2 and glycerol transport, and prevented liver injury in experimental animal models. Using AQP3 knockout mice in a model of liver injury and fibrosis produced by CCl4, we obtained evidence for involvement of AQP3 expression in nuclear factor-κB (NF-κB) cell signaling, hepatic oxidative stress and inflammation in macrophages during liver injury. The activated macrophages caused stellate cell activation, leading to liver injury, by a mechanism involving AQP3-mediated H2O2 transport. Administration of an anti-AQP3 mAb, which targeted an extracellular epitope on AQP3, prevented liver injury by inhibition of AQP3-mediated H2O2 transport and macrophage activation. These findings implicate the involvement of macrophage AQP3 in liver injury, and provide evidence for mAb inhibition of AQP3-mediated H2O2 transport as therapy for macrophage-dependent liver injury.


Assuntos
Anticorpos Monoclonais/farmacologia , Aquaporina 3/antagonistas & inibidores , Aquaporina 3/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Animais , Aquaporina 3/genética , Células CHO , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Quimiocina CCL4/efeitos adversos , Cricetulus , Modelos Animais de Doenças , Descoberta de Drogas , Glicerol/metabolismo , Peróxido de Hidrogênio/metabolismo , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Medicina Molecular , NF-kappa B/metabolismo , Estresse Oxidativo , Transdução de Sinais , Transcriptoma
8.
Neurol India ; 68(5): 1144-1150, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33109865

RESUMO

Background: Folic acid and multivitamin supplements ((FAMVS) and genetics involvement is one of the major roles in the development of neural tube defects (NTDs). Objective: Our prior aim and objective is to establish an unique guideline and helps the policy decision making for our country India and the World. Materials and Methods: We have collected the data through the literature from the World for their necessary action, rehabilitation part all objectively in PubMed/Medline, Scopous, Embase, Cochrane Review, Hinari, and Google scholar. Statistical Analysis: Statistical analysis was performed with very simple and logistic statistics, percentage, mean, total as collection through the available software SPSS with new version 17.0. Results: The overall (70-95%) we find out those infants with neural tube defects (NTDs) associated with genes involvement and maternal vitamin intake (MVI). Before pregnancy relative risk (PRR) prior to non intake noted as 90% significantly reduced their risk of the NTDs. Now (40-60%) of the women of child-bearing age (CBA) don't use the folic acid intake and supplements (FAISs) in proper way in villages, urban, industrial and sewage areas. We find out that the genetic variants of the fourteen special reported genes, had the major risk factor (MRF) for the (NTDs) and associated abnormalities rate (AAR) within the developmental process in the human brain. Conclusions: The (45-55%) people still having at ignorant zone, due to lack of education, genetic counseling, and awareness till date.


Assuntos
Medicina Molecular , Defeitos do Tubo Neural , Suplementos Nutricionais , Feminino , Ácido Fólico , Humanos , Índia , Defeitos do Tubo Neural/genética , Gravidez
9.
EMBO Mol Med ; 12(11): e11131, 2020 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-33047515

RESUMO

Sarcomas are heterogeneous and clinically challenging soft tissue and bone cancers. Although constituting only 1% of all human malignancies, sarcomas represent the second most common type of solid tumors in children and adolescents and comprise an important group of secondary malignancies. More than 100 histological subtypes have been characterized to date, and many more are being discovered due to molecular profiling. Owing to their mostly aggressive biological behavior, relative rarity, and occurrence at virtually every anatomical site, many sarcoma subtypes are in particular difficult-to-treat categories. Current multimodal treatment concepts combine surgery, polychemotherapy (with/without local hyperthermia), irradiation, immunotherapy, and/or targeted therapeutics. Recent scientific advancements have enabled a more precise molecular characterization of sarcoma subtypes and revealed novel therapeutic targets and prognostic/predictive biomarkers. This review aims at providing a comprehensive overview of the latest advances in the molecular biology of sarcomas and their effects on clinical oncology; it is meant for a broad readership ranging from novices to experts in the field of sarcoma.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Sarcoma , Neoplasias de Tecidos Moles , Adolescente , Criança , Humanos , Medicina Molecular , Sarcoma/genética , Sarcoma/terapia
10.
Trends Mol Med ; 26(9): 797-798, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32857967
12.
Nat Commun ; 11(1): 2768, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32488016

RESUMO

Fibrotic disorders are some of the most devastating and poorly treated conditions in developed nations, yet effective therapeutics are not identified for many of them. A major barrier for the identification of targets and successful clinical translation is a limited understanding of the human fibrotic microenvironment. Here, we construct a stromal cell atlas of human fibrosis at single cell resolution from patients with Dupuytren's disease, a localized fibrotic condition of the hand. A molecular taxonomy of the fibrotic milieu characterises functionally distinct stromal cell types and states, including a subset of immune regulatory ICAM1+ fibroblasts. In developing fibrosis, myofibroblasts exist along an activation continuum of phenotypically distinct populations. We also show that the tetraspanin CD82 regulates cell cycle progression and can be used as a cell surface marker of myofibroblasts. These findings have important implications for targeting core pathogenic drivers of human fibrosis.


Assuntos
Contratura de Dupuytren/imunologia , Contratura de Dupuytren/metabolismo , Fibrose/imunologia , Fibrose/metabolismo , Células Estromais/metabolismo , Actinas/metabolismo , Biomarcadores/metabolismo , Quimiocinas CXC/metabolismo , Contratura de Dupuytren/patologia , Fibrose/patologia , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Medicina Molecular , Miofibroblastos/metabolismo , Tetraspaninas/metabolismo , Microambiente Tumoral/fisiologia
13.
Nat Commun ; 11(1): 1923, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32317663

RESUMO

Drug resistance mediated by clonal evolution is arguably the biggest problem in cancer therapy today. However, evolving resistance to one drug may come at a cost of decreased fecundity or increased sensitivity to another drug. These evolutionary trade-offs can be exploited using 'evolutionary steering' to control the tumour population and delay resistance. However, recapitulating cancer evolutionary dynamics experimentally remains challenging. Here, we present an approach for evolutionary steering based on a combination of single-cell barcoding, large populations of 108-109 cells grown without re-plating, longitudinal non-destructive monitoring of cancer clones, and mathematical modelling of tumour evolution. We demonstrate evolutionary steering in a lung cancer model, showing that it shifts the clonal composition of the tumour in our favour, leading to collateral sensitivity and proliferative costs. Genomic profiling revealed some of the mechanisms that drive evolved sensitivity. This approach allows modelling evolutionary steering strategies that can potentially control treatment resistance.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Evolução Molecular , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Evolução Clonal , Biologia Computacional , Simulação por Computador , Gefitinibe/farmacologia , Genótipo , Humanos , Neoplasias Pulmonares/patologia , Modelos Teóricos , Medicina Molecular , Piridonas/farmacologia , Pirimidinonas/farmacologia , Processos Estocásticos
14.
J Nucl Med ; 61(7): 951-961, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32303601

RESUMO

Radionuclide imaging of myocardial perfusion, function, and viability has been established for decades and remains a robust, evidence-based and broadly available means for clinical workup and therapeutic guidance in ischemic heart disease. Yet, powerful alternative modalities have emerged for this purpose, and their growth has resulted in increasing competition. But the potential of the tracer principle goes beyond the assessment of physiology and function, toward the interrogation of biology and molecular pathways. This is a unique selling point of radionuclide imaging, which has been underrecognized in cardiovascular medicine until recently. Now, molecular imaging methods for the detection of myocardial infiltration, device infection, and cardiovascular inflammation are successfully gaining clinical acceptance. This is further strengthened by the symbiotic quest of cardiac imaging and therapy for an increasing implementation of molecule-targeted procedures, in which specific therapeutic interventions require specific diagnostic guidance toward the most suitable candidates. This review will summarize the current advent of clinical cardiovascular molecular imaging and highlight its transformative contribution to the evolution of cardiovascular therapy beyond mechanical interventions and broad blockbuster medication, toward a future of novel, individualized molecule-targeted and molecular imaging-guided therapies.


Assuntos
Cardiologia , Doenças Cardiovasculares/diagnóstico por imagem , Imagem Molecular/métodos , Medicina Molecular , Medicina Nuclear , Humanos
15.
Nat Commun ; 11(1): 1733, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32265441

RESUMO

Dysregulation of extracellular signal-regulated kinases (ERK1/2) is linked to several diseases including heart failure, genetic syndromes and cancer. Inhibition of ERK1/2, however, can cause severe cardiac side-effects, precluding its wide therapeutic application. ERKT188-autophosphorylation was identified to cause pathological cardiac hypertrophy. Here we report that interference with ERK-dimerization, a prerequisite for ERKT188-phosphorylation, minimizes cardiac hypertrophy without inducing cardiac adverse effects: an ERK-dimerization inhibitory peptide (EDI) prevents ERKT188-phosphorylation, nuclear ERK1/2-signaling and cardiomyocyte hypertrophy, protecting from pressure-overload-induced heart failure in mice whilst preserving ERK1/2-activity and cytosolic survival signaling. We also examine this alternative ERK1/2-targeting strategy in cancer: indeed, ERKT188-phosphorylation is strongly upregulated in cancer and EDI efficiently suppresses cancer cell proliferation without causing cardiotoxicity. This powerful cardio-safe strategy of interfering with ERK-dimerization thus combats pathological ERK1/2-signaling in heart and cancer, and may potentially expand therapeutic options for ERK1/2-related diseases, such as heart failure and genetic syndromes.


Assuntos
Cardiotoxicidade , Peptídeos Penetradores de Células/farmacologia , Dimerização , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Sistema de Sinalização das MAP Quinases , Animais , Técnicas de Cultura de Células , Peptídeos Penetradores de Células/síntese química , Peptídeos Penetradores de Células/toxicidade , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Sistemas de Liberação de Medicamentos , MAP Quinases Reguladas por Sinal Extracelular/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Medicina Molecular , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
16.
Biomaterials ; 246: 119971, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32247202

RESUMO

Photodynamic therapy (PDT) is an effective and noninvasive therapeutic strategy employing light-triggered singlet oxygen (SO) and reactive oxygen species (ROS) to kill lesional cells. However, for effective in vivo delivery of PDT agent into the cancer cells, various biological obstacles including blood circulation and condense extracellular matrix (ECM) in the tumor microenvironment (TME) need to be overcome. Furthermore, the enormous challenge in design of smart drug delivery systems is meeting the difference, even contradictory required functions, in different steps of the complicated delivery process. To this end, we present that TME-activatable circular pyrochlorophyll A (PA)-aptamer-PEG (PA-Apt-CHO-PEG) nanostructures, which combine the advantages of PEG and aptamer, would be able to realize efficient in vivo imaging and PDT. Upon intravenous (i.v.) injection, PA-Apt-CHO-PEG shows "stealth-like" long circulation in blood compartments without specific recognition capacity, but once inside solid tumor, PA-Apt-CHO-PEG nanostructures are cleaved and then form PA-Apt Aptamer-drug conjugations (ApDCs) in situ, allowing deep penetration into the solid tumor and specific recognition of cancer cells, both merits, considering anticipated future clinical translation of ApDCs.


Assuntos
Fotoquimioterapia , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Medicina Molecular , Microambiente Tumoral
17.
Trends Ecol Evol ; 35(5): 380-383, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32294420

RESUMO

Pollinators have been declining worldwide, and pesticides have contributed to these declines. High-resolution approaches from molecular medicine can provide unparalleled insight into organismal physiology and health. Applying these approaches to pollinators can significantly improve the efficiency and sensitivity of pesticide research and evaluation, and thus the sustainability of modern agriculture.


Assuntos
Praguicidas , Agricultura , Medicina Molecular
19.
J Grad Med Educ ; 12(1): 92-97, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32089799

RESUMO

Background: Medical innovation depends on translation, the process of applying clinical insights to solve biological problems, and vice versa, yet existing training programs provide few opportunities for physician-scientists to integrate their clinical and research training. Objective: We developed and determined the feasibility and acceptability of a rotation on the Molecular Medicine Investigation Unit (MMIU), a novel program that engages trainees in the deliberate linkage of patient care and scientific inquiry to cultivate their interest and skills in translation. Methods: Between July 2017 and January 2019, fourth-year medical students and internal medicine residents were offered a 4-week elective rotation on the MMIU. Supervised by 2 part-time faculty, trainees evaluated patients with unusual and perplexing presentations with the goal of generating hypotheses and a research plan to elucidate the underlying mechanisms of disease. We tracked the development of research hypotheses and resulting projects and surveyed participants about their satisfaction with the program. Results: Over 18 months, 21 trainees (11 medical students and 10 residents) participated in the program and evaluated a total of 70 patients. Trainees generated a mechanistic hypothesis in 45 (64%) cases, and this resulted in a patient-centered research project in 38 (54%) cases. Trainees unanimously agreed that the program gave them an opportunity to integrate their clinical and research training, and many expressed that it reinforced their interests in translational research. Conclusions: With modest funding support, it was feasible to deliver authentic experiences of translational inquiry for medical students and internal medical residents, and these experiences were valued by trainees.


Assuntos
Atitude do Pessoal de Saúde , Medicina Molecular/educação , Médicos/psicologia , Pesquisa/educação , Estudantes de Medicina/psicologia , Educação de Graduação em Medicina , Humanos , Internato e Residência , Pessoal de Laboratório , Avaliação de Programas e Projetos de Saúde , Pesquisadores , São Francisco
20.
J Cyst Fibros ; 19 Suppl 1: S25-S32, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31902693

RESUMO

The treatment of cystic fibrosis (CF) has been transformed by orally-bioavailable small molecule modulators of the cystic fibrosis transmembrane conductance regulator (CFTR), which restore function to CF mutants. However, CFTR modulators are not available to all people with CF and better modulators are required to prevent disease progression. Here, we review selectively recent advances in CFTR folding, function and pharmacology. We highlight ensemble and single-molecule studies of CFTR folding, which provide new insight into CFTR assembly, its perturbation by CF mutations and rescue by CFTR modulators. We discuss species-dependent differences in the action of the F508del-CFTR mutation on CFTR expression, stability and function, which might influence pharmacological studies of CFTR modulators in CF animal models. Finally, we illuminate the identification of combinations of two CFTR potentiators (termed co-potentiators), which restore therapeutically-relevant levels of CFTR activity to rare CF mutations. Thus, mechanistic studies of CFTR folding, function and pharmacology inform the development of highly effective CFTR modulators.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Moduladores de Transporte de Membrana/farmacologia , Terapia de Alvo Molecular , Animais , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Humanos , Medicina Molecular/métodos , Medicina Molecular/tendências , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Mutação , Testes Farmacogenômicos
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