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1.
Stud Health Technol Inform ; 290: 12-16, 2022 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-35672961

RESUMO

Measurement concepts are essential to observational healthcare research; however, a lack of concept harmonization limits the quality of research that can be done on multisite research networks. We developed five methods that used a combination of automated, semi-automated and manual approaches for generating measurement concept sets. We validated our concept sets by calculating their frequencies in cohorts from the Columbia University Irving Medical Center (CUIMC) database. For heart transplant patients, the preoperative frequencies of basic metabolic panel concept sets, which we generated by a semi-automated approach, were greater than 99%. We also made concept sets for lumbar puncture and coagulation panels, by automated and manual methods respectively.


Assuntos
Armazenamento e Recuperação da Informação , Logical Observation Identifiers Names and Codes , Bases de Dados Factuais , Humanos , Systematized Nomenclature of Medicine
2.
Stud Health Technol Inform ; 290: 268-272, 2022 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-35673015

RESUMO

While the PICO framework is widely used by clinicians for clinical question formulation when querying the medical literature, it does not have the expressiveness to explicitly capture medical findings based on any standard. In addition, findings extracted from the literature are represented as free-text, which is not amenable to computation. This research extends the PICO framework with Observation elements, which capture the observed effect that an Intervention has on an Outcome, forming Intervention-Observation-Outcome triplets. In addition, we present a framework to normalize Observation elements with respect to their significance and the direction of the effect, as well as a rule-based approach to perform the normalization of these attributes. Our method achieves macro-averaged F1 scores of 0.82 and 0.73 for identifying the significance and direction attributes, respectively.

3.
Stud Health Technol Inform ; 290: 297-300, 2022 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-35673021

RESUMO

Electronic healthcare records data promises to improve the efficiency of patient eligibility screening, which is an important factor in the success of clinical trials and observational studies. To bridge the sociotechnical gap in cohort identification by end-users, who are clinicians or researchers unfamiliar with underlying EHR databases, we previously developed a natural language query interface named Criteria2Query (C2Q) that automatically transforms free-text eligibility criteria to executable database queries. In this study, we present a comprehensive evaluation of C2Q to generate more actionable insights to inform the design and evaluation of future natural language user interfaces for clinical databases, towards the realization of Augmented Intelligence (AI) for clinical cohort definition via e-screening.


Assuntos
Inteligência Artificial , Processamento de Linguagem Natural , Bases de Dados Factuais , Definição da Elegibilidade , Humanos , Inteligência
4.
Stud Health Technol Inform ; 290: 309-313, 2022 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-35673024

RESUMO

The rapid growth of clinical trials launched in recent years poses significant challenges for accurate and efficient trial search. Keyword-based clinical trial search engines require users to construct effective queries, which can be a difficult task given complex information needs. In this study, we present an interactive clinical trial search interface that retrieves trials similar to a target clinical trial. It enables user configuration of 13 clinical trial features and 4 metrics (Jaccard similarity, semantic-based similarity, temporal overlap and geographical distance) to measure pairwise trial similarities. Among 1,007 coronavirus disease 2019 (COVID-19) trials conducted in the United States, 91.9% were found to have similar trials with the similarity threshold being 0.85 and 43.8% were highly similar with the threshold 0.95. A simulation study using 3 groups of similar trials curated by COVID-19 clinical trial reviews demonstrates the precision and recall of the search interface.


Assuntos
COVID-19 , Benchmarking , Coleta de Dados , Humanos , Ferramenta de Busca , Semântica
5.
Stud Health Technol Inform ; 290: 617-621, 2022 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-35673090

RESUMO

Sample size is an important indicator of the power of randomized controlled trials (RCTs). In this paper, we designed a total sample size extractor using a combination of syntactic and machine learning methods, and evaluated it on 300 Covid-19 abstracts (Covid-Set) and 100 generic RCT abstracts (General-Set). To improve the performance, we applied transfer learning from a large public corpus of annotated abstracts. We achieved an average F1 score of 0.73 on the Covid-Set testing set, and 0.60 on the General-Set using exact matches. The F1 scores for loose matches on both datasets were over 0.74. Compared with the state-of-the-art tool, our extractor reports total sample sizes directly and improved F1 scores by at least 4% without transfer learning. We demonstrated that transfer learning improved the sample size extraction accuracy and minimized human labor on annotations.


Assuntos
COVID-19 , COVID-19/epidemiologia , Humanos , Aprendizado de Máquina , Processamento de Linguagem Natural , Ensaios Clínicos Controlados Aleatórios como Assunto , Tamanho da Amostra
6.
Stud Health Technol Inform ; 290: 1054-1055, 2022 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-35673202

RESUMO

Bidirectional recurrent neural networks (RNN) improved performance of various natural language processing tasks and recently have been used for diagnosis prediction. Advantages of general bidirectional RNN, however, are not readily applied to diagnosis prediction task. In this study, we present a simple way to efficiently apply bidirectional RNN for diagnosis prediction without using any additional networks or parameters.


Assuntos
Processamento de Linguagem Natural , Redes Neurais de Computação
7.
JAMIA Open ; 5(2): ooac042, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35663114

RESUMO

The identification of delirium in electronic health records (EHRs) remains difficult due to inadequate assessment or under-documentation. The purpose of this research is to present a classification model that identifies delirium using retrospective EHR data. Delirium was confirmed with the Confusion Assessment Method for the Intensive Care Unit. Age, sex, Elixhauser comorbidity index, drug exposures, and diagnoses were used as features. The model was developed based on the Columbia University Irving Medical Center EHR data and further validated with the Medical Information Mart for Intensive Care III dataset. Seventy-six patients from Surgical/Cardiothoracic ICU were included in the model. The logistic regression model achieved the best performance in identifying delirium; mean AUC of 0.874 ± 0.033. The mean positive predictive value of the logistic regression model was 0.80. The model promises to identify delirium cases with EHR data, thereby enable a sustainable infrastructure to build a retrospective cohort of delirium.

8.
Nat Commun ; 13(1): 3428, 2022 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-35701404

RESUMO

Clinical and epidemiological studies have shown that circulatory system diseases and nervous system disorders often co-occur in patients. However, genetic susceptibility factors shared between these disease categories remain largely unknown. Here, we characterized pleiotropy across 107 circulatory system and 40 nervous system traits using an ensemble of methods in the eMERGE Network and UK Biobank. Using a formal test of pleiotropy, five genomic loci demonstrated statistically significant evidence of pleiotropy. We observed region-specific patterns of direction of genetic effects for the two disease categories, suggesting potential antagonistic and synergistic pleiotropy. Our findings provide insights into the relationship between circulatory system diseases and nervous system disorders which can provide context for future prevention and treatment strategies.


Assuntos
Doenças Cardiovasculares , Doenças do Sistema Nervoso , Doenças Cardiovasculares/genética , Pleiotropia Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica , Humanos , Doenças do Sistema Nervoso/genética , Polimorfismo de Nucleotídeo Único
9.
Stud Health Technol Inform ; 290: 592-596, 2022 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-35673085

RESUMO

Complex interventions are ubiquitous in healthcare. A lack of computational representations and information extraction solutions for complex interventions hinders accurate and efficient evidence synthesis. In this study, we manually annotated and analyzed 3,447 intervention snippets from 261 randomized clinical trial (RCT) abstracts and developed a compositional representation for complex interventions, which captures the spatial, temporal and Boolean relations between intervention components, along with an intervention normalization pipeline that automates three tasks: (i) treatment entity extraction; (ii) intervention component relation extraction; and (iii) attribute extraction and association. 361 intervention snippets from 29 unseen abstracts were included to report on the performance of the evaluation. The average F-measure was 0.74 for treatment entity extraction on an exact match and 0.82 for attribute extraction. The F-measure for relation extraction of multi-component complex interventions was 0.90. 93% of extracted attributes were correctly attributed to corresponding treatment entities.


Assuntos
Armazenamento e Recuperação da Informação , Processamento de Linguagem Natural , Humanos
10.
Nat Med ; 2022 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-35710995

RESUMO

Chronic kidney disease (CKD) is a common complex condition associated with high morbidity and mortality. Polygenic prediction could enhance CKD screening and prevention; however, this approach has not been optimized for ancestrally diverse populations. By combining APOL1 risk genotypes with genome-wide association studies (GWAS) of kidney function, we designed, optimized and validated a genome-wide polygenic score (GPS) for CKD. The new GPS was tested in 15 independent cohorts, including 3 cohorts of European ancestry (n = 97,050), 6 cohorts of African ancestry (n = 14,544), 4 cohorts of Asian ancestry (n = 8,625) and 2 admixed Latinx cohorts (n = 3,625). We demonstrated score transferability with reproducible performance across all tested cohorts. The top 2% of the GPS was associated with nearly threefold increased risk of CKD across ancestries. In African ancestry cohorts, the APOL1 risk genotype and polygenic component of the GPS had additive effects on the risk of CKD.

11.
Stud Health Technol Inform ; 294: 392-396, 2022 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-35612103

RESUMO

Anecdotally, 38.5% of clinical outcome descriptions in randomized controlled trial publications contain complex text. Existing terminologies are insufficient to standardize outcomes and their measures, temporal attributes, quantitative metrics, and other attributes. In this study, we analyzed the semantic patterns in the outcome text in a sample of COVID-19 trials and presented a data-driven method for modeling outcomes. We conclude that a data-driven knowledge representation can benefit natural language processing of outcome text from published clinical studies.


Assuntos
COVID-19 , Humanos , Processamento de Linguagem Natural , Semântica
12.
BMC Genomics ; 23(1): 385, 2022 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-35590255

RESUMO

BACKGROUND: As genomic sequencing moves closer to clinical implementation, there has been an increasing acceptance of returning incidental findings to research participants and patients for mutations in highly penetrant, medically actionable genes. A curated list of genes has been recommended by the American College of Medical Genetics and Genomics (ACMG) for return of incidental findings. However, the pleiotropic effects of these genes are not fully known. Such effects could complicate genetic counseling when returning incidental findings. In particular, there has been no systematic evaluation of psychiatric manifestations associated with rare variation in these genes. RESULTS: Here, we leveraged a targeted sequence panel and real-world electronic health records from the eMERGE network to assess the burden of rare variation in the ACMG-56 genes and two psychiatric-associated genes (CACNA1C  and TCF4) across common mental health conditions in 15,181 individuals of European descent. As a positive control, we showed that this approach replicated the established association between rare mutations in LDLR and hypercholesterolemia with no visible inflation from population stratification. However, we did not identify any genes significantly enriched with rare deleterious variants that confer risk for common psychiatric disorders after correction for multiple testing. Suggestive associations were observed between depression and rare coding variation in PTEN (P = 1.5 × 10-4), LDLR (P = 3.6 × 10-4), and CACNA1S (P = 5.8 × 10-4). We also observed nominal associations between rare variants in KCNQ1 and substance use disorders (P = 2.4 × 10-4), and APOB and tobacco use disorder (P = 1.1 × 10-3). CONCLUSIONS: Our results do not support an association between psychiatric disorders and incidental findings in medically actionable gene mutations, but power was limited with the available sample sizes. Given the phenotypic and genetic complexity of psychiatric phenotypes, future work will require a much larger sequencing dataset to determine whether incidental findings in these genes have implications for risk of psychopathology.


Assuntos
Exoma , Testes Genéticos , Testes Genéticos/métodos , Variação Genética , Genômica/métodos , Humanos , Mutação , Fenótipo
13.
J Am Med Inform Assoc ; 29(7): 1142-1151, 2022 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-35396996

RESUMO

OBJECTIVE: Artificial intelligence (AI) models may propagate harmful biases in performance and hence negatively affect the underserved. We aimed to assess the degree to which data quality of electronic health records (EHRs) affected by inequities related to low socioeconomic status (SES), results in differential performance of AI models across SES. MATERIALS AND METHODS: This study utilized existing machine learning models for predicting asthma exacerbation in children with asthma. We compared balanced error rate (BER) against different SES levels measured by HOUsing-based SocioEconomic Status measure (HOUSES) index. As a possible mechanism for differential performance, we also compared incompleteness of EHR information relevant to asthma care by SES. RESULTS: Asthmatic children with lower SES had larger BER than those with higher SES (eg, ratio = 1.35 for HOUSES Q1 vs Q2-Q4) and had a higher proportion of missing information relevant to asthma care (eg, 41% vs 24% for missing asthma severity and 12% vs 9.8% for undiagnosed asthma despite meeting asthma criteria). DISCUSSION: Our study suggests that lower SES is associated with worse predictive model performance. It also highlights the potential role of incomplete EHR data in this differential performance and suggests a way to mitigate this bias. CONCLUSION: The HOUSES index allows AI researchers to assess bias in predictive model performance by SES. Although our case study was based on a small sample size and a single-site study, the study results highlight a potential strategy for identifying bias by using an innovative SES measure.


Assuntos
Inteligência Artificial , Asma , Asma/diagnóstico , Viés , Criança , Atenção à Saúde , Humanos , Aprendizado de Máquina , Classe Social
14.
J Am Med Inform Assoc ; 29(7): 1161-1171, 2022 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-35426943

RESUMO

OBJECTIVE: To combine machine efficiency and human intelligence for converting complex clinical trial eligibility criteria text into cohort queries. MATERIALS AND METHODS: Criteria2Query (C2Q) 2.0 was developed to enable real-time user intervention for criteria selection and simplification, parsing error correction, and concept mapping. The accuracy, precision, recall, and F1 score of enhanced modules for negation scope detection, temporal and value normalization were evaluated using a previously curated gold standard, the annotated eligibility criteria of 1010 COVID-19 clinical trials. The usability and usefulness were evaluated by 10 research coordinators in a task-oriented usability evaluation using 5 Alzheimer's disease trials. Data were collected by user interaction logging, a demographic questionnaire, the Health Information Technology Usability Evaluation Scale (Health-ITUES), and a feature-specific questionnaire. RESULTS: The accuracies of negation scope detection, temporal and value normalization were 0.924, 0.916, and 0.966, respectively. C2Q 2.0 achieved a moderate usability score (3.84 out of 5) and a high learnability score (4.54 out of 5). On average, 9.9 modifications were made for a clinical study. Experienced researchers made more modifications than novice researchers. The most frequent modification was deletion (5.35 per study). Furthermore, the evaluators favored cohort queries resulting from modifications (score 4.1 out of 5) and the user engagement features (score 4.3 out of 5). DISCUSSION AND CONCLUSION: Features to engage domain experts and to overcome the limitations in automated machine output are shown to be useful and user-friendly. We concluded that human-computer collaboration is key to improving the adoption and user-friendliness of natural language processing.


Assuntos
COVID-19 , Inteligência Artificial , Definição da Elegibilidade/métodos , Humanos , Processamento de Linguagem Natural , Seleção de Pacientes
15.
JMIR Public Health Surveill ; 8(5): e35311, 2022 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-35486806

RESUMO

BACKGROUND: COVID-19 messenger RNA (mRNA) vaccines have demonstrated efficacy and effectiveness in preventing symptomatic COVID-19, while being relatively safe in trial studies. However, vaccine breakthrough infections have been reported. OBJECTIVE: This study aims to identify risk factors associated with COVID-19 breakthrough infections among fully mRNA-vaccinated individuals. METHODS: We conducted a series of observational retrospective analyses using the electronic health records (EHRs) of the Columbia University Irving Medical Center/New York Presbyterian (CUIMC/NYP) up to September 21, 2021. New York City (NYC) adult residences with at least 1 polymerase chain reaction (PCR) record were included in this analysis. Poisson regression was performed to assess the association between the breakthrough infection rate in vaccinated individuals and multiple risk factors-including vaccine brand, demographics, and underlying conditions-while adjusting for calendar month, prior number of visits, and observational days in the EHR. RESULTS: The overall estimated breakthrough infection rate was 0.16 (95% CI 0.14-0.18). Individuals who were vaccinated with Pfizer/BNT162b2 (incidence rate ratio [IRR] against Moderna/mRNA-1273=1.66, 95% CI 1.17-2.35) were male (IRR against female=1.47, 95% CI 1.11-1.94) and had compromised immune systems (IRR=1.48, 95% CI 1.09-2.00) were at the highest risk for breakthrough infections. Among all underlying conditions, those with primary immunodeficiency, a history of organ transplant, an active tumor, use of immunosuppressant medications, or Alzheimer disease were at the highest risk. CONCLUSIONS: Although we found both mRNA vaccines were effective, Moderna/mRNA-1273 had a lower incidence rate of breakthrough infections. Immunocompromised and male individuals were among the highest risk groups experiencing breakthrough infections. Given the rapidly changing nature of the SARS-CoV-2 pandemic, continued monitoring and a generalizable analysis pipeline are warranted to inform quick updates on vaccine effectiveness in real time.


Assuntos
COVID-19 , /administração & dosagem , Adulto , COVID-19/epidemiologia , COVID-19/prevenção & controle , Feminino , Humanos , Masculino , Cidade de Nova Iorque/epidemiologia , Estudos Retrospectivos , Fatores de Risco
16.
JAMA Oncol ; 8(6): 835-844, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35446370

RESUMO

Importance: Knowledge about the spectrum of diseases associated with hereditary cancer syndromes may improve disease diagnosis and management for patients and help to identify high-risk individuals. Objective: To identify phenotypes associated with hereditary cancer genes through a phenome-wide association study. Design, Setting, and Participants: This phenome-wide association study used health data from participants in 3 cohorts. The Electronic Medical Records and Genomics Sequencing (eMERGEseq) data set recruited predominantly healthy individuals from 10 US medical centers from July 16, 2016, through February 18, 2018, with a mean follow-up through electronic health records (EHRs) of 12.7 (7.4) years. The UK Biobank (UKB) cohort recruited participants from March 15, 2006, through August 1, 2010, with a mean (SD) follow-up of 12.4 (1.0) years. The Hereditary Cancer Registry (HCR) recruited patients undergoing clinical genetic testing at Vanderbilt University Medical Center from May 1, 2012, through December 31, 2019, with a mean (SD) follow-up through EHRs of 8.8 (6.5) years. Exposures: Germline variants in 23 hereditary cancer genes. Pathogenic and likely pathogenic variants for each gene were aggregated for association analyses. Main Outcomes and Measures: Phenotypes in the eMERGEseq and HCR cohorts were derived from the linked EHRs. Phenotypes in UKB were from multiple sources of health-related data. Results: A total of 214 020 participants were identified, including 23 544 in eMERGEseq cohort (mean [SD] age, 47.8 [23.7] years; 12 611 women [53.6%]), 187 234 in the UKB cohort (mean [SD] age, 56.7 [8.1] years; 104 055 [55.6%] women), and 3242 in the HCR cohort (mean [SD] age, 52.5 [15.5] years; 2851 [87.9%] women). All 38 established gene-cancer associations were replicated, and 19 new associations were identified. These included the following 7 associations with neoplasms: CHEK2 with leukemia (odds ratio [OR], 3.81 [95% CI, 2.64-5.48]) and plasma cell neoplasms (OR, 3.12 [95% CI, 1.84-5.28]), ATM with gastric cancer (OR, 4.27 [95% CI, 2.35-7.44]) and pancreatic cancer (OR, 4.44 [95% CI, 2.66-7.40]), MUTYH (biallelic) with kidney cancer (OR, 32.28 [95% CI, 6.40-162.73]), MSH6 with bladder cancer (OR, 5.63 [95% CI, 2.75-11.49]), and APC with benign liver/intrahepatic bile duct tumors (OR, 52.01 [95% CI, 14.29-189.29]). The remaining 12 associations with nonneoplastic diseases included BRCA1/2 with ovarian cysts (OR, 3.15 [95% CI, 2.22-4.46] and 3.12 [95% CI, 2.36-4.12], respectively), MEN1 with acute pancreatitis (OR, 33.45 [95% CI, 9.25-121.02]), APC with gastritis and duodenitis (OR, 4.66 [95% CI, 2.61-8.33]), and PTEN with chronic gastritis (OR, 15.68 [95% CI, 6.01-40.92]). Conclusions and Relevance: The findings of this genetic association study analyzing the EHRs of 3 large cohorts suggest that these new phenotypes associated with hereditary cancer genes may facilitate early detection and better management of cancers. This study highlights the potential benefits of using EHR data in genomic medicine.


Assuntos
Gastrite , Síndromes Neoplásicas Hereditárias , Pancreatite , Doença Aguda , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Masculino
17.
Front Mol Biosci ; 9: 837971, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35463945

RESUMO

Angiogenin (ANG) is the first human tumor-derived angiogenic protein, which can promote angiogenesis and tumor growth. In a previous study, we identified alpha-actinin 2 (ACTN2), a cytoskeletal protein, as a direct interacting protein with angiogenin. However, the interaction between ANG and ACTN2 was not characterized in detail, which may provide information on the molecular mechanisms of ANG functions. In this study, we mapped the accurate binding domain and sites in ANG and ACTN2, respectively. In ANG, the residues from 83 to 105 are the smallest motif that can bind to ACTN2. We then use site mutation analysis to identify the precise binding sites of ANG in the interaction and found that the 101st residue arginine (R101) represents the critical residue involved in the ANG-ACTN2 interaction. In ACTN2, the residues from 383 to 632, containing two spectrin domains in the middle of the rod structure of ACTN2, play an important role in the interaction. Furthermore, we validated the interaction of ACTN2-383-632 to ANG by glutathione-S-transferase (GST) pull-down assay. In functional analysis, overexpressed ACTN2-383-632 could impair tumor cell motility observably, including cell migration and invasion. Meanwhile, ACTN2-383-632 overexpression inhibited tumor cell proliferation and survival as well. These data suggest that an excess expression of ACTN2 segment ACTN2-383-632 can inhibit tumor cell motility and proliferation by interfering with the interaction between ANG and ACTN2, which provides a potential mechanism of ANG action in tumor growth and metastasis.

18.
Artigo em Inglês | MEDLINE | ID: mdl-35485600

RESUMO

OBJECTIVE: The Genomic Medicine Working Group of the National Advisory Council for Human Genome Research virtually hosted its 13th genomic medicine meeting titled "Developing a Clinical Genomic Informatics Research Agenda". The meeting's goal was to articulate a research strategy to develop Genomics-based Clinical Informatics Tools and Resources (GCIT) to improve the detection, treatment, and reporting of genetic disorders in clinical settings. MATERIALS AND METHODS: Experts from government agencies, the private sector, and academia in genomic medicine and clinical informatics were invited to address the meeting's goals. Invitees were also asked to complete a survey to assess important considerations needed to develop a genomic-based clinical informatics research strategy. RESULTS: Outcomes from the meeting included identifying short-term research needs, such as designing and implementing standards-based interfaces between laboratory information systems and electronic health records, as well as long-term projects, such as identifying and addressing barriers related to the establishment and implementation of genomic data exchange systems that, in turn, the research community could help address. DISCUSSION: Discussions centered on identifying gaps and barriers that impede the use of GCIT in genomic medicine. Emergent themes from the meeting included developing an implementation science framework, defining a value proposition for all stakeholders, fostering engagement with patients and partners to develop applications under patient control, promoting the use of relevant clinical workflows in research, and lowering related barriers to regulatory processes. Another key theme was recognizing pervasive biases in data and information systems, algorithms, access, value, and knowledge repositories and identifying ways to resolve them.

19.
Int J Biol Sci ; 18(4): 1491-1507, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35280687

RESUMO

Clear cell renal cell carcinoma (ccRCC) is a primary kidney cancer with high aggressive phenotype and extremely poor prognosis. Accumulating evidence suggests that circular RNAs (circRNAs) play pivotal roles in the occurrence and development of various human cancers. However, the expression, clinical significance and regulatory role of circRNAs in ccRCC remain largely unclear. Here we report that circDVL1 to be reduced in the serums and tissues from ccRCC patients, and to negatively correlate with ccRCC malignant features. Overexpression of circDVL1 inhibits proliferation, induces G1/S arrest, triggers apoptosis, and reduces migration and invasion in different ccRCC cells in vitro. Correspondingly, circDVL1 overexpression suppresses ccRCC tumorigenicity in a mouse xenograft model. Mechanistically, circDVL1 serves as a sponge for oncogenic miR-412-3p, thereby preventing miR-412-3p-mediated repression of its target protocadherin 7 (PCDH7) in ccRCC cells. Collectively, our results demonstrate that circDVL1 exerts tumor-suppressive function during ccRCC progression through circDVL1/miR-412-3p/PCDH7 axis, and suggest that circDVL1 could be a novel diagnostic and prognositc marker and therapeutic target for ccRCC.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , MicroRNAs , Animais , Caderinas/metabolismo , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias Renais/metabolismo , Masculino , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética
20.
Mol Ther Nucleic Acids ; 27: 1010-1022, 2022 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-35228896

RESUMO

Mature microRNA (miRNA) decay is a key step in miRNA turnover and gene expression regulation. Angiogenin (ANG), the first human tumor-derived angiogenic protein and also a member of the RNase A superfamily, can promote tumor growth and metastasis by regulating rRNA biogenesis and tiRNA production. However, its effect on miRNA has not been explored. In this study, we find that ANG exclusively downregulates mature miR-141 in human umbilical endothelial cells (HUVECs) via its ribonuclease activity and preferably cleaves single-stranded miR-141 at the A5/C6, U7/G8, and U14/A15 sites via endonucleolytic digestion. By downregulating miR-141, ANG promotes HUVECs proliferation, migration, tube formation, and angiogenesis both in vitro and in vivo. Conversely, downregulated ANG inhibits ANG-mediated miR-141 decay, thus decreasing the angiogenesis process of HUVECs. We also find an inverse correlation between ANG and miR-141 expression in colorectal cancer (CRC) tissues. Our study indicates that ANG regulates CRC progression by disrupting miR-141 and its regulation on angiogenesis-related target genes, not only revealing a new mechanism of ANG action but also newly identifying miR-141 as a substrate of ANG. This study suggests that targeting ANG nuclease activity might be valuable in treating angiogenesis-related diseases through coordinately regulating the metabolism of rRNA, tiRNA, and miRNA.

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