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1.
Proc Natl Acad Sci U S A ; 114(36): 9629-9634, 2017 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-28827320

RESUMO

Activating mutations in BRAF are found in 50% of melanomas and although treatment with BRAF inhibitors (BRAFi) is effective, resistance often develops. We now show that recently discovered NRAS isoform 2 is up-regulated in the setting of BRAF inhibitor resistance in melanoma, in both cell lines and patient tumor tissues. When isoform 2 was overexpressed in BRAF mutant melanoma cell lines, melanoma cell proliferation and in vivo tumor growth were significantly increased in the presence of BRAFi treatment. shRNA-mediated knockdown of isoform 2 in BRAFi resistant cells restored sensitivity to BRAFi compared with controls. Signaling analysis indicated decreased mitogen-activated protein kinase (MAPK) pathway signaling and increased phosphoinositol-3-kinase (PI3K) pathway signaling in isoform 2 overexpressing cells compared with isoform 1 overexpressing cells. Immunoprecipitation of isoform 2 validated a binding affinity of this isoform to both PI3K and BRAF/RAF1. The addition of an AKT inhibitor to BRAFi treatment resulted in a partial restoration of BRAFi sensitivity in cells expressing high levels of isoform 2. NRAS isoform 2 may contribute to resistance to BRAFi by facilitating PI3K pathway activation.


Assuntos
GTP Fosfo-Hidrolases/genética , Melanoma/tratamento farmacológico , Melanoma/genética , Proteínas de Membrana/genética , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Movimento Celular , Resistencia a Medicamentos Antineoplásicos/genética , GTP Fosfo-Hidrolases/antagonistas & inibidores , GTP Fosfo-Hidrolases/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Indóis/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Melanoma/metabolismo , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Mutação , Fosfatidilinositol 3-Quinases/metabolismo , Isoformas de Proteínas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Neoplasias Cutâneas/metabolismo , Sulfonamidas/uso terapêutico , Regulação para Cima , Vemurafenib
2.
J Surg Oncol ; 118(3): 501-509, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30132912

RESUMO

BACKGROUND AND OBJECTIVES: MicroRNAs (miRs) are noncoding RNAs that regulate protein translation and melanoma progression. Changes in plasma miR expression following surgical resection of metastatic melanoma are under-investigated. We hypothesize differences in miR expression exist following complete surgical resection of metastatic melanoma. METHODS: Blood collection pre- and post-surgical resection was performed in six individuals with solitary melanoma metastases. miR expression in extracted RNA was quantified using the NanoString nCounter Digital Analyzer. RESULTS: Pre- and post-surgical plasma samples contained 216 miRs with expression above baseline. Comparison of postsurgical to preresection samples revealed differential expression of 25 miRs: miR-let-7a, miR-let7g, miR-15a, miR-16, miR-22, miR-30b, miR-126, miR-140, miR-145, miR-148a, miR-150-5p, miR-191, miR-378i, miR-449c, miR-494, miR-513b, miR-548aa, miR-571, miR-587, miR-891b, miR-1260a, miR 1268a, miR-1976, miR-4268, miR-4454 (P < 0.05). Utilizing P < 0.0046 as a cutoff to control for one false positive among the 216 miRs revealed that postsurgical melanoma plasma samples had upregulation of miR-1260a (P = 0.0007) and downregulation of miR-150-5p (P = 0.0026) relative to pre-surgical samples. CONCLUSIONS: Differential expression of miR-150-5p and miR-1260a is present in plasma following surgical resection of metastatic melanoma in this small sample (n = 6) of melanoma patients. Therefore, further investigation of these plasma miRs as noninvasive biomarkers for melanoma is warranted.


Assuntos
Regulação Neoplásica da Expressão Gênica , Melanoma/genética , MicroRNAs/genética , Recidiva Local de Neoplasia/genética , Idoso , Biomarcadores Tumorais , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Metástase Linfática , Masculino , Melanoma/secundário , Melanoma/cirurgia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Taxa de Sobrevida
3.
J Surg Res ; 205(2): 350-358, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27664883

RESUMO

BACKGROUND: Melanoma skin cancer remains the leading cause of skin cancer-related deaths. Spitz lesions represent a subset of melanocytic skin lesions characterized by epithelioid or spindled melanocytes organized in nests. These lesions occupy a spectrum ranging from benign Spitz and atypical Spitz lesions all the way to malignant Spitz tumors. Appropriate management is reliant on accurate diagnostic classification, yet this effort remains challenging using current light microscopic techniques. The discovery of novel biomarkers such as microRNAs (miR) may ultimately be a useful diagnostic adjunct for the evaluation of Spitz lesions. miR expression profiles have been suggested for non-Spitz melanomas but have yet to be ascribed to Spitz lesions. We hypothesized that distinct miR expression profiles would be associated with different lesions along the Spitz spectrum. MATERIALS AND METHODS: RNAs extracted from paraffin-embedded, formalin-fixed tissues of 11 resected skin lesions including benign nevi (n = 2), benign Spitz lesions (n = 3), atypical Spitz lesions (n = 3), and malignant Spitz tumors (n = 3) were analyzed by the NanoString platform for simultaneous evaluation of over 800 miRs in each patient sample. RESULTS: Benign Spitz lesions had increased expression of miR-21-5p and miR-363-3p compared with those of benign nevi. Malignant Spitz lesions exhibited overexpression of miR-21-5p, miR-155-5p, and miR-1283 relative to both benign nevi and benign Spitz tumors. Notably, atypical Spitz tumors had increased expression of miR-451a and decreased expression of miR-155-5p expression relative to malignant Spitz lesions. Conversely, atypical Spitz lesions had increased expression of miR-21-5p, miR-34a-5p, miR-451a, miR-1283, and miR-1260a relative to benign Spitz tumors. CONCLUSIONS: Overall, distinct miR profiles are suggested among Spitz lesions of varying malignant potential with some similarities to non-Spitz melanoma tumors. This work demonstrates the feasibility of this analytic method and forms the basis for further validation studies.


Assuntos
Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , Nevo de Células Epitelioides e Fusiformes/diagnóstico , Neoplasias Cutâneas/diagnóstico , Transcriptoma , Adolescente , Adulto , Estudos de Casos e Controles , Diagnóstico Diferencial , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Masculino , Nevo de Células Epitelioides e Fusiformes/genética , Neoplasias Cutâneas/genética , Adulto Jovem
4.
PLoS Comput Biol ; 8(1): e1002350, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22291585

RESUMO

Gene expression signatures that are predictive of therapeutic response or prognosis are increasingly useful in clinical care; however, mechanistic (and intuitive) interpretation of expression arrays remains an unmet challenge. Additionally, there is surprisingly little gene overlap among distinct clinically validated expression signatures. These "causality challenges" hinder the adoption of signatures as compared to functionally well-characterized single gene biomarkers. To increase the utility of multi-gene signatures in survival studies, we developed a novel approach to generate "personal mechanism signatures" of molecular pathways and functions from gene expression arrays. FAIME, the Functional Analysis of Individual Microarray Expression, computes mechanism scores using rank-weighted gene expression of an individual sample. By comparing head and neck squamous cell carcinoma (HNSCC) samples with non-tumor control tissues, the precision and recall of deregulated FAIME-derived mechanisms of pathways and molecular functions are comparable to those produced by conventional cohort-wide methods (e.g. GSEA). The overlap of "Oncogenic FAIME Features of HNSCC" (statistically significant and differentially regulated FAIME-derived genesets representing GO functions or KEGG pathways derived from HNSCC tissue) among three distinct HNSCC datasets (pathways:46%, p<0.001) is more significant than the gene overlap (genes:4%). These Oncogenic FAIME Features of HNSCC can accurately discriminate tumors from control tissues in two additional HNSCC datasets (n = 35 and 91, F-accuracy = 100% and 97%, empirical p<0.001, area under the receiver operating characteristic curves = 99% and 92%), and stratify recurrence-free survival in patients from two independent studies (p = 0.0018 and p = 0.032, log-rank). Previous approaches depending on group assignment of individual samples before selecting features or learning a classifier are limited by design to discrete-class prediction. In contrast, FAIME calculates mechanism profiles for individual patients without requiring group assignment in validation sets. FAIME is more amenable for clinical deployment since it translates the gene-level measurements of each given sample into pathways and molecular function profiles that can be applied to analyze continuous phenotypes in clinical outcome studies (e.g. survival time, tumor volume).


Assuntos
Carcinoma de Células Escamosas/genética , Perfilação da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidade , Estudos de Coortes , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Curva ROC
5.
Public Health Rep ; 138(3): 509-517, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36891993

RESUMO

OBJECTIVES: Quarantine after exposure to COVID-19 has resulted in substantial loss of in-person learning in schools from prekindergarten through grade 12. Test to Stay (TTS), a strategy that limits the spread of SARS-CoV-2 while prioritizing in-person learning, requires substantial investment in resources. The objective of this study was to assess the perceived benefits, barriers, and facilitators of implementing TTS in an urban school district in the Midwest serving primarily Black or African American people with low income. METHODS: In December 2021, we used a concurrent mixed-methods approach to understand perceived benefits, barriers, and facilitators of implementing TTS by combining quantitative analysis of telephone surveys conducted with parents (n = 124) and a qualitative inquiry involving key informants from the school district and local health department (n = 22). We analyzed quantitative data using descriptive statistics. We used thematic analysis to analyze qualitative data. RESULTS: Quantitative findings showed that parents supported TTS because it was convenient (n = 83, 97%) and effective (n = 82, 95%) in keeping students learning in person (n = 82, 95%) and preventing the spread of COVID-19 (n = 80, 93%). Qualitative interviews with informants found that having a clear protocol and assigning staff to specified tasks allowed for successful TTS implementation. However, insufficient staffing and testing resources, parent mistrust of testing, and lack of communication from schools were perceived barriers. CONCLUSION: The school community strongly supported TTS despite the many implementation challenges faced. This study emphasized the importance of ensuring resources for equitable implementation of COVID-19 prevention strategies and the critical role of communication.


Assuntos
Negro ou Afro-Americano , Teste para COVID-19 , COVID-19 , Acessibilidade aos Serviços de Saúde , Retorno à Escola , Humanos , COVID-19/diagnóstico , COVID-19/epidemiologia , COVID-19/prevenção & controle , Pobreza , Pesquisa Qualitativa , SARS-CoV-2 , Estados Unidos/epidemiologia
6.
J Exp Biol ; 214(Pt 15): 2560-8, 2011 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-21753050

RESUMO

Teleost fish have oxygen-sensitive neuroepithelial cells (NECs) in the gills that appear to mediate physiological responses to hypoxia, but little is known about oxygen sensing in amphibious fish. The mangrove rivulus, Kryptolebias marmoratus, is an amphibious fish that respires via the gills and/or the skin. First, we hypothesized that both the skin and gills are sites of oxygen sensing in K. marmoratus. Serotonin-positive NECs were abundant in both gills and skin, as determined by immunohistochemical labelling and fluorescence microscopy. NECs retained synaptic vesicles and were found near nerve fibres labelled with the neuronal marker zn-12. Skin NECs were 42% larger than those of the gill, as estimated by measurement of projection area, and 45% greater in number. Moreover, for both skin and gill NECs, NEC area increased significantly (30-60%) following 7 days of exposure to hypoxia (1.5 mg l(-1) dissolved oxygen). Another population of cells containing vesicular acetylcholine transporter (VAChT) proteins were also observed in the skin and gills. The second hypothesis we tested was that K. marmoratus emerse in order to breathe air cutaneously when challenged with severe aquatic hypoxia, and this response will be modulated by neurochemicals associated chemoreceptor activity. Acute exposure to hypoxia induced fish to emerse at 0.2 mg l(-1). When K. marmoratus were pre-exposed to serotonin or acetylcholine, they emersed at a significantly higher concentration of oxygen than untreated fish. Pre-exposure to receptor antagonists (ketanserin and hexamethonium) predictably resulted in fish emersing at a lower concentration of oxygen. Taken together, these results suggest that oxygen sensing occurs at the branchial and/or cutaneous surfaces in K. marmoratus and that serotonin and acetylcholine mediate, in part, the emersion response.


Assuntos
Ciprinodontiformes/fisiologia , Brânquias/fisiologia , Células Neuroepiteliais/citologia , Oxigênio/metabolismo , Respiração , Fenômenos Fisiológicos da Pele , Animais , Células Quimiorreceptoras/citologia , Células Quimiorreceptoras/efeitos dos fármacos , Brânquias/citologia , Hexametônio/farmacologia , Hipóxia/fisiopatologia , Imuno-Histoquímica , Ketanserina/farmacologia , Microscopia de Fluorescência , Células Neuroepiteliais/efeitos dos fármacos , Antagonistas Nicotínicos/farmacologia , Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Pele/citologia , Absorção Cutânea , Proteínas Vesiculares de Transporte de Acetilcolina/metabolismo
7.
BMC Genet ; 11: 35, 2010 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-20441595

RESUMO

BACKGROUND: Idiopathic epilepsy in the Belgian shepherd dog is known to have a substantial genetic component. The objective of this study was to identify genomic regions associated with the expression of generalized seizures in the Belgian Tervuren and Sheepdog. RESULTS: DNA from 366 dogs, of which 74 were classified as epileptic, representing two extended families were subjected to a genome-wide linkage scan using 410 microsatellite markers yielding informative coverage averaging 5.95 +/- 0.21 Mb. Though previous studies based on pedigree analyses proposed a major gene of influence, the present study demonstrated the trait to be highly polygenic. Studies of complex disorders in humans indicate that a liberal composite evaluation of genetic linkage is needed to identify underlying quantitative trait loci (QTLs). Four chromosomes yielded tentative linkage based upon LOD scores in excess of 1.0. Possible QTLs within these regions were supported also by analyses of multipoint linkage, allele frequency, TDT, and transmission of haplotype blocks. CONCLUSIONS: Taken together the data tentatively indicate six QTLs, three on CFA 2, and one on each of CFA 6, 12, and 37, that support fine mapping for mutations associated with epilepsy in the Belgian shepherd. The study also underscores the complexity of genomic linkage studies for polygenic disorders.


Assuntos
Doenças do Cão/genética , Epilepsia/genética , Epilepsia/veterinária , Ligação Genética , Animais , Mapeamento Cromossômico , Cães , Feminino , Masculino , Repetições de Microssatélites , Locos de Características Quantitativas
8.
Am J Vet Res ; 69(2): 222-7, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18241019

RESUMO

OBJECTIVE: To characterize heritability and mode of inheritance of cataracts and primary lens luxation in Jack Russell Terriers. ANIMALS: 872 Jack Russell Terriers from which buccal epithelial cells were collected and phenotypes for cataracts and lens luxation were determined and an additional 1,898 Jack Russell Terriers without phenotypic information used to complete pedigree relationships and that were included in the analyses. PROCEDURES: Narrow-sense heritabilities and genetic correlation for cataracts and lens luxation were modeled by use of threshold analysis, whereas complex segregation analysis was used to characterize mode of inheritance. For the analyses, dogs < 6 years old, unless confirmed as having cataracts or lens luxation, were classified as an unknown phenotype. The possible involvement of an HSF4 mutation in cataracts was determined by DNA sequencing. RESULTS: Cataracts and primary lens luxation were highly heritable and genetically correlated, and neither was controlled by a single gene. Cataracts were not associated with an HSF4 mutation. CONCLUSIONS AND CLINICAL RELEVANCE: Analysis of the data indicated that concerted selection against both cataracts and primary lens luxation when choosing breeding animals can be used to improve ocular health in Jack Russell Terriers.


Assuntos
Catarata/veterinária , Doenças do Cão/genética , Anormalidades do Olho/veterinária , Animais , Catarata/genética , Cães , Anormalidades do Olho/genética , Feminino , Predisposição Genética para Doença , Masculino
9.
AMIA Jt Summits Transl Sci Proc ; 2017: 247-256, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28815138

RESUMO

Computational methods for drug combination predictions are needed to identify effective therapies that improve durability and prevent drug resistance in an efficient manner. In this paper, we present SynGeNet, a computational method that integrates transcriptomics data characterizing disease and drug z-score profiles with network mining algorithms in order to predict synergistic drug combinations. We compare SynGeNet to other available transcriptomics-based tools to predict drug combinations validated across melanoma cell lines in three genotype groups: BRAF-mutant, NRAS-mutant and combined. We showed that SynGeNet outperforms other available tools in predicting validated drug combinations and single agents tested as part of additional drug pairs. Interestingly, we observed that the performance of SynGeNet decreased when the network construction step was removed and improved when the proportion of matched-genotype validation cell lines increased. These results suggest that delineating functional information from transcriptomics data via network mining and genomic features can improve drug combination predictions.

10.
BMC Syst Biol ; 11(Suppl 5): 86, 2017 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-28984195

RESUMO

BACKGROUND: Due to advances in next generation sequencing technologies and corresponding reductions in cost, it is now attainable to investigate genome-wide gene expression and variants at a patient-level, so as to better understand and anticipate heterogeneous responses to therapy. Consequently, it is feasible to inform personalized drug treatment decisions using personal genomics data. However, these efforts are limited due to a lack of reliable computational approaches for predicting effective drugs for individual patients. The reverse gene set enrichment analysis (i.e., connectivity mapping) approach and its variants have been widely and successfully used for drug prediction. However, the performance of these methods is limited by undefined mechanism of action (MoA) of drugs and reliance on cohorts of patients rather than personalized predictions for individual patients. RESULTS: In this study, we have developed and evaluated a computational approach, known as Mechanism and Drug Miner (MD-Miner), using a network-based computational approach to predict effective drugs and reveal potential drug mechanisms of action at the level of signaling pathways. Specifically, the patient-specific signaling network is constructed by integrating known disease associated genes with patient-derived gene expression profiles. In parallel, a drug mechanism of action network is constructed by integrating drug targets and z-score profiles of drug-induced gene expression (pre vs. post-drug treatment). Potentially effective candidate drugs are prioritized according to the number of common genes between the patient-specific dysfunctional signaling network and drug MoA network. We evaluated the MD-Miner method on the PC-3 prostate cancer cell line, and showed that it significantly improved the success rate of discovering effective drugs compared with the random selection, and could provide insight into potential mechanisms of action. CONCLUSIONS: This work provides a signaling network-based drug repositioning approach. Compared with the reverse gene signature based drug repositioning approaches, the proposed method can provide clues of mechanism of action in terms of signaling transduction networks.


Assuntos
Biologia Computacional/métodos , Mineração de Dados/métodos , Reposicionamento de Medicamentos/métodos , Medicina de Precisão/métodos , Linhagem Celular Tumoral , Aprovação de Drogas , Humanos , Transdução de Sinais/efeitos dos fármacos
11.
Bioinform Biol Insights ; 11: 1177932217694837, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28469417

RESUMO

Melanoma remains the leading cause of skin cancer-related deaths. Surgical resection and adjuvant therapies can result in disease-free intervals for stage III and stage IV disease; however, recurrence is common. Understanding microRNA (miR) dynamics following surgical resection of melanomas is critical to accurately interpret miR changes suggestive of melanoma recurrence. Plasma of 6 patients with stage III (n = 2) and stage IV (n = 4) melanoma was evaluated using the NanoString platform to determine pre- and postsurgical miR expression profiles, enabling analysis of more than 800 miRs simultaneously in 12 samples. Principal component analysis detected underlying patterns of miR expression between pre- vs postsurgical patients. Group A contained 3 of 4 patients with stage IV disease (pre- and postsurgical samples) and 2 patients with stage III disease (postsurgical samples only). The corresponding preoperative samples to both individuals with stage III disease were contained in group B along with 1 individual with stage IV disease (pre- and postsurgical samples). Group A was distinguished from group B by statistically significant analysis of variance changes in miR expression (P < <0001). This analysis revealed that group A vs group B had downregulation of let-7b-5p, miR-520f, miR-720, miR-4454, miR-21-5p, miR-22-3p, miR-151a-3p, miR-378e, and miR-1283 and upregulation of miR-126-3p, miR-223-3p, miR-451a, let-7a-5p, let-7g-5p, miR-15b-5p, miR-16-5p, miR-20a-5p, miR-20b-5p, miR-23a-3p, miR-26a-5p, miR-106a-5p, miR-17-5p, miR-130a-3p, miR-142-3p, miR-150-5p, miR-191-5p, miR-199a-3p, miR-199b-3p, and miR-1976. Changes in miR expression were not readily evident in individuals with distant metastatic disease (stage IV) as these individuals may have prolonged inflammatory responses. Thus, inflammatory-driven miRs coinciding with tumor-derived miRs can blunt anticipated changes in expression profiles following surgical resection.

12.
J Vis Exp ; (118)2016 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-28060329

RESUMO

The promise of drug repurposing is that existing drugs may be used for new disease indications in order to curb the high costs and time for approval. The goal of computational methods for drug repurposing is to enable solutions for safer, cheaper and faster drug discovery. Towards this end, we developed a novel method that integrates genetic and clinical phenotype data from large-scale GWAS and PheWAS studies with detailed drug information on the concept of transitive Drug-Gene-Disease triads. We created "RE:fine Drugs," a freely available, interactive dashboard that automates gene, disease and drug-based searches to identify drug repurposing candidates. This web-based tool supports a user-friendly interface that includes an array of advanced search and export options. Results can be prioritized in a variety of ways, including but not limited to, biomedical literature support, strength and statistical significance of GWAS and/or PheWAS associations, disease indications and molecular drug targets. Here we provide a protocol that illustrates the functionalities available in the "RE:fine Drugs" system and explores the different advanced options through a case study.


Assuntos
Descoberta de Drogas , Reposicionamento de Medicamentos , Humanos , Software
13.
AMIA Annu Symp Proc ; 2016: 1149-1158, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28269912

RESUMO

Clinical trial coordinators refer to both structured and unstructured sources of data when evaluating a subject for eligibility. While some eligibility criteria can be resolved using structured data, some require manual review of clinical notes. An important step in automating the trial screening process is to be able to identify the right data source for resolving each criterion. In this work, we discuss the creation of an eligibility criteria dataset for clinical trials for patients with two disparate diseases, annotated with the preferred data source for each criterion (i.e., structured or unstructured) by annotators with medical training. The dataset includes 50 heart-failure trials with a total of 766 eligibility criteria and 50 trials for chronic lymphocytic leukemia (CLL) with 677 criteria. Further, we developed machine learning models to predict the preferred data source: kernel methods outperform simpler learning models when used with a combination of lexical, syntactic, semantic, and surface features. Evaluation of these models indicates that the performance is consistent across data from both diagnoses, indicating generalizability of our method. Our findings are an important step towards ongoing efforts for automation of clinical trial screening.


Assuntos
Ensaios Clínicos como Assunto , Registros Eletrônicos de Saúde , Processamento de Linguagem Natural , Seleção de Pacientes , Definição da Elegibilidade/métodos , Insuficiência Cardíaca , Humanos , Armazenamento e Recuperação da Informação , Leucemia Linfocítica Crônica de Células B , Aprendizado de Máquina
14.
Artigo em Inglês | MEDLINE | ID: mdl-27189611

RESUMO

The process of discovering new drugs has been extremely costly and slow in the last decades despite enormous investment in pharmaceutical research. Drug repurposing enables researchers to speed up the process of discovering other conditions that existing drugs can effectively treat, with low cost and fast FDA approval. Here, we introduce 'RE:fine Drugs', a freely available interactive website for integrated search and discovery of drug repurposing candidates from GWAS and PheWAS repurposing datasets constructed using previously reported methods in Nature Biotechnology. 'RE:fine Drugs' demonstrates the possibilities to identify and prioritize novelty of candidates for drug repurposing based on the theory of transitive Drug-Gene-Disease triads. This public website provides a starting point for research, industry, clinical and regulatory communities to accelerate the investigation and validation of new therapeutic use of old drugs.Database URL: http://drug-repurposing.nationwidechildrens.org.


Assuntos
Biologia Computacional/métodos , Bases de Dados de Produtos Farmacêuticos , Reposicionamento de Medicamentos , Interface Usuário-Computador , Tratamento Farmacológico , Humanos
15.
Onco Targets Ther ; 9: 5931-5941, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27729802

RESUMO

BACKGROUND: MicroRNAs (miRNAs) are short noncoding RNAs that function to repress translation of mRNA transcripts and contribute to the development of cancer. We hypothesized that miRNA array-based technologies work best for miRNA profiling of patient-derived plasma samples when the techniques and patient populations are precisely defined. METHODS: Plasma samples were obtained from five sources: melanoma clinical trial of interferon and bortezomib (12), purchased normal donor plasma samples (four), gastrointestinal tumor bank (nine), melanoma tumor bank (ten), or aged-matched normal donors (eight) for the tumor bank samples. Plasma samples were purified for miRNAs and quantified using NanoString® arrays or by the company Exiqon. Standard biostatistical array approaches were utilized for data analysis and compared to a rank-based analytical approach. RESULTS: With the prospectively collected samples, fewer plasma samples demonstrated visible hemolysis due to increased attention to eliminating factors, such as increased pressure during phlebotomy, small gauge needles, and multiple punctures. Cancer patients enrolled in a melanoma clinical study exhibited the clearest pattern of miRNA expression as compared to normal donors in both the rank-based analytical method and standard biostatistical array approaches. For the patients from the tumor banks, fewer miRNAs (<5) were found to be differentially expressed and the false positive rate was relatively high. CONCLUSION: In order to obtain consistent results for NanoString miRNA arrays, it is imperative that patient cohorts have similar clinical characteristics with a uniform sample preparation procedure. A clinical workflow has been optimized to collect patient samples to study plasma miRNAs.

16.
Stud Health Technol Inform ; 216: 663-7, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26262134

RESUMO

The worldwide incidence of melanoma is rising faster than any other cancer, and prognosis for patients with metastatic disease is poor. Current targeted therapies are limited in their durability and/or effect size in certain patient populations due to acquired mechanisms of resistance. Thus, the development of synergistic combinatorial treatment regimens holds great promise to improve patient outcomes. We have previously shown that a model for in-silico knowledge discovery, Translational Ontology-anchored Knowledge Discovery Engine (TOKEn), is able to generate valid relationships between bimolecular and clinical phenotypes. In this study, we have aggregated observational and canonical knowledge consisting of melanoma-related biomolecular entities and targeted therapeutics in a computationally tractable model. We demonstrate here that the explicit linkage of therapeutic modalities with biomolecular underpinnings of melanoma utilizing the TOKEn pipeline yield a set of informed relationships that have the potential to generate combination therapy strategies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sistemas de Informação em Farmácia Clínica/organização & administração , Bases de Dados de Produtos Farmacêuticos/classificação , Bases de Conhecimento , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/classificação , Mineração de Dados/métodos , Sistemas de Apoio a Decisões Clínicas/organização & administração , Aprendizado de Máquina , Melanoma/classificação , Processamento de Linguagem Natural , Neoplasias Cutâneas/classificação
17.
Stud Health Technol Inform ; 216: 414-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26262083

RESUMO

Liver cancer, the fifth most common cancer and second leading cause of cancer-related death among men worldwide, is plagued by not only lack of clinical research, but informatics tools for early detection. Consequently, it presents a major health and cost burden. Among the different types of liver cancer, hepatocellular carcinoma (HCC) is the most common and deadly form, arising from underlying liver disease. Current models for predicting risk of HCC and liver disease are limited to clinical data. A domain analysis of existing research related to screening for HCC and liver disease suggests that metabolic syndrome (MetS) may present oppportunites to detect early signs of liver disease. The purpose of this paper is to (i) provide a domain analysis of the relationship between HCC, liver disease, and metabolic syndrome, (ii) a review of the current disparate sources of data available for MetS diagnosis, and (iii) recommend informatics solutions for the diagnosis of MetS from available administrative (Biometrics, PHA, claims) and laboratory data, towards early prediction of liver disease. Our domain analysis and recommendations incorporate best practices to make meaningful use of available data with the goal of reducing cost associated with liver disease.


Assuntos
Carcinoma Hepatocelular/economia , Mineração de Dados/métodos , Detecção Precoce de Câncer/economia , Custos de Cuidados de Saúde/estatística & dados numéricos , Neoplasias Hepáticas/economia , Síndrome Metabólica/economia , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/epidemiologia , Causalidade , Controle de Custos/economia , Controle de Custos/métodos , Detecção Precoce de Câncer/métodos , Registros Eletrônicos de Saúde/estatística & dados numéricos , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/epidemiologia , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/epidemiologia , Prevalência , Medição de Risco/métodos , Integração de Sistemas , Estados Unidos/epidemiologia
18.
BMC Med Genomics ; 8: 66, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26470881

RESUMO

BACKGROUND: Traditionally, the CD56(dim)CD16(+) subset of Natural Killer (NK) cells has been thought to mediate cellular cytotoxicity with modest cytokine secretion capacity. However, studies have suggested that this subset may exert a more diverse array of immunological functions. There exists a lack of well-developed functional models to describe the behavior of activated NK cells, and the interactions between signaling pathways that facilitate effector functions are not well understood. In the present study, a combination of genome-wide microarray analyses and systems-level bioinformatics approaches were utilized to elucidate the transcriptional landscape of NK cells activated via interactions with antibody-coated targets in the presence of interleukin-12 (IL-12). METHODS: We conducted differential gene expression analysis of CD56(dim)CD16(+) NK cells following FcR stimulation in the presence or absence of IL-12. Next, we functionally characterized gene sets according to patterns of gene expression and validated representative genes using RT-PCR. IPA was utilized for biological pathway analysis, and an enriched network of interacting genes was generated using GeneMANIA. Furthermore, PAJEK and the HITS algorithm were employed to identify important genes in the network according to betweeness centrality, hub, and authority node metrics. RESULTS: Analyses revealed that CD56(dim)CD16(+) NK cells co-stimulated via the Fc receptor (FcR) and IL-12R led to the expression of a unique set of genes, including genes encoding cytotoxicity receptors, apoptotic proteins, intracellular signaling molecules, and cytokines that may mediate enhanced cytotoxicity and interactions with other immune cells within inflammatory tissues. Network analyses identified a novel set of connected key players, BATF, IRF4, TBX21, and IFNG, within an integrated network composed of differentially expressed genes in NK cells stimulated by various conditions (immobilized IgG, IL-12, or the combination of IgG and IL-12). CONCLUSIONS: These results are the first to address the global mechanisms by which NK cells mediate their biological functions when encountering antibody-coated targets within inflammatory sites. Moreover, this study has identified a set of high-priority targets for subsequent investigation into strategies to combat cancer by enhancing the anti-tumor activity of CD56(dim)CD16(+) NK cells.


Assuntos
Interleucina-12/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Receptores Fc/metabolismo , Transcriptoma/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Genômica , Humanos , Imunoglobulina G/imunologia , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Análise de Sequência com Séries de Oligonucleotídeos
19.
BMC Med Genomics ; 7 Suppl 1: S2, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25079962

RESUMO

BACKGROUND: The current state of the art for measuring stromal response to targeted therapy requires burdensome and rate limiting quantitative histology. Transcriptome measures are increasingly affordable and provide an opportunity for developing a stromal versus cancer ratio in xenograft models. In these models, human cancer cells are transplanted into mouse host tissues (stroma) and together coevolve into a tumour microenvironment. However, profiling the mouse or human component separately remains problematic. Indeed, laser capture microdissection is labour intensive. Moreover, gene expression using commercial microarrays introduces significant and underreported cross-species hybridization errors that are commonly overlooked by biologists. METHOD: We developed a customized dual-species array, H&M array, and performed cross-species and species-specific hybridization measurements. We validated a new methodology for establishing the stroma vs cancer ratio using transcriptomic data. RESULTS: In the biological validation of the H&M array, cross-species hybridization of human and mouse probes was significantly reduced (4.5 and 9.4 fold reduction, respectively; p < 2x10-16 for both, Mann-Whitney test). We confirmed the capability of the H&M array to determine the stromal to cancer cells ratio based on the estimation of cellularity index of mouse/human mRNA content in vitro. This new metrics enable to investigate more efficiently the stroma-cancer cell interactions (e.g. cellularity) bypassing labour intensive requirement and biases of laser capture microdissection. CONCLUSION: These results provide the initial evidence of improved and cost-efficient analytics for the investigation of cancer cell microenvironment, using species-specificity arrays specifically designed for xenografts models.


Assuntos
Transformação Celular Neoplásica , Perfilação da Expressão Gênica , Genômica/métodos , Terapia de Alvo Molecular , Neoplasias/genética , Neoplasias/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Humanos , Camundongos , Anotação de Sequência Molecular , Neoplasias/tratamento farmacológico , Hibridização de Ácido Nucleico , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Especificidade da Espécie , Células Estromais/metabolismo , Células Estromais/patologia , Microambiente Tumoral
20.
J Am Med Inform Assoc ; 20(4): 619-29, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23355459

RESUMO

BACKGROUND: While genome-wide association studies (GWAS) of complex traits have revealed thousands of reproducible genetic associations to date, these loci collectively confer very little of the heritability of their respective diseases and, in general, have contributed little to our understanding the underlying disease biology. Physical protein interactions have been utilized to increase our understanding of human Mendelian disease loci but have yet to be fully exploited for complex traits. METHODS: We hypothesized that protein interaction modeling of GWAS findings could highlight important disease-associated loci and unveil the role of their network topology in the genetic architecture of diseases with complex inheritance. RESULTS: Network modeling of proteins associated with the intragenic single nucleotide polymorphisms of the National Human Genome Research Institute catalog of complex trait GWAS revealed that complex trait associated loci are more likely to be hub and bottleneck genes in available, albeit incomplete, networks (OR=1.59, Fisher's exact test p < 2.24 × 10(-12)). Network modeling also prioritized novel type 2 diabetes (T2D) genetic variations from the Finland-USA Investigation of Non-Insulin-Dependent Diabetes Mellitus Genetics and the Wellcome Trust GWAS data, and demonstrated the enrichment of hubs and bottlenecks in prioritized T2D GWAS genes. The potential biological relevance of the T2D hub and bottleneck genes was revealed by their increased number of first degree protein interactions with known T2D genes according to several independent sources (p<0.01, probability of being first interactors of known T2D genes). CONCLUSION: Virtually all common diseases are complex human traits, and thus the topological centrality in protein networks of complex trait genes has implications in genetics, personal genomics, and therapy.


Assuntos
Estudo de Associação Genômica Ampla , Modelos Genéticos , Mapas de Interação de Proteínas/genética , Biologia Computacional/métodos , Humanos , Polimorfismo de Nucleotídeo Único , Mapeamento de Interação de Proteínas
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