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1.
Sci Data ; 11(1): 892, 2024 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-39152166

RESUMO

Next-generation sequencing (NGS) has revolutionized genomic research by enabling high-throughput, cost-effective genome and transcriptome sequencing accelerating personalized medicine for complex diseases, including cancer. Whole genome/transcriptome sequencing (WGS/WTS) provides comprehensive insights, while targeted sequencing is more cost-effective and sensitive. In comparison to short-read sequencing, which still dominates the field due to high speed and cost-effectiveness, long-read sequencing can overcome alignment limitations and better discriminate similar sequences from alternative transcripts or repetitive regions. Hybrid sequencing combines the best strengths of different technologies for a more comprehensive view of genomic/transcriptomic variations. Understanding each technology's strengths and limitations is critical for translating cutting-edge technologies into clinical applications. In this study, we sequenced DNA and RNA libraries of reference samples using various targeted DNA and RNA panels and the whole transcriptome on both short-read and long-read platforms. This study design enables a comprehensive analysis of sequencing technologies, targeting protocols, and library preparation methods. Our expanded profiling landscape establishes a reference point for assessing current sequencing technologies, facilitating informed decision-making in genomic research and precision medicine.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Humanos , RNA-Seq , Análise de Sequência de DNA/métodos , Transcriptoma , Análise de Sequência de RNA , Medicina de Precisão
2.
medRxiv ; 2023 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-38076828

RESUMO

Vertebrates differ greatly in responses to pro-inflammatory agonists such as bacterial lipopolysaccharide (LPS), complicating use of animal models to study human sepsis or inflammatory disorders. We compared transcriptomes of resting and LPS-exposed blood from six LPS-sensitive species (rabbit, pig, sheep, cow, chimpanzee, human) and four LPS-resilient species (mice, rats, baboon, rhesus), as well as plasma proteomes and lipidomes. Unexpectedly, at baseline, sensitive species already had enhanced expression of LPS-responsive genes relative to resilient species. After LPS stimulation, maximally different genes in resilient species included genes that detoxify LPS, diminish bacterial growth, discriminate sepsis from SIRS, and play roles in autophagy and apoptosis. The findings reveal the molecular landscape of species differences in inflammation, and may inform better selection of species for pre-clinical models.

3.
Infect Dis (Lond) ; 55(10): 694-705, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37395107

RESUMO

OBJECTIVES: We examined the temporal changes of the CSF proteome in patients with herpes simplex encephalitis (HSE) during the course of the disease, in relation to anti-N-methyl-D-aspartate receptor (NMDAR) serostatus, corticosteroid treatment, brain MRI and neurocognitive performance. METHODS: Patients were retrospectively included from a previous prospective trial with a pre-specified CSF sampling protocol. Mass spectrometry data of the CSF proteome were processed using pathway analysis. RESULTS: We included 48 patients (110 CSF samples). Samples were grouped based on time of collection relative to hospital admission - T1: ≤ 9 d, T2: 13-28 d, T3: ≥ 68 d. At T1, a strong multi-pathway response was seen including acute phase response, antimicrobial pattern recognition, glycolysis and gluconeogenesis. At T2, most pathways activated at T1 were no longer significantly different from T3. After correction for multiplicity and considering the effect size threshold, 6 proteins were significantly less abundant in anti-NMDAR seropositive patients compared to seronegative: procathepsin H, heparin cofactor 2, complement factor I, protein AMBP, apolipoprotein A1 and polymeric immunoglobulin receptor. No significant differences in individual protein levels were found in relation to corticosteroid treatment, size of brain MRI lesion or neurocognitive performance. CONCLUSIONS: We show a temporal change in the CSF proteome in HSE patients during the course of the disease. This study provides insight into quantitative and qualitative aspects of the dynamic pathophysiology and pathway activation patterns in HSE and prompts for future studies on the role of apolipoprotein A1 in HSE, which has previously been associated with NMDAR encephalitis.


Assuntos
Encefalite por Herpes Simples , Doenças do Sistema Nervoso , Humanos , Encefalite por Herpes Simples/complicações , Encefalite por Herpes Simples/patologia , Proteoma , Apolipoproteína A-I , Estudos Retrospectivos
5.
Genome Biol ; 23(1): 141, 2022 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-35768876

RESUMO

BACKGROUND: Clinical laboratories routinely use formalin-fixed paraffin-embedded (FFPE) tissue or cell block cytology samples in oncology panel sequencing to identify mutations that can predict patient response to targeted therapy. To understand the technical error due to FFPE processing, a robustly characterized diploid cell line was used to create FFPE samples with four different pre-tissue processing formalin fixation times. A total of 96 FFPE sections were then distributed to different laboratories for targeted sequencing analysis by four oncopanels, and variants resulting from technical error were identified. RESULTS: Tissue sections that fail more frequently show low cellularity, lower than recommended library preparation DNA input, or target sequencing depth. Importantly, sections from block surfaces are more likely to show FFPE-specific errors, akin to "edge effects" seen in histology, while the inner samples display no quality degradation related to fixation time. CONCLUSIONS: To assure reliable results, we recommend avoiding the block surface portion and restricting mutation detection to genomic regions of high confidence.


Assuntos
Formaldeído , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Inclusão em Parafina , Análise de Sequência de DNA , Fixação de Tecidos
6.
Chest ; 162(5): 1116-1126, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35526605

RESUMO

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by intractable fatigue, postexertional malaise, and orthostatic intolerance, but its pathophysiology is poorly understood. Pharmacologic cholinergic stimulation was used to test the hypothesis that neurovascular dysregulation underlies exercise intolerance in ME/CFS. RESEARCH QUESTION: Does neurovascular dysregulation contribute to exercise intolerance in ME/CFS, and can its treatment improve exercise capacity? STUDY DESIGN AND METHODS: Forty-five subjects with ME/CFS were enrolled in a single-center, randomized, double-blind, placebo-controlled trial. Subjects were assigned in a 1:1 ratio to receive a 60-mg dose of oral pyridostigmine or placebo after an invasive cardiopulmonary exercise test (iCPET). A second iCPET was performed 50 min later. The primary end point was the difference in peak exercise oxygen uptake (Vo2). Secondary end points included exercise pulmonary and systemic hemodynamics and gas exchange. RESULTS: Twenty-three subjects were assigned to receive pyridostigmine and 22 to receive placebo. The peak Vo2 increased after pyridostigmine but decreased after placebo (13.3 ± 13.4 mL/min vs -40.2 ± 21.3 mL/min; P < .05). The treatment effect of pyridostigmine was 53.6 mL/min (95% CI, -105.2 to -2.0). Peak vs rest Vo2 (25.9 ± 15.3 mL/min vs -60.8 ± 25.6 mL/min; P < .01), cardiac output (-0.2 ± 0.6 L/min vs -1.9 ± 0.6 L/min; P < .05), and right atrial pressure (1.0 ± 0.5 mm Hg vs -0.6 ± 0.5 mm Hg; P < .05) were greater in the pyridostigmine group compared with placebo. INTERPRETATION: Pyridostigmine improves peak Vo2 in ME/CFS by increasing cardiac output and right ventricular filling pressures. Worsening peak exercise Vo2, cardiac output, and right atrial pressure following placebo may signal the onset of postexertional malaise. We suggest that treatable neurovascular dysregulation underlies acute exercise intolerance in ME/CFS. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT03674541; URL: www. CLINICALTRIALS: gov.


Assuntos
Síndrome de Fadiga Crônica , Humanos , Síndrome de Fadiga Crônica/tratamento farmacológico , Brometo de Piridostigmina/uso terapêutico , Exercício Físico/fisiologia , Teste de Esforço
7.
Aging Cell ; 21(4): e13595, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35343058

RESUMO

Although it is well known that metabolic control plays a crucial role in regulating the health span and life span of various organisms, little is known for the systems metabolic profile of centenarians, the paradigm of human healthy aging and longevity. Meanwhile, how to well characterize the system-level metabolic states in an organism of interest remains to be a major challenge in systems metabolism research. To address this challenge and better understand the metabolic mechanisms of healthy aging, we developed a method of genome-wide precision metabolic modeling (GPMM) which is able to quantitatively integrate transcriptome, proteome and kinetome data in predictive modeling of metabolic networks. Benchmarking analysis showed that GPMM successfully characterized metabolic reprogramming in the NCI-60 cancer cell lines; it dramatically improved the performance of the modeling with an R2 of 0.86 between the predicted and experimental measurements over the performance of existing methods. Using this approach, we examined the metabolic networks of a Chinese centenarian cohort and identified the elevated fatty acid oxidation (FAO) as the most significant metabolic feature in these long-lived individuals. Evidence from serum metabolomics supports this observation. Given that FAO declines with normal aging and is impaired in many age-related diseases, our study suggests that the elevated FAO has potential to be a novel signature of healthy aging of humans.


Assuntos
Envelhecimento Saudável , Longevidade , Idoso de 80 Anos ou mais , Envelhecimento/genética , Envelhecimento/metabolismo , Humanos , Longevidade/genética , Metabolômica , Transcriptoma/genética
8.
Genome Biol ; 23(1): 2, 2022 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-34980216

RESUMO

BACKGROUND: Reproducible detection of inherited variants with whole genome sequencing (WGS) is vital for the implementation of precision medicine and is a complicated process in which each step affects variant call quality. Systematically assessing reproducibility of inherited variants with WGS and impact of each step in the process is needed for understanding and improving quality of inherited variants from WGS. RESULTS: To dissect the impact of factors involved in detection of inherited variants with WGS, we sequence triplicates of eight DNA samples representing two populations on three short-read sequencing platforms using three library kits in six labs and call variants with 56 combinations of aligners and callers. We find that bioinformatics pipelines (callers and aligners) have a larger impact on variant reproducibility than WGS platform or library preparation. Single-nucleotide variants (SNVs), particularly outside difficult-to-map regions, are more reproducible than small insertions and deletions (indels), which are least reproducible when > 5 bp. Increasing sequencing coverage improves indel reproducibility but has limited impact on SNVs above 30×. CONCLUSIONS: Our findings highlight sources of variability in variant detection and the need for improvement of bioinformatics pipelines in the era of precision medicine with WGS.


Assuntos
Genoma Humano , Polimorfismo de Nucleotídeo Único , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação INDEL , Reprodutibilidade dos Testes , Sequenciamento Completo do Genoma
9.
Drug Discov Today ; 27(1): 337-346, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34607018

RESUMO

Drug labeling informs physicians and patients on the safe and effective use of medication. However, recent studies suggested discrepancies in labeling of the same drug between different regulatory agencies. Here, we evaluated the hepatic safety information in labeling for 549 medications approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Limited discrepancies were found regarding risk for hepatic adverse drug reactions (ADRs) (8.7% in hepatic ADR warnings and 21.3% in contraindication for liver disease), while caution should be exercised over drugs with inconsistencies in contraindications for liver disease and evidence for hepatotoxicity (4.9%). Most discrepancies were attributable to less-severe hepatic events and low-frequency hepatic ADR reports and had limited implication on clinical outcomes.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Rotulagem de Medicamentos , Gestão da Segurança , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Aprovação de Drogas/estatística & dados numéricos , Rotulagem de Medicamentos/métodos , Rotulagem de Medicamentos/normas , União Europeia/estatística & dados numéricos , Humanos , Gestão da Segurança/métodos , Gestão da Segurança/organização & administração , Gestão da Segurança/estatística & dados numéricos , Estados Unidos
10.
Healthcare (Basel) ; 9(10)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34682970

RESUMO

One in four myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients are estimated to be severely affected by the disease, and these house-bound or bedbound patients are currently understudied. Here, we report a comprehensive examination of the symptoms and clinical laboratory tests of a cohort of severely ill patients and healthy controls. The greatly reduced quality of life of the patients was negatively correlated with clinical depression. The most troublesome symptoms included fatigue (85%), pain (65%), cognitive impairment (50%), orthostatic intolerance (45%), sleep disturbance (35%), post-exertional malaise (30%), and neurosensory disturbance (30%). Sleep profiles and cognitive tests revealed distinctive impairments. Lower morning cortisol level and alterations in its diurnal rhythm were observed in the patients, and antibody and antigen measurements showed no evidence for acute infections by common viral or bacterial pathogens. These results highlight the urgent need of developing molecular diagnostic tests for ME/CFS. In addition, there was a striking similarity in symptoms between long COVID and ME/CFS, suggesting that studies on the mechanism and treatment of ME/CFS may help prevent and treat long COVID and vice versa.

11.
Am J Infect Control ; 49(12): 1457-1463, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34536502

RESUMO

BACKGROUND: Despite several outbreaks of SARS-CoV-2 amongst healthcare personnel (HCP) exposed to COVID-19 patients globally, risk factors for transmission remain poorly understood. METHODS: We conducted an outbreak investigation and case-control study to evaluate SARS-CoV-2 transmission risk in an outbreak among HCP at an academic medical center in California that was confirmed by whole genome sequencing. RESULTS: A total of 7/9 cases and 93/182 controls completed a voluntary survey about risk factors. Compared to controls, cases reported significantly more patient contact time. Cases were also significantly more likely to have performed airway procedures on the index patient, particularly placing the patient on high flow nasal cannula, continuous positive airway pressure (CPAP), or bilevel positive airway pressure (BiPAP) (OR = 11.6; 95% CI = 1.7 -132.1). DISCUSSION: This study highlights the risk of nosocomial infection of SARS-CoV-2 from patients who become infectious midway into their hospitalization. Our findings also reinforce the importance of patient contact time and aerosol-generating procedures as key risk factors for HCP infection with SARS-CoV-2. CONCLUSIONS: Re-testing patients for SARS-CoV-2 after admission in suspicious cases and using N95 masks for all aerosol-generating procedures regardless of initial patient SARS-CoV-2 test results can help reduce the risk of SARS-COV-2 transmission to HCP.


Assuntos
COVID-19 , SARS-CoV-2 , Estudos de Casos e Controles , Atenção à Saúde , Surtos de Doenças , Pessoal de Saúde , Humanos , Fatores de Risco , Centros de Atenção Terciária
12.
BMC Bioinformatics ; 21(1): 409, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938389

RESUMO

An amendment to this paper has been published and can be accessed via the original article.

13.
Nucleic Acids Res ; 48(15): 8320-8331, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32749457

RESUMO

The rat is an important model organism in biomedical research for studying human disease mechanisms and treatments, but its annotated transcriptome is far from complete. We constructed a Rat Transcriptome Re-annotation named RTR using RNA-seq data from 320 samples in 11 different organs generated by the SEQC consortium. Totally, there are 52 807 genes and 114 152 transcripts in RTR. Transcribed regions and exons in RTR account for ∼42% and ∼6.5% of the genome, respectively. Of all 73 074 newly annotated transcripts in RTR, 34 213 were annotated as high confident coding transcripts and 24 728 as high confident long noncoding transcripts. Different tissues rather than different stages have a significant influence on the expression patterns of transcripts. We also found that 11 715 genes and 15 852 transcripts were expressed in all 11 tissues and that 849 house-keeping genes expressed different isoforms among tissues. This comprehensive transcriptome is freely available at http://www.unimd.org/rtr/. Our new rat transcriptome provides essential reference for genetics and gene expression studies in rat disease and toxicity models.


Assuntos
Genoma/genética , Anotação de Sequência Molecular , RNA-Seq/métodos , Transcriptoma/genética , Processamento Alternativo/genética , Animais , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Ratos , Sequenciamento do Exoma
14.
J Mol Diagn ; 22(6): 770-781, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32247862

RESUMO

Circulating tumor cells (CTCs) have a great potential for noninvasive diagnosis and real-time monitoring of cancer. A comprehensive evaluation of four whole genome amplification (WGA)/next-generation sequencing workflows for genomic analysis of single CTCs, including PCR-based (GenomePlex and Ampli1), multiple displacement amplification (Repli-g), and hybrid PCR- and multiple displacement amplification-based [multiple annealing and loop-based amplification cycling (MALBAC)] is reported herein. To demonstrate clinical utilities, copy number variations (CNVs) in single CTCs isolated from four patients with squamous non-small-cell lung cancer were profiled. Results indicate that MALBAC and Repli-g WGA have significantly broader genomic coverage compared with GenomePlex and Ampli1. Furthermore, MALBAC coupled with low-pass whole genome sequencing has better coverage breadth, uniformity, and reproducibility and is superior to Repli-g for genome-wide CNV profiling and detecting focal oncogenic amplifications. For mutation analysis, none of the WGA methods were found to achieve sufficient sensitivity and specificity by whole exome sequencing. Finally, profiling of single CTCs from patients with non-small-cell lung cancer revealed potentially clinically relevant CNVs. In conclusion, MALBAC WGA coupled with low-pass whole genome sequencing is a robust workflow for genome-wide CNV profiling at single-cell level and has great potential to be applied in clinical investigations. Nevertheless, data suggest that none of the evaluated single-cell sequencing workflows can reach sufficient sensitivity or specificity for mutation detection required for clinical applications.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Variações do Número de Cópias de DNA , Neoplasias Pulmonares/genética , Células Neoplásicas Circulantes/metabolismo , Análise de Célula Única/métodos , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/patologia , Análise Mutacional de DNA/métodos , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologia , Células PC-3 , Reação em Cadeia da Polimerase/métodos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Sequenciamento Completo do Genoma/métodos
15.
BMC Bioinformatics ; 21(1): 67, 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32085724

RESUMO

BACKGROUND: Constraint-based metabolic modeling has been applied to understand metabolism related disease mechanisms, to predict potential new drug targets and anti-metabolites, and to identify biomarkers of complex diseases. Although the state-of-art modeling toolbox, COBRA 3.0, is powerful, it requires substantial computing time conducting flux balance analysis, knockout analysis, and Markov Chain Monte Carlo (MCMC) sampling, which may limit its application in large scale genome-wide analysis. RESULTS: Here, we rewrote the underlying code of COBRA 3.0 using C/C++, and developed a toolbox, termed FastMM, to effectively conduct constraint-based metabolic modeling. The results showed that FastMM is 2~400 times faster than COBRA 3.0 in performing flux balance analysis and knockout analysis and returns consistent outputs. When applied to MCMC sampling, FastMM is 8 times faster than COBRA 3.0. FastMM is also faster than some efficient metabolic modeling applications, such as Cobrapy and Fast-SL. In addition, we developed a Matlab/Octave interface for fast metabolic modeling. This interface was fully compatible with COBRA 3.0, enabling users to easily perform complex applications for metabolic modeling. For example, users who do not have deep constraint-based metabolic model knowledge can just type one command in Matlab/Octave to perform personalized metabolic modeling. Users can also use the advance and multiple threading parameters for complex metabolic modeling. Thus, we provided an efficient and user-friendly solution to perform large scale genome-wide metabolic modeling. For example, FastMM can be applied to the modeling of individual cancer metabolic profiles of hundreds to thousands of samples in the Cancer Genome Atlas (TCGA). CONCLUSION: FastMM is an efficient and user-friendly toolbox for large-scale personalized constraint-based metabolic modeling. It can serve as a complementary and invaluable improvement to the existing functionalities in COBRA 3.0. FastMM is under GPL license and can be freely available at GitHub site: https://github.com/GonghuaLi/FastMM.


Assuntos
Redes e Vias Metabólicas , Software , Genoma , Humanos , Modelos Biológicos , Neoplasias/genética , Neoplasias/metabolismo
17.
Sci China Life Sci ; 62(7): 895-904, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31114935

RESUMO

High-throughput next generation sequencing (NGS) is a shotgun approach applied in a parallel fashion by which the genome is fragmented and sequenced through small pieces and then analyzed either by aligning to a known reference genome or by de novo assembly without reference genome. This technology has led researchers to conduct an explosion of sequencing related projects in multidisciplinary fields of science. However, due to the limitations of sequencing-based chemistry, length of sequencing reads and the complexity of genes, it is difficult to determine the sequences of some portions of the human genome, leaving gaps in genomic data that frustrate further analysis. Particularly, some complex genes are difficult to be accurately sequenced or mapped because they contain high GC-content and/or low complexity regions, and complicated pseudogenes, such as the genes encoding xenobiotic metabolizing enzymes and transporters (XMETs). The genetic variants in XMET genes are critical to predicate inter-individual variability in drug efficacy, drug safety and susceptibility to environmental toxicity. We summarized and discussed challenges, wet-lab methods, and bioinformatics algorithms in sequencing "complex" XMET genes, which may provide insightful information in the application of NGS technology for implementation in toxicogenomics and pharmacogenomics.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Análise de Sequência de DNA/métodos , Biologia Computacional , Regulação da Expressão Gênica no Desenvolvimento , Genoma Humano , Genótipo , Humanos , Proteínas de Membrana Transportadoras/metabolismo , Medicina de Precisão , Regiões Promotoras Genéticas , Medição de Risco , Xenobióticos/metabolismo
18.
Hum Immunol ; 79(2): 77-86, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29247682

RESUMO

For over 50 years, the International HLA and Immunogenetics Workshops (IHIW) have advanced the fields of histocompatibility and immunogenetics (H&I) via community sharing of technology, experience and reagents, and the establishment of ongoing collaborative projects. Held in the fall of 2017, the 17th IHIW focused on the application of next generation sequencing (NGS) technologies for clinical and research goals in the H&I fields. NGS technologies have the potential to allow dramatic insights and advances in these fields, but the scope and sheer quantity of data associated with NGS raise challenges for their analysis, collection, exchange and storage. The 17th IHIW adopted a centralized approach to these issues, and we developed the tools, services and systems to create an effective system for capturing and managing these NGS data. We worked with NGS platform and software developers to define a set of distinct but equivalent NGS typing reports that record NGS data in a uniform fashion. The 17th IHIW database applied our standards, tools and services to collect, validate and store those structured, multi-platform data in an automated fashion. We have created community resources to enable exploration of the vast store of curated sequence and allele-name data in the IPD-IMGT/HLA Database, with the goal of creating a long-term community resource that integrates these curated data with new NGS sequence and polymorphism data, for advanced analyses and applications.


Assuntos
Coleta de Dados , Antígenos HLA/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Imunogenética , Armazenamento e Recuperação da Informação , Software , Automação Laboratorial , Congressos como Assunto , Bases de Dados Genéticas , Teste de Histocompatibilidade , Humanos , Estados Unidos
19.
Mol Ther ; 25(8): 1974-1987, 2017 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-28716575

RESUMO

Trauma-induced heterotopic ossification (tHO) is a condition of pathologic wound healing, defined by the progressive formation of ectopic bone in soft tissue following severe burns or trauma. Because previous studies have shown that genetic variants of HO, such as fibrodysplasia ossificans progressiva (FOP), are caused by hyperactivating mutations of the type I bone morphogenetic protein receptor (T1-BMPR) ACVR1/ALK2, studies evaluating therapies for HO have been directed primarily toward drugs for this specific receptor. However, patients with tHO do not carry known T1-BMPR mutations. Here we show that, although BMP signaling is required for tHO, no single T1-BMPR (ACVR1/ALK2, BMPR1a/ALK3, or BMPR1b/ALK6) alone is necessary for this disease, suggesting that these receptors have functional redundancy in the setting of tHO. By utilizing two different classes of BMP signaling inhibitors, we developed a translational approach to treatment, integrating treatment choice with existing diagnostic options. Our treatment paradigm balances either immediate therapy with reduced risk for adverse effects (Alk3-Fc) or delayed therapy with improved patient selection but greater risk for adverse effects (LDN-212854).


Assuntos
Receptores de Proteínas Morfogenéticas Ósseas/genética , Marcação de Genes , Ossificação Heterotópica/etiologia , Ossificação Heterotópica/patologia , Ferimentos e Lesões/complicações , Receptores de Ativinas Tipo I/deficiência , Animais , Anti-Inflamatórios/farmacologia , Biomarcadores , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/deficiência , Técnicas de Inativação de Genes , Predisposição Genética para Doença , Humanos , Ligantes , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Neutrófilos/metabolismo , Ossificação Heterotópica/prevenção & controle , Inibidores de Proteínas Quinases/farmacologia
20.
Nucleic Acids Res ; 45(D1): D908-D914, 2017 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-27789704

RESUMO

A cornerstone of modern biomedical research is the use of animal models to study disease mechanisms and to develop new therapeutic approaches. In order to help the research community to better explore the similarities and differences of genomic response between human inflammatory diseases and murine models, we developed KERIS: kaleidoscope of gene responses to inflammation between species (available at http://www.igenomed.org/keris/). As of June 2016, KERIS includes comparisons of the genomic response of six human inflammatory diseases (burns, trauma, infection, sepsis, endotoxin and acute respiratory distress syndrome) and matched mouse models, using 2257 curated samples from the Inflammation and the Host Response to Injury Glue Grant studies and other representative studies in Gene Expression Omnibus. A researcher can browse, query, visualize and compare the response patterns of genes, pathways and functional modules across different diseases and corresponding murine models. The database is expected to help biologists choosing models when studying the mechanisms of particular genes and pathways in a disease and prioritizing the translation of findings from disease models into clinical studies.


Assuntos
Biologia Computacional/métodos , Bases de Dados de Ácidos Nucleicos , Regulação da Expressão Gênica , Inflamação/genética , Software , Animais , Modelos Animais de Doenças , Perfilação da Expressão Gênica/métodos , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Camundongos , Especificidade da Espécie , Navegador
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