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1.
Artigo em Inglês | MEDLINE | ID: mdl-31373364

RESUMO

Mobile health (mHealth) interventions have demonstrated promise in improving outcomes by motivating patients to adopt and maintain healthy lifestyle changes as well as improve adherence to guideline-directed medical therapy. Early results combining behavioral economic strategies with mHealth delivery have demonstrated mixed results. In reviewing these studies, we propose that the success of a mHealth intervention links more strongly with how well it connects patients back to routine clinical care, rather than its behavior modification technique in isolation. This underscores the critical role of clinician-patient partnerships in the design and delivery of such interventions, while also raising important questions regarding long-term sustainability and scalability. Further exploration of our hypothesis may increase opportunities for multidisciplinary clinical teams to connect with and engage patients using mHealth technologies in unprecedented ways.

2.
Redox Biol ; 24: 101221, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31153039

RESUMO

To test our hypothesis that proatherogenic lysophosphatidylcholine (LPC) upregulates trained immunity pathways (TIPs) in human aortic endothelial cells (HAECs), we conducted an intensive analyses on our RNA-Seq data and histone 3 lysine 14 acetylation (H3K14ac)-CHIP-Seq data, both performed on HAEC treated with LPC. Our analysis revealed that: 1) LPC induces upregulation of three TIPs including glycolysis enzymes (GE), mevalonate enzymes (ME), and acetyl-CoA generating enzymes (ACE); 2) LPC induces upregulation of 29% of 31 histone acetyltransferases, three of which acetylate H3K14; 3) LPC induces H3K14 acetylation (H3K14ac) in the genomic DNA that encodes LPC-induced TIP genes (79%) in comparison to that of in LPC-induced effector genes (43%) including ICAM-1; 4) TIP pathways are significantly different from that of EC activation effectors including adhesion molecule ICAM-1; 5) reactive oxygen species generating enzyme NOX2 deficiency decreases, but antioxidant transcription factor Nrf2 deficiency increases, the expressions of a few TIP genes and EC activation effector genes; and 6) LPC induced TIP genes(81%) favor inter-chromosomal long-range interactions (CLRI, trans-chromatin interaction) while LPC induced effector genes (65%) favor intra-chromosomal CLRIs (cis-chromatin interaction). Our findings demonstrated that proatherogenic lipids upregulate TIPs in HAECs, which are a new category of qualification markers for chronic disease risk factors and conditional DAMPs and potential mechanisms for acute inflammation transition to chronic ones. These novel insights may lead to identifications of new cardiovascular risk factors in upregulating TIPs in cardiovascular cells and novel therapeutic targets for the treatment of metabolic cardiovascular diseases, inflammation, and cancers. (total words: 245).

3.
Artigo em Inglês | MEDLINE | ID: mdl-31238160

RESUMO

BACKGROUND: Patients with hereditary angioedema (HAE) present to the emergency department (ED), where their symptoms are often incorrectly attributed to common allergic and gastrointestinal conditions, resulting in major delays in diagnosis and treatment. OBJECTIVE: To develop a rapid triage HAE (Hereditary AngioEdema Rapid Triage [HAE-RT]) tool for ED settings. METHODS: A mixed-methods approach was used in 3 phases: Phase 1: A literature review on the current management of patients with HAE in the ED. Phase 2: A Delphi study with HAE specialists (N = 9) and Patient Advocacy Group Members (N = 3) to reach consensus on the predictor variables (PVs) to be included in the HAE-RT tool. Phase 3: A retrospective chart review to assess the performance of the PVs for HAE. RESULTS: The literature review informed the final list of PVs included in the HAE-RT prototype. Nine experts participated in the Delphi study. Of 8 identified HAE-specific PVs, 3 reached consensus: (1) absence of urticaria, (2) recurrent abdominal pain/swelling, and (3) lack of response to allergic-directed therapy. The retrospective study included 107 patients (N = 66 with HAE; N = 41 non-HAE). Patients with HAE were more likely to have a family history of HAE (71%; P < .0001), previous recurrent angioedema (96%; P < .002), and previous recurrent abdominal pain (77%; P < .0001), and only 6% responded to allergy treatments (P < .0001). The HAE-RT tool had 98% sensitivity and specificity. CONCLUSIONS: Expert consensus led to the identification and prioritization of variables that when incorporated into an HAE-RT tool were associated with a high level of sensitivity and specificity when applied to known patients.

4.
Redox Biol ; 24: 101222, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31153037

RESUMO

Recent clinical trials reported that increasing high-density lipoprotein-cholesterol (HDL-C) levels does not improve cardiovascular outcomes. We hypothesize that HDL proteome dynamics determine HDL cardioprotective functions. In this study, we characterized proteome profiles in HDL subclasses and established their functional connection. Mouse plasma was fractionized by fast protein liquid chromatography, examined for protein, cholesterial, phospholipid and trigliceride content. Small, medium and large (S/M/L)-HDL subclasseses were collected for proteomic analysis by mass spectrometry. Fifty-one HDL proteins (39 in S-HDL, 27 in M-HDL and 29 in L-HDL) were identified and grouped into 4 functional categories (lipid metabolism, immune response, coagulation, and others). Eleven HDL common proteins were identified in all HDL subclasses. Sixteen, 3 and 7 proteins were found only in S-HDL, M-HDL and L-HDL, respectively. We established HDL protein dynamic distribution in S/M/L-HDL and developed a model of protein composition change during HDL maturation. We found that cholesterol efflux and immune response are essential functions for all HDL particles, and amino acid metabolism is a special function of S-HDL, whereas anti-coagulation is special for M-HDL. Pon1 is recruited into M/L-HDL to provide its antioxidative function. ApoE is incorporated into L-HDL to optimize its cholesterial clearance function. Next, we acquired HDL proteome data from Pubmed and identified 12 replicated proteins in human and mouse HDL particle. Finally, we extracted 3 shared top moleccular pathways (LXR/RXR, FXR/RXR and acute phase response) for all HDL particles and 5 top disease/bio-functions differentially related to S/M/L-HDL subclasses, and presented one top net works for each HDL subclass. We conclude that beside their essencial functions of cholesterol efflux and immune response, HDL aquired antioxidative and cholesterol clearance functions by recruiting Pon1 and ApoE during HDL maturation.

6.
JMIR Mhealth Uhealth ; 7(5): e14124, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-31094337

RESUMO

The explosion of mobile health (mHealth) interventions has prompted significant investment and exploration that has extended past industry into academia. Although research in this space is emerging, it focuses on the clinical and population level impact across different populations. To realize the full potential of mHealth, an intimate understanding of how mHealth is being used by patients and potential differences in usage between various demographic groups must also be prioritized. In this viewpoint, we use our experiences in building an mHealth intervention that incorporates an iOS app, Bluetooth-enabled blood pressure cuff, and Apple Watch to share knowledge on (1) how user interaction data can be tracked in the context of health care privacy laws, (2) what is required for effective, nuanced communication between clinicians and engineers to design mHealth interventions that are patient-centered and have high clinical impact, and (3) how to handle and set up a process to handle user interaction data efficiently.

7.
Circ Cardiovasc Qual Outcomes ; 12(5): e005509, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31043065

RESUMO

BACKGROUND: Unplanned readmissions after hospitalization for acute myocardial infarction are among the leading causes of preventable morbidity, mortality, and healthcare costs. Digital health interventions could be an effective tool in promoting self-management, adherence to guideline-directed therapy, and cardiovascular risk reduction. A digital health intervention developed at Johns Hopkins-the Corrie Health Digital Platform (Corrie)-includes the first cardiology Apple CareKit smartphone application, which is paired with an Apple Watch and iHealth Bluetooth-enabled blood pressure cuff. Corrie targets: (1) self-management of cardiac medications, (2) self-tracking of vital signs, (3) education about cardiovascular disease through articles and animated videos, and (4) care coordination that includes outpatient follow-up appointments. METHODS AND RESULTS: The 3 phases of the MiCORE study (Myocardial infarction, Combined-device, Recovery Enhancement) include (1) the development of Corrie, (2) a pilot study to assess the usability and feasibility of Corrie, and (3) a prospective research study to primarily compare time to first readmission within 30 days postdischarge among patients with Corrie to patients in the historical standard of care comparison group. In Phase 2, the feasibility of deploying Corrie in an acute care setting was established among a sample of 60 patients with acute myocardial infarction. Phase 3 is ongoing and patients from 4 hospitals are being enrolled as early as possible during their hospital stay if they are 18 years or older, admitted with acute myocardial infarction (ST-segment-elevation myocardial infarction or type I non-ST-segment-elevation myocardial infarction), and own a smartphone. Patients are either being enrolled with their own personal devices or they are provided an iPhone and/or Apple Watch for the duration of the study. Phase 3 started in October 2017 and we aim to recruit 140 participants. CONCLUSIONS: This article will provide an in-depth understanding of the feasibility associated with implementing a digital health intervention in an acute care setting and the potential of Corrie as a self-management tool for acute myocardial infarction recovery.

8.
JAMA ; 321(10): 946-955, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30794314

RESUMO

Importance: There are currently no approved treatments for peanut allergy. Objective: To assess the efficacy and adverse events of epicutaneous immunotherapy with a peanut patch among peanut-allergic children. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled trial conducted at 31 sites in 5 countries between January 8, 2016, and August 18, 2017. Participants included peanut-allergic children (aged 4-11 years [n = 356] without a history of a severe anaphylactic reaction) developing objective symptoms during a double-blind, placebo-controlled food challenge at an eliciting dose of 300 mg or less of peanut protein. Interventions: Daily treatment with peanut patch containing either 250 µg of peanut protein (n = 238) or placebo (n = 118) for 12 months. Main Outcomes and Measures: The primary outcome was the percentage difference in responders between the peanut patch and placebo patch based on eliciting dose (highest dose at which objective signs/symptoms of an immediate hypersensitivity reaction developed) determined by food challenges at baseline and month 12. Participants with baseline eliciting dose of 10 mg or less were responders if the posttreatment eliciting dose was 300 mg or more; participants with baseline eliciting dose greater than 10 to 300 mg were responders if the posttreatment eliciting dose was 1000 mg or more. A threshold of 15% or more on the lower bound of a 95% CI around responder rate difference was prespecified to determine a positive trial result. Adverse event evaluation included collection of treatment-emergent adverse events (TEAEs). Results: Among 356 participants randomized (median age, 7 years; 61.2% male), 89.9% completed the trial; the mean treatment adherence was 98.5%. The responder rate was 35.3% with peanut-patch treatment vs 13.6% with placebo (difference, 21.7% [95% CI, 12.4%-29.8%; P < .001]). The prespecified lower bound of the CI threshold was not met. TEAEs, primarily patch application site reactions, occurred in 95.4% and 89% of active and placebo groups, respectively. The all-causes rate of discontinuation was 10.5% in the peanut-patch group vs 9.3% in the placebo group. Conclusions and Relevance: Among peanut-allergic children aged 4 to 11 years, the percentage difference in responders at 12 months with the 250-µg peanut-patch therapy vs placebo was 21.7% and was statistically significant, but did not meet the prespecified lower bound of the confidence interval criterion for a positive trial result. The clinical relevance of not meeting this lower bound of the confidence interval with respect to the treatment of peanut-allergic children with epicutaneous immunotherapy remains to be determined. Trial Registration: ClinicalTrials.gov Identifier: NCT02636699.


Assuntos
Alérgenos/administração & dosagem , Arachis/imunologia , Dessensibilização Imunológica/métodos , Hipersensibilidade a Amendoim/terapia , Adesivo Transdérmico , Administração Cutânea , Criança , Pré-Escolar , Intervalos de Confiança , Método Duplo-Cego , Ingestão de Alimentos/imunologia , Feminino , Humanos , Masculino , Hipersensibilidade a Amendoim/imunologia , Adesivo Transdérmico/efeitos adversos , Resultado do Tratamento
9.
J Allergy Clin Immunol Pract ; 7(6): 1793-1802.e2, 2019 Jul - Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30772477

RESUMO

BACKGROUND: For the prevention of attacks of hereditary angioedema (HAE), the efficacy and safety of subcutaneous human C1-esterase inhibitor (C1-INH[SC]; HAEGARDA, CSL Behring) was established in the 16-week Clinical Study for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy (COMPACT). OBJECTIVE: To assess the long-term safety, occurrence of angioedema attacks, and use of rescue medication with C1-INH(SC). METHODS: Open-label, randomized, parallel-arm extension of COMPACT across 11 countries. Patients with frequent angioedema attacks, either study treatment-naive or who had completed COMPACT, were randomly assigned (1:1) to 40 IU/kg or 60 IU/kg C1-INH(SC) twice per week, with conditional uptitration to optimize prophylaxis (ClinicalTrials.gov registration no. NCT02316353). RESULTS: A total of 126 patients with a monthly attack rate of 4.3 in 3 months before entry in COMPACT were enrolled and treated for a mean of 1.5 years; 44 patients (34.9%) had more than 2 years of exposure. Mean steady-state C1-INH functional activity increased to 66.6% with 60 IU/kg. Incidence of adverse events was low and similar in both dose groups (11.3 and 8.5 events per patient-year for 40 IU/kg and 60 IU/kg, respectively). For 40 IU/kg and 60 IU/kg, median annualized attack rates were 1.3 and 1.0, respectively, and median rescue medication use was 0.2 and 0.0 times per year, respectively. Of 23 patients receiving 60 IU/kg for more than 2 years, 19 (83%) were attack-free during months 25 to 30 of treatment. CONCLUSIONS: In patients with frequent HAE attacks, long-term replacement therapy with C1-INH(SC) is safe and exhibits a substantial and sustained prophylactic effect, with the vast majority of patients becoming free from debilitating disease symptoms.

10.
BMC Syst Biol ; 13(1): 13, 2019 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-30670065

RESUMO

It was highlighted that the original article [1] contained a typesetting error in the last name of Allon Canaan. This was incorrectly captured as Allon Canaann in the original article which has since been updated.

11.
J Allergy Clin Immunol Pract ; 7(5): 1610-1618.e4, 2019 May - Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30682573

RESUMO

BACKGROUND: Hereditary angioedema (HAE) with C1 inhibitor deficiency (C1-INH) is characterized by swelling of subcutaneous and/or submucosal tissues. OBJECTIVE: To evaluate efficacy/safety of fixed-dose subcutaneous plasma-derived C1-INH (pdC1-INH) liquid for HAE attack prevention (NCT02584959). METHODS: Eligible patients were ≥12 years with ≥2 monthly attacks prescreening or pre-long-term prophylaxis. In a partial crossover design, 80% of patients were randomized to placebo or pdC1-INH liquid for 14 weeks and crossed over from active to placebo or vice versa for another 14 weeks. The remainder were randomized to pdC1-INH liquid for 28 weeks. The primary efficacy endpoint was normalized number of attacks (NNA) versus placebo. Key additional endpoints were the proportion of patients achieving NNA reduction ≥50%, attack severity, number of attack-free days, and safety. RESULTS: Seventy-five patients were randomized and 58 (77%) completed the study. Mean age 41 years; 88% HAE type I. Least-squares means of NNA were reduced from 3.9 with placebo to 1.6 with pdC1-INH (from day 1; P < .0001). Most patients had ≥50% NNA reduction with pdC1-INH (from day 1, 78%). A total of 8.8% of placebo-treated patients were attack-free and 5.3%, 22.8%, and 63.2% had mild, moderate, and severe attacks, respectively; 37.5% of pdC1-INH-treated patients were attack-free and 8.9%, 26.8%, and 26.8% had mild, moderate, and severe attacks, respectively. Treatment-emergent adverse event rates were similar between groups (52% vs 56% for pdC1-INH crossover vs placebo, respectively). CONCLUSIONS: Fixed-dose subcutaneous pdC1-INH liquid was superior to placebo in preventing HAE attacks and demonstrated a favorable safety profile.

12.
Cancer Res ; 79(7): 1646-1657, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30659022

RESUMO

The mechanisms by which breast cancers progress from relatively indolent ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) are not well understood. However, this process is critical to the acquisition of metastatic potential. MAPK-interacting serine/threonine-protein kinase 1 (MNK1) signaling can promote cell invasion. NODAL, a morphogen essential for embryogenic patterning, is often reexpressed in breast cancer. Here we describe a MNK1/NODAL signaling axis that promotes DCIS progression to IDC. We generated MNK1 knockout (KO) or constitutively active MNK1 (caMNK1)-expressing human MCF-10A-derived DCIS cell lines, which were orthotopically injected into the mammary glands of mice. Loss of MNK1 repressed NODAL expression, inhibited DCIS to IDC conversion, and decreased tumor relapse and metastasis. Conversely, caMNK1 induced NODAL expression and promoted IDC. The MNK1/NODAL axis promoted cancer stem cell properties and invasion in vitro. The MNK1/2 inhibitor SEL201 blocked DCIS progression to invasive disease in vivo. In clinical samples, IDC and DCIS with microinvasion expressed higher levels of phospho-MNK1 and NODAL versus low-grade (invasion-free) DCIS. Cumulatively, our data support further development of MNK1 inhibitors as therapeutics for preventing invasive disease. SIGNIFICANCE: These findings provide new mechanistic insight into progression of ductal carcinoma and support clinical application of MNK1 inhibitors to delay progression of indolent ductal carcinoma in situ to invasive ductal carcinoma.

13.
J Immunol ; 202(5): 1573-1581, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30665938

RESUMO

Antibody diversity is initiated by activation-induced deaminase (AID), which deaminates cytosine to uracil in DNA. Uracils in the Ig gene loci can be recognized by uracil DNA glycosylase (UNG) or mutS homologs 2 and 6 (MSH2-MSH6) proteins, and then processed into DNA breaks. Breaks in switch regions of the H chain locus cause isotype switching and have been extensively characterized as staggered and blunt double-strand breaks. However, breaks in V regions that arise during somatic hypermutation are poorly understood. In this study, we characterize AID-dependent break formation in JH introns from mouse germinal center B cells. We used a ligation-mediated PCR assay to detect single-strand breaks and double-strand breaks that were either staggered or blunt. In contrast to switch regions, V regions contained predominantly single-strand breaks, which peaked 10 d after immunization. We then examined the pathways used to generate these breaks in UNG- and MSH6-deficient mice. Surprisingly, both DNA repair pathways contributed substantially to break formation, and in the absence of both UNG and MSH6, the frequency of breaks was severely reduced. When the breaks were sequenced and mapped, they were widely distributed over a 1000-bp intron region downstream of JH3 and JH4 exons and were unexpectedly located at all 4 nt. These data suggest that during DNA repair, nicks are generated at distal sites from the original deaminated cytosine, and these repair intermediates could generate both faithful and mutagenic repair. During mutagenesis, single-strand breaks would allow entry for low-fidelity DNA polymerases to generate somatic hypermutation.

14.
Front Biosci (Landmark Ed) ; 24: 96-132, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30468648

RESUMO

We took an experimental database mining analysis to determine the expression of 28 co-signaling receptors in 32 human tissues in physiological/pathological conditions. We made the following significant findings: 1) co-signaling receptors are differentially expressed in tissues; 2) heart, trachea, kidney, mammary gland and muscle express co-signaling receptors that mediate CD4+T cell functions such as priming, differentiation, effector, and memory; 3) urinary tumor, germ cell tumor, leukemia and chondrosarcoma express high levels of co-signaling receptors for T cell activation; 4) expression of inflammasome components are correlated with the expression of co-signaling receptors; 5) CD40, SLAM, CD80 are differentially expressed in leukocytes from patients with trauma, bacterial infections, polarized macrophages and in activated endothelial cells; 6) forward and reverse signaling of 50% co-inhibition receptors are upregulated in endothelial cells during inflammation; and 7) STAT1 deficiency in T cells upregulates MHC class II and co-stimulation receptors. Our results have provided novel insights into co-signaling receptors as physiological regulators and potentiate identification of new therapeutic targets for the treatment of sterile inflammatory disorders.


Assuntos
Tolerância Imunológica/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Antígeno B7-1/genética , Antígeno B7-1/imunologia , Antígenos CD40/genética , Antígenos CD40/imunologia , Diferenciação Celular/genética , Expressão Gênica/imunologia , Perfilação da Expressão Gênica , Humanos , Tolerância Imunológica/genética , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Transdução de Sinais/genética , Linfócitos T/metabolismo
15.
BMC Syst Biol ; 12(Suppl 7): 119, 2018 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-30547775

RESUMO

BACKGROUND: Accumulation of amyloid ß-peptide (Aß) is implicated in the pathogenesis and development of Alzheimer's disease (AD). Neuron-enriched miRNA was aberrantly regulated and may be associated with the pathogenesis of AD. However, regarding whether miRNA is involved in the accumulation of Aß in AD, the underlying molecule mechanism remains unclear. Therefore, we conduct a systematic identification of the promising role of miRNAs in Aß deposition, and shed light on the molecular mechanism of target miRNAs underlying SH-SY5Y cells treated with Aß-induced cytotoxicity. RESULTS: Statistical analyses of microarray data revealed that 155 significantly upregulated and 50 significantly downregulated miRNAs were found on the basis of log2 | Fold Change | ≥ 0.585 and P < 0.05 filter condition through 2588 kinds of mature miRNA probe examined. PCR results show that the expression change trend of the selected six miRNAs (miR-6845-3p, miR-4487, miR-4534, miR-3622-3p, miR-1233-3p, miR-6760-5p) was consistent with the results of the gene chip. Notably, Aß25-35 downregulated hsa-miR-4487 and upregulated hsa-miR-6845-3p in SH-SY5Y cell lines associated with Aß-mediated pathophysiology. Increase of hsa-miR-4487 could inhibit cells apoptosis, and diminution of hsa-miR-6845-3p could attenuate axon damage mediated by Aß25-35 in SH-SY5Y. CONCLUSIONS: Together, these findings suggest that dysregulation of hsa-miR-4487 and hsa-miR-6845-3p contributed to the pathogenesis of AD associated with Aß25-35 mediated by triggering cell apoptosis and synaptic dysfunction. It might be beneficial to understand the pathogenesis and development of clinical diagnosis and treatment of AD. Further, our well-designed validation studies will test the miRNAs signature as a prognostication tool associated with clinical outcomes in AD.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/toxicidade , MicroRNAs/genética , Fragmentos de Peptídeos/toxicidade , Apoptose/efeitos dos fármacos , Apoptose/genética , Axônios/efeitos dos fármacos , Axônios/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Humanos , Transcriptoma/efeitos dos fármacos
16.
BMC Syst Biol ; 12(Suppl 7): 114, 2018 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-30547798

RESUMO

BACKGROUND: Single-cell RNA sequencing (scRNA-seq) technology provides an effective way to study cell heterogeneity. However, due to the low capture efficiency and stochastic gene expression, scRNA-seq data often contains a high percentage of missing values. It has been showed that the missing rate can reach approximately 30% even after noise reduction. To accurately recover missing values in scRNA-seq data, we need to know where the missing data is; how much data is missing; and what are the values of these data. METHODS: To solve these three problems, we propose a novel model with a hybrid machine learning method, namely, missing imputation for single-cell RNA-seq (MISC). To solve the first problem, we transformed it to a binary classification problem on the RNA-seq expression matrix. Then, for the second problem, we searched for the intersection of the classification results, zero-inflated model and false negative model results. Finally, we used the regression model to recover the data in the missing elements. RESULTS: We compared the raw data without imputation, the mean-smooth neighbor cell trajectory, MISC on chronic myeloid leukemia data (CML), the primary somatosensory cortex and the hippocampal CA1 region of mouse brain cells. On the CML data, MISC discovered a trajectory branch from the CP-CML to the BC-CML, which provides direct evidence of evolution from CP to BC stem cells. On the mouse brain data, MISC clearly divides the pyramidal CA1 into different branches, and it is direct evidence of pyramidal CA1 in the subpopulations. In the meantime, with MISC, the oligodendrocyte cells became an independent group with an apparent boundary. CONCLUSIONS: Our results showed that the MISC model improved the cell type classification and could be instrumental to study cellular heterogeneity. Overall, MISC is a robust missing data imputation model for single-cell RNA-seq data.


Assuntos
Análise de Sequência de RNA/métodos , Análise de Célula Única , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia
17.
BMC Syst Biol ; 12(Suppl 7): 116, 2018 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-30547805

RESUMO

BACKGROUND: Nowadays, because of the huge economic burden on society causing by obesity and diabetes, they turn into the most serious public health challenges in the world. To reveal the close and complex relationships between diabetes, obesity and other diseases, search the effective treatment for them, a novel model named as representative latent Dirichlet allocation (RLDA) topic model is presented. RESULTS: RLDA was applied to a corpus of more than 337,000 literatures of diabetes and obesity which were published from 2007 to 2016. To unveil those meaningful relationships between diabetes mellitus, obesity and other diseases, we performed an explicit analysis on the output of our model with a series of visualization tools. Then, with the clinical reports which were not used in the training data to show the credibility of our discoveries, we find that a sufficient number of these records are matched directly. Our results illustrate that in the last 10 years, for obesity accompanying diseases, scientists and researchers mainly focus on 17 of them, such as asthma, gastric disease, heart disease and so on; for the study of diabetes mellitus, it features a more broad scope of 26 diseases, such as Alzheimer's disease, heart disease and so forth; for both of them, there are 15 accompanying diseases, listed as following: adrenal disease, anxiety, cardiovascular disease, depression, heart disease, hepatitis, hypertension, hypothalamic disease, respiratory disease, myocardial infarction, OSAS, liver disease, lung disease, schizophrenia, tuberculosis. In addition, tumor necrosis factor, tumor, adolescent obesity or diabetes, inflammation, hypertension and cell are going be the hot topics related to diabetes mellitus and obesity in the next few years. CONCLUSIONS: With the help of RLDA, the hotspots analysis-relation discovery results on diabetes and obesity were achieved. We extracted the significant relationships between them and other diseases such as Alzheimer's disease, heart disease and tumor. It is believed that the new proposed representation learning algorithm can help biomedical researchers better focus their attention and optimize their research direction.


Assuntos
Biologia Computacional/métodos , Complicações do Diabetes , Obesidade/complicações , Algoritmos , PubMed
18.
BMC Syst Biol ; 12(Suppl 7): 117, 2018 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-30547817

RESUMO

BACKGROUND: Adenocarcinoma in situ (AIS) is a pre-invasive lesion in the lung and a subtype of lung adenocarcinoma. The patients with AIS can be cured by resecting the lesion completely. In contrast, the patients with invasive lung adenocarcinoma have very poor 5-year survival rate. AIS can develop into invasive lung adenocarcinoma. The investigation and comparison of AIS and invasive lung adenocarcinoma at the genomic level can deepen our understanding of the mechanisms underlying lung cancer development. RESULTS: In this study, we identified 61 lung adenocarcinoma (LUAD) invasive-specific differentially expressed genes, including nine long non-coding RNAs (lncRNAs) based on RNA sequencing techniques (RNA-seq) data from normal, AIS, and invasive tissue samples. These genes displayed concordant differential expression (DE) patterns in the independent stage III LUAD tissues obtained from The Cancer Genome Atlas (TCGA) RNA-seq dataset. For individual invasive-specific genes, we constructed subnetworks using the Genetic Algorithm (GA) based on protein-protein interactions, protein-DNA interactions and lncRNA regulations. A total of 19 core subnetworks that consisted of invasive-specific genes and at least one putative lung cancer driver gene were identified by our study. Functional analysis of the core subnetworks revealed their enrichment in known pathways and biological progresses responsible for tumor growth and invasion, including the VEGF signaling pathway and the negative regulation of cell growth. CONCLUSIONS: Our comparison analysis of invasive cases, normal and AIS uncovered critical genes that involved in the LUAD invasion progression. Furthermore, the GA-based network method revealed gene clusters that may function in the pathways contributing to tumor invasion. The interactions between differentially expressed genes and putative driver genes identified through the network analysis can offer new targets for preventing the cancer invasion and potentially increase the survival rate for cancer patients.


Assuntos
Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Biologia de Sistemas , Progressão da Doença , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Genômica , Humanos , Mutação , Invasividade Neoplásica
19.
N Engl J Med ; 379(21): 1991-2001, 2018 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-30449234

RESUMO

BACKGROUND: Peanut allergy, for which there are no approved treatment options, affects patients who are at risk for unpredictable and occasionally life-threatening allergic reactions. METHODS: In a phase 3 trial, we screened participants 4 to 55 years of age with peanut allergy for allergic dose-limiting symptoms at a challenge dose of 100 mg or less of peanut protein (approximately one third of a peanut kernel) in a double-blind, placebo-controlled food challenge. Participants with an allergic response were randomly assigned, in a 3:1 ratio, to receive AR101 (a peanut-derived investigational biologic oral immunotherapy drug) or placebo in an escalating-dose program. Participants who completed the regimen (i.e., received 300 mg per day of the maintenance regimen for approximately 24 weeks) underwent a double-blind, placebo-controlled food challenge at trial exit. The primary efficacy end point was the proportion of participants 4 to 17 years of age who could ingest a challenge dose of 600 mg or more, without dose-limiting symptoms. RESULTS: Of the 551 participants who received AR101 or placebo, 496 were 4 to 17 years of age; of these, 250 of 372 participants (67.2%) who received active treatment, as compared with 5 of 124 participants (4.0%) who received placebo, were able to ingest a dose of 600 mg or more of peanut protein, without dose-limiting symptoms, at the exit food challenge (difference, 63.2 percentage points; 95% confidence interval, 53.0 to 73.3; P<0.001). During the exit food challenge, the maximum severity of symptoms was moderate in 25% of the participants in the active-drug group and 59% of those in the placebo group and severe in 5% and 11%, respectively. Adverse events during the intervention period affected more than 95% of the participants 4 to 17 years of age. A total of 34.7% of the participants in the active-drug group had mild events, as compared with 50.0% of those in the placebo group; 59.7% and 44.4% of the participants, respectively, had events that were graded as moderate, and 4.3% and 0.8%, respectively, had events that were graded as severe. Efficacy was not shown in the participants 18 years of age or older. CONCLUSIONS: In this phase 3 trial of oral immunotherapy in children and adolescents who were highly allergic to peanut, treatment with AR101 resulted in higher doses of peanut protein that could be ingested without dose-limiting symptoms and in lower symptom severity during peanut exposure at the exit food challenge than placebo. (Funded by Aimmune Therapeutics; PALISADE ClinicalTrials.gov number, NCT02635776 .).

20.
BMC Med Genomics ; 11(Suppl 5): 106, 2018 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-30453959

RESUMO

BACKGROUND: Non-small cell lung cancer (NSCLC) represents more than about 80% of the lung cancer. The early stages of NSCLC can be treated with complete resection with a good prognosis. However, most cases are detected at late stage of the disease. The average survival rate of the patients with invasive lung cancer is only about 4%. Adenocarcinoma in situ (AIS) is an intermediate subtype of lung adenocarcinoma that exhibits early stage growth patterns but can develop into invasion. METHODS: In this study, we used RNA-seq data from normal, AIS, and invasive lung cancer tissues to identify a gene module that represents the distinguishing characteristics of AIS as AIS-specific genes. Two differential expression analysis algorithms were employed to identify the AIS-specific genes. Then, the subset of the best performed AIS-specific genes for the early lung cancer prediction were selected by random forest. Finally, the performances of the early lung cancer prediction were assessed using random forest, support vector machine (SVM) and artificial neural networks (ANNs) on four independent early lung cancer datasets including one tumor-educated blood platelets (TEPs) dataset. RESULTS: Based on the differential expression analysis, 107 AIS-specific genes that consisted of 93 protein-coding genes and 14 long non-coding RNAs (lncRNAs) were identified. The significant functions associated with these genes include angiogenesis and ECM-receptor interaction, which are highly related to cancer development and contribute to the smoking-free lung cancers. Moreover, 12 of the AIS-specific lncRNAs are involved in lung cancer progression by potentially regulating the ECM-receptor interaction pathway. The feature selection by random forest identified 20 of the AIS-specific genes as early stage lung cancer signatures using the dataset obtained from The Cancer Genome Atlas (TCGA) lung adenocarcinoma samples. Of the 20 signatures, two were lncRNAs, BLACAT1 and CTD-2527I21.15 which have been reported to be associated with bladder cancer, colorectal cancer and breast cancer. In blind classification for three independent tissue sample datasets, these signature genes consistently yielded about 98% accuracy for distinguishing early stage lung cancer from normal cases. However, the prediction accuracy for the blood platelets samples was only 64.35% (sensitivity 78.1%, specificity 50.59%, and AUROC 0.747). CONCLUSIONS: The comparison of AIS with normal and invasive tumor revealed diseases-specific genes and offered new insights into the mechanism underlying AIS progression into an invasive tumor. These genes can also serve as the signatures for early diagnosis of lung cancer with high accuracy. The expression profile of gene signatures identified from tissue cancer samples yielded remarkable early cancer prediction for tissues samples, however, relatively lower accuracy for boold platelets samples.

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