scholarly journals Systems Approaches to Treatment Response to Imatinib in Severe Asthma: A Pilot Study

2021 ◽  
Vol 11 (4) ◽  
pp. 240
Author(s):  
Seung Han Baek ◽  
Dinah Foer ◽  
Katherine N. Cahill ◽  
Elliot Israel ◽  
Enrico Maiorino ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Trial ◽  
Systems Biology ◽  
Pilot Study ◽  
Severe Asthma ◽  
Treated Patient ◽  
Expression Patterns ◽  
Airflow Limitation ◽  
Response To Treatment ◽  
Imatinib Treatment

There is an acute need for advances in pharmacologic therapies and a better understanding of novel drug targets for severe asthma. Imatinib, a tyrosine kinase inhibitor, has been shown to improve forced expiratory volume in 1 s (FEV1) in a clinical trial of patients with severe asthma. In a pilot study, we applied systems biology approaches to epithelium gene expression from these clinical trial patients treated with imatinib to better understand lung function response with imatinib treatment. Bronchial brushings from ten imatinib-treated patient samples and 14 placebo-treated patient samples were analyzed. We used personalized perturbation profiles (PEEPs) to characterize gene expression patterns at the individual patient level. We found that strong responders—patients with greater than 20% increase in FEV1—uniquely shared multiple downregulated mitochondrial-related pathways. In comparison, weak responders (5–10% FEV1 increase), and non-responders to imatinib shared none of these pathways. The use of PEEP highlights its potential for application as a systems biology tool to develop individual-level approaches to predicting disease phenotypes and response to treatment in populations needing innovative therapies. These results support a role for mitochondrial pathways in airflow limitation in severe asthma and as potential therapeutic targets in larger clinical trials.

scholarly journals Systems Biology Analysis of the Antagonizing Effects of HIV-1 Tat Expression in the Brain over Transcriptional Changes Caused by Methamphetamine Sensitization

Viruses ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 426 ◽  
Author(s):  
Liana V. Basova ◽  
James P. Kesby ◽  
Marcus Kaul ◽  
Svetlana Semenova ◽  
Maria Cecilia Garibaldi Marcondes
Keyword(s):  
Gene Expression ◽  
Systems Biology ◽  
Gene Transcription ◽  
Gene Networks ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Global Gene Expression ◽  
Sirtuin 1 ◽  
The Brain ◽  
Hiv 1

Methamphetamine (Meth) abuse is common among humans with immunodeficiency virus (HIV). The HIV-1 regulatory protein, trans-activator of transcription (Tat), has been described to induce changes in brain gene transcription that can result in impaired reward circuitry, as well as in inflammatory processes. In transgenic mice with doxycycline-induced Tat protein expression in the brain, i.e., a mouse model of neuroHIV, we tested global gene expression patterns induced by Meth sensitization. Meth-induced locomotor sensitization included repeated daily Meth or saline injections for seven days and Meth challenge after a seven-day abstinence period. Brain samples were collected 30 min after the Meth challenge. We investigated global gene expression changes in the caudate putamen, an area with relevance in behavior and HIV pathogenesis, and performed pathway and transcriptional factor usage predictions using systems biology strategies. We found that Tat expression alone had a very limited impact in gene transcription after the Meth challenge. In contrast, Meth-induced sensitization in the absence of Tat induced a global suppression of gene transcription. Interestingly, the interaction between Tat and Meth broadly prevented the Meth-induced global transcriptional suppression, by maintaining regulation pathways, and resulting in gene expression profiles that were more similar to the controls. Pathways associated with mitochondrial health, initiation of transcription and translation, as well as with epigenetic control, were heavily affected by Meth, and by its interaction with Tat in anti-directional ways. A series of systems strategies have predicted several components impacted by these interactions, including mitochondrial pathways, mTOR/RICTOR, AP-1 transcription factor, and eukaryotic initiation factors involved in transcription and translation. In spite of the antagonizing effects of Tat, a few genes identified in relevant gene networks remained downregulated, such as sirtuin 1, and the amyloid precursor protein (APP). In conclusion, Tat expression in the brain had a low acute transcriptional impact but strongly interacted with Meth sensitization, to modify effects in the global transcriptome.

Gene-Expression Patterns in Drug-Resistant Acute Lymphoblastic Leukemia Cells and Response to Treatment

2004 ◽  
Vol 351 (6) ◽  
pp. 533-542 ◽  
Author(s):  
Amy Holleman ◽  
Meyling H. Cheok ◽  
Monique L. den Boer ◽  
Wenjian Yang ◽  
Anjo J.P. Veerman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Expression Patterns ◽  
Response To Treatment ◽  
Leukemia Cells ◽  
Gene Expression Patterns ◽  
Drug Resistant

scholarly journals Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa

Gut ◽  
2020 ◽  
pp. gutjnl-2020-320946
Author(s):  
Laura Reyes-Uribe ◽  
Wenhui Wu ◽  
Ozkan Gelincik ◽  
Prashant V Bommi ◽  
Alejandro Francisco-Cruz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Trial ◽  
Lynch Syndrome ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Gene Expression Profiles ◽  
Predictive Biomarkers ◽  
Colorectal Mucosa ◽  
Genetically Engineered Mouse Model ◽  
Increased Risk

ObjectivePatients with Lynch syndrome (LS) are at markedly increased risk for colorectal cancer. It is being increasingly recognised that the immune system plays an essential role in LS tumour development, thus making an ideal target for cancer prevention. Our objective was to evaluate the safety, assess the activity and discover novel molecular pathways involved in the activity of naproxen as primary and secondary chemoprevention in patients with LS.DesignWe conducted a Phase Ib, placebo-controlled, randomised clinical trial of two dose levels of naproxen sodium (440 and 220 mg) administered daily for 6 months to 80 participants with LS, and a co-clinical trial using a genetically engineered mouse model of LS and patient-derived organoids (PDOs).ResultsOverall, the total number of adverse events was not different across treatment arms with excellent tolerance of the intervention. The level of prostaglandin E2 in the colorectal mucosa was significantly decreased after treatment with naproxen when compared with placebo. Naproxen activated different resident immune cell types without any increase in lymphoid cellularity, and changed the expression patterns of the intestinal crypt towards epithelial differentiation and stem cell regulation. Naproxen demonstrated robust chemopreventive activity in a mouse co-clinical trial and gene expression profiles induced by naproxen in humans showed perfect discrimination of mice specimens with LS and PDOs treated with naproxen and control.ConclusionsNaproxen is a promising strategy for immune interception in LS. We have discovered naproxen-induced gene expression profiles for their potential use as predictive biomarkers of drug activity.Trial registration numbergov Identifier: NCT02052908

scholarly journals Mechanistic Computational Models of MicroRNA-Mediated Signaling Networks in Human Diseases

2019 ◽  
Vol 20 (2) ◽  
pp. 421 ◽  
Author(s):  
Chen Zhao ◽  
Yu Zhang ◽  
Aleksander Popel
Keyword(s):  
Gene Expression ◽  
Systems Biology ◽  
Complex Disease ◽  
Expression Patterns ◽  
Regulation Of Gene Expression ◽  
Phenotypic Expression ◽  
Human Diseases ◽  
Regulatory Function ◽  
Regulatory Pathways ◽  
Disease Pathways

MicroRNAs (miRs) are endogenous non-coding RNA molecules that play important roles in human health and disease by regulating gene expression and cellular processes. In recent years, with the increasing scientific knowledge and new discovery of miRs and their gene targets, as well as the plentiful experimental evidence that shows dysregulation of miRs in a wide variety of human diseases, the computational modeling approach has emerged as an effective tool to help researchers identify novel functional associations between differential miR expression and diseases, dissect the phenotypic expression patterns of miRs in gene regulatory networks, and elucidate the critical roles of miRs in the modulation of disease pathways from mechanistic and quantitative perspectives. Here we will review the recent systems biology studies that employed different kinetic modeling techniques to provide mechanistic insights relating to the regulatory function and therapeutic potential of miRs in human diseases. Some of the key computational aspects to be discussed in detail in this review include (i) models of miR-mediated network motifs in the regulation of gene expression, (ii) models of miR biogenesis and miR–target interactions, and (iii) the incorporation of such models into complex disease pathways in order to generate mechanistic, molecular- and systems-level understanding of pathophysiology. Other related bioinformatics tools such as computational platforms that predict miR-disease associations will also be discussed, and we will provide perspectives on the challenges and opportunities in the future development and translational application of data-driven systems biology models that involve miRs and their regulatory pathways in human diseases.

scholarly journals Bronchial Thermoplasty in the Treatment of Severe Asthma

2020 ◽  
pp. 1-9
Author(s):  
Nightingale Syabbalo ◽  
Keyword(s):  
Severe Asthma ◽  
Inhaled Corticosteroids ◽  
Airway Disease ◽  
Airflow Limitation ◽  
Response To Treatment ◽  
High Dose ◽  
Eosinophilic Asthma ◽  
Bronchial Thermoplasty ◽  
Long Acting ◽  
Refractory Asthma

Asthma is a chronic inflammatory airway disease with several distinct phenotypes, characterized by different immunopathological pathways, clinical presentation, severity of the disease, and response to treatment. The phenotypes of asthma include eosinophilic, neutrophilic, mixed granulocytic, and paucigranulocytic asthma. Approximately 3.6-10% of patients with asthma have severe refractory disease, which is unresponsive to high dose inhaled corticosteroids (ICS), and long-acting β2-agonists (LABA). Most patients with eosinophilic asthma are responsive to corticosteroids, and interleukintargeted biologics, whereas, patients from other phenotypes, such as neutrophillic and paucigranullocytic asthma are resistant to treatment with ICS and biotherapeutics. The hallmark of severe refractory asthma is airway hyperresponsiveness, and remodeling. Histopathologically, patients with severe asthma have airway smooth muscle (ASM) hyperplasia and hypertrophy; subepithelial basement membrane thickening and fibrosis; all which contribute to fixed airflow limitation. Severe refractory asthma is very difficult to treat pharmacologically. It requires innovative therapies, such as bronchial thermoplasty which reduces the hypertrophied ASM mass and relieves the AHR, and broncoconstriction. Bronchial thermoplasty has been shown to improve asthma control, reduce severe exacerbations, hospitalizations, emergency room visits, and improve the quality of life, which persist up to 5 years following the procedure

A Systems Biology Approach for miRNA-mRNA Expression Patterns Analysis in Rheumatoid Arthritis.

2020 ◽  
Vol 23 ◽  
Author(s):  
Fataneh Tavasolian ◽  
Ahmad Zavaran Hosseini ◽  
Sara Soudi ◽  
Mahmood Naderi ◽  
Amirhossein Sahebkar
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Vitamin D ◽  
Systems Biology ◽  
Vitamin D Receptor ◽  
Expression Patterns ◽  
Gene Expression Omnibus ◽  
Ncbi Gene Expression Omnibus ◽  
Comprehensive Knowledge ◽  
Microarray Datasets

Objective: Considering the molecular complexity and heterogeneity of rheumatoid arthritis (RA), the identification of novel molecular contributors involved in RA initiation and progression using systems biology approaches will open up potential therapeutic strategies. The bioinformatics method allows the detection of associated miRNA-mRNA as both therapeutic and prognostic targets for RA. Method: This research used a system biology approach based on a systematic re-analysis of the RA-related microarray datasets in the NCBI Gene Expression Omnibus (GEO) database to find out deregulated miRNAs. We then studied the deregulated miRNA-mRNA using Enrichr and MolecularSignatures Database (MSigDB) to identify novel RA-related markers followed by an overview of miRNA-mRNA interaction networks and RA-related pathways. Results: This research mainly focused on mRNA and miRNA interactions in all tissues and blood/serum associated with RA to obtain a comprehensive knowledge on RA. Recent systems biology approach analyzed seven independent studies and presented important RA-related deregulated miRNAs (miR-145-5p, miR-146a-5p, miR-155-5p, miR-15a-5p, miR-29c-3p, miR103a-3p, miR-125a-5p, miR-125b-5p, miR-218); upregulation of miR-125b is shown in the study (GSE71600). While the findings of the Enrichr showed cytokine and vitamin D receptor pathways and inflammatory pathways. Further analysis revealed a negative correlation between the vitamin D receptor (VDR) and miR-125b in RA-associated gene expression. Conclusion: Since vitamin D is capable of regulating the immune homeostasis and decreasing the autoimmune process through its receptor (VDR), it is regarded as a potential target for RA. According to the results obtained, a comparative correlation between negative expression of the vitamin D receptor (VDR) and miR-125b was suggested in RA. The increasing miR-125b expression would reduce the VitD uptake through its receptor.

scholarly journals Network analysis of temporal effects of intermittent and sustained hypoxia on rat lungs

2008 ◽  
Vol 36 (1) ◽  
pp. 24-34 ◽  
Author(s):  
Wei Wu ◽  
Nilesh B. Dave ◽  
Guoying Yu ◽  
Patrick J. Strollo ◽  
Elizabeta Kovkarova-Naumovski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Systems Biology ◽  
Intermittent Hypoxia ◽  
Expression Patterns ◽  
Quantitative Real Time Pcr ◽  
Temporal Expression ◽  
Rat Lungs ◽  
Induced Genes ◽  
Sustained Hypoxia ◽  
Lung Response

The molecular networks underlying the lung response to hypoxia are not fully understood. We employed systems biology approaches to study temporal effects of intermittent or sustained hypoxia on gene expression in rat lungs. We obtained gene expression profiles from rats exposed to intermittent or sustained hypoxia lasting 0–30 days and identified differentially expressed genes, their patterns, biological processes, and regulatory networks critical for lung response to intermittent or sustained hypoxia. We validated selected genes with quantitative real-time PCR. Intermittent and sustained hypoxia induced two distinct sets of genes in rat lungs that displayed different temporal expression patterns. Intermittent hypoxia induced genes mostly involved in ion transport and homeostasis, neurological processes, and steroid hormone receptor activity, while sustained hypoxia induced genes principally participating in immune responses. The intermittent hypoxia-activated network suggested a role for cross talk between estrogen receptor 1 (ESR1) and other key proteins in hypoxic responses. The sustained hypoxia-activated network was indicative of vascular remodeling and pulmonary hypertension. We confirmed the temporal expression changes of 12 genes (including the Esr1 gene and 4 ESR1 target genes) in intermittent hypoxia and 8 genes in sustained hypoxia with quantitative real-time PCR. Conclusions: intermittent and sustained hypoxia induced distinct gene expression patterns in rat lungs. The functional characteristics of genes activated by these two distinct perturbations suggest their roles in the downstream physiological effects of intermittent and sustained hypoxia. Our results demonstrate the discovery potential of applying systems biology approaches to the understanding of mechanisms underlying hypoxic lung response.

scholarly journals Genetic Determinants of Poor Response to Treatment in Severe Asthma

2021 ◽  
Vol 22 (8) ◽  
pp. 4251
Author(s):  
Ricardo G. Figueiredo ◽  
Ryan S. Costa ◽  
Camila A. Figueiredo ◽  
Alvaro A. Cruz
Keyword(s):  
Severe Asthma ◽  
Inhaled Corticosteroids ◽  
Association Studies ◽  
Airway Remodeling ◽  
Expression Patterns ◽  
Poor Response ◽  
Response To Treatment ◽  
Genome Wide Association Studies ◽  
Genetic Determinants ◽  
Increased Risk

Severe asthma is a multifactorial disorder with marked phenotypic heterogeneity and complex interactions between genetics and environmental risk factors, which could, at least in part, explain why during standard pharmacologic treatment, many patients remain poorly controlled and at an increased risk of airway remodeling and disease progression. The concept of “precision medicine” to better suit individual unique needs is an emerging trend in the management of chronic respiratory diseases. Over the past few years, Genome-Wide Association Studies (GWAS) have revealed novel pharmacogenetic variants related to responses to inhaled corticosteroids and the clinical efficacy of bronchodilators. Optimal clinical response to treatment may vary between racial/ethnic groups or individuals due to genetic differences. It is also plausible to assume that epigenetic factors play a key role in the modulation of gene expression patterns and inflammatory cytokines. Remarkably, specific genetic variants related to treatment effectiveness may indicate promising pathways for novel therapies in severe asthma. In this review, we provide a concise update of genetic determinants of poor response to treatment in severe asthma and future directions in the field.

scholarly journals Differential Subcutaneous Adipose Tissue Gene Expression Patterns in a Randomized Clinical Trial of Efavirenz or Lopinavir-Ritonavir in Antiretroviral-Naive Patients

2014 ◽  
Vol 58 (11) ◽  
pp. 6717-6723 ◽  
Author(s):  
L. Egaña-Gorroño ◽  
E. Martínez ◽  
P. Domingo ◽  
M. Loncà ◽  
T. Escribà ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Trial ◽  
Adipose Tissue ◽  
Randomized Clinical Trial ◽  
Subcutaneous Adipose Tissue ◽  
Expression Patterns ◽  
Expression Change ◽  
Adipose Tissue Gene Expression ◽  
Subcutaneous Adipose ◽  
Tissue Gene Expression

ABSTRACTGene expression studies of subcutaneous adipose tissue may help to better understand the mechanisms behind body fat changes in HIV-infected patients who initiate antiretroviral therapy (ART). Here, we evaluated early changes in adipose tissue gene expression and their relationship to fat changes in ART-naive HIV-infected patients randomly assigned to initiate therapy with emtricitabine/tenofovir plus efavirenz (EFV) or ritonavir-boosted lopinavir (LPV/r). Patients had abdominal subcutaneous adipose tissue biopsies at baseline and week 16 and dual-energy-X-ray absorptiometry at baseline and weeks 16 and 48. mRNA changes of 11 genes involved in adipogenesis, lipid and glucose metabolism, mitochondrial energy, and inflammation were assessed through reverse transcription-quantitative PCR (RT-qPCR). Additionally, correlations between gene expression changes and fat changes were evaluated. Fat increased preferentially in the trunk with EFV and in the limbs with LPV/r (P< 0.05). After 16 weeks of exposure to the drug regimen, transcripts ofCEBP/A,ADIPOQ,GLUT4,LPL, andCOXIVwere significantly down-regulated in the EFV arm compared to the LPV/r arm (P< 0.05). Significant correlations were observed betweenLPLexpression change and trunk fat change at week 16 in both arms and betweenCEBP/AorCOXIVchange and trunk fat change at the same time point only in the EFV arm and not in the LPV/r arm. When combined with emtricitabine/tenofovir as standard backbone therapy, EFV and LPV/r induced differential early expression of genes involved in adipogenesis and energy metabolism. Moreover, these mRNA expression changes correlated with trunk fat change in the EFV arm. (This was a substudy of a randomized clinical trial [LIPOTAR study] registered atClinicalTrials.govunder identifier NCT00759070.)

Rituximab Plus Chlorambucil As Initial Treatment for Elderly Patients with Chronic Lymphocytic Leukemia (CLL): Effect of Pre-Treatment Biological Characteristics and Gene Expression Patterns on Response to Treatment

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 294-294 ◽  
Author(s):  
Robin Foa ◽  
Stefania Ciolli ◽  
Francesco Di Raimondo ◽  
Giovanni Del Poeta ◽  
Francesco Lauria ◽  
...  
Keyword(s):  
Gene Expression ◽  
Elderly Patients ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Gene Expression Signature ◽  
Standard Of Care ◽  
Response To Treatment ◽  
Induction Treatment ◽  
Induction Phase ◽  
Pre Treatment

Abstract Abstract 294 Rituximab plus fludarabine/cyclophosphamide (R-FC) is currently the standard of care for fit patients with untreated or relapsed CLL. However, patients with CLL are predominantly an elderly population and many of these patients may have comorbidities that make them less suitable to receive fludarabine-containing therapy. Chlorambucil-based treatments are frequently used for these patients despite the fact that clinical benefits are limited. There is a need for well-tolerated and more efficacious treatment regimens for these patients. The ML21445 study evaluated the combination of rituximab and chlorambucil (R-chlorambucil) as first-line treatment for patients with CLL considered ineligible for treatment with the current standard of care, R-FC. Patients aged >65 years (or 60–65 years and ineligible for fludarabine) were treated with eight 28-day cycles of chlorambucil (8 mg/m2/day Days 1–7) with rituximab administered on Day 1 of cycle 3 (375 mg/m2) and cycles 4–8 (500 mg/m2). Patients with a response at the end of induction were randomized to rituximab maintenance therapy (375 mg/m2 every 8 weeks for 2 years) or observation. The induction phase of the study is complete while the maintenance phase is still ongoing. The overall response rate (ORR) in 85 patients who received at least one dose of rituximab during induction was 81.2% (n = 69) with 16.5% (n = 14) achieving a complete response (CR) and 2.4% (n = 2) a CR with incomplete bone marrow recovery (CRi). ORR and CR rates were similar across the different Binet stages (ORR: Binet A 86.4%, Binet B 79.6%, Binet C 78.6%) and age categories (ORR: 60–64 years 84.6%, 65–69 years 85.2%, 70–74 years 75.0%, ≥75 years 81.0%). Two of four patients aged ≥80 years responded to induction treatment. Logistic regression analysis revealed no correlation between known biological prognostic factors – CD38, cytogenetics, IGHV mutational status, ZAP-70, thymidine kinase, soluble CD23, and beta-2 microglobulin – and response to treatment. To further investigate possible factors influencing response, pre-treatment patterns of gene expression were analyzed in different patient subgroups. Material was available for 62 patients, including 16 with CR/CRi, 41 partial responders and 5 non-responders. In an exploratory analysis, mRNA expression was examined using Affymetrix® Human Genome U133 microarrays. This revealed marked differences in pre-treatment gene expression profiles between response groups. Non-responders showed a homogeneous gene expression signature involving up-modulation of transcripts involved in anti-apoptotic and pro-proliferative pathways, including K-ras and N-ras. CR/CRi patients also showed a homogeneous pattern of gene expression that was clearly distinct from non-responding patients, while patients with a partial response showed a more heterogeneous pattern of gene expression before treatment. These initial findings reflect the heterogeneity of CLL and suggest that microarray analysis of gene expression may be useful in predicting response to R-chlorambucil in elderly patients with CLL. Disclosures: Foa: Roche: Consultancy, Speakers Bureau. Cuneo:Roche: Consultancy, Speakers Bureau. Montillo:Roche: Membership on an entity's Board of Directors or advisory committees. Alietti:Roche: Employment. Runggaldier:Roche: Employment. Gamba:Roche Italia: Employment.

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