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BACKGROUND: The lack of reliable biomarkers in response to anti-TNFα biologicals hinders personalized therapy for Crohn's disease (CD) patients. The motivation behind our study is to shift the paradigm of anti-TNFα biomarker discovery toward specific immune cell sub-populations using single-cell RNA sequencing and an innovative approach designed to uncover PBMCs gene expression signals, which may be masked due to the treatment or ongoing inflammation; Methods: The single-cell RNA sequencing was performed on PBMC samples from CD patients either naïve to biological therapy, in remission while on adalimumab, or while on ustekinumab but previously non-responsive to adalimumab. Sieves for stringent downstream gene selection consisted of gene ontology and independent cohort genomic profiling. Replication and meta-analyses were performed using publicly available raw RNA sequencing files of sorted immune cells and an association analysis summary. Machine learning, Mendelian randomization, and oligogenic risk score methods were deployed to validate DEGs highly relevant to anti-TNFα therapy response; Results: This study found PLCB1 in CD4+ T cells and CRTAM in double-negative T cells, which met the stringent statistical thresholds throughout the analyses. An additional assessment proved causal inference of both genes in response to anti-TNFα therapy; Conclusions: This study, jointly with an innovative design, uncovered novel candidate genes in the anti-TNFα response landscape of CD, potentially obscured by therapy or inflammation.
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RATIONALE: Early identification of children with poorly controlled asthma is imperative for optimizing treatment strategies. The analysis of exhaled volatile organic compounds (VOCs) is an emerging approach to identify prognostic and diagnostic biomarkers in pediatric asthma. OBJECTIVES: To assess the accuracy of gas chromatography-mass spectrometry based exhaled metabolite analysis to differentiate between controlled and uncontrolled pediatric asthma. METHODS: This study encompassed a discovery (SysPharmPediA) and validation phase (U-BIOPRED, PANDA). Firstly, exhaled VOCs that discriminated asthma control levels were identified. Subsequently, outcomes were validated in two independent cohorts. Patients were classified as controlled or uncontrolled, based on asthma control test scores and number of severe attacks in the past year. Additionally, potential of VOCs in predicting two or more future severe asthma attacks in SysPharmPediA was evaluated. MEASUREMENTS AND MAIN RESULTS: Complete data were available for 196 children (SysPharmPediA=100, U-BIOPRED=49, PANDA=47). In SysPharmPediA, after randomly splitting the population into training (n=51) and test sets (n=49), three compounds (acetophenone, ethylbenzene, and styrene) distinguished between uncontrolled and controlled asthmatics. The area under the receiver operating characteristic curve (AUROCC) for training and test sets were respectively: 0.83 (95% CI: 0.65-1.00) and 0.77 (95% CI: 0.58-0.96). Combinations of these VOCs resulted in AUROCCs of 0.74 ±0.06 (UBIOPRED) and 0.68 ±0.05 (PANDA). Attacks prediction tests, resulted in AUROCCs of 0.71 (95% CI 0.51-0.91) and 0.71 (95% CI 0.52-0.90) for training and test sets. CONCLUSIONS: Exhaled metabolites analysis might enable asthma control classification in children. This should stimulate further development of exhaled metabolites-based point-of-care tests in asthma.
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Psoriasis is a chronic, immune-mediated and inflammatory skin disease. Although various biological drugs are available for psoriasis treatment, some patients have poor responses or do not respond to treatment. The aim of the present study was to highlight the molecular mechanism of responsiveness to current biological drugs for psoriasis treatment. To this end, we reviewed previously published articles that reported genes associated with treatment response to biological drugs in psoriasis, and gene ontology analysis was subsequently performed using the Cytoscape platform. Herein, we revealed a statistically significant association between NF-kappaB signaling (p value = 3.37 × 10-9), regulation of granulocyte macrophage colony-stimulating factor production (p value = 6.20 × 10-6), glial cell proliferation (p value = 2.41 × 10-5) and treatment response in psoriatic patients. To the best of our knowledge, we are the first to directly associate glial cells with treatment response. Taken together, our study revealed gene ontology (GO) terms, some of which were previously shown to be implicated in the molecular pathway of psoriasis, as novel GO terms involved in responsiveness in psoriatic disease patients.
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Epigenetic studies on the role of DNA-modifying enzymes in HNSCC tumorigenesis have focused on a single enzyme or a group of enzymes. To acquire a more comprehensive insight into the expression profile of methyltransferases and demethylases, in the present study, we examined the mRNA expression of the DNA methyltransferases DNMT1, DNMT3A, and DNMT3B, the DNA demethylases TET1, TET2, TET3, and TDG, and the RNA methyltransferase TRDMT1 by RT-qPCR in paired tumor-normal tissue samples from HNSCC patients. We characterized their expression patterns in relation to regional lymph node metastasis, invasion, HPV16 infection, and CpG73 methylation. Here, we show that tumors with regional lymph node metastases (pN+) exhibited decreased expression of DNMT1, 3A and 3B, and TET1 and 3 compared to non-metastatic tumors (pN0), suggesting that metastasis requires a distinct expression profile of DNA methyltransferases/demethylases in solid tumors. Furthermore, we identified the effect of perivascular invasion and HPV16 on DNMT3B expression in HNSCC. Finally, the expression of TET2 and TDG was inversely correlated with the hypermethylation of CpG73, which has previously been associated with poorer survival in HNSCC. Our study further confirms the importance of DNA methyltransferases and demethylases as potential prognostic biomarkers as well as molecular therapeutic targets for HNSCC.
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Multiple sclerosis is a common immune-mediated inflammatory and demyelinating disease. Lower cholecalciferol levels are an established environmental risk factor in multiple sclerosis. Although cholecalciferol supplementation in multiple sclerosis is widely accepted, optimal serum levels are still debated. Moreover, how cholecalciferol affects pathogenic disease mechanisms is still unclear. In the present study, we enrolled 65 relapsing-remitting multiple sclerosis patients who were double-blindly divided into two groups with low and high cholecalciferol supplementation, respectively. In addition to clinical and environmental parameters, we obtained peripheral blood mononuclear cells to analyze DNA, RNA, and miRNA molecules. Importantly, we investigated miRNA-155-5p, a previously published pro-inflammatory miRNA in multiple sclerosis known to be correlated to cholecalciferol levels. Our results show a decrease in miR-155-5p expression after cholecalciferol supplementation in both dosage groups, consistent with previous observations. Subsequent genotyping, gene expression, and eQTL analyses reveal correlations between miR-155-5p and the SARAF gene, which plays a role in the regulation of calcium release-activated channels. As such, the present study is the first to explore and suggest that the SARAF miR-155-5p axis hypothesis might be another mechanism by which cholecalciferol supplementation might decrease miR-155 expression. This association highlights the importance of cholecalciferol supplementation in multiple sclerosis and encourages further investigation and functional cell studies.
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MicroRNAs , Esclerose Múltipla , Humanos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/genética , Esclerose Múltipla/patologia , Regulação para Cima , Colecalciferol , Leucócitos Mononucleares/patologia , MicroRNAs/genética , Suplementos NutricionaisRESUMO
AIMS: Understanding of the molecular mechanisms of anti-TNFα therapy non-response and reliable biomarkers are essential for personalized medicine in Crohn's disease (CD) patients. Using RNA-seq data adjusted for deconvoluted fractions of peripheral blood cells, we recently described MMD gene, coding for a monocyte to macrophage differentiation factor, as a biomarker of adalimumab (anti-TNFα) therapy response in CD. The results also suggest that cell subtype-specific biomarkers may be superior to those measured in bulk peripheral blood. Here, we used functional cell model to further investigate the role of the monocyte to macrophage differentiation in adalimumab treatment response and evaluate monocyte/macrophage specific expression of the inflammatory cytokines as potential biomarkers for (non)response to adalimumab in CD patients. MAIN METHODS: The peripheral monocytes of CD patients responsive and non-responsive to adalimumab were isolated, differentiated into macrophages, and exposed to inflammation and concurrent adalimumab therapy in vitro. The results were correlated to the clinical response of the donor patients. KEY FINDINGS: Correlation is shown of the expression of two macrophage differentiation related genes- CD68 and MMD, with the expression of the inflammatory cytokines TNF, IL1B, IL6 and CXCL8. Monocytes and in vitro differentiated macrophages of adalimumab non-responders express more inflammatory cytokines than those of responders. The biggest difference was in the IL1B expression. Additionally, IL1B expression in the in vitro differentiated macrophages of CD patients correlates negatively with their clinical response to adalimumab. SIGNIFICANCE: We propose the IL1B expression in the macrophages as a possible biomarker for adalimumab response in CD patients.
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Doença de Crohn , Humanos , Adalimumab/farmacologia , Adalimumab/uso terapêutico , Doença de Crohn/tratamento farmacológico , Leucócitos Mononucleares , Citocinas , Biomarcadores , Interleucina-1betaRESUMO
Asthma is the most prevalent pediatric chronic disease. Bronchodilator drug response (BDR) and fractional exhaled nitric oxide (FeNO) are clinical biomarkers of asthma. Although DNA methylation (DNAm) contributes to asthma pathogenesis, the influence of DNAm on BDR and FeNO is scarcely investigated. This study aims to identify DNAm markers in whole blood associated either with BDR or FeNO in pediatric asthma. We analyzed 121 samples from children with moderate-to-severe asthma. The association of genome-wide DNAm with BDR and FeNO has been assessed using regression models, adjusting for age, sex, ancestry, and tissue heterogeneity. Cross-tissue validation was assessed in 50 nasal samples. Differentially methylated regions (DMRs) and enrichment in traits and biological pathways were assessed. A false discovery rate (FDR) < 0.1 and a genome-wide significance threshold of p < 9 × 10-8 were used to control for false-positive results. The CpG cg12835256 (PLA2G12A) was genome-wide associated with FeNO in blood samples (coefficient= -0.015, p = 2.53 × 10-9) and nominally associated in nasal samples (coefficient = -0.015, p = 0.045). Additionally, three CpGs were suggestively associated with BDR (FDR < 0.1). We identified 12 and four DMRs associated with FeNO and BDR (FDR < 0.05), respectively. An enrichment in allergic and inflammatory processes, smoking, and aging was observed. We reported novel associations of DNAm markers associated with BDR and FeNO enriched in asthma-related processes.
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Endometrial cancer is the most common gynecologic malignancy in the developed world. Risk stratification and treatment approaches are changing due to better understanding of tumor biology. Upregulated Wnt signaling plays an important role in cancer initiation and progression with promising potential for development of specific Wnt inhibitor therapy. One of the ways in which Wnt signaling contributes to progression of cancer, is by activating epithelial-to-mesenchymal transition (EMT) in tumor cells, causing the expression of mesenchymal markers, and enabling tumor cells to dissociate and migrate. This study analyzed the expression of Wnt signaling and EMT markers in endometrial cancer. Wnt signaling and EMT markers were significantly correlated with hormone receptors status in EC, but not with other clinico-pathological characteristics. Expression of Wnt antagonist, Dkk1 was significantly different between the ESGO-ESTRO-ESP patient risk assessment categories using integrated molecular risk assessment.
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Molecular diagnostic tests help clinicians understand the underlying biological mechanisms of their patients' breast cancer (BC) and facilitate clinical management. Several tissue-based mRNA tests are used routinely in clinical practice, particularly for assessing the BC recurrence risk, which can guide treatment decisions. However, blood-based mRNA assays have only recently started to emerge. This review explores the commercially available blood mRNA diagnostic assays for BC. These tests enable differentiation of BC from non-BC subjects (Syantra DX, BCtect), detection of small tumours <10 mm (early BC detection) (Syantra DX), detection of different cancers (including BC) from a single blood sample (multi-cancer blood test Aristotle), detection of BC in premenopausal and postmenopausal women and those with high breast density (Syantra DX), and improvement of diagnostic outcomes of DNA testing (variant interpretation) (+RNAinsight). The review also evaluates ongoing transcriptomic research on exciting possibilities for future assays, including blood transcriptome analyses aimed at differentiating lymph node positive and negative BC, distinguishing BC and benign breast disease, detecting ductal carcinoma in situ, and improving early detection further (expression changes can be detected in blood up to eight years before diagnosing BC using conventional approaches, while future metastatic and non-metastatic BC can be distinguished two years before BC diagnosis).
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BACKGROUND: Uncontrolled asthma can lead to severe exacerbations and reduced quality of life. Research has shown that the microbiome may be linked with asthma characteristics; however, its association with asthma control has not been explored. We aimed to investigate whether the gastrointestinal microbiome can be used to discriminate between uncontrolled and controlled asthma in children. METHODS: 143 and 103 feces samples were obtained from 143 children with moderate-to-severe asthma aged 6 to 17 years from the SysPharmPediA study. Patients were classified as controlled or uncontrolled asthmatics, and their microbiome at species level was compared using global (alpha/beta) diversity, conventional differential abundance analysis (DAA, analysis of compositions of microbiomes with bias correction), and machine learning [Recursive Ensemble Feature Selection (REFS)]. RESULTS: Global diversity and DAA did not find significant differences between controlled and uncontrolled pediatric asthmatics. REFS detected a set of taxa, including Haemophilus and Veillonella, differentiating uncontrolled and controlled asthma with an average classification accuracy of 81% (saliva) and 86% (feces). These taxa showed enrichment in taxa previously associated with inflammatory diseases for both sampling compartments, and with COPD for the saliva samples. CONCLUSION: Controlled and uncontrolled children with asthma can be differentiated based on their gastrointestinal microbiome using machine learning, specifically REFS. Our results show an association between asthma control and the gastrointestinal microbiome. This suggests that the gastrointestinal microbiome may be a potential biomarker for treatment responsiveness and thereby help to improve asthma control in children.
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Asma , Microbiota , Humanos , Criança , Qualidade de Vida , Asma/tratamento farmacológico , Bactérias , Fezes/microbiologiaRESUMO
Crohn's disease (CD), rheumatoid arthritis, psoriatic arthritis and other inflammatory diseases comprise a group of chronic diseases with immune-mediated pathogenesis which share common pathological pathways, as well as treatment strategies including anti-TNF biologic therapy. However, the response rate to anti-TNF therapy among those diseases varies, and approximately one third of patients do not respond. Since pharmacogenetic studies for anti-TNF therapy have been more frequent for other related diseases and are rare in CD, the aim of our study was to further explore markers associated with anti-TNF response in other inflammatory diseases in Slovenian CD patients treated with the anti-TNF drug adalimumab (ADA). We enrolled 102 CD patients on ADA, for which the response was defined after 4, 12, 20 and 30 weeks of treatment, using an IBDQ questionnaire and blood CRP value. We genotyped 41 SNPs significantly associated with response to anti-TNF treatment in other diseases. We found novel pharmacogenetic association between SNP rs755622 in the gene MIF (macrophage migration inhibitory factor) and SNP rs3740691 in the gene ARFGAP2 in CD patients treated with ADA. The strongest and most consistent association with treatment response was found for the variant rs2275913 in gene IL17A (p = 9.73 × 10-3).
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Artrite Reumatoide , Doença de Crohn , Fatores Inibidores da Migração de Macrófagos , Humanos , Adalimumab/uso terapêutico , Doença de Crohn/genética , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Oxirredutases IntramolecularesRESUMO
BACKGROUND: Uncontrolled pediatric asthma has a large impact on patients and their caregivers. More insight into determinants of uncontrolled asthma is needed. We aim to compare treatment regimens, inhaler techniques, medication adherence and other characteristics of children with controlled and uncontrolled asthma in the: Systems Pharmacology approach to uncontrolled Paediatric Asthma (SysPharmPediA) study. MATERIAL AND METHODS: 145 children with moderate to severe doctor-diagnosed asthma (91 uncontrolled and 54 controlled) aged 6-17 years were enrolled in this multicountry, (Germany, Slovenia, Spain, and the Netherlands) observational, case-control study. The definition of uncontrolled asthma was based on asthma symptoms and/or exacerbations in the past year. Patient-reported adherence and clinician-reported medication use were assessed, as well as lung function and inhalation technique. A logistic regression model was fitted to assess determinants of uncontrolled pediatric asthma. RESULTS: Children in higher asthma treatment steps had a higher risk of uncontrolled asthma (OR (95%CI): 3.30 (1.56-7.19)). The risk of uncontrolled asthma was associated with a larger change in FEV1% predicted post and pre-salbutamol (OR (95%CI): 1.08 (1.02-1.15)). Adherence and inhaler techniques were not associated with risk of uncontrolled asthma in this population. CONCLUSION: This study showed that children with uncontrolled moderate-to-severe asthma were treated in higher treatment steps compared to their controlled peers, but still showed a higher reversibility response to salbutamol. Self-reported adherence and inhaler technique scores did not differ between controlled and uncontrolled asthmatic children. Other determinants, such as environmental factors and differences in biological profiles, may influence the risk of uncontrolled asthma in this moderate to severe asthmatic population.
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Antiasmáticos , Asma , Criança , Humanos , Antiasmáticos/uso terapêutico , Estudos de Casos e Controles , Administração por Inalação , Asma/tratamento farmacológico , Albuterol/uso terapêuticoRESUMO
The prevention and treatment of skin diseases remains a major challenge in medicine. The search for natural active ingredients that can be used to prevent the development of the disease and complement treatment is on the rise. Natural extracts of ginger and hemp offer a wide range of bioactive compounds with potential health benefits. This study evaluates the effectiveness of hemp and ginger extract as a supportive treatment for skin diseases. It reports a synergistic effect of hemp and ginger extract. The contents of cannabinoids and components of ginger are determined, with the highest being CBD (587.17 ± 8.32 µg/g) and 6-gingerol (60.07 ± 0.40 µg/g). The minimum inhibitory concentration for Staphylococcus aureus (156.5 µg/mL), Escherichia coli (625.2 µg/mL) and Candida albicans (78.3 µg/mL) was also analyzed. Analysis of WM-266-4 cells revealed the greatest decrease in metabolic activity in cells exposed to the extract at a concentration of 1.00 µg/mL. Regarding the expression of genes associated with cellular processes, melanoma aggressiveness, resistance and cell survival, a significant difference was found in the expression of ABCB5, CAV1 and S100A9 compared with the control (cells not exposed to the extract).
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Cannabis , Zingiber officinale , Extratos Vegetais/farmacologia , Extratos Vegetais/análise , Testes de Sensibilidade MicrobianaRESUMO
BACKGROUND: Acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) represent a group of hematological malignancies characterized by the pathogenic clonal expansion of leukemic myeloid cells. The diagnosis and clinical outcome of AML and CML are complicated by genetic heterogeneity of disease; therefore, the identification of novel molecular biomarkers and pharmacological targets is of paramount importance. METHODS: RNA-seq-based transcriptome data from a total of five studies were extracted from NCBI GEO repository and subjected to an in-depth bioinformatics analysis to identify differentially expressed genes (DEGs) between AML and CML. A systemic literature survey and functional gene ontology (GO) enrichment analysis were performed for the top 100 DEGs to identify novel candidate genes and biological processes associated with AML and CML. RESULTS: LINC01554, PTMAP12, LOC644936, RPS27AP20 and FAM133CP were identified as novel risk genes for AML and CML. GO enrichment analysis showed that DEGs were significantly associated with pre-RNA splicing, reactive oxygen species and glycoprotein metabolism, the cellular endomembrane system, neutrophil migration and antimicrobial immune response. CONCLUSIONS: Our study revealed novel biomarkers and specific biological processes associated with AML and CML. Further studies are required to evaluate their value as molecular targets for managing and treating the myeloid malignancies.
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Crohn's disease is a consequence of dysregulated inflammatory response to the host's microbiota. Although anti-TNF treatment improves the quality of the patient's life, a large proportion of patients lose response to the treatment. The past decade of research has led to a continuum of studies showcasing the heterogeneity of anti-TNF response; thus, the aim of the present study was to dissect transcriptome-wide findings to transcript isoform specific levels and combine the analyses with refined information of immune cell landscapes in colon tissue, and subsequently select promising candidates using gene ontology and genomic integration. We enrolled Slovenian Crohn's disease patients who were naïve with respect to adalimumab treatment. We performed colon tissue RNA sequencing and peripheral blood mononuclear cell DNA genotyping with a subsequent contemporary integrative approach to combine immune cell deconvoluted isoform transcript specific transcriptome analysis, gene ontology layering and genomic data. We identified nine genes (MACF1, CTSE, HDLBP, HSPA9, HLA-DMB, TAP2, LGMN, ANAPC11, ACP5) with 15 transcripts and 16 variants involved in the adalimumab response. Our study identified loci, some of which were previously shown to contribute to inflammatory bowel disease susceptibility, as novel loci involved in adalimumab response in Crohn's disease patients.
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Anti-TNF therapy has significantly improved disease control in rheumatoid arthritis, but a fraction of rheumatoid arthritis patients do not respond to anti-TNF therapy or lose response over time. Moreover, the mechanisms underlying non-response to anti-TNF therapy remain largely unknown. To date, many single biomarkers of response to anti-TNF therapy have been published but they have not yet been analyzed as a system of interacting nodes. The aim of our study is to systematically elucidate the biological processes underlying non-response to anti-TNF therapy in rheumatoid arthritis using the gene ontologies of previously published predictive biomarkers. Gene networks were constructed based on published biomarkers and then enriched gene ontology terms were elucidated in subgroups using gene ontology software tools. Our results highlight the novel role of proteasome-mediated protein catabolic processes (p = 2.91 × 10-15) and plasma lipoproteins (p = 4.55 × 10-11) in anti-TNF therapy response. The results of our gene ontology analysis help elucidate the biological processes underlying non-response to anti-TNF therapy in rheumatoid arthritis and encourage further study of the highlighted processes.
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BACKGROUND: Asthma exacerbations are a serious public health concern due to high healthcare resource utilization, work/school productivity loss, impact on quality of life, and risk of mortality. The genetic basis of asthma exacerbations has been studied in several populations, but no prior study has performed a multi-ancestry meta-analysis of genome-wide association studies (meta-GWAS) for this trait. We aimed to identify common genetic loci associated with asthma exacerbations across diverse populations and to assess their functional role in regulating DNA methylation and gene expression. METHODS: A meta-GWAS of asthma exacerbations in 4989 Europeans, 2181 Hispanics/Latinos, 1250 Singaporean Chinese, and 972 African Americans analyzed 9.6 million genetic variants. Suggestively associated variants (p ≤ 5 × 10-5 ) were assessed for replication in 36,477 European and 1078 non-European asthma patients. Functional effects on DNA methylation were assessed in 595 Hispanic/Latino and African American asthma patients and in publicly available databases. The effect on gene expression was evaluated in silico. RESULTS: One hundred and twenty-six independent variants were suggestively associated with asthma exacerbations in the discovery phase. Two variants independently replicated: rs12091010 located at vascular cell adhesion molecule-1/exostosin like glycosyltransferase-2 (VCAM1/EXTL2) (discovery: odds ratio (ORT allele ) = 0.82, p = 9.05 × 10-6 and replication: ORT allele = 0.89, p = 5.35 × 10-3 ) and rs943126 from pantothenate kinase 1 (PANK1) (discovery: ORC allele = 0.85, p = 3.10 × 10-5 and replication: ORC allele = 0.89, p = 1.30 × 10-2 ). Both variants regulate gene expression of genes where they locate and DNA methylation levels of nearby genes in whole blood. CONCLUSIONS: This multi-ancestry study revealed novel suggestive regulatory loci for asthma exacerbations located in genomic regions participating in inflammation and host defense.
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Asma , Estudo de Associação Genômica Ampla , Asma/genética , Predisposição Genética para Doença , Hispânico ou Latino/genética , Humanos , Polimorfismo de Nucleotídeo Único , Qualidade de VidaRESUMO
Metformin and 2-deoxy-D-glucose (2DG) exhibit multiple metabolic and immunomodulatory anti-cancer effects, such as suppressed proliferation or PD-L1 expression. Their combination or 2DG alone induce triple-negative breast cancer (TNBC) cell detachment, but their effects on mitochondria, crucial for anchorage-independent growth and metastasis formation, have not yet been evaluated. In the present study, we explored the effects of metformin, 2DG and their combination (metformin + 2DG) on TNBC cell mitochondria in vitro. Metformin + 2DG increased mitochondrial mass in TNBC cells. This was associated with an increased size but not number of morphologically normal mitochondria and driven by the induction of mitochondrial biogenesis rather than suppressed mitophagy. 2DG and metformin + 2DG strongly induced the unfolded protein response by inhibiting protein N-glycosylation. Together with adequate energy stress, this was one of the possible triggers of mitochondrial enlargement. Suppressed N-glycosylation by 2DG or metformin + 2DG also caused PD-L1 deglycosylation and reduced surface expression in MDA-MB-231 cells. PD-L1 was increased in low glucose and normalized by both drugs. 2DG and metformin + 2DG reduced PD-1 expression in Jurkat cells beyond the effects on activation, while cytokine secretion was mostly preserved. Despite increasing mitochondrial mass in TNBC cells, metformin and 2DG could therefore potentially be used as an adjunct therapy to improve anti-tumor immunity in TNBC.
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Transcriptome studies of peripheral blood cells can advance our understanding of the systemic immune response to the presence of cancer and the mechanisms underlying cancer onset and progression. This enables the identification of novel minimally invasive immune biomarkers for early cancer detection and personalized cancer management and may bring forward new immunotherapy options. Recent blood gene expression analyses in breast cancer (BC) identified distinct patient subtypes that differed in the immune reaction to cancer and were distinct from the clinical BC subtypes, which are categorized based on expression of specific receptors on tumor cells. Introducing new BC subtypes based on peripheral blood gene expression profiles may be appropriate, since it may assist in BC prognosis, the identification of patients likely to benefit from immunotherapy, and treatment efficacy monitoring. Triple-negative breast cancer (TNBC) is an aggressive, heterogeneous, and difficult-to-treat disease, and identification of novel biomarkers for this BC is crucial for clinical decision-making. A few studies have reported TNBC-enriched blood transcriptional signatures, mostly related to strong inflammation and augmentation of altered immune signaling, that can differentiate TNBC from other classical BC subtypes and facilitate diagnosis. Future research is geared toward transitioning from expression signatures in unfractionated blood cells to those in immune cell subpopulations.