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Neoadjuvant chemotherapy is the foundation treatment for triple-negative breast cancer (TNBC) and frequently results in pathological complete response (pCR). However, there are large differences in clinical response and survival after neoadjuvant chemotherapy of TNBC patients. The aim was to identify genes whose expression significantly associates with the efficacy of neoadjuvant chemotherapy in patients with TNBC. Transcriptomes of 46 formalin-fixed paraffin-embedded (FFPE) tumor samples from TNBC patients were analyzed by RNA-seq by comparing 26 TNBCs with pCR versus 20 TNBCs with pathological partial remission (pPR). Subsequently, we narrowed down the list of genes to those that strongly correlated with drug sensitivity of 63 breast cancer cell lines based on Dependency Map Consortium data re-analysis. Furthermore, the list of genes was limited to those presenting specific expression in breast tumor cells as revealed in three large published single-cell RNA-seq breast cancer datasets. Finally, we analyzed which of the selected genes were significantly associated with overall survival (OS) in TNBC TCGA dataset. A total of 105 genes were significantly differentially expressed in comparison between pPR versus pCR. As revealed by PLSR analysis in breast cancer cell lines, out of 105 deregulated genes, 42 were associated with sensitivity to docetaxel, doxorubicin, paclitaxel, and/or cyclophosphamide. We found that 24 out of 42 sensitivity-associated genes displayed intermediate or strong expression in breast malignant cells using single-cell RNAseq re-analysis. Finally, 10 out of 24 genes were significantly associated with overall survival in TNBC TCGA dataset. Our RNA-seq-based findings suggest that there might be transcriptomic signature consisted of 24 genes specifically expressed in tumor malignant cells for predicting neoadjuvant response in FFPE samples from TNBC patients prior to treatment initiation. Additionally, nine out of 24 genes were potential survival predictors in TNBC. This group of 24 genes should be further investigated for its potential to be translated into a predictive test(s).
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Nanosecond pulsed electric field (nsPEF) has emerged as a promising approach for inducing cell death in melanoma, either as a standalone treatment or in combination with chemotherapeutics. However, to date, there has been a shortage of studies exploring the impact of nsPEF on the expression of cancer-specific molecules. In this investigation, we sought to assess the effects of nsPEF on melanoma-specific MAGE (Melanoma Antigen Gene Protein Family) expression. To achieve this, melanoma cells were exposed to nsPEF with parameters set at 8 kV/cm, 200 ns duration, 100 pulses, and a frequency of 10 kHz. We also aimed to comprehensively describe the consequences of this electric field on melanoma cells' invasion and proliferation potential. Our findings reveal that following exposure to nsPEF, melanoma cells release microvesicles containing MAGE antigens, leading to a simultaneous increase in the expression and mRNA content of membrane-associated antigens such as MAGE-A1. Notably, we observed an unexpected increase in the expression of PD-1 as well. While we did not observe significant differences in the cells' proliferation or invasion potential, a remarkable alteration in the cells' metabolomic and lipidomic profiles towards a less aggressive phenotype was evident. Furthermore, we validated these results using ex vivo tissue cultures and 3D melanoma culture models. Our study demonstrates that nsPEF can elevate the expression of membrane-associated proteins, including melanoma-specific antigens. The mechanism underlying the overexpression of MAGE antigens involves the initial release of microvesicles containing MAGE antigens, followed by a gradual increase in mRNA levels, ultimately resulting in elevated expression of MAGE antigens post-experiment. These findings shed light on a novel method for modulating cancer cells to overexpress cancer-specific molecules, thereby potentially enhancing their sensitivity to targeted anticancer therapy.
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Exocitose , Antígenos Específicos de Melanoma , Melanoma , Humanos , Melanoma/metabolismo , Melanoma/patologia , Melanoma/genética , Melanoma/imunologia , Linhagem Celular Tumoral , Antígenos Específicos de Melanoma/metabolismo , Antígenos Específicos de Melanoma/genética , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Antígenos de Neoplasias/metabolismo , Antígenos de Neoplasias/genéticaRESUMO
Intellectual disability with speech delay and behavioural abnormalities, as well as hypotonia, seizures, feeding difficulties and craniofacial dysmorphism, are the main symptoms associated with pathogenic variants of the ZMYND11 gene. The range of clinical manifestations of the ZMYND phenotype is constantly being expanded by new cases described in the literature. Here, we present two previously unreported paediatric patients with neurodevelopmental challenges, who were diagnosed with missense variants in the ZMYND11 gene. It should be noted that one of the individuals manifested with hyperinsulinaemic hypoglycaemia (HH), a symptom that was not described before in published works. The reason for the occurrence of HH in our proband is not clear, so we try to explain the origin of this symptom in the context of the ZMYND11 syndrome. Thus, this paper contributes to knowledge on the range of possible manifestations of the ZMYND disease and provides further evidence supporting its association with neurodevelopmental challenges.
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Anormalidades Múltiplas , Deficiência Intelectual , Criança , Humanos , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/diagnóstico , Proteínas de Ciclo Celular/genética , Proteínas Correpressoras/genética , Proteínas de Ligação a DNA/genética , Deficiência Intelectual/genética , Deficiência Intelectual/diagnóstico , Mutação de Sentido Incorreto , Fenótipo , SíndromeRESUMO
The present study had the following aims: 1) to compare gut microbiota composition in patients with schizophrenia and controls and 2) to investigate the association of differentially abundant bacterial taxa with markers of inflammation, intestinal permeability, lipid metabolism, and glucose homeostasis as well as clinical manifestation. A total of 115 patients with schizophrenia during remission of positive and disorganization symptoms, and 119 controls were enrolled. Altogether, 32 peripheral blood markers were assessed. A higher abundance of Eisenbergiella, Family XIII AD3011 group, Eggerthella, Hungatella, Lactobacillus, Olsenella, Coprobacillus, Methanobrevibacter, Ligilactobacillus, Eubacterium fissicatena group, and Clostridium innocuum group in patients with schizophrenia was found. The abundance of Paraprevotella and Bacteroides was decreased in patients with schizophrenia. Differentially abundant genera were associated with altered levels of immune-inflammatory markers, zonulin, lipid profile components, and insulin resistance. Moreover, several correlations of differentially abundant genera with cognitive impairment, higher severity of negative symptoms, and worse social functioning were observed. The association of Methanobrevibacter abundance with the level of negative symptoms, cognition, and social functioning appeared to be mediated by the levels of interleukin-6 and RANTES. In turn, the association of Hungatella with the performance of attention was mediated by the levels of zonulin. The findings indicate that compositional alterations of gut microbiota observed in patients with schizophrenia correspond with clinical manifestation, intestinal permeability, subclinical inflammation, lipid profile alterations, and impaired glucose homeostasis. Subclinical inflammation and impaired gut permeability might mediate the association of gut microbiota alterations with psychopathological symptoms and cognitive impairment.
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Microbioma Gastrointestinal , Esquizofrenia , Humanos , Inflamação , Glucose , LipídeosRESUMO
Clostridioides difficile is a predominant nosocomial pathogen within the healthcare setting able to produce biofilms. Sub-minimum inhibitory concentrations (sub-MICs) of antibiotics trigger mechanisms affecting bacterial virulence, including increased adhesion and biofilm formation. The aim of this study was to investigate how sub-MICs of metronidazole affect the biofilm formation of C. difficile strains. We tested 14 reference and clinical C. difficile strains, including hypervirulent strains of RT027. The MICs of metronidazole for the tested strains were determined using the broth microdilution method. Biofilm formation was evaluated using confocal laser scanning microscopy. The C. difficile strains belonging to RT027 produced the highest amounts of biofilm. The results of confocal laser scanning microscopy showed that all the tested C. difficile strains developed larger biofilms with diversified architectures upon exposure to sub-MICs of metronidazole. In our study, we reveal that sub-MIC concentrations of metronidazole affect the biofilm formation of clinical and reference strains of C. difficile. Importantly, metronidazole induces biofilm formation via hypervirulent RT027 strains.
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Esophageal atresia (EA) is the most common malformation of the upper gastrointestinal tract. The estimated incidence of EA is 1 in 3500 births. EA is more frequently observed in boys and in twins. The exact cause of isolated EA remains unknown; a multifactorial etiology, including epigenetic gene expression modifications, is considered. The study included six pairs of twins (three pairs of monozygotic twins and three pairs of dizygotic twins) in which one child was born with EA as an isolated defect, while the other twin was healthy. DNA samples were obtained from the blood and esophageal tissue of the child with EA as well as from the blood of the healthy twin. The reduced representation bisulfite sequencing (RRBS) technique was employed for a whole-genome methylation analysis. The analyses focused on comparing the CpG island methylation profiles between patients with EA and their healthy siblings. Hypermethylation in the promoters of 219 genes and hypomethylation in the promoters of 78 genes were observed. A pathway enrichment analysis revealed the statistically significant differences in methylation profile of 10 hypermethylated genes in the Rho GTPase pathway, previously undescribed in the field of EA (ARHGAP36, ARHGAP4, ARHGAP6, ARHGEF6, ARHGEF9, FGD1, GDI1, MCF2, OCRL, and STARD8).
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Atresia Esofágica , Masculino , Criança , Humanos , Atresia Esofágica/genética , Gêmeos Monozigóticos/genética , Gêmeos Dizigóticos , Ilhas de CpG/genética , Epigênese Genética , Proteínas Proto-Oncogênicas , Fatores de Troca do Nucleotídeo Guanina , Fatores de Troca de Nucleotídeo Guanina RhoRESUMO
BACKGROUND: Most surgical margins for lentigo maligna melanomas reported in the literature are clinical and not histologic. OBJECTIVES: We sought to determine whether histologic margin status is an independent predictor of progression. METHODS: Clinicopathologic information of 268 invasive lentigo maligna melanomas diagnosed from 1990-2019 were analyzed. Statistical analyses were performed using Cox proportional hazards model and Boruta method. RESULTS: A total of 75% of the lesions were located on the head and neck. The range of follow-up for all patients was 0 to 31.8 years (median, 10.2 years). Time to local recurrence ranges from 0 to 20 years (median, 3 years). Progression developed in 54 (20.1%) of 268 patients. Local recurrence was seen only in 36 (13.4%), both local recurrence and subsequent metastasis in 7 (2.6%), and only metastasis in 11 (4.1%) of 268 patients. Histologic margin status (positive and close/<3 mm) and tumor site (head and neck location) significantly correlated with worse progression-free survival. LIMITATIONS: Single institution and retrospective study. CONCLUSIONS: Histologic margin status is the strongest predictor of progression for lentigo maligna melanoma. Patients with positive or close/<3 mm histologic margins should consider a re-excision due to the increased risk of relapse.
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Specific mechanisms underlying gut microbiota alterations in schizophrenia remain unknown. We aimed to compare gut microbiota between patients with schizophrenia and controls, taking into consideration exposure stress across lifespan, dietary habits, metabolic parameters and clinical manifestation. A total of 142 participants, including 89 patients with schizophrenia and 52 controls, were recruited. Gut microbiota were analyzed using the 16 S rRNA sequencing. Additionally, biochemical parameters related to glucose homeostasis, lipid profile and inflammation were assessed. Increased abundance of Lactobacillus and Limosilactobacillus as well as decreased abundance of Faecalibacterium and Paraprevotella were found in patients with schizophrenia. The machine learning analysis demonstrated that between-group differences in gut microbiota were associated with psychosocial stress (a history of childhood trauma, greater cumulative exposure to stress across lifespan and higher level of perceived stress), poor nutrition (lower consumption of vegetables and fish products), lipid profile alterations (lower levels of high-density lipoproteins) and cognitive impairment (worse performance of attention). Our findings indicate that gut microbiota alterations in patients with schizophrenia, including increased abundance of lactic acid bacteria (Lactobacillus and Limosilactobacillus) and decreased abundance of bacteria producing short-chain fatty acids (Faecalibacterium and Paraprevotella) might be associated with exposure to stress, poor dietary habits, lipid profile alterations and cognitive impairment.
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Microbioma Gastrointestinal , Esquizofrenia , Animais , Inflamação , Lipídeos , RNA Ribossômico 16S/genéticaRESUMO
BACKGROUND: Previous studies have reported a variety of gut microbiota alterations in patients with schizophrenia. However, none of these studies has investigated gut microbiota in patients with the deficit subtype of schizophrenia (D-SCZ) that can be characterized by primary and enduring negative symptoms. Therefore, in this study we aimed to profile gut microbiota of individuals with D-SCZ, compared to those with non-deficit schizophrenia (ND-SCZ) and healthy controls (HCs). METHODS: A total of 115 outpatients (44 individuals with D-SCZ and 71 individuals with ND-SCZ) during remission of positive and disorganization symptoms as well as 120 HCs were enrolled. Gut microbiota was analyzed using the 16 rRNA amplicon sequencing. Additionally, the levels of C-reactive protein (CRP), glucose and lipid metabolism markers were determined in the peripheral blood samples. RESULTS: Altogether 14 genera showed differential abundance in patients with D-SCZ compared to ND-SCZ and HCs, including Candidatus Soleaferrea, Eubacterium, Fusobacterium, Lachnospiraceae UCG-002, Lachnospiraceae UCG-004, Lachnospiraceae UCG-010, Libanicoccus, Limosilactobacillus, Mogibacterium, Peptococcus, Prevotella, Prevotellaceae NK3B31 group, Rikenellaceae RC9 gut group, and Slackia after adjustment for potential confounding factors. Observed alterations were significantly associated with cognitive performance in both groups of patients. Moreover, several significant correlations of differentially abundant genera with the levels of CRP, lipid profile parameters, glucose and insulin were found across all subgroups of participants. CONCLUSION: Findings from the present study indicate that individuals with D-SCZ show a distinct profile of gut microbiota alterations that is associated with cognitive performance, metabolic parameters and subclinical inflammation.
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Microbioma Gastrointestinal , Esquizofrenia , Humanos , Microbioma Gastrointestinal/genética , Esquizofrenia/microbiologia , Estudos de Casos e Controles , Glucose , ClostridialesRESUMO
Two accepted possible pathways for Merkel cell carcinoma (MCC) pathogenesis include the clonal integration of the Merkel cell polyomavirus (MCPyV) into the neoplastic cells and by UV irradiation. We hypothesize that, in UV etiology, the expression of genes associated with epithelial-mesenchymal transition (EMT) would be higher in MCPyV-negative MCCs. We compared RNA expression in 16 MCPyV-negative with that in 14 MCPyV-positive MCCs in 30 patients using NanoString panel of 760 gene targets as an exploratory method. Subsequently, we confirmed the findings with a publicly available RNA sequencing data set. The NanoString method showed that 29 of 760 genes exhibited significant deregulation. Ten genes (CD44, COL6A3, COL11A1, CXCL8, INHBA, MMP1, NID2, SPP1, THBS1, and THY1) were part of the EMT pathway. The expression of CDH1/E-cadherin, a key EMT gene, and TWIST1, regulator gene of EMT, was higher in MCPyV-negative tumors. To further investigate the expression of EMT genes in MCPyV-negative MCCs, we analyzed publicly available RNA sequencing data of 111 primary MCCs. Differential expression and gene set enrichment analysis of 35 MCPyV-negative versus 76 MCPyV-positive MCCs demonstrated significantly higher expression of EMT-related genes and associated pathways such as Notch signaling, TGF-ß signaling, and Hedgehog signaling, and UV response pathway in MCPyV-negative MCCs. The significance of the EMT pathway in MCPyV-negative MCCs was confirmed independently by a coexpression module analysis. One of the modules (M3) was specifically activated in MCPyV-negative MCCs and showed significant enrichment for genes involved in EMT. A network analysis of module M3 revealed that CDH1/E-cadherin was among the most connected genes (hubs). E-cadherin and LEF1 immunostains demonstrated significantly more frequent expression in MCPvV-negative versus MCPyV-positive tumors (P < .0001). In summary, our study showed that the expression of EMT-associated genes is higher in MCPyV-negative MCC. Because EMT-related proteins can be targeted, the identification of EMT pathways in MCPyV-negative MCCs is of potential therapeutic relevance.
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Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , Infecções por Polyomavirus , Neoplasias Cutâneas , Infecções Tumorais por Vírus , Humanos , Carcinoma de Célula de Merkel/genética , Carcinoma de Célula de Merkel/metabolismo , Carcinoma de Célula de Merkel/patologia , Neoplasias Cutâneas/metabolismo , Poliomavírus das Células de Merkel/genética , Infecções Tumorais por Vírus/complicações , Infecções Tumorais por Vírus/genética , Infecções por Polyomavirus/complicações , Infecções por Polyomavirus/genética , Transição Epitelial-Mesenquimal/genética , Proteínas Hedgehog , CaderinasRESUMO
Light can be guided without diffraction in prefabricated structures: optical fibers and waveguides or in actively created spatial solitons in optically nonlinear media. Here, an approach in which a self-stabilized optical waveguide develops from a reservoir of building blocks-spherical polymer microparticles (MPs)-and is pushed through an optically passive medium-water-is presented. The optical waveguide, formed by a chain of these microparticles and one microsphere wide, is self-stabilized and propelled by the guided light, while its geometrical and dynamical properties depend on the diameter-to-wavelength ratio. The smallest investigated particles, 500 nm in diameter, form single-mode waveguides up to tens of micrometers long, with the length limited only by optical losses. In contrast, waveguides constructed of larger MPs, 1 and 2.5 µm in diameter, are limited in length to only a few particles due to interference of different modes and beating of light intensity.
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The immense progress in molecular biology observed in the last decades has led to a fundamental change in our understanding of the etiology of human diseases. Whole genome analyses, both DNA sequencing and microarray comparative genomic hybridization, allowed for identification of previously unknown diseases and syndromes. Therefore, in difficulttodiagnose cases, clinical diagnosis is being replaced by molecular diagnosis (molecular dysmorphology, genomic medicine). For both scientific development of human genetics and clinical characteristics of rare genetic diseases, the construction and sharing of internationally available large databases has become crucial. However, genetic data have to be considered on the individual level too; therefore, they have to be treated as sensitive personal information. The context of ethical and legal risks involved in genetic testing has been long analyzed, although recognition of personal data protection issues is a more recent topic. The respective legal acts and protective measures should take into account several different aspects. The present paper explores major benefits and risks associated with international sharing of vast databases of genetic material, and presents legal provisions applied in the European Union, the United States, and China. The latter part is based on the respective acts themselves, as well as on analyses and commentaries by other scholars.
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Testes Genéticos , Medicina Genômica , Humanos , Estados Unidos , Hibridização Genômica Comparativa , Segurança ComputacionalRESUMO
BACKGROUND: To investigate the association between single nucleotide polymorphisms (SNPs) of PDCD1, CD274, and HAVCR2 genes with the risk and outcomes of non-small cell lung cancer (NSCLC) subtypes: squamous cell lung cancer (LUSC) and lung adenocarcinoma (LUAD). METHODS: TaqMan SNP genotyping assays or polymerase chain reaction-restriction fragment length polymorphism methods were used to determine genotypes of: PDCD1: rs36084323, rs7421861, rs11568821, rs2227981, rs10204525; CD274: rs822335, rs10815225, rs17718883, rs2297136, rs4742098, rs4143815; HAVCR2: rs10057302, rs1036199. Among 383 NSCLC patients, 112 were diagnosed with LUAD and 116 with LUSC. The control group consisted of 433 unrelated, cancer-free subjects. RESULTS: A CC genotype of rs4143815 and GG genotype of rs4742098 were associated with two times higher risk of developing LUSC (CC vs. GG + GC, OR = 2.31; 95% CI = 1.32, 4.06; P = 0.003; GG vs. AA + AG, OR = 2.26; 95% CI = 1.17, 4.36; P = 0.016, respectively). Moreover, rs4143815 was an independent predictor of the age at diagnosis of LUAD. The carriers of C allele were diagnosed 4.81 years later (95% CI = 1.47, 8.15; P = 0.006) than patients with the GG genotype. The rs10057302 CA genotype was an independent predictor of overall survival in LUSC (adjusted HR = 0.13; 95% CI = 0.02, 0.93; P = 0.043). NSCLC carriers of rs11568821 T allele had almost double the risk of death (adjusted HR = 2.05; 95% CI = 1.28, 3.29; P = 0.003) compared to carriers of CC genotype. CONCLUSIONS: Our results provided additional evidence that SNPs of genes for PD-1, PD-L1 and TIM-3 differentially modulate the risk and prognosis of LUSC and LUAD.
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Adenocarcinoma de Pulmão , Adenocarcinoma , Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Receptor de Morte Celular Programada 1/genética , Antígeno B7-H1/genética , Predisposição Genética para Doença , Adenocarcinoma/genética , Carcinoma de Células Escamosas/genética , Polimorfismo de Nucleotídeo Único , Prognóstico , Receptor Celular 2 do Vírus da Hepatite A/genéticaRESUMO
There is no published data regarding the molecular alterations of Polish patients with primary uveal melanoma. We performed whole exome sequencing of 20 primary uveal melanomas (UMs), 10 metastasizing and 10 non-metastasizing cases to identify significant molecular alterations. We detected mutations and copy number variants in the BAP1 gene in 50% (10 cases) of the cases. GNA11 mutations were detected in 50% (10 cases) including nine p.Q209L and one p.R183C. GNAQ mutations gene were detected in 40% (8 cases) and all were p.Q209P. SF3B1, EIF1AX, PLCB4 , and PALB2 mutations were detected in one case each. Genetic aberrations of FBXW7 were detected in 55% of cases, with copy number loss of 10 and missense mutation in one. Gain or loss of copy number was observed in 60%, 60%, and 10% of cases in MYC, MLH1 , and CDKN2A genes, respectively. BAP1 and GNAQ tumor suppressor genes are more often mutated in UM with metastasis, while GNA11 mutations are more frequently detected in non-metastasizing tumors. MYC copy gain was present twice as frequently (80% versus 40%) in cases with versus those without metastases. BAP1 mutation correlated with worse overall survival; while GNA11 mutation and CDKN2A loss correlated with better and worse progression-free survival, respectively. We have confirmed BAP1 prognostic potential and documented frequent MYC amplification in metastasizing cases. Although GNA11 mutation and CDKN2A loss significantly correlated with progression-free survival in our study, our sample size is small. The prognostic significance of GNAQ/GNA11 mutation and CDKN2A loss would require further investigation.
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Melanoma , Neoplasias Cutâneas , Neoplasias Uveais , Humanos , Análise Mutacional de DNA , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Melanoma/patologia , Mutação , Polônia , Ubiquitina Tiolesterase , Neoplasias Uveais/genéticaRESUMO
PURPOSE: Since molecular assays are not accessible to all uveal melanoma patients, we aim to identify cost-effective prognostic tool in risk stratification using machine learning models based on routine histologic and clinical variables. EXPERIMENTAL DESIGN: We identified important prognostic parameters in a discovery cohort of 164 enucleated primary uveal melanomas from 164 patients without prior therapies. We then validated the prognostic prediction of top important parameters identified in the discovery cohort using 80 uveal melanomas from the Tumor Cancer Genome Atlas database with available gene expression prognostic signature (GEPS). The performance of three different survival analysis models (Cox proportional hazards (CPH), random survival forest (RSF), and survival gradient boosting (SGB)) was compared against GEPS using receiver operating curves (ROC). RESULTS: In all three selection methods, BAP1 status, nucleoli size, age, mitotic rate per 1 mm2, and ciliary body infiltration were identified as significant overall survival (OS) predictors; and BAP1 status, nucleoli size, largest basal tumor diameter, tumor-infiltrating lymphocyte density, and tumor-associated macrophage density were identified as significant progression-free survival (PFS) predictors. ROC plots for the median survival time point showed that significant parameters in SGB studied model can predict OS better than GEPS. For PFS, SGB model performed similarly to GEPS. The time-dependent area under the curve (AUC) showed SGB model performing better than GEPS in predicting OS and metastatic risk. CONCLUSIONS: Our study shows that routine histologic and clinical variables are adequate for patient risk stratification in comparison with not readily accessible GEPS.
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Melanoma , Neoplasias Uveais , Humanos , Aprendizado de Máquina , Melanoma/patologia , Prognóstico , Transcriptoma , Neoplasias Uveais/genética , Neoplasias Uveais/patologiaRESUMO
BACKGROUND: The stage of colorectal cancer (CRC) at the day of diagnosis has the greatest influence on survival rate. Thus, for CRC, which is mainly identified as advanced disease, non-invasive, molecular blood or stool tests could boost the diagnosis and lower mortality. Evaluation of miRNA expression levels in serum of patients diagnosed with CRC is a potential tool in early screening. Screening can be supported by machine learning (ML) as a tool for developing a cancer risk predictive model based on genetic data. MATERIALS AND METHODS: miRNA was isolated from the serum of 8 patients diagnosed with CRC and 10 patients from a control group matched for age and sex. The expression of 179 miRNAs was determined using a serum/plasma panel (Exiqon). Determinations were conducted using real-time PCR technique on an Applied Biosystems QuantStudio3 device in 96-well plates. A predictive model was developed through the Azure Machine Learning platform. RESULTS: A wide panel of 29 up-regulated miRNAs in CRC were identified and divided into two subgroups: 1) miRNAs with significantly higher serum level in cancer patients vs. controls (24 miRNAs) and 2) miRNAs detected only in cancer patients and not in controls (5 miRNAs). Re-analysis of published miRNA profiles of CRC tumours or CRC exosomes revealed that only 2 out of 29 miRNAs were up-regulated in all datasets including ours (miR-34a and miR-25-3p). CONCLUSION: Our research suggests the potential role of overexpressed miRNAs as diagnostic or prognostic biomarkers among CRC patients. Such clustering of miRNAs may be a potential direction for discovering new diagnostic panels of cancer (including CRC), especially using ML. The low correspondence between deregulation of miRNAs in serum and tumour tissue revealed in our study confirms previously published reports.
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Neoplasias Colorretais , MicroRNAs , Biomarcadores Tumorais/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Aprendizado de Máquina , MicroRNAs/genéticaRESUMO
OBJECTIVE: The motility and genotype of the ï¬agellin ï¬iC and fliD genes were investigated in 82 Clostridioides difï¬cile isolates belonging to the ribotypes (RTs): 027 (n = 41), 176 (n = 17), 023 (n = 8), 017 (n = 6) and 046 (n = 10). The reference C. difficile strains 630 and M120 were included as controls for the motility assay. METHODS: A Multiple Locus Variable-number Tandem Repeat Analysis (MLVA) was used to exclude the genetic relatedness of C. difficile isolates belonging to the same RT. The variability of the fliC and fliD genes was determined by PCR-restriction fragment length polymorphism (RFLP) analysis and Sanger sequencing. The motility assay was carried out with 0.175% BHI agar tubes and BHI solid media plates with 0.4% agar. RESULTS: The highest motility was observed in C. difficile RT023 isolates (p < 0.01), followed by RTs 027 and 176. C. difficile isolates of RTs 017 and 046 were less motile than RTs 027, 176 and 023 (p < 0.01). The fliC and fliD genes were present in all clinical isolates irrespective of the motility results. In the fliC gene analysis, four different RFLP groups were identified (I, II, VII, X). The fliC group VII was identified in two RTs (027 and 176), whereas the remaining three groups (I, II and X) belonged to a single RT 046, 017 and 023, respectively. The fliD gene analysis identified four new RFLP groups (a, b, c and d). CONCLUSIONS: C. difficile RT023 is highly motile and its motility is comparable to the hypervirulent RT027 and its genetic relative RT176.
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Clostridioides difficile , Infecções por Clostridium , Proteínas de Bactérias/genética , Clostridioides , Clostridioides difficile/genética , Flagelina/genética , Genótipo , Humanos , RibotipagemRESUMO
Physical activity is a strong stimulus influencing the overall physiology of the human body. Exercises lead to biochemical changes in various tissues and exert an impact on gene expression. Exercise-induced changes in gene expression may be mediated by epigenetic modifications, which rearrange the chromatin structure and therefore modulate its accessibility for transcription factors. One of such epigenetic mark is DNA methylation that involves an attachment of a methyl group to the fifth carbon of cytosine residue present in CG dinucleotides (CpG). DNA methylation is catalyzed by a family of DNA methyltransferases. This reversible DNA modification results in the recruitment of proteins containing methyl binding domain and further transcriptional co-repressors leading to the silencing of gene expression. The accumulation of CpG dinucleotides, referred as CpG islands, occurs at the promoter regions in a great majority of human genes. Therefore, changes in DNA methylation profile affect the transcription of multiple genes. A growing body of evidence indicates that exercise training modulates DNA methylation in muscles and adipose tissue. Some of these epigenetic markers were associated with a reduced risk of chronic diseases. This review summarizes the current knowledge about the influence of physical activity on the DNA methylation status in humans.
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Tecido Adiposo/metabolismo , Doença Crônica/prevenção & controle , Metilação de DNA/genética , Exercício Físico/fisiologia , Músculo Esquelético/metabolismo , Tecido Adiposo/citologia , Ilhas de CpG/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Epigênese Genética , Humanos , Músculo Esquelético/citologia , Regiões Promotoras Genéticas/genéticaRESUMO
This paper analyzes the energy efficiency of a Micro Fiber Composite (MFC) piezoelectric system. It is based on a smart Lead Zirconate Titanate material that consists of a monolithic PZT (piezoelectric ceramic) wafer, which is a ceramic-based piezoelectric material. An experimental test rig consisting of a wind tunnel and a developed measurement system was used to conduct the experiment. The developed test rig allowed changing the air velocity around the tested bluff body and the frequency of forced vibrations as well as recording the output voltage signal and linear acceleration of the tested object. The mechanical vibrations and the air flow were used to find the optimal performance of the piezoelectric energy harvesting system. The performance of the proposed piezoelectric wind energy harvester was tested for the same design, but of different masses. The geometry of the hybrid bluff body is a combination of cuboid and cylindrical shapes. The results of testing five bluff bodies for a range of wind tunnel air flow velocities from 4 to 15 m/s with additional vibration excitation frequencies from 0 to 10 Hz are presented. The conducted tests revealed the areas of the highest voltage output under specific excitation conditions that enable supplying low-power sensors with harvested energy.