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1.
Cancers (Basel) ; 16(16)2024 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-39199687

RESUMO

There is a rich body of literature on the distribution of cancer incidence and mortality in socioeconomically different world regions, but none of the studies has compared the spatial distribution of mortality and incidence to see if they are consistent with each other. All malignant neoplasms combined and cervical, colorectal, breast, pancreatic, lung, and oral cancers separately were studied in the Hungarian population aged 25-64 years for 2007-2018 at the municipality level by sex. In each case, the spatial distribution of incidence and mortality were compared with each other and with the level of deprivation using disease mapping, spatial regression, risk analysis, and spatial scan statistics. A positive association between deprivation and mortality was found for each type of cancer, but there was no significant association for male colorectal cancer (relative risk (RR) 1.00; 95% credible interval (CI) 0.99-1.02), pancreatic cancer (RR: 1.01; 95%CI 0.98-1.04), and female colorectal cancer incidence (RR: 1.01; 95%CI 0.99-1.03), whereas a negative association for breast cancer (RR: 0.98; 95%CI 0.96-0.99) was found. Disease mapping analyses showed only partial overlap between areas of high incidence and mortality, often independent of deprivation. Our results highlight not only the diverse relationship between cancer burden and deprivation, but also the inconsistent relationship between cancer incidence and mortality, pointing to areas with populations that require special public health attention.

3.
Int J Mol Sci ; 25(8)2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38673837

RESUMO

The aim of this study was to apply a state-of-the-art quantitative lipidomic profiling platform to uncover lipid alterations predictive of melanoma progression. Our study included 151 melanoma patients; of these, 83 were without metastasis and 68 with metastases. Plasma samples were analyzed using a targeted Lipidyzer™ platform, covering 13 lipid classes and over 1100 lipid species. Following quality control filters, 802 lipid species were included in the subsequent analyses. Total plasma lipid contents were significantly reduced in patients with metastasis. Specifically, levels of two out of the thirteen lipid classes (free fatty acids (FFAs) and lactosylceramides (LCERs)) were significantly decreased in patients with metastasis. Three lipids (CE(12:0), FFA(24:1), and TAG47:2-FA16:1) were identified as more effective predictors of melanoma metastasis than the well-known markers LDH and S100B. Furthermore, the predictive value substantially improved upon combining the lipid markers. We observed an increase in the cumulative levels of five lysophosphatidylcholines (LPC(16:0); LPC(18:0); LPC(18:1); LPC(18:2); LPC(20:4)), each individually associated with an elevated risk of lymph node metastasis but not cutaneous or distant metastasis. Additionally, seventeen lipid molecules were linked to patient survival, four of which (CE(12:0), CE(14:0), CE(15:0), SM(14:0)) overlapped with the lipid panel predicting metastasis. This study represents the first comprehensive investigation of the plasma lipidome of melanoma patients to date. Our findings suggest that plasma lipid profiles may serve as important biomarkers for predicting clinical outcomes of melanoma patients, including the presence of metastasis, and may also serve as indicators of patient survival.


Assuntos
Lipidômica , Lipídeos , Melanoma , Humanos , Melanoma/sangue , Melanoma/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Lipídeos/sangue , Lipidômica/métodos , Idoso , Biomarcadores Tumorais/sangue , Adulto , Metástase Neoplásica , Metástase Linfática , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/patologia
4.
Geroscience ; 46(2): 2017-2031, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37798385

RESUMO

The demographic transition poses a significant challenge for health systems, especially in Central and Eastern European (CEE) countries, where the healthcare needs of aging populations are on the rise. This study aimed to describe and compare the health status and utilization of health services among the elderly residing in urban and rural areas of the most deprived region in Hungary. A comprehensive health survey was conducted in 2022, involving a randomly selected sample of 443 older adults (≥ 65 years) in Northeast Hungary. Multivariable logistic regression models adjusting for age, sex, education, financial status, chronic diseases, and activity limitations were used to investigate the association between type of residence and health service use. Among the study participants, 62.3% were female, 38.3% attained primary education, 12.5% reported a bad or very bad financial situation and 52.6% lived in urban areas. Overall, 24% of the elderly rated their health as very good or good (27.8% in urban and 19.7% in rural areas), while 57.8% (52.6% and 63.5% in urban and rural areas) reported limitations in daily activities. Compared to urban residents, rural residents reported lower rates of dentist visits (p = 0.006), specialist visits (p = 0.028), faecal occult blood testing (p < 0.001), colorectal cancer screening with colonoscopy (p = 0.014), and breast cancer screening (p = 0.035), and a higher rate of blood pressure measurement (p = 0.042). Multivariable models indicated that urban residence was positively associated with faecal occult blood testing (OR = 2.32, p = 0.014), but negatively associated with blood pressure (OR = 0.42, p = 0.017) and blood glucose measurements (OR = 0.48, p = 0.009). These findings highlight the influence of residence on health service utilization among older adults in Hungary. Further comprehensive studies are needed to better understand the health needs of the elderly population and to develop policies aimed at promoting healthy aging in CEE countries.


Assuntos
Serviços de Saúde , Aceitação pelo Paciente de Cuidados de Saúde , Humanos , Feminino , Idoso , Masculino , População Urbana , Hungria/epidemiologia , Nível de Saúde
6.
BMC Cancer ; 23(1): 540, 2023 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-37312079

RESUMO

BACKGROUND: The current management of lung cancer patients has reached a high level of complexity. Indeed, besides the traditional clinical variables (e.g., age, sex, TNM stage), new omics data have recently been introduced in clinical practice, thereby making more complex the decision-making process. With the advent of Artificial intelligence (AI) techniques, various omics datasets may be used to create more accurate predictive models paving the way for a better care in lung cancer patients. METHODS: The LANTERN study is a multi-center observational clinical trial involving a multidisciplinary consortium of five institutions from different European countries. The aim of this trial is to develop accurate several predictive models for lung cancer patients, through the creation of Digital Human Avatars (DHA), defined as digital representations of patients using various omics-based variables and integrating well-established clinical factors with genomic data, quantitative imaging data etc. A total of 600 lung cancer patients will be prospectively enrolled by the recruiting centers and multi-omics data will be collected. Data will then be modelled and parameterized in an experimental context of cutting-edge big data analysis. All data variables will be recorded according to a shared common ontology based on variable-specific domains in order to enhance their direct actionability. An exploratory analysis will then initiate the biomarker identification process. The second phase of the project will focus on creating multiple multivariate models trained though advanced machine learning (ML) and AI techniques for the specific areas of interest. Finally, the developed models will be validated in order to test their robustness, transferability and generalizability, leading to the development of the DHA. All the potential clinical and scientific stakeholders will be involved in the DHA development process. The main goals aim of LANTERN project are: i) To develop predictive models for lung cancer diagnosis and histological characterization; (ii) to set up personalized predictive models for individual-specific treatments; iii) to enable feedback data loops for preventive healthcare strategies and quality of life management. DISCUSSION: The LANTERN project will develop a predictive platform based on integration of multi-omics data. This will enhance the generation of important and valuable information assets, in order to identify new biomarkers that can be used for early detection, improved tumor diagnosis and personalization of treatment protocols. ETHICS COMMITTEE APPROVAL NUMBER: 5420 - 0002485/23 from Fondazione Policlinico Universitario Agostino Gemelli IRCCS - Università Cattolica del Sacro Cuore Ethics Committee. TRIAL REGISTRATION: clinicaltrial.gov - NCT05802771.


Assuntos
Neoplasias Pulmonares , Medicina de Precisão , Humanos , Inteligência Artificial , Multiômica , Qualidade de Vida , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia
7.
Mol Cell Probes ; 67: 101888, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36513244

RESUMO

Recently, liquid biopsy, as a promising approach was introduced for the analysis of different tumor-derived circulating markers including tumor DNA and cell free DNA (ct/cfDNA). Identification of mutations in cfDNA may allow the early detection of tumors, as well as predicting and monitoring treatment responses in a minimally invasive way. In the present study, we used commercially available gene panels to verify the mutation overlap between liquid biopsy and abnormalities detected in colorectal tumor tissue. The two panels (Archer®VariantPlex®Solid Tumor and LIQUIDPlexTM ctDNA) overlap in 23 genes, which enables a comprehensive view of tumor-plasma mutational status by next generation sequencing. We successfully analyzed 16 plasma and 16 tumor samples. We found that 87% of tumor tissues contained 44 mutations in 12 genes and 43.8% of cfDNA harbored 13 mutations in 5 genes. To verify whether the mutation pattern of the tumor DNA could be consistently detected in plasma cfDNA, we compared the alterations between cfDNA and matched tissue DNA in nine patients. Six of the 9 tumor tissues harbored mutations in TP53, KRAS or MET genes, those were not detectable by the ctDNA kit, even eventhough the exons of these genes overlap in both panels. Comparing the mutational patterns of the matched samples, we found that only one cfDNA had the same mutations (KRAS, SMAD4 and TP53) in the paired tissue. The results of the comparison between tumor tissue DNA and matched plasma cfDNA underline the importance of studying the paired solid tumor and plasma samples together.


Assuntos
Ácidos Nucleicos Livres , DNA Tumoral Circulante , Neoplasias Colorretais , Humanos , DNA Tumoral Circulante/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Mutação , Biópsia Líquida , Neoplasias Colorretais/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Biomarcadores Tumorais/genética
8.
J Cardiovasc Dev Dis ; 9(9)2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36135440

RESUMO

This study aims to provide an overview of multivariable prognostic modelling studies developed for coronary heart disease (CHD) in the general population and to explore the optimal prognostic model by comparing the models' performance. A systematic review was performed using Embase, PubMed, Cochrane, Web of Science, and Scopus databases until 30 November 2019. In this work, only prognostic studies describing conventional risk factors alone or a combination of conventional and genomic risk factors, being developmental and/or validation prognostic studies of a multivariable model, were included. A total of 4021 records were screened by titles and abstracts, and 72 articles were eligible. All the relevant studies were checked by comparing the discrimination, reclassification, and calibration measures. Most of the models were developed in the United States and Canada and targeted the general population. The models included a set of similar predictors, such as age, sex, smoking, cholesterol level, blood pressure, BMI, and diabetes mellitus. In this study, many articles were identified and screened for consistency and reliability using CHARM and GRIPS statements. However, the usefulness of most prognostic models was not demonstrated; only a limited number of these models supported clinical evidence. Unfortunately, substantial heterogeneity was recognized in the definition and outcome of CHD events. The inclusion of genetic risk scores in addition to conventional risk factors might help in predicting the incidence of CHDs; however, the generalizability of the existing prognostic models remains open. Validation studies for the existing developmental models are needed to ensure generalizability, improve the research quality, and increase the transparency of the study.

9.
Front Cardiovasc Med ; 8: 647416, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34765649

RESUMO

Background: Interactions between genetic and environmental risk factors (GxE) contribute to an increased risk of venous thromboembolism (VTE). Understanding how these factors interact provides insight for the early identification of at-risk groups within a population and creates an opportunity to apply appropriate preventive and curative measures. Objective: To estimate and compare GxE for VTE risk in the general Hungarian and Roma populations. Methods: The study was based on data extracted from a database consisting of results previously obtained from a complex health survey with three pillars (questionnaire-based, physical, and laboratory examinations) involving 406 general Hungarian and 395 Roma subjects. DNA was genotyped for rs121909567 (SERPINC1), rs1799963 (F2), rs2036914 (F11), rs2066865 (FGG), rs6025 (F5), and rs8176719 (ABO) polymorphisms. After allele frequency comparisons, the odds ratio (OR) was calculated for individual SNPs. Furthermore, genetic risk scores (weighted GRS, unweighted GRS) were computed to estimate the joint effect of the genetic factors. Multivariable linear regression analysis was applied to test the impact of GxE on VTE risk after interaction terms were created between genetic and VTE risk factors [diabetes mellitus (DM), cancer, chronic kidney diseases (CKD), coronary artery diseases (CAD), migraine, depression, obesity, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high density lipoprotein (HDL-C), triglyceride (TG), and smoking]. Results: Interestingly, the rs121909567 (SERPINC1, ATBp3 mutation) SNP was not present in the general population at all. However, the risk allele frequency was 1% among the Roma population, which might suggest a founder effect in this minority. This polymorphism multiplicatively interacted with CAD, CKD, cancer, DM, depression, migraine, and obesity. Even though interactions were not statistically significant, the trend of interaction showed the probability of an incremental VTE risk among the Roma population. The risk of VTE was 4.7 times higher (p > 0.05) for Roma subjects who had ≥3 wGRS (median value) compared with individuals having lower wGRS values but lower for the general subjects (OR = 3.1 × 10-8). Additionally, the risk of VTE was 6.6 times higher in the Roma population that had ≥3 risk alleles (median value) than in individuals with the 0-1 risk allele, and the overall risk was much higher for the Roma population (OR = 6.6; p > 0.05) than for the general Hungarian population (OR = 1.5; p > 0.05). Five positive and significant GxE interactions were identified in the Roma population. The risk of VTE was higher among depressive Roma subjects who carried the risk variant rs2036914 (ß = 0.819, p = 0.02); however, this interaction was not significant for the general subjects. The joint presence of high levels of LDL-C and rs2066865 (FGG) increased the VTE risk only among Roma individuals (ß = 0.389, p = 0.002). The possibility of VTE risk increment, as a result of a multiplicative interaction between rs8176719 (ABO) and cancer, was identified, which was higher for the Roma population (ß = 0.370, p < 0.001) than for the general population (ß = -0.042, p = 0.6). The VTE risk increased in the Roma population (ß = 0.280, p = 0.001), but was higher in the general population (ß = 0.423, p = 0.001) as a result of the multiplicative interaction between CAD and rs2036914 (F11). The presence of a multiplicative interaction between rs2066865 (FGG) and CAD increased the VTE risk for the Roma population (ß = 0.143, p = 0.046) but not for the general population (ß = -0.329, p < 0.001). Conclusions: rs121909567 (SERPINC1, ATBp3) was confirmed as a founder mutation in the Roma population. Our study revealed some evidence on the burden of the joint presence of genetic and environmental risk factors on VTE, although the finding is highly subjected to the selection and observational biases due to the very small number of VTE cases and the observational nature of the study design, respectively. As a result of higher genetic load and GxE interactions, this minority Roma population is at higher risk of VTE than the general Hungarian population. Thus, our results suggest the need for an intensive search for the rs121909567 (SERPINC1; ATBp3) founder mutation, which might be an important factor for the assessment of thrombotic disease susceptibility among the Roma population. In addition, we strongly recommend further studies among a large number of VTE cases to explore the more precise impact of genetic and environmental risk factors on VTE in the study populations.

10.
Pathol Oncol Res ; 27: 581395, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34257527

RESUMO

Osteopontin (OPN) is a multifunctional phosphoprotein that is expressed in different types of cancers, including melanoma. OPN overexpression is associated with tumor progression and metastasis formation; however, the role of OPN in cell invasion and metastasis formation is not completely understood. In this study we aimed to define OPN expression in melanoma tissues and cell lines and investigate the effect of OPN expression on cell proliferation and invasion after inhibiting OPN expression with small interfering RNA (siRNA). OPN gene expression was determined by qRT-PCR, while protein expression was examined using a Proteome Profiler Oncology Array. siRNA-mediated OPN knockdown led to decreased OPN expression in melanoma cell lines, which was associated with decreased cell proliferation and invasion. Proteome profile analysis revealed significantly different protein expression between the original and transfected cell lines. The altered expression of the differently expressed proteins was validated at the mRNA level. Furthermore, OPN-specific siRNA was able to reduce OPN expression and inhibit the invasiveness of melanoma cells. Our results revealed for the first time that silencing the OPN gene influences proliferation and invasion of melanoma cells by effecting EGFR, tenascin C, survivin, galectin-3 and enolase 2 expression. To predict protein-protein interactions along with putative pathways we used STRING analysis for the differentially expressed proteins. These proteins formed multiple clusters, including extracellular matrix organization, regulation of angiogenesis, cell death and cell migration, PI3K-Akt, MAPK and focal adhesion signaling pathways. Taken together these data suggest that OPN might be an ideal target for drug development and therapies.


Assuntos
Proliferação de Células/genética , Melanoma/genética , Osteopontina/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Melanoma/metabolismo , Melanoma/patologia , Osteopontina/metabolismo , Mapas de Interação de Proteínas , RNA Interferente Pequeno/genética , Transdução de Sinais/genética
11.
Artigo em Inglês | MEDLINE | ID: mdl-33808833

RESUMO

It is a matter of speculation whether the high prevalence of smoking among Hungarian Roma (HR) is related to genetic, gene-environmental interactions or cultural factors. Our aim is to compare the genetic susceptibility and possible effects of determinants associated with smoking behaviours in the Hungarian general (HG) and Roma populations. A complex health survey including three pillars (questionnaire, physical and laboratory examinations) was carried out (NHG = 412 and NHR = 402). Risk allele frequencies of ten single-nucleotide polymorphisms (SNPs) were compared, and their combined effect was estimated by computing unweighted and weighted genetic risk scores (GRS, wGRS). The effects of genetic and environmental factors were investigated in regression analyses after confounders were introduced. Socio-economic status (SES) was calculated based on the Kuppuswamy scale 2019. Risk allele frequencies of only four SNPs were found to be different between populations (p < 0.01). Median values of GRS did not differ, while the wGRS median was slightly higher among Roma individuals (5.2 vs. 4.9; p = 0.02). Roma individuals were more likely to be heavy smokers (ORmales = 2.05, 95% CI [1.47-2.86]; ORfemales = 1.89, 95% CI [1.58-2.25]. Smokers have lower SES compared to never smokers (SES ßHR = -0.039, p = 0.023; ßHG = -0.010, p = 0.049). An inverse relationship was found between SES and smoking behaviours (p < 0.0001) and was found to be a better predictor of smoking behaviours than genetic susceptibility. Our study findings suggest that the high prevalence of smoking behaviours and nicotine-dependence were not revealed to have a genetic susceptibility among HR individuals; therefore, the highest efforts should be focused on targeting SES-related factors in the Roma population. Strengths of the study: This is the first study carried out to investigate and detect the most relevant factors and the possible genetic background of the extremely high prevalence of smoking based in the Roma population. Limitations of the study: No standard instrument has been used to assess the intensity of addiction to nicotine. Because of some participants' unwillingness to define themselves as Roma, the overall HR population was not represented by the sample of this study.


Assuntos
Predisposição Genética para Doença , Roma (Grupo Étnico) , Feminino , Humanos , Hungria , Masculino , Roma (Grupo Étnico)/genética , Fumar , Classe Social
12.
Sci Rep ; 11(1): 3085, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33542357

RESUMO

Cardiovascular diseases (CVDs) are the number one cause of death globally, and the early identification of high risk is crucial to prevent the disease and to reduce healthcare costs. Short life expectancy and increased mortality among the Roma are generally accepted (although not indeed proven by mortality analyses) which can be partially explained by the high prevalence of cardiovascular risk factors (CVRF) among them. This study aims to elaborate on the prevalence of the most important CVD risk factors, assess the estimation of a 10-year risk of development of fatal and nonfatal CVDs based on the most used risk assessment scoring models, and to compare the Hungarian general (HG) and Roma (HR) populations. In 2018 a complex health survey was accomplished on the HG (n = 380) and HR (n = 347) populations. The prevalence of CVRS was defined and 10-year cardiovascular risk was estimated for both study populations using the following systems: Framingham Risk Score for hard coronary heart disease (FRSCHD) and for cardiovascular disease (FRSCVD), Systematic COronary Risk Evaluation (SCORE), ACC/AHA Pooled Cohort Equations (PCE) and Revised Pooled Cohort Equations (RPCE). After the risk scores had been calculated, the populations were divided into risk categories and all subjects were classified. For all CVD risk estimation scores, the average of the estimated risk was higher among Roma compared to the HG independently of the gender. The proportion of high-risk group in the Hungarian Roma males population was on average 1.5-3 times higher than in the general one. Among Roma females, the average risk value was higher than in the HG one. The proportion of high-risk group in the Hungarian Roma females population was on average 2-3 times higher compared to the distribution of females in the general population. Our results show that both genders in the Hungarian Roma population have a significantly higher risk for a 10-year development of cardiovascular diseases and dying from them compared to the HG one. Therefore, cardiovascular interventions should be focusing not only on reducing smoking among Roma but on improving health literacy and service provision regarding prevention, early recognition, and treatment of lipid disorders and diabetes among them.


Assuntos
Doenças Cardiovasculares/epidemiologia , Fatores de Risco de Doenças Cardíacas , Medição de Risco , Roma (Grupo Étnico) , Adulto , Doenças Cardiovasculares/patologia , Feminino , Humanos , Hungria/epidemiologia , Masculino , Pessoa de Meia-Idade
13.
Biomedicines ; 9(2)2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33498201

RESUMO

HA15 is a new anti-melanoma drug that triggers endoplasmic reticulum (ER) stress and causes deleterious effects on melanoma cell viability due to autophagy and apoptosis, regardless of driver mutations or drug resistance. In this study, we investigated the effect of HA15 on the viability/proliferation of BRAFV600E-mutant melanoma cells using different culture conditions. In contrast to the published data, we did not detect significant melanoma cell death under normal culture conditions using HA15 treatment. Indeed, only cells that were cultured under long-term starvation conditions were sensitive to the drug. Quantitative measurements of ER stress and autophagy markers showed that the compound HA15 does not trigger stress alone but synergistically enhances ER stress under starvation conditions. Importantly, we observed that the viability of normal melanocytes decreased significantly with treatment, even at low HA15 concentrations. Finally yet importantly, we were able to generate HA15-resistant cell lines, which failed by Cerezo et al. In summary, HA15 only influences the viability of cells that are starved for several hours before and during treatment. However, this in vitro setting is far from the in vivo conditions. In addition, our data clearly show that melanoma cells can acquire HA15 resistance. Further studies are needed to prove that HA15 is an effective anti-cancer agent.

14.
Pathol Oncol Res ; 26(4): 2557-2566, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32613561

RESUMO

In vitro cell cultures are frequently used to define the molecular background of drug resistance. The majority of currently available data have been obtained from 2D in vitro cultures, however, 3D cell culture systems (spheroids) are more likely to behave similarly to in vivo conditions. Our major aim was to compare the gene expression signature of 2D and 3D cultured BRAFV600E mutant melanoma cell lines. We successfully developed BRAF-drug resistant cell lines from paired primary/metastatic melanoma cell lines in both 2D and 3D in vitro cultures. Using Affymetrix Human Gene 1.0 ST arrays, we determined the gene expression pattern of all cell lines. Our analysis revealed 1049 genes (562 upregulated and 487 downregulated) that were differentially expressed between drug-sensitive cells grown under different cell cultures. Pathway analysis showed that the differently expressed genes were mainly associated with the cell cycle, p53, and other cancer-related pathways. The number of upregulated genes (72 genes) was remarkably fewer when comparing the resistant adherent cells to cells that grow in 3D, and were associated with cell adhesion molecules and IGF1R signalling. Only 1% of the upregulated and 5.6% of the downregulated genes were commonly altered between the sensitive and the resistant spheroids. Interestingly, we found several genes (BNIP3, RING1 and ABHD4) with inverse expression signature between sensitive and resistant spheroids, which are involved in anoikis resistance and cell cycle regulation. In summary, our study highlights gene expression alterations that might help to understand the development of acquired resistance in melanoma cells in tumour tissue.


Assuntos
Técnicas de Cultura de Células/métodos , Resistencia a Medicamentos Antineoplásicos/genética , Melanoma/genética , Esferoides Celulares , Células Tumorais Cultivadas , Humanos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Transcriptoma
15.
Exp Dermatol ; 29(1): 39-50, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31602702

RESUMO

Tumor cell invasion is one of the key processes during cancer progression, leading to life-threatening metastatic lesions in melanoma. As methylation of cancer-related genes plays a fundamental role during tumorigenesis and may lead to cellular plasticity which promotes invasion, our aim was to identify novel epigenetic markers on selected invasive melanoma cells. Using Illumina BeadChip assays and Affymetrix Human Gene 1.0 microarrays, we explored the DNA methylation landscape of selected invasive melanoma cells and examined the impact of DNA methylation on gene expression patterns. Our data revealed predominantly hypermethylated genes in the invasive cells affecting the neural crest differentiation pathway and regulation of the actin cytoskeleton. Integrative analysis of the methylation and gene expression profiles resulted in a cohort of hypermethylated genes (IL12RB2, LYPD6B, CHL1, SLC9A3, BAALC, FAM213A, SORCS1, GPR158, FBN1 and ADORA2B) with decreased expression. On the other hand, hypermethylation in the gene body of the EGFR and RBP4 genes was positively correlated with overexpression of the genes. We identified several methylation changes that can have role during melanoma progression, including hypermethylation of the promoter regions of the ARHGAP22 and NAV2 genes that are commonly altered in locally invasive primary melanomas as well as during metastasis. Interestingly, the down-regulation of the methylcytosine dioxygenase TET2 gene, which regulates DNA methylation, was associated with hypermethylated promoter region of the gene. This can probably lead to the observed global hypermethylation pattern of invasive cells and might be one of the key changes during the development of malignant melanoma cells.


Assuntos
Metilação de DNA , Melanoma/genética , Melanoma/secundário , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Citoesqueleto de Actina/genética , Citoesqueleto de Actina/metabolismo , Diferenciação Celular/genética , Linhagem Celular Tumoral , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Dioxigenases , Epigênese Genética , Proteínas Ativadoras de GTPase/genética , Expressão Gênica/genética , Perfilação da Expressão Gênica , Humanos , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Fenótipo , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas/genética
16.
Public Health Genomics ; 22(5-6): 208-214, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31805565

RESUMO

Medical practitioners are increasingly adopting a personalized medicine (PM) approach involving individually tailored patient care. The Personalized Prevention of Chronic Diseases (PRECeDI) consortium project, funded within the Marie Sklodowska Curie Action (MSCA) Research and Innovation Staff Exchange (RISE) scheme, had fostered collaboration on PM research and training with special emphasis on the prevention of chronic diseases. From 2014 to 2018, the PRECeDI consortium trained 50 staff members on personalized prevention of chronic diseases through training and research. The acquisition of skills from researchers came from dedicated secondments from academic and nonacademic institutions aimed at training on several research topics related to personalized prevention of cancer and cardiovascular and neurodegenerative diseases. In detail, 5 research domains were addressed: (1) identification and validation of biomarkers for the primary prevention of cardiovascular diseases, secondary prevention of Alzheimer disease, and tertiary prevention of head and neck cancer; (2) economic evaluation of genomic applications; (3) ethical-legal and policy issues surrounding PM; (4) sociotechnical analysis of the pros and cons of informing healthy individuals on their genome; and (5) identification of organizational models for the provision of predictive genetic testing. Based on the results of the research carried out by the PRECeDI consortium, in November 2018, a set of recommendations for policy makers, scientists, and industry has been issued, with the main goal to foster the integration of PM approaches in the field of chronic disease prevention.


Assuntos
Doença Crônica/terapia , Prestação Integrada de Cuidados de Saúde/organização & administração , Genômica/organização & administração , Medicina de Precisão/métodos , Medicina Preventiva/organização & administração , Humanos
17.
BMJ Open ; 9(9): e027296, 2019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31494598

RESUMO

OBJECTIVES: The objectives of our study were (1) to investigate the association between gender of the general practitioner (GP) and the quality of primary care in Hungary with respect to process indicators for GP performance and (2) to assess the size of the gender impact. STUDY DESIGN: A nation-wide cross-sectional study was performed in 2016. SETTING AND PARTICIPANTS: The study covered all general medical practices in Hungary (n=4575) responsible for the provision of primary healthcare (PHC) for adults. All GPs in their private practices are solo practitioners. MAIN OUTCOME MEASURES: Multilevel logistic regression models were used to analyse the association between GP gender and process indicators of PHC, and attributable proportion (AP) was calculated. RESULTS: 48% of the GPs (n=2213) were women in the study. The crude rates of care provided by female GPs were significantly higher for seven out of eight evaluated indicators than those provided by male GPs. Adjusted for practice, physician and patient factors, GP gender was associated with the haemoglobin A1c (HbA1c) measurement: OR=1.18, 95% CI (1.14 to 1.23); serum creatinine measurement: OR=1.14, 95% CI (1.12 to 1.17); lipid measurement: OR=1.14, 95% CI (1.11 to 1.16); eye examination: OR=1.06, 95% CI (1.03 to 1.08); mammography screening: OR=1.05, 95% CI (1.03 to 1.08); management of patients with chronic obstructive pulmonary disease: OR=1.05, 95% CI (1.01 to 1.09) and the composite indicator: OR=1.08, 95% CI (1.07 to 1.1), which summarises the number of care events and size of target populations of each indicator. The AP at the specific indicators varied from 0.97% (95% CI 0.49% to 1.44%) of influenza immunisation to 8.04% (95% CI 7.4% to 8.67%) of eye examinations. CONCLUSION: Female GP gender was an independent predictor of receiving higher quality of care. The actual size of the gender effect on the quality of services seemed to be notable. Factors behind the gender effect should receive more attention in quality improvement particularly in countries where the primary care is organised around solo practices.


Assuntos
Clínicos Gerais , Atenção Primária à Saúde , Prática Profissional/organização & administração , Fatores Sexuais , Estudos Transversais , Feminino , Clínicos Gerais/normas , Clínicos Gerais/estatística & dados numéricos , Humanos , Hungria , Masculino , Pessoa de Meia-Idade , Padrões de Prática Médica/estatística & dados numéricos , Atenção Primária à Saúde/normas , Atenção Primária à Saúde/estatística & dados numéricos , Melhoria de Qualidade , Indicadores de Qualidade em Assistência à Saúde , Desempenho Profissional
18.
Cent Eur J Public Health ; 27(1): 24-31, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30927393

RESUMO

OBJECTIVE: The poor health of Roma is well documented, but there is only limited data regarding the health of Roma children. The aim of this study was to describe the socioeconomic status, health related behaviour, and health of children living in segregated Roma settlements, and to compare the data with that of non-Roma children. METHODS: In March-April of 2011, a cross-sectional questionnaire-based survey among 11-year-old (211 boys and 252 girls) and 13-year-old (205 boys and 247 girls) children living in Roma settlements was performed (response rate: 91.5%). These data were compared with data from the Health Behaviour in School-Aged Children (HBSC) survey carried out in 2009/2010. RESULTS: The parents of Roma children were substantially less educated and less likely to be actively employed, and Roma children reported lower material welfare than non-Roma ones. The prevalence of consuming sweets and soft drinks at least 5 times per week was 1.5-2 times higher among Roma children. The prevalence of regular intense physical activity was higher at the age of 13 years among Roma boys, while physical inactivity was substantially higher in both age groups among Roma girls. Almost one quarter of Roma children and approximately 14% of non-Roma children had tried smoking at the age of 11. More Roma boys tried alcohol at the age of 11 than non-Roma ones. One in ten Roma children was obese in both age groups. The self-rated health status of Roma children was worse than that of non-Roma children. CONCLUSIONS: Children living in Roma settlements reported poorer socioeconomic conditions, higher consumption of sweets and soft drinks, earlier smoking and alcohol initiation, and worse self-rated health, but with some exceptions do not differ in fruit or vegetable consumption and BMI from general child population. To promote health of children living in Roma settlements, a multi-sector approach, special health education, plus social and health promotion programmes are needed.


Assuntos
Comportamentos Relacionados com a Saúde/etnologia , Nível de Saúde , Características de Residência/estatística & dados numéricos , Roma (Grupo Étnico)/estatística & dados numéricos , Adolescente , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/etnologia , Criança , Estudos Transversais , Feminino , Inquéritos Epidemiológicos/métodos , Humanos , Hungria/epidemiologia , Masculino , Prevalência , Roma (Grupo Étnico)/etnologia , Fumar/epidemiologia , Fumar/etnologia , Classe Social , Fatores Socioeconômicos , Inquéritos e Questionários
19.
Melanoma Res ; 29(4): 390-400, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30741840

RESUMO

Selective inhibition of the mutant BRAF protein is a highly promising therapeutic approach for melanoma patients carrying the BRAF mutation. Despite the remarkable clinical response, most patients develop resistance and experience tumour regrowth. To clarify the molecular background of BRAF inhibitor resistance, we generated four drug-resistant melanoma cell lines from paired primary/metastatic cell lines using a vemurafenib analogue PLX4720. Three of the resistant cell lines showed decreased proliferation after drug withdrawal, but the proliferation of one cell line (WM278) increased notably. Furthermore, we observed opposite phenomena in which a 'drug holiday' could not only be beneficial but also contribute to tumour progression. Using genomic and proteomic approaches, we found significantly different alterations between the sensitive and resistant cell lines, some of which have not been reported previously. In addition to several other changes, copy number gains were observed in all resistant cell lines on 8q24.11-q24.12 and 8q21.2. Gene expression analysis showed that most genes upregulated in the resistant cell lines were associated with cell motility and angiogenesis. Increased expression of six proteins (ANGPLT4, EGFR, Endoglin, FGF2, SerpinE1 and VCAM-1) and decreased expression of two proteins (osteopontin and survivin) were observed consistently in all resistant cell lines. In summary, we identified new genomic alterations and characterized the protein expression patterns associated with the resistant phenotype. Although several proteins have been shown to be associated with BRAF resistance, our study is the first to describe the association of VCAM-1 and osteopontin with BRAF resistance.


Assuntos
Indóis/farmacologia , Melanoma/tratamento farmacológico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Sulfonamidas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Humanos , Melanoma/genética , Melanoma/metabolismo , Melanoma/patologia , Terapia de Alvo Molecular , Mutação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Taxa de Sobrevida
20.
BMC Fam Pract ; 19(1): 67, 2018 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-29778099

RESUMO

BACKGROUND: Cervical cancer is a preventable disease. Unfortunately, its mortality is high in Hungary: 9.2 deaths /100000 women/year in 2015. The Hungarian organized, nationwide cervical screening program was launched in 2003, but it could improve the coverage rate of cervical cancer screening only by a few percentage points. The vast majority of women still uses opportunistic screening and the organized screening program had little impact on participation by women who never or rarely consult their gynecologists. We assessed whether involving general practitioners in the cervical cancer screening process would increase participation. METHODS: The study consisted of two parts: 1. A questionnaire-based health survey was conducted using a representative sample of women aged 25 to 65 years from 11 Hungarian counties, in which we studied where women obtained information about cervical cancer screening. 2. Additionally, a model program and its evaluation were implemented in the practices of general practitioners in one of the 11 counties (Zala county). In this program, general practitioners were informed of their patients' participation in the cervical cancer screening program, and they motivated those who refused the invitation. RESULTS: Questionnaire-based health survey: A total of 74% (95% confidence interval (CI): 70-77%) of the target population had a screening examination within the previous 3 years. The majority (58, 95% CI: 54-62%) of the target population did not ask for information about cervical cancer screening at all. Only 21% (95% CI: 17-26%) consulted their general practitioners about cancer screening. Evaluation of the model program: the general practitioners effectively motivated 24 out of 88 women (27, 95% CI: 18-38%) who initially refused to participate in the screening program. CONCLUSION: The majority of Hungarian women are not informed about cervical cancer screening beyond the invitation letter. General practitioners could play a more important role in mobilizing the population to utilize preventive services. The involvement of general practitioners in the organization of the cervical cancer screening program could increase the participation of those women who generally refuse the services.


Assuntos
Detecção Precoce de Câncer/métodos , Clínicos Gerais , Neoplasias do Colo do Útero , Adulto , Feminino , Clínicos Gerais/organização & administração , Clínicos Gerais/normas , Inquéritos Epidemiológicos , Humanos , Hungria/epidemiologia , Programas de Rastreamento/organização & administração , Programas de Rastreamento/normas , Pessoa de Meia-Idade , Modelos Organizacionais , Avaliação de Programas e Projetos de Saúde , Melhoria de Qualidade , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/epidemiologia
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