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1.
Dent Med Probl ; 59(4): 555-564, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36524983

RESUMO

BACKGROUND: Due to their low specificity, non-enzymatic antioxidants play a significant role in the protection of organisms against free radicals. They are normally sourced from the diet, and independently react with oxidizing molecules and their products. OBJECTIVES: The study aimed to determine the concentrations of selected non-enzymatic antioxidants (uric acid (UA), reduced glutathione (GSH) and polyphenols) in the gingival fluid and saliva of patients diagnosed with periodontitis according to the current criteria. MATERIAL AND METHODS: This prospective case-control study included 50 patients with periodontitis, who were divided into 2 groups depending on disease severity, along with 25 healthy controls. Unstimulated saliva, stimulated saliva and gingival crevicular fluid (GCF) were collected from all subjects, and nonenzymatic antioxidant concentrations were determined. RESULTS: Significantly lower concentrations of all tested non-enzymatic antioxidants were observed in the gingival fluid as well as in the unstimulated and stimulated saliva of patients with periodontitis (p < 0.05). Moreover, the concentration of GSH was a parameter that differentiated the various degrees of periodontitis (p < 0.05). A significantly lower concentration of GSH was found in the stimulated saliva of patients with moderate progression as compared to those with fast progression of the disease (p < 0.05). CONCLUSIONS: The continuation of research on the GSH concentrations in the gingival fluid and saliva may be useful in the context of biomarkers for periodontitis progression.


Assuntos
Antioxidantes , Periodontite , Humanos , Antioxidantes/análise , Saliva/química , Estudos de Casos e Controles , Líquido do Sulco Gengival/química
2.
Nat Biotechnol ; 39(12): 1589-1596, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34282324

RESUMO

A substantial fraction of the human genome displays high sequence similarity with at least one other genomic sequence, posing a challenge for the identification of somatic mutations from short-read sequencing data. Here we annotate genomic variants in 2,658 cancers from the Pan-Cancer Analysis of Whole Genomes (PCAWG) cohort with links to similar sites across the human genome. We train a machine learning model to use signals distributed over multiple genomic sites to call somatic events in non-unique regions and validate the data against linked-read sequencing in an independent dataset. Using this approach, we uncover previously hidden mutations in ~1,700 coding sequences and in thousands of regulatory elements, including in known cancer genes, immunoglobulins and highly mutated gene families. Mutations in non-unique regions are consistent with mutations in unique regions in terms of mutation burden and substitution profiles. The analysis provides a systematic summary of the mutation events in non-unique regions at a genome-wide scale across multiple human cancers.


Assuntos
Genoma Humano , Neoplasias , Genoma Humano/genética , Genômica , Humanos , Mutação/genética , Neoplasias/genética , Sequências Reguladoras de Ácido Nucleico
3.
Biol Trace Elem Res ; 199(6): 2138-2144, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32839915

RESUMO

With the growing interest in new applications of metals in modern technologies, an increase in their concentration in the environment can be observed, which, in consequence, may constitute a hazard to human health. That is why it is of a great importance to establish "reference" levels of particular elements (essential or toxic) in human biological samples.The aim of this paper was to determine nickel in autopsy tissues of non-occupationally exposed subjects in Southern Poland (n = 60). Measurements were performed by means of electrothermal atomic absorption spectrometry after microwave-assisted acid digestion according to previously optimized and validated procedure. The results obtained indicate that data cover the wide range of concentrations and generally are consistent with other published findings. Nickel levels in the brain, stomach, liver, kidneys, lungs and heart (wet weight) were between 2.15-79.4 ng/g, 0.5-44.2 ng/g,7.85-519 ng/g, 12.8-725 ng/g, 8.47-333 ng/g and 2.3-97.7 ng/g, respectively. Females had generally lower levels of nickel in tissues than males (statistically significant relationships were found for the liver, kidneys and lungs), and median nickel concentrations in all studied material within all age groups had very similar values, with the exception of stomach.


Assuntos
Metais , Níquel , Feminino , Humanos , Fígado/química , Masculino , Níquel/análise , Polônia , Espectrofotometria Atômica
4.
Arch Med Sadowej Kryminol ; 70(1): 19-43, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32876420

RESUMO

AIM OF THE STUDY: Analysis of forensic medical opinions in the field of obstetrics prepared at the Department of Forensic Medicine, Jagiellonian University Medical College in Krakow, in 2010-2016, in order to evaluate changes in the number of filed cases involving an alleged medical error over the years, and determine the most common situations where medical errors are suspected by patients, and the most prevalent types of medical errors in obstetrics. MATERIAL AND METHODS: The opinions were divided into two groups. In the first group, the medical management was appropriate, while in the second group medical errors were identified. The medical errors were categorised as diagnostic/therapeutic, technical, and organisational. The effects of medical errors were classified as death, impairment to health, exposure to death, and exposure to impairment to health, by considering them separately for post-natal women, and for foetuses and neonates (during the first days of life). RESULTS: A total of 73 forensic medical opinions were analysed. In 25 cases, a medical error was identified. The most common situations in which a medical error was committed, and in which the suspicion of medical error proved to be unfounded, were listed. Overall, there were 17 diagnostic/therapeutic errors, 7 organisational errors, and 4 technical errors. In cases where a medical error was identified, there were 15 deaths, and in cases without a medical error - 31 deaths. CONCLUSIONS: It was found that 66% of the analysed forensic medical opinions involved no medical errors. In most of these cases, a therapeutic failure occurred, including perinatal haemorrhage, tight wrapping of the umbilical cord around the foetal neck (nuchal cord), premature birth, and septic complications. A few cases involved uncooperative patients. The most prevalent medical error was failure to perform or delaying a caesarean section when it was needed (because of emergency or urgent indications). The second most common medical error was related to incorrect CTG interpretation.


Assuntos
Competência Clínica/legislação & jurisprudência , Prova Pericial/legislação & jurisprudência , Medicina Legal/legislação & jurisprudência , Imperícia/legislação & jurisprudência , Complicações do Trabalho de Parto/patologia , Centros Médicos Acadêmicos , Prova Pericial/normas , Feminino , Humanos , Erros Médicos , Gravidez
5.
Dent Med Probl ; 56(1): 89-96, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30951624

RESUMO

BACKGROUND: Many factors influence decisions regarding gerodontological treatment. Apart from the clinical condition of a patient, there is a complex of crucial socioeconomic factors, comorbidities, place of residence, and psychological aspects. Therefore, gerodontological treatment plans are significantly diversified. OBJECTIVES: One of the goals of our cross-sectional epidemiological study of Lower Silesia seniors aged 65-74 was to identify all their needs related to gerodontological treatment. MATERIAL AND METHODS: From the randomly selected sample group of 1,600 people, 387 inhabitants of Wroclaw and Olawa reported to take part in the study. The anamnestic study identified demographic and socioeconomic determinants, coexistence of general diseases and behavioral variables related to oral health behaviors. In the clinical study, the decayed-missing-filled (DMF) index, the community periodontal index (CPI), oral hygiene indices, clinical pathological lesions in oral mucosa, and the index of prosthetic reconstruction of missing teeth according to the World Health Organization (WHO) were determined. Criteria for the need for prosthetic treatment, dental caries treatment, periodontal disease treatment, improvement of oral hygiene, and treatment of mucosal diseases, including potentially pre-cancerous and cancerous disorders, were defined. RESULTS: As many as 95.6% of all respondents required at least 1 form of dental treatment. The most common need (75%) was prosthetic treatment of missing teeth either in the maxilla or in the mandible. Forty-nine per cent of the respondents needed treatment of caries in the clinical crown or root of at least 1 tooth. Further, these needs were related to the following factors: treatment of oral mucosal diseases (35.4%), professional periodontal treatment (35%), improvement of very bad oral hygiene (29.2%), and oncological treatment of pre-cancerous and cancerous lesions in the oral cavity (9.6%). CONCLUSIONS: The needs for gerodontological treatment found in the regional study of young Lower Silesian seniors are very high and cannot be met by services provided and funded by the state.


Assuntos
Cárie Dentária , Doenças Periodontais , Idoso , Estudos Transversais , Cárie Dentária/epidemiologia , Humanos , Higiene Bucal , Doenças Periodontais/epidemiologia , Índice Periodontal , Polônia/epidemiologia
6.
Przegl Epidemiol ; 73(4): 531-547, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32237702

RESUMO

INTRODUCTION: The number of teeth in the elderly is the most essential epidemiological data in gerodontological studies. It depends mainly on two medical causes in the form of caries and periodontitis, as well as many risk factors and indicators for tooth preservation and loss. The goals of the cross-sectional study among the residents of Wroclaw and Olawa aged 65-74 have been to assess the number of preserved teeth, severe tooth loss and edentulism in a 30-year trend and in relation to current European regional data. In addition, the most important risk indicators for tooth preservation and loss in the assessed population will be determined. MATERIAL AND METHODS: After applying the two-tier stratification method from a group of 1,200 people, 387 volunteered for the study. The examination was conducted in dental offices in Wroclaw and Olawa, it consisted from clinical and anamnestic parts. The average number of preserved teeth in the entire group was 13.07 (median 15), there were 21.2% persons with functional dentition, 21.4% with severe tooth loss and 14.2% with edentulism. The main direct reason of tooth loss was caries and its complications, which concerned 81.9% of the teeth removed, on average over 12 teeth in the examined person. RESULTS: Referring the results of the obtained study to previous observations can be seen, that in the 30-year trend for Wroclaw in people aged 65 to 74 years, the average number of teeth as well as the percentage of edentulism have improved, but they are still worse than the results of regional European studies. The main risk indicators of earlier loss of teeth by seniors in Lower Silesia are low income, past incorrect pro-health behaviours towards the oral cavity as well as current smoking and history of cardiovascular incidence.


Assuntos
Assistência Odontológica/estatística & dados numéricos , Cárie Dentária/epidemiologia , Perda de Dente/epidemiologia , Idoso , Estudos Transversais , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Higiene Bucal/estatística & dados numéricos , Polônia/epidemiologia , Fatores de Risco
7.
Dent Med Probl ; 55(4): 405-410, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30648365

RESUMO

BACKGROUND: The morbidity of certain oral pathologies, for example denture-related stomatitis, burning mouth syndrome (BMS) and benign neoplasms is higher in the elderly. It is necessary to periodically assess the changes in the profile of the occurrence of these diseases and determine the dominant risk factors associated with their incidence. OBJECTIVES: The aim of the study was to evaluate the prevalence of oral mucosal pathologies (in particular, potentially malignant and cancerous disorders) in a randomly selected population of 65-74-year-old residents of Wroclaw and Olawa, Poland. MATERIAL AND METHODS: A group of 1,600 persons aged 65-74 years, living in Wroclaw (a large city) and Olawa (a small town) were randomly selected to participate in the study. 285 people from Wroclaw and 102 from Olawa were examined. In a clinical dental examination, the following parameters were assessed: the number of teeth; probing/pocket depth (PD) and clinical attachment level (CAL) for all the teeth at 4 measuring points (on this basis, periodontal diagnoses were made according to American recommendations - of the American Center for Disease Control and Prevention and the American Academy of Periodontology (CDC/AAP)); and the presence of prosthetic restorations and their quality. In the anamnestic study, variables concerning the socioeconomic status, systemic conditions (comorbidity of selected general diseases, nicotine addiction status, body mass) and selected behaviors promoting oral health were determined. RESULTS: The most common clinical changes in the oral mucosa were denture-related stomatitis (6.7%), hemangiomas (5.9%) and fibromas (4.1%). Potentially malignant disorders and cancerous lesions were diagnosed in 59 persons (15.2% of the respondents). One case of tongue cancer was diagnosed in an inhabitant of Olawa. CONCLUSIONS: More than 1/3 of the examined persons were diagnosed with certain clinical, pathological oral mucosal lesions requiring treatment, of which nearly half were potentially malignant and cancerous. Poor tooth brushing efficiency was associated with a higher incidence of pre-cancerous and cancerous lesions in the oral cavity.


Assuntos
Doenças da Boca/epidemiologia , Idoso , Feminino , Bolsa Gengival/epidemiologia , Humanos , Masculino , Doenças da Boca/patologia , Mucosa Bucal/patologia , Neoplasias Bucais/epidemiologia , Neoplasias Bucais/patologia , Perda da Inserção Periodontal/epidemiologia , Índice Periodontal , Polônia/epidemiologia , Prevalência
8.
Adv Clin Exp Med ; 26(3): 505-514, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28791827

RESUMO

BACKGROUND: The current level of knowledge indicates a relationship between periodontitis and diabetes and/or cardiovascular diseases (CVD). Periodontitis can be not only a risk factor for these diseases, but also a condition modifying other primary risk factors associated with the occurrence of cardiovascular complications (lipid disorders, arterial hypertension, etc.) or diabetes. OBJECTIVES: The aim of the study was an analysis of the correlation between the state of periodontal tissues and selected risk factors for myocardial infarction (MI) in patients after recent myocardial infarction. MATERIAL AND METHODS: The study included 417 patients (92 women, 325 men) hospitalized due to recent MI. The inclusion criteria were MI history and age below 70 years. The state of periodontal tissues (plaque index, bleeding on probing, pocket depth and clinical attachment loss, CPI index) and selected risk factors for periodontitis and CVD were recorded. RESULTS: An analysis of the results showed no statistically significant correlation between the depth, the number, percentage of periodontal pockets and the average clinical attachment level on one hand and BMI on the other hand. Whereas a statistically significant correlation was observed between tobacco smoking and the degree of severity of periodontal diseases measured by the average pocket depth, the number and percentage of pockets above 4 mm and the average clinical attachment loss, as well as between hypertension and the state of oral hygiene and between diabetes and the number of preserved teeth and the number of pockets above 4 mm. CONCLUSIONS: The degree of severity of periodontal disease can impact hypertension and diabetes, which could potentially influence the occurrence and course of CVD.


Assuntos
Infarto do Miocárdio/etiologia , Infarto do Miocárdio/patologia , Periodontite/etiologia , Periodontite/patologia , Periodonto/patologia , Adulto , Idoso , Feminino , Humanos , Hipertensão/etiologia , Hipertensão/patologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fumar/efeitos adversos
9.
Folia Med Cracov ; 57(1): 23-28, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28608859

RESUMO

The main goal of this study was to investigate possible residua of thymic tissue in 100 adult cadavers with no thoracic pathology known before, by dissection of standard locations of thymic tissue in perithyroid, periaortic, peritracheal and retrotracheal spaces, as well as areas located next to the course of phrenic, vagus and left recurrent laryngeal nerves. Thus obtained tissue samples were studied by two pathologists independently. The remnants of the thymic tissue were found in 61 out of 100 specimens studied. It means that residua of ectopic thymic tissue is common, which may have a huge impact on the results of treatment of many diseases i.e. myasthenia gravis in course of thymoma.


Assuntos
Coristoma/patologia , Doenças do Mediastino/patologia , Miastenia Gravis/patologia , Adulto , Cadáver , Feminino , Humanos , Masculino , Neoplasias do Timo/patologia
10.
Arch Orthop Trauma Surg ; 137(2): 277-283, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28012095

RESUMO

OBJECTIVES: The goal of our study was to analyze the prevalence of variations, branching patterns, and histology of the ulnar nerve (UN) in Guyon's canal to address its importance in hand surgery, particularly decompression of the UN. METHODS: Fifty fresh cadavers were dissected bilaterally, and the nerve in the area of Guyon's canal was visualized. Samples for histology were also taken and prepared. The collected data were then analyzed. RESULTS: Morphometric measurements of the hands and histological studies were not found to have significant differences when compared by left or right side or by sex. Three major branching patterns were found, with division into deep and superficial UN being the most common (85%). Additional findings included a majority (70%) presenting with a cutaneous branch within the canal and/or with an anastomosis of its distant branches with those of the median nerve (57%). CONCLUSION: The UN is most commonly found to divide into a superficial and deep ulnar branch within Guyon's canal. However, additional branches and anastomoses are common and should be taken into careful consideration when approached during surgery in the area, particularly during decompression procedures of Guyon's canal.


Assuntos
Mãos/anatomia & histologia , Nervo Ulnar/anatomia & histologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Cadáver , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
11.
Nat Commun ; 7: 13701, 2016 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-27922010

RESUMO

Lung cancer is the leading cause of cancer deaths, and effective treatments are urgently needed. Loss-of-function mutations in the DNA damage response kinase ATM are common in lung adenocarcinoma but directly targeting these with drugs remains challenging. Here we report that ATM loss-of-function is synthetic lethal with drugs inhibiting the central growth factor kinases MEK1/2, including the FDA-approved drug trametinib. Lung cancer cells resistant to MEK inhibition become highly sensitive upon loss of ATM both in vitro and in vivo. Mechanistically, ATM mediates crosstalk between the prosurvival MEK/ERK and AKT/mTOR pathways. ATM loss also enhances the sensitivity of KRAS- or BRAF-mutant lung cancer cells to MEK inhibition. Thus, ATM mutational status in lung cancer is a mechanistic biomarker for MEK inhibitor response, which may improve patient stratification and extend the applicability of these drugs beyond RAS and BRAF mutant tumours.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Proliferação de Células/efeitos dos fármacos , Neoplasias Pulmonares/prevenção & controle , Mutação , Inibidores de Proteínas Quinases/farmacologia , Animais , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Benzamidas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Difenilamina/análogos & derivados , Difenilamina/farmacologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos Nus , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Piridonas/farmacologia , Pirimidinonas/farmacologia , Interferência de RNA , Tiofenos/farmacologia , Ureia/análogos & derivados , Ureia/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas ras/genética , Proteínas ras/metabolismo
12.
PLoS Genet ; 12(9): e1006279, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27588951

RESUMO

Patterns of somatic mutations in cancer genes provide information about their functional role in tumourigenesis, and thus indicate their potential for therapeutic exploitation. Yet, the classical distinction between oncogene and tumour suppressor may not always apply. For instance, TP53 has been simultaneously associated with tumour suppressing and promoting activities. Here, we uncover a similar phenomenon for GATA3, a frequently mutated, yet poorly understood, breast cancer gene. We identify two functional classes of frameshift mutations that are associated with distinct expression profiles in tumours, differential disease-free patient survival and gain- and loss-of-function activities in a cell line model. Furthermore, we find an estrogen receptor-independent synthetic lethal interaction between a GATA3 frameshift mutant with an extended C-terminus and the histone methyltransferases G9A and GLP, indicating perturbed epigenetic regulation. Our findings reveal important insights into mutant GATA3 function and breast cancer, provide the first potential therapeutic strategy and suggest that dual tumour suppressive and oncogenic activities are more widespread than previously appreciated.


Assuntos
Neoplasias da Mama/genética , Epigênese Genética , Fator de Transcrição GATA3/genética , Antígenos de Histocompatibilidade/genética , Histona-Lisina N-Metiltransferase/genética , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/genética , Estrogênios/genética , Estrogênios/metabolismo , Feminino , Mutação da Fase de Leitura , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/uso terapêutico
13.
Bioinformatics ; 32(5): 657-63, 2016 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-26545822

RESUMO

MOTIVATION: Calling changes in DNA, e.g. as a result of somatic events in cancer, requires analysis of multiple matched sequenced samples. Events in low-mappability regions of the human genome are difficult to encode in variant call files and have been under-reported as a result. However, they can be described accurately through thesaurus annotation-a technique that links multiple genomic loci together to explicate a single variant. RESULTS: We here describe software and benchmarks for using thesaurus annotation to detect point changes in DNA from matched samples. In benchmarks on matched normal/tumor samples we show that the technique can recover between five and ten percent more true events than conventional approaches, while strictly limiting false discovery and being fully consistent with popular variant analysis workflows. We also demonstrate the utility of the approach for analysis of de novo mutations in parents/child families. AVAILABILITY AND IMPLEMENTATION: Software performing thesaurus annotation is implemented in java; available in source code on github at GeneticThesaurus (https://github.com/tkonopka/GeneticThesaurus) and as an executable on sourceforge at geneticthesaurus (https://sourceforge.net/projects/geneticthesaurus). Mutation calling is implemented in an R package available on github at RGeneticThesaurus (https://github.com/tkonopka/RGeneticThesaurus). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. CONTACT: tomasz.konopka@ludwig.ox.ac.uk.


Assuntos
Variação Genética , Genoma Humano , Genômica , Humanos , Software , Vocabulário Controlado
14.
Przegl Epidemiol ; 69(3): 537-42, 643-7, 2015.
Artigo em Inglês, Polonês | MEDLINE | ID: mdl-26519852

RESUMO

INTRODUCTION: The goal of this study was the evaluation of the periodontal health by means of CPI score in inhabitants of big and small cities in the age range from 65 to 74 and making comparison with previous Polish and European studies from XXI century. Also an average number of natural teeth, the edentulous persons percentage, the percentage of people with oral function maintenance and prevalence of oral mucosal diseases were evaluated. There were also attempts to evaluate essential behaviours related to the oral health and the percentage of people that are treated with use of non-reimbursed or reimbursed services. MATERIAL AND METHODS: Studies were conducted in 5 big cities: Warszawa, Szczecin, Wroclaw, Bialystok and Torun, as well as in 4 towns, such as Olawa, Police, Lobez and Elk. From sampling 7400 people aged from 65 to 74 years for the study reported only 807 people. In the mouth evaluated CPI score, number of natural teeth and prevalence of pathological lesions on cavity mucosa. Answers for questions on selected attitudes and health-seeking behaviours related to the oral health and the range of dental treatment were also analysed. RESULTS: Distribution of values of CPI codes in the whole group was as follows: CPI0-1.2%, CPI1-9.4%, CPI2-16.6%, CPI3-21.8%, CPI4-19.7% and the number of people excluded from examinations (1 tooth in the sextant or edentulous 31.3%). The state of the periodontium was worse in big cities and in men. An average number of teeth was 13.7 and was higher in big cities and in men. The percentage of edentulous persons was 28.9% and was higher in towns and in woman. The percentage of people with oral function maintenance was 25.15% and was higher in big cities and in men. The most three common pathologies of the oral cavity were leukoplakia and leukokeratosis that were found in 10.5% of examined people, candidiasis 5.82% and lichen planus 2.2%. CONCLUSION: The state of the periodontium of Poles at the age from 65 to 74 has not been improved in XXI century, but also does not significantly differ from an average European level. An average number of remaining teeth of Poles at this age has increased, but remains under a European average; also the prevalence of edentulism has decreased, but still remains one of the highest in Europe. The percentage of people with oral function maintenance is very low, thus needs for prosthetic treatment and rehabilitation of masticatory ability remain high. Precancerous lesions in the oral cavity are quite common in this age group. Health-seeking behaviours related to the oral health of older Poles are inadequate and result from a low level of knowledge on dental prophylaxis.


Assuntos
Necessidades e Demandas de Serviços de Saúde/estatística & dados numéricos , Saúde Bucal/estatística & dados numéricos , Higiene Bucal/estatística & dados numéricos , Doenças Periodontais/epidemiologia , Idoso , Cárie Dentária/epidemiologia , Inquéritos de Saúde Bucal , Placa Dentária/epidemiologia , Feminino , Humanos , Masculino , Polônia/epidemiologia , Prevalência
15.
Cell Rep ; 13(2): 277-89, 2015 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-26440892

RESUMO

Little is known about how RNA editing operates in cancer. Transcriptome analysis of 68 normal and cancerous breast tissues revealed that the editing enzyme ADAR acts uniformly, on the same loci, across tissues. In controlled ADAR expression experiments, the editing frequency increased at all loci with ADAR expression levels according to the logistic model. Loci-specific "editabilities," i.e., propensities to be edited by ADAR, were quantifiable by fitting the logistic function to dose-response data. The editing frequency was increased in tumor cells in comparison to normal controls. Type I interferon response and ADAR DNA copy number together explained 53% of ADAR expression variance in breast cancers. ADAR silencing using small hairpin RNA lentivirus transduction in breast cancer cell lines led to less cell proliferation and more apoptosis. A-to-I editing is a pervasive, yet reproducible, source of variation that is globally controlled by 1q amplification and inflammation, both of which are highly prevalent among human cancers.


Assuntos
Adenosina Desaminase/genética , Neoplasias da Mama/genética , Edição de RNA , Proteínas de Ligação a RNA/genética , Transcriptoma , Apoptose , Sequência de Bases , Proliferação de Células , Feminino , Dosagem de Genes , Humanos , Interferon Tipo I/genética , Interferon Tipo I/metabolismo , Células MCF-7 , Dados de Sequência Molecular
16.
Nucleic Acids Res ; 43(10): e68, 2015 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-25820428

RESUMO

Detecting genetic variation is one of the main applications of high-throughput sequencing, but is still challenging wherever aligning short reads poses ambiguities. Current state-of-the-art variant calling approaches avoid such regions, arguing that it is necessary to sacrifice detection sensitivity to limit false discovery. We developed a method that links candidate variant positions within repetitive genomic regions into clusters. The technique relies on a resource, a thesaurus of genetic variation, that enumerates genomic regions with similar sequence. The resource is computationally intensive to generate, but once compiled can be applied efficiently to annotate and prioritize variants in repetitive regions. We show that thesaurus annotation can reduce the rate of false variant calls due to mappability by up to three orders of magnitude. We apply the technique to whole genome datasets and establish that called variants in low mappability regions annotated using the thesaurus can be experimentally validated. We then extend the analysis to a large panel of exomes to show that the annotation technique opens possibilities to study variation in hereto hidden and under-studied parts of the genome.


Assuntos
Variação Genética , Genoma Humano , Genômica/métodos , Vocabulário Controlado , Linhagem Celular Tumoral , Exoma , Humanos , Anotação de Sequência Molecular , Sequências Repetitivas de Ácido Nucleico
17.
Endocr Relat Cancer ; 22(2): 205-16, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25691441

RESUMO

The contribution of intratumor heterogeneity to thyroid metastatic cancers is still unknown. The clonal relationships between the primary thyroid tumors and lymph nodes (LN) or distant metastases are also poorly understood. The objective of this study was to determine the phylogenetic relationships between matched primary thyroid tumors and metastases. We searched for non-synonymous single-nucleotide variants (nsSNVs), gene fusions, alternative transcripts, and loss of heterozygosity (LOH) by paired-end massively parallel sequencing of cDNA (RNA-Seq) in a patient diagnosed with an aggressive papillary thyroid cancer (PTC). Seven tumor samples from a stage IVc PTC patient were analyzed by RNA-Seq: two areas from the primary tumor, four areas from two LN metastases, and one area from a pleural metastasis (PLM). A large panel of other thyroid tumors was used for Sanger sequencing screening. We identified seven new nsSNVs. Some of these were early events clonally present in both the primary PTC and the three matched metastases. Other nsSNVs were private to the primary tumor, the LN metastases and/or the PLM. Three new gene fusions were identified. A novel cancer-specific KAZN alternative transcript was detected in this aggressive PTC and in dozens of additional thyroid tumors. The PLM harbored an exclusive whole-chromosome 19 LOH. We have presented the first, to our knowledge, deep sequencing study comparing the mutational spectra in a PTC and both LN and distant metastases. This study has yielded novel findings concerning intra-tumor heterogeneity, clonal evolution and metastases dissemination in thyroid cancer.


Assuntos
Carcinoma/genética , Neoplasias da Glândula Tireoide/genética , Idoso , Carcinoma/patologia , Carcinoma Papilar , Cromossomos Humanos Par 19/genética , Evolução Clonal , Humanos , Perda de Heterozigosidade , Metástase Linfática , Masculino , Polimorfismo de Nucleotídeo Único , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/patologia , Transcriptoma
18.
Nat Methods ; 10(10): 965-71, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24161985

RESUMO

Knockout collections are invaluable tools for studying model organisms such as yeast. However, there are no large-scale knockout collections of human cells. Using gene-trap mutagenesis in near-haploid human cells, we established a platform to generate and isolate individual 'gene-trapped cells' and used it to prepare a collection of human cell lines carrying single gene-trap insertions. In most cases, the insertion can be reversed. This growing library covers 3,396 genes, one-third of the expressed genome, is DNA-barcoded and allows systematic screens for a wide variety of cellular phenotypes. We examined cellular responses to TNF-α, TGF-ß, IFN-γ and TNF-related apoptosis-inducing ligand (TRAIL), to illustrate the value of this unique collection of isogenic human cell lines.


Assuntos
Biblioteca Gênica , Haploidia , Mutagênese Insercional/métodos , Genética Reversa/métodos , Linhagem Celular Tumoral , Genoma Humano , Humanos , Dados de Sequência Molecular
19.
J Med Chem ; 56(17): 6626-37, 2013 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-23845202

RESUMO

We designed and synthesized 48 aryl-1H-imidazole derivatives and investigated their in vitro growth inhibitory activity in cancer cell lines known to present various levels of resistance to proapoptotic stimuli. The IC50 in vitro growth inhibitory concentration of these compounds ranged from >100 µM to single digit µM. Among the most active compounds, 2i displayed similar in vitro growth inhibition in cancer cells independent of the cells' levels of resistance to proapoptotic stimuli and was found to be cytostatic in melanoma cell lines. Compound 2i was then tested by the National Cancer Institute Human Tumor Cell Line Anti-Cancer Drug Screen, and the NCI COMPARE algorithm did not reveal any correlation between its growth inhibition profiles with the NCI database compound profiles. The use of transcriptomically characterized melanoma models then enabled us to highlight mitochondrial targeting by 2i. This hypothesis was further confirmed by reactive oxygen production measurement and oxygen consumption analysis.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Imidazóis/farmacologia , Melanoma/patologia , Mitocôndrias/efeitos dos fármacos , Neoplasias/patologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Biológicos , Transcriptoma
20.
Nucleic Acids Res ; 41(7): e86, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23408855

RESUMO

High-throughput sequencing is becoming a popular research tool but carries with it considerable costs in terms of computation time, data storage and bandwidth. Meanwhile, some research applications focusing on individual genes or pathways do not necessitate processing of a full sequencing dataset. Thus, it is desirable to partition a large dataset into smaller, manageable, but relevant pieces. We present a toolkit for partitioning raw sequencing data that includes a method for extracting reads that are likely to map onto pre-defined regions of interest. We show the method can be used to extract information about genes of interest from DNA or RNA sequencing samples in a fraction of the time and disk space required to process and store a full dataset. We report speedup factors between 2.6 and 96, depending on settings and samples used. The software is available at http://www.sourceforge.net/projects/triagetools/.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Software , Algoritmos , Genes , Genes Neoplásicos , Humanos , Receptor Notch1/genética , Análise de Sequência de DNA/métodos , Análise de Sequência de RNA/métodos
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