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1.
BMC Bioinformatics ; 21(1): 8, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31914944

RESUMO

BACKGROUND: Cell nuclei segmentation is a fundamental task in microscopy image analysis, based on which multiple biological related analysis can be performed. Although deep learning (DL) based techniques have achieved state-of-the-art performances in image segmentation tasks, these methods are usually complex and require support of powerful computing resources. In addition, it is impractical to allocate advanced computing resources to each dark- or bright-field microscopy, which is widely employed in vast clinical institutions, considering the cost of medical exams. Thus, it is essential to develop accurate DL based segmentation algorithms working with resources-constraint computing. RESULTS: An enhanced, light-weighted U-Net (called U-Net+) with modified encoded branch is proposed to potentially work with low-resources computing. Through strictly controlled experiments, the average IOU and precision of U-Net+ predictions are confirmed to outperform other prevalent competing methods with 1.0% to 3.0% gain on the first stage test set of 2018 Kaggle Data Science Bowl cell nuclei segmentation contest with shorter inference time. CONCLUSIONS: Our results preliminarily demonstrate the potential of proposed U-Net+ in correctly spotting microscopy cell nuclei with resources-constraint computing.


Assuntos
Núcleo Celular/patologia , Microscopia , Aprendizado Profundo , Humanos , Processamento de Imagem Assistida por Computador/métodos
2.
Gut ; 69(2): 355-364, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-30979717

RESUMO

OBJECTIVES: Polyploidy is a fascinating characteristic of liver parenchyma. Hepatocyte polyploidy depends on the DNA content of each nucleus (nuclear ploidy) and the number of nuclei per cell (cellular ploidy). Which role can be assigned to polyploidy during human hepatocellular carcinoma (HCC) development is still an open question. Here, we investigated whether a specific ploidy spectrum is associated with clinical and molecular features of HCC. DESIGN: Ploidy spectra were determined on surgically resected tissues from patients with HCC as well as healthy control tissues. To define ploidy profiles, a quantitative and qualitative in situ imaging approach was used on paraffin tissue liver sections. RESULTS: We first demonstrated that polyploid hepatocytes are the major components of human liver parenchyma, polyploidy being mainly cellular (binuclear hepatocytes). Across liver lobules, polyploid hepatocytes do not exhibit a specific zonation pattern. During liver tumorigenesis, cellular ploidy is drastically reduced; binuclear polyploid hepatocytes are barely present in HCC tumours. Remarkably, nuclear ploidy is specifically amplified in HCC tumours. In fact, nuclear ploidy is amplified in HCCs harbouring a low degree of differentiation and TP53 mutations. Finally, our results demonstrated that highly polyploid tumours are associated with a poor prognosis. CONCLUSIONS: Our results underline the importance of quantification of cellular and nuclear ploidy spectra during HCC tumorigenesis.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Poliploidia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Estudos de Casos e Controles , Diferenciação Celular/genética , Núcleo Celular/patologia , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Feminino , Hepatócitos/patologia , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
3.
Ceska Gynekol ; 84(5): 324-330, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31826627

RESUMO

OBJECTIVE: The aim of this study was to analyse the clinical outcome of patients with diagnosis of leiomyoma with bizarre nuclei (LBN) undergoing uterus saving surgery due to fertility preservation. DESIGN: Retrospective clinical study. SETTING: Department of Obstetrics and Gynaecology, First Faculty of Medicine, Charles University, General University Hospital, Prague. METHODS: This was a retrospective clinical study of patients with LBN diagnosis after myomectomy between January 2002 and June 2017 which were searched in our database. The data were obtained from medical documentation and from correspondence with patients. RESULTS: We identified 37 patients meeting the criteria in our database. The median age of the patients was 34.0 years. 30 patients (81.1%) underwent laparoscopic procedure, 7 (18.9.%) had open myomectomy. The perioperative appearance of fibroid was found normal in 27 cases (73.0%), in the rest the appearance was described somehow abnormal. The follow-up data were obtained from 35 women; the median follow-up time was 48 months. 9 patients (25.7%) needed re-intervention for fibroids with 2 specimens (22.2%) classified as LBN again. The overall pregnancy rate was 63.6% and life birth rate was 33.3%. We did not observe any distant recurrence of the disease or malignant recurrence or death related to the diagnosis. CONCLUSION: Uterus sparing surgery for treatment of LBN seems to be safe and reasonable therapy for women wishing to preserve fertility.


Assuntos
Laparoscopia , Leiomioma/cirurgia , Miomectomia Uterina , Neoplasias Uterinas/cirurgia , Adulto , Núcleo Celular/patologia , Feminino , Células Gigantes/patologia , Procedimentos Cirúrgicos em Ginecologia , Humanos , Laparoscopia/métodos , Leiomioma/patologia , Recidiva Local de Neoplasia , Preservação de Órgãos , Gravidez , Estudos Retrospectivos , Neoplasias Uterinas/patologia
4.
PLoS Pathog ; 15(9): e1007921, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31568537

RESUMO

Humans are frequently exposed to bacterial genotoxins involved in digestive cancers, colibactin and Cytolethal Distending Toxin (CDT), the latter being secreted by many pathogenic bacteria. Our aim was to evaluate the effects induced by these genotoxins on nuclear remodeling in the context of cell survival. Helicobacter infected mice, coculture experiments with CDT- and colibactin-secreting bacteria and hepatic, intestinal and gastric cells, and xenograft mouse-derived models were used to assess the nuclear remodeling in vitro and in vivo. Our results showed that CDT and colibactin induced-nuclear remodeling can be associated with the formation of deep cytoplasmic invaginations in the nucleus of giant cells. These structures, observed both in vivo and in vitro, correspond to nucleoplasmic reticulum (NR). The core of the NR was found to concentrate ribosomes, proteins involved in mRNA translation, polyadenylated RNA and the main components of the complex mCRD involved in mRNA turnover. These structures are active sites of mRNA translation, correlated with a high degree of ploidy, and involve MAPK and calcium signaling. Additional data showed that insulation and concentration of these adaptive ribonucleoprotein particles within the nucleus are dynamic, transient and protect the cell until the genotoxic stress is relieved. Bacterial genotoxins-induced NR would be a privileged gateway for selected mRNA to be preferably transported therein for local translation. These findings offer new insights into the context of NR formation, a common feature of many cancers, which not only appears in response to therapies-induced DNA damage but also earlier in response to genotoxic bacteria.


Assuntos
Toxinas Bacterianas/toxicidade , Helicobacter/patogenicidade , Ribonucleoproteínas/metabolismo , Animais , Linhagem Celular , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Núcleo Celular/patologia , Sobrevivência Celular , Dano ao DNA , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/patologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Mutagênicos/toxicidade , Peptídeos/toxicidade , Policetídeos/toxicidade , RNA Mensageiro/metabolismo
5.
Int J Nanomedicine ; 14: 5865-5874, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31534328

RESUMO

Purpose: To investigate the effect of precise modeling for Monte Carlo simulations of gold nanoparticles (GNPs) dose-enhanced radiotherapy, two models characterized by their distribution of GNPs in a simulated macroscopic cubic tumor were introduced. The motivation was the widely documented tendency of GNPs to localize around the cell nucleus. Methods: The introduced models composed of 2.7×107 ellipsoid cells, each of them containing a centrally located nucleus as the target for dose evaluation. In the first model, the spheres of GNP are homogeneously distributed in the whole tumor volume, and in the latter, GNPs are localized in the cytoplasms surrounded the nuclei. Results: The results achieved through applying Monte Carlo radiation transports using the Mont Carlo N-Particle eXtended code (MCNPX) show an underestimation of nuclear dose enhancement caused by homogeneous model compared with that of heterogeneous distribution. By investigating various quantities, it was found that subcellular location of GNPs strongly governs the sensitivity of dose enhancement to the number and concentration of GNPs targeted in the tumor. Other obvious differences are revealed by studying the dose enhancement curves in depth of the tumor. While the heterogeneous model predicts an approximately constant dose enhancement in depth for primary photon energies of 50 keV and more, the homogeneous model estimates an energy-dependent increase of about 11 to 30%. Conclusion: It can be concluded that defining a model in accordance with the experimental observations can effectively account for accurate prediction of macroscopic dose enhancement in the target of interest.


Assuntos
Ouro/química , Nanopartículas Metálicas/química , Dosagem Radioterapêutica , Núcleo Celular/patologia , Núcleo Celular/efeitos da radiação , Humanos , Método de Monte Carlo , Neoplasias/patologia , Neoplasias/radioterapia , Fótons
6.
Aquat Toxicol ; 216: 105293, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31522060

RESUMO

The organic UV filter benzophenone-3 (BP-3), widely used in the commercial formulations of sunscreens and personal care products, is considered an emerging pollutant and has been associated with several human and environmental health concerns. However, knowledge about their mode of action and ecotoxicity on aquatic biota is scarce. In this scenario, the objective of this work was to evaluate the genotoxic, mutagenic, and erythrotoxicity effects of BP-3 in the guppy Poecilia reticulata after acute exposure. Adult females of P. reticulata were exposed to three non-lethal and environmentally relevant concentrations of BP-3 (10, 100, and 1000 ng L-1) during 96 h of exposure, and the somatic parameter [Fulton condition factor (K)], genotoxicity (comet assay), mutagenicity [micronucleus (MN) and erythrocyte nuclear abnormalities (ENA) tests] and erythrotoxicity parameters (such as total cell area and nucleus-cytoplasmic ratio) were analyzed. Results showed that the general physiological condition (K value) of fish was not affected by acute exposure to BP-3. However, BP-3 induced DNA damage at 100 and 1000 ng L-1 and increased the frequency of total ENA at 1000 ng L-1, specially lobed nucleus, when compared to control group, indicating its genotoxic and mutagenic effects. Furthermore, the BP-3 did not induce significant changes in the total cell area and nucleus-cytoplasmic ratio. In summary, results showed that the BP-3 at environmentally relevant concentration was genotoxic to freshwater fish P. reticulata, confirming its environmental risk.


Assuntos
Benzofenonas/toxicidade , Exposição Ambiental , Mutagênicos/toxicidade , Poecilia/fisiologia , Animais , Benzofenonas/química , Biomarcadores/análise , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/patologia , Ensaio Cometa , Dano ao DNA , Eritrócitos/efeitos dos fármacos , Feminino , Água Doce , Testes para Micronúcleos , Poluentes Químicos da Água/toxicidade
8.
Int J Nanomedicine ; 14: 5147-5157, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371953

RESUMO

Background: Kaempferol (K) is a recognized anticancer drug that can conjugate with small-size gold nanoclusters (AuNCs). Materials and methods: K-AuNCs were synthesized and their use as an anticancer drug was explored using A549 lung cancer cells. Colony formation and cell migration assays were carried out. The morphology of the K-AuNCs treated A549 cells was explored using bio-atomic force microscopy. Results: The K-AuNCs were 1-3 nm in diameter and emitted strong fluorescent at 650 nm following excitation at 550 nm. The stretching and bending nature of the K-AuNCs were analyzed by the Fourier transform infrared spectroscopy. The presence of kaempferol in the AuNCs were confirmed by the PL spectroscopy. Conclusion: The synthesized K-AuNCs mainly targeted and damaged the nuclei of the cancer cells. This composite nanocluster was less toxicity to the normal human cell and higher toxicity to the A549 lunch cancer cell and these material is potential for anticancer drug delivery and bio imaging applications.


Assuntos
Antineoplásicos/uso terapêutico , Ouro/química , Quempferóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas Metálicas/química , Células A549 , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/patologia , Proliferação de Células/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Humanos , Quempferóis/farmacologia , Nanopartículas Metálicas/toxicidade , Nanopartículas Metálicas/ultraestrutura , Fenômenos Ópticos , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
10.
Comput Math Methods Med ; 2019: 3041250, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281408

RESUMO

Residual cancer burden (RCB) has been proposed to measure the postneoadjuvant breast cancer response. In the workflow of RCB assessment, estimation of cancer cellularity is a critical task, which is conventionally achieved by manually reviewing the hematoxylin and eosin- (H&E-) stained microscopic slides of cancer sections. In this work, we develop an automatic and direct method to estimate cellularity from histopathological image patches using deep feature representation, tree boosting, and support vector machine (SVM), avoiding the segmentation and classification of nuclei. Using a training set of 2394 patches and a test set of 185 patches, the estimations by our method show strong correlation to those by the human pathologists in terms of intraclass correlation (ICC) (0.94 with 95% CI of (0.93, 0.96)), Kendall's tau (0.83 with 95% CI of (0.79, 0.86)), and the prediction probability (0.93 with 95% CI of (0.91, 0.94)), compared to two other methods (ICC of 0.74 with 95% CI of (0.70, 0.77) and 0.83 with 95% CI of (0.79, 0.86)). Our method improves the accuracy and does not rely on annotations of individual nucleus.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/fisiopatologia , Diagnóstico por Computador , Processamento de Imagem Assistida por Computador/métodos , Algoritmos , Núcleo Celular/patologia , Feminino , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Modelos Lineares , Reconhecimento Automatizado de Padrão , Probabilidade , Curva ROC , Reprodutibilidade dos Testes , Máquina de Vetores de Suporte , Fluxo de Trabalho
11.
Dement Geriatr Cogn Disord ; 47(4-6): 274-280, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31319413

RESUMO

BACKGROUND: The hypothalamic medial mamillary (MMN) and the tuberomamillary (TMN) nuclei are important hubs in memory circuits. Previous studies determining the neuronal Golgi complex size showed decreased metabolic activity of the TMN neurons in both Alzhei-mer's disease (AD) and vascular dementia (VD), and no obvious decline in the MMN of these patients. OBJECTIVES: In the present study, we aimed at determining whether other morphometric parameters that are informative about the neuronal metabolic activity are changed in the MMN of AD and VD patients and whether they can be related to the expression of the nuclear estrogen receptor α (ERα) that can mediate neurotrophic effects of estrogens in the brain. METHOD: The size of neuronal nuclei and perikarya was determined in AD, VD, and nondemented control patients, in relation to the expression of the nuclear ERα. RESULTS: We found that neuronal nuclear and perikaryal sizes were significantly larger in the MMN in VD than in control patients (p < 0.01). Neuronal nuclei (p < 0.05), but not perikarya were larger in AD than in control patients. Neuronal nuclei and perikarya were larger if nuclear ERα staining was present. The intensity of ERα in the neuronal nuclei was significantly correlated with both nuclear and perikaryal sizes (p < 0.007). CONCLUSIONS: The human MMN shows a remarkable activation in aging and extra activation in dementias (AD and VD) that may be mediated by nuclear ERα. This makes it so far a unique brain area to study compensatory mechanisms that may prevent neurodegeneration.


Assuntos
Doença de Alzheimer/patologia , Núcleo Celular/patologia , Demência Vascular/patologia , Receptor alfa de Estrogênio/metabolismo , Neurônios/patologia , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Tamanho Celular , Feminino , Humanos , Masculino , Polimorfismo Genético , Receptores Estrogênicos
12.
J Clin Pathol ; 72(11): 748-754, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31262952

RESUMO

AIMS: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a newly recognised entity in the WHO 2016 classification defined as the germline mutation of FH gene. Fumaratehydratase-deficient renal cell carcinoma (FH-deficient RCC) is recommended for tumours with FH deficiency but lacking of genetic evidences of FH germline mutation. In this study, we described the clinicopathological and molecular changes of 13 FH-deficient RCCs. METHODS AND RESULTS: Histology features, clinicopathological data, radiology performance and outcomes were collected for each patient. Next-generation sequencing and DNA sequencing of FH gene were performed to examine FH mutations. The patient group included five females and eight males. Different morphological patterns of papillary, nested, adenoid, foam adenoid, cribriform, tubular, tubulocystic, cystic and loose oedema stroma were observed. Except typical big nuclei with or without eosinophilic nucleoli and perinucleolar halos, raisin-like, hobnail-like and even low-grade nuclei were also observed in these tumours. Eleven cases with high-grade nuclei showed disease progression or death, but no disease progression was detected in two cases with low-grade nuclei and eosinophilic cytoplasm. FH expression was absent in tumour cells except for case 11. Next-generation sequencing and DNA sequencing verified seven FH germline mutations and four somatic mutations out of 13 cases. CONCLUSIONS: FH-deficient RCC is a rare renal tumour and has a wide morphological spectrum. Most of the tumours had high-grade nuclei and were aggressive. However, we observed a morphological subtype of FH-deficient RCC with low-grade nuclei and eosinophilic cytoplasm, which might mainly occur in young women and show a relatively good prognosis.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Renais/genética , Fumarato Hidratase/genética , Mutação em Linhagem Germinativa , Neoplasias Renais/genética , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/deficiência , Biópsia , Carcinoma de Células Renais/enzimologia , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/terapia , Núcleo Celular/patologia , Citoplasma/patologia , Análise Mutacional de DNA/métodos , Feminino , Fumarato Hidratase/deficiência , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Neoplasias Renais/enzimologia , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Fenótipo
13.
PLoS One ; 14(7): e0218757, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31314779

RESUMO

Current cancer diagnosis involves the use of nuclear morphology and chromatin condensation signatures for accurate advanced stage classification. While such diagnostic approaches rely on high resolution imaging of the cell nucleus using expensive microscopy systems, developing portable mobile microscopes to visualize nuclear and chromatin condensation patterns is desirable at clinical settings with limited infrastructure. In this study, we develop a portable fluorescent mobile microscope capable of acquiring high resolution images of the nucleus and chromatin. Using this we extracted nuclear morphometric and chromatin texture based features and were able to discriminate between normal and cancer cells with similar accuracy as wide-field fluorescence microscopy. We were also able to detect subtle changes in nuclear and chromatin features in cells subjected to compressive forces, cytoskeletal perturbations and cytokine stimulation, thereby highlighting the sensitivity of the portable microscope. Taken together, we present a versatile platform to exploit nuclear morphometrics and chromatin condensation features as physical biomarkers for point-of-care diagnostic solutions.


Assuntos
Cromatina/genética , Cromossomos/genética , Microscopia de Fluorescência , Biomarcadores Tumorais/genética , Núcleo Celular/genética , Núcleo Celular/patologia , Heterocromatina/genética , Humanos , Processamento de Imagem Assistida por Computador , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/patologia
14.
Artif Cells Nanomed Biotechnol ; 47(1): 3079-3086, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31352799

RESUMO

The engineering of multifunctional therapeutics in an integrated single platform is demonstrated using three-dimensional SBA-16 (S-16). 10 wt% iron oxide nanoparticles (Fe) were loaded into the cage type of cubic pores through enforced adsorption technique. Fe/S-16 is then functionalized with amine-based silane (A), polyacrylic acid (P) and cisplatin (Cp). The physicochemical textural analysis showed the formation of nano metal oxide distributions at pore walls of S-16 with magnetization of 2.39 emu/g. S-16 based nanoformulations showed high percentage of Cp adsorption (90%) and percentage cumulative release (60%). in vitro study of Fe/S-16-A-Cp showed high toxicity against breast cancer cell line MCF-7 and normal cell line Human foreskin fibroblast (HFF-1) compared to Fe/S-16 indicating cisplatin profusion inside the cells than free cisplatin. While skin fibroblast seems to be resistant to Fe/S-16-AP-Cp with very high LC50 in compare to MCF-7. This indicates the unrelease of cisplatin in skin fibroblast after Fe/S-16-AP-Cp treatment due to effective encapsulation inside the cubic pores and core blockage due to pH-sensitive polyacrylic acid. Also, these treatments resulted in morphological changes in the cells such as DNA condensation and nuclear fragmentation.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/patologia , Cisplatino/química , Cisplatino/farmacologia , Imãs/química , Dióxido de Silício/química , Resinas Acrílicas/química , Aminas/química , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/patologia , Relação Dose-Resposta a Droga , Portadores de Fármacos/química , Humanos , Células MCF-7 , Nanopartículas/química
16.
Endocr Pathol ; 30(3): 189-200, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31338752

RESUMO

A re-named diagnosis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) likely impacts the prevalence of thyroid cancer and risk of malignancy in populations based on the established Bethesda System of Reporting Thyroid Cytopathology (TBSRTC). This study was done to investigate the prevalence and cytological distribution of NIFTP. PRISMA guided systematic review was done from a database search of Pubmed, EMBASE, and Medline using the search terms "non-invasive follicular thyroid neoplasm with papillary-like nuclear features", "non-invasive follicular variant of papillary carcinoma", "niftp", and "Bethesda" until November 2018. Original articles with surgically proven diagnoses of NIFTP using strict NIFTP criteria were included. Twenty-nine studies with 1563 cases of NIFTP were included. The pooled prevalence of NIFTP in cases which would be classified previously as the follicular variant of papillary thyroid cancer (FVPTC) and papillary thyroid cancer (PTC) were 43.5% (95% CI 33.5-54.0%) and 4.4% (95% CI 2.0-9.0%) respectively. The pooled TBSRTC distribution of cases diagnosed as NIFTP was: from the non-diagnostic category 3.6% (95% CI 2.4-5.3%), benign 10.0% (95% CI 7.2-13.6%), AUS/FLUS 34.2% (95% CI 28.2-40.8%), FN/SFN 22.7% (95% CI 17.2-29.4%), suspicious for malignancy 22.4% (95% CI 17.7-27.9%), and malignant 7.5% (95% CI 4.2-12.9%). While a significant reduction in FVPTC prevalence is anticipated, a modest reduction of PTC prevalence is also expected with adoption of the NIFTP terminology that would be distributed mainly among lesions classified as indeterminate thyroid nodules. Further studies are needed to identify unique clinical characteristics of these lesions preoperatively.


Assuntos
Carcinoma Papilar, Variante Folicular , Núcleo Celular/patologia , Citodiagnóstico/métodos , Citodiagnóstico/estatística & dados numéricos , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide , Biópsia por Agulha Fina/normas , Biópsia por Agulha Fina/estatística & dados numéricos , Carcinoma Papilar, Variante Folicular/diagnóstico , Carcinoma Papilar, Variante Folicular/epidemiologia , Carcinoma Papilar, Variante Folicular/patologia , Citodiagnóstico/normas , Diagnóstico Diferencial , Fidelidade a Diretrizes/normas , Fidelidade a Diretrizes/estatística & dados numéricos , Humanos , Valor Preditivo dos Testes , Prevalência , Câncer Papilífero da Tireoide/diagnóstico , Câncer Papilífero da Tireoide/epidemiologia , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/diagnóstico , Nódulo da Glândula Tireoide/epidemiologia , Nódulo da Glândula Tireoide/patologia
17.
PLoS Med ; 16(7): e1002847, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31265453

RESUMO

BACKGROUND: The identification of patients with high-risk prostate cancer (PC) is a major challenge for clinicians, and the improvement of current prognostic parameters is an unmet clinical need. We and others have identified an association between the nuclear localization of NF-κB p65 and biochemical recurrence (BCR) in PC in small and/or single-centre cohorts of patients. METHODS AND FINDINGS: In this study, we accessed 2 different multi-centre tissue microarrays (TMAs) representing cohorts of patients (Test-TMA and Validation-TMA series) of the Canadian Prostate Cancer Biomarker Network (CPCBN) to validate the association between p65 nuclear frequency and PC outcomes. Immunohistochemical staining of p65 was performed on the Test-TMA and Validation-TMA series, which include PC tissues from patients treated by first-line radical prostatectomy (n = 250 and n = 1,262, respectively). Two independent observers evaluated the p65 nuclear frequency in digital images of cancer tissue and benign adjacent gland tissue. Kaplan-Meier curves coupled with a log-rank test and univariate and multivariate Cox regression models were used for statistical analyses of continuous values and dichotomized data (cutoff of 3%). Multivariate analysis of the Validation-TMA cohort showed that p65 nuclear frequency in cancer cells was an independent predictor of BCR using continuous (hazard ratio [HR] 1.02 [95% CI 1.00-1.03], p = 0.004) and dichotomized data (HR 1.33 [95% CI 1.09-1.62], p = 0.005). Using a cutoff of 3%, we found that this biomarker was also associated with the development of bone metastases (HR 1.82 [95% CI 1.05-3.16], p = 0.033) and PC-specific mortality (HR 2.63 [95% CI 1.30-5.31], p = 0.004), independent of clinical parameters. BCR-free survival, bone-metastasis-free survival, and PC-specific survival were shorter for patients with higher p65 nuclear frequency (p < 0.005). As the small cores on TMAs are a limitation of the study, a backward validation of whole PC tissue section will be necessary for the implementation of p65 nuclear frequency as a PC biomarker in the clinical workflow. CONCLUSIONS: We report the first study using the pan-Canadian multi-centre cohorts of CPCBN and validate the association between increased frequency of nuclear p65 frequency and a risk of disease progression.


Assuntos
Biomarcadores Tumorais/análise , Núcleo Celular/química , Imuno-Histoquímica , Neoplasias da Próstata/química , Fator de Transcrição RelA/análise , Idoso , Neoplasias Ósseas/secundário , Canadá , Núcleo Celular/patologia , Progressão da Doença , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Variações Dependentes do Observador , Valor Preditivo dos Testes , Intervalo Livre de Progressão , Prostatectomia , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Análise Serial de Tecidos
19.
Int J Nanomedicine ; 14: 4091-4103, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31239669

RESUMO

Introduction: Curcuma wenyujin is a plant which belongs to the family of Zingiberaceae, found in South Asia and China. C. wenyujin is a major constituent in Chinese traditional medicine and is used to treat liver diseases, blood clots, and is also prescribed as a painkiller. C. wenyujin possesses antioxidant, antiproliferative, and antitumorogenic properties, and many researchers have proved the efficacy of C. wenyujin against various types of cancer. The major drawback of this historical drug is it's low bioavailability. Methods: This study synthesized gold nanoparticles using C. wenyujin and assessed its potency against in vitro renal cancer cells. The biosynthesized C. wenyujin gold nanoparticles (CWAuNPs) were characterized using UV-Spec, DLS, FTIR, SAED, TEM, EDAX, and Atomic Force analysis. The cytotoxicity of CWAuNPs against renal cancer cell lines A498 and SW-156 was assessed with MTT assay. The induction of apoptosis by CWAuNPs in A498 cell was measured using apoptotic staining DAPI, Rhodamine 123, and H2DCFDA. The apoptotic activity of CWAuNPs was further confirmed with flow cytometric analysis. The molecular mechanism of CWAuNPs was analyzed with qPCR and immunoblotting analysis of caspases, proapoptotic, and antiapoptotic proteins. Results: The characterization of results of synthesized CWAuNPs satisfy the distinctive properties of a potent nanodrug. The results of apoptotic staining techniques confirm the induction of CWAuNPs in A498 by increasing the apoptotic Caspase 3,9, Bid, and Bad, and decreasing the antiapoptotic protein Bcl-2, Bcl-xl expressions, which is authentically proven by the qPCR and immunoblotting analysis. Conclusion: In conclusion, these results confirmed that biosynthesized CWAuNPs is a potent anticancer agent which induces apoptosis in the A498 renal carcinoma cell line.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Curcuma/química , Ouro/farmacologia , Neoplasias Renais/tratamento farmacológico , Nanopartículas Metálicas/química , Extratos Vegetais/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/genética , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Nanopartículas Metálicas/ultraestrutura , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Extratos Vegetais/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier
20.
Cancer Sci ; 110(9): 2982-2991, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31237072

RESUMO

Adult T-cell leukemia/lymphoma (ATLL) is a mature T-cell neoplasm, and is divided into 2 indolent (smoldering and chronic) and 2 aggressive (acute and lymphoma) clinical subtypes. Based on previous integrated molecular analyses suggesting the importance of the JAK-STAT pathway in ATLL, we attempted to clarify the clinicopathological significance of this pathway. Clinical and morphological findings were reviewed in 116 cases with ATLL. The nuclear localizations of phosphorylated STAT3 (pSTAT3), pSTAT5, and pSTAT6 were analyzed by immunohistochemistry. Targeted sequencing was undertaken on the portion of STAT3 encoding the Src homology 2 domain. Expression of pSTAT3 was observed in 43% (50/116) of ATLL cases, whereas pSTAT5 and pSTAT6 were largely undetected. Cases with the lymphoma type showed significantly less frequent pSTAT3 expression (8/45, 18%) than those with the other subtypes (41/66, 62%; P < .001). STAT3 mutations were detected in 36% (10/28) and 19% (12/64) of cases with the smoldering and aggressive types of ATLL, respectively. The correlation between STAT3 mutation and pSTAT3 expression was not significant (P = .07). Both univariate and multivariate analysis revealed that pSTAT3 expression was significantly associated with better overall survival and progression-free survival in the smoldering type of ATLL, whereas STAT3 mutation was not related to a line of clinical outcome. Collectively, our data show that only the lymphoma type showed a low prevalence of tumor cells positive for pSTAT3 expression, and raises the possibility that pSTAT3 expression is a novel biomarker to predict better prognosis in the smoldering type of ATLL.


Assuntos
Leucemia-Linfoma de Células T do Adulto/patologia , Fator de Transcrição STAT3/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Núcleo Celular/patologia , Feminino , Humanos , Leucemia-Linfoma de Células T do Adulto/genética , Leucemia-Linfoma de Células T do Adulto/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Fosforilação , Prognóstico , Intervalo Livre de Progressão , Fator de Transcrição STAT3/genética
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