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1.
Sci Rep ; 13(1): 632, 2023 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-36635367

RESUMO

Biological features of neoplastic disease affecting mammary gland tissue are shared between canines and humans. Research performed in either species has translational value and early phase clinical trials performed in canines with spontaneous disease could be informative for human trials. The purpose of this study was to investigate the somatic genetic aberrations occurring in canine mammary neoplasia by exome capture and next generation sequencing. Based on 55 tumor-normal pairs we identified the PIK3CA gene as the most commonly mutated gene in canine mammary tumors, with 25% of samples carrying mutations in this gene. A recurrent missense mutation was identified, p.H1047R, which is homologous to the human PIK3CA hotspot mutation found in different types of breast neoplasia. Mutations homologous to other known human mutation hotspots such as the PIK3CA p.E545K and the KRAS p.G12V/D were also identified. We identified copy number aberrations affecting important tumor suppressor and oncogenic pathways including deletions affecting the PTEN tumor suppressor gene. We suggest that activation of the KRAS or PIK3CA oncogenes or loss of the PTEN suppressor gene may be important for mammary tumor development in dogs. This data endorses the conservation of cancer across species and the validity of studying cancer in non-human species.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases , Neoplasias Mamárias Animais , Animais , Cães , Feminino , Humanos , Neoplasias da Mama/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Neoplasias Mamárias Animais/genética , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas p21(ras)/genética
2.
Sensors (Basel) ; 21(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34450741

RESUMO

Anthropomorphic robotic hands are designed to attain dexterous movements and flexibility much like human hands. Achieving human-like object manipulation remains a challenge especially due to the control complexity of the anthropomorphic robotic hand with a high degree of freedom. In this work, we propose a deep reinforcement learning (DRL) to train a policy using a synergy space for generating natural grasping and relocation of variously shaped objects using an anthropomorphic robotic hand. A synergy space is created using a continuous normalizing flow network with point clouds of haptic areas, representing natural hand poses obtained from human grasping demonstrations. The DRL policy accesses the synergistic representation and derives natural hand poses through a deep regressor for object grasping and relocation tasks. Our proposed synergy-based DRL achieves an average success rate of 88.38% for the object manipulation tasks, while the standard DRL without synergy space only achieves 50.66%. Qualitative results show the proposed synergy-based DRL policy produces human-like finger placements over the surface of each object including apple, banana, flashlight, camera, lightbulb, and hammer.


Assuntos
Procedimentos Cirúrgicos Robóticos , Robótica , Dedos , Mãos , Força da Mão , Humanos
3.
Comput Methods Programs Biomed ; 157: 85-94, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29477437

RESUMO

BACKGROUND AND OBJECTIVE: Automatic detection and classification of the masses in mammograms are still a big challenge and play a crucial role to assist radiologists for accurate diagnosis. In this paper, we propose a novel Computer-Aided Diagnosis (CAD) system based on one of the regional deep learning techniques, a ROI-based Convolutional Neural Network (CNN) which is called You Only Look Once (YOLO). Although most previous studies only deal with classification of masses, our proposed YOLO-based CAD system can handle detection and classification simultaneously in one framework. METHODS: The proposed CAD system contains four main stages: preprocessing of mammograms, feature extraction utilizing deep convolutional networks, mass detection with confidence, and finally mass classification using Fully Connected Neural Networks (FC-NNs). In this study, we utilized original 600 mammograms from Digital Database for Screening Mammography (DDSM) and their augmented mammograms of 2,400 with the information of the masses and their types in training and testing our CAD. The trained YOLO-based CAD system detects the masses and then classifies their types into benign or malignant. RESULTS: Our results with five-fold cross validation tests show that the proposed CAD system detects the mass location with an overall accuracy of 99.7%. The system also distinguishes between benign and malignant lesions with an overall accuracy of 97%. CONCLUSIONS: Our proposed system even works on some challenging breast cancer cases where the masses exist over the pectoral muscles or dense regions.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Diagnóstico por Computador/instrumentação , Aprendizado de Máquina , Mamografia/métodos , Neoplasias da Mama/classificação , Feminino , Humanos , Redes Neurais de Computação , Probabilidade , Sistemas de Informação em Radiologia , Reprodutibilidade dos Testes
4.
PLoS Genet ; 12(5): e1006029, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27158822

RESUMO

Canine mammary tumours (CMT) are the most common neoplasia in unspayed female dogs. CMTs are suitable naturally occurring models for human breast cancer and share many characteristics, indicating that the genetic causes could also be shared. We have performed a genome-wide association study (GWAS) in English Springer Spaniel dogs and identified a genome-wide significant locus on chromosome 11 (praw = 5.6x10-7, pperm = 0.019). The most associated haplotype spans a 446 kb region overlapping the CDK5RAP2 gene. The CDK5RAP2 protein has a function in cell cycle regulation and could potentially have an impact on response to chemotherapy treatment. Two additional loci, both on chromosome 27, were nominally associated (praw = 1.97x10-5 and praw = 8.30x10-6). The three loci explain 28.1±10.0% of the phenotypic variation seen in the cohort, whereas the top ten associated regions account for 38.2±10.8% of the risk. Furthermore, the ten GWAS loci and regions with reduced genetic variability are significantly enriched for snoRNAs and tumour-associated antigen genes, suggesting a role for these genes in CMT development. We have identified several candidate genes associated with canine mammary tumours, including CDK5RAP2. Our findings enable further comparative studies to investigate the genes and pathways in human breast cancer patients.


Assuntos
Doenças do Cão/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias Mamárias Animais/genética , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proteínas de Ciclo Celular , Doenças do Cão/patologia , Cães , Feminino , Haplótipos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Mamárias Animais/patologia , Proteínas do Tecido Nervoso/genética , RNA Nucleolar Pequeno/genética
5.
Annu Int Conf IEEE Eng Med Biol Soc ; 2016: 2700-2703, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28268878

RESUMO

Changes in the left ventricle function produce alternans in the hemodynamic and electric behavior of the cardiovascular system. A total of 49 cardiomyopathy patients have been studied based on the blood pressure signal (BP), and were classified according to the left ventricular ejection fraction (LVEF) in low risk (LR: LVEF>35%, 17 patients) and high risk (HR: LVEF≤35, 32 patients) groups. We propose to characterize these patients using a linear and a nonlinear methods, based on the spectral estimation and the recurrence plot, respectively. From BP signal, we extracted each systolic time interval (STI), upward systolic slope (BPsl), and the difference between systolic and diastolic BP, defined as pulse pressure (PP). After, the best subset of parameters were obtained through the sequential feature selection (SFS) method. According to the results, the best classification was obtained using a combination of linear and nonlinear features from STI and PP parameters. For STI, the best combination was obtained considering the frequency peak and the diagonal structures of RP, with an area under the curve (AUC) of 79%. The same results were obtained when comparing PP values. Consequently, the use of combined linear and nonlinear parameters could improve the risk stratification of cardiomyopathy patients.


Assuntos
Pressão Sanguínea , Cardiomiopatias , Função Ventricular Esquerda , Idoso , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Dinâmica não Linear , Volume Sistólico , Sístole
6.
Genome Biol ; 14(12): R132, 2013 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-24330828

RESUMO

BACKGROUND: Canine osteosarcoma is clinically nearly identical to the human disease, but is common and highly heritable, making genetic dissection feasible. RESULTS: Through genome-wide association analyses in three breeds (greyhounds, Rottweilers, and Irish wolfhounds), we identify 33 inherited risk loci explaining 55% to 85% of phenotype variance in each breed. The greyhound locus exhibiting the strongest association, located 150 kilobases upstream of the genes CDKN2A/B, is also the most rearranged locus in canine osteosarcoma tumors. The top germline candidate variant is found at a >90% frequency in Rottweilers and Irish wolfhounds, and alters an evolutionarily constrained element that we show has strong enhancer activity in human osteosarcoma cells. In all three breeds, osteosarcoma-associated loci and regions of reduced heterozygosity are enriched for genes in pathways connected to bone differentiation and growth. Several pathways, including one of genes regulated by miR124, are also enriched for somatic copy-number changes in tumors. CONCLUSIONS: Mapping a complex cancer in multiple dog breeds reveals a polygenic spectrum of germline risk factors pointing to specific pathways as drivers of disease.


Assuntos
Neoplasias Ósseas/veterinária , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Doenças do Cão/genética , Estudo de Associação Genômica Ampla , Osteossarcoma/veterinária , Animais , Neoplasias Ósseas/genética , Variações do Número de Cópias de DNA , Cães , Evolução Molecular , Predisposição Genética para Doença , Variação Genética , Genoma , Humanos , MicroRNAs/genética , Osteossarcoma/genética
7.
BMC Vet Res ; 9: 69, 2013 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-23574728

RESUMO

BACKGROUND: The limited within-breed genetic heterogeneity and an enrichment of disease-predisposing alleles have made the dog a very suitable model for the identification of genes associated with risk for specific diseases. Canine mammary cancer is an example of such a disease. However, the underlying inherited risk factors for canine mammary tumours (CMTs) are still largely unknown. In this study, 52 single nucleotide polymorphisms (SNPs) in ten human cancer-associated genes were genotyped in two different datasets in order to identify genes/alleles associated with the development of CMTs. The first dataset consisted of English Springer Spaniel (ESS) CMT cases and controls. ESS is a dog breed known to be at increased risk of developing CMTs. In the second dataset, dogs from breeds known to have a high frequency of CMTs were compared to dogs from breeds with a lower occurrence of these tumours. RESULTS: We found significant associations to CMT for SNPs and haplotypes in the estrogen receptor 1 (ESR1) gene in the ESS material (best PBonf = 0.021). A large number of SNPs, among them several SNPs in ESR1, showed significantly different allele frequencies between the high and low risk breed groups (best PBonf = 8.8E-32, best PBPerm = 0.076). CONCLUSIONS: The identification of CMT-associated SNPs in ESR1 in two independent datasets suggests that this gene might be involved in CMT development. These findings also support that CMT may serve as a good model for human breast cancer research.


Assuntos
Doenças do Cão/genética , Receptor alfa de Estrogênio/genética , Neoplasias Mamárias Animais/genética , Alelos , Animais , Cães , Feminino , Estudos de Associação Genética/veterinária , Predisposição Genética para Doença , Haplótipos/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Alinhamento de Sequência/veterinária
8.
Cancer Res ; 69(22): 8770-4, 2009 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-19887619

RESUMO

Breast cancer is a major contributor to overall morbidity and mortality in women. Several genes predisposing to breast cancer have been identified, but the majority of risk factors remain unknown. Even less is known about the inherited risk factors underlying canine mammary tumors (CMT). Clear breed predispositions exist, with 36% of English springer spaniels (ESS) in Sweden being affected. Here, we evaluate 10 human breast cancer genes (BRCA1, BRCA2, CHEK2, ERBB2, FGFR2, LSP1, MAP3K1, RCAS1, TOX3, and TP53) for association with CMTs. Sixty-three single-nucleotide polymorphisms (SNPs; four to nine SNPs per gene) were genotyped by iPLEX in female ESS dogs, 212 CMT cases and 143 controls. Two genes, BRCA1 and BRCA2, were significantly associated with CMT (Bonferroni corrected P = 0.005 and P = 0.0001, respectively). Borderline association was seen for FGFR2. Benign and malignant cases were also analyzed separately. Those findings supported the association to BRCA1 and BRCA2 but with a stronger association to BRCA1 in malignant cases. Both BRCA1 and BRCA2 showed odds ratios of approximately 4. In conclusion, this study indicates that BRCA1 and BRCA2 contribute to the risk of CMT in ESS, suggesting that dogs may serve as a good model for human breast cancer.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/veterinária , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Animais , Cães , Feminino , Humanos , Polimorfismo de Nucleotídeo Único
9.
Int J Oncol ; 34(2): 505-10, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19148486

RESUMO

Thymidine kinase 1 (TK), which is involved in the synthesis of DNA precursors, is only expressed in S-G2 cells. Serum TK levels correlate to the proliferative activity of tumor disease. Determinations of TK levels have so far relied on radio enzyme assay (REA) and experimental ELISA methods, which have limited the clinical use of this biomarker, although recent studies in dogs with malignant lymphoma (ML) demonstrate its wide potential. A non-radiometric method based on a competitive immunoassay with specific anti-3'-azido-deoxythymidine monophosphate (AZTMP) antibodies has been further developed into the fully automated Liaison TK assay (DiaSorin). Sera from healthy dogs (n=30), and dogs with leukemia (LEUK) (n=35), ML (n=84), non-hematological tumors (n=50), and inflammatory disease (n=14) were tested using both methods. Lymphoma and LEUK samples were available before and during chemotherapy. The coefficients of variation for the Liaison TK assay in this study were 6.3 and 3.4% (low/high TK, respectively), and the correlation between TK REA (X) and the Liaison TK assay (Y) was y=0.9203x+1.3854 (R2=0.9501). The TK1 levels measured during chemotherapy gave very clear differences between dogs in complete remission and dogs out of remission. A Tukey-Kramer analysis showed that all LEUKs and MLs out of remission differed significantly from the other groups. The Liaison TK assay showed high precision, high sensitivity and a good correlation to the TK REA. The Liaison TK assay provides valuable clinical information in the treatment and management of canine LEUK and ML, with a potential to be further validated in human trials.


Assuntos
Doenças do Cão/tratamento farmacológico , Leucemia/veterinária , Linfoma/veterinária , Neoplasias/veterinária , Animais , Antineoplásicos/uso terapêutico , Ciclo Celular , Doenças do Cão/patologia , Cães , Leucemia/tratamento farmacológico , Leucemia/patologia , Linfoma/tratamento farmacológico , Linfoma/patologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Proibitinas , Indução de Remissão , Resultado do Tratamento
10.
J Immunother ; 31(4): 377-84, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18391758

RESUMO

Cutaneous canine melanomas are usually benign in contrast to human malignant melanoma. However, the canine oropharyngeal, uveal, and mucocutaneous neoplasms are aggressive and have metastatic potential. Surgery and to a lesser extent radiotherapy and chemotherapy are widely adopted treatments but are seldom curative in advanced stages. The similarities between human and canine melanoma make spontaneous canine melanoma an excellent disease model for exploring novel therapies. Herein, we report the first 2 adenovector CD40L immunogene (AdCD40L) treatments of aggressive canine malignant melanoma. Case no. 1 was an advanced stage III oral melanoma that was cured from malignant melanoma with 2 intratumor AdCD40L injections before cytoreductive surgery. After treatment, the tumor tissue was infiltrated with T lymphocytes and B lymphocytes suggesting immune activation. This dog survived 401 days after the first round of gene therapy and was free of melanoma at autopsy. Case no. 2 had a conjunctival malignant melanoma with a rapid progression. This case was treated with 6 AdCD40L injections over 60 days. One hundred and twenty days after start of gene therapy and 60 days after the last injection, the tumor had regressed dramatically, and the dog had a minimal tumor mass and no signs of progression or metastasis. Our results indicate that AdCD40L immunogene therapy is beneficial in canine malignant melanoma and could be considered for human malignant melanoma as well.


Assuntos
Ligante de CD40/imunologia , Ligante de CD40/uso terapêutico , Neoplasias da Túnica Conjuntiva/veterinária , Doenças do Cão/terapia , Imunoterapia Ativa , Melanoma/veterinária , Neoplasias Bucais/veterinária , Adenoviridae , Animais , Ligante de CD40/genética , Neoplasias da Túnica Conjuntiva/imunologia , Neoplasias da Túnica Conjuntiva/terapia , Doenças do Cão/imunologia , Cães , Feminino , Vetores Genéticos , Interferon gama/imunologia , Interferon gama/metabolismo , Masculino , Melanoma/imunologia , Melanoma/terapia , Neoplasias Bucais/imunologia , Neoplasias Bucais/terapia , Indução de Remissão , Linfócitos T/imunologia , Transdução Genética
11.
Bol. Hosp. San Juan de Dios ; 36(6): 422-4, nov.-dic. 1989. ilus
Artigo em Espanhol | LILACS | ID: lil-84687

RESUMO

Se presentan 2 casos de síndrome de TAR (trombocitopenia y aplasia radial uni o bilateral), correspondiente a dos hermanos. El cuadro se caracteriza por trombocitopenia con ausencia de megacariocitos en la médula; leucocitos y aplasia radial uni o bilateral. Pueden asociarse también variadas otras alteraciones esqueléticas. El diagnóstico diferencial se plantea con los síndromes de Holt-Oram y de Aase y con la anemia de Fanconi. El 40% de los casos fallecen durante el primer año de vida debido a hemorragias digestivas o del sistema nervioso central


Assuntos
Recém-Nascido , Humanos , Feminino , Anormalidades Musculoesqueléticas , Trombocitopenia , Síndrome
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