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1.
Vet Clin Pathol ; 50(2): 236-239, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33797110

RESUMO

Currently, canine soft tissue sarcoma (STS) grading is based on histopathology. In humans, several studies have demonstrated concordance between cytologic grading systems for STS and histologic grade. The aim of this study was to correlate several cytologic parameters (smear cellularity, anisokaryosis, nucleolar malignancy score, multinucleation, and the number of mitotic figures per 200 cells) that form part of a human STS cytologic grading system, with histologic grades of canine cutaneous and subcutaneous STS. Three observers (blinded) reviewed the cytologic preparations independently from cases with confirmed histologic diagnoses of STS. A cytologic grading score was assigned for each parameter. Correlations between cytologic grading scores (averaged between observers) and histologic grades were assessed using Spearman's correlation coefficient, with statistical significance defined as P < .05. Twenty-one cases were included in the study (10 Grade I STS, nine Grade II STS, and two Grade III STS). The number of mitotic figures (≥3) per 200 cells was the only parameter that showed a significant but weak, positive correlation with histologic grade (rs  = .469; P = .032). No Grade I tumors had ≥3 mitotic figures per 200 cells; however, ≥3 mitotic figures per 200 cells were only observed in 33% of Grade II tumors and 50% (one out of two) of the Grade III tumors. This pilot study suggests that an increased number of mitotic figures seen on cytology might correlate with higher grade STS; however, the sensitivity of this parameter for grading STS appears to be low.


Assuntos
Doenças do Cão , Sarcoma , Neoplasias de Tecidos Moles , Animais , Citodiagnóstico/veterinária , Doenças do Cão/patologia , Cães , Projetos Piloto , Sarcoma/patologia , Sarcoma/veterinária , Pele/patologia , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/veterinária
2.
Vet Radiol Ultrasound ; 62(3): E20-E25, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-30892784

RESUMO

An 8-year-old male intact miniature poodle presented for blindness, obtundation, tetraparesis, and vestibular signs. Magnetic resonance imaging, radiography, and ultrasound revealed a left piriform lobe lesion, right cerebellar and left brainstem lesions, and hydrocephalus and bilateral calvarial defects. Histopathology confirmed a choroid plexus carcinoma with meningeal and intraventricular metastases. The calvarial defect did not show evidence of necrosis, osteoclastic resorption, inflammation or neoplastic infiltration, reflecting a quiescent calvarial atrophy or dysplasia. These novel findings supported inclusion of bone atrophy secondary to chronic increased intracranial pressure as a differential diagnosis for large calvarial defects in dogs with choroid plexus carcinoma.


Assuntos
Carcinoma/veterinária , Neoplasias do Plexo Corióideo/veterinária , Doenças do Cão/diagnóstico por imagem , Imageamento por Ressonância Magnética/veterinária , Imagem Multimodal/veterinária , Crânio/patologia , Ultrassonografia/veterinária , Animais , Carcinoma/diagnóstico por imagem , Neoplasias do Plexo Corióideo/diagnóstico por imagem , Cães , Masculino , Crânio/diagnóstico por imagem , Ultrassonografia/métodos
3.
Vet Comp Oncol ; 19(2): 242-252, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33247533

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is the most common haematopoietic tumour in dogs and recognized as clinical model for its human counterpart. Recently, neutrophil-to-lymphocyte (NLR) and lymphocyte-to-monocyte (LMR) ratios have been shown to predict time-to-progression (TTP) and lymphoma-specific survival (LSS) in dogs with DLBCL treated with CHOP-based chemotherapy. We retrospectively evaluated in 59 dogs diagnosed with DLBCL the prognostic value of haematological parameters and derived ratios: NLR, LMR, platelet-to-lymphocyte (PLR) and platelet-to-neutrophil (PNR) ratios for TTP, LSS and associated secondary end-points (time-to-progression-rate [TTPR] and lymphoma-specific survival-rate [LSSR]) as rates at 180 and 365 days. PNR is an independent prognostic marker (p ≤ .001) for TTPR/180 and 365 days, dogs with a PNR above 0.032 were more likely to progress before 180 days (sensitivity 46.5%, specificity 87.5%, p = .004). On univariate analysis, NLR showed a prognostic significance for LSSR/180 (p = .006) and LSSR/365 (p = .009). A baseline NLR value below 7.45 was positively associated with survival at 180 days (sensitivity 52%, specificity 85.3%, p = .025). The presence of substage b, was associated with early progression and decreased survival at 180 days (p = .031). Anaemia significantly reduced LSSR at 365 days (p = .028). This is the first study evaluating PLR and PNR in canine DLBCL and demonstrates that PNR could be a predictor of early lymphoma progression. Since peripheral blood cell composition can be affected by several non-oncological causes, the development of larger multicenter studies with homogeneous inclusion criteria could help to better determine the true predictive values of blood cell ratios in dogs' DLBCL treated with CHOP chemotherapy.

4.
Vet Comp Oncol ; 19(1): 183-190, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33068307

RESUMO

Lymphoma is the most common haematological malignancy in dogs and its aetiology is largely unknown. The presence of canine vector-borne agents (CVBD) in lymphoma tissues has been described and its causative effects questioned. We intended to evaluate the presence and extent of Leishmania infantum, Ehrlichia canis, Anaplasma phagocytophilum and Bartonella henselae infection in dogs with lymphoma. Sixty-one dogs, living in the Lisbon metropolitan area, with a diagnosis of lymphoma were enrolled. Immunofluorescence assays were used to detect serum IgG's. The presence of DNA from CVBD agents in tumour tissue was assessed by PCR. All dogs tested negative for B. henselae, A. phagocytophilum and E. canis by both serology and PCR. Regarding L. infantum, 8.2% (n = 5) of the dogs had a positive serologic result. L. infantum DNA was detected in two samples of diffuse large B-cell lymphoma (DLBCL). These results show an increased, but not significant, seropositivity (8.2% vs 7.9%) and molecular detection (3.3% vs 1.2%) for L. infantum in dogs with lymphoma, when compared to the reported canine population in the same geographical area. We could not identify an association between lymphoma and E. canis, A. phagocytophilum, B. henselae or Leishmania infantum infection in the studied population. Nevertheless, further studies, following dogs trough their CVBD disease evolution, are worthwhile and may help clarify a possible role of CVBD agents in lymphomagenesis.

5.
Vet Res Commun ; 45(1): 21-30, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33301127

RESUMO

Cellular senescence is a molecular hallmark of ageing that is associated with multiple pathologies, and DNA damage marker γH2AX, together with cell cycle inhibitor p21, have been used as senescence markers in multiple species including dogs. Idiopathic canine chronic hepatitis has recognised breed-related differences in predisposition and prognosis, but reasons behind this are poorly understood. This retrospective study using archived post mortem tissue aimed to provide insight into liver ageing in 51 microscopically normal canine livers across seven breed categories, including those with and without increased risk of chronic hepatitis. Immunohistochemistry was conducted for γH2AX, p21, and cell proliferation marker Ki67, and the mean number of positive hepatocytes per high power field was determined. All three markers were strongly correlated to each other, but no age-dependent expression was seen in the combined study population. Overall expression levels were low in most dogs, with median values representing less than 1.5% of hepatocytes, but this increased to 20-30% in individual dogs at the upper end of the range. Individual breed differences were noted in two breeds that have increased risk of chronic hepatitis, with English Springer Spaniels having lower expression of Ki67 than other dogs, and Labradors having higher expression of Ki67 and γH2AX than other dogs. These results warrant further investigation in these breeds and highlight a need to validate reliable markers of cellular senescence in dogs.


Assuntos
Envelhecimento/fisiologia , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Cães/metabolismo , Histonas/metabolismo , Antígeno Ki-67/metabolismo , Fígado/metabolismo , Envelhecimento/genética , Animais , Senescência Celular , Inibidor de Quinase Dependente de Ciclina p21/genética , Cães/classificação , Cães/genética , Regulação da Expressão Gênica/fisiologia , Histonas/genética , Antígeno Ki-67/genética , Estudos Retrospectivos
7.
Nat Commun ; 10(1): 353, 2019 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-30664638

RESUMO

Mucosal melanoma is a rare and poorly characterized subtype of human melanoma. Here we perform a cross-species analysis by sequencing tumor-germline pairs from 46 primary human muscosal, 65 primary canine oral and 28 primary equine melanoma cases from mucosal sites. Analysis of these data reveals recurrently mutated driver genes shared between species such as NRAS, FAT4, PTPRJ, TP53 and PTEN, and pathogenic germline alleles of BRCA1, BRCA2 and TP53. We identify a UV mutation signature in a small number of samples, including human cases from the lip and nasal mucosa. A cross-species comparative analysis of recurrent copy number alterations identifies several candidate drivers including MDM2, B2M, KNSTRN and BUB1B. Comparison of somatic mutations in recurrences and metastases to those in the primary tumor suggests pervasive intra-tumor heterogeneity. Collectively, these studies suggest a convergence of some genetic changes in mucosal melanomas between species but also distinctly different paths to tumorigenesis.


Assuntos
Carcinogênese/genética , Regulação Neoplásica da Expressão Gênica , Mutação em Linhagem Germinativa , Melanoma/genética , Neoplasias Bucais/genética , Proteínas de Neoplasias/genética , Neoplasias Cutâneas/genética , Animais , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Caderinas/genética , Caderinas/metabolismo , Carcinogênese/metabolismo , Carcinogênese/patologia , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Variações do Número de Cópias de DNA , Cães , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Cavalos , Humanos , Melanoma/metabolismo , Melanoma/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Membrana Mucosa/metabolismo , Membrana Mucosa/patologia , Proteínas de Neoplasias/metabolismo , Recidiva Local de Neoplasia , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/genética , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Especificidade da Espécie , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
8.
J Vet Intern Med ; 33(1): 141-150, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30499209

RESUMO

BACKGROUND: Reports of chronic hepatitis in dogs caused by Leptospira spp. are confined to small case series. Fluorescence in situ hybridization (FISH) allows the identification of spirochetes in liver samples. Consequently, this technique may help elucidate the role of Leptospira spp. in cases of chronic hepatitis. OBJECTIVES: To describe cases of hepatic leptospirosis in dogs diagnosed by FISH and subsequent polymerase chain reaction (PCR) speciation, with the absence of clinically relevant renal involvement. ANIMALS: Ten client-owned dogs. METHODS: Retrospective case series from the University of Cambridge presented between 2013 and 2016 or cases consulted by telephone advice during this time period. Cases were selected based on histopathologically confirmed granulomatous hepatitis and leptospiral organisms identified by FISH and PCR speciation (Leptospira interrogans/kirschneri). RESULTS: All cases had increased liver enzyme activities, and FISH in combination with PCR speciation-confirmed infection with L. interrogans/kirschneri. Four dogs underwent repeat liver biopsy, FISH and PCR speciation 4-15 months after initial presentation and doxycycline treatment with 1 dog undergoing repeat sampling at necropsy. Three dogs that underwent repeat biopsy remained positive for L. interrogans/kirschneri infection. Six dogs were alive at the time of manuscript preparation and 4 dogs were euthanized as a result of progressive liver disease. CONCLUSIONS AND CLINICAL IMPORTANCE: The presence of hepatic leptospiral organisms may be associated with chronic granulomatous hepatitis without clinical evidence of renal involvement. Further studies are necessary to elucidate the etiological role of these organisms in the disease.


Assuntos
Doenças do Cão/microbiologia , Leptospira , Leptospirose/veterinária , Hepatopatias/veterinária , Animais , Doenças do Cão/patologia , Cães , Feminino , Hibridização in Situ Fluorescente/veterinária , Leptospirose/microbiologia , Leptospirose/patologia , Fígado/microbiologia , Fígado/patologia , Hepatopatias/microbiologia , Hepatopatias/patologia , Masculino , Reação em Cadeia da Polimerase/veterinária , Estudos Retrospectivos
10.
Vet Rec Open ; 5(1): e000270, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29868172

RESUMO

The objectives of this study were fourfold: technical validation of a commercial canine 1,2-o-dilauryl-rac-glycero glutaric acid-(6'-methylresorufin) ester (DGGR) lipase assay, to calculate a reference interval for DGGR lipase by the indirect a posteriori method, to establish biological validity of the assay, and to assess agreement between DGGR lipase and specific canine pancreatic lipase (Spec cPL) assays. Dogs with histologically confirmed acute pancreatitis (n=3), chronic pancreatitis (n=8) and normal pancreatic tissue (n=7) with stored (-80°C) serum samples were identified. Relevant controls were selected. Precision, reproducibility and linearity of DGGR lipase, and the effect of sample haemolysis and freezing, were assessed. Sensitivity and specificity of DGGR lipase and Spec cPL were determined. Agreement between these two parameters was calculated using Cohen's kappa coefficient (κ). The DGGR lipase assay demonstrated excellent precision, reproducibility and linearity. Sample haemolysis and storage at -80°C for 12 months did not influence the assay. DGGR lipase (>245IU/l) and Spec cPL (>400µg/l) both showed poor sensitivity but excellent specificity for acute pancreatitis, and poor to moderate sensitivity but excellent specificity for chronic pancreatitis. Substantial agreement (κ=0.679) was found between DGGR lipase and Spec cPL. The validated DGGR lipase assay had similar sensitivity and specificity for the diagnosis of acute and chronic pancreatitis to Spec cPL. DGGR lipase is a reliable alternative to Spec cPL for the diagnosis of pancreatitis.

11.
Oncol Lett ; 15(1): 129-136, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29387214

RESUMO

The aim of the present prospective-retrospective study was to evaluate the response of high-risk canine mast cell tumours (MCTs) to tyrosine kinase inhibitors (TKIs) and to correlate this with prognostic factors. A total of 24 dogs presented with macroscopic cutaneous MCTs at disease stage II or III, and therefore, at high-risk of associated mortality, were included in the study and treated with masitinib (n=20) or toceranib (n=4). A total of 12/24 dogs achieved an objective response and the overall survival (OS) for all subjects was 113 days. Dogs responding to treatment had a significant increase in OS compared to non-responders (146.5 days vs. 47 days, P=0.02). Internal tandem duplications in exon 11 of the c-kit gene were identified in 6/24 cases. Ki67, KIT immunolabelling and c-kit mutation did not provide information regarding prognosis or prediction of response to TKIs in this population. Initial response to TKIs appears to be the most reliable prognostic factor for survival duration.

12.
BMC Res Notes ; 11(1): 67, 2018 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-29361972

RESUMO

OBJECTIVE: This study was designed to estimate the percentage of non-malignant skin tumours (papillomas) progressing to malignant squamous cell carcinomas (SCCs) in a carcinogenesis study using established transgenic mouse models. In our skin cancer model, we conditionally induced oncogenic point mutant alleles of p53 and k-ras in undifferentiated, basal cells of the epidermis. RESULTS: Upon activation of the transgenes through administration of tamoxifen, the vast majority of mice (> 80%) developed skin papillomas, yet primarily around the mouth. Since these tumours hindered the mice eating, they rapidly lost weight and needed to be culled before the papillomas progressed to SCCs. The mouth papillomas formed regardless of the route of application, including intraperitoneal injections, local application to the back skin, or subcutaneous insertion of a tamoxifen pellet. Implantation of a slow releasing tamoxifen pellet into 18 mice consistently led to papilloma formation, of which only one progressed to a malignant SCC. Thus, the challenges for skin carcinogenesis studies using this particular cancer mouse model are low conversion rates of papillomas to SCCs and high frequencies of mouth papilloma formation.


Assuntos
Carcinoma de Células Escamosas/patologia , Papiloma/patologia , Neoplasias Cutâneas/patologia , Pele/patologia , Animais , Carcinoma de Células Escamosas/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes ras/genética , Camundongos Transgênicos , Papiloma/genética , Pele/efeitos dos fármacos , Pele/metabolismo , Neoplasias Cutâneas/genética , Tamoxifeno/administração & dosagem , Proteína Supressora de Tumor p53/genética
13.
Nature ; 554(7690): 62-68, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29364867

RESUMO

The poor correlation of mutational landscapes with phenotypes limits our understanding of the pathogenesis and metastasis of pancreatic ductal adenocarcinoma (PDAC). Here we show that oncogenic dosage-variation has a critical role in PDAC biology and phenotypic diversification. We find an increase in gene dosage of mutant KRAS in human PDAC precursors, which drives both early tumorigenesis and metastasis and thus rationalizes early PDAC dissemination. To overcome the limitations posed to gene dosage studies by the stromal richness of PDAC, we have developed large cell culture resources of metastatic mouse PDAC. Integration of cell culture genomes, transcriptomes and tumour phenotypes with functional studies and human data reveals additional widespread effects of oncogenic dosage variation on cell morphology and plasticity, histopathology and clinical outcome, with the highest KrasMUT levels underlying aggressive undifferentiated phenotypes. We also identify alternative oncogenic gains (Myc, Yap1 or Nfkb2), which collaborate with heterozygous KrasMUT in driving tumorigenesis, but have lower metastatic potential. Mechanistically, different oncogenic gains and dosages evolve along distinct evolutionary routes, licensed by defined allelic states and/or combinations of hallmark tumour suppressor alterations (Cdkn2a, Trp53, Tgfß-pathway). Thus, evolutionary constraints and contingencies direct oncogenic dosage gain and variation along defined routes to drive the early progression of PDAC and shape its downstream biology. Our study uncovers universal principles of Ras-driven oncogenesis that have potential relevance beyond pancreatic cancer.


Assuntos
Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Evolução Molecular , Dosagem de Genes , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Alelos , Animais , Carcinogênese/genética , Proteínas de Ciclo Celular , Inibidor p16 de Quinase Dependente de Ciclina/genética , Progressão da Doença , Feminino , Genes myc , Genes p53 , Humanos , Masculino , Camundongos , Mutação , Subunidade p52 de NF-kappa B/genética , Metástase Neoplásica/genética , Proteínas Nucleares/genética , Fenótipo , Fosfoproteínas/genética , Fatores de Transcrição/genética , Transcriptoma/genética , Fator de Crescimento Transformador beta1/genética
14.
In Vivo ; 32(1): 7-17, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29275293

RESUMO

BACKGROUND/AIM: Histiocytic sarcoma (HS) represents a group of malignant canine tumors to which Bernese Mountain Dogs (BMD) and Flatcoated Retrievers (FCR) are predisposed. The differential diagnosis for HS is broad, encompassing round cell tumors, sarcomas and other histiocytic diseases. The aim of this study was to establish morphological and immunohistochemical criteria for routine use on formalin-fixed, paraffin-embedded samples and cytological smears for the recognition and differentiation of canine HS and its subtypes. MATERIALS AND METHODS: Retrospectively, tumor sections were reviewed from 449 BMD and 380 FCR with confirmed or suspected HS, other histiocytic conditions, or a disease of the differential diagnosis of HS. RESULTS: In a large proportion of cases, 47.5% for histology and for 46.3% cytology, the initial diagnosis was changed after the revision process. A large variation in morphological features of HS was observed in this study, making the existence of several subtypes in dogs also very likely. Furthermore, the different percentage of morphological features between BMD and FCR indicates the different mixture of cell type origins resulting possibly from genetic or environmental differences at the onset of HS in those breeds. CONCLUSION: This study stresses the value of a strictly applied and standardized scoring system for microscopic evaluation of tumor sections and smears, and the implementation of review and revision of pathological diagnoses.


Assuntos
Citodiagnóstico/métodos , Doenças do Cão/patologia , Sarcoma Histiocítico/veterinária , Animais , Citodiagnóstico/veterinária , Diagnóstico Diferencial , Cães/classificação , Sarcoma Histiocítico/patologia , Imuno-Histoquímica/veterinária , Estudos Retrospectivos , Especificidade da Espécie
15.
JFMS Open Rep ; 1(2): 2055116915593968, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-28491372

RESUMO

Case summary An 11-year old neutered female domestic shorthair cat presented for investigation of a large, partially ulcerated skin mass in the area of the left scapula. The cat had been vaccinated 6 weeks previously in the same area. Haematology showed a marked neutrophilia and monocytosis. Tru-cut biopsies were taken and histopathology was consistent with a high-grade soft tissue sarcoma. Thoracic radiographs and abdominal ultrasound revealed no abnormalities. Moderate mixed (palisading, brush border and smooth) periosteal reaction was seen on the diaphysis of long bones at the time of the radiographic examination. Magnetic resonance imaging of the mass showed infiltration within deeper tissues and the owners elected euthanasia. Post-mortem examination confirmed the presence of hypertrophic osteopathy with a concurrent injection-site sarcoma. No evidence of intra-thoracic or intra-abdominal disease was found. Relevance and novel information To our knowledge, this is the first report where hypertrophic osteopathy has been described in a cat with a soft tissue sarcoma, most likely an injection-site sarcoma.

16.
Nat Genet ; 47(1): 47-56, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25485836

RESUMO

Here we describe a conditional piggyBac transposition system in mice and report the discovery of large sets of new cancer genes through a pancreatic insertional mutagenesis screen. We identify Foxp1 as an oncogenic transcription factor that drives pancreatic cancer invasion and spread in a mouse model and correlates with lymph node metastasis in human patients with pancreatic cancer. The propensity of piggyBac for open chromatin also enabled genome-wide screening for cancer-relevant noncoding DNA, which pinpointed a Cdkn2a cis-regulatory region. Histologically, we observed different tumor subentities and discovered associated genetic events, including Fign insertions in hepatoid pancreatic cancer. Our studies demonstrate the power of genetic screening to discover cancer drivers that are difficult to identify by other approaches to cancer genome analysis, such as downstream targets of commonly mutated human cancer genes. These piggyBac resources are universally applicable in any tissue context and provide unique experimental access to the genetic complexity of cancer.


Assuntos
Transformação Celular Neoplásica/genética , Elementos de DNA Transponíveis/genética , Redes Reguladoras de Genes , Mutagênese Insercional , Neoplasias Pancreáticas/genética , Sequência de Aminoácidos , Animais , Fatores de Transcrição Forkhead/análise , Fatores de Transcrição Forkhead/antagonistas & inibidores , Fatores de Transcrição Forkhead/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Técnicas de Introdução de Genes , Genes Sintéticos , Genes p16 , Humanos , Camundongos , Camundongos Transgênicos , Dados de Sequência Molecular , Mariposas/genética , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Neoplasias Pancreáticas/química , Neoplasias Pancreáticas/patologia , ATPases Translocadoras de Prótons/genética , RNA Interferente Pequeno/farmacologia , Proteínas Repressoras/análise , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/genética , Transgenes , Transposases/genética , Transposases/fisiologia
17.
Cancer Cell ; 24(1): 15-29, 2013 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-23845441

RESUMO

We show that BRAF(V600E) initiates an alternative pathway to colorectal cancer (CRC), which progresses through a hyperplasia/adenoma/carcinoma sequence. This pathway underlies significant subsets of CRCs with distinctive pathomorphologic/genetic/epidemiologic/clinical characteristics. Genetic and functional analyses in mice revealed a series of stage-specific molecular alterations driving different phases of tumor evolution and uncovered mechanisms underlying this stage specificity. We further demonstrate dose-dependent effects of oncogenic signaling, with physiologic Braf(V600E) expression being sufficient for hyperplasia induction, but later stage intensified Mapk-signaling driving both tumor progression and activation of intrinsic tumor suppression. Such phenomena explain, for example, the inability of p53 to restrain tumor initiation as well as its importance in invasiveness control, and the late stage specificity of its somatic mutation. Finally, systematic drug screening revealed sensitivity of this CRC subtype to targeted therapeutics, including Mek or combinatorial PI3K/Braf inhibition.


Assuntos
Neoplasias Colorretais/etiologia , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Animais , Transformação Celular Neoplásica , Neoplasias Colorretais/tratamento farmacológico , Inibidor p16 de Quinase Dependente de Ciclina , Ensaios de Seleção de Medicamentos Antitumorais , Sistema de Sinalização das MAP Quinases , Camundongos , Instabilidade de Microssatélites , Invasividade Neoplásica , Proteínas de Neoplasias/fisiologia , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteína Supressora de Tumor p53/fisiologia , Via de Sinalização Wnt
18.
J Feline Med Surg ; 14(12): 932-7, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22791561

RESUMO

A 14-year-old male domestic shorthair cat presented with an acute onset of aggressive behaviour, fear and hypersalivation. Neurological examination revealed bilateral mydriasis and left-sided facial twitching and hemiparesis. Magnetic resonance imaging (MRI) showed moderate bilateral symmetrical T2-hyperintensity along the entire hippocampus and bilateral asymmetric T2-hyperintensity in the pyriform lobes. Marked bilateral contrast enhancement of the hippocampus was evident on post-contrast T1-weighted images. The partial complex seizures were refractory to medical treatment and the cat was euthanased 4 days after admission. The clinical and MRI findings were consistent with feline hippocampal necrosis (FHN). On histopathology, neuronal necrosis and astrocytosis were present in the hippocampi and pyriform lobes. In addition, an oligodendroglioma was detected in the right pyriform lobe. Contrary to previous reports of FHN in which no underlying cause could be identified, we believe that in this case the seizure focus arose from a neoplastic lesion within the right pyriform lobe. This unique case report represents the so-called 'dual pathology' of temporal lobe epilepsy in humans, in which an extrahippocampal lesion within the temporal lobe results in hippocampal sclerosis.


Assuntos
Neoplasias Encefálicas/veterinária , Doenças do Gato/patologia , Doenças do Gato/cirurgia , Epilepsia do Lobo Temporal/veterinária , Oligodendroglioma/veterinária , Animais , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/patologia , Gatos , Epilepsia do Lobo Temporal/complicações , Epilepsia do Lobo Temporal/patologia , Evolução Fatal , Imageamento por Ressonância Magnética/veterinária , Masculino , Necrose/veterinária , Oligodendroglioma/complicações , Oligodendroglioma/patologia
19.
Res Vet Sci ; 93(1): 318-20, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21925690

RESUMO

The causes of clinical signs associated with syringomyelia in the Cavalier King Charles Spaniel (CKCS) are incompletely understood. In this study we compared expression of two pain-related neuropeptides: substance P (SP) and calcitonin gene related peptide (CGRP), in the spinal cord dorsal horn of normal dogs with that in CKCS with and without clinical signs of syringomyelia. There was a decrease in expression of both peptides in CKCS with 'symptomatic' syringomyelia that was also associated with significant asymmetry in SP-I and similar, though non-significant, asymmetry in CGRP-I compared with other groups. The asymmetric distribution of these pain-related peptides may be a consequence of syrinx-associated damage to grey matter but may also play a role in generation of pain.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/análise , Doenças do Cão/metabolismo , Medula Espinal/química , Substância P/análise , Siringomielia/veterinária , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Doenças do Cão/patologia , Cães , Medula Espinal/metabolismo , Medula Espinal/patologia , Substância P/metabolismo , Siringomielia/metabolismo , Siringomielia/patologia
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