RESUMO
We are currently witnessing the endemization of urogenital schistosomiasis in southern Europe. The incriminated parasite is a hybrid between a human parasite and a livestock parasite. Using an experimental evolutionary protocol, we created hybrid lines from pure strains of both parasite species. We showed that the host spectrum of the human parasite is enlarged to the livestock parasite after genomic introgression. We also evidenced that the tropism of the parasites within the host changes and that some hybrid lines are more virulent than the parental strains. These results engage a paradigm shift from human to zoonotic transmission of urogenital schistosomiasis.
Assuntos
Hibridização Genética , Zoonoses , Animais , Humanos , Zoonoses/transmissão , Zoonoses/parasitologia , Esquistossomose Urinária/transmissão , Esquistossomose Urinária/parasitologia , Schistosoma haematobium/genética , CamundongosRESUMO
Aptamers are small nucleic acids that fold in a three-dimensional conformation allowing them to bind specifically to a target. This target can be an organic molecule, free or carried in cells or tissues, or inorganic components, such as metal ions. Analogous to monoclonal antibodies, aptamers however have certain advantages over the latter: e.g., high specificity for their target, no to low immunogenicity and easy in vitro selection. Since their discovery more than 30 years ago, aptamers have led to various applications, although mainly restricted to basic research. This work reviews the applications of aptamers in veterinary science to date. First, we present aptamers, how they are selected and their properties, then we give examples of applications in food and environmental safety, as well as in diagnosis and medical treatment in the field of veterinary medicine. Because examples of applications in veterinary medicine are scarce, we explore the potential avenues for future applications based on discoveries made in human medicine. Aptamers may offer new possibilities for veterinarians to diagnose certain diseases-particularly infectious diseases-more rapidly or "at the patient's bedside". All the examples highlight the growing interest in aptamers and the premises of a potential market. Aptamers may benefit animals as well as their owners, breeders and even public health in a "One Health" approach.
Assuntos
Doenças dos Animais/diagnóstico , Aptâmeros de Nucleotídeos/análise , Inocuidade dos Alimentos/métodos , Gado , Aves Domésticas , Medicina Veterinária/métodos , AnimaisRESUMO
BACKGROUND: Oestrogen receptor-negative (ER-) breast cancer is intrinsically sensitive to chemotherapy. However, tumour response is often incomplete, and relapse occurs with high frequency. The aim of this work was to analyse the molecular characteristics of residual tumours and early response to chemotherapy in patient-derived xenografts (PDXs) of breast cancer. METHODS: Gene and protein expression profiles were analysed in a panel of ER- breast cancer PDXs before and after chemotherapy treatment. Tumour and stromal interferon-gamma expression was measured in xenografts lysates by human and mouse cytokine arrays, respectively. RESULTS: The analysis of residual tumour cells in chemo-responder PDX revealed a strong overexpression of IFN-inducible genes, induced early after AC treatment and associated with increased STAT1 phosphorylation, DNA-damage and apoptosis. No increase in IFN-inducible gene expression was observed in chemo-resistant PDXs upon chemotherapy. Overexpression of IFN-related genes was associated with human IFN-γ secretion by tumour cells. CONCLUSIONS: Treatment-induced activation of the IFN/STAT1 pathway in tumour cells is associated with chemotherapy response in ER- breast cancer. Further validations in prospective clinical trials will aim to evaluate the usefulness of this signature to assist therapeutic strategies in the clinical setting.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Interferon gama/efeitos dos fármacos , Receptores de Estrogênio/metabolismo , Fator de Transcrição STAT1/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal , Animais , Antígenos/efeitos dos fármacos , Antígenos/genética , Antígenos/metabolismo , Western Blotting , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Capecitabina/farmacologia , Proteínas de Transporte/efeitos dos fármacos , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Caspase 3/efeitos dos fármacos , Caspase 3/genética , Caspase 3/metabolismo , Caspase 7/efeitos dos fármacos , Caspase 7/genética , Caspase 7/metabolismo , Cisplatino/farmacologia , Citocinas/efeitos dos fármacos , Citocinas/genética , Citocinas/metabolismo , Proteínas do Citoesqueleto/efeitos dos fármacos , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Hibridização In Situ , Interferon beta/efeitos dos fármacos , Interferon beta/genética , Interferon beta/metabolismo , Interferon gama/genética , Interferon gama/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/efeitos dos fármacos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Nus , Proteínas Mitocondriais/efeitos dos fármacos , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Proteínas de Resistência a Myxovirus/efeitos dos fármacos , Proteínas de Resistência a Myxovirus/genética , Proteínas de Resistência a Myxovirus/metabolismo , Transplante de NeoplasiasRESUMO
Metabolic adaptations and changes in the expression of nutrient transporters are known to accompany tumorigenic processes. Nevertheless, in the context of solid tumors, studies of metabolism are hindered by a paucity of tools allowing the identification of cell surface transporters on individual cells. Here, we developed a method for the dissociation of human breast cancer tumor xenografts combined with quantification of cell surface markers, including metabolite transporters. The expression profiles of four relevant nutrient transporters for cancer cells' metabolism, Glut1, ASCT2, PiT1 and PiT2 (participating to glucose, glutamine and inorganic phosphate, respectively), as detected by new retroviral envelope glycoprotein-derived ligands, were distinctive of each tumor, unveiling underlying differences in metabolic pathways. Our tumor dissociation procedure and nutrient transporter profiling technology provides opportunities for future basic research, clinical diagnosis, prognosis and evaluation of therapeutic responses, as well as for drug discovery and development.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Citometria de Fluxo/métodos , Proteínas de Membrana Transportadoras/metabolismo , Análise de Variância , Animais , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Sobrevivência Celular/fisiologia , Feminino , Humanos , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Imuno-Histoquímica/métodos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Reprodutibilidade dos Testes , Transplante HeterólogoRESUMO
Dogs and cats may suffer from a variety of diseases, mainly immune mediated, that require the administration of immunosuppressive drugs. Such therapies can cause adverse effects either by the toxicity of the drugs or as a consequence of immune suppression and associated opportunistic infections. Here we present an, yet unknown, association of Toxoplasma gondii and Alternaria fungus, within cutaneous lesions in a dog under long-term immunosuppressive therapy. The diagnosis of such infections is laborious and not obvious at first glance, since the clinical signs of cutaneous toxoplasmosis, neosporosis or alternariosis are not specific. A further laboratory confirmation is needed. Therefore, we currently recommend that dogs and cats should undergo serologic testing for toxoplasmosis or neosporosis prior to immunosuppressive therapy and a regular dermatological evaluation during the immunosuppressive therapy.
RESUMO
INTRODUCTION: Identification of new therapeutic agents for breast cancer (BC) requires preclinical models that reproduce the molecular characteristics of their respective clinical tumors. In this work, we analyzed the genomic and gene expression profiles of human BC xenografts and the corresponding patient tumors. METHODS: Eighteen BC xenografts were obtained by grafting tumor fragments from patients into Swiss nude mice. Molecular characterization of patient tumors and xenografts was performed by DNA copy number analysis and gene expression analysis using Affymetrix Microarrays. RESULTS: Comparison analysis showed that 14/18 pairs of tumors shared more than 56% of copy number alterations (CNA). Unsupervised hierarchical clustering analysis showed that 16/18 pairs segregated together, confirming the similarity between tumor pairs. Analysis of recurrent CNA changes between patient tumors and xenografts showed losses in 176 chromosomal regions and gains in 202 chromosomal regions. Gene expression profile analysis showed that less than 5% of genes had recurrent variations between patient tumors and their respective xenografts; these genes largely corresponded to human stromal compartment genes. Finally, analysis of different passages of the same tumor showed that sequential mouse-to-mouse tumor grafts did not affect genomic rearrangements or gene expression profiles, suggesting genetic stability of these models over time. CONCLUSIONS: This panel of human BC xenografts maintains the overall genomic and gene expression profile of the corresponding patient tumors and remains stable throughout sequential in vivo generations. The observed genomic profile and gene expression differences appear to be due to the loss of human stromal genes. These xenografts, therefore, represent a validated model for preclinical investigation of new therapeutic agents.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Transcriptoma , Animais , Análise por Conglomerados , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Feminino , Instabilidade Genômica , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Transplante HeterólogoRESUMO
Androgen-dependent and castration-resistant prostate cancer (PC) is usually sensitive to docetaxel chemotherapy. Nevertheless, docetaxel resistance frequently appears after several cycles of treatment, raising the problem of salvage treatment for docetaxel-resistant PC patients. Although the combination of docetaxel and estramustine prolongs metastasis-free and overall survival of patients with androgen-independent PC, the use of this modality remains limited in elderly patients or patients with several comorbidities, especially vascular disease or gastrointestinal toxicity, because of unacceptable toxicity including venous thrombosis. The aims of this study were therefore (i) to evaluate the in-vivo efficacy of estramustine combined with docetaxel since initial tumor growth and following the appearance of docetaxel resistance in the androgen-dependent human PC xenograft PAC120, and (ii) to evaluate the efficacy of estramustine in six human androgen-independent PC models derived from PAC120. In docetaxel-resistant tumor-bearing mice, estramustine alone induced a TGD2 of 18 days, whereas the combination of docetaxel and estramustine induced a TGD2 of 50 days (P<0.05) with no significantly different overall survival of mice treated by docetaxel and estramustine since day 1 or since the onset of resistance to docetaxel. Among the six human androgen-independent tumors treated with estramustine alone, two highly sensitive models, two intermediate responding tumors, and two resistant models were observed. Altogether, these results suggest that estramustine should be combined with docetaxel in PC patients, but the use of this treatment could be limited, particularly in elderly patients, to docetaxel-resistant cases.
Assuntos
Antineoplásicos Hormonais/farmacologia , Estramustina/farmacologia , Gastroenteropatias , Neoplasias da Próstata/tratamento farmacológico , Taxoides/farmacologia , Doenças Vasculares , Idoso , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Comorbidade , Docetaxel , Avaliação Pré-Clínica de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Gastroenteropatias/epidemiologia , Humanos , Masculino , Camundongos , Camundongos Nus , Neoplasias Hormônio-Dependentes/sangue , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Neoplasias Hormônio-Dependentes/epidemiologia , Orquiectomia , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/epidemiologia , Taxa de Sobrevida , Doenças Vasculares/epidemiologia , Trombose Venosa/induzido quimicamente , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
This case describes a subcutaneous soft tissue tumour in a German Shepherd dog. Histologically, the lesion was characterized by proliferating ovoid cells, loosely arranged in a collagenous to myxoid stroma, and by numerous pseudoglandular structures lined by neoplastic cells. Immunohistochemically, neoplastic cells were labelled with vimentin, glial fibrillary acidic protein and S100 antibodies, but not with cytokeratin, desmin and smooth muscle actin antibodies. Ultrastructurally, neoplastic cells were characterized by numerous mitochondria surrounded by endoplasmic reticulum and contained few secondary lysosomes. This tumour was diagnosed as a subcutaneous peripheral nerve sheath tumour (PNST) with pseudoglandular architecture. This case illustrates the morphological diversity of PNST and provides new insight into the differential diagnosis of cutaneous tumours of similar morphology in the dog.
Assuntos
Doenças do Cão/patologia , Neoplasias de Bainha Neural/veterinária , Neoplasias de Tecidos Moles/veterinária , Animais , Cães , Feminino , Imuno-Histoquímica/veterinária , Microscopia Eletrônica de Transmissão/veterinária , Neoplasias de Bainha Neural/patologia , Neoplasias de Bainha Neural/ultraestrutura , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/ultraestruturaRESUMO
The success of treatment of advanced non-small-cell lung cancer (NSCLC) remains very poor. The aim of this study was, on a series of NSCLC xenografts, to compare the efficacy of standard cisplatin-based or docetaxel-based chemotherapy. Seven human xenografts were obtained from six patients (two xenografts were derived from primary or metastatic tumors of the same patient). Three xenografts were adenocarcinomas and four were squamous cell carcinomas. All xenografts reproduced the same histology as that of the patient's original tumor. Docetaxel, administered as single-agent chemotherapy, induced a significant response in five of the seven NSCLC xenografts (71%), without significant increase after combination with cisplatin, vinorelbine, or gemcitabine. Relative expression of genes putatively involved in drug response was also studied in all xenografts and did not explain the variability of drug sensitivity. In conclusion, this panel of human NSCLC xenografts reliably reproduces the data obtained in patient tumors and the relative sensitivity to docetaxel reported in NSCLC patients.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Taxoides/uso terapêutico , Idoso , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Cisplatino/farmacologia , Docetaxel , Resistencia a Medicamentos Antineoplásicos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes p53/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Taxoides/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
We report herein a feline salivary gland adenocarcinoma with widespread metastases to draining lymph nodes, liver and lung, as well as an unusual metastasis to the spleen. Histologically, the primary salivary gland tumor consisted of low columnar to polygonal epithelial cells forming tubules and trabeculae. The spleen was infiltrated with sheets of poorly differentiated large round cells. Interestingly, morphologic change in epithelial cells was accompanied with the acquisition of vimentin intermediate filaments, a feature particularly evident in the splenic metastasis. This study highlights the role of epithelial cell plasticity during carcinogenesis and metastasis.
Assuntos
Adenocarcinoma/veterinária , Doenças do Gato/metabolismo , Neoplasias das Glândulas Salivares/veterinária , Vimentina/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Doenças do Gato/patologia , Gatos , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/veterinária , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/veterinária , Masculino , Neoplasias das Glândulas Salivares/metabolismo , Neoplasias das Glândulas Salivares/patologia , Neoplasias Esplênicas/metabolismo , Neoplasias Esplênicas/secundário , Neoplasias Esplênicas/veterinária , Vimentina/genéticaRESUMO
A hepatic mass was identified in a 5-year-old, female mixed-breed cat that died spontaneously after a clinical history of progressive emaciation, ptyalism, and persistent coryza. At necropsy, a 7-cm-diameter, yellow-brown, firm, multilobulated tumor was identified in the liver. Microscopically, the mass consisted of neoplastic cells arranged in small, closely packed nests within a thin fibrovascular stroma. These cells were of medium sized and polygonal, with fine argyrophilic cytoplasmic granules. Nuclei were predominantly round with finely stippled chromatin and indistinct nucleoli. Mitotic figures were numerous. Immunohistochemically, most of the neoplastic cells were immunoreactive for chromogranin A, neuron-specific enolase (NSE), and cytokeratin AE1/AE3 and weakly labeled for synaptophysin. The tumor was negative for glial fibrillary acidic protein (GFAP), vimentin, and cytokeratins 5, 6, 8, and 17. Vascular emboli and intrahepatic micrometastasis were also identified with chromogranin A. All these features were consistent with a hepatic neuroendocrine carcinoma and emphasized the importance of using a panel of antibodies to diagnose such rare tumors.
Assuntos
Carcinoma Neuroendócrino/veterinária , Doenças do Gato/patologia , Neoplasias Hepáticas/veterinária , Animais , Carcinoma Neuroendócrino/patologia , Gatos , Evolução Fatal , Feminino , Imuno-Histoquímica/veterinária , Neoplasias Hepáticas/patologiaRESUMO
Mammary gland adenomyoepitheliomas are benign complex mammary gland tumors composed of neoplastic cells of epithelial and myoepithelial origins, described in many species (humans, dogs, cats, rats) and rarely in mice. We report here an adenomyoepithelioma in a C57BL/6 female mouse. Histologically, tubes and cords formed by neoplastic epithelial cells were separated by bundles of neoplastic myoepithelial cells in a clear and partially mucinous matrix. The tumor displayed characteristics of a benign neoplastic proliferation with a compressive growth pattern, and moderate cellular pleomorphism and mitotic index. At immunohistochemistry, the epithelial cells were strongly cytokeratin positive; the myoepithelial cells were weakly cytokeratin positive and strongly smooth muscle actin positive. This is to our knowledge, the first report of a mammary gland adenomyoepithelioma in a C57BL/6 mouse.
Assuntos
Neoplasias Mamárias Animais/patologia , Mioepitelioma/patologia , Mioepitelioma/veterinária , Animais , Feminino , Imuno-Histoquímica , Neoplasias Mamárias Animais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mioepitelioma/metabolismoRESUMO
Histiocytic sarcoma is the most frequent hematopoietic tumor in rats. We report here a histiocytic sarcoma infiltrating the liver, the spleen and the pancreas from a Wistar rat. In the liver, the tumor was associated with oval cell and bile duct hyperplasia. The cells looked like neoplastic histocytic cells described in this species but with some particularities (e.g. lack of multinucleated giant cells). At immunohistochemistry, neoplastic cells in the liver were vimentine positive but lysozyme and CD68 negative. In the kidney, lysozyme-positive cytoplasmic droplets were observed. We describe here an atypical case of histiocytic sarcoma in the rat and we compare the nature of these neoplastic cells to other species.
Assuntos
Sarcoma Histiocítico/patologia , Neoplasias Hepáticas/patologia , Neoplasias Pancreáticas/patologia , Neoplasias Esplênicas/patologia , Animais , Antígenos CD/biossíntese , Antígenos de Diferenciação Mielomonocítica/biossíntese , Sarcoma Histiocítico/metabolismo , Imuno-Histoquímica , Rim/metabolismo , Rim/patologia , Neoplasias Hepáticas/metabolismo , Masculino , Muramidase/biossíntese , Neoplasias Pancreáticas/metabolismo , Ratos , Ratos Wistar , Neoplasias Esplênicas/metabolismo , Vimentina/biossínteseRESUMO
Conjugated linoleic acids (CLAs) consist of a series of positional and geometrical isomers of linoleic acid. CLA have been reported to beneficially affect cardiovascular risk factors in animal models. In order to assess the role of individual CLA isomers on lipoprotein cholesterol concentration, 30 hamsters were fed for 12 weeks an hyperlipidic diet containing pure cis-9,trans-11 CLA (c9,t11) or pure trans-10, cis-12 CLA (t10,c12) isomers given alone or as a mixture. Plasma total cholesterol, LDL and HDL cholesterol concentrations were significantly lower in the c9,t11 CLA isomer fed hamsters relative to the Control group, with the most substantially effect on LDL cholesterol (-56%; P < 0.05). Plasma triacylglycerol concentrations did not differ significantly regarding those two groups. Plasma cholesterol parameters showed a tendency to decrease in the t10,c12 CLA isomer and CLA mixture fed hamsters compared with the Control group, but differences were not significant. For the first time, the atherogenic fraction of small dense LDL was investigated. Plasma small dense LDL cholesterol concentration was lower in the c9,t11 CLA relative to Control, while the t10,c12 and CLA mixture groups showed only a non significant tendency to decrease. Taken together, these data indicate that feeding rumenic acid (c9,t11 CLA) may beneficially affect lipoprotein profile in hamster fed a cholesterol- and lipid-enriched semi-purified diet, when t10,c12 CLA isomer or CLA mixture would be less active.
Assuntos
LDL-Colesterol/sangue , Ácidos Linoleicos Conjugados/farmacologia , Lipoproteínas LDL/sangue , Animais , Colesterol na Dieta/administração & dosagem , HDL-Colesterol/sangue , Cricetinae , Gorduras na Dieta/administração & dosagem , Hiperlipidemias/sangue , Hiperlipidemias/prevenção & controle , Ácidos Linoleicos Conjugados/administração & dosagem , Masculino , Mesocricetus , Triglicerídeos/sangueRESUMO
The cyanobacterial hepatotoxin microcystin-LR (MC-LR) is a specific potent PP1 and PP2A protein phosphatase inhibitor. In view to obtain an integrated whole-body, understanding of the key target organs of MC-LR subsequent to embryonic exposure on the anatomy of medaka fish hatchlings, embryos at stage 19 were microinjected with a sublethal dose of MC-LR corresponding to 0.2 pg/vitellus. MC-LR-induced histo-pathological modifications of the alimentary system (i.e. digestive tract, pancreas, liver) were analysed in newly hatched embryos. Our data are indicative of an MC-LR-induced inhibition of both yolk sac resorption and gas concentrating swimbladder expansion. In contrast to control hatchlings, (i) no mucus-secreting cells in the oesophagus, (ii) a decreased folding of the stomach and intestine, (iii) a clear reduction in size of the exocrine pancreas associated with a destructuration of acinar units, and (iv) a strong decrease in the mass and size of the liver were observed in MC-LR treated embryos. Furthermore, as an indication of MC-LR-induced hepatic glycogen store depletion, unstained cytoplasmic areas present in control hatchling hepatocytes, were fully absent in all liver examined in treated embryos. Finally, as a general observation in MC-LR-treated embryos, our data clearly indicated terminal differentiation disorders in all organs associated with the digestive tract.
Assuntos
Sistema Digestório/efeitos dos fármacos , Toxinas Marinhas/farmacologia , Oryzias/embriologia , Oryzias/crescimento & desenvolvimento , Peptídeos Cíclicos/farmacologia , Animais , Sistema Digestório/embriologia , Sistema Digestório/crescimento & desenvolvimento , Embrião não Mamífero/efeitos dos fármacos , Larva/efeitos dos fármacos , MicrocistinasRESUMO
Abstract- Bovine nodular thelitis in dairy cows is a chronic and enzootic infection. Four stages were distinguished: early stage, evolutive stage, ulcerative stage and final stage. Lesions were located mainly in the lower part of the udder or on the teat and recognized as solid papules and nodules. The histopathological study revealed a tuberculoid granulomatous pattern characterized by a subacute focal dermatitis with lymphoid cells, macrophages, epitheloid cells and a variable number of multinucleate giant cells (Langhans type) but no necrosis. Acid-fast bacilli were demonstrated in two of 14 cases. Three strains of acid fast bacilli were isolated but the only one identified was Mycobacterium terrae. M. terrae is a non-pathogenic slowly growing, non-photochromogenic mycobacterium. Its role in tuberculosis-like skin lesion is the bovine udder is uncertain. Résumé- La thélite nodulaire est une infection chronique et enzootique chez les vaches laitières. On distingue 4 phases: une phase précoce, une phase évolutive, une phase ulcérative et une phase finale. Vingt échantillons histologiques, mammelles et trayons, ont été examinés. Les lésions étaient localisées essentiellement à la partie basse de la mammelle ou sur le trayon et se présentaient sous l'aspect de papules solides ou de nodules. Les échantillons étaient divisés en deux parties: l'une destinée à l'isolement de mycobactéries, l'autre à l'examen histologique. Les lésions histologiques des trayons étaient des granulomes tuberculoïdes, caractérisés par une dermatite subaigue focale avec présence de lymphocytes, macrophages, cellules épithélioïdes et une nombre variable de cellules multinucléées géantes (type Langhans). Les infiltrats inflammatoires étaient principalement périvasculaires. Parfois, ils infiltraient toute la paroi du trayon. Aucune nécrose n'a été observée. Des bacilles acidoalcoolorésistants furent mis en évidence de manière inconstante (2 cas sur 14). Trois types de bacilles acidoalcoolorésistants ont été isolés raais, un seul a été identifié comme étant Mycobacterium terrae. M. terrae est une mycobactérie non pathogène, de croissance lente et non photochromogène. L'implication de cet organisme dans les lésions de type tuberculeux dans la mammelle de la vache est discutée. Zusammenfassung- Bei Milchkühen stellt die bovine noduläre Thelitis eine chronische und enzootische Infektion dar. Vier Stadien lassen sich unterscheiden: Früstadium evolutorisches Stadium, ulzeratives Stadium und Endstadium. 20 pathologische Proben von Euter und Zitzen wurden untersucht. Die Veränderungen waren hauptsächlich am unteren Teil des Euters oder an den Zitzen lokalisiert und ließen sich als solide Papeln oder Knoten ansprechen. Das Untersuchungsgul wurde für die Isolierung von Mykobakterien und für eine histopathologische Untersuchung geteilt. Die histopathologischen Veränderungen der Zitzen zeigten ein tuberkuloides granulomatöses Bild, das durch subakute fokale Dermatitis mit lymphyoiden Zellen, Makrophagen, Epitheloidzellen und einer variablen Anzahl von vielkernigen Riesenzellen (Langhans-Typ) gekennzeichnet war. Die entzündlichen Infiltrate befanden sich hauptsächlich perivaskulär. Manchmal ließen sie sich aber auch in der gesamten Zitzenwand nachweisen. Nekrosen bestaznden nicht. Säurefeste Bazillus-Keime waren inkonstant vorhanden (2 von 14 Fällen). Drei Arten von säurefesten Bazillus-Keimen wurden isoliert, aber nur eine wurde speziell identifiziert (Mycobacterium terrae). M. terrae ist ein nicht pathogenes, langsam wachsendes und nich photochromogenes Mykobakterium. Die Beteiligung dieses Organismus bei den tuberkulose-ähnlichen Hautveränderungen am bovinen Euter wird diskutiert. Resumen La Telitis Nodular Bovina es una infección enzoótica crónica de las vacas lecheras. Se distinguen cuatro etapas: etapa inicial, etapa evolutiva, etapa ulcerativa y etapa final. En el presente trabajo se examinaron 20 muestras de mama y de pezón. Las lesiones se localizaban principalmente en la parte inferior de la glándula mamaria o en el pezón y consistían en pápulas sólidas y en nódulos. Las muestras se dividían en dos partes, una para el aislamiento de micobacterias y la otra para los estudios histopatológicos. Las lesiones histopatológicas consistían en una reacción granulomatosa de tipo tuberculoide, caracterizada por una dermatitis focal subaguda con células linfoides, macrófagos, células epitelioides y un número variable de células gigantes multinucleadas (tipo Langhans). Los infiltrados inflamatorios estaban localizados predominantemente en la zone perivascular. En ocasiones, aparecían a lo largo de toda la pared de la glándula mamaria. No se observó necrosis. Se han aislado tres cepas de bacilos acido-alcohol resistentes, pero sólo una fue identificada específicamente como Mycobacterium terrae. M. Terrae es una micobacteria no fotocromogénica de crecimiento lento y no patógena. Se discute la posible participación de este microorganismo en la génesis de las lesiones pseudotuberculosas observadas en estos animales.
RESUMO
A quantitative method for the informative evaluation of teaching activities was devised using a survey from 33 experts. It is based on an evaluation, by students and two peers, of the four steps of the instructional methodology: analysis of training needs, statement of learning objectives, delivery of teaching session, and testing of student performance. Faculty evaluation is optional, and results are strictly confidential. Results of a three-year trial of this protocol at the Alfort veterinary school are presented and discussed. Each year the method has been assessed and some changes have been implemented. It is now felt that evaluation questionnaires for lectures and tutorial sessions have been validated, while those for laboratories and clinical teaching have to be tested through a larger number of settings. A the same time, a change from informative to summative evaluation is under consideration.
Assuntos
Educação em Veterinária , Docentes de Medicina , Inquéritos e Questionários/normas , Animais , França , Humanos , Avaliação de Programas e Projetos de Saúde , Reprodutibilidade dos TestesRESUMO
In vitro studies suggested that sub-millisecond pulses of radiation elicit less genomic instability than continuous, protracted irradiation at the same total dose. To determine the potential of ultrahigh dose-rate irradiation in radiotherapy, we investigated lung fibrogenesis in C57BL/6J mice exposed either to short pulses (≤ 500 ms) of radiation delivered at ultrahigh dose rate (≥ 40 Gy/s, FLASH) or to conventional dose-rate irradiation (≤ 0.03 Gy/s, CONV) in single doses. The growth of human HBCx-12A and HEp-2 tumor xenografts in nude mice and syngeneic TC-1 Luc(+) orthotopic lung tumors in C57BL/6J mice was monitored under similar radiation conditions. CONV (15 Gy) triggered lung fibrosis associated with activation of the TGF-ß (transforming growth factor-ß) cascade, whereas no complications developed after doses of FLASH below 20 Gy for more than 36 weeks after irradiation. FLASH irradiation also spared normal smooth muscle and epithelial cells from acute radiation-induced apoptosis, which could be reinduced by administration of systemic TNF-α (tumor necrosis factor-α) before irradiation. In contrast, FLASH was as efficient as CONV in the repression of tumor growth. Together, these results suggest that FLASH radiotherapy might allow complete eradication of lung tumors and reduce the occurrence and severity of early and late complications affecting normal tissue.
Assuntos
Raios gama , Neoplasias/patologia , Animais , Apoptose/efeitos da radiação , Vasos Sanguíneos/efeitos da radiação , Brônquios/efeitos da radiação , Relação Dose-Resposta à Radiação , Feminino , Humanos , Pulmão/irrigação sanguínea , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: Patients with luminal breast cancer (LBC) often become endocrine resistant over time. We investigated the molecular changes associated with acquired hormonoresistances in patient-derived xenografts of LBC. EXPERIMENTAL DESIGN: Two LBC xenografts (HBCx22 and HBCx34) were treated with different endocrine treatments (ET) to obtain xenografts with acquired resistances to tamoxifen (TamR) and ovariectomy (OvaR). PI3K pathway activation was analyzed by Western blot analysis and IHC and responses to ET combined to everolimus were investigated in vivo. Gene expression analyses were performed by RT-PCR and Affymetrix arrays. RESULTS: HBCx22 TamR xenograft was cross-resistant to several hormonotherapies, whereas HBCx22 OvaR and HBCx34 TamR exhibited a treatment-specific resistance profile. PI3K pathway was similarly activated in parental and resistant xenografts but the addition of everolimus did not restore the response to tamoxifen in TamR xenografts. In contrast, the combination of fulvestrant and everolimus induced tumor regression in vivo in HBCx34 TamR, where we found a cross-talk between the estrogen receptor (ER) and PI3K pathways. Expression of several ER-controlled genes and ER coregulators was significantly changed in both TamR and OvaR tumors, indicating impaired ER transcriptional activity. Expression changes associated with hormonoresistance were both tumor and treatment specific and were enriched for genes involved in cell growth, cell death, and cell survival. CONCLUSIONS: PDX models of LBC with acquired resistance to endocrine therapies show a great diversity of resistance phenotype, associated with specific deregulations of ER-mediated gene transcription. These models offer a tool for developing anticancer therapies and to investigate the dynamics of resistance emerging during pharmacologic interventions. Clin Cancer Res; 20(16); 4314-25. ©2014 AACR.
Assuntos
Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Receptor alfa de Estrogênio/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Receptor ErbB-2/metabolismo , Tamoxifeno/farmacologia , Animais , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Western Blotting , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Receptor alfa de Estrogênio/genética , Feminino , Humanos , Técnicas Imunoenzimáticas , Camundongos , Camundongos Nus , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptor ErbB-2/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Triple-negative breast cancers (TNBC) have an aggressive phenotype with a relatively high rate of recurrence and poor overall survival. To date, there is no approved targeted therapy for TNBCs. Aurora kinases act as regulators of mammalian cell division. They are important for cell-cycle progression and are frequently overexpressed or mutated in human tumors, including breast cancer. In this study, we investigated the therapeutic potential of targeting Aurora kinases in preclinical models of human breast cancers using a pan-inhibitor of Aurora kinases, AS703569. In vitro, AS703569 was tested in 15 human breast cancer cell lines. TNBC cell lines were more sensitive to AS703569 than were other types of breast cancer cells. Inhibition of proliferation was associated with cell-cycle arrest, aneuploidy, and apoptosis. In vivo, AS703569 administered alone significantly inhibited tumor growth in seven of 11 patient-derived breast cancer xenografts. Treatment with AS703569 was associated with a decrease of phospho-histone H3 expression. Finally, AS703569 combined to doxorubicin-cyclophosphamide significantly inhibited in vivo tumor recurrence, suggesting that Aurora kinase inhibitors could be used both in monotherapy and in combination settings. In conclusion, these data indicate that targeting Aurora kinases could represent a new effective approach for TNBC treatment.