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Although it is held that proinflammatory changes precede the onset of breast cancer, the underlying mechanisms remain obscure. Here, we demonstrate that FRS2ß, an adaptor protein expressed in a small subset of epithelial cells, triggers the proinflammatory changes that induce stroma in premalignant mammary tissues and is responsible for the disease onset. FRS2ß deficiency in mouse mammary tumor virus (MMTV)-ErbB2 mice markedly attenuated tumorigenesis. Importantly, tumor cells derived from MMTV-ErbB2 mice failed to generate tumors when grafted in the FRS2ß-deficient premalignant tissues. We found that colocalization of FRS2ß and the NEMO subunit of the IκB kinase complex in early endosomes led to activation of nuclear factor-κB (NF-κB), a master regulator of inflammation. Moreover, inhibition of the activities of the NF-κB-induced cytokines, CXC chemokine ligand 12 and insulin-like growth factor 1, abrogated tumorigenesis. Human breast cancer tissues that express higher levels of FRS2ß contain more stroma. The elucidation of the FRS2ß-NF-κB axis uncovers a molecular link between the proinflammatory changes and the disease onset.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Neoplasias de la Mama/etiología , Neoplasias de la Mama/metabolismo , Neoplasias Mamarias Experimentales/etiología , Neoplasias Mamarias Experimentales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/inmunología , Animales , Neoplasias de la Mama/inmunología , Carcinogénesis , Citocinas/metabolismo , Femenino , Humanos , Inflamación/etiología , Inflamación/metabolismo , Neoplasias Mamarias Experimentales/inmunología , Virus del Tumor Mamario del Ratón , Ratones , Ratones Noqueados , FN-kappa B/metabolismo , Embarazo , Receptor ErbB-2/metabolismo , Infecciones por Retroviridae , Microambiente Tumoral/inmunología , Infecciones Tumorales por VirusRESUMEN
High-fat intake by young Asian women impacts the risk of breast cancer. Understanding the underlying molecular mechanisms may be essential for disease prevention in Asia as well as globally. We aimed to examine the effects of corn oil- and animal fat-based high-fat diets (32.9 and 31.4%, respectively, of fat energy ratio as compared to 12.3% in the standard diet) on mammary carcinogenesis and alterations in gene expression and epigenetic statuses in the mammary gland during the growth stages in a rat model. An increased incidence of carcinomas was observed after the cessation of high-fat feeding. In addition, rapid tumor growth and elevations in Celsr2 expression, which may be a result of DNA hypomethylation patterns in the 3' untranslated region of the gene were noted in the animal fat group. In the human breast carcinoma cell line MCF7, a marginal decrease in cell viability was observed following the knockdown of Celsr2, suggesting that the animal fat-associated risk of cancer is partly due to the deregulation of mammary cell proliferation via non-metabolic gene functions. The present results will contribute to the development of strategies for controlling the food-associated risk of breast cancer, particularly in younger age groups.
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Neoplasias de la Mama , Neoplasias Mamarias Experimentales , Ratas , Humanos , Femenino , Animales , Dieta Alta en Grasa/efectos adversos , Neoplasias de la Mama/etiología , Neoplasias de la Mama/complicaciones , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/patología , Incidencia , Proliferación Celular , Grasas de la Dieta/efectos adversos , Cadherinas , Receptores Acoplados a Proteínas GRESUMEN
Nestin, a class VI intermediate filament protein, is known to be expressed in various types of human neoplasms, including breast cancer, and is associated with their progression. However, its expression and role in canine mammary tumors remain unknown. We analyzed nestin expression in canine mammary tumors using in situ hybridization and immunohistochemistry. We also investigated its role in a canine mammary carcinoma cell line using RNA interference. Nestin expression was not observed in luminal epithelial cells of any of the 62 cases of benign mammary lesions examined, although myoepithelial cells showed its expression in most cases. In 16/50 (32%) primary mammary carcinomas and 6/15 (40%) metastases of mammary carcinomas, cytoplasmic nestin expression was detected in luminal epithelial cells. In luminal cells of primary mammary carcinomas, its expression was positively related to several pathological parameters that indicate high-grade malignancy, including histological grading (P < .01), vascular/lymphatic invasion (P < .01), Ki-67 index (P < .01), and metastasis (P < .05). Immunohistochemistry revealed that nestin expression was related to vimentin expression in mammary carcinomas (P < .01). This relationship was confirmed using reverse transcription-quantitative polymerase chain reaction using 9 cell lines derived from canine mammary carcinoma (P < .01). Finally, nestin knockdown in canine mammary carcinoma cells using small interfering RNA inhibited cell proliferation and migration based on WST-8, Boyden chamber, and cell-tracking assays. These findings suggest that nestin may at least partially mediate these behaviors of canine mammary carcinoma cells.
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Carcinoma , Enfermedades de los Perros , Neoplasias Mamarias Animales , Nestina , Animales , Carcinoma/genética , Carcinoma/veterinaria , Enfermedades de los Perros/genética , Perros , Femenino , Inmunohistoquímica , Neoplasias Mamarias Animales/genética , Nestina/genéticaRESUMEN
Patients with dominantly inherited Li-Fraumeni syndrome have a loss-of-function mutation in TP53 and develop diverse mesenchymal and epithelial neoplasms at multiple sites. Trp53 +/- female mice with the BALB/c background provide unique characteristics for the study of breast cancer in Li-Fraumeni syndrome; however, we previously found that female C3H-Trp53+/ - mice did not spontaneously develop mammary tumors. Therefore, we obtained F1 and N2-N4 female mice by backcrossing the BALB/c strain and examined the incidence of mammary and other tumors in lifetime studies. Malignant lymphomas, osteosarcomas, and uterine adenocarcinomas spontaneously developed in approximately 20% or more of Trp53+/ - mice with the C3H background. In contrast, the incidence of uterine adenocarcinomas showed a tendency to decrease, while that of mammary adenocarcinomas gradually increased in mice with the BALB/c strain backcross. Wild-type BALB/c female mice are predisposed to a wide spectrum of neoplasms, including mammary tumors, partly due to genetic factors, whereas uterine tumors are uncommon not only in BALB/c mice but also C3H mice. Thus, genetic factors appear to contribute to a strain-specific predisposition to malignant neoplasms in Trp53+/- mice, and further studies are needed to clarify the detailed mechanisms.
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A 16-year-old male mixed-breed dog presented with a mass with hemorrhage at the right conjunctiva. Five months after the initial visit, the right eye protruded and had a firm and irregular mass measuring approximately 1.00 cm in diameter with conjunctival hemorrhage. Microscopically, the mass was comprised polygonal or round tumor cells with distinct cell borders arranged in a nested and diffuse pattern. The tumor cells had round-to-oval fine hyperchromatic nuclei containing distinct multiple nucleoli and abundant eosinophilic or pale cytoplasm. Multiple giant cells were frequently observed. The mitotic index was 12.60/high power field. Extensive necrosis, hemorrhage and part of the cord-like and papillary epithelioid cells were observed in the intra-tumor tissue. Immunohistochemically, the tumor cells were positive for vimentin and α-smooth muscle actin and negative for cytokeratin, desmin and PNL2. On the other hand, the cord-like and papillary epithelioid cells were positive for vimentin, S100 and neuron-specific enolase. The tumor was diagnosed as an epithelioid leiomyosarcoma. This case considered to have occurred in the ocular region, although the ocular structure was destroyed.
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An 11-year-old male Miniature Dachshund dog was presented with dyschezia. Computed tomography examination 35 days after the initial visit revealed a prostate mass (4.0 × 3.5 × 2.7 cm) and prostatectomy and orchiectomy were performed 13 days later. Grossly, the prostate was rubbery and the cut surface of the mass was swollen. The mass was whitish and demarcated from the surrounding tissues. Microscopically, the mass had a capsulate consisting of atypical spindloid stromal cells arranged in a phyllode pattern and also in a fasciculated pattern admixed with acinar ductal cells. Atypical stromal cells contained round-to-oval finely hyperchromatic nuclei that had distinct nuclei and abundant eosinophilic cytoplasm. Immunohistochemically, the atypical stromal cells were positive for vimentin, CD34, desmin, α-smooth muscle actin, progesterone receptor and androgen receptor but negative for cytokeratin AE1/AE3, p63, c-Kit, DOG-1 and SOX10. On the basis of these findings, the tumour was diagnosed as a prostatic stromal tumour of uncertain malignant potential.
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Enfermedades de los Perros , Neoplasias de los Tejidos Blandos , Animales , Perros , Masculino , Enfermedades de los Perros/patología , Próstata/patología , Proteínas Proto-Oncogénicas c-kit , Neoplasias de los Tejidos Blandos/patología , Neoplasias de los Tejidos Blandos/veterinariaRESUMEN
A 10-year-old spayed mixed breed dog presented with severe neurological signs. Computed tomography revealed a cranial mediastinal mass, osteolysis of the right second rib and second thoracic vertebra, tracheobronchial and mesenteric lymph node enlargement, pneumonia and pleural effusion. Magnetic resonance imaging detected lesions in the white matter of the right frontal lobe and left cerebral hemisphere with contrast-enhanced T1-weighted images showing demarcated enhancement. On cut section, the surface of the right cerebral frontal lobe and left cerebral hemisphere corticomedullary junctions were indistinct and the white matter was discoloured. Microscopically, multicentric granulomatous inflammation was seen in the brain, cranial mediastinal mass, masses on the right second rib, tracheobronchial and mesenteric lymph nodes, heart, kidneys, lungs and oesophagus. Necrosis and hyaline fungal structures were frequently observed in the centre of the granulomas. These fungi had septae, Y-shaped branching and were 2-3 µm in width. Sequence analysis of DNA from formalin-fixed paraffin-embedded samples identified the fungi as Schizophyllum commune. Based on these findings, this case was diagnosed as disseminated S. commune infection. This is the first report of granulomatous encephalitis caused by S. commune in a dog.
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Enfermedades de los Perros , Encefalitis , Schizophyllum , Animales , Perros , Enfermedades de los Perros/microbiología , Enfermedades de los Perros/patología , Encefalitis/veterinaria , Granuloma/veterinaria , Femenino , Micosis/veterinariaRESUMEN
We examined the clinical signs and necropsy findings of a mountain hawk-eagle (Nisaetus nipalensis) that died during rehabilitation. The bird was rescued and treated for open fracture of the right forearm. During rehabilitation, the bird could not stand up or fly. Part of the right secondary and left and right primary feathers were removed during rehabilitation; additional fracture was found in the right tibiotarsus and treated. However, the bird died 92 days after rescue and necropsy was performed. Severe hepatic lipidosis and capture myopathy were confirmed by histopathological examinations. These lesions may be associated with the cause of death of this animal. Accumulation of information is expected to contribute to the improvement of effective rehabilitation techniques for raptors.
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Enfermedades de las Aves , Águilas , Halcones , Rapaces , Animales , Enfermedades de las Aves/diagnósticoRESUMEN
Mammary adenocarcinoma, the most common cancer in female dogs, often exhibits the lymph node and lung metastases and has a higher mortality rate. However, mammary adenocarcinoma has no established treatment, except early surgical excision. Canine mammary carcinoma has many common features with human mammary carcinoma, including clinical characteristics, heterogeneity, and genetic aberrations, making it an excellent spontaneous tumor model for human breast cancer. Diverse cancers comprised heterogeneous cell populations originating from cancer stem cells (CSCs) with self-renewal ability. Therefore, in addition to conventional therapy, therapeutic strategies targeting CSCs are essential for cancer eradication. The present study aimed to extract inhibitors of canine mammary CSCs that suppress their self-renewal ability. Sphere-formation assay, which evaluates self-renewal ability, was performed for the canine mammary cancer cell lines CTBp and CNMp. The spheres formed in this assay were used in inhibitor library screening, which identified various signaling pathways such as proteosome, stress inducer, and mammalian target of rapamycin (mTOR). The present study focused on the mTOR signaling pathway. Western blotting showed higher levels of phosphorylated mTOR in sphere-forming CTBp and CNMp cells than in adherent cells. Drug sensitivity examination using the mTOR inhibitors everolimus and temsirolimus revealed dose-dependent reductions in viability among both sphere-forming cells and adherent cells. Expression of phosphorylated mTOR in adherent and sphere-forming cells decreased by everolimus and temsirolimus treatment. In mice transplanted with CTBp-derived spheres, everolimus treatment significantly decreased tumor volume compared to control. These results reveal that the mTOR signaling pathway may be a potential to be a therapeutic target in both cancer cells and CSCs. Novel therapeutic strategies for canine mammary carcinoma are expected to benefit to human breast carcinoma as well.
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Patient-derived xenograft (PDX) tumor models are known to maintain the genomic and phenotypic profiles, including the histopathological structures, of the parental tumors. On the other hand, unique enrichment of single-nucleotide variants or copy number aberrations has been reported in several types of tumors. However, an understanding of endometrial carcinoma PDXs is limited. The purpose of the present study was to clarify the presence or absence of the molecular properties of endometrial carcinomas in PDXs passaged up to eight times. Established PDXs of endometrioid carcinomas maintained their histopathological characteristics, but those of carcinosarcomas predominantly consisted of sarcomatous components when compared to the parental tumors. Alterations in the proportion of cells with positive/negative immunohistochemical staining for estrogen receptor, PTEN, PAX8, and PAX2 were observed, whereas the proportions of cells with AE1/AE3, TP53, ARID1A, PMS2, and MSH6 staining were unchanged. Variants of cancer-associated genes were compared between PDXs and parental tumors. Mutations in POLE and a frameshift deletion in BRCA1 were observed in the parental tumor tissue in each of the six cases, and additional genomic alterations, which were not apparently related to histopathological and immunohistochemical alterations, were found in the PDXs of these cases. The genomic and phenotypic alterations observed between endometrial carcinoma PDXs and parental tumors were partly associated with endometrial cancer-specific characteristics related to cellular differentiation and gene mutations.
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Carcinoma Endometrioide , Neoplasias Endometriales , Femenino , Humanos , Xenoinjertos , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Carcinoma Endometrioide/patología , MutaciónRESUMEN
The chromatin-associated AAA+ ATPases Tip48 and Tip49 are the core components of various complexes implicated in diverse nuclear events such as DNA repair and gene regulation. Although they are frequently overexpressed in many human cancers, their functional significance remains unclear. Here, we show that loss of Tip49 triggered p53-dependent apoptosis and inhibited leukemia development in vivo. To examine the impact of chemical inhibition of this complex on leukemia, we have developed the novel compound DS-4950, which interferes with the ATPase activity of the Tip48/49. Administration of DS-4950 was well-tolerated in healthy mice, and the drug effectively reduced tumor burden and improved survival. We also provide evidence that the dependency on Tip48/49 is widely conserved in non-hematologic malignancies with wild type p53. These results demonstrated that the Tip48/49 ATPases are functionally necessary and therapeutically targetable for the treatment of human cancers.
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ADN Helicasas , Leucemia Mieloide Aguda , Humanos , Ratones , Animales , ADN Helicasas/genética , Proteínas Portadoras/genética , Proteína p53 Supresora de Tumor/genética , Adenosina Trifosfatasas/genética , ATPasas Asociadas con Actividades Celulares Diversas/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genéticaRESUMEN
The Amami rabbit (Pentalagus furnessi) is found only on the two islands of Amami-Oshima and Tokunoshima in southwest Japan. It has a primitive appearance and ecology, is an evolutionarily valuable animal and has been assigned to the International Union for Conservation of Nature Red List of Threatened Species. We describe a case with mild purulent wounds on the distal digital skin of both forelimbs and multiple nodular lesions in various organs, including the heart and kidney. Microscopically, the heart lesions were characterized by disruption of the mitral valve and multifocal myocardial necrosis and abscesses due to infection with gram-positive cocci. Similar bacterial infarctions were also found in other organs, including the kidneys. The bacteria were identified as Staphylococcus aureus by immunohistochemical and molecular biological examinations. This first report of infective endocarditis and systemic infarctions caused by S. aureus in an Amami rabbit indicates the importance of monitoring purulent injuries, even if mild, to prevent secondary infections in this species.
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Embolia , Endocarditis Bacteriana , Endocarditis , Infarto del Miocardio , Infecciones Estafilocócicas , Conejos , Animales , Staphylococcus aureus , Endocarditis Bacteriana/microbiología , Endocarditis Bacteriana/veterinaria , Endocarditis/complicaciones , Endocarditis/veterinaria , Infecciones Estafilocócicas/veterinaria , Válvula Mitral , Infarto del Miocardio/complicaciones , Infarto del Miocardio/veterinaria , Embolia/veterinariaRESUMEN
A 12-year-old castrated male Beagle dog presented with a 1-month history of progressive loss of appetite and cough. One month after the initial visit, a detailed clinical examination was performed due to weight loss and persistent cough. Computed tomography demonstrated diffuse opacification of the entire right lung and cranial lobe of the left lung. Samples of the pulmonary lesions obtained by fine-needle aspiration (FNA) were highly cellular with scattered and clustered foci of large round cells, suggestive of a round cell tumour. Ten days after the FNA, the dog was euthanized due to decreased activity and severe respiratory symptoms. At necropsy, enlargement of the entire right lung and cranial lobe of the left lung was seen. The external and cut surfaces of the lungs were homogeneously grey-white. Histopathological examination of sections of the right lung and the cranial lobe of the left lung revealed proliferation of large round or polygonal neoplastic cells arranged in nests of variable size separated by a thin fibrous stroma. Neoplastic cells were immunopositive for cytokeratin and thyroid transcription factor-1 but negative for vimentin, CD204, chromogranin A and synaptophysin. On the basis of these findings, the tumour was diagnosed as pulmonary solid adenocarcinoma.
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Adenocarcinoma del Pulmón , Enfermedades de los Perros , Neoplasias Pulmonares , Perros , Masculino , Animales , Neoplasias Pulmonares/veterinaria , Tos/patología , Tos/veterinaria , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/veterinaria , Pulmón/patología , Tomografía Computarizada por Rayos X , Enfermedades de los Perros/patologíaRESUMEN
Drug resistance limits the efficacy of chemotherapy and targeted cancer treatments, calling for the identification of druggable targets to overcome it. Here we show that the mitochondria-shaping protein Opa1 participates in resistance against the tyrosine kinase inhibitor gefitinib in a lung adenocarcinoma cell line. Respiratory profiling revealed that oxidative metabolism was increased in this gefitinib-resistant lung cancer cell line. Accordingly, resistant cells depended on mitochondrial ATP generation, and their mitochondria were elongated with narrower cristae. In the resistant cells, levels of Opa1 were increased and its genetic or pharmacological inhibition reverted the mitochondrial morphology changes and sensitized them to gefitinib-induced cytochrome c release and apoptosis. In vivo, the size of gefitinib-resistant lung orthotopic tumors was reduced when gefitinib was combined with the specific Opa1 inhibitor MYLS22. The combo gefitinib-MYLS22 treatment increased tumor apoptosis and reduced its proliferation. Thus, the mitochondrial protein Opa1 participates in gefitinib resistance and can be targeted to overcome it.
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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Gefitinib/farmacología , Carcinoma de Pulmón de Células no Pequeñas/patología , Resistencia a Antineoplásicos , Línea Celular Tumoral , Neoplasias Pulmonares/patología , Inhibidores de Proteínas Quinasas/farmacología , Mitocondrias/metabolismo , Pulmón/metabolismo , Proliferación Celular , Apoptosis , Antineoplásicos/farmacología , GTP Fosfohidrolasas/metabolismoRESUMEN
Cow-specific feature hepatic lesion, termed as eosinophilic proliferative phlebitis (EPP), has been mainly detected in Japanese black cattle and identified histologically eosinophilic infiltration and endothelial hyperplasia in portal areas. We previously proposed EPP as a food allergy from the pathological characteristics and a significant increase of serum immunoglobulin E specific to curly dock (Rumex crispus) in allergens testing, however, first report had regarded EPP an atypical type of bovine fascioliasis. In EPP lesions, eosinophilic infiltration was observed to the hypertrophic endothelium and not to the intrahepatic bile duct, and that was related to eotaxin-1 expression. In EPP, the mast cells increased as well as in fascioliasis, and the mast cells producing tryptase without chymase increased with interleukin-4 production. In this context, hyperplasia of periendothelium expressing proteinase-activated receptor-2 (PAR-2) and not angiotensin II was observed. Contrastably, in fascioliasis, unique mast cells producing neither tryptase nor chymase infiltrated, and the periendothelium expressed neither PAR-2 nor angiotensin II. Interestingly, EPP had not occurred liver injury with raised hepatic enzymes like fascioliasis, and suggested to a correlation with severe serum hypo-vitamin A. Overall, this study suggests that EPP is an allergic disease by main difference between adaptive immunity to allergens and innate immunity to parasites.
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CASE SUMMARY: A 4-year-old castrated male domestic shorthair cat with a continuous cough was brought to a private veterinary clinic for detailed examination. Radiography of the thoracic cavity revealed a severe radiopaque region in the caudal lobe of the right lung. At 108 days after the initial visit, CT showed a mass of 27 × 23 × 18 mm in the caudal lobe of the right lung. At that time, no abnormalities in other organs except for the lung were detected on CT and peripheral blood and blood biochemistry tests. The mass in the caudal lobe of the right lung was resected by lobectomy; it had a white surface and was firm. Histopathologically, the mass was non-encapsulated, showing an unclear boundary with surrounding tissues. The mass comprised large, round or polygonal neoplastic cells arranged in a diffuse pattern. Immunohistochemically, neoplastic cells were diffusely positive for CD20, feline leukaemia virus (FeLV) p27 and FeLV glycoprotein 70 but negative for CD3, CD204 and E-cadherin. Based on these findings, diffuse large B-cell lymphoma associated with FeLV infection was diagnosed. Although the cat showed no clinical signs of gastrointestinal or respiratory injury, a routine ultrasonography revealed thickening in the jejunum wall 196 days after lobectomy, and subsequent fine-needle aspiration examination confirmed high-grade lymphoma. RELEVANCE AND NOVEL INFORMATION: This is the first report of primary pulmonary diffuse large B-cell lymphoma associated with FeLV infection in a young cat.
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Background: Chondrosarcoma is a common form of malignant bone tumor with limited treatment options. Approximately half of chondrosarcomas harbor gain-of-function mutations in isocitrate dehydrogenase (IDH), and mutant IDH produces 2-hydroxyglutarate (2-HG), which is an oncometabolite that contributes to malignant transformation. Therefore, inhibiting 2-HG production is a novel and promising treatment for advanced chondrosarcoma. 2-HG is also expected to be a useful biomarker for the diagnosis and treatment of IDH-mutant tumors. However, few studies have confirmed this using chondrosarcoma clinical specimens. Non-invasive monitoring of 2-HG levels is useful to infer that mutant IDH inhibitors reach therapeutic targets and to confirm their therapeutic efficacy in clinical practice. Methods: To evaluate the clinical utility of 2-HG as a surrogate biomarker for diagnosis and therapeutic efficacy, we measured intra-tumor and serum levels of 2-HG using frozen tissues and peripheral blood from patients with chondrosarcoma. We also developed a non-invasive method to detect intra-tumor 2-HG signals in vivo using magnetic resonance spectroscopy (MRS). Results: Both intratumoral and serum 2-HG levels were significantly elevated in IDH-mutant tumors, and these levels correlated with decreased survival. Furthermore, we detected intratumoral 2-HG peaks using MR spectroscopy in a xenograft model of IDH-mutant chondrosarcoma, and observed that 2-HG peak signals disappeared after administering an inhibitor of mutant IDH1. Conclusions: Our findings suggest that both intratumoral and serum 2-HG levels represent potentially useful biomarkers for IDH-mutant tumors and that the 2-HG signal in MR spectra has potential value as a non-invasive biomarker. Taken together, these findings may positively impact the clinical development of mutant IDH inhibitors for the treatment of advanced chondrosarcoma.
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A 12-year-old spayed Shiba dog with a nasal neuroendocrine carcinoma and multiple hepatic nodules was necropsied. Histologically, proliferated blast cells with a monolayer or multilayered structure were observed in the kidney. This blast cell proliferation extended from Bowman's capsule epithelium to the proximal tubule in approximately 3% of nephrons. Immunohistochemistry revealed that blast cells were positive for vimentin, Wilm's tumour protein 1 (WT1), paired box 2 (PAX2) and CD10, but negative for cytokeratin (CK) AE1/AE3, CK19, CAM5.2, synaptophysin and chromogranin A. On the basis of these findings, adenomatous hyperplasia of Bowman's capsule epithelium was diagnosed. Multiple yellowishâwhite nodules (1-3 cm) were found in the liver and diagnosed as neuroendocrine carcinoma with metastases to the lungs, adrenal glands and pancreaticoduodenal lymph nodes.
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Carcinoma Neuroendocrino , Enfermedades de los Perros , Neoplasias Hepáticas , Animales , Cápsula Glomerular/metabolismo , Cápsula Glomerular/patología , Carcinoma Neuroendocrino/veterinaria , Enfermedades de los Perros/patología , Perros , Epitelio/patología , Hiperplasia/patología , Hiperplasia/veterinaria , Neoplasias Hepáticas/veterinariaRESUMEN
Chemical carcinogens, such as 7,12-dimethylbenz[a]anthracene (DMBA) and 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP), are known to induce mammary carcinomas in mice and rats. In the present study, the phenotypic and genotypic characteristics of carcinogen-induced mammary carcinogenesis in heterozygous BALB/c tumor protein p53 (Trp53) knockout mice were examined with reference to published data surrounding human breast cancer. A significantly accelerated induction of mammary carcinomas was observed following a single dose of DMBA (50 mg/kg of body weight at 7 weeks of age), and a modest acceleration was induced by PhIP (50 mg/kg of body weight) administered by gavage 6 times/2 weeks from 7 weeks of age. DMBA-induced mammary carcinomas were histopathologically characterized by distinct biphasic structures with luminal and myoepithelial cells, as well as a frequent estrogen receptor expression, and PhIP-induced carcinomas with solid/microacinar structures consisted of pleomorphic cells. Of note, DMBA-induced mammary carcinomas were characterized by a HRas proto-oncogene (Hras) mutation at codon 61, and gene/protein expression indicating MAPK stimulation. PhIP-induced lesions were suspected to be caused by different molecular mechanisms, including Wnt/ß-catenin signaling and/or gene mutation-independent PI3K/AKT signaling activation. In conclusion, the present mouse mammary carcinogenesis models, induced by a combination of genetic and exogenous factors, may be utilized (such as the DMBA-induced model with Trp53 gene function deficiency as a model of adenomyoepithelioma, characterized by distinct biphasic cell constituents and Hras mutations), but PhIP-induced models are required to further analyze the genetic/epigenetic mechanisms promoting mammary carcinomas.
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A 20-year-old Dutch Warmblood gelding was referred with clinical signs of anorexia, weight loss, intermittent fever, cough, subcutaneous oedema and exercise intolerance. Haematological examination revealed the presence of blast cells, decreased lymphocytes, mild thrombocytopenia and anaemia but no leucocytosis. Serum analyses detected elevated aspartate aminotransferase and gamma-glutamyl transferase activities and triglyceride concentrations. Twenty-two days after the initial visit, the horse died after showing clinical signs of decreased appetite, increased body temperature, tachypnoea and tachycardia. At necropsy, there was mild splenomegaly but enlarged lymph nodes, masses or nodules were not seen in any organ. Histologically, neoplastic cells were seen in the subcapsular and medullary lymph sinus of the mediastinal, axillary, mesenteric and renal lymph nodes. The bone marrow was densely cellular with numerous large round neoplastic cells that had round nuclei with clear nucleoli and scant cytoplasm. The neoplastic cells were immunopositive for CD3 but negative for CD20, BLA36, CD204, Iba-1, CD204 and granzyme B. Based on these findings, the neoplasm was diagnosed as subleukaemic T-lymphoblastic leukaemia, which, to the best of our knowledge, is the first report of this neoplasm in horses.