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1.
Int J Mol Sci ; 24(6)2023 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-36982737

RESUMO

Estrogen receptor-positive breast cancers (ER+ BCas) are the most common form of BCa and are increasing in incidence, largely due to changes in reproductive practices in recent decades. Tamoxifen is prescribed as a component of standard-of-care endocrine therapy for the treatment and prevention of ER+ BCa. However, it is poorly tolerated, leading to low uptake of the drug in the preventative setting. Alternative therapies and preventatives for ER+ BCa are needed but development is hampered due to a paucity of syngeneic ER+ preclinical mouse models that allow pre-clinical experimentation in immunocompetent mice. Two ER-positive models, J110 and SSM3, have been reported in addition to other tumour models occasionally shown to express ER (for example 4T1.2, 67NR, EO771, D2.0R and D2A1). Here, we have assessed ER expression and protein levels in seven mouse mammary tumour cell lines and their corresponding tumours, in addition to their cellular composition, tamoxifen sensitivity and molecular phenotype. By immunohistochemical assessment, SSM3 and, to a lesser extent, 67NR cells are ER+. Using flow cytometry and transcript expression we show that SSM3 cells are luminal in nature, whilst D2.0R and J110 cells are stromal/basal. The remainder are also stromal/basal in nature; displaying a stromal or basal Epcam/CD49f FACS phenotype and stromal and basal gene expression signatures are overrepresented in their transcript profile. Consistent with a luminal identity for SSM3 cells, they also show sensitivity to tamoxifen in vitro and in vivo. In conclusion, the data indicate that the SSM3 syngeneic cell line is the only definitively ER+ mouse mammary tumour cell line widely available for pre-clinical research.


Assuntos
Neoplasias da Mama , Receptores de Estrogênio , Tamoxifeno , Humanos , Linhagem Celular Tumoral , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Animais , Camundongos , Modelos Animais de Doenças , Receptores de Estrogênio/genética , Tamoxifeno/farmacologia , Fenótipo , Imuno-Histoquímica , Citometria de Fluxo , Transcriptoma , Camundongos da Linhagem 129 , RNA-Seq , Células Epiteliais , Glândulas Mamárias Animais/citologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/genética
2.
Front Immunol ; 12: 708554, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34421913

RESUMO

Allogenic hematopoietic stem cell transplant (allo-HSCT) can lead to sinusoidal obstruction syndrome (SOS) and graft-versus-host disease (GvHD) in some individuals. GvHD is characterised by an immune triggered response that arises due to donor T cells recognizing the recipient tissue as "foreign". SOS results in impaired liver function due to microvascular thrombosis and consequent obstruction of liver sinusoids. Endothelial damage occurs following chemotherapy and allo-HSCT and is strongly associated with GvHD onset as well as hepatic SOS. Animal models of GvHD are rarely clinically relevant, and endothelial dysfunction remains uncharacterised. Here we established and characterised a clinically relevant model of GvHD wherein Balb/C mice were subjected to myeloablative chemotherapy followed by transplantation of bone marrow (BM) cells± splenic T-cells from C57Bl6 mice, resulting in a mismatch of major histocompatibility complexes (MHC). Onset of disease indicated by weight loss and apoptosis in the liver and intestine was discovered at day 6 post-transplant in mice receiving BM+T-cells, with established GvHD detectable by histology of the liver within 3 weeks. Together with significant increases in pro-inflammatory cytokine gene expression in the liver and intestine, histopathological signs of GvHD and a significant increase in CD4+ and CD8+ effector and memory T-cells were seen. Endothelial activation including upregulation of vascular cell adhesion molecule (VCAM)- 1 and downregulation of endothelial nitric oxide synthase (eNOS) as well as thrombosis in the liver indicated concomitant hepatic SOS. Our findings confirm that endothelial activation is an early sign of acute GvHD and SOS in a clinically relevant mouse model of GvHD based on myeloablative chemotherapy. Preventing endothelial activation may be a viable therapeutic strategy to prevent GvHD.


Assuntos
Células Endoteliais/metabolismo , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Linfócitos T/transplante , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Agonistas Mieloablativos/toxicidade , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos
3.
Sci Rep ; 10(1): 18170, 2020 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-33097782

RESUMO

Stroke is caused by obstructed blood flow (ischaemia) or unrestricted bleeding in the brain (haemorrhage). Global brain ischaemia occurs after restricted cerebral blood flow e.g. during cardiac arrest. Following ischaemic injury, restoration of blood flow causes ischaemia-reperfusion (I/R) injury which worsens outcome. Secondary injury mechanisms after any stroke are similar, and encompass inflammation, endothelial dysfunction, blood-brain barrier (BBB) damage and apoptosis. We developed a new model of transient global forebrain I/R injury (dual carotid artery ligation; DCAL) and compared the manifestations of this injury with those in a conventional I/R injury model (middle-cerebral artery occlusion; MCAo) and with intracerebral haemorrhage (ICH; collagenase model). MRI revealed that DCAL produced smaller bilateral lesions predominantly localised to the striatum, whereas MCAo produced larger focal corticostriatal lesions. After global forebrain ischaemia mice had worse overall neurological scores, although quantitative locomotor assessment showed MCAo and ICH had significantly worsened mobility. BBB breakdown was highest in the DCAL model while apoptotic activity was highest after ICH. VCAM-1 upregulation was specific to ischaemic models only. Differential transcriptional upregulation of pro-inflammatory chemokines and cytokines and TLRs was seen in the three models. Our findings offer a unique insight into the similarities and differences in how biological processes are regulated after different types of stroke. They also establish a platform for analysis of therapies such as endothelial protective and anti-inflammatory agents that can be applied to all types of stroke.


Assuntos
Circulação Cerebrovascular/fisiologia , Acidente Vascular Cerebral Hemorrágico/patologia , AVC Isquêmico/patologia , Prosencéfalo/irrigação sanguínea , Traumatismo por Reperfusão/patologia , Animais , Anti-Inflamatórios/uso terapêutico , Apoptose/imunologia , Barreira Hematoencefálica/diagnóstico por imagem , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Artérias Carótidas/fisiopatologia , Circulação Cerebrovascular/efeitos dos fármacos , Colagenases/administração & dosagem , Colagenases/efeitos adversos , Citocinas/genética , Citocinas/imunologia , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Acidente Vascular Cerebral Hemorrágico/tratamento farmacológico , Acidente Vascular Cerebral Hemorrágico/imunologia , Acidente Vascular Cerebral Hemorrágico/fisiopatologia , Humanos , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/imunologia , AVC Isquêmico/fisiopatologia , Ligadura , Locomoção/fisiologia , Imageamento por Ressonância Magnética , Masculino , Camundongos , Artéria Cerebral Média/fisiopatologia , Prosencéfalo/diagnóstico por imagem , Prosencéfalo/efeitos dos fármacos , Prosencéfalo/patologia , Substâncias Protetoras/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/fisiopatologia , Receptores Toll-Like/genética , Ativação Transcricional/imunologia
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