Assuntos
Sistema de Sinalização das MAP Quinases/genética , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Neoplasias Testiculares/genética , Neoplasias Testiculares/patologia , Adulto , Humanos , Masculino , Mieloma Múltiplo/metabolismo , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Neoplasias Testiculares/metabolismoRESUMO
Mean platelet volume (MPV) is an early marker of platelet activation. Larger platelets, compared to small ones, increase platelet adhesion and aggregation, and present a higher thrombotic activity. Some studies have explored the association between MPV and the morbidity of portal vein thrombosis (PVT). The aim of this study was to evaluate the predictive effect of MPV in patients with PVT by a meta-analysis. We searched Pubmed, Web of Science, SCOPUS, OVID, CNKI and CBMD from database inception to September 13,2017. Seven studies in accordance with selection criteria were included. The extraction of basic data was independently conducted by two reviewers. The mean difference in MPV between PVT patients and controls were pooled with weighted mean difference (WMD) and 95% confidence interval of 0.88 fl (95% CI: 0.61-1.15). A random-effect model was chosen for an obvious heterogeneity in the pooling (Chi-square=27.12, df=6, P<000l, I2=77.9%). The sources of heterogeneity were from the difference of primary disease of participants and portal vein diameter. Taken together, our results reveal that MPV is a predictive indicator in patients with PVT.
Assuntos
Volume Plaquetário Médio/normas , Veia Porta/patologia , Trombose Venosa/sangue , Humanos , Valor Preditivo dos Testes , Trombose Venosa/epidemiologiaRESUMO
INTRODUCTION: The occurrence of skeletal metastases in cancer, e.g. breast cancer (BC), deteriorates patient life expectancy and quality-of-life. Current treatment options against tumor-associated bone disease are limited to anti-resorptive therapies and aimed towards palliation. There remains a lack of therapeutic approaches, which reverse or even prevent the development of bone metastases. Recent studies demonstrate that not only osteoclasts (OCs), but also osteoblasts (OBs) play a central role in the pathogenesis of skeletal metastases, partly by producing hepatocyte growth factor (HGF), which promotes tumor cell migration and seeding into the bone. OBs consist of a heterogeneous cell pool with respect to their maturation stage and function. Recent studies highlight the critical role of pre-OBs in hematopoiesis. Whether the development of bone metastases can be attributed to a particular OB maturation stage is currently unknown. METHODS AND RESULTS: Pre-OBs were generated from healthy donor (HD)-derived bone marrow stromal cells (BMSC) as well as the BMSC line KM105 and defined as ALPlow OPNlow RUNX2high OSX high CD166high. Conditioned media (CM) of pre-OBs, but not of undifferentiated cells or mature OBs, enhanced migration of metastatic BC cells. Importantly, HGF mRNA was significantly up-regulated in pre-OBs versus mature OBs, and CM of pre-OBs activated the MET signaling pathway. Highlighting a key role for HGF, CM from HGF-negative pre-OBs derived from the BMSC line HS27A did not support migration of BC cells. Genetically (siMET) or pharmacologically (INCB28060) targeting MET inhibited both HGF- and pre-OB CM- mediated BC cell migration. CONCLUSIONS: Our data demonstrate for the first time a role for pre-OBs in mediating HGF/MET- dependent migration of BC cells and strongly support the clinical evaluation of INCB28060 and other MET inhibitors to limit and/or prevent BC-associated bone metastases.
Assuntos
Neoplasias da Mama/genética , Fator de Crescimento de Hepatócito/genética , Células-Tronco Mesenquimais/metabolismo , Osteoblastos/metabolismo , Proteínas Proto-Oncogênicas c-met/genética , Benzamidas/farmacologia , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Técnicas de Cocultura , Meios de Cultivo Condicionados/farmacologia , Feminino , Regulação da Expressão Gênica , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Imidazóis , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , TriazinasRESUMO
Neurotransmitter gamma-aminobutyric acid (GABA) release to the synaptic clefts is mediated by the formation of a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, which includes two target SNAREs syntaxin 1A and SNAP-25 and one vesicle SNARE VAMP-2. The target SNAREs syntaxin 1A and SNAP-25 form a heterodimer, the putative intermediate of the SNARE complex. Neurotransmitter GABA clearance from synaptic clefts is carried out by the reuptake function of its transporters to terminate the postsynaptic signaling. Syntaxin 1A directly binds to the neuronal GABA transporter GAT-1 and inhibits its reuptake function. However, whether other SNARE proteins or SNARE complex regulates GABA reuptake remains unknown. Here we demonstrate that SNAP-25 efficiently inhibits GAT-1 reuptake function in the presence of syntaxin 1A. This inhibition depends on SNAP-25/syntaxin 1A complex formation. The H3 domain of syntaxin 1A is identified as the binding sites for both SNAP-25 and GAT-1. SNAP-25 binding to syntaxin 1A greatly potentiates the physical interaction of syntaxin 1A with GAT-1 and significantly enhances the syntaxin 1A-mediated inhibition of GAT-1 reuptake function. Furthermore, nitric oxide, which promotes SNAP-25 binding to syntaxin 1A to form the SNARE complex, also potentiates the interaction of syntaxin 1A with GAT-1 and suppresses GABA reuptake by GAT-1. Thus our findings delineate a further molecular mechanism for the regulation of GABA reuptake by a target SNARE complex and suggest a direct coordination between GABA release and reuptake.