RESUMO
Despite progress in the treatment of MM, including the use of high-dose chemotherapy and autologous stem cell transplantation, a considerable proportion of patients are refractory to all therapies. This resistance is related to the molecular genetic heterogeneity in MM cells as well as to the contributions from the BM, which is one of the key determinants of treatment outcome. Our previous studies using fluorescent tracers revealed that MM heterogeneity is correlated with the presence of quiescent stem-like cancer cells, which prefer to reside within the osteoblastic niche of the BM. In this report, we identified a novel protein, tripartite motif containing 44 (TRIM44), which is overexpressed in the osteoblastic niche of the BM, enabling MM cells to compete with HSCs for niche support. TRIM44 expression in MM cells promoted cell quiescence but increased bone destruction in xenograft mice, similar to what is observed in MM patients. TRIM44 functions as a deubiquitinase for hypoxia inducible factor-1α (HIF-1α), which stabilizes HIF-1α expression during hypoxia and normoxia. Stabilized HIF-1α stimulates MM cell growth and survival during hypoxia. Our work is the first report to reveal signaling in quiescent MM cells and the functions of TRIM44.
Assuntos
Proteínas de Transporte/metabolismo , Proliferação de Células , Subunidade alfa do Fator 1 Induzível por Hipóxia/química , Hipóxia , Mieloma Múltiplo/patologia , Células-Tronco Neoplásicas/patologia , Osteoblastos/patologia , Animais , Biomarcadores Tumorais , Proteínas de Transporte/genética , Ciclo Celular , Células Cultivadas , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos Endogâmicos NOD , Camundongos SCID , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Células-Tronco Neoplásicas/metabolismo , Osteoblastos/metabolismo , Estabilidade Proteica , Transdução de Sinais , Proteínas com Motivo Tripartido , Ubiquitinação , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We theoretically demonstrated a new optical imaging technique based on reverse-time migration (RTM) for reconstructing optical structures in homogeneous media for the first time. RTM is a powerful wave-equation-based method to reconstruct the image of the structure by modeling the wave propagation inside the media with both forward modeling and reverse-time extrapolation. While RTM is commonly used with acoustic seismic waves, this paper represents the first effort to develop optical RTM imaging method for biomedical research. To refine the image quality, we further developed new methods to suppress the low-wavenumber artifact (LWA). When compared with the conventional means for LWA suppression such as Laplacian filtering, illumination normalization, and the ratio method, our new derivative-based and power-image methods are able to significantly reduce LWA, resulting in high-quality reconstructed images with sufficient contrasts and spatial resolutions for structure identification. The optical RTM imaging technique may provide a new platform for non-invasive optical imaging of structures in deep layers of tissues for biomedical applications.
Assuntos
Encéfalo/anatomia & histologia , Processamento de Imagem Assistida por Computador/métodos , Imagem Óptica/métodos , Algoritmos , DNA/ultraestrutura , Humanos , Modelos Biológicos , Imagens de FantasmasRESUMO
We demonstrated a mechanical iris-based fiber optic probe with adjustable spatial offsets for spatially offset Raman spectroscopy (SORS). In the fiber probe, the excitation fiber was fixed at the center of the iris, and the collection fibers were movable with blades of the iris. Moreover, we studied the gap effect between the probe and the sample and demonstrated this fiber optic probe can be used as a platform for surface-enhanced SORS applications. This fiber probe design could potentially provide a design-efficient and cost-effective solution for various Raman applications.
Assuntos
Fibras Ópticas , Análise Espectral Raman/instrumentação , Animais , Engenharia Biomédica , Diagnóstico por Imagem/instrumentação , Desenho de Equipamento , Fenômenos Ópticos , Politetrafluoretileno , Resinas SintéticasRESUMO
Nanocomposites consisting of oblong ultrathin plate shaped calcium phosphate nanoparticles and graphene oxide microflakes were synthesized and have demonstrated markedly synergistic effect in accelerating stem cell differentiation to osteoblasts.
Assuntos
Fosfatos de Cálcio/farmacologia , Grafite/farmacologia , Células-Tronco Mesenquimais/fisiologia , Nanocompostos/química , Osteoblastos/citologia , Osteogênese/fisiologia , Diferenciação Celular/efeitos dos fármacos , Humanos , Células-Tronco Mesenquimais/citologia , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Nanocompostos/ultraestrutura , Medicina Regenerativa/métodosRESUMO
To investigate the role of the LIM-kinase (LIMK) family in the regulation of ADF/cofilin phosphorylation and synaptic function in the mammalian central nervous system (CNS), we conducted biochemical and electrophysiological analysis using mice that were genetically altered in the expression of LIMK-1 and LIMK-2. We showed here that while LIMK-2 knockout mice exhibited minimal abnormalities, the LIMK-1/2 double knockout mice were more severely impaired in both ADF/cofilin phosphorylation and excitatory synaptic function in the CA1 region of the hippocampus. These results indicate a critical role for the LIMK family in the regulation of ADF/cofilin and synaptic function in the brain.
