RESUMEN
CRIPTO (CR-1, TDGF1) is a cell surface/secreted oncoprotein actively involved in development and cancer. Here, we report that high expression of CRIPTO correlates with poor survival in stratified risk groups of prostate cancer (PCa) patients. CRIPTO and its signaling partner glucose-regulated protein 78 (GRP78) are highly expressed in PCa metastases and display higher levels in the metastatic ALDHhigh sub-population of PC-3M-Pro4Luc2 PCa cells compared with non-metastatic ALDHlow. Coculture of the osteotropic PC-3M-Pro4Luc2 PCa cells with differentiated primary human osteoblasts induced CRIPTO and GRP78 expression in cancer cells and increases the size of the ALDHhigh sub-population. Additionally, CRIPTO or GRP78 knockdown decreases proliferation, migration, clonogenicity and the size of the metastasis-initiating ALDHhigh sub-population. CRIPTO knockdown reduces the invasion of PC-3M-Pro4Luc2 cells in zebrafish and inhibits bone metastasis in a preclinical mouse model. These results highlight a functional role for CRIPTO and GRP78 in PCa metastasis and suggest that targeting CRIPTO/GRP78 signaling may have significant therapeutic potential.
Asunto(s)
Neoplasias Óseas/secundario , Proteínas Ligadas a GPI/metabolismo , Proteínas de Choque Térmico/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias de la Próstata/patología , Animales , Neoplasias Óseas/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Chaperón BiP del Retículo Endoplásmico , Proteínas Ligadas a GPI/genética , Técnicas de Silenciamiento del Gen , Proteínas de Choque Térmico/genética , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Estimación de Kaplan-Meier , Masculino , Ratones , Ratones Desnudos , Proteínas de Neoplasias/genética , Trasplante de Neoplasias , Neoplasias de la Próstata/genéticaRESUMEN
PURPOSE: The aim of this study was to develop a Dutch language version of the Foot and Ankle Outcome Score (FAOS-DLV) and evaluate its measurement properties according to the definitions of the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). METHODS: After a standard forward-backward translation procedure, the Dutch version of the FAOS was evaluated for reliability and validity in 110 patients with various hind foot and ankle complaints. Reliability was evaluated by calculation of intraclass correlation coefficients (ICC), Cronbach's alpha for internal consistency, and the smallest detectable change (SDC). Construct validity of the FAOS was assessed by calculation of Spearman's correlation coefficients with similar and dissimilar domains of the SF-36 health survey, American Orthopedic Foot and Ankle Society Ankle and Hindfoot Scale, and visual analogue scales for pain and disability. Dimensionality was tested with confirmatory factor analysis. RESULTS: Reliability of the FAOS-DLV was good. The ICC of the subscales ranged from 0.83 to 0.88. The minimal value of Cronbach's alpha was 0.76. The SDC at individual level ranged from 18 to 21 and at group level between 2.1 and 2.5. Construct validity was supported by confirmation of 85 % of the hypothesized correlations. Unidimensionality of the FAOS-DLV domains was moderate. CONCLUSION: The Dutch version of the FAOS seems to have acceptable measurement properties. The questionnaire can be used for functional assessment of patients with varying hindfoot and ankle symptoms. It is, however, more suitable for clinical evaluation at group level than for monitoring a specific patient. LEVEL OF EVIDENCE: Diagnostic study, Level I.
Asunto(s)
Articulación del Tobillo/fisiopatología , Evaluación de la Discapacidad , Pie/fisiopatología , Calidad de Vida , Encuestas y Cuestionarios , Adulto , Femenino , Humanos , Masculino , Países Bajos , Psicometría , Reproducibilidad de los Resultados , TraduccionesRESUMEN
For measuring the in-vivo range of motion of the hindfoot, a CT-based bone contour registration method (CT-BCM) was developed to determine the three-dimensional position and orientation of bones. To validate this technique, we hypothesized that the range of motion in the hindfoot is equally, accurately measured by roentgen stereophotogrammetric analysis (RSA) as by the CT-BCM technique. Tantalum bone markers were placed in the distal tibia, talus and calcaneus of one cadaver specimen. With a fixed lower leg, the cadaveric foot was held in neutral and subsequently loaded in eight extreme positions. Immediately after acquiring a CT-scan with the foot in a position, RSA radiographs were made. Bone contour registration and RSA was performed. Helical axis parameters were calculated for talocrural and subtalar joint motion from neutral to extreme positions and between opposite extreme positions. Differences between CT-BCM and RSA were calculated. Compared with RSA, the CT-BCM data registered an overall root mean square difference (RMSd) of 0.21 degrees for rotation about the helical axis, and 0.20mm translation along the helical axis for the talocrural and subtalar joint and for all motions combined. The RMSd of the position and direction of the helical axes was 3.3mm and 2.4 degrees , respectively. The latter errors were larger with smaller helical rotations. The differences are similar to those reported for validated RSA and thus are not clinically relevant. Concluding, CT-BCM is an accurate and accessible alternative for studying joint motion, as it does not have the risk of infection and overlapping bone markers.
