A clinical feasibility study to evaluate the safety and efficacy of PEOT/PBT implants for human donor site filling during mosaicplasty

Mosaicplasty has become a well-accepted treatment modality for articular cartilage lesions in the knee. Postoperative bleeding remains potentially concerning. This study evaluates the porous poly(ethylene oxide)terephthalate/poly(butylene terephthalate) (PEOT/PBT) implants used for donor site filling. Empty donor sites were the controls. After 9 months, MRI, macroscopical and histological analysis were carried out. Treated defects did not cause postoperative bleeding. No adverse events or inflammatory response was observed. PEOT/PBT implants were well integrated. Empty controls occasionally showed protrusion of repair tissue at the defect margins. Surface stiffness was minimally improved compared to controls. Existing polymer fragments indicated considerable biodegradation. Histological evaluation of the filled donor sites revealed congruent fibrocartilaginous surface repair with proteoglycan-rich domains and subchondral cancellous bone formation with interspersed fibrous tissue in all implanted sites. The PEOT/PBT implants successfully reduce donor site morbidity and postoperative bleeding after mosaicplasty

Loss of c-Met Disrupts Gene Expression Program Required for G2/M Progression during Liver Regeneration in Mice

conditional knockout mice to determine the effects of c-Met dysfunction in hepatocytes on kinetics of liver regeneration. primary hepatocytes and partially restored expression levels of mitotic cell cycle regulators albeit to a lesser degree as compared to control cultures.In conclusion, our results assign a novel non-redundant function for HGF/c-Met signaling in regulation of G2/M gene expression program via maintaining a persistent Erk1/2 activation throughout liver regeneration

Transitional cell and clear cell renal carcinoma: differentiation of distinct histological types with multiphase CT

BACKGROUND: Transitional cell carcinoma (TCC) may mimic renal cell carcinoma (RCC) when it develops in a similar location, therefore, differentiation with imaging techniques might be challenging. Preoperative differentiation may have a significant role indicating the type of surgical treatment (nephrectomy vs. ureteronephrectomy). PURPOSE: To retrospectively analyze the differences in the contrast enhancement of TCC and RCC. MATERIAL AND METHODS: Images of 20 RCC and 12 TCC (mean ages, 62.3 +/- 14.1 and 67.4 +/- 12.0 years, respectively) were analyzed from patients who underwent multiphase computed tomography (CT) examinations following 1.5 mL/kg non-ionic contrast agent administration. Unenhanced corticomedullary (30-45 s), nephrographic (70-90 s), and excretory (300-480 s) phases were imaged. The attenuation characteristics of RCC and TCC were compared to the attenuation of the normal renal cortex. RESULTS: Significant differences were found in the attenuation ratios between RCC or TCC in the corticomedullary (P = 0.040) and nephrographic (P = 0.004) phases using three regions of interest (ROIs) of 10 mm2 size. If measuring ROIs comprising the complete tumor lesion instead of three small ROIs, no significant difference was observed in the attenuation ratios between RCC in TCC in any phases. CONCLUSION: Our study reports significant attenuation differences between RCC and TCC in the corticomedullary and nephrographic phases by multiphase CT. The findings underscore the importance of multiphase CT in the differentiation of these two different entities. Using multiple small (three) ROIs is more accurate than measuring the whole tumor attenuation

Central role of c-Myc during malignant conversion in human hepatocarcinogenesis

Hepatocarcinogenesis is a multistage process in which precursor lesions progress into early hepatocellular carcinomas (eHCC) by sequential accumulation of multiple genetic and epigenetic alterations. To decode the molecular events during early stages of liver carcinogenesis, we performed gene expression profiling on cirrhotic (regenerative) and dysplastic nodules (DN), as well as eHCC. Although considerable heterogeneity was observed at the regenerative and dysplastic stages, overall, 460 differentially expressed genes were detected between DN and eHCC. Functional analysis of the significant gene set identified the MYC oncogene as a plausible driver gene for malignant conversion of the DNs. In addition, gene set enrichment analysis revealed global activation of the MYC up-regulated gene set in eHCC versus dysplasia. Presence of the MYC signature significantly correlated with increased expression of CSN5, as well as with higher overall transcription rate of genes located in the 8q chromosome region. Furthermore, a classifier constructed from MYC target genes could robustly discriminate eHCC from high-grade and low-grade DNs. In conclusion, our study identified unique expression patterns associated with the transition of high-grade DNs into eHCC and showed that activation of the MYC transcription signature is strongly associated with the malignant conversion of preneoplastic liver lesions

Hepatocyte-specific c-Met Deletion Disrupts Redox Homeostasis and Sensitizes to Fas-mediated Apoptosis*

The hepatocyte growth factor and its receptor c-Met direct a pleiotropic signal transduction pathway that controls cell survival. We previously demonstrated that mice lacking c-Met (Met-KO) in hepatocytes were hypersensitive to Fas-induced liver injury. In this study, we used primary hepatocytes isolated from Met-KO and control (Cre-Ctrl) mice to address more directly the protective effects of c-Met signaling. Loss of c-Met function increased sensitivity to Fas-mediated apoptosis. Hepatocyte growth factor suppressed apoptosis in Cre-Ctrl but not Met-KO hepatocytes concurrently with up-regulation of NF-κB and major antiapoptotic proteins Bcl-2 and Bcl-xL. Intriguingly, Met-KO hepatocytes exhibited intrinsic activation of NF-κBas well as Bcl-2 and Bcl-xL. Furthermore, unchallenged Met-KO cells displayed oxidative stress as evidenced by overproduction of reactive oxygen species, which was associated with greater NADPH and Rac1 activities, was blocked by the known NADPH oxidase inhibitors, and was paralleled by increased lipid peroxidation and reduced glutathione (GSH) content. N-Acetylcysteine, an antioxidant and GSH precursor, significantly reduced Jo2-induced cell death. Conversely, the GSH-depleting agent buthionine sulfoximine completely abolished the protective effects of N-acetylcysteine in Met-KO hepatocytes. In conclusion, genetic inactivation of c-Met in mouse hepatocytes caused defects in redox regulation, which may account for the increased sensitivity to Fas-induced apoptosis and adaptive up-regulation of NF-κB survival signaling. These data provide evidence that intact c-Met signaling is a critical factor in the protection against excessive generation of endogenous reactive oxygen species