Glioma Cell Migration on Three-dimensional Nanofiber Scaffolds Is Regulated by Substrate Topography and Abolished by Inhibition of STAT3 Signaling

A hallmark of malignant gliomas is their ability to disperse through neural tissue, leading to long-term failure of all known therapies. Identifying new antimigratory targets could reduce glioma recurrence and improve therapeutic efficacy, but screens based on conventional migration assays are hampered by the limited ability of these assays to reproduce native cell motility. Here, we have analyzed the motility, gene expression, and sensitivity to migration inhibitors of glioma cells cultured on scaffolds formed by submicron-sized fibers (nanofibers) mimicking the neural topography. Glioma cells cultured on aligned nanofiber scaffolds reproduced the elongated morphology of cells migrating in white matter tissue and were highly sensitive to myosin II inhibition but only moderately affected by stress fiber disruption. In contrast, the same cells displayed a flat morphology and opposite sensitivity to myosin II and actin inhibition when cultured on conventional tissue culture polystyrene. Gene expression analysis indicated a correlation between migration on aligned nanofibers and increased STAT3 signaling, a known driver of glioma progression. Accordingly, cell migration out of glioblastoma-derived neurospheres and tumor explants was reduced by STAT3 inhibitors at subtoxic concentrations. Remarkably, these inhibitors were ineffective when tested at the same concentrations in a conventional two-dimensional migration assay. We conclude that migration of glioma cells is regulated by topographical cues that affect cell adhesion and gene expression. Cell migration analysis using nanofiber scaffolds could be used to reproduce native mechanisms of migration and to identify antimigratory strategies not disclosed by other in vitro models.     

Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells

Substantial evidence indicates that exposure to bisphenol A (BPA) during early development may increase breast cancer risk later in life. The changes may persist into puberty and adulthood, suggesting an epigenetic process being imposed in differentiated breast epithelial cells. The molecular mechanisms by which early memory of BPA exposure is imprinted in breast progenitor cells and then passed onto their epithelial progeny are not well understood. The aim of this study was to examine epigenetic changes in breast epithelial cells treated with low-dose BPA. We also investigated the effect of BPA on the ERα signaling pathway and global gene expression profiles. Compared to control cells, nuclear internalization of ERα was observed in epithelial cells preexposed to BPA. We identified 170 genes with similar expression changes in response to BPA. Functional analysis confirms that gene suppression was mediated in part through an ERα-dependent pathway. As a result of exposure to BPA or other estrogen-like chemicals, the expression of lysosomal-associated membrane protein 3 (LAMP3) became epigenetically silenced in breast epithelial cells. Furthermore, increased DNA methylation in the LAMP3 CpG island was this repressive mark preferentially occurred in ERα-positive breast tumors. These results suggest that the in vitro system developed in our laboratory is a valuable tool for exposure studies of BPA and other xenoestrogens in human cells. Individual and geographical differences may contribute to altered patterns of gene expression and DNA methylation in susceptible loci. Combination of our exposure model with epigenetic analysis and other biochemical assays can give insight into the heritable effect of low-dose BPA in human cells.     

Comparison of continuous and intermittent vibration effects on rat-tail artery and nerve

Hand-transmitted vibration from powered-tools can cause peripheral vasospasm and neuropathy. A rat-tail model was used to investigate whether the pattern of vibration influenced the type and severity of tissue damage. The tails of awake rats were vibrated continuously or intermittently for a total of 4 hours at 60 HZ, 49 m/s(2). Nerves and arteries were harvested immediately or 24 hours after treatment. Tails subjected to intermittent vibration showed transiently increased sensitivity to thermal stimuli. Intermittent vibration caused the most nerve injury immediately and 24 hours after vibration. Continuous vibration invoked a persistent reduction in vascular lumen size. Compared to epinephrine-induced transient vacuolation in vascular smooth muscle cells, both continuous and intermittent vibration caused greater persistence of vacuoles, indicating a vibration-induced pathological process. All vibration groups exhibited elevated nitrotyrosine immunoreactivity indicative of free-radical damage. Pattern of vibration exposure may exert a major influence on the type of vibration injury.     

Lemierre syndrome caused by Arcanobacterium haemolyticum

A54-year-old male smoker was admitted to our hospital after undergoing the drainage of a left peritonsillar abscess.Ten days prior to admission (day 1),he complained of a "scratchy" throat with a fever of 38.5°C.He had an enlarged left tonsil with prominent exudate;white blood cell count (WCC) 8.8×109/L;platelet count (Pit) 103 × 109/L;chest X-ray was normal in a medical clinic.Then the patient received an intravenous injection of 4 million units of penicillin G every 6 hours and 500 mg of oral azithromycin once daily.But his condition worsened with a temperature of 41°C and laryngoscopy confirmed a marked left-sided peritonsillar abscess which was drained.On day 10,the patient was transferred to our hospital after developing persistent fever,rigors,left-sided neck pain,pain on swallowing and purulent bloody sputum.On examination,his temperature was 39.6°C,pulse 95 beats/min;respiratory rate 25 breaths/min and blood pressure 110/80 mmHg (1 mmHg=0.133 kPa).The left side of his neck was swollen and tender,anterior to the sternocleidomastoid muscle.     

Independent component analysis of DTI reveals multivariate microstructural correlations of white matter in the human brain

It has recently been demonstrated that specific patterns of correlation exist in diffusion tensor imaging (DTI) parameters across white matter tracts in the normal human brain. These microstructural correlations are thought to reflect phylogenetic and functional similarities between different axonal fiber pathways. However, this earlier work was limited in three major respects: (1) the analysis was restricted to only a dozen selected tracts; (2) the DTI measurements were averaged across whole tracts, whereas metrics such as fractional anisotropy (FA) are known to vary considerably within single tracts; and (3) a univariate measure of correlation was used. In this investigation, we perform an automated multivariate whole-brain voxel-based study of white matter FA correlations using independent component analysis (ICA) of tract-based spatial statistics computed from 3T DTI in 53 healthy adult volunteers. The resulting spatial maps of the independent components show voxels for which the FA values within each map co-vary across individuals. The strongest FA correlations were found in anatomically recognizable tracts and tract segments, either singly or in homologous pairs. Hence, ICA of DTI provides an automated unsupervised decomposition of the normal human brain into multiple separable microstructurally correlated white matter regions, many of which correspond to anatomically familiar classes of white matter pathways. Further research is needed to determine whether whole-brain ICA of DTI represents a novel alternative to tractography for feature extraction in studying the normal microstructure of human white matter as well as the abnormal white matter microstructure found in neurological and psychiatric disorders.     

Penetrance of a rare familial mutation predisposing to papillary thyroid cancer

Familial non-medullary thyroid cancer (FNMTC) is clinically defined as two or more first-degree relatives with NMTC and appears to follow an autosomal dominant inheritance pattern. Approximately 5–7% of NMTC is hereditary and affects multiple generations with a young age of onset. The primary aim of this study was to determine the age-specific penetrance of NMTC in individuals from a large family with FNMTC with a previously identified private mutation at 4q32, with a secondary aim to determine the penetrance for benign thyroid disease in this family. We present a large family with NMTC in which we had previously described a culpable mutation. Participants provided their personal medical history and family history. The germline 4q32 A?>?C mutation was detected in 34 of 68 tested individuals. Age-specific penetrance of thyroid cancer and benign thyroid disease was determined using the inverted Kaplan–Meier method of segregation analysis. Individuals who tested positive for the 4q32 mutation have a 68.9% (95% CI 46.5–88.7) risk of developing thyroid cancer by age 70 and a 65.3% (95% CI 46.0–83.8) risk of developing benign thyroid disease by age 70. The 4q32 A?>?C mutation significantly increases the risk to develop thyroid cancer but not benign thyroid disease in members of this family. The female:male sex ratio of 1.33 that we observed in affected mutation carriers differs greatly from the ratio of approximately 3:1 observed in PTC, supporting a central role of the mutation. Early thyroid surveillance with annual ultrasound is recommended to individuals testing positive for this private familial mutation.