Analysis of Surgically Treated Intraspinal Tumors in Southern Taiwan

The medical records of 117 patients with spinal tumors who underwent surgery with pathologic confirmation from January 1999 to April 2004 at Kaohsiung Medical University Hospital were reviewed. Data from this review were compared with those obtained from the same institution 10 years earlier (covering the period 1988-1995) and from other reported series. There were 69 male and 48 female patients aged from 13 to 87 years old (mean age, 51.9). The most common pathologic findings were metastasis in 45.3% (53/117), nerve sheath tumors in 28.2% (33/117), menin-giomas in 12% (14/117) and neuroepithelial tumors in 6% (7/117). The peak ages at diagnosis were 41-50 years and 61–70 years. A slight male predominance was noted for all tumors, except meningiomas. Motor weakness, even paralysis, was the major clinical presentation (64–86%), followed by sensory deficits (50%) and pain (42%). The location of tumors was most often in the thoracic (50.4%; 59/117), lumbosacral (27.4%; 32/117) and cervical spine (22.2%; 26/117) segments. Among the metastatic tumors, the lung (22.6%) and breast (15.1%) were the most common primary sites of origin, followed by unknown origin, the liver (hepatocellular carcinoma), the gastrointestinal tract and the nasopharynx (nasopharyngeal cancer)

Serotonin receptor HTR6-mediated mTORC1 signaling regulates dietary restriction-induced memory enhancement

Dietary restriction (DR; sometimes called calorie restriction) has profound beneficial effects on physiological, psychological, and behavioral outcomes in animals and in humans. We have explored the molecular mechanism of DR-induced memory enhancement and demonstrate that dietary tryptophan-a precursor amino acid for serotonin biosynthesis in the brain-and serotonin receptor 5-hydroxytryptamine receptor 6 (HTR6) are crucial in mediating this process. We show that HTR6 inactivation diminishes DR-induced neurological alterations, including reduced dendritic complexity, increased spine density, and enhanced long-term potentiation (LTP) in hippocampal neurons. Moreover, we find that HTR6-mediated mechanistic target of rapamycin complex 1 (mTORC1) signaling is involved in DR-induced memory improvement. Our results suggest that the HTR6-mediated mTORC1 pathway may function as a nutrient sensor in hippocampal neurons to couple memory performance to dietary intake

Deciphering the Preference and Predicting the Viability of Circular Permutations in Proteins

Circular permutation (CP) refers to situations in which the termini of a protein are relocated to other positions in the structure. CP occurs naturally and has been artificially created to study protein function, stability and folding. Recently CP is increasingly applied to engineer enzyme structure and function, and to create bifunctional fusion proteins unachievable by tandem fusion. CP is a complicated and expensive technique. An intrinsic difficulty in its application lies in the fact that not every position in a protein is amenable for creating a viable permutant. To examine the preferences of CP and develop CP viability prediction methods, we carried out comprehensive analyses of the sequence, structural, and dynamical properties of known CP sites using a variety of statistics and simulation methods, such as the bootstrap aggregating, permutation test and molecular dynamics simulations. CP particularly favors Gly, Pro, Asp and Asn. Positions preferred by CP lie within coils, loops, turns, and at residues that are exposed to solvent, weakly hydrogen-bonded, environmentally unpacked, or flexible. Disfavored positions include Cys, bulky hydrophobic residues, and residues located within helices or near the protein's core. These results fostered the development of an effective viable CP site prediction system, which combined four machine learning methods, e.g., artificial neural networks, the support vector machine, a random forest, and a hierarchical feature integration procedure developed in this work. As assessed by using the hydrofolate reductase dataset as the independent evaluation dataset, this prediction system achieved an AUC of 0.9. Large-scale predictions have been performed for nine thousand representative protein structures; several new potential applications of CP were thus identified. Many unreported preferences of CP are revealed in this study. The developed system is the best CP viability prediction method currently available. This work will facilitate the application of CP in research and biotechnology

Liposomal β-Sitosterol Suppresses Metastasis of CT26/luc Colon Carcinoma via Inhibition of MMP-9 and Evoke of Immune System

β-sitosterol (SITO) has been reported with anticancer effects; however, with poor bioavailability. The current study aimed to investigate whether liposomal encapsulated β-sitosterol (LS) has a better inhibition effect on tumor metastasis than β-sitosterol in a CT26/luc lung metastasis mouse model and the possible underlying mechanism. LS was liposomal-encapsulated SITO and was delivered to mice by oral gavage. The cell viability was determined by the MTT assay, and invasiveness of the tumor cells and related protein expression were evaluated with the invasion assay and Western blotting. For therapeutic efficacy evaluation, male BALB/c mice were treated with PBS, SITO, and LS once a day for 7 days prior to intravenous injections of CT26/luc cells; treatments were continued twice a week post-cell inoculation throughout the entire experiment. Tumor growth inhibition was monitored by bioluminescent imaging (BLI). IL-12, IL-18, and IFN-γ in the intestinal epithelium were determined by ELISA. The results show that LS treatment had a better invasion inhibition with lower cytotoxicity than SITO when the same dose was utilized. Notably, mice treated with LS significantly exhibited fewer metastases to the lungs and other tissues/organs compared with the Control and SITO groups. Additionally, the IL-12, IL-18, and IFN-γ levels were significantly increased in the LS-treated mice compared with the Control and SITO groups. The underlying mechanism may be through the inhibition of MMP-9 and elicitation of the antitumoral Th1 immune response, such as increasing CD4+ and CD8+ T cells, IL-12, IL-18, and IFN-γ

CP Viability Prediction Performance of Various Procedures.

a<p>Random forest was applied in this experiment to the assess the prediction power of closeness and farness.</p>b<p>A combination of the four machine learning methods (HI, ANN, RF and SVM) by averaging their probability scores into a single score. See the main text for details.</p>c<p>These results were obtained with 10-fold cross-validation.</p

Probability Scores of DHFR.

<p>The structure of the dihydrofolate reductase from <i>Escherichia coli</i> (PDB entry: 1RX4) is shown as a cross-eye stereo image, in which the thickness of backbone of a residue is in proportion to the probability score computed by our prediction system for that residue. In addition, probability scores are color-coded — a color closer to red represents a higher score. Gray- to black-colored residues have scores increasingly lower than 0.5. Among the 67 residues with probability scores ≥0.5, only 6 are inviable CP sites (shown in blue). The other 61 residues are experimentally-verified viable CP sites <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031791#pone.0031791-Iwakura1" target="_blank">[29]</a>. Thus, at a probability score threshold of 0.5, the precision of the developed prediction system for this independent evaluation dataset is 90% (61/67).</p

Performance of Predictions for Dataset T at Various Decision Thresholds of the Probability Score.

<p>Performance of Predictions for Dataset T at Various Decision Thresholds of the Probability Score.</p

Distributions and ROC Curves of Propensity Scores.

<p>Here, a propensity score was calculated as the relative propensity of a pattern between the background and viable CP sites weighted by 1 – <i>p-</i>value (see Formula 1). A high relative propensity and a small <i>p-</i>value resulted in a high score. A zero score means that there was no obvious difference between the frequencies of the pattern in the background and viable CP sites, or the difference was statistically insignificant. These plots show distributions of several propensity scores for the viable (red bars) and inviable (blue bars) CP sites of Dataset L and their ROC curves. Plots (<b>a</b>)–(<b>c</b>) and (<b>d</b>)–(<b>f</b>) respectively exhibit the results of sequence-based and secondary structure-based propensity scores. The distributions of the sequence-based propensity scores are not very different between the viable and inviable CP sites, and their AUCs are only ∼0.6. The distributions of secondary structure-based propensity scores were rather different between viable and inviable CP sites, and thus the AUCs were higher than those of sequence-based scores. The lower <i>x</i> axis in each plot indicates the propensity score. The left <i>y</i> axis indicates the frequency, <i>i.e.</i>, the proportion of residues falling into each score group. The upper <i>x</i> axis and right <i>y</i> axis represent the false positive rate and true positive rate, respectively, for the ROC curve.</p

Classification Tree of the 46 Selected Features.

<p>These features were selected based on their discriminatory performance for viable and inviable CPs in Dataset T. Redundant features (correlation coefficient >0.7) were screened out. The classification was done manually according to the similarities of biological meaning of these features. The purpose of this classification was to perform the hierarchical feature integration procedure developed in this work. The number following each feature abbreviation was the weight of that feature used in the hierarchical integration procedure. These weights were determined with the training Dataset T by exhaustive performance screening (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031791#s3" target="_blank"><b>Materials and Methods</b></a>). <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031791#pone.0031791.s013" target="_blank">Table S2</a> lists the complete meanings of the features abbreviated here.</p