Ki67 Antigen as a Predictive Factor for Prognosis of Sinonasal Mucosal Melanoma

ObjectivesSinonasal mucosal melanoma is a rare and aggressive disease. The aim of this study was to analyze the clinical features of patients with sinonasal mucosal melanoma and to determine the role of Ki67 antigen as a predictor of prognosis in sinonasal mucosal melanoma.MethodsThis was a retrospective case-series study at a single institution, an academic tertiary referral center. From 1995 to 2007, 27 patients with sinonasal mucosal melanoma were reviewed retrospectively, and the expression of Ki67 antigen was assessed by immunohistochemistry.ResultsThe overall 5-yr survival rate was 33.9%. No significant differences were observed in 5-yr survival according to age, sex, stage, or the presence of melanin. The rates of local failure, regional failure, and distant failure were 37.0%, 14.8%, and 11.1%, respectively. Patients with spindle or mixed cell types had better prognoses than those with other cell types. At a cut-off value of 35%, patients with lower Ki67 scores showed better survival than those with higher Ki67 scores.ConclusionThe presence of spindle or mixed cell types may indicate a better prognosis than other cell types. Ki67 immunostaining may be a useful predictor of prognosis in patients with mucosal malignant melanoma of the sinonasal tract

γ-Aminobutyric Acid (GABA) Is an Autocrine Excitatory Transmitter in Human Pancreatic β-Cells

OBJECTIVE: Paracrine signaling via gamma-aminobutyric acid (GABA) and GABA(A) receptors (GABA(A)Rs) has been documented in rodent islets. Here we have studied the importance of GABAergic signaling in human pancreatic islets. RESEARCH DESIGN AND METHODS: Expression of GABA(A)Rs in islet cells was investigated by quantitative PCR, immunohistochemistry, and patch-clamp experiments. Hormone release was measured from intact islets. GABA release was monitored by whole-cell patch-clamp measurements after adenoviral expression of alpha(1)beta(1) GABA(A)R subunits. The subcellular localization of GABA was explored by electron microscopy. The effects of GABA on electrical activity were determined by perforated patch whole-cell recordings. RESULTS: PCR analysis detected relatively high levels of the mRNAs encoding GABA(A)R alpha(2), beta(3,) gamma(2), and pi subunits in human islets. Patch-clamp experiments revealed expression of GABA(A)R Cl(-) channels in 52% of beta-cells (current density 9 pA/pF), 91% of delta-cells (current density 148 pA/pF), and 6% of alpha-cells (current density 2 pA/pF). Expression of GABA(A)R subunits in islet cells was confirmed by immunohistochemistry. beta-Cells secreted GABA both by glucose-dependent exocytosis of insulin-containing granules and by a glucose-independent mechanism. The GABA(A)R antagonist SR95531 inhibited insulin secretion elicited by 6 mmol/l glucose. Application of GABA depolarized beta-cells and stimulated action potential firing in beta-cells exposed to glucose. CONCLUSIONS: Signaling via GABA and GABA(A)R constitutes an autocrine positive feedback loop in human beta-cells. The presence of GABA(A)R in non-beta-cells suggests that GABA may also be involved in the regulation of somatostatin and glucagon secretion

Serum Anti-Saccharomyces Cerevisiae Antibodies in Greek Patients with Behcet's Disease

We tested 59 Greek patients with Behcet's Disease (BD) for serum anti-Saccharomyces cerevisiae antibodies. No increase of these antibodies was detected in the cases compared to 55 healthy unrelated blood donors from the same population. This finding is in contrast with the correlation between Saccharomyces cerevisiae antibodies and BD as reported in other populations. It seems that environmental factors may contribute to disease expression in different populations, producing different effects according to the individual's genetic predisposition. Saccharomyces cerevisiae antibodies do not seem to be of any significance in the Greek population

Dynamical friction in constant density cores: a failure of the Chandrasekhar formula

Using analytic calculations and N-body simulations we show that in constant density (harmonic) cores, sinking satellites undergo an initial phase of very rapid (super-Chandrasekhar) dynamical friction, after which they experience no dynamical friction at all. For density profiles with a central power law profile of log-slope, $-\alpha$, the infalling satellite heats the background and causes $\alpha$ to decrease. For $\alpha < 0.5$ initially, the satellite generates a small central constant density core and stalls as in the $\alpha = 0$ case. We discuss some astrophysical applications of our results to decaying satellite orbits, galactic bars and mergers of supermassive black hole binaries. In a companion paper we show that a central constant density core can provide a natural solution to the timing problem for Fornax's globular clusters.Comment: 11 pages, 7 figures. Final version accepted for publication in MNRA

An “Electronic Fluorescent Pictograph” Browser for Exploring and Analyzing Large-Scale Biological Data Sets

Background. The exploration of microarray data and data from other high-throughput projects for hypothesis generation has become a vital aspect of post-genomic research. For the non-bioinformatics specialist, however, many of the currently available tools provide overwhelming amounts of data that are presented in a non-intuitive way. Methodology/Principal Findings. In order to facilitate the interpretation and analysis of microarray data and data from other large-scale data sets, we have developed a tool, which we have dubbed the electronic Fluorescent Pictograph – or eFP – Browser, available a

Epidermal progenitors give rise to Merkel cells during embryonic development and adult homeostasis

Lineage-tracing experiments show that the origin of specialized mechanosensory Merkel cells in the skin is epidermal progenitors, not the neural crest

Deletion of PTH Rescues Skeletal Abnormalities and High Osteopontin Levels in Klotho−/− Mice

Maintenance of normal mineral ion homeostasis is crucial for many biological activities, including proper mineralization of the skeleton. Parathyroid hormone (PTH), Klotho, and FGF23 have been shown to act as key regulators of serum calcium and phosphate homeostasis through a complex feedback mechanism. The phenotypes of Fgf23−/− and Klotho−/− (Kl−/−) mice are very similar and include hypercalcemia, hyperphosphatemia, hypervitaminosis D, suppressed PTH levels, and severe osteomalacia/osteoidosis. We recently reported that complete ablation of PTH from Fgf23−/− mice ameliorated the phenotype in Fgf23−/−/PTH−/− mice by suppressing serum vitamin D and calcium levels. The severe osteomalacia in Fgf23−/− mice, however, persisted, suggesting that a different mechanism is responsible for this mineralization defect. In the current study, we demonstrate that deletion of PTH from Kl−/− (Kl−/−/PTH−/− or DKO) mice corrects the abnormal skeletal phenotype. Bone turnover markers are restored to wild-type levels; and, more importantly, the skeletal mineralization defect is completely rescued in Kl−/−/PTH−/− mice. Interestingly, the correction of the osteomalacia is accompanied by a reduction in the high levels of osteopontin (Opn) in bone and serum. Such a reduction in Opn levels could not be observed in Fgf23−/−/PTH−/− mice, and these mice showed sustained osteomalacia. This significant in vivo finding is corroborated by in vitro studies using calvarial osteoblast cultures that show normalized Opn expression and rescued mineralization in Kl−/−/PTH−/− mice. Moreover, continuous PTH infusion of Kl−/− mice significantly increased Opn levels and osteoid volume, and decreased trabecular bone volume. In summary, our results demonstrate for the first time that PTH directly impacts the mineralization disorders and skeletal deformities of Kl−/−, but not of Fgf23−/− mice, possibly by regulating Opn expression. These are significant new perceptions into the role of PTH in skeletal and disease processes and suggest FGF23-independent interactions of PTH with Klotho

Modeling HIV-1 Drug Resistance as Episodic Directional Selection

The evolution of substitutions conferring drug resistance to HIV-1 is both episodic, occurring when patients are on antiretroviral therapy, and strongly directional, with site-specific resistant residues increasing in frequency over time. While methods exist to detect episodic diversifying selection and continuous directional selection, no evolutionary model combining these two properties has been proposed. We present two models of episodic directional selection (MEDS and EDEPS) which allow the a priori specification of lineages expected to have undergone directional selection. The models infer the sites and target residues that were likely subject to directional selection, using either codon or protein sequences. Compared to its null model of episodic diversifying selection, MEDS provides a superior fit to most sites known to be involved in drug resistance, and neither one test for episodic diversifying selection nor another for constant directional selection are able to detect as many true positives as MEDS and EDEPS while maintaining acceptable levels of false positives. This suggests that episodic directional selection is a better description of the process driving the evolution of drug resistance