On the Price of Anarchy of Highly Congested Nonatomic Network Games

We consider nonatomic network games with one source and one destination. We examine the asymptotic behavior of the price of anarchy as the inflow increases. In accordance with some empirical observations, we show that, under suitable conditions, the price of anarchy is asymptotic to one. We show with some counterexamples that this is not always the case. The counterexamples occur in very simple parallel graphs.Comment: 26 pages, 6 figure

Partial Order Optimum Likelihood (POOL): Maximum Likelihood Prediction of Protein Active Site Residues Using 3D Structure and Sequence Properties

A new monotonicity-constrained maximum likelihood approach, called Partial Order Optimum Likelihood (POOL), is presented and applied to the problem of functional site prediction in protein 3D structures, an important current challenge in genomics. The input consists of electrostatic and geometric properties derived from the 3D structure of the query protein alone. Sequence-based conservation information, where available, may also be incorporated. Electrostatics features from THEMATICS are combined with multidimensional isotonic regression to form maximum likelihood estimates of probabilities that specific residues belong to an active site. This allows likelihood ranking of all ionizable residues in a given protein based on THEMATICS features. The corresponding ROC curves and statistical significance tests demonstrate that this method outperforms prior THEMATICS-based methods, which in turn have been shown previously to outperform other 3D-structure-based methods for identifying active site residues. Then it is shown that the addition of one simple geometric property, the size rank of the cleft in which a given residue is contained, yields improved performance. Extension of the method to include predictions of non-ionizable residues is achieved through the introduction of environment variables. This extension results in even better performance than THEMATICS alone and constitutes to date the best functional site predictor based on 3D structure only, achieving nearly the same level of performance as methods that use both 3D structure and sequence alignment data. Finally, the method also easily incorporates such sequence alignment data, and when this information is included, the resulting method is shown to outperform the best current methods using any combination of sequence alignments and 3D structures. Included is an analysis demonstrating that when THEMATICS features, cleft size rank, and alignment-based conservation scores are used individually or in combination THEMATICS features represent the single most important component of such classifiers

The critical role of ERK in death resistance and invasiveness of hypoxia-selected glioblastoma cells

<p>Abstract</p> <p>Background</p> <p>The rapid growth of tumor parenchyma leads to chronic hypoxia that can result in the selection of cancer cells with a more aggressive behavior and death-resistant potential to survive and proliferate. Thus, identifying the key molecules and molecular mechanisms responsible for the phenotypic changes associated with chronic hypoxia has valuable implications for the development of a therapeutic modality. The aim of this study was to identify the molecular basis of the phenotypic changes triggered by chronic repeated hypoxia.</p> <p>Methods</p> <p>Hypoxia-resistant T98G (HRT98G) cells were selected by repeated exposure to hypoxia and reoxygenation. Cell death rate was determined by the trypan blue exclusion method and protein expression levels were examined by western blot analysis. The invasive phenotype of the tumor cells was determined by the Matrigel invasion assay. Immunohistochemistry was performed to analyze the expression of proteins in the brain tumor samples. The Student T-test and Pearson Chi-Square test was used for statistical analyses.</p> <p>Results</p> <p>We demonstrate that chronic repeated hypoxic exposures cause T98G cells to survive low oxygen tension. As compared with parent cells, hypoxia-selected T98G cells not only express higher levels of anti-apoptotic proteins such as Bcl-2, Bcl-X_L, and phosphorylated ERK, but they also have a more invasive potential in Matrigel invasion chambers. Activation or suppression of ERK pathways with a specific activator or inhibitor, respectively, indicates that ERK is a key molecule responsible for death resistance under hypoxic conditions and a more invasive phenotype. Finally, we show that the activation of ERK is more prominent in malignant glioblastomas exposed to hypoxia than in low grade astrocytic glial tumors.</p> <p>Conclusion</p> <p>Our study suggests that activation of ERK plays a pivotal role in death resistance under chronic hypoxia and phenotypic changes related to the invasive phenotype of HRT98G cells compared to parent cells.</p

Prognostic significance of bcl-2 expression in stage III breast cancer patients who had received doxorubicin and cyclophosphamide followed by paclitaxel as adjuvant chemotherapy

BACKGROUND: Bcl-2 is positively regulated by hormonal receptor pathways in breast cancer. A study was conducted to assess the prognostic significances of clinico-pathologic variables and of ER, PR, p53, c-erbB2, bcl-2, or Ki-67 as markers of relapse in breast cancer patients who had received the identical adjuvant therapy at a single institution. METHODS: A cohort of 151 curatively resected stage III breast cancer patients (M:F = 3:148, median age 46 years) who had 4 or more positive lymph nodes and received doxorubicin and cyclophosphamide followed by paclitaxel (AC/T) as adjuvant chemotherapy was analyzed for clinico-pathologic characteristics including disease-free survival (DFS) and overall survival (OS). Patients with positive ER and/or PR expression received 5 years of tamoxifen following AC/T. The protein expressions of biomarkers were assessed immunohistochemically. RESULTS: The median follow-up duration was 36 months, and 37 patients (24.5%) experienced a recurrence. Univariate analyses indicated that the tumor size (P = 0.038) and the number of involved lymph nodes (P < 0.001) significantly affected the recurrences. However, the type of surgery, the histology, histologic grade, the presence of endolymphatic emboli, and a close resection margin did not. Moreover, ER positivity (P = 0.013), bcl-2 positivity (P = 0.002) and low p53 expression (P = 0.032) were found to be significantly associated with a prolonged DFS. Furthermore, multivariate analysis identified 10 or more involved lymph nodes (HR 7.366; P < 0.001), negative bcl-2 expression (HR 2.895; P = 0.030), and c-erbB2 over-expression (HR 3.535; P = 0.001) as independent indicators of poorer DFS. In addition, bcl-2 expression was found to be significantly correlated with the expressions of ER and PR, and inversely correlated with the expressions of p53, c-erbB2 and Ki-67. Patients with bcl-2 expression had a significantly longer DFS than those without, even in the ER (+) subgroup. Moreover, OS was significantly affected by ER, bcl-2 and c-erbB2. CONCLUSION: Bcl-2 is an independent prognostic factor of DFS in curatively resected stage III breast cancer patients and appears to be a useful prognostic factor in combination with c-erbB2 and the number of involved lymph nodes

T Cells Contribute to Tumor Progression by Favoring Pro-Tumoral Properties of Intra-Tumoral Myeloid Cells in a Mouse Model for Spontaneous Melanoma

Tumors affect myelopoeisis and induce the expansion of myeloid cells with immunosuppressive activity. In the MT/ret model of spontaneous metastatic melanoma, myeloid cells are the most abundant tumor infiltrating hematopoietic population and their proportion is highest in the most aggressive cutaneous metastasis. Our data suggest that the tumor microenvironment favors polarization of myeloid cells into type 2 cells characterized by F4/80 expression, a weak capacity to secrete IL-12 and a high production of arginase. Myeloid cells from tumor and spleen of MT/ret mice inhibit T cell proliferation and IFNγ secretion. Interestingly, T cells play a role in type 2 polarization of myeloid cells. Indeed, intra-tumoral myeloid cells from MT/ret mice lacking T cells are not only less suppressive towards T cells than corresponding cells from wild-type MT/ret mice, but they also inhibit more efficiently melanoma cell proliferation. Thus, our data support the existence of a vicious circle, in which T cells may favor cancer development by establishing an environment that is likely to skew myeloid cell immunity toward a tumor promoting response that, in turn, suppresses immune effector cell functions

Chronic allergen challenge induces bronchial mast cell accumulation in BALB/c but not C57BL/6 mice and is independent of IL-9

As genetically engineered mutant mice deficient in single genes are usually generated on a C57BL/6 background, to study mast cell trafficking in mutant mice, we initially investigated whether mast cells accumulated in bronchi in C57BL/6 mice challenged with OVA allergen acutely or chronically for 1 to 3 months. The total number of bronchial mast cells were quantitated using toluidine blue staining in airways of different sizes, i.e. , small (<90 µm), medium (90–155 µm), or large (>150 µm) airways. Non-OVA challenged and acute OVA challenged mice (C57BL/6 and BALB/c) had no detectable bronchial mast cells. Chronic OVA challenge in BALB/c mice for 1 or 3 months induced a significant increase in the number of bronchial mast cells in small-, medium-, and large-sized airways but minimal change in the number of bronchial mast cells in C57BL/6 mice. Both BALB/c and C57BL/6 mice developed significant lung eosinophilia following acute or chronic OVA challenge. Studies of IL-9-deficient mice on a BALB/c background demonstrated a significant increase in the number of bronchial mast cells in IL-9-deficient mice suggesting that IL-9 was not required for the bronchial accumulation of mast cells. Overall, these studies demonstrate that the chronic OVA challenge protocol we have utilized in BALB/c mice provides a model to study the mechanism of bronchial mast cell accumulation and that bronchial mast cell accumulation in chronic OVA challenged mice is independent of IL-9 in this model

Global Developmental Gene Expression and Pathway Analysis of Normal Brain Development and Mouse Models of Human Neuronal Migration Defects

Heterozygous LIS1 mutations are the most common cause of human lissencephaly, a human neuronal migration defect, and DCX mutations are the most common cause of X-linked lissencephaly. LIS1 is part of a protein complex including NDEL1 and 14-3-3ε that regulates dynein motor function and microtubule dynamics, while DCX stabilizes microtubules and cooperates with LIS1 during neuronal migration and neurogenesis. Targeted gene mutations of Lis1, Dcx, Ywhae (coding for 14-3-3ε), and Ndel1 lead to neuronal migration defects in mouse and provide models of human lissencephaly, as well as aid the study of related neuro-developmental diseases. Here we investigated the developing brain of these four mutants and wild-type mice using expression microarrays, bioinformatic analyses, and in vivo/in vitro experiments to address whether mutations in different members of the LIS1 neuronal migration complex lead to similar and/or distinct global gene expression alterations. Consistent with the overall successful development of the mutant brains, unsupervised clustering and co-expression analysis suggested that cell cycle and synaptogenesis genes are similarly expressed and co-regulated in WT and mutant brains in a time-dependent fashion. By contrast, focused co-expression analysis in the Lis1 and Ndel1 mutants uncovered substantial differences in the correlation among pathways. Differential expression analysis revealed that cell cycle, cell adhesion, and cytoskeleton organization pathways are commonly altered in all mutants, while synaptogenesis, cell morphology, and inflammation/immune response are specifically altered in one or more mutants. We found several commonly dysregulated genes located within pathogenic deletion/duplication regions, which represent novel candidates of human mental retardation and neurocognitive disabilities. Our analysis suggests that gene expression and pathway analysis in mouse models of a similar disorder or within a common pathway can be used to define novel candidates for related human diseases

The role of PET/CT in detection of gastric cancer recurrence

<p>Abstract</p> <p>Background</p> <p>In the course of surveillance of gastric cancer recurrence after curative resection, contrast CT scan is used in general. However, new findings from CT scan are not always confirmatory for the recurrence. In this case, we usually use short-term follow up strategy or therapeutic intervention with clinical decision. Recently, the use of fusion Positron Emission Tomography/Computed Tomography (PET/CT) is increasing. The purpose of this study is to evaluate the efficacy and usefulness of PET/CT for detecting recurrence of gastric cancer after curative resection.</p> <p>Methods</p> <p>Fifty two patients who received curative resection of gastric cancer and had undergone PET/CT and contrast CT for surveillance of recurrence until Dec 2006 in Seoul National University Hospital were analyzed retrospectively. Recurrence of gastric cancer was validated by histologic confirmation (n = 17) or serial contrast CT follow up with at least 5 month interval (n = 35). McNemar's test and Fisher's exact test were used to evaluate sensitivity and specificity of PET/CT and contrast CT.</p> <p>Results</p> <p>Of 52 patients, 38 patients were confirmed as recurrence. The sensitivity was 68.4% (26/38) for PET/CT and 89.4% (34/38) for contrast CT (p = 0.057). The specificity was 71.4% (10/14) and 64.2% (9/14), respectively (p = 1.0). In terms of the recurred sites, the sensitivity and specificity of PET/CT were similar to those of contrast CT in all sites except peritoneum. Contrast CT was more sensitive than PET/CT (p = 0.039) for detecting peritoneal seeding. Additional PET/CT on contrast CT showed no further increase of positive predictive value regardless of sites. Among 13 patients whose image findings between two methods were discordant and tissue confirmation was difficult, the treatment decision was made in 7 patients based on PET/CT, showing the final diagnostic accuracy of 42.8% (3/7).</p> <p>Conclusion</p> <p>PET/CT was as sensitive and specific as contrast CT in detection of recurred gastric cancer except peritoneal seeding. However, additional PET/CT on contrast CT did not increase diagnostic accuracy in detection of recurred gastric cancer. Further studies are warranted to validate the role of PET/CT in detection of gastric cancer recurrence.</p

Differential effects of selenium and knock-down of glutathione peroxidases on TNFα and flagellin inflammatory responses in gut epithelial cells

Selenium (Se) is essential for human health. Despite evidence that Se intake affects inflammatory responses, the mechanisms by which Se and the selenoproteins modulate inflammatory signalling, especially in the gut, are not yet defined. The aim of this work was to assess effects of altered Se supply and knock-down of individual selenoproteins on NF-κB activation in gut epithelial cells. Caco-2 cells were stably transfected with gene constructs expressing luciferase linked either to three upstream NF-κB response elements and a TATA box or only a TATA box. TNFα and flagellin activated NF-κB-dependent luciferase activity and increased IL-8 expression. Se depletion decreased expression of glutathione peroxidase1 (GPX1) and selenoproteins H and W and increased TNFα-stimulated luciferase activity, endogenous IL-8 expression and reactive oxygen species (ROS) production. These effects were not mimicked by independent knock-down of either GPX1, selenoprotein H or W; indeed, GPX1 knock-down lowered TNFα-induced NF-κB activation and did not affect ROS levels. GPX4 knock-down decreased NF-κB activation by flagellin but not by TNFα. We hypothesise that Se depletion alters the pattern of expression of multiple selenoproteins that in turn increases ROS and modulates NF-κB activation in epithelial cells, but that the effect of GPX1 knock-down is ROS-independent

Identification and Characterization of a Mef2 Transcriptional Activator in Schistosome Parasites

Myocyte enhancer factor 2 protein (Mef2) is an evolutionarily conserved activator of transcription that is critical to induce and control complex processes in myogenesis and neurogenesis in vertebrates and insects, and osteogenesis in vertebrates. In Drosophila, Mef2 null mutants are unable to produce differentiated muscle cells, and in vertebrates, Mef2 mutants are embryonic lethal. Schistosome worms are responsible for over 200 million cases of schistosomiasis globally, but little is known about early development of schistosome parasites after infecting a vertebrate host. Understanding basic schistosome development could be crucial to delineating potential drug targets. Here, we identify and characterize Mef2 from the schistosome worm Schistosoma mansoni (SmMef2). We initially identified SmMef2 as a homolog to the yeast Mef2 homolog, Resistance to Lethality of MKK1P386 overexpression (Rlm1), and we show that SmMef2 is homologous to conserved Mef2 family proteins. Using a genetics approach, we demonstrate that SmMef2 is a transactivator that can induce transcription of four separate heterologous reporter genes by yeast one-hybrid analysis. We also show that Mef2 is expressed during several stages of schistosome development by quantitative PCR and that it can bind to conserved Mef2 DNA consensus binding sequences