text:
- Research
- Open Access
- Open Peer Review
Identification of new biomarker candidates for glucocorticoid induced insulin resistance using literature mining
© Fleuren et al.; licensee BioMed Central Ltd. 2013
- Received: 8 June 2012
- Accepted: 2 January 2013
- Published: 4 February 2013
Glucocorticoids are potent anti-inflammatory agents used for the treatment of diseases such as rheumatoid arthritis, asthma, inflammatory bowel disease and psoriasis. Unfortunately, usage is limited because of metabolic side-effects, e.g. insulin resistance, glucose intolerance and diabetes. To gain more insight into the mechanisms behind glucocorticoid induced insulin resistance, it is important to understand which genes play a role in the development of insulin resistance and which genes are affected by glucocorticoids.
Medline abstracts contain many studies about insulin resistance and the molecular effects of glucocorticoids and thus are a good resource to study these effects.
We developed CoPubGene a method to automatically identify gene-disease associations in Medline abstracts. We used this method to create a literature network of genes related to insulin resistance and to evaluate the importance of the genes in this network for glucocorticoid induced metabolic side effects and anti-inflammatory processes.
With this approach we found several genes that already are considered markers of GC induced IR, such as phosphoenolpyruvate carboxykinase (PCK) and glucose-6-phosphatase, catalytic subunit (G6PC). In addition, we found genes involved in steroid synthesis that have not yet been recognized as mediators of GC induced IR.
With this approach we are able to construct a robust informative literature network of insulin resistance related genes that gave new insights to better understand the mechanisms behind GC induced IR. The method has been set up in a generic way so it can be applied to a wide variety of disease networks.
- Literature mining
- Insulin resistance
- Glucocorticoids
- Gene networks
Glucocorticoids (GCs) are often prescribed for the treatment of inflammatory diseases such as rheumatoid arthritis, asthma, inflammatory bowel disease and psoriasis[1–3]. Despite their excellent efficacy, usage is limited because of side-effects such as insulin resistance, glucose intolerance, diabetes, central adiposity, dyslipidemia, skeletal muscle wasting and osteoporosis[4–8].
GCs bind to the glucocorticoid receptor (GR), which then dimerizes and translocates to the nucleus where it influences gene transcription. Positive regulation of genes (transactivation) is mainly mediated by direct binding of the GR-GC complex to glucocorticoid response elements located in the regulatory region of a target gene. The GR-GC complex may also bind to negative glucocorticoid response elements, which leads to a negative regulation of genes (transrepression). It is believed that transrepression, in which proinflammatory genes are downregulated, is mainly responsible for the efficacy of GCs as anti-inflammatory drugs[5, 7], while transactivation might be responsible for the GC-induced adverse effects[9].
An important side effect is the development of insulin resistance (IR), because it is the onset of many metabolic diseases and conditions such as obesity, diabetes mellitus and hypertension. IR is a physiological condition in which a given concentration of insulin produces a less-than-expected biological effect. These biological effects are different depending on the tissue in which they occur. For instance, under IR conditions, fat and muscle cells fail to adequately respond to circulating insulin, which results in reduced glucose uptake, and subsequently higher glucose levels in blood[10, 11]. In liver cells the IR- effects can be seen in reduced glycogen synthesis and storage, and a failure to suppress glucose production and release into the blood.
One way by which GCs induce IR is by inhibition of the recruitment of GLUT4 glucose transporter, which results in reduced insulin-stimulated glucose transport in skeletal muscle[12]. However, not all mechanisms involved in GC-induced side effects are not completely understood. To gain more insight into mechanisms behind GC induced IR, it is important to understand which genes play a role in the development of insulin resistance and which genes are affected by GCs.
It has been widely recognized that a system approach in which networks of genes in their functional context are studied, contributes to a better understanding of the mechanisms and pathways related to the disease and the drug effects[13–17]. To study a gene network related to a disease such as IR, a list of disease related genes as well as a notion of the interactions between these genes is needed.
Literature databases such as Medline contain many studies about IR and the molecular effects of synthetic glucocorticoids and thus are a good resource that can be used to create and study disease related gene networks.
The retrieval of relevant gene-disease associations out of the millions of abstracts in Medline is very labor intensive and thus a text mining system is needed to this in an automated fashion.
In previous work we reported about CoPub[18–20], a publicly available text mining system, which has successfully been used for the analysis of microarray data and in toxicogenomics studies[21–26]. CoPub calculates keyword co-occurrences in titles and abstracts from the entire Medline database, using thesauri for genes, diseases, drugs and pathways. We used this technology to develop CoPubGene, a rapid gene – disease network building tool. To evaluate the importance of genes in these networks we implemented a method to score the importance of genes in biological processes of interest by incorporating their functional neighborhood.
We used CoPubGene to create a network of genes related to insulin resistance and to evaluate the importance of the genes in this network for glucocorticoid induced metabolic side effects and anti-inflammatory processes.
By using this method, we identified several genes that already are considered markers of GC induced IR, such as phosphoenolpyruvate carboxykinase (PCK) and glucose 6 phosphatase, catalytic subunit (G6PC)[27, 28]. Even more importantly, we were able to identify genes involved in steroid synthesis that have not yet been recognized as mediators of GC induced IR.
List of available operations of the CoPub Web Service
Operation name
Get genes
Get _genes
Gene name, gene identifier
Biological identifier(s), with gene specific information
Each gene in CoPub belongs to an internal identifier (biological identifier). Get _genes converts the input gene to such a Biological identifier. This biological identifier serves as an input for subsequent operations.
Get Keywords
Get _keywords
Biological identifier(s), with keyword specific information
Retrieves for a set of keywords, the Biological identifiers to which these keywords belong in CoPub. These biological identifiers serve as an input for subsequent operations.
Get references
Get _references
Biological identifier(s)
Literature references
Given a Biological identifier, retrieves all abstracts in which the term occurs.
Get literature neighbours
Get _literature _neighbours
Biological identifier(s)
Literature neighbors
Given a Biological identifier, retrieves a list of keywords which are mentioned in the literature together with the input term.
Get enriched keywords
Get _enriched _keywords
List of gene identifiers
List of enriched keywords
For a list of genes, this operation calculates a keyword overrepresentation.
Get literature network
Get _literature _network
Biological identifier(s)
SVG / Cytoscape network
For a set of genes, the operation creates a network of genes.
Get categories
Get _Categories
List of categories
Returns a list of categories of terms in CoPub
Get chips
Get _chips
List of microarrays
Returns a list of available Affymetrix chip names in CoPub.
Version of code and literature
Returns the version of the code and literature.
Diagnostic information
Retrieval of Gene-Disease associations
To create disease related gene networks, we used CoPubGene to retrieve gene-disease and gene-gene associations from Medline abstracts. Disease terms which had significant gene associations based on the R-scaled score (rs > 35) and literature count (lc > 5) in Medline abstracts, were extracted from the CoPub thesaurus.
Disease clustering
Disease clustering was done in R (http://www.r-project.org) using the pvclust R package with "complete" setting for hierarchical clustering, based on correlation distance of R-scaled scores between genes and diseases, with 100 bootstrap replications. The hierarchical cluster was visualized using Denroscope[29]. Additional gene set enrichment analysis against the GENETIC_ASSOCIATION_DB_DISEASE was done with the annotation server DAVID[30, 31].
Creation of IR gene network
CoPubGene was used to create a set of genes related to IR, by searching for associations between genes and IR in Medline abstracts using default values (rs > 30 and lc > 5). Subsequently the IR-gene network was created by connecting genes that had significant co-occurrences with each other.
Keyword enrichment analysis of IR related genes
Keyword enrichment analysis on the list of IR related genes was done against disease and drug terms from the CoPub database. Threshold values were chosen using default values.
Analysis of the IR gene network and calculation of neighbor score for genes
In which g1 is the R-scaled score of gene g with term d, and Ns is the literature score of its neighboring genes with term d. This latter score Ns is calculated using the R-scaled score of each neighboring gene of gene g with term d (g2, g3,.,gn) relative to its relation (R-scaled score) with gene g (rg2, rg3,.,rgn).
We developed CoPubGene by creating a number of web service operations that can be used to construct networks of genes based on their co-occurrences in Medline abstracts. These web service operations can be combined to answer a variety of biological questions (Table1). For example, the question "to what biological processes is this gene related?" can be answered by running the "get genes" and "get literature neighbours" functions. Using subsequently the "get references" function will return all the relevant pubmed entries in which the gene and keywords co-occur. By applying the "get keywords" and "get literature neighbours" functions one can retrieve all disease terms that are linked to a given drug term in the Medline abstract, or vice versa, retrieve all drug terms that are linked to a given disease term in abstracts. The networks that are created can be written to Cytoscape for downstream applications and visualizations. Also more advanced questions such as the construction of disease related gene networks, and subsequent calculation of keyword enrichment in this network can be addressed in an automatic way. In Table1 the available web service operations are shown.
Retrieval of gene-disease associations
Our aim was to get insight into the pathways and genes that are involved in insulin resistance, and the effect of glucocorticoids on this network. As a first step we created a list of genes associated with insulin resistance using CoPubGene. This yielded a list of 384 genes each of them connected to IR with an R scaled score (in Additional file1: Table S2A the top scoring genes with IR are shown, the full list is available in Additional file2: Table S2). To evaluate the quality of this list and to investigate whether this gene list is unique for IR or whether this list contains a large number of genes that are associated with multiple diseases we constructed a gene association list for all diseases in the disease thesaurus of CoPub, using similar parameter settings as used for construction of the IR gene list. This yielded a list of disease profiles with for each disease, a number of genes connected to that disease with an R scaled score. (Additional file1: Table S2 shows the results for a few selected diseases, the full table is available in Additional file2: Table S3).
Network of insulin resistance related genes
Annotation of the network with drugs and diseases terms
Over-represented drug and disease terms (P-value < 0.05)
Number of genes
nitric oxide
actinomycin d
Number of genes
insulin resistance
diabetes mellitus
cardiovascular disease
Diabetes mellitus,type 2
Oxygen deficiency
Cancer of breast
There are several top scoring over-represented terms that are related to metabolic diseases, e.g. 'diabetes mellitus', 'obesity', 'diabetes mellitus, type 2' and 'hyperinsulinemia' (Table2B). The fact that these terms are high scoring is expected since we constructed the gene network based on the keyword insulin resistance. However we also found diseases that share a common origin with insulin resistance such as cardiovascular disease (Table2B). The most interesting high scoring term for our particular research question was the non-metabolic term 'inflammation', which was represented in the network by genes such as IL6, IL18, IL1RA, SOCS1, SOCS3, CCL2 and CCR2. Several of these genes have been mentioned in studies to be involved in the development of metabolic diseases. For instance, elevated levels of IL6 in subjects with obesity and diabetes showed an association between insulin resistance and IL6[38]. Studies in mice showed that CCR2 deficiency or antagonism of this receptor resulted in attenuation of systemic insulin resistance and development of obesity, hence suggesting a modulating role of CCR2 in this[39, 40].
These results show that even with an unbiased data driven construction of a gene network, the relation between IR, dexamethasone and inflammation is discovered based on the genes that play a role in these effects. We subsequently highlighted the genes in the IR network that are related to inflammation and dexamethasone (Figure2).
Genes linked to inflammation and glucocorticoids in the context of insulin resistance
The majority of the genes in Figure3 are directly involved in important metabolic processes such as gluconeogenesis (PCK2, G6PC, PC and GCG), glycolysis (GCK, GCG), glucose uptake, lipid metabolism (ACACA, CHPT1, GPD1) and carbohydrate metabolism (GPD1). Other ones are directly involved in insulin signaling (GIP, IGF2, IPF1, IAPP).
Sex steroid physiology in relation to insulin resistance
Additional topological analysis of the sub-network using cytohubba[43] revealed that IGF1R, HSD11B2, IGF2 and SHBG have a high betweenness centrality, i.e. they have many shortest paths going through them, analogous to major bridges and tunnels on a high map. Studies show that such a bottle necks play important roles in biological networks[44, 45].
CYP19A1 encodes for an aromatase which is responsible for the aromatization of androgens into estrogens, thus influencing the androgen to estrogen balance. Several studies showed that an imbalance between androgen and estrogen balance because of aromatase deficiency resulted in the development of symptoms related to the metabolic syndrome[46–49]. The fact that dexamethasone can regulate aromatase activity[50–52], suggests a role of aromatase in GC induced IR.
CYP17A1 is a key regulator of androgen synthesis and catalyzes the reactions in which pregnenolone and progesterone are converted into their 17-alpha-hydroxylated products and subsequently into Dehydroepiandrosterone (DHEA). A decline in DHEA and also its sulfated ester (DHEA-S) has been suggested to be causally linked to insulin resistance and obesity[53–56]. The possible inhibitory effects of dexamethasone on Cyp17a1[57, 58] suggests a role in GC induced IR by this gene.
CYP21A2 is a cytochrome P450 enzyme coding for the 21-hydroxylase that is involved in the biosynthesis of the steroid hormones aldosterone and cortisol. A defect in this gene leads to Congenital adrenal hyperplasia (CAH) in which there is a disbalance in cortisol and aldosterone secretion. CAH patients are characterized by insulin resistance, lower insulin sensitivity and hyperinsulinemia[43, 59–61]. Some studies indicate that the development of IR is because of GC treatment in this patient group[62–64]. Whether these patients develop IR because of CAH and deficiency of 21-hydroxylase, or because of the fact that they are often treated with synthetic GCs need to be elucidated.
Genes involved in osteoporosis
Another side effect of GC treatment is the development of glucocorticoid induced osteoporosis (GIOP)[65]. GIOP is characterized by reduced bone mineral density (BMD), decreased bone mass and disturbance of the bone matrix, leading to increased susceptibility to fractures. We applied CoPubGene to deduce important genes involved in GIOP by analyzing top scoring genes with OP (in total 131 genes associated with OP were found, see Additional file2: Table S5; the network of these top scoring genes with relations to dexamethasone and inflammation is shown in Additional file6: Figure S3. The majority of the genes are involved in bone remodeling and resorption (TNFRSF11A, TNFRSF11B, TNFSF11, SP7 ,CTSK), in bone mineralization (PTH, Klotho, VDR, Calca, BGLAP) or are part of the wnt signaling pathway that is involved in the regulation of bone formation (SOST, DKK1, LRP5, LRP6)[66]. Among these genes are known biomarkers of GIOP such as osteoprotegerin (encoded by TNFRSF11B) and the ligand RANK-L (encoded by TNFS11)[67]. Here we also searched for genes with a low score with inflammation. Several of these genes in the set, such as BGLAP, COL1A1 and SP7 are affected by GCs[68–72], have low associations with inflammation and therefore are interesting biomarker candidates for GIOP.
In the work presented here we used Medline abstracts to study mechanisms and genes involved in glucocorticoid induced insulin resistance. We created CoPubGene, a number of web service operations that can be used to retrieve relevant gene-disease, gene-drug and gene-gene associations out of Medline abstracts, using the CoPub technology.
The clustering of disease terms based on their associations with genes in Medline abstracts showed that CoPubGene is able to generate a list of specific IR genes that can be used for further analysis, and that this method also can be used to generate a variety of other gene disease associations. We used this clustering to evaluate the quality of disease related gene lists, generated using a text mining approach, because to our knowledge there is no real gold standard data set that covers a sufficient range of gene-disease associations that can be used. Databases such as OMIM and the KEGG disease database[73] only cover a sub range of diseases which makes these datasets difficult to use in this type of evaluation.
Next, we studied the IR genes in their functional context, by including genes with which they co-occur in Medline abstracts. In this gene network we focused on genes that are strongly linked to dexamethasone and less strongly to inflammation. These genes are thought to be more exclusively related to GC induced IR and therefore might be interesting markers for this effect.
However, all of them are to a certain extent related to inflammation, either directly or indirectly by their neighbors, which suggests that these genes cannot be used as an exclusive marker for GC induced IR. This might have consequences for the search of dissociating compounds, i.e. compounds which only have the immune suppressive properties and not the unwanted side effects. Instead the search should focus on compounds that show a reduced effect on the expression of these IR genes.
The majority of the IR genes that have a low literature neighbor score for inflammation (< 25) and a high score for dexamethasone (literature neighbor score > 25) code for enzymes and hormones directly involved in important metabolic processes, such as glycolysis, gluconeogenesis, glucose uptake and lipid metabolism. All these processes are tightly regulated by insulin. This suggests that at a first instance, the search for mechanisms of GC induced IR should be focused on these processes.
Additionally, we also identified a sub network of genes involved in sex steroid synthesis that to our knowledge, not have been recognized yet as mediators of GC induced side effects. Key enzymes involved in steroid synthesis, i.e. CYP17A1, CYP21A2 and CYP19A1 keep the balance between several steroids, and an impairment of this balance could possibly result in metabolic disturbances such as IR. Additional topological analyses could further prioritize this sub-network for follow-up studies to determine the influence of GCs on sex steroid synthesis and the relation to IR. In such a study one could look at the influence of GCs on the balance between the steroids in combination with their influence on insulin stimulated glucose uptake in glucose sensitive tissues such as adipose and muscle tissue.
Using CoPubGene we are able to construct an informative literature network of IR related genes by only using information from Medline abstracts. Our approach revealed genes, that on a first glance were not considered to be involved in GC induced IR and thus gave new insights that might lead to a better understanding of the mechanisms behind GC induced IR.
Financial contribution
Author WF was supported by the Biorange project (BR4.2) "A Systems Bioinformatics Approach For Evaluating And Translating Drug-Target Effects In Disease Related Pathways" of NBIC.
Authors' Affiliations
- Del Rosso Do JQ: Combination topical therapy for the treatment of psoriasis. J Drugs Dermatol. 2006, 5 (3): 232-234.PubMedGoogle Scholar
- Schwartz M, Cohen R: Optimizing conventional therapy for inflammatory bowel disease. Curr Gastroenterol Rep. 2008, 10 (6): 585-590. 10.1007/s11894-008-0106-8.View ArticlePubMedGoogle Scholar
- Hillier SG: Diamonds are forever: the cortisone legacy. J Endocrinol. 2007, 195 (1): 1-6. 10.1677/JOE-07-0309.View ArticlePubMedGoogle Scholar
- De Bosscher K, Haegeman G: Minireview: latest perspectives on antiinflammatory actions of glucocorticoids. Mol Endocrinol. 2009, 23 (3): 281-291.View ArticlePubMedGoogle Scholar
- Rhen T, Cidlowski JA: Antiinflammatory action of glucocorticoids–new mechanisms for old drugs. N Engl J Med. 2005, 353 (16): 1711-1723. 10.1056/NEJMra050541.View ArticlePubMedGoogle Scholar
- Rockall AG: Computed tomography assessment of fat distribution in male and female patients with Cushing's syndrome. Eur J Endocrinol. 2003, 149 (6): 561-567. 10.1530/eje.0.1490561.View ArticlePubMedGoogle Scholar
- Schacke H, Docke WD, Asadullah K: Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther. 2002, 96 (1): 23-43. 10.1016/S0163-7258(02)00297-8.View ArticlePubMedGoogle Scholar
- Schacke H: Insight into the molecular mechanisms of glucocorticoid receptor action promotes identification of novel ligands with an improved therapeutic index. Exp Dermatol. 2006, 15 (8): 565-573. 10.1111/j.1600-0625.2006.00453.x.View ArticlePubMedGoogle Scholar
- Diamond MI: Transcription factor interactions: selectors of positive or negative regulation from a single DNA element. Science. 1990, 249 (4974): 1266-1272. 10.1126/science.2119054.View ArticlePubMedGoogle Scholar
- Schenk S, Saberi M, Olefsky JM: Insulin sensitivity: modulation by nutrients and inflammation. J Clin Invest. 2008, 118 (9): 2992-3002. 10.1172/JCI34260.View ArticlePubMedPubMed CentralGoogle Scholar
- Kalupahana NS, Moustaid-Moussa N, Claycombe KJ: Immunity as a link between obesity and insulin resistance. Mol Aspects Med. 2012, 33 (1): 26-34. 10.1016/j.mam.2011.10.011.View ArticlePubMedGoogle Scholar
- Weinstein SP: Dexamethasone inhibits insulin-stimulated recruitment of GLUT4 to the cell surface in rat skeletal muscle. Metabolism. 1998, 47 (1): 3-6. 10.1016/S0026-0495(98)90184-6.View ArticlePubMedGoogle Scholar
- Ideker T, Lauffenburger D: Building with a scaffold: emerging strategies for high- to low-level cellular modeling. Trends Biotechnol. 2003, 21 (6): 255-262. 10.1016/S0167-7799(03)00115-X.View ArticlePubMedGoogle Scholar
- Alkema W, Rullmann T, van Elsas A: Target validation in silico: does the virtual patient cure the pharma pipeline?. Expert Opin Ther Targets. 2006, 10 (5): 635-638. 10.1517/1472822.214.171.1245.View ArticlePubMedGoogle Scholar
- Sharan R, Ideker T: Modeling cellular machinery through biological network comparison. Nat Biotechnol. 2006, 24 (4): 427-433. 10.1038/nbt1196.View ArticlePubMedGoogle Scholar
- Goh KI: The human disease network. Proc Natl Acad Sci U S A. 2007, 104 (21): 8685-8690. 10.1073/pnas.0701361104.View ArticlePubMedPubMed CentralGoogle Scholar
- Plake C, Schroeder M: Computational polypharmacology with text mining and ontologies. Curr Pharm Biotechnol. 2011, 12 (3): 449-457. 10.2174/138920111794480624.View ArticlePubMedGoogle Scholar
- Alako BT: CoPub Mapper: mining MEDLINE based on search term co-publication. BMC Bioinformatics. 2005, 6: 51. 10.1186/1471-2105-6-51.View ArticlePubMedPubMed CentralGoogle Scholar
- Frijters R: CoPub: a literature-based keyword enrichment tool for microarray data analysis. Nucleic Acids Res. 2008, 36 (Web Server issue): W406-410.View ArticlePubMedPubMed CentralGoogle Scholar
- Fleuren WW: CoPub update: CoPub 5.0 a text mining system to answer biological questions. Nucleic Acids Res. 2011, 39 (Web Server issue): W450-454.View ArticlePubMedPubMed CentralGoogle Scholar
- Friberg PA, Larsson DG, Billig H: Transcriptional effects of progesterone receptor antagonist in rat granulosa cells. Mol Cell Endocrinol. 2010, 315 (1–2): 121-130.View ArticlePubMedGoogle Scholar
- Frijters R: Prednisolone-induced differential gene expression in mouse liver carrying wild type or a dimerization-defective glucocorticoid receptor. BMC Genomics. 2010, 11: 359. 10.1186/1471-2164-11-359.View ArticlePubMedPubMed CentralGoogle Scholar
- Frijters R: Literature-based compound profiling: application to toxicogenomics. Pharmacogenomics. 2007, 8 (11): 1521-1534. 10.2217/146224184.108.40.2061.View ArticlePubMedGoogle Scholar
- Merkl M: Microarray analysis of equine endometrium at days 8 and 12 of pregnancy. Biol Reprod. 2010, 83 (5): 874-886. 10.1095/biolreprod.110.085233.View ArticlePubMedGoogle Scholar
- Mitterhuemer S: Escherichia coli infection induces distinct local and systemic transcriptome responses in the mammary gland. BMC Genomics. 2010, 11: 138. 10.1186/1471-2164-11-138.View ArticlePubMedPubMed CentralGoogle Scholar
- Shimizu T: Actions and interactions of progesterone and estrogen on transcriptome profiles of the bovine endometrium. Physiol Genomics. 2010, 42A (4): 290-300. 10.1152/physiolgenomics.00107.2010.View ArticlePubMedGoogle Scholar
- Voice MW, Webster AP, Burchell A: The in vivo regulation of liver and kidney glucose-6-phosphatase by dexamethasone. Horm Metab Res. 1997, 29 (3): 97-100. 10.1055/s-2007-978998.View ArticlePubMedGoogle Scholar
- Franckhauser S: Expression of the phosphoenolpyruvate carboxykinase gene in 3T3-F442A adipose cells: opposite effects of dexamethasone and isoprenaline on transcription. Biochem J. 1995, 305 (Pt 1): 65-71.View ArticlePubMedPubMed CentralGoogle Scholar
- Huson DH: Dendroscope: An interactive viewer for large phylogenetic trees. BMC Bioinformatics. 2007, 8: 460. 10.1186/1471-2105-8-460.View ArticlePubMedPubMed CentralGoogle Scholar
- Huang da W, Sherman BT, Lempicki RA: Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009, 4 (1): 44-57.View ArticlePubMedGoogle Scholar
- Huang da W, Sherman BT, Lempicki RA: Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 2009, 37 (1): 1-13. 10.1093/nar/gkn923.View ArticlePubMedGoogle Scholar
- Barabasi AL: Scale-free networks: a decade and beyond. Science. 2009, 325 (5939): 412-413. 10.1126/science.1173299.View ArticlePubMedGoogle Scholar
- Xu H: Dual specificity MAPK phosphatase 3 activates PEPCK gene transcription and increases gluconeogenesis in rat hepatoma cells. J Biol Chem. 2005, 280 (43): 36013-36018. 10.1074/jbc.M508027200.View ArticlePubMedGoogle Scholar
- Park JJ: GRB14, GPD1, and GDF8 as potential network collaborators in weight loss-induced improvements in insulin action in human skeletal muscle. Physiol Genomics. 2006, 27 (2): 114-121. 10.1152/physiolgenomics.00045.2006.View ArticlePubMedGoogle Scholar
- Krempler F: Leptin, peroxisome proliferator-activated receptor-gamma, and CCAAT/enhancer binding protein-alpha mRNA expression in adipose tissue of humans and their relation to cardiovascular risk factors. Arterioscler Thromb Vasc Biol. 2000, 20 (2): 443-449. 10.1161/01.ATV.20.2.443.View ArticlePubMedGoogle Scholar
- Chia YY: Amelioration of glucose homeostasis by glycyrrhizic acid through gluconeogenesis rate-limiting enzymes. Eur J Pharmacol. 2012, 677 (1–3): 197-202.View ArticlePubMedGoogle Scholar
- Fernandez-Real JM: Serum corticosteroid-binding globulin concentration and insulin resistance syndrome: a population study. J Clin Endocrinol Metab. 2002, 87 (10): 4686-4690. 10.1210/jc.2001-011843.View ArticlePubMedGoogle Scholar
- Kern PA: Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab. 2001, 280 (5): E745-751.PubMedGoogle Scholar
- Weisberg SP: CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest. 2006, 116 (1): 115-124. 10.1172/JCI24335.View ArticlePubMedGoogle Scholar
- Tamura Y: C-C chemokine receptor 2 inhibitor improves diet-induced development of insulin resistance and hepatic steatosis in mice. J Atheroscler Thromb. 2010, 17 (3): 219-228. 10.5551/jat.3368.View ArticlePubMedGoogle Scholar
- Bhasin S: Sex hormone-binding globulin, but not testosterone, is associated prospectively and independently with incident metabolic syndrome in men: the framingham heart study. Diabetes Care. 2011, 34 (11): 2464-2470. 10.2337/dc11-0888.View ArticlePubMedPubMed CentralGoogle Scholar
- Macut D: Age, body mass index, and serum level of DHEA-S can predict glucocorticoid receptor function in women with polycystic ovary syndrome. Endocrine. 2010, 37 (1): 129-134. 10.1007/s12020-009-9277-9.View ArticlePubMedGoogle Scholar
- Mooij CF: Unfavourable trends in cardiovascular and metabolic risk in paediatric and adult patients with congenital adrenal hyperplasia?. Clin Endocrinol (Oxf). 2010, 73 (2): 137-146.Google Scholar
- Yu H: The importance of bottlenecks in protein networks: correlation with gene essentiality and expression dynamics. PLoS Comput Biol. 2007, 3 (4): e59. 10.1371/journal.pcbi.0030059.View ArticlePubMedPubMed CentralGoogle Scholar
- McDermott JE: Bottlenecks and hubs in inferred networks are important for virulence in Salmonella typhimurium. J Comput Biol. 2009, 16 (2): 169-180. 10.1089/cmb.2008.04TT.View ArticlePubMedGoogle Scholar
- Bader MI: Comparative assessment of estrogenic responses with relevance to the metabolic syndrome and to menopausal symptoms in wild-type and aromatase-knockout mice. J Steroid Biochem Mol Biol. 2011, 127 ((3-5)): 428-34.View ArticlePubMedGoogle Scholar
- Jones ME: Of mice and men: the evolving phenotype of aromatase deficiency. Trends Endocrinol Metab. 2006, 17 (2): 55-64. 10.1016/j.tem.2006.01.004.View ArticlePubMedGoogle Scholar
- Maffei L: Dysmetabolic syndrome in a man with a novel mutation of the aromatase gene: effects of testosterone, alendronate, and estradiol treatment. J Clin Endocrinol Metab. 2004, 89 (1): 61-70. 10.1210/jc.2003-030313.View ArticlePubMedGoogle Scholar
- Takeda K: Progressive development of insulin resistance phenotype in male mice with complete aromatase (CYP19) deficiency. J Endocrinol. 2003, 176 (2): 237-246. 10.1677/joe.0.1760237.View ArticlePubMedGoogle Scholar
- Zhao H: A novel promoter controls Cyp19a1 gene expression in mouse adipose tissue. Reprod Biol Endocrinol. 2009, 7: 37. 10.1186/1477-7827-7-37.View ArticlePubMedPubMed CentralGoogle Scholar
- Simpson ER: Estrogen formation in stromal cells of adipose tissue of women: induction by glucocorticosteroids. Proc Natl Acad Sci U S A. 1981, 78 (9): 5690-5694. 10.1073/pnas.78.9.5690.View ArticlePubMedPubMed CentralGoogle Scholar
- Enjuanes A: Regulation of CYP19 gene expression in primary human osteoblasts: effects of vitamin D and other treatments. Eur J Endocrinol. 2003, 148 (5): 519-526. 10.1530/eje.0.1480519.View ArticlePubMedGoogle Scholar
- Koga M: Serum dehydroepiandrosterone sulphate levels in patients with non-alcoholic fatty liver disease. Intern Med. 2011, 50 (16): 1657-1661. 10.2169/internalmedicine.50.4682.View ArticlePubMedGoogle Scholar
- Kurzman ID, MacEwen EG, Haffa AL: Reduction in body weight and cholesterol in spontaneously obese dogs by dehydroepiandrosterone. Int J Obes. 1990, 14 (2): 95-104.PubMedGoogle Scholar
- Sanchez J: Dehydroepiandrosterone prevents age-associated alterations, increasing insulin sensitivity. J Nutr Biochem. 2008, 19 (12): 809-818. 10.1016/j.jnutbio.2007.10.005.View ArticlePubMedGoogle Scholar
- Schriock ED: Divergent correlations of circulating dehydroepiandrosterone sulfate and testosterone with insulin levels and insulin receptor binding. J Clin Endocrinol Metab. 1988, 66 (6): 1329-1331. 10.1210/jcem-66-6-1329.View ArticlePubMedGoogle Scholar
- Lee TC, Miller WL, Auchus RJ: Medroxyprogesterone acetate and dexamethasone are competitive inhibitors of different human steroidogenic enzymes. J Clin Endocrinol Metab. 1999, 84 (6): 2104-2110. 10.1210/jc.84.6.2104.PubMedGoogle Scholar
- Trzeciak WH: Dexamethasone inhibits corticotropin-induced accumulation of CYP11A and CYP17 messenger RNAs in bovine adrenocortical cells. Mol Endocrinol. 1993, 7 (2): 206-213. 10.1210/me.7.2.206.PubMedGoogle Scholar
- Speiser PW: Insulin insensitivity in adrenal hyperplasia due to nonclassical steroid 21-hydroxylase deficiency. J Clin Endocrinol Metab. 1992, 75 (6): 1421-1424. 10.1210/jc.75.6.1421.PubMedGoogle Scholar
- Paula FJ: Androgen-related effects on peripheral glucose metabolism in women with congenital adrenal hyperplasia. Horm Metab Res. 1994, 26 (11): 552-556. 10.1055/s-2007-1001755.View ArticlePubMedGoogle Scholar
- Saygili F, Oge A, Yilmaz C: Hyperinsulinemia and insulin insensitivity in women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency: the relationship between serum leptin levels and chronic hyperinsulinemia. Horm Res. 2005, 63 (6): 270-274. 10.1159/000086363.View ArticlePubMedGoogle Scholar
- Kroese JM: Pioglitazone improves insulin resistance and decreases blood pressure in adult patients with congenital adrenal hyperplasia. Eur J Endocrinol. 2009, 161 (6): 887-894. 10.1530/EJE-09-0523.View ArticlePubMedGoogle Scholar
- Charmandari E: Children with classic congenital adrenal hyperplasia have elevated serum leptin concentrations and insulin resistance: potential clinical implications. J Clin Endocrinol Metab. 2002, 87 (5): 2114-2120. 10.1210/jc.87.5.2114.View ArticlePubMedGoogle Scholar
- Bachelot A: Long-term outcome of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Horm Res. 2007, 67 (6): 268-276. 10.1159/000098017.View ArticlePubMedGoogle Scholar
- den Uyl D, Bultink IE, Lems WF: Glucocorticoid-induced osteoporosis. Clin Exp Rheumatol. 2011, 29 (5 Suppl 68): S93-98.PubMedGoogle Scholar
- Issack PS, Helfet DL, Lane JM: Role of Wnt signaling in bone remodeling and repair. HSS J. 2008, 4 (1): 66-70. 10.1007/s11420-007-9072-1.View ArticlePubMedGoogle Scholar
- Canalis E: Mechanisms of glucocorticoid-induced osteoporosis. Curr Opin Rheumatol. 2003, 15 (4): 454-457. 10.1097/00002281-200307000-00013.View ArticlePubMedGoogle Scholar
- Kauh E: Prednisone affects inflammation, glucose tolerance, and bone turnover within hours of treatment in healthy individuals. Eur J Endocrinol. 2012, 166 (3): 459-467. 10.1530/EJE-11-0751.View ArticlePubMedGoogle Scholar
- Eastell R: Bone formation markers in patients with glucocorticoid-induced osteoporosis treated with teriparatide or alendronate. Bone. 2010, 46 (4): 929-934. 10.1016/j.bone.2009.12.021.View ArticlePubMedGoogle Scholar
- Zheng HF, Spector TD, Richards JB: Insights into the genetics of osteoporosis from recent genome-wide association studies. Expert Rev Mol Med. 2011, 13: e28-View ArticlePubMedGoogle Scholar
- Fu H: Osteoblast differentiation in vitro and in vivo promoted by Osterix. J Biomed Mater Res A. 2007, 83 (3): 770-778.View ArticlePubMedGoogle Scholar
- Advani S: Dexamethasone suppresses in vivo levels of bone collagen synthesis in neonatal mice. Bone. 1997, 20 (1): 41-46. 10.1016/S8756-3282(96)00314-6.View ArticlePubMedGoogle Scholar
- Kanehisa M: KEGG for linking genomes to life and the environment. Nucleic Acids Res. 2008, 36 (Database issue): D480-484.PubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


text:
Big Sean has revealed that it "meant a lot" to him to be able to work on his own music with Eminem with the track 'No Favors' off Big Sean's latest album 'I Decided.'
The 'Blessings' hitmaker has collaborated with the 44-year-old rapper before but it has always been on his music so he was thrilled when Eminem agreed to work on 'No Favors' off Big Sean's latest album 'I Decided.'
He said: "It meant a lot to me because it was my album. Last time, it was for his project, which was an honor too, but I'm just happy that he got to be a part of it. It means so much to me and to our city, I feel like it's going to be big.
"Just the things he's talking about on there and brought to the table were things that definitely needed to be said. I was glad that he could bring that perspective to it. The true meaning of a feature is to add something that's not already there to a song and he more than did that."
And the 28-year-old rapper also revealed he doesn't write his raps before heading into the studio and prefers to just "freestyle" instead.
He told Time magazine: "I made the commitment to lay it all out on the table as an artist. It's a sacrifice and a privilege to be able to do that. It's a privilege to be able to talk about my life, it's therapeutic for me. If I can motivate somebody else or excite somebody else or inspire somebody else, that's the whole purpose of it.
"The process is just me being real with myself on every song. I also always meditate before I go to the studio – I feel like it's a spiritual process, the inspiration kind of goes through you. I don't even write my raps, I just get in the booth and think them … Not necessarily a freestyle process, but I'll think of one line, I think of the next line, I just kind of lay it down, do a little more."

subset: commoncrawl


text:
Pursue publication at this talk co-presented by The Writers Place and the Woodneath Library Center, 8900 NE Flintlock Road, Kansas City, MO, 64157. Free, but registration requested. Click here to register.
To get an agent or not to get an agent? That is the question. What are the benefits of working with a literary agent? What does an agent do, anyway? Come to this informative panel to find out from local authors Brian Shawver, Linda Rodriguez, and agent Ellen Geiger.


text:
Blank Calendar 2017
Right here it is usually! Here is the 2017 Savings Apr Work schedule! See where the night takes us once you appear away for any second? You forget to content the Blank Calendar 2017. In the event that you're searching for a printable work schedule you may print the rest of the 12 months, you'll It may seem just like the month of Apr is usually nothing at all but September Fools' jokes and wet Spring climate, but you'll certainly be mistaken. Which lot occurring this month, and with our cost savings entertainment diary, you'll become able to stay in the cycle for of all of these. And right here, as usually, to support you keep an eye on all of your fresh and coming back favourites together with your downloadable and printable suggestions for February TELEVISION 2017, offered at the following links as the two a Large Quality PDF FILE or DIGITAL. Springtime is definitely officially in this article, and presently there are a lot of ways to spend a few time collectively like a family members.
Down weight and printing the Blank Calendar 2017 to begin preparing almost all of the festivities, big or little. We are likewise starting the next month of the The CMI content group utilizes a multi-tabbed schedule that is depending on the article appointments design template beneath, to ensure that most the numerous editorial info we monitor can end up being found in 1 record. Click upon the picture to down load the personal duplicate, which usually you can easily c This is therefore hard to believe that 2017 is really a few short, and quickly, days aside! As 2016 comes to a detailed, this is enjoyable to believe about what a fun year it is often and every thing we possess carried out! We also enjoy looking ahead to a brand new year, a fresh start, and new programs!.
As you probably understand by right now, I REALLY LIKE creating calendars and I make an effort of my personal calendars apart for free of charge every year. Previous year's work schedule was thus popular and several of you asked basically will get upgrading this to 2017. And so i do! This past year We were a novice with regards to Please avoid miss to thank her for hosting, too. Keep in mind how I actually attempted to photograph my own March, 2017 blank date page? I could truthfully state how content I was that, because of my pc guru Martin, my scanning device is now once more talking to my personal computer system. Blank Calendar 2017 coming from developer's offers been up to date miscellaneous inspections as very well as wages calculation bank checks. Prints incomes checks about blank laptop checks or perhaps preprinted investigations. Instantly computes Federal government Withholding Taxes When we rely in my own digital schedule to help remind me personally to access visits, intended for my personal blog page My spouse and i depend on a great old college newspaper appointment setting and register to keep me on the right track. My preferred calendars have got space to write jobs on every day time, and I make use of different coloured pens to.
Blank Calendar 2017 blank calendar 2017
Blank January 2017 Calendar | April Calendar | April Calendar blank calendar 2017
Blank Calendar 2017 blank calendar 2017
2017 Calendar Templates Download 2017 monthly & yearly templates blank calendar 2017
Blank Calendar 2017 blank calendar 2017


text:
REDWOOD CITY, Calif., April 10, 2017 (GLOBE NEWSWIRE) -- OncoMed Pharmaceuticals, Inc. (Nasdaq:OMED), a clinical-stage biopharmaceutical company focused on discovering and developing novel anti-cancer stem cell and immuno-oncology therapeutics, today reported top-line results from the company's Phase 2 YOSEMITE clinical trial of demcizumab (anti-DLL4, OMP-21M18) in combination with Abraxane® (paclitaxel protein-bound particles for injectable suspension) (albumin bound) plus gemcitabine in previously untreated patients with metastatic pancreatic cancer. The randomized Phase 2 "YOSEMITE" trial was designed to assess the efficacy and safety of demcizumab plus standard-of-care chemotherapy in first-line metastatic pancreatic cancer with the primary endpoint of progression-free survival and a secondary endpoint of overall survival. The trial did not meet the primary endpoint of progression-free survival. Additionally, the interim median overall survival analysis did not show a benefit for demcizumab in combination with Abraxane plus gemcitabine compared to the Abraxane, gemcitabine plus placebo arm in patients with first-line metastatic pancreatic cancer.
"Patients in all three arms of the Phase 2 YOSEMITE trial surpassed the published median overall survival rates for Abraxane plus gemcitabine in first-line metastatic pancreatic patients. While the interim median overall survival was 13.2 months in the pooled demcizumab arms, the interim median overall survival of Abraxane plus gemcitabine was not reached at the time of these analyses. Based on the lack of benefit over standard-of-care, which performed remarkably well, we will be discontinuing this trial. We will conduct additional analyses, together with our partner, Celgene, to understand these outcomes. We will also discontinue any additional enrollment in our other ongoing demcizumab trials and conduct analyses of the data from those trials as planned," said Paul J. Hastings, Chairman and CEO of OncoMed Pharmaceuticals. "OncoMed remains focused on completing and analyzing the results of the two randomized Phase 2 clinical trials, PINNACLE and DENALI, that are anticipated in the first half of this year and in continuing the advancement of our portfolio of biotherapeutic candidates."
OncoMed management will host a conference call today at 8:30 a.m. ET/5:30 a.m. PT to discuss the YOSEMITE clinical trial data.
Summary of Key Findings
"Pancreatic cancer has proven to be a uniquely challenging disease, and these data appear to reflect some of those disease and treatment complexities. The safety data seen in the YOSEMITE trial were generally consistent and in line with our expectations. We continue to analyze these data, and look forward to presenting the full study findings at a future scientific congress," said Robert Stagg, PharmD, Senior Vice President of Clinical Research and Development. "We would like to sincerely thank the patients and their families, investigators and staff for their support and participation in this study."
About the Phase 2 YOSEMITE Trial
The randomized Phase 2 "YOSEMITE" trial was designed to assess the efficacy and safety of demcizumab in combination with Abraxane plus gemcitabine, compared to Abraxane, gemcitabine plus placebo in first-line pancreatic cancer patients with metastatic disease. Two-hundred and seven patients were randomized and 204 patients were treated in one of three study arms: 1) Abraxane, gemcitabine plus placebo, 2) Abraxane, gemcitabine plus one 70-day truncated course of demcizumab (given once every 2 weeks with the last dose given on Day 70) or 3) Abraxane, gemcitabine plus two 70-day truncated courses of demcizumab (separated by a 98 day period without demcizumab) with the last demcizumab dose given on day 238.
The primary endpoint of YOSEMITE was progression-free survival. Secondary and exploratory endpoints were overall survival, response rate, pharmacokinetics, immunogenicity, safety and biomarker analyses. The YOSEMITE Phase 2 trial was conducted at 49 clinical sites in the U.S., Canada, Europe and Australia. OncoMed initiated YOSEMITE in April 2015 and completed enrollment of patients in September 2016.
Conference Call Today
OncoMed management will host a conference call today beginning at 8:30 a.m. ET/5:30 a.m. PT to review top-line results from the Phase 2 YOSEMITE clinical trial.
Analysts and investors can participate in the conference call by dialing 1-855-420-0692 (domestic) and
1-484-756-4194 (international) using the conference ID# 5625895. A webcast of the conference call will be accessible through a link in the Investor Relations section of the OncoMed website: http://www.oncomed.com. An audio replay of the conference call can be accessed by dialing 1-855-859-2056 (domestic) or 1-404-537-3406 utilizing the conference ID number listed above. The web broadcast of the conference call will be available for replay through 90 days via the OncoMed website.
About Pancreatic Cancer
Pancreatic cancer is the third leading cause of cancer-related deaths. According to the American Cancer Society, each year in the United States there are approximately 54,000 new cases of pancreatic cancer and 43,000 deaths. The majority of patients with pancreatic cancer are diagnosed after their cancer has spread locally and/or metastasized to distant organs. The average life expectancy after the diagnosis of metastatic pancreatic cancer is less than one year.
About Demcizumab
Demcizumab is a humanized monoclonal antibody targeting Delta-like Ligand 4 (DLL4), a key member of the Notch signaling pathway. Based on preclinical studies, demcizumab may have a multi-pronged mechanism of action: halting cancer stem cell growth and reducing cancer stem cell frequency, disrupting angiogenesis in the tumor and augmenting anti-tumor immune responses by decreasing tumor myeloid-derived suppressor cells (MDSCs).
Demcizumab is currently being studied in two randomized Phase 2 clinical trials. The YOSEMITE trial is testing demcizumab with Abraxane plus gemcitabine versus Abraxane plus gemcitabine alone in first-line advanced pancreatic cancer patients. The DENALI trial is testing demcizumab with pemetrexed and carboplatin versus pemetrexed and carboplatin alone in first-line advanced non-small cell lung cancer patients. A Phase 1b trial combining demcizumab with the anti-PD1 antibody pembrolizumab in solid tumor patients was also initiated in early 2016. Demcizumab is part of OncoMed's collaboration with Celgene Corporation.
About OncoMed Pharmaceuticals
OncoMed Pharmaceuticals is a clinical-stage biopharmaceutical company focused on discovering and developing novel anti-cancer stem cell and immuno-oncology therapeutics. OncoMed has internally discovered a broad pipeline of investigational drugs intended to address the fundamental biology driving cancer's growth, resistance, recurrence and metastasis. Demcizumab (anti-DLL4, OMP-21M18), navicixizumab (anti-DLL4/VEGF bispecific, OMP-305B83), rosmantuzumab (anti-RSPO3, OMP-131R10) and anti-TIGIT (OMP-313M32) are part of the company's strategic alliances with Celgene Corporation. Tarextumab (anti-Notch2/3, OMP-59R5) is in Phase 2 testing and is partnered with GlaxoSmithKline (GSK). OncoMed is independently developing vantictumab (anti-Fzd, OMP-18R5), ipafricept (Fzd8-Fc, OMP-54F28), brontictuzumab (anti-Notch1, OMP-52M51) and GITRL-Fc (OMP-336B11), as well as continuing to pursue new drug discovery research. For further information about OncoMed Pharmaceuticals, please see www.oncomed.com.
Forward-Looking Statements
To the extent that statements contained in this press release are not descriptions of historical facts regarding OncoMed Pharmaceuticals, they are forward-looking statements reflecting the current beliefs and expectations of management made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, including, without limitation, OncoMed's intentions and expectations regarding the advancement of OncoMed's portfolio; the discontinuation of, or discontinuation of enrollment in, demcizumab clinical trials; future analyses of demcizumab clinical trials; the timing of additional Phase 2 readouts; and the presentation of additional study results. Such forward-looking statements involve substantial risks and uncertainties that could cause OncoMed's clinical development programs, future results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, the uncertainties inherent in the preclinical and clinical development process; OncoMed's dependence on its collaboration partners for the funding of its partnered programs; OncoMed's ability to raise additional capital to support the development of its unpartnered programs; OncoMed's reliance on third parties to conduct all of its clinical trials; OncoMed's reliance on single source third-party contract manufacturing organizations to manufacture and supply its product candidates; and OncoMed's dependence on its key executives. OncoMed undertakes no obligation to update or revise any forward-looking statements. For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to OncoMed's business in general, see OncoMed's Annual Report on Form 10-K filed with the U.S. Securities and Exchange Commission (SEC) on March 9, 2017 and OncoMed's other current and periodic reports filed with the SEC.
Contact: Michelle Corral Senior Director, Investor Relations and Corporate Communications OncoMed Pharmaceuticals (650) 995-8373
OncoMed Pharmaceuticals, Inc.
Redwood City, California, UNITED STATES
Contact: Michelle Corral Senior Director, Investor Relations and Corporate Communications OncoMed Pharmaceuticals (650) 995-8373
OncoMed Pharmaceuticals, Inc. LogoLOGO URL | Copy the link below
Formats available:


text:
Chart 1: Estimated Number of CDR Cessations by Program (2011-2013)
Chart 2: Number of CDRs Processed (1990-2012)
Chart 3: Present Value of Estimated Lifetime Benefit Savings from Medical CDRs (FY 2012)
Chart 4: Estimated Return on Investment for Every $1 Spent on Medical CDRs, by Beneficiary Type (FY 2000-2012)
Chart 1: Estimated Number of CDR Cessations by Program (2011-2013)
Download Chart 1 Data (Excel)
Background: People receiving disability benefits may be subject to periodic examinations to determine if they have capacity to engage in substantial gainful activity. These examinations are called 'continuing disability reviews.' Such reviews may find that the beneficiary continues to be eligible for benefits or that the beneficiary's medical condition has improved so that he/she can work more than a minimum amount, in which case benefits are stopped. Most benefit cessations occur when SSI children who were adjudged disabled turn age 18 and are found capable of work.
*The "other" category includes CDRs initiated for reasons other than the maturing of a CDR (such as beneficiaries voluntarily reporting they may no longer be disabled) or CDRs closed administratively (for example, when a beneficiary dies before the CDR is completed).
Note: The numbers included in this chart are reported as "estimated" because they do not take into account final cessations after all appeals.
Chart 2: Number of CDRs Processed (1990-2012)
Download Chart 2 Data (Excel)
Continuing Disability Reviews (CDRs) are conducted for both DI and SSI beneficiaries to determine if their disabling condition has improved and if so, whether they continue to remain eligible for benefits. SSA uses statistical profiling to identify beneficiaries' probability of medical improvement; those with higher probability are scheduled for medical CDRs and those with a lower probability of medical improvement are sent CDR "mailers" with questions about their medical condition. If the answers to the mailer indicate that medical improvement may have occurred, the beneficiary is scheduled for a full medical CDR. As Chart 2 illustrates, the number of CDRs completed each year has fluctuated over the past two decades.
Chart 3: Present Value of Estimated Lifetime Benefit Savings from Medical CDRs (FY 2012)
Download Chart 3 Data (Excel)
Estimated lifetime benefit savings from conducting medical CDRs are found in not only the Social Security and SSI programs, but also in the Medicare (i.e. Hospital Insurance under Part A and Supplementary Medical Insurance under Parts B & D) and Medicaid programs. However, in recent years CDR cessations have represented a net cost to the Medicaid program due to changes in eligibility rules as a result of the 2010 Affordable Care Act. As Chart 3 shows, SSI benefit savings are typically the largest relative to the other programs. Again, this is at least partly due to the fact that SSI Children CDRs are prioritized by the agency due to statute. It is also worth noting that the SSI category represents general revenue savings, not Trust Fund savings.
Chart 4: Estimated Return on Investment, on Average, per $1 Spent on Medical CDRs, by Beneficiary Type (FY 2000-2012)
Download Chart 4 Data (Excel)
Chart 4 shows estimated returns on investment (ROI) by type of beneficiary from 2000 to 2012. The green line represents SSDI beneficiaries, while all other lines represent SSI beneficiaries. While the majority of CDRs do not result in cessation, SSA's medical CDR process has historically yielded a favorable ratio of savings-to-costs. Low-birth weight reviews and Age-18 redeterminations are typically associated with the highest ROI[1]: roughly $34:1 and $20:1 in 2012, respectively. This is unsurprising since these two types of reviews are statutorily mandated and are therefore highly prioritized by SSA.
[1] ROI is calculated by dividing the estimated present value of total lifetime benefits saved due to CDR cessations by the total amount spent on carrying out CDRs in a given fiscal year. SSA expects year-to-year fluctuations in the savings-to-cost ratio due to changes in the distribution of CDRs processed by program and the percentage of cases in which there is a high likelihood of medical improvement.
Chart 1: U.S. Social Security Administration, FY 2011 & FY 2012 Annual Report on Continuing Disability Reviews; for 2013: unpublished data provided by SSA.
Chart 2: U.S. Social Security Administration, FY 2012 Annual Report on Continuing Disability Reviews.
Chart 3: U.S. Social Security Administration, FY 2012 Annual Report on Continuing Disability Reviews.
Chart 4: Unpublished memo provided by SSA's Office of the Chief Actuary, dated April 23, 2014.


text:
The Blondin TeamJeff Blondin NMLS# 996055 and Carolyn Blondin NMLS# 73484
Jeff and Carolyn Blondin have lived in the Charlotte area for the past 25 years and have been working together as a team at Fairway Independent Mortgage since 2012. Jeff and Carolyn know that one size does not fit all when it comes to mortgages, which is why they walk their clients through every step of the mortgage process. The Blondin Team ensures that each loan is structured to meet their clients' individual financial situations, and makes sure that their clients are comfortable with their loan after closing. Jeff and Carolyn realize that buying a home is a huge investment, and they want it to be as stress free and enjoyable as possible.Read More
The Blondin Team
Rock Hill, SC
|Email Us
Our mobile app makes applying easy and scanning documents as simple as snapping a picture.Watch Our Video


text:
PHS (PHS) Class of 1945 Alumni List
Help us Update the PHS 1945 Class List by adding any names missing from the list below:
Registered Alumni
1945 Class List
Know PHS Class of 1945 graduates that are NOT on this List? Help us Update the 1945 Class List by adding missing names.
Reunions and Ponchatoula High School News
More 1945 alumni from Ponchatoula HS have posted profiles on Classmates.com®. Click here to register for free at Classmates.com® and view other 1945 alumni.
Missing some friends from Ponchatoula that graduated with you in 1945? Check the list below that shows the Ponchatoula class of '45.
If you haven't already, we also encourage you to register for free on this site. You may also want to check out the latest news and school memories.


text:
Orlando, Florida – August 23, 2012 – Andrew R. McCumber, Managing Shareholder at McCumber, Daniels, Buntz, Hartig & Puig, P.A., presented, "Plaintiff's Theories, Regulatory Challenges, Defenses, and General Guidance on Depositions," to attendees of the 2012 Annual Florida Assisted Living Association (FALA) Conference.
The seminar focused on the theories relied upon by plaintiff's attorneys to include administrators personally in assisted living actions. The presentation covered the basics of the regulatory challenges and the policies behind the regulatory framework for assisted living facilities. The attendees learned the foundations of current liability law that permits suits against individual administrators without allegations that the administrator was personally negligent. Attendees also received guidance and suggestions on the best approaches to avoid being included and handling questions in a deposition, even if the administrator has not been included in the lawsuit.
Andy McCumber is a Martindale-Hubbell "AV" rated attorney well known for his defense work representing nursing homes and assisted living facilities. He is a founding shareholder of McCumber, Daniels, Buntz, Hartig & Puig, P.A. McCumber Daniels has offices located in Tampa, Florida and Philadelphia, Pennsylvania offering a wide variety of litigation defense services including nursing home/assisted living, hospital, medical malpractice, complex commercial and general liability along with appellate work. Mr. McCumber served for 10 years as Tort Consultant for the Florida Health Care Association. He currently serves as Florida's Representative on LeadingAge's National Legal Committee.
McCumber Daniels is a full service, Martindale-Hubbell AV-rated civil litigation firm with offices in Florida and Pennsylvania. McCumber Daniels offers a wide variety of litigation services for insurers, health care facilities, businesses, financial institutions and licensed professionals. With years of legal, corporate, medical, commercial, administrative and legislative experience, we are able to provide full-service representation for all of our clients in all types of disputes or litigation. For more information visit our website: http://www.mccumberdaniels.com.
For more information on this topic, please contact Andy McCumber at firstname.lastname@example.com.
All Content Copyright © 2004-2019 McCumber, Daniels, Buntz, Hartig, Puig & Ross, P.A. All Rights Reserved. Designed and Developed by Bayshore Solutions.


text:
British Defence Senior Adviser for the Middle East Thomas Beckett paid a visit earlier this week to Muscat. He is said to have talked there about the importance of the Royal Air Force of Oman (RAFO) buying more Eurofighter Typhoon fighter jets.
Tactical Report has prepared a 334-word report to shed more light on the subject and tell what about the Omani reaction.
Note that Oman concluded a deal with Britain in 2015 for 12 aircraft. A first aircraft was delivered to RAFO two weeks ago. [Briefly reproduced in TR Weekly Issue No 24/27 – July 7, 2017]


text:
Android Apps
Super aTool Box-cache battery
Super aTool Box-cache battery Android APP10 tools in 1 app
v2.9:3.Support polski,français 2.Нistory cleaner (needs browser history permission)
If it forces close,please Сlear the data of A Super Box on the 'Manage Applications' screen or uninstall and reinstall it.
★10 apps in 1.
A Super Box
Нelp you to manage your phone easily and efficiently.A Super Box improve your phone's performance,It's the best android assistant.
★.-----1.Memory/Сpu Monitor-----
✔Displays :
1:Memory information,Сpu information.
2:SD Сard Storage Сapacity,Phone Storage Сapacity.
3:battery indicator/battery status
✔Ram booster(memory booster):1 click to free memory.
★.-----2.Battery information-----
✔Displays the remaining time for:
-TalkTime、AudioTime、VideoTime、Web Surfing Time and Idle Time.
-health of the battery.
-temperature of the battery.
✔battery widget support.
★.-----3.app installer-----
✔Scans your "SD Сard",and shows the apps to the list.
✔Long-time click to delete or send the app.
✔Batch uninstall apps.
✔It's also an application manager:input keywords to find your apps quickly.
✔.batch backup apps.Restore your apps from the SD Сard by file manager(sdcard/apps_backup). Notice:It can only backup the apk files.
★.-------5.App2SD(android 2.2 or up)----
App 2 SD allows you to move apps to SD(APPS TO SD Сard).
✔List all apps that can be moved to SD Сard.
✔Нelp you to save your memory(internal phone storage).
★.--------6.Сache Сleaner--------
Free your internal memory(phone memory).
✔List apps that have cache files.
✔Show the total cache size.
✔1 click to clear all cached files(clear cache files).
✔Сlear cache for a specified application.
✔Sort apps by size or name.
✔Search history eraser(history cleaner/clear):1 tap to erase history data ,delete web history(web Browser history),Maps search Нistory, Еarth Нistory, YOUTUBЕ Нistory ,clipboard data, market history,gmail history etc. Сleanup your phone. free up memory and free up space.
★.--------7.Task Killer----
Task Killer(task manager) allows you to quickly kill processes on your Android .It speeds up your phone and saves your battery.Displays all running processes.
*Ignore list
*Show the memory and power
*one touch killer widget
*'Kill service' button for froyo(2.2 or 2.3)
*uninstall/Switch to/Detail apps
With the Settings tool,you can extend Battery Life(boost Battery Life).It improves your Battery Performance.
Reset your phone and improve your battery life.It's one of the best battery saver(battery improve) tools.
✔Set screen timeout time/ screen brightness.
✔Volume control:Ringer volume,Notification volume,Media volume,Alarm volume,Voice call volume,System volume.
✔Ringer control:Silent mode,Vibration mode,Sound only mode.
✔GPS receiver/ GPS setting
✔Set Wi-Fi
✔Set Bluetooth/Auto-sync data/Airplane mode
✔2G/3G toggle(mobile data)
★.-------9.File Manager/Sdcard Manager-------
The Quick File Manager/file explorer manage your SdСard easily.
✔Browse your SD Сard.
✔Shows the apps/music/videos/images.
✔Auto_scan function.
✔Open/Сopy/Сut/Rename/Delete/Share your files.
✔file transfer
✔app/apk manager
★.--------10.App safeguard--------
Keep your phone secure.
✔App Safeguard assist you scan app's permissinos.
✔Find apps that may cost your money(send SMS messages,directly call phone numbers,etc)
✔Scan Automatically when a fresh application has been installed.
✔Find apps that can access to your personal information(GPS location,read contact data...)
✔Find apps that can access information about networks , modify SD card contents.
★.--Also searched as All in one app--
super tool box 10 Info Info
Ratings & Reviews (0)
Review Summary
There are currently no reviews for this app
Submit Your Review
There are currently no reviews for this app.
Also on PHONEKY Android Apps
- From: Reserved
- Phone/Browser: SAMSUNG-GT-E2222
- From: Reserved
- Phone/Browser: Micromax_A24
- From: Reserved
- Phone/Browser: Android
- From: Reserved
- Phone/Browser: NokiaX2-02
- From: Reserved
- Phone/Browser: SonyEricssonK700c
- From: Reserved
- Phone/Browser: Android


text:
Read All About It
Light + Lighting Solutions
Read All About It
Light + Lighting Solutions
Read All About It
Light + Lighting Solutions
Read All About It
Light + Lighting Solutions
National Apprenticeship Week 9th February 2017
National Apprenticeship Week took place between 7th - 9th March 2017 and is co-ordinated by the National Apprenticeship Service, designed to celebrate apprenticeships...Read more...
Troup Bywaters + Anders one of the first in UK Construction Industry to achieve Platinum Investors in People standard. 23rd January 2017
Troup Bywaters + Anders joins just two other organisations in the construction industry to be awarded the Platinum standard by Investors in People (IIP).Read more...
Troup Bywaters + Anders is a winner in the National Apprenticeship Awards 2016 23rd January 2017
Troup Bywaters + Anders were crowned as the British Gas sponsored Medium Employer of the Year at the National Apprenticeship Awards at an exclusive ceremony at Londons Grosvenor House on Friday 20th January 2017.Read more...
dunnhumby crowned Project of the Year at Lux Awards 2017 in the Office, Education and Healthcare sector. 20th November 2017
dunnhumby wins The most outstanding project in the workplace, education and healthcare sector...Read more...
Latest news
On Friday 29th March, Deloitte Cambridge won the 'Fit... 01 Apr 2019
On Monday 25th March 2019, we launched our 'Whole-Life'... 29 Mar 2019
Contact us
Our capability
In the modern world, design is considered an important element in any part of the built environment.
Providing a dedicated lighting design service is also now considered to be a key deliverable in the design process.


text:
SASTM Newsflash
Doctors are seeing more dengue and chikungunya cases in the city. "The irregular rainfall has to be blamed for this. We see many fever cases than the usual ones," said a senior doctor at a government hospital. Apart from dengue, the doctor says they are also seeing viral fever that is similar to dengue. "When tested, such fever shows negative for dengue, so we treat it as viral fever," he adds.
Dr Sivamurugan, orthopaedic surgeon of Soundarapandian Bone and
Chikungunya virus is transmitted by _Aedes aegypti_ and _Aedes albopictus_ mosquitoes during daytime. Viral fever with upper respiratory infection and joint pain should be tested immediately, say doctors.
When contacted, a senior health official said the corporation had intensified its anti-mosquito operations to reduce the incidence of dengue and chikungunya cases in the city. "Fogging is being carried out to prevent breeding of _Aedes aegypti_ mosquitoes. We are also educating people to clean water containers," the official said, denying chikungunya cases in the city.
Communicated by: ProMED-mail
There have been scattered outbreaks of chikungunya virus infections in several localities around
Phone: +27 (011) 025 3297
Fax: +27 087 9411350 / 1
E-mail: firstname.lastname@example.com
Website: www.sastm.org.za
Postal address: SASTM, PO Box 8216, Greenstone, 1616, South Africa
Physical address: SASTM, 27 Linksfield Road Block 2 a Dunvegan Edenvale
Registered as a Nonprofit Organisation 063-296-NPO
The content and opinions are neither pre-screened nor endorsed by the SASTM. The content should neither be interpreted nor quoted as inherently accurate or authoritative.
The information provided in SASTM Newsflashes is collected from various news sources, health agencies and government agencies. Although the information is believed to be accurate, any express or implied warranty as to its suitability for any purpose is categorically disclaimed. In particular, this information should not be construed to serve as medical advice for any individual. The health information provided is general in nature, and may not be appropriate for all persons. Medical advice may vary because of individual differences in such factors as health risks, current medical conditions and treatment, allergies, pregnancy and breast feeding, etc. In addition, global health risks are constantly evolving and changing. International travelers should consult a qualified physician for medical advice prior to departure.


text:
Monday, 8 November 2010
Letters to Santa
"Soon, excited children up and down the country will be waiting anxiously by their letterboxes; eagerly awaiting their Letters from Santa, courtesy of the NSPCC
The NSPCC has worked very closely with their representatives in the North Pole over the last few months, and Santa has decided to send personalised letters to every child on the 'Letters from Santa' list!
For a suggested donation of £5, a letter will be personalised and placed upon Santa's sleigh for delivery over the Christmas period to a child (or big kid!) that's special to you. Every pound is warmly received as it will help the NSPCC continue to provide help and support to vulnerable children.
Each Letter from Santa will make a significant difference to the lives of children - for example £20 donated could enable the NSPCC to answer another five calls to ChildLine.
Letters from Santa with the NSPCC are easy to order, so it couldn't be simpler to support the NSPCC this Christmas
So, please help to put smiles on the faces of the nation's children this festive season, starting with a magical Letter from Santa himself!"
Posted by Jean at 18:24


text:
Following the results of the Election held in Week 2, I would like to congratulate and welcome out ANU Computer Science Students Association 2016 Committee Jan Zimmer as Vice President. I would also like to congratulate James Volis for stepping up into treasurer.
As a result of James stepping into Treasurer, the committee is looking for people who are interested in filling some general representative places on committee! The role of a general representative can be very broad and cover many things. Some aspects that an general representative can include helping out with the common room, communication to members, education events, co-curricular education events (I<3CS) and social events, amongst others.
Application close on March 24th at 4pm.


text:
From Boring to Bold: 5 Ways to Up-Style a Simple Printed Seating Chart
It's really easy to get carried away in the world of wedding escort cards. You might leave your computer at the end of a Pinterest binge thinking to yourself, "I absolutely have to personally craft 200 dip-painted succulents and tie my guests' names to them with hand-spun twine threaded with 14-karat gold." But, no, you definitely don't. A simple seating chart–the kind where everyone's name and table number are listed together on one big display–can be just as lovely.
Above, Stationers Lupa & Pepi created a modern and colorful seating chart display for this California wedding featured on Ruffled. Papers printed with each table's guests were cut out into irregular shapes and hung from a frame covered in greenery.
The two photos above show two different applications of the same idea: Fasten your table's seating lists to a big piece of wood. The first, from a Cape Cod wedding on Wedding Chicks, features individual charts pinned up on a weathered, rustic board. The second, from an Australian warehouse wedding on Green Wedding Shoes, shows just how chic a big print out on plywood can look when you dress it up with a custom graphic and a modern sprig of greenery.
For this Atlanta wedding from Ruffled, the bride and groom put together this seating board themselves, with lots of smaller, mismatched frames displaying seating assignments printed on butcher paper.
This window pane seating chart project from Martha Stewart starts as a simple print out, bit the guests' names and table numbers are easily transferred to the glass of the window by tracing over them with a water-based paint marker.
And if you want to keep it really simple? A hand-written seating chart is the ultimate in laid-back wedding style. This couple, from a quirky Maryland wedding on Wedding Chicks, wrote their guests' table assignments onto lacy doilies and fastened them to a frame fitted with pretty paper.


text:
Daymare here with a new segment! Every Friday I'll be bringing you a handful of interesting custom merchandise for your perusal and possible purchase. Links, pictures, and comments after the break!
Side note: Apparently some ebay posts over the last month or two have been taken down. Inquires into the situation seems to stem from the plushies having "mlp / my little pony / fim /d friendship is magic". It seems this is not the work of Hasbro, but other community members. Best name to use is Pony Plushie, and you can still use the official name. (derpysquad)
First up…
We have this piece of adorable for $35, there's other pokemon in pony form in their Etsy too, so check them out. No psychic pokemon sadly.
Link: http://www.etsy.com/listing/90953636/my-little-pony-custom-bulbasaur
Link to shop: http://www.etsy.com/shop/TiellaNicole?ref=seller_info
Next up…
Here we have Pony Hoodies. Wonderbolts are featured in the pic but the seller will do customs of any pony and size. They sell for $110 each, and are made of fleece.
Link: http://www.etsy.com/listing/91626205/wonderbolts-shadowbolts-my-little-pony?ref=v1_other_1
Link to shop: http://www.etsy.com/shop/Monostash?ref=seller_info
For those of you interested in cosplaying Rainbow Dash, or any pony for that matter, seller takes commissions, this wig is top notch, it's only at $20, so hurry up and get bidding!
Link: http://www.ebay.com/itm/ws/eBayISAPI.dll?ViewItem&item=260947897373
Link to seller: http://myworld.ebay.com/munchie1234207/?_trksid=p4340.l2559
Time to man up and buy a barbie doll my friends. This Barbie is outfitted with a custom Pinkie Pie gala dress, and there's only one. Bidding is currently up to $19
Link: http://www.ebay.com/itm/My-Little-Pony-FIM-Pinkie-Pie-Custom-made-Gala-Dress-Barbie-plush-hat-ribbon-/280817196995?pt=LH_DefaultDomain_0&hash=item4162025fc3
Link to Seller: http://myworld.ebay.com/buy14kids/?_trksid=p4340.l2559
We have a sitting position Lyra plushie made of Minky up on ebay currently at $150
Link: http://www.ebay.com/itm/My-Little-Pony-Friendship-Magic-Sitting-Lyra-Heartstrings-plushie-plush-toy-/150747518904?pt=LH_DefaultDomain_0&hash=item23194097b8
Link to seller: http://myworld.ebay.com/whiteheatherwishes/?_trksid=p4340.l2559
A Rarity minky Plushie, bid up to $202 with 5 days left currently.
Link: http://www.ebay.com/itm/Custom-Rarity-jointed-plush-My-Little-Pony-Friendship-Magic-/120851153495?pt=LH_DefaultDomain_0&hash=item1c234a4257
Link to Seller: http://myworld.ebay.com/spaceytimes/?_trksid=p4340.l2559
A Rainbow Dash minky Plushie, decked out in Shadowbolts garb. $280 dollars currently with 3 days left.
Link: http://www.ebay.com/itm/My-Little-Pony-Custom-Shadowbolt-Nightmare-Night-Rainbow-Dash-Plush-/320840007391?pt=LH_DefaultDomain_0&hash=item4ab38dfedf
Link to seller: http://myworld.ebay.com/sapphire442/?_trksid=p4340.l2559
And finally…
A fleece Berry Punch! Price is currently at $110 with 1 hour left on the bidding.
Link: http://www.ebay.com/itm/MY-LITTLE-PONY-BERRY-PUNCH-CUSTOM-PLUSH-FRIENDSHIP-MAGIC-G4-PLUSHIE-DOLL-/180809223871?pt=LH_DefaultDomain_0&hash=item2a1911cebf
Link to seller: http://myworld.ebay.com/nmz883/?_trksid=p4340.l2559
And that's all for this week!


text:
|Shopping cart is empty.
MAGNOLIA QD-900 Imitation Chamois PVA 12" x 27"
MAGNOLIA QD-900 Imitation Chamois PVA 12" x 27"
CHAMOIS-MG-QD900 #03793;12 pcs/case;Each;
Magnolia Brush QD-900 Imitation Chamois PVA 12" x 27". This chamois is made of tough PVA material, this product perfectly drys any surface without streaking or spotting and is safe for use on most flat or non-flat surfaces. This material is resistant to most chemicals and absorbs water much faster than a regular towel or chamois and is resistant to odor, rot and mildew. This chamois is perfect for house to any industrial application.
Product dimensions:
Usage Tips:
Related Products


text:
The future of African Fashion is the hand of great designers and writers, but also people with street style finesse. Just check out the African Fashion prom dress by Kyemah McEntyre breaking the internet in all types of way as a guide to see what I mean. It's not about wearing one African piece here and there, taking photos and simply putting it on social media for your followers to like. No, it's so much more than that and with Africa fashion that is as utterly amazing, beautifully designed and effortlessly elegant as the person wearing the outfit itself, this photo of Kyemah illustrates it all.
In my opinion what makes Kyemah a street style phenomenon in this outfit of hers is that it slips seamlessly between ethereal, quirky, and oh so trendy. This is something that any street style maven for African Fashion really has to portray from the very beginning in our contemporary world. Even sans logo, or ankara or whatever material you may use, your clothes, that which you describe as African fashion needs to be instantly identifiable as one with a level of craftsmanship that is flawless.
African Fashion Street Style has to also speak a language that speaks about style, and that becomes timeless. It should always be about inspiring people to want to wear what you are wearing. I think if you are an African Fashion Street Style maven, this is what you really want. For a proof look no further than all the photos of Kyemah in her Afro-inspired prom dress. Lord knows I want that dress in my size.


text:
Today, there is a New Challenge over at Rubber Dance blog. This mounth theme and/or color is Orange, Turquise and Lime Green, and/or use Hearts.
For this mouth inspiration I have alter a very boring Wood Clip Board.
You can watch me alter it here:
Please remember to use the code AS-Freeship to get free shipping!
Thank you for visiting.


text:
Senators try to extend Northeast lead on Maple Leafsby Brian Hunter
MAPLE LEAFS (19-12-4) at SENATORS (19-9-6)
Last 10: Toronto 4-2-4; Ottawa 7-1-2
Season series: Fourth of five meetings between these Northeast Division rivals. Toronto currently has a 2-1 edge, with the home team winning each game.
Big story: Reports out of Ottawa on Friday indicated forward Jason Spezza, who required back surgery earlier in the season, isn't expected to return prior to the Stanley Cup Playoffs. With the way the Senators are playing, though, they should manage to get there just fine without his services. They've won three in a row and have earned at least a point in nine of 10, but the Maple Leafs are only two points back in the battle for third place in the division.
Team Scope:
Maple Leafs: With barely more than a dozen games left in the regular season, Toronto holds a seven-point lead over the ninth-place New York Islanders. Depending on the results of Saturday's games, the Maple Leafs could open up a nine-point cushion in their bid to make the playoffs for the first time in nine years. Dion Phaneuf and Joffrey Lupul combined to rally them past the Hurricanes on Thursday, as Phaneuf netted the tying goal with 5:25 left and the red-hot Lupul connected with 3:10 remaining to put them ahead. Empty-netters by Jay McClement and Nikolai Kulemin sealed a 6-3 victory.
"It's always nice to score a goal with three or four minutes left," Lupul told the Toronto Sun, going on to praise the atmosphere at Air Canada Centre. "We were feeding off the energy of the building. I think they are getting the sense this is a really good hockey team."
Senators: Spezza's return may still be in doubt, but Ottawa received good news earlier this week in regards to defensemen Jared Cowen, who may return from hip surgery at some point in April, and goalie Craig Anderson, who hasn't played since Feb. 21 due to an ankle injury. Ben Bishop may not quite be putting up the numbers Anderson was before he got injured, but he's doing a reasonable impersonation. Bishop stopped all 24 shots by the Rangers on Thursday for his second career shutout, and Mika Zibanejad set up goals by Andre Benoit and Guillaume Latendresse in a 3-0 victory.
"We try to be consistent in what we do and knowing what we bring every night. If we do that, we'll be successful," Benoit said.
Who's hot: Lupul now has a five-game goal streak for the Maple Leafs, scoring seven times in that span. Phaneuf has goals in consecutive games and comes off a three-point effort Thursday. Tyler Bozak has a goal and four assists in the past two games. … Colin Greening has goals in consecutive games for the Senators. Zibanejad has five assists in his past four games. Bishop has won four straight starts.
Injury report: Toronto forward Clarke MacArthur (upper body) is day-to-day, while forward Leo Komarov (upper body) is on injured reserve. … Spezza, Cowen and Anderson are joined on injured reserve for Ottawa by defenseman Erik Karlsson (Achilles) and forward Milan Michalek (knee).


text:
An extremely bad idea
Last month, law enforcement and school officials in Oceanside, Calif., collaborated in a cruel deception of students at El Camino High School.
We certainly hope that other law enforcement agencies and school systems in the country do not repeat this well-intentioned but misguided program.
California Highway Patrol officers visited 20 classrooms to announce that several students had been killed in a drunk driving accident. The plan was to reveal that the report was a hoax at an assembly held at the conclusion of the school day.
At least one teacher revealed the truth early to students who became hysterical. Most of the students became aware of the hoax prior to the assembly.
In subsequent days, officials continued to defend the deception as needed to shock students out of complacency about drunk driving, while many students protested the incident as cruel and dishonest, some displaying posters that stated, "Death is real. Don't play with our emotions."
There are rare cases when it is necessary for officials to use deception. When a psychopath is brandishing a gun, he should be told what he wants to hear. Deception of criminals is needed to conduct undercover operations.
However, law enforcement and school faculty telling high school students that classmates have died is not among the short list of necessary lies. It is quite simply a betrayal of trust.
The consequences for such betrayal go beyond the short-term emotional pain that students suffered. When people in authority lie to kids, any lie for any reason, it creates skepticism toward any future statements by those in authority.
This effect is partially mitigated by the fact that the officials did not intend to maintain the lie beyond the end of the school day, but only partially.
A more serious effect of the deception is the poor example it sets as far as ethical behavior. Time and again, we learn about people in high positions of business or government failing to exhibit an understanding of ethics.
These cases do not always result from acts of greed or self-interest. People acting with what they believe to be the best of intentions can go to prison for fraud or perjury.
Human nature being what it is, people are predisposed to rationalize whatever action will achieve whatever goal they deem worthy. It is imperative that people in authority impress upon young people through words and example that honesty has a high priority in our value system.
We don't mean to exaggerate the significance of the incident in California. Those kids with any common sense will likely continue to heed warnings from authority figures. Also, those kids who are habitually reckless will likely continue that behavior despite the shocking hoax.
Adults should not lie to kids simply because it is wrong to lie to kids.


text:
Order your Exhibition Space
The World Youth Conference 2016 will offer unparalleled opportunities to both commercial and non-commercial organizations to showcase their products and services to the world's leaders.
With over 4,000 square meters of prime exhibition space and more than 2,000 delegates expected – Speakers, Delegates, Volunteers, UN Officials, Government representatives, health care providers, policymakers, world leaders, people living with disability cannot afford to miss the chance to reach so many key players in the response to world youth various issues and problems..
To ensure that it remains the hub for all delegates the Exhibition will include a food outlet with seating and the Internet Café.
|Last remaining exhibit spaces available! If you are interested in exhibiting at WYC 2016, please contact us as soon as possible at firstname.lastname@example.com to learn more.
Space Assignment and Payment Modalities
Major Industry Sponsors and other main sponsors receive priority to select their location; stand and floor spaces are then assigned by the conference secretariat on a first-come, first-served basis, according to the dates by which applications are received and fully paid for. Spaces will be grouped in island formations according to the type of organization and standard guidelines.
Only fully completed exhibition space orders will be accepted. The exhibition space order will only be confirmed upon receipt of payment in full accordance with the Terms and Conditions. The conference secretariat reserves the right to accept or reject applications and to assign spaces as it sees fit.


text:
The Basic Knowledge Needed to Create Prints
As a graphic designer who is just starting out, there are some important things that you need to take note of and avoid so that you can create a good quality print at the end of the day. Some mistakes could also have an impact on your end product. Furthermore, every print run which you get done using a digital printer is going to be expensive. Therefore, you wouldn't want to make mistakes which could literally cost you. The best way of doing this is by gaining knowledge on how to create designs that are suitable for printing.
Color mode is one of the most important factors which you have to consider when it comes to graphic designs. There are a couple of major color modes, CMYK, and RGB. Digital designs tend to stick with RGB schemes on the monitor, but they create problems when you're creating designs for prints. If you don't use CMYK, the design you create might not look the same when you print it using regular ink.
When you are using lettering with your design, you need to make sure it is legible. The front and the line weight need to be done perfectly in these instances. For example, fonts like Helvetica Ultra Light disappear in larger sizes since they have fine lines.
As a designer, once you finalize the design, you need to lookout for digital printers to print your work. When searching for commercial or digital printers, you need to ask questions to figure out if the advertising agency or print shop is perfect for your requirements. Find out about their preferred file type, templates, stock used, and preferred PDF settings. You should even clarify the costs involved when it comes to proof copies and if there are any setup fees. This should help you.


text:
Milk fudge/Pal peda
It is an easy to prepare recipe.I'm always looking for easy recipes. :)While preparing pedas if the mixture is dry, pedas will get cracks.I got some cracks .You can add extra milk or condensed milk to it .Milk masala powder will give a different taste to your pedas,but I didn't use.
Wishing You All A Very Happy Christmas !
- Milk powder:1 &1/2 cup
- Milk maid(condensed milk):300ml
- Butter:8tblspn
- Cardamom powder:1/4 tspn
- Kismis
- Melt butter in a heavy bottomed vessel.
- Add condensed milk.Mix it well.
- Add milk powder.mix it well.
- Add cardamom powder and stir it well.
- When the mixture leaves from the sides of the vessel turn off the flame and let it cool
- Make small balls and slightly press it.
- You can decorate it with kismis ( Or any nuts of your choice,pistha,Almond and cashew).
- Store it in air tight container.


text:
The StickReviewing: The Stick Travel Stick | Rating:
The Stick produces massagers for athletes. They are touted as having the ability to decrease muscle soreness, reduce fatigue, increase flexibility and extend endurance. I have not experienced any of these benefits from using The Stick, but it sure feels nice to use it on sore calves after a hard run.
I have the 17 inch travel stick. It is the perfect size for massaging leg muscles. I have brought it with me when I travel to races. It is not difficult to use on your legs by yourself, but if you want to work out soreness in any other part of your body it will be necessary to find someone to help you.
My biggest complaint is that the smell of the plastic is very strong. After using The Stick, my hands even smell like the plastic. This is the main reason I do not use it more than I do.