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Myeloid malignant diseases comprise chronic (including myelodysplastic syndromes, myeloproliferative neoplasms and chronic myelomonocytic leukemia) and acute (acute myeloid leukemia) stages. They are clonal diseases arising in hematopoietic stem or progenitor cells. Mutations responsible for these diseases occur in several genes whose encoded proteins belong principally to five classes: signaling pathways proteins (e.g. CBL, FLT3, JAK2, RAS), transcription factors (e.g. CEBPA, ETV6, RUNX1), epigenetic regulators (e.g. ASXL1, DNMT3A, EZH2, IDH1, IDH2, SUZ12, TET2, UTX), tumor suppressors (e.g. TP53), and components of the spliceosome (e.g. SF3B1, SRSF2). Large-scale sequencing efforts will soon lead to the establishment of a comprehensive repertoire of these mutations, allowing for a better definition and classification of myeloid malignancies, the identification of new prognostic markers and therapeutic targets, and the development of novel therapies. Given the importance of epigenetic deregulation in myeloid diseases, the use of drugs targeting epigenetic regulators appears as a most promising therapeutic approach.
Myeloid malignancies are clonal diseases of hematopoietic stem or progenitor cells. They result from genetic and epigenetic alterations that perturb key processes such as self-renewal, proliferation and differentiation. They comprise chronic stages such as myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) and acute stages, i.e acute myeloid leukemia (AML). AML can occur de novo (~80% of the cases) or follow a chronic stage (secondary AML). According to the karyotype, AMLs can be subdivided into AML with favorable, intermediate or unfavorable cytogenetic risk [1]. MPNs comprise a variety of disorders such as chronic myeloid leukemia (CML) and non-CML MPNs such as polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF).
Molecular biology has always been important in hematology, especially myeloid malignant diseases. Currently however, except in some specific examples such as the BCR-ABL1 fusion in CML, and NPM1 or FLT3 mutations in de novo AML, molecular data are not associated with optimal clinical and therapeutic exploitation in the clinic. This may change with the flurry of new data that are being generated. It all started with the discovery of the JAK2V617F mutation in MPNs [2-5]. Like the characterization of the BCR-ABL1 fusion kinase, which has led to the development of an efficient targeted therapy [6], this breakthrough showed how much progress can be made by the identification of a single molecular event regarding disease definition, understanding and classification, prognosis assessment, clinical monitoring and treatment. Since then, many new mutated genes have been identified. They affect various cell processes such as signaling, regulation of gene transcription and epigenetics, mRNA splicing and others. The aim of this review is not to describe these results in detail; this has been done in several excellent recently-published reviews [7-16]. Without putting emphasis on a particular gene, disease or cell process, it is more to discuss how the new data may improve our global vision of leukemogenesis and may be used for progress in at least three directions.
The genetic events involved in leukemogenesis have been deciphered by using two approaches. First, genomic alterations have been identified by using karyotype analysis and DNA hybridization onto oligonucleotide arrays (SNP-arrays, array-CGH); several types of genomic profiles have been found: lack of detectable changes, uniparental disomies (UPD), losses of chromosomes or large chromosomal regions, trisomies, losses or gains of small regions or genes. Second, small gene mutations have been detected by classical Sanger sequencing [17-22] or, more recently, by the use of new technologies such as next generation sequencing (NGS) [23-31].
These studies, together with previous ones that had identified JAK2, NPM1, MPL, RAS and RUNX1 mutations, among others, led to the discovery of several major players in leukemogenesis: ASXL1[21], BCORL1[25], CBL[19], DNMT3A[24,32], EZH2[20,22], IDH1/IDH2[26], TET2[18] and UTX[33]. The mutational frequencies of these genes range from a few percent to more than 50%, or even virtually 100%, depending on the gene, the disease and the series studied. Thus, almost all cases of PV have a mutation of JAK2[34,35]. Not counting the latter, mutations in ASXL1 and TET2 are frequently observed throughout the whole myeloid spectrum (Figure (Figure1),1), reaching 40-50% in CMML [33,36]. Mutations in DNMT3A and IDH1/2 are rare in the chronic stages but reach 15-20% in AML and exhibit a strong association with monocytic features [30]. Genes encoding components of the splicing machinery that is involved in the splicing of introns during pre-mRNA maturation (mainly SF3B1, SRSF2, U2AF35/U2AF1, and ZRSR2) have been found frequently mutated in MDSs and CMML, and more rarely in MPNs and AML (Figure (Figure1)1) [31,37-42]. Mutations in splicing factors are found in more than 60% of MDS with ring sideroblasts and in more than 50% of CMML [31].
Mutations in leukemogenic genes have been described in detail in recent reviews [7,9,10,12-16,43]; and will not be reviewed here. We will rather delve on the questions aroused by these recent data.
We may have identified (most of) the major culprits [14]. First, there are hundreds of background mutations (i.e. that do not provide selective advantage) but only a limited number of driver mutations (i.e. that cause the disease) in each malignant disease. Second, many of the newly discovered mutated genes may affect the same pathways or networks as the major mutated genes. For example, deletions and mutations of NF1, which have been recently identified [17,44,45], or PTPN11[46] are thought to have the same effect as a RAS mutation; a mutation of the SHKBP1 gene [47] or a duplication of the SH3KBP1 gene [48], which both encode cytoplasmic regulators of the CBL pathway, may have the same effect as a CBL mutation [49,50]. Because EZH2, EED and SUZ12 proteins all belong to the same polycomb complex 2 (PRC2) the rare deletions or mutations of the EED[23,51] and SUZ12 genes [17,51] could have the same effect as EZH2 mutations. Third, several genes (e.g. ETV6[52] or RUNX1) can be structurally altered by mechanisms other than mutation, such as deletions and breakages. Fourth, some important regulatory genes could be affected not by structural alteration but through other mechanisms such as abnormal DNA methylation (e.g. CDKN2A/B[53], TRIM33[54], CTNNA1[55], SOCS1[56,57]), histone modifications, mRNA splicing, microRNA or long non-coding RNA (lncRNA) modulation, or product degradation. Fifth, when all known mutated genes are analyzed in a series of cases, the percentage of samples with at least one mutated candidate driver gene varies from 50% [58] to over 90% (in CMML; [33]; Gelsi-Boyer et al., submitted). Moreover, most samples studied by NGS were shown to harbor gene mutations [23,26]. Thus, we are soon approaching the days where all cases can be defined by combination of several alterations. The practical definition of leukemogenesis will then be based on a specific and limited repertoire of alterations, including translocations, mutations and copy number changes, affecting a defined set of driver genes.
However, some issues still need be addressed. First, many genes may be mutated or deleted with a very low frequency (i.e. under 1%); their involvement and recurrence may be hard to demonstrate. Second, because NGS studies of several malignancies have shown that hundreds of genes can be mutated in a single tumor, background mutations should be discarded and driver genes validated. Third, we still miss information in some diseases such as essential thrombocythemia (ET), in which JAK2 mutations are found in only half the cases, and TET2 mutations in less than 10%. We also lack knowledge about the targeted genes of some frequent genomic alterations such as the 20q11-q13 deletion (ASXL1 and DNMT3B, more centromeric, are not involved). Fortunately, this lack of information is bound to disappear. The example of refractory anemia with ring sideroblasts (RARS) is instructive; in three-quarters of RARS, mutations have been recently found in SF3B1, a gene encoding a subunit of a splicing factor (U2 snRNP) and histone acetyltransferase (STAGA) complexes [27,29,31].
Gene fusions (e.g. BCR-ABL1, PML-RARA, FGFR1-associated fusions…), 5q deletion and JAK2 mutations are specific of some forms of myeloid diseases, although JAK2 mutations occur in three distinct subtypes of MPN. RUNX1 mutations are frequent in MDSs, CMML and AML but rare in MPNs. Among splicing factor genes, mutations in SF3B1 are highly specific of MDS with ring sideroblasts and SRSF2 mutations are most frequent in CMML [31]. In contrast, some mutated genes (e.g. ASXL1, DNMT3A, EZH2, TET2) occur in a wide range of myeloid diseases and with various frequencies. Future studies may identify mutations or combinations of mutations that drive a specific phenotype.
Leukemogenic alterations mainly affect five classes of proteins (Figure (Figure2):2): signaling pathway components, such as ABL, CBL, CBLB, FGFR1, FLT3, JAK2, KIT, LNK, MPL, PDGFRs, PTPN11, PTPRT [23,59] and RAS, transcription factors (TFs) such as CEBPA, ETV6 [58], GATA2 [30], IKZF1 [60], RARA and RUNX1, epigenetic regulators (ERs), such as ASXL1, BCORL1 [25], DAXX [23], DNMT3A, EZH2 [20,22], MLL, MYST3, NSD1 [30], PHF6 [61], SUZ12 [17,51], TET2 and UTX [28], tumor suppressors (TSG), such as CDKN2A, TP53, and WT1 and components of the spliceosome [27,29,31,38,39,41,42]. However, additional alterations occur in genes encoding proteins that it is too early to classified into these defined categories, such as DIS3, DDX41 [23], mitochondrial NAPDH dehydrogenase ND4 [62], or cohesin complex proteins [23,63].
In chronic stages, alterations in signaling molecules can be grouped in two major categories, a first one that is found in MPNs and affects oncogenic tyrosine kinases (ABL1, JAK2, FGFR1, PDGFRs) and the downstream JAK-STAT and/or PI3-kinase pathways, and a second one that is mutated in CMML and affect the RAS-MAP kinase pathway (RAS, PTPN11, NF1). CBL alterations occur in a wide variety of myeloid diseases [50].
TFs and ERs constitute the largest classes, which involve several categories of proteins (Figure (Figure3);3); because there are many ways to affect gene expression it is probable that not all of these categories are known yet. The existence of epigenetic alterations in myeloid malignancies has been known for long time [64,65]. For example, alterations of MLL, a histone methyltransferase (HMT), and MYST3, a histone acetyltransferase (HAT), have shown the importance of epigenetic deregulation in AMLs with translocation [45,64,65]. However, in chronic diseases and in AMLs with normal karyotype, the extent, causes, identities, exact roles and consequences of epigenetic alterations have long remained elusive. Molecular studies have recently shown that both DNA methylation and histone regulation are affected, and that epigenetic alterations may be due to genetic alterations, (i.e. mutations in genes encoding epigenetic regulators). The latter phenomenon has been observed in genome-wide analyses of many neoplasias [28,66,67]. However, not all epigenetic alterations may be due to an abnormal genetic background [1,53,54].
The recent reports of the interrelated functions of IDH1/2 and TET2 in DNA methylation represent a major breakthrough in our understanding of leukemogenesis [68]. It was initially hard to associate mutations of IDH1 and IDH2, two metabolic enzymes, with mutations in TET2, an unknown gene product, and as hard to suspect their role on DNA methylation. A very rapid series of elegant studies have shown i) that IDH1/2 and TET2 mutations are mutually exclusive in myeloid malignancies [68], ii) that mutated IDH1 and IDH2 produce 2-hydroxyglutarate instead of alpha-ketoglutarate (αKG) [69,70], iii) that TET2 encodes an αKG–dependent methyl cytosine dioxygenase whose mutation alters the conversion of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) [68,71] and iv) that both IDH1/2 and TET2 mutations impact on DNA methylation and are involved in the same biochemical pathway [72]. In addition, TET proteins can generate from 5-hmC 5-formylcytosine and 5-carboxylcytosine, but their roles are currently unknown [73]. The recent studies on TET proteins suggest a role in removing aberrant DNA methylation to ensure DNA methylation fidelity [74]. This has opened a new area of research since first, other factors involved in DNA demethylation may exist and second, several αKG–dependent enzymes, such as jumonji histone demethylases [75] are epigenetic regulators; therefore, some of these proteins could also be involved in malignancies. However, IDH1/2 and TET2 mutations, while mutually exclusive, are not equivalent because IDH1/2 mutations are more frequent in acute than in chronic myeloid diseases, whereas it is not the case for TET2 alterations, which are more evenly distributed between chronic and acute stages. Inactivation of TET2 increases self-renewal in hematopoietic stem cells and induces a disease resembling CMML in mouse models [76,77]. Mutated IDH1/2 enzymes may impact on self-renewal but with a different strength. The likely explanation is that IDH1/2 and TET2 have other, non-overlapping functions on the regulation of DNA methylation and histone marks. Also, an IDH-mutated product may depend on another, rate-limiting factor to exert a leukemogenic effect. DNMT3A is a de novo DNA methyltransferase involved in the formation of 5-mC and has complex interactions with polycomb and HMT proteins [78]. How DNMT3A mutations affect DNA methylation remains to be defined [24,30,79]; they probably do so in a different way from TET2 or IDH1/2 mutations since they may co-occur with either of them. A recent study showed that DNMT3A loss leads to upregulation of hematopoietic stem cell genes and downregulation of differentiation genes but is alone insufficient to induce a malignant disease in a mouse model [79].
Mutations in regulators of histone marks have become a major subject of research and the relationships between them are quickly unveiled. Central regulators of myelopoiesis and key players in leukemogenesis seem to be the polycomb regulatory complexes, especially PRC2, which, in addition to direct defects of its components (EED, EZH2, SUZ12), could be affected in its concerted action with several ERs, such as ASXL1, cohesins, DNMT3A, IDH1/2, MLL, TET2 and UTX. TET proteins could regulate pluripotency and self-renewal through interaction with PRC2 [74,80,81]. The cohesin complex is encoded by four genes (SMC1, SMC3, RAD21 and STAG2), which have been found mutated [23] and deleted [63]. A major interactor of cohesin complex is CTCF. PRC2 is recruited to specific loci through interaction of SUZ12 with CTCF [82]. Another main leukemogenic interactor of PRC2 components is ASXL1. A recent study showed that ASXL1 loss affects PRC2 complexes and H3K27me3 histone marks, and induces a strong hematopoietic phenotype consistent with an MDS in a conditional knock-out mouse model [83]. ASXL1 would direct PRC2 to leukemogenic loci such as HOXA genes. Thus, through direct alterations of its components or of proteins or lncRNAs [84] that recruit the complex, PRC2 has emerged as a key node in a network regulating hematopoietic stem cell self-renewal and proliferation and as a major factor in myeloid leukemogenesis. This is also true for T-cell leukemogenesis [85]. Correct functioning of polycomb repressive complex 1 (PRC1) seems also to be important for myeloid cells since the loss of BMI1 (a component of PRC1) in the mouse leads to a disease similar to PMF [86]. Structural alterations of the BMI1 gene occur but are rare in human myeloid diseases [87].
Whether other chromatin-associated complexes play a role in leukemogenesis should soon be revealed. ASXL1 could play a role in a cross-talk between major chromatin silencing systems, PRC1/PRC2, HP1α/CBX5 heterochromatin repressive complex and polycomb repressive deubiquitinase (PR-DUB) complex. Mutations in BCOR and BCORL1 suggest that the RAF/BCOR complex [84,88] might be involved in AML. The recent identification of a mutation in the DAXX gene in an AML case [23] further supports a wide participation of chromatin-regulatory complexes in leukemogenesis and cancer in general. DAXX and ATRX (which is mutated in X-linked α-thalassemia) are subunits of a chromatin remodeling complex and are both mutated in solid tumors [89,90].
The importance of the fifth class of mutated genes was more unexpected. Mutations in components of the spliceosome, which are mutually exclusive, lead to splicing defects including exon skipping, intron retention and use of incorrect splice site [31]. A recent study showed that a consequence of splicing gene mutations is accumulation of unspliced transcripts affecting a specific subset of mRNAs [41].
The dominant-positive effects of oncogenes such as BCR-ABL1, mutated FLT3, JAK2 or RAS, have been easy to apprehend. CBL and LNK mutations inactivate brakes on signaling pathways and may have a dominant-negative effect. TET2 is inactivated in the manner of a tumor suppressor. EZH2 is frequently associated with UPD and acts as a TSG. A frequent form of defect seems to be haplo-insufficiency [91], which could be associated with the (generally) heterozygous loss or mutation of ASXL1, NF1, NPM1, TP53, RUNX1 or TET2. Neo-functionalization results from IDH1/2 mutations, which are always mono-allelic. For genes altered through different mechanisms (mutations, deletions or translocations) such as RUNX1 or with different types of mutations (hotspot or dispersed) such as DNMT3A, the function might be variably affected and some mutants may have a dominant-negative effect. Mutations in spliceosome genes are mostly missense and could result in proteins with a modified but not inactivated function.
Mutations in signaling pathways, transcription networks and splicing machinery have many downstream consequences. Modifications in epigenetic regulation of DNA and histones may have a strong amplifying effect since they impact on the transcription of thousands of genes. This in turn impacts on the properties of hematopoietic stem cells, favoring self-renewal and proliferation over differentiation, thus promoting leukemogenesis [92]. However, chimeric proteins involving TFs and ERs (e.g. MLL, MYST3, NSD1 …) may induce a stronger effect than mutations in other TFs and ERs (such as ASXL1, EZH2 or TET2), which may need to co-occur with several other alterations to trigger AML, often after a chronic phase. Perhaps like the difference between a water jet and a sprinkling rain, this difference may have to do with the specific functions of TFs and ERs [64]. TF and ER fusion proteins assemble in complexes that are directly recruited to their target genes where they modify the local histone marks, drastically altering transcription. In contrast, mutated ERs may moderately perturb the epigenetic network, resulting in global gene deregulation.
Mutations in spliceosome components may lead to several types of deregulation, including alterations of the epigenetic control of differentiation and self-renewal; they may thus result in the same defects as TF and ER mutations. This may derive from splicing aberrations of leukemogenic genes (e.g. RUNX1) [41] or from other specific but indirect defects. SF3B1 for example interacts with components of the polycomb repressor complex 1 (PRC1) and SF3B1 mutations may compromise PRC1 regulation of leukemogenic loci [93]. Reciprocally, the function of the pre-mRNA splicing machinery involves the reading of histone marks, and defective chromatin regulators may affect splicing [94]. Directly or indirectly, SF3B1 mutations, which are associated with the presence of ring sideroblasts, are likely to affect genes involved in red cell biology and mitochondria function. Because mutations in splicing genes, in TFs and in ERs are not mutually exclusive it is probable that the three types of alterations have additive rather than interchangeable effects.
Two driver mutations may never occur together (mutual exclusion) in the same cell because of epistasis (two hits in the same pathway are not selected because they do not provide a growth advantage) or synthetic lethality (two hits are counter-selected because they compromise the life of the leukemic cell). Associations and cooperation can occur in all other cases.
Some chronic myeloid malignancies, such as CMML (myeloproliferative form, MP-CMML) and MPNs, have a proliferative component. This component is driven by alterations in signaling molecules, such as CBL, CBLB, FLT3, JAK2, LNK, MPL, NF1, PTPN11 or RAS. These mutations are generally mutually exclusive. However, JAK2 mutations can be found in patients with mutations of CBLLNK or MPL[95-97]. In most cases when two signaling mutations are found in the same patient they are not in the same cellular clone. Signaling mutations associate with mutations in genes from the other classes (TSGs, TFs, ERs). CBL and KIT mutations are more frequent in AML with t(8;21) and inv(16), i.e. with alterations of the core binding factor (CBF), a dimeric transcriptional factor containing the RUNX1 protein [98].
With rare exceptions, mutations in genes encoding splicing factors do not synergize and are mutually exclusive [31,38,41,42].
As already mentioned, IDH1 or IDH2 mutations are mutually exclusive with TET2 mutations. Except for this, TET2 mutations seem to be able to cooperate with either of the other recurrent alterations. ASXL1 mutations, which occur preferentially in secondary AML, are mutually exclusive with NPM1 mutations, which occur in de novo AML [99]. Although ASXL1 interacts with PRC2 proteins [83]ASXL1 and EZH2 mutations are not mutually exclusive [58]. Mutations in EED and SUZ12 may even be found in the same AML case [23]; however, they may affect different clones. RUNX1 mutations are frequently associated with ASXL1 defects in MDSs [100]. Mutations in ASXL1 and TET2 can be concomitant (Figure (Figure1),1), and each can co-occur with mutations in signaling molecules [58,100]. In MDSs, U2AF1 mutations are more frequent in ASXL1-mutated than in ASXL1-wildtype cases [38,42]. TP53 mutations and losses, likely associated with genetic instability, are found in MDSs with karyotypic alterations but not in cases with normal karyotype [58]. DNMT3A mutations are more frequent in AML with NPM1 and FLT3 mutations, infrequently found in ASXL1-mutated cases, and very rare in cases with translocations [24,101]. Overall, while IDH1/2 and TET2 mutations are equally distributed, there seem to be two major associations in AMLs with intermediate cytogenetic risk, ASXL1/RUNX1 on the one hand (secondary, dysplastic AMLs), NPM1/FLT3/DNMT3A on the other hand (primary, non-dysplastic AMLs) [99]. These and other associations and exclusions not described here or yet to be discovered will help understand the major leukemogenic pathways. An important issue is to demonstrate that mutations found in the same case are actually cooperating mutations that co-occur in the same cell progeny and not in different clones.
Early studies of chronic and acute hematopoietic malignant diseases have shown that some cases may display a single mutational event whereas others harbor several hits [100]. This difference may just be due to the low mutational frequency of many driver genes (e.g. NF1A, EED) [102] and to our current ignorance of other targets. Actually, NGS studies have shown that the general rule is to find several altered genes in each case [23,26,59,103] and murine models have shown that single alterations are, except in rare cases, not sufficient to cause AML [104,105]. In the years to come mouse models will have to challenge many combinations of mutations.
The study of matched chronic and acute stages has shown that progression is associated with additional alterations. However, the chronic stages are already characterized by the presence of several mutations. We found that many cases of CMML have already four mutations [36], and this was without counting mutations in splicing factors. JAK2 and TET2 concomitant mutations are frequent in MPNs [16,37]. Whether they are both necessary for the various phases of the disease and their order of appearance are a matter of debate [106]. An NGS study indeed showed that the ten mutations identified in an MDS patient can be detected together in most studied single cells, suggesting a linear evolution of the disease and the existence of a dominant clone [103]. Regarding evolution of AML after therapy, a recent NGS study has revealed two major patterns at relapse [23]; the first pattern is the persistence of a dominant clone and the second pattern is the selection and expansion of a minor clone; in both cases the relapse clone had gained additional mutations. Another recent NGS study showed that genetic evolution of secondary AML is a dynamic process shaped by multiple cycles of mutation acquisition and clonal selection. MDS are oligoclonal with founding clones; these clones persist in secondary AML, which shows at least an additional subclone with new "progression" mutations [107]. Founding mutations may occur in various genes, such as U2AF1[39] or TET2. Many different genes may be involved in progression. Thus, several steps are necessary to trigger a myeloid disease, even a so-called chronic one, and progression involves additional hits.
A first step in the leukemogenic process is likely to be a mere clonal expansion. Several gene mutations may play a role at this stage. Their identity may depend on whether they target a hematopoietic stem cell or a progenitor. In the first case the initial hit should provide a proliferation boost, in the second the hit should bestow self-renewal on the proliferating progenitor [108]. Mutations in a TSG, splicing gene, or in some ERs such as TET2, could occur at this initial step. It is also possible that, in a susceptible background, several clones emerge independently early on [12,109].
Then, because of increasing proliferation and genetic instability, a cell from the affected clone (or clones) undergoes various additional mutations (including many background mutations), leading to an oligoclonal malignant tumor. Some of the early mutations may not be present in the clone that eventually becomes leukemic. Thus, for each case, only the determination of all potential mutations and the reconstitution of the mutation profile and clonal evolution will help understand the pathophysiology of the disease. This is now achievable by using NGS. How many steps can eventually be individualized may depend on how many clones are initially expanded, on the level of genetic instability that results from the initial hits, and on the impact of the mutations on self-renewal, differentiation and proliferation. Some mutations in epigenetic regulators may have a milder effect on genetic reprogramming than a gene fusion involving a master transcription factor, which will induce a strong block of differentiation in a hematopoietic precursor [92]. The latter event is prominent in de novo AMLs, which accordingly display only few or none of the other recently-discovered mutated genes.
A previous scheme of leukemogenesis [110] was based on the minimal cooperation of two oncogene classes, proliferation-drivers (kinases, RAS) and differentiation-blockers (mostly transcription factors), to trigger AML. The ever-increasing molecular complexity of myeloid malignancies is now obvious and calls for an update of this model. First, it is now routinely possible to observe the cooperation, already at the chronic stage, of three, four or more mutated genes (to speak only of known or suspected drivers), whose products belong to at least five classes, class I signaling molecules class II TFs, class III ERs, class IV TSGs and class V splicing factors [100]. Second, not all mutations of a class are equivalent; mutations in ASXL1, RUNX1 or TET2 occur almost as frequently at the chronic stages as in AML whereas mutations of IDH1/2 or DNMT3A are preferentially found at the acute stage. The reason for this remains obscure but may have to do with the different intensities in the differentiation block induced by the mutations. Third, the classes are not well individualized. For example, EZH2, RUNX1 and TET2 are both TSGs and TF/ERs. NF1 is both a TSG and a regulator of signaling pathways. Because it induces phosphorylation of histone H3 and PRMT5 arginine methyltransferase, JAK2V617F may also be an ER [111]. Fourth, all classes may not be systematically affected in each case. Fifth, if classes I and V are relatively well individualized, with genes whose mutations are generally mutually exclusive, the definition of the other classes may evolve. However, despite all this, the initial schematic model might not be so far off. The two key processes of differentiation and self-renewal seem to be always altered and proliferation is frequently affected. It may just be that the oncogenic hits required to achieve each step might be more numerous than initially expected. This model will apply to cases with intermediate or normal cytogenetic risk; a different leukemogenesis pathway linked to genetic instability may be involved in cases with TP53 mutation and complex karyotype [112].
Considering all this, several pathways to leukemia can be envisaged (Figure (Figure4).4). The first pathway could be direct and trigger de novo AML with a gene fusion as the major event and few other alterations. The second pathway is characterized by NPM1 mutations, which are rarely associated with mutations in other known TFs or ERs except in DNMT3A and IDH1/2[23,101]. AML with complex karyotype can derive from genetic instability, with or without TP53 mutations. A fourth pathway would be the accumulation of several hits in signaling molecules, TFs, ERs and splicing factors, which induce either secondary AML after a chronic phase (Figure (Figure5)5) or de novo AML; however, some so-called de novo AMLs with several ER mutations could actually be secondary to a non-detected chronic phase. Mutations in TFs and ERs are not major events in chronic myeloid leukemia (CML), which is triggered by the BCR-ABL1 fusion; however, mutations in ERs such as ASXL1, IDH1/2 and TET2 may participate to CML progression to AML [113,114].
Overall, the development of an AML may follow a "slot machine" model (Figure (Figure6),6), in which the late steps would be, to some point, constrained by the initial ones (clonal dominance, cooperations/exclusions). Oligoclonality would be due to several possible draws at each step. It is important that we determine the exact number of "reels" (hits) and "symbols" (genes) and the possible combinations.
Understanding and modeling leukemogenesis will have a major impact on the management and treatment of hematopoietic malignancies. Molecular biology already helps establish the diagnosis (JAK2), classification (BCR-ABL1, FGFR1, PDGFRs), prognosis (FLT3, NPM1, CEBPA) and treatment (BCR-ABL, 5q-, JAK2) of myeloid diseases. Due to the increasing simplification and accessibility to clinical laboratories of NGS equipment, the repertoire of all genetic alterations will soon be determined for any new case as a routine practice.
The establishment of a precise taxonomy comprising homogeneous pathophysiological entities is a major goal in hematology. It relies heavily on molecular data. It started with the karyotype and has continued with gene expression profiles [115,116]. Gene mutations will nicely complete the picture. Other factors such as microRNAs and long non-coding RNAs status [1], methylation profiles [117] and histone marks may have to be integrated too.
Several studies have shown that gene mutations have indeed a major impact on prognosis of myeloid diseases. This is the case in MDSs for mutations in five genes, ASXL1, ETV6, EZH2, TP53 and RUNX1[58]. Mutations in ASXL1 seem to be associated with an aggressive phenotype in all myeloid malignancies [8]: they are frequent in high-risk MDSs and correlate with poor prognosis in MDSs [118-120] and with acute progression in CMML [36], they are more frequent in myelofibrosis than in other MPNs [37,121], and characterize secondary AML. DNMT3A mutations are frequent in younger patients with AML and are associated with an unfavorable prognosis in MDS and AML [15,24,30,101]. Among splicing gene mutations, those in U2AF1 and SRSF2 seem to be associated with aggressive forms of myeloid diseases and those in SF3B1 with good prognosis [38,39,41,42]. Molecular data will allow the establishment of an upgraded index of prognosis. For example, in MDSs, it is highly conceivable that the current prognostic index used for the evaluation of the disease (IPSS), which already includes karyotypic data, can be improved by a molecular index regrouping the mutations that impact on the patient's outcome [112]. Whether TET2 mutations are to be included is a matter of debate [122-124]. In AML, a thorough study of 18 genes, including ASXL1 and DNMT3A, proposed an updated and precise risk stratification based on gene mutations [125].
New therapeutic targets can be found in two of the five major classes of leukemogenic genes. Following the successful use of imatinib in CML, abnormal signaling pathways associated with myeloproliferation, be it the JAK-STAT pathway [126-128] or another pathway, represent appealing targets. Drugs targeting epigenetic modifications, i.e. epidrugs, such as histone deacetylase inhibitors and hypomethylating agents (DNMT inhibitors), are currently developed or used in clinics, and many new ones are studied in preclinical assays and clinical trials [1]. Targeting histone methyltransferases (e.g. MLL) or lysine acetyltransferases (e.g. P300) [129] is also a promising area of development. The determination of gene mutations and their consequence on gene regulation and cell programming will help treat myeloid malignancies in providing a rationale for the use and development of new epidrugs, in directing the choice of the drug cocktails, and in allowing the design of drug delivery and the monitoring of drug response and disease progression. For example, agents directed against TET2-, IDH- and DNMT3A-associated methylation defects may represent a new area of development. To date, the use of TET2 mutations status to evaluate the response to DNMT inhibitors is still debated [130,131]. Because many mutations compromise PRC2 function drugs antagonizing this defect hold great promise.
Proteins of two other leukemogenic classes may also serve as therapeutic targets. For example, the antitumor macrolide pladienolide targets SF3B1 [132] opening new opportunities to develop treatments against RARS. Compounds aiming at restoring a normal P53 pathway are in development [133,134].
The existence of concomitant mutations is an incentive for combinatorial therapies; for example, therapeutic synergy may be obtained by the combined use of signaling inhibitors and epidrugs.
Finally, the complete determination of the mutation repertoire will provide novel therapeutic targets. For some diseases, such as CMML, it is already possible to identify at least one target for nearly nine cases out of ten [33,36]. However, the development of resistance, as observed with imatinib [135], is a critical issue. Hopefully, target identification will allow for the development of new combinatorial strategies, such as the one based on synthetic lethality [136,137]. If two mutations never occur together it may mean that their combined effect is deleterious. Thus, opportunities for deriving synthetic lethality drugs could stem from the observation of exclusions in mutations patterns.
Thus, mutations and models ("M and Ms") will help manage myeloid malignancies. The eventual comprehensive determination in any given case and at diagnosis, of the set of altered genes, underlying affected pathways and disease stage, will guide towards an optimal treatment based on an appropriate combination of drugs targeting the various affected processes of the disease. Clinically-oriented laboratories should already be preparing for that challenge. Meanwhile, there is much to mull over the "M and Ms" of myeloid malignancies.
The authors have no competing interests.
All authors have contributed ideas, discussions, and have participated in the writing of the manuscript. All authors read and approved the final manuscript.
The pre-publication history for this paper can be accessed here:
We are grateful to O. Bernard for his critical reading of the manuscript. Work in our laboratory on this subject is supported by Inserm, Institut Paoli-Calmettes and grants from the Association pour la Recherche contre le Cancer (DB) and Association Laurette Fugain (MJM).
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


text:
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subset: commoncrawl


text: Can anybody tell me whether its better to have phonebook contacts stored on my phone or my sim ? At the moment they appear to be on both as when I use smart dial it shows each name twice (one with a picture icon and the other with a sim icon). I presume that contacts have to be stored on the phone in order to sync them with facebook for their profile pics ? If so, how can I hide the sim contacts ? Thanks


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MOVIE SYNOPSIS [ General Audiences ] Under the direction of Brandon Bergin, Derick Snow leads the cast of this film of USA, with script in English (subtitled), whose presentation to the public was scheduled for 2013. You can watch Self-Delusion and Other Obstacles online on TV cable or theaters with original audio in English at different dates. This film premiered in theaters in 2013.
Rating: 5 by 18 users./
Runtime: 90 minutes
Derick Snow, Cassie Self, Michael Remington, Jeff Howard, Xavier Santiago, Katie Burgess, Cooper Cox, Rich Bentz, Marla Taylor, Katy Stefanic, Doug Bauer, Paige Bergin, Emily Boyd, Ryan Andrew Brandt, Kristin Brown and Cassandra Bushell.
90-minute film (full movie) directed by Brandon Bergin.
The original audio of Self-Delusion and Other Obstacles has dialogues in Dolby Digital, it was produced in USA.
It premiered in cinemas or television in 2013.
Screenplay written by Brandon Bergin.
Bobby Dodd.
Jeff Howard, Mark Mason and Mark Hine.
This film was produced and / or financed by Four Six Films.
Composed by Pat Savage and Bobby Hamilton.
Without commercial breaks, the full movie Self-Delusion and Other Obstacles has a duration of 90 minutes; the official trailer can be watched in streaming on the Internet. You can watch this full movie free in EnglishDolby Digital in movie TV channels, renting the DVD or with VoD services (Video On Demand player, Hulu) and PPV (Pay Per View, Netflix).
See the page of this full movie, Self-Delusion and Other Obstacles in FULLTV Movies.


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I love cheesecake and raspberries! I enjoy making baked cheesecakes so when I saw the recipe title I put the needed items on my grocery list and waited anticipated the Sunday Dinner when I would have dessert as my assignment. When it arrived I was disappointed that it wasn't an actual cheesecake, but learned my lesson to read the entire recipe and not just look at the pictures in the book. Even though I felt miss lead it turned out tasty and was a hit with my niece Jessica as well as everyone else. I made some modifications on how I would actually put the cake together--you start to think differently about presentation if you think you are actually going to take a picture of the darn thing and share it with others---LOL. It has brought a fun challenge to meal prep and my family finds it enjoyable too.
**This recipe is similar to one my sister Sherri makes with her wonderful homemade white cake. Which she makes in to a memorable Strawberry Shortcake of sorts
1 package white cake mix
2 -8 oz packages of cream cheese softened at room temperature
4 cups powdered sugar
1 pint whipping cream whipped (I tried Lion House Stabilized cream recipe--great!)
2 16 oz cans raspberry pie filling (When I make this again I will use the Danish Junket that my mother ALWAYS uses. I had been taught better than to used canned! Junket taste SO MUCH BETTER!!!)
Preheat oven to 350. Grease and flour two 9 x 13 baking pans. Prepared cake according to package directions. Pour half of cake batter into each pan. Bake for 20 minutes or until cake test done. Remove from oven and cool.
In a medium bowl, whip cream cheese and powdered sugar together until fluffy. Whip whipping cream separately, then add to cream cheese mixture. Divide the mixture and spread half of it onto each cake. Refrigerate until ready to serve. Makes 24 to 30 servings.


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Weiler® Dualife® Cable Twist Knot Wire Wheels, Steel
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$24.99 Each
Dualife® Wire Wheel Brush is a heavy-duty rugged knot-type wire wheel brush. Dualife® 4" OD x 1/4" Cable twist knot wire wheel brush comes with 24 knots and features a trim length of 7/8". Wheel brush with wire of size 0.02" is made of steel for durability and is used for removing powder-coating or epoxy based paint.
- Material: Steel
- Diameter: 4-inch; Face width: 1/4-inch
- Wire size: 0.02-inch
- Number of knots: 24
- Trim length: 7/8-inch
- Used for removing powder-coating, epoxy based paints, and rubberized coatings
- Weld preparation and cleaning; Cleaning scale and heavy corrosion; removing heavy burrs from large pieces after cutting
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- Used with straight grinders, bench/pedestal grinders, and right angle grinders
|Brand : Weiler
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text:
Local family works with state leaders to develop new alert system
PHILADELPHIA (WTXF) - A Philadelphia family stricken with tragedy is turning their loss into public policy designed to make the road safer and to help police catch hit-and-run suspects more quickly.
Ayeshia Poole is working with state leaders to develop a new alert system after a hit-and-run claimed the life of her 8-year-old daughter Jayanna Powell last November.
Ayeshia and her sister say they had an idea for what they call a Jay Alert and took it to State Senator Anthony Williams of Philadelphia. They say it would work like the Amber Alert system only instead of reporting missing children it will send out notices of hit-and-run crashes.
The program would also get state certified auto shops in the loop--reporting suspect vehicles that come in to police when the driver is still on the loose.
"I don't want to have to see another parent be on the news crying or another aunt or uncle hurt because they lost a family member to a hit -and-run," Ayeshia explained.
State senator Williams says he believes he'll get the bipartisan support needed for the bill calling it a common sense law about public safety. He hopes to have it on the governor's desk and signed into law within the year.


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Tuesday 16 February 2010
It was Tuesday, under the sign of Aquarius. The US president was Barack Obama (Democratic).
In that special week of February people in US were listening to TiK ToK by Ke$ha.
Le silence de la mer, directed by Jean-Pierre Melville, was one of the most viewed movies released in 2010
while Dear John by Nicholas Sparks was one of the best selling books.
On TV people were watching Julie & Brandy: In Your Box Office.
If you liked videogames you were probably playing Crunchball 3000 or Dead or Alive Paradise.
But much more happened that day: find out below..
You can also have a look at the whole 2010 or at February 16 across the years.
Old Newspapers
Have a look at the old newspapers from 16 February 2010 and get them!
TV Series
Which were the most popular TV series released in the last 30 days ?
Which were the most popular movies released in the last 30 days ?
Find out your future
Get a FREE Numerology report based on the digits of 16 February 2010!
Wish him/her..
Historical Events
Which were the important events of 16 February 2010 ?
- Saint Juliana
- Saint Lucilla
- Remembrance of Lambertus
- Saint Jeremias
- Saints Daniel, Samuel and Elias
- Kyoto Protocol Day (2005)
- Lithuania - Independence Day (1918)
Famous Birthdays:See famous people born on 16 February
Famous Deaths:
- Wan Chi Keung: Hong Kong soccer player and actor.
- Assassination of a senior Hamas military commander in Dubai:
- Dubai police release the passport photographs of 11 "Europeans" suspected of the murder of Mahmoud al-Mabhouh. (BBC)
- It emerges those suspected used fake British and Irish passports with Dublin saying it did not issue passports under their names, there is no evidence of their names on official Irish records and the counterfeits contain passport numbers with incorrect combinations of letters and digits. (''The Daily Telegraph'')
- The ''Queen Mary 2'' arrives at the Port of Shanghai, making her first port call in China since her maiden voyage in 2004. (Xinhuanet)
- Queen Rania of Jordan meets with CEOs of mobile operators from around the world in Barcelona on Monday to rally support for the 1GOAL global education campaign. (Jordantimes)
- EMI places its Abbey Road Studios in St John's Wood, London, up for sale in an attempt to ease the debt burden created by Terra Firma Capital Partners' leveraged buyout of the company. (Financial Times)
Featured Contents
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Music Charts
Which were the top hits in that special week of February 2010 ?
Top #10 songs in the USA
Search For Your Ancestors
Sport Games on 16 February 2010
ChampionshipFootball (United Kingdom)
- Blackpool - Middlesbrough : 2 - 0
- Bristol City - Leicester : 1 - 1
- Cardiff - West Brom : 1 - 1
- Derby - Preston : 5 - 3
ConferenceFootball (United Kingdom)
- Altrincham - Eastbourne Borough : 3 - 0
- Gateshead - Barrow : 2 - 1
- Oxford - Rushden & D : 1 - 0
- Salisbury - Tamworth : 1 - 0
Division 1Football (United Kingdom)
- Queen of Sth - Ayr : 3 - 0
Division 2Football (United Kingdom)
- Dumbarton - Stirling : 2 - 4
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Make this date unforgettable
Genealogy: find out your family heritage
Magazine Covers
What news were making the headlines those days in February 2010?
- Time: Defense Secretary Robert Gates
- SportsIllustrated: Sports Illustrated: no.11385
- SportsIllustrated: Sports Illustrated: no.11384
Which were the most popular books released in the last weeks ?
Remember when
What videogames would you be playing back in the days ?


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It is hard to have young children get the most out of their daily treatments for asthma, cystic fibrosis, or other respiratory conditions. The Medical Department Store understands the difficulty in treating childhood conditions, which is why we offer unique nebulizers for children to make treatment time fun.
The Medical Department Store offers many fun machines that make the kids feel like they are not even going through another treatment. These nebulizers for children offer the same treatments as a regular machine would, but come in different shapes and characters.
Helping your child get through difficult times is what parenting is all about, so we have machines that will brighten their day and make your job easier. These machines are smaller and nebulizers for children specifically distract them through the time because it will feel as if they are playing!
The fire truck nebulizer compressor by MedQuip is ideal for the young boy who fantasizes about fighting fires someday when he grows up.
The Digger Dog Children's Nebulizer is great for younger children who need a snug fit during treatment time. For pediatric patients, this mask is comfortable and the ventilation system keeps the mist from flowing towards the child's eyes. The puppy mask fits any standard 22 mm fitting or nebulizer.
Another child friendly nebulizer is the adorable penguin character by MedQuip. This product has a lifetime warranty and is geared towards the little ones because it includes a pacifier to ensure maximum comfort. Your mind can be at ease knowing your child is receiving the care they need while being comforted by a pacifier. They may even forget they are receiving a treatment!
The Invacare Pediatric Panda Bear offers value and reliability at an affordable price. This innovative design uses a mouthpiece to ensure maximum results from the treatment. The teddy bear is an added benefit because it is a great comforting mechanism for your young child who may be new to treatments from a nebulizer.
The Medical Department Store is concerned about people of all ages because we know respiratory conditions do not target a certain age group. We also offer products in our catalog for other respiratory needs.Tags: nebulizers for children


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Sales of new light vehicles in the United States are expected to top 16 million units in 2014, the first time since 2007. While US light vehicle sales may reach the 2007 level in 2014, carmakers are behaving unlike the last time the figure topped 16 million units. Back in 2007, carmakers overproduced and artificially increased demand by throwing blowout sales to eliminate of the excess inventories.
"Back in 2006 and 2007 the industry was on illegal drugs, doing steroids," Jesse Toprak, president of Toprak Consulting told Automotive News. He noted that this time, the auto industry is reaching its sales goal all naturally, on the merit of the product. He added that now, sales are not being fueled by "irresponsible lending or outrageous incentive spending."
The Automotive News Data Center expects the US auto industry to log light-vehicle sales of 15.6 million units in 2013, for an 8-percent gain over 2012. This means that US light vehicle sales need to grow at least 3 percent to hit 16 million units in 2014. The artificial sales growth points to more profit not only for carmakers but also for dealers.
Since 2007, almost 4,000 dealerships have gone under, which means that those who survived the recession are now selling more light vehicles than ever. If the auto industry sells at least 16 billion in 2014, this means that the average sales per US dealership will be more than 900 vehicles, up from about 521 vehicles in 2009 and a peak of 785 in 2005. "The guys that survived are going to do well," Steven Szakaly, chief economist for the National Automobile Dealers Association, told Automotive News.


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Katie Burns
North County Times
Residents of Southern California continue to watch helplessly as their graceful eucalyptus trees wither away, victims of more than a dozen opportunistic pests that eat leaves, bore through wood and spread from tree to tree in devilishly creative ways.
Destruction of the trees via defoliation and weakening of trunks and branches likely will continue, but scientists at UC Riverside and UC Berkeley are trying to repeat past successes with releasing parasitic wasps to kill the pests.
This year, scientists hope to find signs that last summer's release of thousands of the tiny, stingless wasps in San Diego and Riverside counties is having some effect on the three pests that are currently most harmful.
"These parasites have been so successful when they've worked that the management of those problems essentially drops away," said Mark Hoddle, a biological control specialist at UC Riverside.
Wasps already control the populations of the three pests most troublesome in the past -- the blue gum lerp psyllid, eucalyptus snout beetle and eucalyptus longhorned borer. The worst pests of the present are the red gum lerp psyllid, eucalyptus tortoise beetle and a second borer.
"They haven't been here very long," said Timothy Paine, a professor of entomology at UC Riverside. "The initial work is to try and identify insects in their native range in Australia specifically and see whether or not they can be introduced in California as a means of controlling the population of those three new pests."
Importing a solution
Eucalyptus trees are from Australia, as are the pests that kill the trees and the wasps that kill the pests. A constant trickle of pests began arriving two decades ago as international travel and shipping became easier and faster.
To deal with the insect influx, scientists import tiny wasps, the size of a grain of pepper, that attack specific pests. In 2000, scientists set at large in the area four species of predatory wasps. Among these four wasps, two attack both borers, one the red gum lerp psyllid and the last the tortoise beetle.
"The big test will be to see if they come through the winter," Hoddle said.
Paine said it's too soon to tell if the parasitic wasps are effectively killing the pests they target. The species of eucalyptus pests already under control have seen population decreases in the range of 90 percent.
"That doesn't mean that they're gone -- they're still here," said Vincent Lazaneo, urban horticulture farm adviser with the UC Cooperative Extension. "If it eliminated completely the pest it was feeding on, the little parasite or predator would also die."
Until the current wasp release program controls the worst of the pests, almost nothing can be done to save a tree from them, said Derek C. Long, owner of The Branch tree service in San Marcos.
"There's not much to do to them," he said. "You can spray the trees, and that'll kill the insects, but they'll just come right back."
And even spraying the trees can be counterproductive, Lazaneo said, because pesticide also kills the wasps.
A gnawing problem
People are frustrated with being unable to save the eucalyptus trees from the growing number of pests. The insect immigrants, on the other hand, are in heaven.
"When you make it to California, it's fantastic because there are lots of eucalyptus trees and the climate's great and there are not natural predators," Hoddle said. "Then the populations just explode."
Lerp psyllids are the most prevalent pest, with seven species spread across the state. The latest arrival is the lemon gum lerp psyllid, which showed up in Los Angeles County in 2000. Of the lerp psyllids, five are not major problems and the blue gum is under control, but the red gum is the most prevalent eucalyptus pest in the state.
"What it does is it attaches itself to the leaves, and it has a crystalline cover it creates over itself," Long said.
Lerp psyllids hide under a coat of sugar as they suck the juices from leaves. An infested tree has white dots all over its leaves, which gradually drop off the tree. Adult lerp psyllids are strong fliers, and the red gum lerp psyllid has spread throughout California since its arrival in 1998.
The two longhorned borers, one under control and one a problem, feed under the bark of trees stressed by inadequate irrigation. Adult borers fly well, and the earlier borer was the first serious eucalyptus pest in the state, arriving in Orange County in 1984, until being controlled. The later borer showed up in Riverside County in 1995.
The eucalyptus tortoise beetle also appeared first in Riverside County. Since turning up in 1998, the beetles have spread slowly in Southern California because they dislike flying. Nevertheless, the beetle is very effective at chewing notches along leaves that look like little steps.
"A large number of beetles can really chew the leaves down to a very small size," Hoddle said.
The eucalyptus snout beetle also eats leaves, but scientists managed to cut the beetle population to almost undetectable levels a few years after its arrival in 1994.
"It was controlled very quickly and very successfully," Hoddle said.
Two species of wasps -- distinct from the wasps the scientists are releasing -- have reached Southern California since 1995 the same way as the other pests, in cargo or luggage. These wasps lay eggs under the surface of leaves, forming a pimplelike gall. After hatching, wasp larvae will chew an exit hole through the gall. Neither species of wasp has become a serious problem yet.
A solution with teeth -- but no sting
At UC Riverside and UC Berkeley, scientists hope to repeat the success they had with the snout beetle, blue gum lerp psyllid and first borer -- without releasing a wasp that is actually harmful to other plants or animals.
The scientists are following established procedures to find and release wasps that attack the tortoise beetle, red gum lerp psyllid and second borer. Finding the wasps in their native country is the first step.
"When we go to these countries, it's called foreign exploration," Hoddle said. "We're looking for the pest, and we're looking for the parasites that eat that pest. It's like looking for a needle in a haystack. It's really remarkable when we find something."
For the red gum lerp psyllid, UC Berkeley scientists found eight species of wasps. UC Riverside imported a wasp used in South Africa to control a tortoise beetle and also found two species of wasps that attack both borers.
After finding a wasp, Paine said, a research group develops rearing methods for the wasp and the pest it eats. The group also exposes the wasps to other plants and animals to see if they attack anything besides the pest.
"They're very specific to the type of prey that they need to survive," Hoddle said. "That's what makes biological control in many instances very safe."
To test if the small stingless wasps attack people, he said, scientists simply expose their hands to the wasps.
If scientists decide the wasps only attack pests, they release the wasps into affected areas. Last summer, the UC Berkeley group released the most promising wasp in San Diego County to attack the red gum lerp psyllid while UC Riverside scientists released three wasp species in Riverside County to attack the tortoise beetle and the borers.
The wasps attack pests by laying eggs inside either the immature pests or the pests' eggs. A wasp larva feeds on the inside of its hosts before chewing its way out, killing the host. To measure the effect of the wasps on the pest populations, scientists search for the wasps and for parasited pest eggs or larvae.
"Once we do the release, they're little tiny wasps, and trying to do the recapture and the evaluation is time-consuming and complicated," Paine said.
In the case of three pest species, the effort has already been worth it. Time will tell if the newest wasp release program works, giving scientists more experience to face the pests that almost certainly will arrive in the future.
Contact staff writer Katie Burns at (760) 740-5442 or firstname.lastname@example.com


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I Want to Achieve Nirvana,moksha
Personal Stories, Advice, and Support 7 People
Tell Us More of What This Experience Is?i desire more info.
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The Krishna's Butter Ball or Vaanirai Kal (Stone of the Sky God), as it is known to locals, has been sitting on a 45-degree slope in Mahabalipuram for over 1,300 years. The 20ft rock appears to defy gravity, looking like it's going to roll at any moment - and all attempts to move it have been in vain.
While many have said that it was placed in its position by the Gods who wanted to prove their power, or by extra terrestrial beings thousands of years ago, scientists say that the rock is simply a natural formation.
Geologists on the other hand argue that natural corrosion is unlikely to have produced such an abnormal shape.
Hindu folklore offers another suggestion - that deity Lord Krishna would often steal handfuls of butter from his mother's jar, and this natural boulder is attributed to the mass of butter that he pinched.
One of the first individuals to attempt to dislodge the round stone was the Pallava king Narasimhavarman, who ruled southern India from 630 to 668AD.
Not for a lack of trying, the mission was unsuccessful, and a similar endeavour was undertaken in 1908 by the Governor of Madras, Arthur Lawley.
He feared for the safety of the town at the base of the hill and is said to have used seven elephants to try to move it, also without any luck.
Unsurprisingly the abnormal rock is popular with tourists and locals, who pose for daredevil photographs under its base, attempt to push it down the hill (in vain) or simply use it as a sun shield.
Source: www.dailymail.co.uk


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Workgroup Overview
Family violence, and more specifically Intimate Partner Violence (IPV) was identified in the 2015 Community Health Assessment as a health priority because, in years previous years, our domestic violence homicide rate was as high as counties much larger than Buncombe, and the community has build extensive momentum around this issue. Domestic violence is the leading cause of injury and 7th leading cause of death for women in the United States, and it is the number one reason women and children become homeless in the U.S. It is also present in the majority of child maltreatment cases, and a child's exposure to their father abusing their mother is the strongest risk factor for transmitting violent behavior from one generation to the next.
CHIP is an ongoing partner with the Safety Coalition, which is the group leading this work in Buncombe County. In September of 2016, the Safety Coalition began a "Talk to Action" exercise, where the following path was outlined (action items table below will be updated regularly as the work evolves):
The Result this group is working to achieve:
- Buncombe County is the safest place in the universe, building resilient communities free from domestic violence, sexual violence, and child abuse.
- Domestic Violence Homicides
- Child Maltreatment Homicides
- Domestic Violence Arrests
- Sexual Assault Arrests
- Child Abuse and/or Neglect Substantiated Cases
Action Items
- One thing that has grown out of CHIP "Talk to Action" activities is an educators group (made up of educators from Helpmate, Our VOICE, Mountain Child Advocacy Center, Planned Parenthood, Triple P, and others). This group has been meetings since December, working to map the various curricula and educational offerings to maximize impact and reduce unnecessary duplication.
- The Prevention Task Force has begun the big job of drafting a county-wide plan for the primary prevention of IPV, sexual violence, and child abuse. This work is based on strategies in the NC Plan to Prevent Intimate Partner Violence, the NC Plan to Prevent Sexual Violence, and the CDC's document, Preventing Multiple Forms of Violence: A Strategic Approach to Connecting the Dots. (You can find these documents, and more, on the "Resources and Links" page of this blog).


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Click the "Recommended Resources" link above to find useful resources for utilizing sports in the secondary ELA classroom. Enjoy!
Edited Book
Developing Contemporary Literacies through Sports: A Guide for the English Classroom
Edited by Alan Brown and Luke Rodesiler (2016)
Publisher: NCTE Books
Interview with Editors Alan Brown and Luke Rodesiler: Education Talk Radio
Honoring Students' Interests in Sports to Support Literacy Learning: NCTE Blog Posts by Luke Rodesiler and Alan Brown
Seminar on Critical Literacy on the Intersections of Sport and Society: Live Web Seminar Thursday, February 23, 2017
"Sports and YA: Introducing an Approach to Using Sports Literature in the Classroom and a Text Full of Advice" by Dawan Coombs – YA Wednesday Blog
Themed Issue of English Journal
A Whole New Ballgame: Sports and Culture in the English Classroom
Volume 104, Number 1, September 2014
Guest Editors: Alan Brown and Chris Crowe
Interviews with Alan Brown on the topic of Sports Literacy
TheStagazine (Volume 1): Interview by Dr. Bryan Ripley Crandall (see p. 3)
Education Talk Radio: Interview with Alan Brown and Luke Rodesiler
Sports-Related Lesson Plans/Resources
Sports Literature Syllabi & Programs
Paisley IB Magnet School Sports Literacy Program – Alan Brown & Wendell Dunn (Wake Forest University)
Southwest Guilford High School Sports Literacy Program – Alan Brown & Jordan Daniels (Wake Forest University)
Honoring Students' Interests in Sports to Support Literacy Learning – Alan Brown (Wake Forest University)
Building a Sports Literacy Program by Connecting Students and Authors at Newnan High School (GA) – Teacher: Kelli Sowerbrower (NCTE 2016)
Literacy4Hope by Bryan Ripley Crandall (Fairfield University, NCTE 2014)
The Literature of Sport at Scituate High School (MA) – Teacher: Jessica Maguire
Sports Fiction at Mary Washington University – Instructor: Teresa Kennedy
Sports in Literature at The University of Western Ontario – Instructor: Don Morrow
Sports Literature at Nashoba Regional High School (MA) – Teacher: Stephen Kendall
Sports Literature at East Greenwich High School (RI) – Teacher: Marc Brocato
Sports Literature at Iola-Scaninavia High School (WI) – Teacher: Terrell Bonnell
Sports Literature at Tewksbury Memorial High School (MA) – Teacher: Andrew Bellistri
Sports Literature at Timberline High School (WA) – Teacher: Daniel Hardebeck
Sports Literature at Trine University (IN) – Instructor: Dr. Alison Witte
Sports Literature Classes at Southeast Missouri State University
Teaching Sports Literature – The Sport Literature Association
Media Literacy & Social Issues
Digital Media Literacy in a Sports, Popular Culture, and Literature Course by Carolyn Fortuna (The Journal of Media Literacy Education)
Images of the Athlete: Sports and the Social Construction of Gender by David M. Pegram (Paradise Valley Community College; NCTE 2016)
Media Influence on Attitudes and Behaviors by Renee Hobbs (Media Education Lab)
Sports Stories and Critical Media Literacy by Mark A. Fabrizi and Robert D. Ford (English Journal)
Sporty Girls and Tomboys: Negotiating the Rhetoric and Images of Female Athletes by Crystal L. Beach (University of Georgia) and Katie Dredger (James Madison University)
Teach Media Literacy with Super Bowl Ads by Frank W. Baker (MiddleWeb)
Literature Study & Young Adult Literataure
Addiction and Redemption in Smashed: Extending the Discussion of Teen Women and Sports by Melinda McBee Orzulak (Bradley University; NCTE 2014)
Articles of the Week by Kelly Gallagher
Boars and Baseball: Making Connections by Cathy Allen Simon (Urbana, Illinois; ReadWriteThink)
Boy21 Teaching Ideas by Carmen Bartley (Annandale High School, Annandale, VA) and Greg Bartley (Lee High School, Springfield, VA) (NCTE 2013)
Creating Literature Circles Using Sports Memoirs by Ryan Skardall (Wardlaw-Hartridge School, NJ; NCTE 2014)
Crossing Finish Lines: Engaging Students with Chris Crutcher's Sports-Related Young Adult Literature by Caitlin Murphy (Collins High School, Louisville, KY) and Jennifer Bonafide (Langley High School, McLean, VA; NCTE 2013)
Forging Character: The Intersection of Nature, Self, and Extreme Sports by Elizabeth G. Dinkins (Bellarmine University; NCTE 2016)
"From Politics to Pesonal Expression: Representations of Sport in Walter Dean Myers' Young Adult Works" by Ray Schuck
Graphic Novels, Visual Literacy, and Baseball by David M. Pegram (Paradise Valley Community College; NCTE 2014)
If Only Holden Caulfield had been Stupid Fast: Promoting Critical Thinking through Active Imagination by Kelli Sowerbrower (Georgia State University) and Alan Brown (Wake Forest University) (NCTE 2013)
International Sport YAL in Practice: Consideration of Two Postcolonial Titles by Wendy Glenn (University of Connecticut, NCTE 2016)
Legend of Bagger Vance. (n.d.). Retrieved September 29, 2011 from the Human Science Wikia
"More Than Sports Stories" Podcast from ReadWriteThink
Second Reaction: The Impact of Sports Literature on Adolescents and Young Adults – Robert Lipsyte's The Contender by Alan Brown (Wake Forest University)
Teaching and Reading Guides for novels by Chris Crutcher
Vaguely Literary by Sam Rubenstein (SLAM Magazine)
Young Adult Literature: Sports Literature for Young Adults by Chris Crowe (JSTOR link)
A Poem of Possibilities: Thinking about the Future by Susanne Rubenstein (Princeton, MA; ReadWriteThink)
A Race with Grace: Sports Poetry in Motion by Maureen Carroll (Pleasanton, CA; ReadWriteThink)
Baseball Poetry and Songs (Baseball Almanac)
"Casey at the Bat" and Character Trading Cards
Diamante Poems (ReadWriteThink)
"LeBron James" by Nate Marshall (YouTube)
March madness poetry tournament (NCTE)
Poems for sports (Poetry.org)
Poetry Madness: Kobe Edition by Adrienne Raphel (Poetryfoundation.org)
Poetry Man by David Krell (National Baseball Hall of Fame)
"Take a Knee" by Kwame Alexander
The Poets' Corner: Sports Poems
That Sounds Fun! Sound Words and Sports Poetry by Jamie R. Wood (Portland, OR; ReadWriteThink)
Swish! Pow! Whack! Teaching Onomatopoeia Through Sports Poetry by Ann Kelly Cox and Amanda Jenkins (Normal, IL; ReadWriteThink)
"Wrestle the Great Fear: A Performance Poetica" by Jeff Kass
ESPN 30 for 30 Short on Jake by Alfred Slote
Girls in Basketball Texts: Representation, Resiliency, and Writing by Elizabeth Dinkins (Bellarmine University, NCTE 2014)
How Would You Change Your Favorite Sport? by Caroline Crosson Gilpin (The New York Times)
Model Essays, Sports, and Criticality: Examining the Everyday with Top Writers by Mitch Nobis (Seaholm High School, NCTE 2016)
Narrative, Argumentative, and Informative Writing about Baseball by Jonathan Olsen, Sarah Gross, and Katherine Schulten (The New York Times)
Write Like This: Sports as a Vehicle for Real-World Writing by Jordan Daniels and Joan F. Mitchell (Wake Forest University; NCTE 2013)
Write Like This: Teaching Real World Writing through Modeling and Mentor Texts by Kelly Gallagher
See Kelly Gallagher's lesson on Mentor Texts: Rick Reilly's "A Tale of Two Little Leaguers" (p. 149)
Writing a Flashback and Flash-Forward Story Using Movies and Texts as Models by Michelle Kimbro (Oakwood, IL; ReadWriteThink)
Writing the Game: How Athletes and Coaches Use Writing by Rich Kent (University of Maine, NCTE 2014, WritingAthletes.com)
Zines for Kids: Multigenre Texts about Media Icons (ReadWriteThink, NCTE)
Todd Marinovich's Paintings (see also ESPN's 30 for 30 on The Marinovich Project)
Rhetoric Friday by Randy Fair (Milton, GA; The New York Times)
Communication Arts: Going, Going, Gone (National Baseball Hall of Fame)
Research and Inquiry
Sports Opinionaire by Jeffrey Wilhelm (Boise State University, NCTE 2016)
Beyond Solo Pedestrian Reading: Group Inquiry and the Loneliness of the Long Distance Runner by Thomas C. Crocunis and Evan Hallman (Shippensburg University; NCTE 2014)
The Year I Was Born: An Autobiographical Research Project by Patricia Schulze (Yankton, SD; ReadWriteThink)
March Madness: Using Tournament Brackets to Debate Academic Questions (The New York Times)
Current Events and Issues
Capitalizing on Contemporary Issues in Sports: The Concussion Controversy by Rob Ford (North Branford High School, NCTE 2016)
Sports News (Newsela)
Using Current Events to Tell the Story of Our Times by Christopher Brown and Colleen Caulfield (Norwich Free Academy; NCTE 2014)
What is Sport for? (thepointmag.com)
History/Social Studies
Baseball Divided: Segregation and Discrimination in Baseball (PBS)
Baseball, Race Relations, and Jackie Robinson (Library of Congress)
Borrowing from Fantasy Sports to Teach Current Events and Geography (The New York Times)
Civil Rights History: Before You Could Say "Jackie Robinson" (National Baseball Hall of Fame)
Cultural Diversity: Diversity in the Dugout (National Baseball Hall of Fame)
Geography: Coast to Coast (National Baseball Hall of Fame)
Mapping Baseball (PBS)
Negro Leagues Lesson Plans by Historical Time Frame (Negro Leagues Baseball Museum)
Something Like the Gods: A Cultural History of the Athlete from Achilles to LeBron by Stephen Amidon
Sports and Games of the Ancients by Steve Craig
Women in Baseball (PBS)
Women's History: Dirt on their Skirts (National Baseball Hall of Fame)
A Basketball Team Helped by Math by Katherine Schulten (The New York Times)
A Graphical History of Baseball by Michael Bein
Baseball Batting Lineup (Promethean Planet)
Baseball Geometry (PBS)
Busting the Brackets! Mathematics and the NCAA Tournament (The New York Times)
Economics: The Business of Baseball (National Baseball Hall of Fame)
Fantasy Football Project by Kristin McGahan (Wake Forest University)
Finding the Angle that Can Change Her Life by Kristen Meier (Wake Forest University)
Fun with Baseball Stats (NCTM)
Geometry: Circling the Bases (National Baseball Hall of Fame)
Honner, P., & Ojalvo, A. P. (2011, October 26). Put me in, coach! Getting in the quantitative game with fantasy football. The New York Times.
Let's Go Fishing by Matthew Tysinger (Wake Forest University)
Mathletics: How Gamblers, Managers, and Sports Enthusiasts Use Mathematics in Baseball, Basketball, and Football by Wayne L. Winston
Put Me in, Coach! Getting in the Quantitative Game with Fantasy Football (The New York Times)
Sports Mathematics by Cynthia Adams, Christina Cronrath, Tracy Foote, Wayne Miller, Jeanie Shaw, & Leah McCoy
Stadium Consultants (PBS)
Statistics: Batter Up! (National Baseball Hall of Fame)
Aerodynamics of Baseball (NASA)
Health Science: Be a Superior Example (National Baseball Hall of Fame)
Innovation: Tools of the Trade (National Baseball Hall of Fame)
Keeping up with the Joneses by Philip J. Stephens (National Center for Case Study Teaching in Science)
"Laws of Motion" in Pick-up Game: A Full Day of Full Court by Marc Aronson and Charles R. Smith, Jr.
The Olympics: Body and Mind (PBS Newshour Extra)
Physical Science: Science on the Sandlot (National Baseball Hall of Fame)
Reaching for Olympic Glory (AAAS Science Net Links)
Rough Games and the Brain by Peggy Brickman (National Center for Case Study Teaching in Science)
The 2000-Meter Row by Nathan Strong (National Center for Case Study Teaching in Science)
The Ice Hockey Injury by Philip J. Stephens (National Center for Case Study Teaching in Science)
The Science of Sports (Series of books: baseball, basketball, football)
Critical Thinking
Play Ball! Encouraging Critical Thinking through Baseball Questions by Dr. Helen Hoffner (Ridley Park, PA; ReadWriteThink)
All Around the Baseball Field (Kennedy Center for the Performing Arts)
"For Many Goalies, Masks Are an Artful Identity" (The New York Times)
Perfect Pitch (Kennedy Center for the Performing Arts)
2016 Summer Olympics
"Amazement Awaits" by Dr. Maya Angelou
From Athletics to Academics: How to Use Olympic Games to Boost Your Kid's Vocabulary (NBC News Education)
Gold Medal Olympic Activities (Education World)
Olympic Games – Resources for Teachers (TeacherVision)
Teaching about the 2016 Summer Olympics (National Education Association)
Teaching Resources (The Olympic Museum)
The Summer Olympics (ReadWriteThink sponsored by NCTE and ILA)
Books Connecting Sports and Literacy
Literacy lessons to help kids get fit & healthy by Michael Opitz and Jennier Davis-Duerr (see also Fitness Literacy)
More than a game: Sports literature for young adults by Chris Crowe
Writing on the bus: Using athletic team notebooks and journals to advance learning and performance in sports by Rich Kent
Out of bounds: When scholarship athletes become academic scholars by Jabari Mahiri and Derek Van Rheenen
Articles Connecting Sports and Literacy
Alvermann, D. E., Huddleston, A., & Hagood, M. C. (2004). What could professional wrestling and school literacy practice possibly have in common? Journal of Adolescent & Adult Literacy, 47(7), 532-540.
Baker, W. D. (2007). When English language arts, basketball, and poetry collide. English Journal, 96(5), 37-40.
Brown, A. (2014) Second reaction: The Contender. First Opinions, Second Reactions, 7(1), 32-34.
Brown, A., & Crowe, C. (2013). Ball Don't Lie: Connecting Adolescents, Sports, and Literature. The ALAN Review, 41(1), 76-80.
Cantey, C., Bach, J., & Bickmore, S. T. (2009/2010). Why we read what middle school boys are reading. SIGNAL Journal, 33(1), 3-7.
Cowley, J. (2012, January 22). Beyond The Art of Fielding: Why American novelists turn to sports. Slate.
Crowe, C. (2001). Young adult literature: Sports literature for young adults. English Journal, 90(6), 129-133.
Dyson, A. H. (2001). Coach Bombay's kids learn to write: Children's appropriation of media material for school literacy. In Cushman, E., Kintgen, E. R., Kroll, B. M., & Rose, M. (Eds.), Literacy: A critical sourcebook (pp. 325-357). Boston: Bedford/St. Martin's. (Reprinted from Research in the Teaching of English, 33(4), 367-401)
Egwuonwu, O. (2008). The Transitional Voice of Walter Dean Myers. Mosaic, 22. Retrieved from
Johnson Jr., R. (2002). Say it ain't so, Jay: Fitzgerald's use of baseball in The Great Gatsby. The F. Scott Fitzgerald Review, 1(1), 30-44.
Krieger, E. (1992). Reading, writing, and the Red Sox. Journal of Reading, 35(8), 680-681.
Minchew, S. S. (2002). Teaching character through sports literature. The Clearing House, 75(3), 137-141.
Miller, A. M. (2014). Sport: A powerful topic to generate language work. Modern English Teacher, 23(3), 56-59.
Nasir, N. S. (2008). Everyday pedagogy: Lessons from basketball, track, and dominoes. Phi Delta Kappan, 89(7), 529-532.
Spencer, P. (1989). YA novels in the AP classroom: Crutcher meets Camus. English Journal, 78(7), 44-46.
Suen, A. (2011). Read and write sports: Readers theatre and writing activities for grades 3-8.Santa Barbara,CA: Libraries Unlimited.
Wulf, S. (2011, October 3). The [dis]passion of John Henry: One man's Dickensian approach to building a sports empire. ESPN the Magazine.
Young, J. P. (2001). Displaying practices of masculinity: Critical literacy and social contexts. Journal of Adolescent & Adult Literacy, 45(1), 4-14.
Zitlow, C. (1995). Young adult literature: Did Patty Bergen write this poem? Connecting poetry and young adult literature. English Journal, 84(1), 110-113.
Statistics on Education and Sport
Gillis, J. (2007). 7.3 million participants in high school sports. High School Today, 1(2), 6-7.
National Association for Sport and Physical Education (NASPE) (2008). National coaching report: The state of coaching in the U.S. Reston,VA: Author.
National Federation of State High School Associations (NFHS) (2011). High school sports participation continues upward climb. Indianapolis, IN: Author.
Sports Magazines and Other Web Sites
See World-Newspapers.com for a more extensive list of sports magazines and Web sites
Other Book Depositories
Thriftybooks Used Books – Sports
Barnes & Noble Teen Fiction – Sports


text: Another India's Advertisement against Pakistan regarding Crackers Hey Visitors! finally another most funny tv advertisement disclosed by Indian news channels, that's the way he99 is going to share with this another funny cricket advertisement which is against Pakistan team. Have a look at this below. Thursday, February 26, 2015 Videos


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Oskar Almazan's curator insight, November 1, 8:13 AM
En marketing, a great image is often a key component of the message. Constant need for pictures can dig deep into your pocket when using stock photography. If you want a particular image, then it makes sense to pay for the stock images as it will be a lot cheaper than to hire a photographer. What to do when you need images all the time, but their marketing lifespan can be measured only in days, maybe hours? Images for Facebook posts, email newsletters, individual slides in presentations that you use only once… Paying 10 or 20 dollars per image for these adds up. So where do you get free images? I have collected a bunch of sites that give you exactly that… free images for commercial use.
Art Jones's curator insight, November 3, 12:02 PM
The Rise of Visual Storytelling
One picture is worth 60,000 words because the brain process images 60,000 times faster than it can process text. 90% of all information processed by the brain is visual.
Attention is the new commodity and visual storytelling is the perfect currency you can use to acquire the attention of your ideal buyer.
To help you tell more compelling stories, this post includes 39 platforms where you can acquire images for FREE. Be sure to bookmark the page.
Sarah McElrath's curator insight, September 11, 4:13 PM
This is an interesting take on note-taking since one of the most difficult parts of note-taking is getting kids to actually look back at those notes.
Gaby K. Slezák's curator insight, September 15, 5:53 AM
interesting take on a notebook app - to turn your notes into Q&A cards so you'll actually train your brain with what you once deemed noteworthy. Nice idea.


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There's exciting news for chauffeurs around the world after Lamborghini admitted it was considering building a sedan to join its two-seater-only supercars.
The Volkswagen-owned Italian marque unveiled a four-door concept car called the Estoque at the 2008 Paris motor show, and it is now contemplating a production version to reverse a decline in sales.
Lamborghini's global year-on-year sales are down nearly 20 per cent despite a recovery in high-end vehicle markets.
The company believes it could attract new customers with a four-door sports sedan that would rival the likes of the Porsche Panamera, Maserati Quattroporte, Aston Martin Rapide and Ferrari 612 Scaglietti.
"A third model would fit Lamborghini very well," said Lamborghini boss Stephan Winkelmann.
"A four-door car would be a very feasible approach."
Lamborghini hasn't launched an all-new model since the 2003 Gallardo, a supercar that has helped increase sales ten-fold under VW stewardship.
Its next car due soon is a replacement for the ageing Murcielago.
The Gallardo and Murcielago both position their engines behind the driver, but the sedan – if confirmed – can be expected to follow the Estoque concept and place its powerplant up front under what would be a relatively long bonnet for a Lamborghini.
The Estoque was powered by a 5.2-litre V10 capable of propelling the aluminium-bodied four-door to speeds in excess of 300km/h.


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Saturday, May 02, 2009
Enigman at the Crossroads
Tiring of blogging (not so much reading others, as posting my own), it's time for Enigman to retire. There's a local conference in a couple of months, but even if that inspires me with any interesting thoughts, they'd be hopeless for blogging purposes. It seems to take me months to make my thoughts coherent. Incidentally, a lot of my links will stop working soon, as my web-pages are on Geocities, which is closing this summer. I may move those web-pages to this site, probably after re-writing them (most were written a few years ago). The other thing I'll be doing this summer is starting to study theology properly (and catch up on my reading). My philosophical interests were re-ignited ten years ago, via the metaphysics of mathematics, but were nearly quenched by professional analytical philosophy (with few exceptions, e.g. Iris Murdoch). Anyway, thanks for the comments, which made trying my hand at blogging worthwhile.
Posted by Martin Cooke at 5/02/2009
1 comment:
- Natalia said...
Hi, how can I contact you?
I want to start, a list of philosophy BLOGS. A small presentation of the thing, a library or address book. But one question I don't know is, how to contact people through blogs, I'm not familiar with this medium.
If time permits, I want you to make a post here,
It will get stickied and start a list of philosophy blogs. You could write a small intro too, like "Here is a index and library of PHILOSOPHY blogs ...."
Already an index of BBS is here,
Kind regards,
- Niki
- June 03, 2009
Subscribe to: Post Comments (Atom)


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Courses Offered
About Dublin Institute Of Technology
Dublin Institute of Technology is distinguished by its lecturers' commitment to their students' success. To this they bring creativity, experience, expertise and scholarship, combining the academic excellence of a traditional university with career-focused learning. As one of the institute's students you will obtain the knowledge and abilities to contribute to a complex and ever-changing world. When you graduate you will be among the thinkers, doers and leaders who can respond successfully to our globally interdependent and technologically-advanced society.
With a history stretching back over 125 years, Dublin Institute of Technology pioneered technological higher education: the Institute's alumni play important roles in technical and scientific innovation, economic and social development and culture and education both in Ireland and internationally. Dublin Institute of Technology nurtures innovation and creativity across and between disciplines and have been committed to making education accessible to people from diverse backgrounds.
The Dublin Institute of Technology has six main centres in Dublin City. The institution plays a leading role in technological and business education in Ireland. Its technological strengths are centred in the faculties of Engineering, Science, Business,Tourism & Food and the Built Environment. It also has substantial involvement in the area of Applied Arts with particular strengths in music, art & design, media, modern languages, legal studies and social science.
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B.Eng - Civil Enginering
Dublin Institute Of TechnologyIreland
Duration3 yearsIntakesSepTuition fee (entire course)Local-InternationalEUR 31,500
BA - Journalism with a language
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Dublin Institute Of TechnologyIreland
Duration4 yearsIntakesSepTuition fee (entire course)Local-InternationalEUR 46,000