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Chronic myelogenous leukemia (CML) results from the neoplastic transformation of a haematopoietic stem cell. The hallmark genetic abnormality of CML is a chimeric BCR/ABL1 fusion gene resulting from the Philadelphia chromosome rearrangement t(9;22)(q34;q11). Clinical and laboratory studies indicate that the BCR/ABL1 fusion protein is essential for initiation, maintenance and progression of CML, yet the event(s) driving the transformation from chronic phase to blast phase are poorly understood.
Here we report multiple genome aberrations in a collection of 78 CML and 14 control samples by oligonucleotide array comparative genomic hybridization. We found a unique signature of genome deletions within the immunoglobulin heavy chain (IGH) and T cell receptor regions (TCR), frequently accompanied by concomitant loss of sequences within the short arm regions of chromosomes 7 and 9, including IKZF1, HOXA7, CDKN2A/2B, MLLT3, IFNA/B, RNF38, PAX5, JMJD2C and PDCD1LG2 genes.
None of these genome losses were detected in any of the CML samples with myeloid transformation, chronic phase or controls, indicating that their presence is obligatory for the development of a malignant clone with a lymphoid phenotype. Notably, the coincidental deletions at IGH and TCR regions appear to precede the loss of IKZF1 and/or p16 genes in CML indicating a possible involvement of RAG in these deletions.
The BCR/ABL1 fusion, housed in the Philadelphia chromosome and resulting from t(9;22)(q34;q11) or variants, is the hallmark of chronic myeloid leukemia (CML) and the most frequent recurrent genetic aberration in B lymphoid leukemia in adults [1,2]. The BCR/ABL1 fusion gene encodes a constitutively active tyrosine kinase that is necessary and thought sufficient to drive malignant transformation. The natural history of the disease follows progression from a relatively benign chronic phase, through accelerated phase into terminal blast crisis. This course of events can be diverted or aborted by nearly curative therapies, such as tyrosine kinase inhibitors, transplantation and occasionally interferon [3] The staging of CML is based on clinical and pathologic features, including bone marrow and peripheral blood count, cytogenetic evolution and response to therapy rather than biological criteria. Although at present the molecular mechanisms that contribute to the development of the blast crisis are largely unknown, it is well established that the Ph bearing cells acquire additional genetic changes during disease progression [3,4]. There is evidence that the BCR/ABL1 fusion product not only regulates numerous proteins involved in apoptosis, proliferation and cell-cell interactions but also is a driving force behind the acquisition of additional genomic changes through regulation of the nucleotide excision/mismatch repair systems and promoting unfaithful restoration of double strand breaks [5]. This activity could lead to the formation of mutations within the BCR/ABL1 kinase and accumulation of additional genetic lesions, including point mutations, gene amplifications, genome loss and chromosome translocations that are believed to drive the malignant process [6,7]. Mutations or abnormal expression of CDKN2A/2B, EVI-1, RB, MYC and p53 among others have been reported in CML (reviewed in Radich [3]). Gene expression profiling studies have identified a relatively large number of additional genes that are differentially expressed in patients at advanced stages of the disease but no consistent pattern has as yet been established (for review see Guintas-Cardama, 2009 [4]). While recurrent genome gains at a chromosomal level, such as +8, +19, +Ph and/or iso17q, are associated with disease progression, the occurrence of translocations is infrequent[8]. The identification of cryptic deletions at der(9)t(9;22) fuelled expectations that submicroscopic lesions may mark disease evolution [9]. Indeed genome wide searches using array comparative genomic hybridization (aCGH) by us and others clearly demonstrated the accumulation of genome imbalances in advanced stages of the disease [10,11]. As the neoplastic transformation is occurring early in a haematopoietic stem cell, the resulting blast crisis (BC) in CML could be myeloid (BCM), lymphoid (BCL), or indeed mixed (BCmix). Lymphoid BC occurs in about a third of the CML patients [12] . Previous studies have shown that the BCL is characterized by the loss of IKZF1 in the majority of the BCR/ABL1 positive ALL cases and loss of CDKN2A/B in approximately half of the CML/BCL patients [13]. These losses were rarely present in non-BCL patients [14].
Here we report an analysis by oligonucleotide array comparative genomic hybridization (aCGH) showing the detection of universal deletions within both the immunoglobulin heavy chain and T cell receptor loci exclusively present in lymphoid blast crisis CML. These deletions are accompanied in a sub-set of cases by concomitant genome loss of regions within chromosomes 7 and 9, including the IKZF1 and CDKN2A genes, which appear to be associated with variety of structural chromosome changes - from cryptic interstitial deletions to unbalanced rearrangements resulting in short arm or whole chromosome loss.
The fluorescence ratio (FR) standard deviation (SD) for each of the 92 samples analysed with the 105 K array, ranged from 0.057 - 0.187 with a median value of 0.092. In a preliminary analysis of recurrent events, we detected a set of 1,262 loci in the BC cohort with a FR outside a threshold of ±4 SD that were seen in two adjacent probes in at least 3 samples. 410 loci corresponded to known genes after correction for copy number variations (CNV) identified by Redon et al [15]. These genes were found to be associated with Focal adhesion, MAPK signalling and Cell cycle control and their distribution across the genome is shown in Additional file 1: Figure S1.
Additional file 1. Figure S1. Active genome loci in cml.
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(i) Significance Analysis of Microarrays (SAM) identifies concomitant genome losses associated with lymphoid blast transformation
We chose SAM to carry out a 2-class analysis based on myeloid and lymphoid BC CML for 74 samples - 60 CML and 14 control samples (Additional file 2: Table S1). Altogether 435 loci were found with a FDR = 0. We plotted the "expected" versus "actual" values of delta, the metric that quantifies the difference between the two classes and selected for further detailed consideration the top 22 that displayed an enhanced value of delta (Additional file 3: Figure S2). The heat map in Figure 1 illustrates the results of a hierarchical cluster analysis of these probes. The complete set of the 435 significant probes with reference to location, genome assignment and scores are given in the supplementary data (Additional file 4: Table S2). Among the known genes covered by these genome loci are IKZF1, HOXA7, CDKN2A/2B, MLLT3, IFNA/B, RNF38, PAX5, JMJD2C and PDCD1LG2.
Additional file 2. Table S1. Id number, sex and disease stage of the 92 cml samples.
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Additional file 3. Additional Figure 2. Observed vs expected values of delta (Δ) for ~100,000 probes.
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Additional file 4. Additional Table 2. Annotated flourescence ratio data for 105 k arrays: Listing of probes, locations, gene assignments, lineage, gender and sample identifiers.
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The heat map (Figure 1) shows a dramatic demarcation between lymphoid/mixed lineage and the remaining samples where the green coloured columns indicate the consistent genome loss. The top 22 most significant loci are restricted to four chromosome regions, namely 7p12-14, 9p21-24, 14q11.2 and 14q32.33. Their deletion status in the 10 BCL and 2 BCmix samples is shown in Figure 2, where the probes are grouped by their genomic location. None of these probes are consistently deleted in any of the other samples studied. The probes fall into two main groups. The primary group members, highlighted in colour in Figure 2, are nearly always deleted. These include probes covering the regions of IGH, TCR and IKZF1 genes. The gains and losses for all cases in the IGH region are summarised in Figure 3. The locus at chr14:105.41 shows a 100% loss unique to the BCL class (in blue) whereas the loci at chr14:105.61 and chr14:105.62 display either gains or losses typical of CNVs. A region mapping to parts of the T-cell receptor gamma chain complex region (TCRG) extending from chr7:38.27 to chr7:38.32 on chromosome 7p14.1 is also frequently deleted (Figure 4). There are five array probes in this region, three of which are deleted in 11/12 samples (Figure 2). There are three probes in the 105 K arrays covering the IKZF1 (Ikaros) gene, all of which are deleted in 9/12 samples (Figure 2). The remaining probes make up the second group, which represents the full concomitant loss of loci within the 7p12-14, 9p13-24.1 and 14q11.2 regions shared by 7 of the 12 BCL samples (Figure 1 and Figure 2).
Figure 1. Heat map showing the 22 most signigicant probes for the lymphoid/myeloid dichotomy identified by sam analysis. The top 22 probes showing genome loss (in green) from a set of 435 probes identified by SAM analysis in a cohort of 60 CML and 14 control samples as significant for lymphoid blast crisis (BCL). Data fall into three clusters: on the right are 8 BCL cases, on the left are 3 lymphoid together with 2 mixed lineage (BCmix) cases, while myeloid (BCM) and chronic phase (CP) samples make up the center cluster.
Figure 2. Unique genome loss in cml/bcl samples at address 105.41 within the IGH region. Graphic representation of CML/BCL samples (vertical axis) showing imbalances in the IGH region at 14q32.33 for the probes on the 105 K Agilent arrays (genome address shown at the bottom) with squares marking the FR values in excess of ±3 SD (calls), gains shown above and losses below with samples of chronic phase (in green), myeloid blast crisis (red) and lymphoid blast crisis (blue). Note that losses dominate the lymphoid blast samples and that the probe at 105.41 Mbp is lost in all cases.
Figure 3. Concomitant losses in lymphoid blast crisis of cml: top 22 genome loci. The probe ID (Agilent), genome address, chromosome location, gene content and distribution of the losses among the 12 Lymphoid BC in the studied cohort of 78 CML samples are shown.
Figure 4. Unique genome loss in cml/bcl samples at address 38.27-32 within the tarp/tcrg region. Graphic representation of CML/BCL samples (vertical axis) showing imbalances in the TARP & TCR gammaregion at 7p14.1 for the probes on the 105 K Agilent arrays (genome address shown at the bottom) with squares marking the FR values in excess of ±3 SD (calls), gains shown above and losses below with samples of chronic phase (in green), myeloid blast crisis (red) and lymphoid blast crisis (blue). Note that losses are present exclusively in the lymphoid blast samples (arrow).
(ii) Verification of the 105 K array results
Both FISH and aCGH on high-resolution custom oligonucleotide arrays were used to verify of the 105 K array results. FISH analysis of the TCR and IGH data was considered inappropriate due to the small size of the loci involved (2 - 50 k). All FISH tests for deletions of IKZF1, CDKN2A, MLLT3, PAX5, JMJD2C and PDCD1LG2 on cases where chromosome preparation were available were positive. Furthermore, we identified complex clonal heterogeneity as summarized in Figure 5. We applied aCGH at ~1 k resolution to the TCR, IGH and IKZF1 loci on 40 samples, 10 from each group of BCL, BCM, CP and controls (Figure 6 and Additional File 5: Figure S3 and Additional file 6: Figure S4). The copy number aberrations (CNA) identified by the 105 K arrays were confirmed and in particular, the deletions of TCR and IGH were shown to be remarkably consistent. These deletions along with the IKZF1 loss were confirmed to be exclusively present in the BCL samples as indicated by the whole genome study. Furthermore, in case 163, a deletion of 119 Kb covering only exon 3 of the IKZF1 region was revealed thus increasing the involvement of this gene to 10/12 BCL samples (Figure 6).
Figure 5. Clonality and evolution of the concomitant 7p/9p genome loss revealed by fish. Screening by FISH chromosome preparations from CML patients using BAC and fosmid probes confirms the aCGH data and demonstrates the progression of the concomitant loss in lymphoid blast crisis of CML.
Figure 6. Mapping of IKZF1 (IKAROS) deletions at 1 kb resolution. Customized oligonucleotide aCGH results for IKZF1 (Ikaros) (exons 1-8, highlighted) for 9 CML/BCL samples. Cases 156 & 163 (arrowed) are reported normal by 105 K arrays, while the rest are deleted. The genome address is given on the left, where the large blue cross lines indicate the position of 105 K probes. Vertical lines represent results for each case - the hair lines map losses at a resolution of ~1 Kb. The two data sets are consistent for all samples but one (case 163), where the high resolution array revealed deletion of exon 3 only (red arrow), missed by 105 K array
Additional file 5. Figure S3. Mapping of igh deletions at average 1 kb resolution.
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Additional file 6. Figure S4. Mapping of tcr gamma deletions at verage 1 kb resolution.
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A comparison of the location of the IGH probes found as significant for the BCL samples with their corresponding VDJ segments within the IGH@ locus (IMGT database) is shown in Additional file 7: Figure S5. The probe at chr14:105.41 is located between the IGHJ1P and IGHD1-26 loci, while the chr14:105.48 probe - maps between IGHV4-4 and IGHV(II)-1-1. This suggests that the observed deletions in the BCL samples are likely to result from an early VD joining that precedes any rearrangements the IGH@ region (Additional file 7: Figure S5). Likewise, the probes found deleted within the TCRG were located at the V and J segments and could reflect a recurrent rearrangement. There are three probes in the 105 K array covering the TCR A/D region and they actually map within the TCRD sequences as follows: probe chr14:21.98 is located between TRDD2 and TRDD3, chr14:21.99 is located between TRDJ1 and TRDJ4 and chr14:22.00 is located between TRDC and TRDV3 (Additional file 8: Figure S6).
Additional file 7. Figure S5. THE IGH GENE COMPLEX.
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Additional file 8. Figure S6. The TCRG gene complex.
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(iii) G banding and molecular karyotype differ
While the array profile of the 12 samples with lymphoid/or mixed lineage immunophenotype share the concomitant loss of loci harboured by chromosomes 7, 9 and 14, their karyotypes show no recurring pattern. Aberrations ranged from a single Ph chromosome abnormality (4/12) to multiple structural and numerical aberrations of chromosomes 7 and 9 (3/12)(Additional file 9: Table S3). Only two samples (Case 156 and 200) showed chromosome 14q32 aberrations. 4/12 samples registered deletions of chromosomes 7 and 9 consistent with their aCGH profiles. In the samples with segmental deletions losses of the short arm varied in size from 5 to 20 Mb, whilst chromosomes 7 and/or 9 are monozygous (Additional file 10: Figure S7). In cases 156, 163 (mixed lineage) and 181, the IKZNF1 locus was diploid whilst loci within TARP and TCRG at 7p14.1; TCRA at 14q11.2 and IGH at 14q32.33 were all deleted (Figure 2, Additional file 11: Figure S8). Case 181, which by G banding had a Ph chromosome as the sole karyotypic abnormality, was shown by array to be monozygous for the short arm of chromosome 7 with a break within 7p12.2 flanking IKZNF1 (which remains intact) together with a loss of the 9pter-p13.1 including the loci from the concomitant deletion (Additional file 11: Figure S8). Discrepancies between the genome profile and the chromosome findings were also recorded in Case 163 where array analysis showed a genome gain of almost the whole long arm of chromosome 17 and extra copy of an ~8 Mb region at 21q22.12 containing some of the Down Syndrome Critical regions, ERG and ETS2 among other known genes (Additional file 11: Figure S8).
Additional file 9. Table S3. Immunophenotype and karyotype data for 27 samples from patients in blast crisis of cml.
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Additional file 10. Figure S7. Representative array cgh profiles of concomitant loss of chromosomes 7 and 9 in cml lymphoid blast crisis.
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Additional file 11. Figure S8. Representative array cgh profiles of cml/bcl cases with intact ikaros.
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(iv) Evolution of the concomitant genome loss in BCL
FISH analysis was employed to address the discrepancies between the G banding and CGH data with main emphasis on chromosomes 7 and 9. The FISH results obtained in five cases, for which chromosome preparations were available, are summarized in Figure 5. Genome losses were confirmed in all cases studied as illustrated by the results for case 164 (Figure 7). Multiple Ph positive cell clones differing in the scope and composition of the 7p/9p regional loss were identified in 4 of the 5 cases studied ranging in complexity (Additional file 10: Figure S7). Therefore it is unlikely that the concomitant deletions in these cases result from a single event. Instead, a spectrum of consecutive aberrations probably leads to the formation of the concomitant loss.
Figure 7. Case 195: fish interogates discrepanicies between karyotype and acgh results. Summary of molecular cytogenetic results for case 195: (a) G banding; (b) Array CGH (105 K Agilent) profile of chromosomes 7 and 9 with arrows pointing to sites of imbalances at the short arm regions; Representative images of cells with FISH signals showing loss of one copy of (c) IKZF1 (green arrows), (d) PAX5 (yellow arrows), (e) p16 (red arrows) or both copies (green arrows), (f) PDCD1LG2 (red arrow) and (g) bi-allelic loss of MLLT3 (white arrows) thus confirming the aCGH data.
Although the frequency and size of the copy number aberrations varied greatly, samples from both accelerated and blast stage CML showed substantially larger numbers of genome imbalances than chronic phase. These aberration frequencies obtained at a resolution of 33 K by oligonucleotide aCGH are broadly in agreement with earlier investigations of CML samples using BAC [10,11] and SNP array CGH [14].
Altogether 435 loci were identified as significantly different in lymphoid and myeloid BC samples. All loci were located on the short arms of chromosomes 7 & 9, with the exception of 4 from chromosomes 14, 2 from chromosome 2 and a single chromosome 22 probe. Most of the probes mapped to known genes and a number were in regions associated with immune response. We show that deletion of certain regions within TCR (alpha/delta and gamma) (11/12) and IGH (12/12), are almost universal while being accompanied by deletions within IKZF1 (10/12) and, to a lesser extent, CDKN2A and sequences within several other genes in the short arm regions of chromosomes 7 and 9 (7/12). These genome losses were not seen in any of 31 CP, 6 accelerated and 12 BCM samples or controls. Furthermore, they were present in a BCL sample (Case 199) when DNA from the patient's CP was used as reference for the aCGH analysis, thus proving their secondary origin.
A recent genome wide single nucleotide polymorphism (SNP) array analysis of Ph positive samples - 43 ALL (paediatrics and adults) and 23 CML (11 CP, 9 BCM and 3 BCL) [14] - revealed the presence of three common deletions affecting the IKZF1, PAX5 and CDKN2A loci. These deletions, confirmed by FISH and qPCR, also detected in 2 out of 3 CML BCL samples, were not always co-existent. How the reduced activity of IKZF1 and PAX5 genes, that play a key role in regulating B lineage commitment, collaborates with BCR/ABL1 to induce Ph(+) ALL remains unclear [14,16]. The frequency of the genome loss described by Mullighan et al.,[14] in the Ph(+) ALL, is in overall agreement with our findings in CML lymphoid blast crisis. In particular, CDKN2A deletions are 53.5% in Ph(+)ALL . 58.3% in CML/BCL and PAX5 loss is seen in 51.% of Ph(+)ALL vs. 58.3% in CML/BCL, while deletions of IKZNF1 are seen in 20 of 22 adults with Ph(+)ALL (90.9%) [14] and our aCGH analysis at 1 K resolution detected loss in 10/12 CML/BCL samples (83.3%). In contrast with the Ph(+) ALL results, we found that the loss of IKZF1 always precedes the deletions of CDKN2A and that losses of RNF38 were always accompanied by loss of the 9p13-p23.1 region that houses, among others, CDKN2A, IFNA, RNF38, PAX5 and MLLT3. In addition, we demonstrated by FISH the presence of clonal evolution leading to the concomitant 7p/9p loss as seen in less than half of patients (5/12 samples) (see typical aCGH profiles in Additional file 10: Figure S7). Importantly, the cell clone bearing the concomitant loss in the studied cases was dominant and hence, detectable by aCGH.
No imbalances of IGH and/or TCR loci were reported in Ph(+) ALL study by Mullighan et al [14] either alone or in combination with IKZF1, CDKN2A or PAX5. Substantial parts of the IGH and TCR regions are known to show copy number variations (CNVs) in disease free individuals http://projects.tcag.ca/variation webcite, but whereas CNVs are characterised by amplifications and deletions of a specific locus within the sample population, we found a set of probes in the IGH and TCR regions to be universally deleted in exclusively lymphoid BC samples, thus showing features typical of secondary genomic aberrations. That they are not somatic aberrations is illustrated by Case 199, where identical features emerged when the BCL sample was hybridised against patient's DNA from the CP. These deletions characteristic of lymphoid BC were also identified in the 2 samples with mixed immunophenotype (Figure 1).
There are two possible explanations for the origin of these deletions. Either they represent genome losses associated with cross lineage rearrangements known to occur in both ALL and AML, or they represent a bona fide event with oncogenic potential. IGH/TCR rearrangement patterns are widely used to monitor minimal residual disease (MDR) in a range of haematological malignancies, the levels of which significantly correlate with clinical outcome [17]. The immunophenotype data for five of our 12 CML/BC samples that carry concomitant 7p/9p loss (cases 184, 192, 193, 195 & 200, Additional file 12: Table S4) are consistent with early B cell origin of the blast cells (TdT+, CD10+, CD19+, CD22+, CD7 neg, so it could be that the recurrent loss of the TCRG/D region in B cells with legitimate IGH rearrangements represents the lineage infidelity as reported previously in blast phase CML [18-21]. However, the similarity of the deletions within both immunoglobulin genes in BCL does not comply with the notion that IGH and TCR configurations are unique (clonal by origin and patient specific). The common deleted regions could indicate a preferential VDJ rearrangement in the clone that ultimately becomes dominant in the BCL patients. Such preferential VDJ usage has been reported before with a preference for the VH4 family segment in about 35% of children with B-ALL [22]. In our case the deletions in IGH and TCR loci possibly reflect the clonal origin of the malignancy and the stage at which the additional chromosomal aberrations that we observed were initiated. Further work needs to be done to relate these possibilities to the waterfall of changes that characterise blast crisis.
Additional file 12. Table S4. Sample data for 5 cases with lymphoid blast crisis.
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So, how does the loss of a relatively small ~100 Kb region from IGH and TCR contribute to the development of the lymphoid blast transformation? RAG1 and RAG2 (RAG) are the key components of the V(D)J recombinase machinery that catalyses the somatic gene rearrangements of antigen receptor genes during lymphocyte development. B cell progenitors undergo a development program involving ordered IGH gene rearrangements conducted by the RAG enzyme system. Recent evidence suggests that BCR/ABL1 induces expression of activation-induced cytidine deaminase (AID), found exclusively in early B cells. It participates in the class switch recombination and has been shown to lead to single strand breaks in IGH regions in Ph(+)ALL [23]. Therefore, it would appear that the deregulation of AID silencing by transcriptional or epigenetic factors is the key event in compromising the V(D)J recombination/RAG impairment. This could lead to the TCR rearrangements in B cells, which have already undergone IGH rearrangements and are expressing the CD10, CD19 and CD22 antigens. Thus genome losses identified in the BCL samples represent the consequence of cross lineage rearrangement i.e. DJ joining occurring in early B cells and aberrant incomplete recombination in the TCR complex.
This view is supported by Mullighan et al [14] who showed that the mechanism responsible for IKZF1 deletions in Ph(+) ALL appears to involve aberrant RAG mediated recombination as heptamer signal sequences were found internal to the deletion breakpoints. Similarly, CDKN2A loss was linked to RAG activity in lymphoid leukemia [24,25]. Furthermore, the impairment of the RAG system in Ph positive cells could be a direct consequence of the genetic damage caused by BCR/ABL1 [5,23] either through inflicting direct damage via reactive oxygen species or by compromised DNA repair [4,7]. It is also possible that the reduced/abolished expression of c-ABL [26] could further contribute to the impaired V(D)J recombination [27]. In summary, a chain of events initiated by BCR/ABL1 impairs the RAG enzyme system. The compromised V(D)J recombinase machinery is thus instrumental in creating, by means of cross lineage rearrangements, clonal populations of B-cell progenitors carrying IGH and TCR deletions.
We have observed a signature of deletions that is uniquely present in our lymphoid samples. The top 22 most significant loci are restricted to four chromosome regions, namely 7p12-14, 9p21-24, 14q11.2 and 14q32.33. Their common appearance points at an event that is orchestrating the cascade of aberrations leading to the lymphoid BC. Given the high frequency of IGH and TCRG loci deletions we speculate that the evolution into lymphoid blast crisis is initiated by abnormal RAG mediated NHEJ. It appears we are edging nearer to identifying the key aberrations responsible for blast transformation at least in a proportion of the CML patients.
Anonymous bone marrow (BM) archival samples
from chronic myeloid leukemia (CML) patients were collected from 5 European hospitals. Altogether 92 samples were analysed of which 78 were from CML patients, 31 in chronic phase, 10 in lymphoid blast crisis, 15 in myeloid blast crisis, 2 mixed lineage acute phase, 7 unclassified and 6 accelerated phase (Additional file 2: Table S1). In addition, paired chronic and blast phase samples were available for 7 patients, of which two were classified as lymphoid blast crisis. As controls peripheral blood mononuclear cell (PBMC) samples from 11 patients with cardiovascular disease (Approval from Ethical Committee of St Anna Hospital in Sofia, Bulgaria, No 54/28.02.2005) and 3 healthy individuals (Ethical approval by NRES at Royal Free Hospital and Medical School, Ref 09/Ho720/97) were used. Cytogenetic data were available for 25 chronic and 27 blast crisis patients (Additional File 4: Table S2). Presence of the BCR/ABL1 fusion gene was confirmed in all samples by qPCR and/or FISH (D-FISH probe, Vysis, USA). Immunophenotyping data was available for 5 lymphoid blast phase samples (Additional file 12: Table S4).
Array CGH and bioinformatics analysis
was performed with the Agilent 105 K oligonucleotide arrays (Wilmington, DE, USA) following the manufacturer's protocol. 500 ng genomic test DNA was extracted from either peripheral blood or BM samples. Sex mismatched pooled DNA from PBMC of 6 - 8 disease free individuals (Promega, UK) was used as reference in all but the seven CML patients where the matched CP and BC samples were hybridized against each other. Anonymous DNA samples from PBMC of patients with cardiovascular disease and healthy individuals were used as controls. The dye swapped arrays were scanned at 5 μm resolution and the resulting data analyzed using GenePix v6 software http://www.moleculardynamics.com webcite and MIDAS v2.19 http://www.tigr.org webcite. We chose to analyse the results on the basis of the fluorescence ratio (FR) calculated as the normalized ratio of test to reference DNA, using the simple ratio rather than the logarithmic ratio. We used an iterative method to calculate a standard deviation undistorted by outliers for the purposes of establishing a preliminary measure of aberration complexity threshold. The emergence of high throughput technology such as microarrays raises a fundamental statistical issue relating to testing hundreds of hypotheses thus rendering the standard P value meaningless [28]. Instead, the False Discovery Rate (FDR) concept is becoming the key statistical assessment tool replacing the P value. Tusher et al [29] described such a method, Significance Analysis of Microarrays (SAM) and the implementation due to Chu et al [30] has been incorporated by TIGR into their suite of 'MeV' routines. SAM uses permutations of the repeated measurements to estimate the FDR, the percentage of genes identified by chance. We used SAM with a FRD = 0 for the supervised analysis of the myeloid and lymphoid blast crisis, chronic and control samples. Firstly, after removing data for the sex chromosomes, we constructed a table defining the FR for each locus and assigned classes e.g. blast crisis (BC), chronic phase (CP) and Control; Lymphoid or Myeloid; Male or Female. We chose a two class unpaired test using myeloid vs. lymphoid immunophenotype, and applied SAM to ask if there were any probes that were uniquely associated with either blast cell lineage. All genome addresses are derived from build 35 (March 2006) of the Human Genome.
A Customized oligonucleotide array CGH
comprising 8 × 15 k probe sets per slide was manufactured by Agilent to our specification and used to verify the losses identified by the standard whole genome 105 K array. Oligonucleotide probes from Agilent were selected to cover regions at ~1 k intervals except from genome locations where the presence of repetitive sequences disallowed the design of reliable probes. The arrays were scanned, features extracted and the data analysed using an Agilent scanner and DNA Analytics software. High-resolution graphics were generated using Mathematica® http://www.wolfram.com webcite.
FISH mapping
was carried out for further verification of the aCGH results to identify the genome aberrations at a cellular level using Bacterial Artificial Chromosomes (BAC) clones obtained from the BACPAC Resources Center (Children's Hospital Oakland Research Institute, Oakland, CA, USA), the Sanger Centre (Cambridge, U) and Invitrogen (Paisley, UK) following protocols in routine use [31]. Where possible a minimum of 100 interphase and 50 metaphase cells were screened with a dual colour dual FISH assay using BAC/fosmid probes selected for optimal coverage of the regions of I KZF1, CDKN2A, MLLT3, PAX5, PDCD1LG2 and JMJD2C genes. The size of the FISH probes used was in the range of 200 - 400 Kb.
Authors' contributions
EN wrote the grant application and the manuscript, designed and supervised the study; DB performed array CGH and FISH experiments; JHR, AV, MV and HM contributed to G banding and FISH investigations; AC contributed to the analysis of the results and helped draft the manuscript; MA, KG carried out aCGH tests of the control samples and CG undertook the aCGH/SAM analysis and co-wrote the manuscript. All authors read and approved the final manuscript.
The anonymous archival DNA/chromosome suspension samples used in this study were kindly donated by Prof Dr N Cross (Salisbury, UK), Dr A Aventin and Dr F Sole (Barcelona, Spain), Dr D Muhlematter (Lausanne, Swiss), Prof Dr Ch Nachev and Dr M Apostolova (Sofia, Bulgaria) and Royal Free Hospital (London, UK). This work has been support by LRF grant No. 05098, Jean Coubrough Charitable Trust Project to Dr E Nacheva and Grant No G2/2004 of the National Science Fund of Bulgaria to Dr M Apostolova.
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Blood 1995, 85(8):2013-2016. PubMed Abstract | Publisher Full Text
Mullighan CG, Miller CB, Radtke I, Phillips LA, Dalton J, Ma J, White D, Hughes TP, Le Beau MM, Pui CH, Relling MV, Shurtleff SA, Downing JR: BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros.
Nature 2008, 453(7191):110-114. PubMed Abstract | Publisher Full Text
Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD, Fiegler H, Shapero MH, Carson AR, Chen W, Cho EK, Dallaire S, Freeman JL, González JR, Gratacòs M, Huang J, Kalaitzopoulos D, Komura D, MacDonald JR, Marshall CR, Mei R, Montgomery L, Nishimura K, Okamura K, Shen F, Somerville MJ, Tchinda J, Valsesia A, Woodwark C, Yang F, Zhang J, et al.: Global variation in copy number in the human genome.
Nature 2006, 444(7118):444-454. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Mullighan CG, Downing JR: Genome-wide profiling of genetic alterations in acute lymphoblastic leukemia: recent insights and future directions.
Leukemia 2009, 23(7):1209-1218. PubMed Abstract | Publisher Full Text
Velden VH, Hochhaus A, Cazzaniga G, Szczepanski T, Gabert J, van Dongen JJ: Detection of minimal residual disease in hematologic malignancies by real-time quantitative PCR: principles, approaches, and laboratory aspects.
Leukemia 2003, 17(6):1013-1034. PubMed Abstract | Publisher Full Text
Kerim S, Stul M, Mecucci C, Vandenberghe E, Cuneo A, Dal Cin P, Michaux JL, Louwagie A, Cassiman JJ, Berghe H: Rearrangement of immunoglobulin and TCR genes in lymphoid blast crisis of Ph(+) chronic myeloid leukaemia.
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Ohyashiki JH, Ohyashiki K, Tauchi T, Saito M, Nakazawa S, Kimura N, Toyama K: Immunoglobulin and T cell receptor gene rearrangements in Philadelphia chromosome-positive leukemia: a different involvement pattern in blast crisis and acute leukemia.
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Murakami T, Ohyashiki K, Ohyashiki JH, Kawakubo K, Tauchi T, Nakazawa S, Kimura N, Toyama K: Cytogenetic and immunogenotypic alterations of blast crisis cells in chronic myelogenous leukemia independently linked to immunophenotypic expression.
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di Celle PF, Carbone A, Lo Coco F, Guerrasio A, Diverio D, Rosso C, Lopez M, Saglio G: Identical utilization of T-cell receptor gene regions in B-lymphoid blast crisis of chronic myeloid leukemia and B-precursor acute lymphoblastic leukemia.
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Li A, Rue M, Zhou J, Wang H, Goldwasser MA, Neuberg D, Dalton V, Zuckerman D, Lyons C, Silverman LB, Sallan SE, Gribben JG, Dana-Farber Cancer Institute ALL Consortium: Utilization of Ig heavy chain variable diversity, and joining gene segments in children with B-lineage acute lymphoblastic leukemia: implications for the mechanisms of VDJ recombination and for pathogenesis.
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Feldhahn N, Henke N, Melchior K, Duy C, Soh B, Klein F, Von Levetzow G, Giebel B, Li A, Hofmann W, Jumaa H, Muschen M: Activation-induced cytidine deaminase acts as a mutator in BCR-ABL1-transformed acute lymphoblastic leukemia cells.
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Kitagawa Y, Inoue K, Sasaki S, Hayashi Y, Matsuo Y, Lieber MR, Mizoguchi H, Yokota J, Kohno T: Prevalent involvement of illegitimate V(D)J recombination in chromosome 9p21 deletions in lymphoid leukemia.
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Kohno T, Yokota J: Molecular processes of chromosome 9p21 deletions causing inactivation of the p16 tumor suppressor gene in human cancer: deduction from structural analysis of breakpoints for deletions.
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text:
OpalCD-Audio Lux
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- Paperback $9.63
- Publisher: Tantor Media, Inc
- Format: CD-Audio
- Dimensions: 137mm x 191mm x 13mm | 113g
- Publication date: 30 April 2013
- Publication City/Country: Old Saybrook, CT
- Edition: Unabridged
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- Sales rank: 1,464,033
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When Daemon Black set out to prove his feelings for Katy, he wasn't fooling around. Doubting him isn't something Katy will do again and now that they've made it through the rough patches, well, there's a lot of spontaneous combustion going on. But even Daemon can't protect his family from the danger of trying to free those they loved. With help coming from the most unlikely source and Adam's death still lingering with those who loved him, friends will become the deadliest of enemies and the villains will no longer be clear. When each step Katy and Daemon take in discovering the truth puts them in the path of the secret organization responsible for torturing and testing hybrids, the more Katy realizes there is no end to what she's capable of. They won't turn back, even if the outcome will shatter their worlds forever.
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Jennifer L. Armentrout is the "USA Today" bestselling author of the Covenant series and the Lux series. Justine Eyre is a classically trained actress who has narrated over two hundred audiobooks. With a prestigious Audie Award and four "AudioFile" Earphones Awards under her belt, Justine is multilingual and is known for her great facility with accents. Her recent television credits include "Two and a Half Men" and "Mad Men."
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"Armentrout keeps the momentum rolling with her third Lux entry. [Fans] will be enthralled from beginning to end. Katy and Dameon's heat sparks as the intrigue increases, too. Friends and enemies take sides, and the ending will leave [fans] yelling." ---RT Book Reviews

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text: Healthy Recipes Cranberry-Raspberry Jellies Recipe E-mail recipe Print recipe To save this recipe, register now! Quick Info: Servings Nutritional Info (Per serving): Calories: 71, Saturated Fat: 0g, Sodium: 1mg, Dietary Fiber: 1g, Total Fat: 0g, Carbs: 18g, Cholesterol: 0mg, Protein: 1g Carb Choices: 1 Recipe Source: Prep Time: 1 h 30 mins Total Time: 12 h 30 mins Preparation Lightly coat an 8-inch-square baking pan with cooking spray. Line the pan with plastic wrap, allowing it to overhang by 2 inches on two sides. Lightly and evenly coat the plastic wrap all over with cooking spray (the candy will stick to any unsprayed areas).Place 1/2 cup cranberry juice concentrate in a small bowl. Sprinkle gelatin over it and let stand, stirring once or twice.Meanwhile, in a heavy, nonreactive (see Note) Dutch oven, stir together the remaining 1 1/2 cups cranberry juice concentrate, raspberries, cranberries, lemon zest, lemon juice and 3 cups sugar. Bring to a boil, stirring, over medium-high heat. Clip a candy thermometer to the pan, adjusting it so the tip is submerged but not touching the bottom. Boil briskly, stirring frequently, until the mixture cooks down slightly, 6 to 7 minutes. Lower the heat so the mixture boils gently and cook, stirring frequently, until it reaches 244°F, about 25 minutes.Remove from heat. Add the gelatin mixture (it will be very firm by now), stirring until it completely dissolves. Immediately pour the jelly mixture into a fine sieve set over a nonreactive bowl. Force through as much juice and pulp as possible using a heatproof spatula or wooden spoon; work briskly, as the mixture will thicken as it cools. Transfer the jelly to the prepared pan. Let stand, uncovered, on a cooling rack until completely set, 3 to 4 hours. Refrigerate for 4 hours, or overnight, to reduce the stickiness before cutting.Generously dust a large cutting board with granulated sugar. Holding the edges of the plastic, lift the jelly out of the pan. Lay the slab top-side down on the board. Peel off the plastic. Sprinkle the slab all over with some of the remaining 2/3 cup sugar. Using a lightly oiled large sharp knife, trim off and discard the slab edges all around, forming clean edges. Cut the piece lengthwise and crosswise into eighths or tenths, forming individual jelly squares, cleaning and re-oiling the knife as necessary. Roll each square in sugar until coated on all sides. Let the jellies stand, uncovered, to dry for 4 hours, or overnight. Once dry, dust with additional sugar, covering all surfaces. Store the jellies, not touching each other, in single layers separated by wax paper (or in paper candy cups), in a flat, wax paper-lined storage container in the refrigerator. Serve at room temperature. E-mail recipe Print recipe To save this recipe, register now!


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Holly Weber was named the Human Resources Director for University of Wisconsin Intercollegiate Athletics in October 2010. Weber�s previous employment with the State of Wisconsin includes over two years as a Human Resources Program Officer for the State of Wisconsin Department of Health Services (DHS).
In her role at DHS, she oversaw a team of human resources and administrative professional staff in the primary areas of classification, staffing, and compensation for an organization with over 5,000 employees. While at DHS, Weber�s scope of responsibility also included: workforce planning, training, Continuity of Operations, project management, retention, compensation analysis, performance and discipline issues, and workforce reductions.
Prior to DHS, Weber worked at the University of Wisconsin System Administration as a Human Resources Manager for six years. In this role, she handled all aspects of classified and unclassified recruitment, retention, diversity, position classification and reclassification, salary analysis, performance and discipline issues, and assisted in staff benefits and payroll functions.
Weber earned her bachelor�s degree from the University of Wisconsin � Platteville in Business Administration and Human Resources Management. She is a graduate of the DHS Leadership Institute. Originally from Monroe, WI, Weber and her husband Mica have one son, Jaxson.
2015 Board of Regents of the University of Wisconsin System. All rights reserved worldwide.
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We opened our first outlet in Dunedin 1999 with the aim of providing the finest espresso coffee in Otago. Since then we've been helping to wake up the deep south from our Frederick St hub and our on-campus espresso bar at Otago University.
In 2004, after careful research and dedicated testing, we developed our own roasting company using only the highest quality 100% Arabica beans sourced from around the world.
Today we bring you our lovingly tended and unique blends of judiciously roasted beans so you can enjoy your coffee fix any time of day or night, no matter where you are in the country.
The fix is a member of Coffee Kids, so imbibe knowing your choice is globally responsible.
Fix 1: 15 Fredrick Street, Dunedin T: 03 479 2660 | Fix 2: Centre For Innovation, University of Otago, Dunedin T: 03 477 2642
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With the annual Elk County Relay for Life event scheduled for next month, Monday's meeting of the Elk County Commissioners included presentations from the American Cancer Society in a brief overview of the organization's history and impact.
BRADFORD - McKean County law enforcement have tracked down and arrested a Bradford fugitive in Florida, where they say the man fled after giving police the slip by jumping out of a window at his Welch Avenue home.
At about 11:30 a.m. Saturday, a call went out for a possible fire, smoke in the basement at 820 North Broad St. in Ridgway.
Elk County polling places will open at 7 a.m. tomorrow for the municipal primary election.
While last year's general election saw ballots cast by 13,474 or 66.37 percent of Elk County's 20,302 registered voters, the municipal election in 2011 only gathered 7,918 or 39.38 percent voter turnout, this according to the County Elections Office.
In addition, the municipal primary held in that year had even lower turnout, with just over a third of registered voters showing up to cast their votes.
ST. MARYS – In 2006, the Community Nurses held a one-day used book sale offering several hundred books available for purchase for a small fee, and the event was held in the small library adjacent to the cafeteria at Sacred Heart Activity Center to raise money for their hospice program. Since that time, the sale has continued to grow and now typically has over 10,000 used books available for purchase at the St. Marys Catholic Middle School cafeteria over a four-day period.
ST. MARYS – Local police are looking for the person, or persons, responsible for a pair of explosive devices found within days, and miles, of each other in Elk County this week.
Wounded veterans of the wars in Iraq and Afghanistan, amputees and others bearing invisible scars, were in Ridgway Friday for a long-range shooting event, part of a larger initiative intended to aide them in their transitions back into civilian life.
JOHNSONBURG – Effective Aug. 1 the Johnsonburg Fire Department will discontinue operation of its Quick Response Service [QRS].
ST. MARYS – The Pennsylvania Lottery announced yesterday that a $2 million winning ticket in Wednesday's Powerball drawing was purchased at the Sheetz in St. Marys.
WEEDVILLE – With plans to drill near a Jay Township watershed on hold, EQT announced at Thursday's meeting of the township Board of Supervisors that they will begin hydraulic fracturing of four wells, at another location in the township, by month's end.


text:
{1} Venchi Chocolate Cigars
Finally, a cigar that doesn't come with a health warning. Dads shouldn't be too disappointed when they clip the end of one of these smokes – the luxurious sweet is beautifully crafted by one of the world's finest Italian chocolatiers.
£24, 020 3632 1668
© independent.co.uk


text: Jameel Mckay, a versatile 6-8 PF from Indian Hills C.C. picked up an offer from Memphis yesterday, February 12, 2012. I think that would be a good fit for him. He's got another year to decide where he wants to go to school but I think Memphis is definitely a very good option to have.


text:
Statements posted here are those of our readers and do not represent the BaseballThinkFactory. Names are provided by the poster and are not verified. We ask that posters follow our submission policy. Please report any inappropriate comments.101. Random Transaction Generator posted on January 21, 2014 at 12:16 PM #
I find Hughson's voice comfortingly familiar due to the 875,000 hours I played NHL 2001.
On the topic of announcers, I saw Cassie Campbell doing some play-by-play (or more likely colour) during a game a couple weeks ago. Would she be the first female announcer to be in the box for a male sport? I always thought she was capable, and she seemed to be doing a pretty good job.
#148 Though it wasn't done that way it amounted to a straight up trade of Hughson for Cuthbert. CBC wanted a hockey only guy. TSN wanted a hockey plus CFL guy. Hughson wanted to do hockey only and Cuthbert wanted to do more than hockey. Makes perfect sense in that light.
She's a discredit to her gender, but Suzyn Waldman is probably the first long-time female announcer, at least in NA. Checking her wiki page, there were at least two others before her in MLB, Betty Caywood and Mary Shane.
(And/or Canadian TV is really horrible.)
Orphan Black is pretty good. That's about it, really.
So the number of people who choose to watch a sport on television (which dwarfs the number who actually attend, by the way)is the "dumbest" way to measure a sport's popularity, but revenue (most of which comes from, er, TV) is your chosen criterion? So that makes Carlos Slim the most popular man in the world, followed by Bill Gates, Amancio Ortega, and Warren Buffett?
I have yet to watch it, but I hear Slings and Arrows was awesome.
For example, are there hockey coaches who really have no clue as to who their best players are? I can understand if some fans maybe don't really get it, but I don't know about the front offices.
I have yet to watch it, but I hear Slings and Arrows was awesome.
Yet it was just as obvious that McSorley the Protector was by far the most popular player on the team as far as the fans were concerned. The vast majority of fans I saw really didn't care if the Kings won or lost, they just wanted to see a fight. I don't know if it is like that in other arenas around the league. I would guess older cities with long-time franchises probably have fans that are better in tune with what actually wins games and are there to see a skillfully played game?
Pam Ward has done PBP for early-slot college football games on ESPN for a few years now, and last year they had some other woman doing PBP for a few games, but I can't remember her or the games. There were lightly-veiled shots taken at Ward when she started, but no one seems to comment on her now. Worth noting that by either merit or bias she gets consistently terrible assignments.
Eliminate the ####### loser point.
Oddly enough, the NFL is basically the last serious sports organization on earth that doesn't play soccer and still allows ties.
Oddly enough, the NFL is basically the last serious sports organization on earth that doesn't play soccer and still allows ties.
1. End de facto legal holding and hooking for good and all. Aggressively call penalties for hooking and holding until the players get the idea.
2. Enlarge the nets, probably by about four inches in every direction. Hockey's a more entertaining sport when games are 5-3 or 6-4 rather than 2-0 or 3-2.
3. Eliminate the ####### loser point.
The Penguins haven't lost a shootout in two years, and it's not hard to see why.
It seems the only people who complain about hockey being hard to watch are generally fairly hardcore sports fans who don't watch hockey.
Fans pay a lot of money to go to a hockey game, and the overwhelming majority of them feel ripped off if there isn't a winner.
Well sure. They've played four shootouts this season and so far their opponents have put exactly zero pucks (in 13 tries) into the net. Pretty much guarantees that they would win every single one.
What? Goaltending wasn't the reason you were thinking of? Well, in any event, that actually is the reason.
Fleury has severe problems paying attention to what's going on.
Jeff Marek's theory on scoring is that it's down because everybody blocks shots now. I like that theory.
I used to be a big hockey fan, but I haven't watched a full non-Olympic game in probably 15 years. The current style of NHL play is of no interest to me at all. Dump and chase. The whole league has one guy on pace for 100 points, and three goalies with a GAA under 2.00, and its been like that for years. I grew up watching hockey in the 80's when a guy with a career 3.68 GAA (Grant Fuhr) could be talked about as one of the best goalies in the league. Now 2.68 GAA puts you on the bench.
*partly talent, partly that goalies are so much bigger, partly equipment, mostly style changes.Partly that unlike in the high scoring era, goalies are usually the best athletes on the team.
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text:
By Staff Sgt. Kathleen T. Rhem, USAAmerican Forces Press Service
WASHINGTON, Oct. 7, 1999 The National Defense Authorization Act signed into law by President Clinton Oct. 5 was a huge step forward for service members, but just a step, Sgt. Maj. of the Army Robert E. Hall said.
Hall shared the podium with President Clinton, Defense Secretary William S. Cohen and Joint Chiefs Chairman Gen. Henry H. Shelton at the Pentagon signing ceremony. Afterward, he shared his views on the changes contained in the act.
He said he hopes service members see the fiscal 2000 authorization act as "a step in the right direction" rather than as the final step in fixing their pay and benefits.
In his dealing with troops, Hall said, four issues come up the most: pay and entitlements, housing, medical care and retirement benefits. "This bill addresses two of those top four concerns," he said.
Hall called the pay table reform set to take effect July 1, 2000, "a great first step" that recognizes and rewards achievement through promotions and not just longevity. Reform, he said, will prevent such situations as E-6s with time in service making more than certain junior E-7s.
The 4.8 percent pay raise and 15th-anniversary option to reject the Redux retirement system are important because of the message they send to service members. "I think it shows them we value their services," he said.
He said they're also important because these changes will now allow the leadership to work on other issues. And, Hall said, there's no shortage of issues to address.
TRICARE and housing are two subjects Hall said he'd like to see receive more attention.
"We've made great strides in TRICARE, but we have a way to go," he said. "It's not just the medical care we give to (service members) and their families. It's also how you're treated from the time you try to enroll to the time you have to make an appointment to the time you get treated and get well. It's the entire process."
Hall said the Defense Department plans to "put the same energy into the medical system next year as we put into pay and entitlements and retirement this year."
He said quality housing is also important to service members. "No matter how much money you give them, if they come out of the field and they live in a barracks where the roof leaks every time it rains or their family quarters are substandard, they're not going to stay. It's a package deal."


text:
Participants are responsible for their own travel arrangements to and from Shanghai. Students should arrive in Shanghai no later than Sunday 23 November 2014.
Students are strongly advised not to make travel bookings until you have received official notification from Sydney Law School that you have been accepted into the program.
Australian citizens are advised to register their travel and contact details with the Australian Government Department of Foreign Affairs and Trade prior to leaving Australia.
Travel advice for China is available here.
Important information for dual nationals
The Department of Foreign Affairs and Trade advises the following:
The Chinese government does not recognise dual nationality and will not allow consular access by the Australian Embassy or Consulate to Australians detained by Chinese authorities if they have entered China on a Chinese passport, a Hong Kong or Macau identity card or any non-Australian foreign passport. This includes identity cards issued in Taiwan. Consular access is, however, allowed to those who have entered on Australian passports. Therefore, if you are an Australian/Chinese dual national, you should travel on your Australian passport, obtain a visa for China and present yourself as Australian at all times (excerpt from the smartraveller.gov.au website).
Airport transfers
Airport transfers are provided on Saturday 23 and Sunday 24 November only and from Pudong International Airport only. If you arrive on any other day you will have to make your own way to the campus. Some international and most domestic flights land at Hongqiao Airport. Please note that ECUPL is unable to provide airport transfers from Hongqiao Airport. Hongqiao Airport is, however, quite close to the campus.
Airport transfers are NOT provided at the conclusion of the Winter School and you will be required to make your own way to the airport by taxi or public transport. ECUPL staff will assist you in booking taxis on departure, if required. The cost of a taxi to Pudong International Airport is around RMB180 (A$30).
Please note that there may be circumstances in which it is not possible for ECUPL to provide airport transfers. All students will be provided with clear travel instructions in English and Chinese.
Additional information on airport transfers is available here.
Students are responsible for organising their own travel insurance.
Travel insurance is a compulsory requirement for all students, including Chinese nationals. Students will not be permitted to participate in the program if proof of valid travel insurance is not provided.
Please note that your travel insurance policy must provide comprehensive coverage for medical expenses incurred overseas, including medical evacuation, and personal liability coverage. You should also ensure you are covered for cancellation costs in the event that the program is cancelled. Some insurers also cover course fees in their policy. It is strongly recommended that you purchase your travel insurance when you purchase your flight ticket. If you plan on taking a laptop, please ensure that you have arranged appropriate insurance.
Students are strongly advised to ensure they have sufficient funds while in Shanghai to cover the payment of unforseen medical expenses, as most Chinese doctors and hospitals will require cash payment upfront for treatment. These expenses can generally be claimed on return to your home country through your travel insurance provider.
Most students will require a visa. Students are responsible for obtaining a visa from the Chinese Embassy or Consulate and the University of Sydney accepts no responsibility if a student is unable to obtain a Chinese visa.
ECUPL will facilitate the issue of visas by providing supporting documentation to students, if required. For this reason, we require details of the passport on which you will be travelling at the time of application.
Additional information on visas is available here.
It is recommended that participants consult their doctors with respect to vaccinations. Please note that some vaccinations may need to be administered well in advance of departure in order to be effective.


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Pedro — Edward E. Bruce, 58, of Pedro, passed away Monday, April 15, 2013, at the St. Mary's Medical Center-Ironton Campus. Funeral services will be 7 p.m. Friday, April 19, 2013, at Phillips Funeral Home, 1004 South Seventh Street, Ironton, Ohio. Visitation is Friday from 5 to 7 p.m. at the funeral home.
Ashland, Ky. — Charles Collier, 62, of Ashland, Ky., passed away Wednesday, April 17, 2013, at his residence. Funeral service will be 1 p.m. Sunday, April 21, 2013, at Rock Camp United Methodist Church with Brother Wayne Wise officiating. Interment will follow in Highland Memorial Gardens. Visitation will be Saturday from 6 to 9 p.m. at Phillips Funeral Home, 1004 South Seventh Street, Ironton, Ohio and one hour prior to the service at the church.


text:
"Dick Cheney watches television": The four previously unseen 9/11 photos that will make you hate the evil VP all over again
Topics: Unemployment, News
Judging by the state of the econoblogosphere around noon on Friday, after the release of the government's labor report indicated that the economy created only 120,000 jobs in march, the question on every econ-watcher's mind is how seriously should we take a one-month divergence from an existing trend?
At one end of the spectrum, we could interpret the new jobs numbers, which included a sharp decline in retail jobs, a la Matthew Yglesias, as proof of the "death of retail" — slain by the unholy combination of smartphones and online shopping. Maybe so, but it seems like a bit of a stretch. Or we could go in the completely opposite direction: Ryan Avent, economics blogger at the Economist, seems to be suggesting that the best path forward would be to just ignore the new numbers altogether.
Avent's response to the news that U.S. labor markets had underperformed expectations came in the form of a darkly humorous post pointing out that the margin for error on the labor report was so high that the real number of jobs created in March could range anywhere from 20,000 to 200,000. So we really don't have any idea whether March was an outright disaster, a continuation of previous healthy trends, or something in between. And the same goes for all the other numbers in the report:
Reported changes for important subsectors are too small relative to the margin of error to be worth discussing.
Ha ha ha. Very funny. Avent's analysis is difficult to fault, but he should be careful: If all economics commentators followed his rules for reporting on new economic data, it wouldn't be long before there wasn't much of a market for any economics reporting at all.
But Avent does point the finger at an interesting conundrum. If the labor report had produced a "good" number, something above 200,000, there would have been a slew of reports about how the data confirmed the strength of the economic recovery, and very little discussion of how the high margin of error involved implied that it would be foolish to invest the "good" numbers with too much confidence. Not so with a report that virtually every (non-rabidly partisan) commentator considered "disappointing." This time, caution about making too much of a one-month blip was the ubiquitous watchword.
And maybe the numbers aren't so bad. As Felix Salmon noted, six months ago, the news that the economy had created 120,000 jobs would have been "decidedly encouraging." The fact that our expectations have changed is the basis for our disappointment, for sinking feeling in our hearts immediately after the Bureau of Labor Statistics Web page finally loaded after countless fevered clicks at the dot of 8:30 a.m. EST. So maybe we should relax a little? The economy is still growing, albeit at a tortoise-like pace. The explanation for the shortfall could be something as simple as good weather pulling forward hiring that would normally have taken place in March into January or February.
The problem is, the hardest thing to figure out in real-time economy watching is when to spot the definitive beginning of a new trend, but those new trends do end up starting. And the stakes are simply too great right now to ignore any data, no matter how tentative. Control of the White House and Congress could very well hinge on how labor markets perform from now through the summer. If April's numbers are worse than March's, we'll be able to look back and say, a-ha: here is where gas prices really started to bite into economic growth, or here is where Europe's recession proved impossible to shrug off … and here is where Romney's poll numbers started to pick up. Every now and then the canary in the coal mine does indeed die — it would be kind of foolish to blithely wave away this particular dead bird just because it might signify a freak avian heart attack.
How much further we should go is a fraught question. Liberals seized on Friday's part to call for more infrastructure spending. Mitt Romney, as expected, immediately plugged the news into his campaign critique savaging Obama for presiding over only the most tepid of recoveries.
That kind of instant politics-fueled analysis is probably not merited by one month's worth of numbers. But that won't stop anyone, because of the non-negligible chance that their critiques end up being right on the money. So there's your answer, as unsatisfying as it might be. We can't accept Friday's labor report as holy writ, but we can't wish it into nonexistence either. Unless you are Mitt Romney, the number was disappointing.
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Cost Estimate
Provide a total cost estimate for the full project. Provide an activity breakdown for feasibility studies, preliminary engineering, environmental assessment, right-of-way acquisition, construction, construction engineering and inspection, project management, contingencies, and ITS activities. Include other cost categories, as necessary. See Major Project Program Cost Estimating Guidance.
All cost estimates should be expressed on a year-of-expenditure basis and should include a narrative describing assumptions used to arrive at such estimates.
Implementation Plan
Provide a comprehensive description of the project, including, but not limited to, project scope, termini, and interconnections. Describe any proposed phasing for the project and dependencies on other projects. Include a list of all federal, state, and local permits and approvals required for the project and a schedule for obtaining such permits and approvals.
Include the schedule for completing the project, by year, showing estimated costs.
It should be noted that updates to the initial financial plan should ensure consistency in project scope. If costs/schedule change, the changes must be clearly identified to ensure valid comparisons to the initial financial plan.
Financing and Revenues
Sources should include separate line items, as applicable, for Federal, state, and local funds; private investment; any other contributions; market value of right-of-way dedications; bond proceeds (general obligation, revenue, GARVEEs, and others); state infrastructure bank loans; other borrowing (specify); investment income; Federal credit assistance (TIFIA). The total of all funding sources should equal the total of the cost estimate. New funding sources developed after the Initial Financial Plan should be incorporated at the subsequent Annual Update.
Cash Flow
The cash flow pro forma should indicate the level of cash required to fund the project on an annual basis over the period of the financial plan. The pro forma should include beginning and ending balances, all sources and uses of funds, and show annual change in financial position. Total sources and uses should be equal.
Risk Identification and Mitigation Factors
The financial plan should identify risks to project completion and sufficiency of revenues. Examples of risks might include cost escalation, approvals, litigation, construction schedules, ridership/traffic levels, availability of grant funding, and dependence on future legislative action. All risk mitigation strategies should be identified and should include actions that would be taken to address revenue shortfalls including any reserves or other methods of funding which could be applied to this project. There should also be a discussion of any proposed cost containment approaches (e.g. design/build, value engineering, guaranteed maximum price or completion date warranties, or other incentive/disincentive clauses).
The financial plan should identify any performance bonds included in the project financing plan, the level and type of insurance coverage, and any lines of credit and standby financing arrangements.


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On the January 13 edition of Meet the Press, host Tim Russert -- who, with NBC's Brian Williams, will moderate the Democratic presidential debate in Las Vegas on January 15 -- once again cited the "[2002] National Intelligence Estimate, which had a lot of caveats" about Iraq's weapons programs to challenge a Democrat about his or her Iraq war vote, something he did not do in two previous interviews with Sen. John McCain. Russert also aired a statement from Democratic strategist Donna Brazile criticizing former President Bill Clinton's recent comments about Sen. Barack Obama, but not her subsequent remark that "I take the president at his word that he was not being condescending; he was not being insulting."
After falsely asserting that he was showing viewers "exactly what President Clinton said," referring to January 7 comments Bill Clinton made about Sen. Barack Obama, Tim Russert played a truncated quote from Clinton. In addition, Russert read a quote from The New York Times that truncated Hillary Clinton's statement about civil rights, omitting her reference to President Kennedy.
Chris Matthews, Tim Russert, and Chris Wallace each discussed a Politico article that reported: "As New York mayor, Rudy Giuliani billed obscure city agencies for tens of thousands of dollars in security expenses amassed during the time when he was beginning an extramarital relationship with future wife Judith Nathan." But, at no point during these segments did any of the hosts or guests note that Giuliani was having an extramarital affair with Nathan - whom they described merely as his girlfriend -- and that, because of the affair, New York City taxpayers were reportedly paying for both her protection and that of Giuliani's estranged wife.
Interviewing Barack Obama on Meet the Press, Tim Russert read a quote he attributed to Obama to suggest that he has "not been a leader against the [Iraq] war": "In July of 2004, Barack Obama: 'I'm not privy to Senate intelligence reports. ... What would I have done? I don't know,' in terms of how you would have voted on the war." Russert did not quote the very next sentence of Obama's statement, which was, "What I know is that from my vantage point the case was not made" for authorizing the war.
In a blog entry, Politico senior political writer Jonathan Martin wrote that Rudy Giuliani's campaign had circulated a press release titled "Romney's Taxachussetts Hypocrisy" and characterized the campaign as "[n]ot terribly thrilled about having to engage a GOP opponent -- but also recognizing the necessity of letting no dig go unanswered." However, in the blog entry, Martin did not note a relevant statement that Giuliani made two days earlier in an interview with Martin himself: "It's my intention not to attack any other Republicans, absolutely. ... The whole focus of my campaign is I'm going to run against a Democrat." On Meet the Press, David Brody claimed that Giuliani "is talking about Hillary Clinton and nobody else," adding: "I mean, it's invoking the Eleventh Commandment, as Ronald Reagan would say, you know, thou shalt not speak ill of a fellow Republican."
Discussing remarks by Sens. Hillary Rodham Clinton and Barack Obama, and former Sen. John Edwards, that they would not commit "by January of 2013, to have all American troops out of Iraq," NBC's David Gregory described this as "a really measured position," and asserted, "Edwards particularly, who was embracing the left wing of the party's view that you have to end the war now, and the others even voting for cutting off funding." But Gregory's suggestion that Clinton's and Obama's current positions are inconsistent with their having "even vot[ed] for cutting off funding" -- an assertion that is itself misleading -- is false. And Gregory offered no evidence that Edwards has shifted position either.
On Meet the Press, Pat Buchanan said of the September 26 Democratic presidential candidate debate: "I think the Democratic Party doesn't know how far to the left they are moving. I mean, they said there that smoking is going to be a federal crime in public places." In fact, two of the candidates in that debate -- Hillary Clinton and Barack Obama -- said they opposed a federal law at this time banning smoking in public places and voiced their support for letting local communities develop such laws.
On Meet The Press, Christian Broadcasting Network's David Brody asserted: "At the end of the day ... this issue [terrorism] helps the Republicans more than the Democrats because they're going to be able to enforce this idea that the Democrats want to go at this with law enforcement and the Republicans don't." Neither Tim Russert nor his other guest, CNBC's John Harwood, challenged Brody's assertions; in fact, Democrats have offered strategies for fighting both Al Qaeda in Iraq and the main Al Qaeda terrorist organization.
On Meet the Press, NBC News' Richard Engel asserted that "if you pull back the troops, the troops themselves are going to be furious. They have done so much and worked so hard ... that if you start pulling them back ... they're going to be livid." However, neither host Tim Russert nor other guests mentioned recent reports indicating that some members of the military would not be opposed to drawing down troop levels in Iraq.
Karl Rove asserted that Sen. Hillary Rodham Clinton "enters the general election campaign with the highest negatives of any candidate in the history of the Gallup Poll," and added: "The only person who comes close is ... hers are at 49. The only other candidate to come close was Al Gore with 34, I believe." In fact, Gallup's polling results show that President Bush's unfavorability ratings as he entered the 2004 general election campaign were consistently above what Rove claimed to be "close[st]" to Clinton's unfavorability rating -- "Al Gore with 34" percent.
In appearances by Karl Rove on Sunday morning talk shows on Fox, CBS, and NBC, not one interviewer asked whether an August 19 Washington Post article was accurate in stating that, according to White House officials, one of Rove's "two basic rules" in putting together briefings for political appointees was "to make sure they complied with the Hatch Act," a federal law that limits political activities by federal employees. As the article noted, "the Office of the Special Counsel ... has concluded that the Hatch Act was violated" during a briefing that was conducted by a Rove aide for political appointees in the General Services Administration.
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Dame Helen Mirren has given her support to a Bristol-based charity's appeal by donating her Winter Fuel Payment for those who need it more than she does.
The Oscar-winning actress made the £200 donation in aid of Surviving Winter, the appeal run by the Bristol-based Quartet Community Foundation and supported by Saga, to raise money to help older and vulnerable people stay warm and well.
The charity has made its final call for donations for this winter as many of those struggling with the cold weather start to receive their winter fuel bills.
Dame Helen, 67, joined hundreds of generous pensioners who have pledged to "recycle their payment".
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Locally, the money comes in to Quartet Community Foundation, an independent charity which works with local philanthropists to meet local needs. Quartet quickly turns donations around by giving grants to community groups that support individuals in dire need.
Surviving Winter grants pay for fuel bills, warmth packs, boiler repairs and hot meals. With temperatures below freezing most nights and one of the worst winters on record, demand for help is increasing.
Dame Helen said: "I believe passionately that we need to support the vulnerable and elderly in our local communities. It's a tragedy that thousands of older people struggle to get through the winter months. By donating my Winter Fuel Payment to the appeal, I know I am helping an elderly person enjoy a warm and healthy winter."
Jilly Edwards, development manager, at Quartet Community Foundation said: "This winter has been exceptionally cold. We all complain, but for older and seriously ill people it can be life-threatening, and we're finding more people asking for help.
"With energy price rises, increasing costs of other basic life essentials, and for some, falling incomes, it is inevitable that growing numbers of households will be affected. This has been a harsh winter and we are still in the middle of a cold snap.
"More than 90 local people have already donated, helping us raise more than £39,000. We very much appreciate every donation from the generous public, including many from people who have given up their winter fuel payment. Anyone can donate, not just those receiving a winter fuel payment."
For details visit www.quartetcf.org.uk or call 01225 420300.


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StubHub's lawsuit a 'reluctant' step Comments on Indiana's controversial law Sports more willing to take a stand NFL aggressive on concussion settlement Media has moved on from concussion suit WME, IMG execs take retreat NFL concussion hearing a prelude Decision 2014: A closer look at the data When the home team plays, candidates pay Decision 2014: Where was it spent?
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SBJ/June 2-8, 2014/Law and Politics
NFL retirees question the $675M figure in proposed settlement
Published June 2, 2014, Page 4
For many, that $675 million is not seen as enough. And last week, in a new wrinkle in the case, a group of seven retired players who contend the settlement does not properly account for their situations, charged that the $675 million is not even a true reflection of the value of the settlement compensation because the cash would be paid over many years.
"[T]here is no defense of the $675 million monetary award fund — already questioned by this Court — which, of course, is not really a $675 million fund," the players stated in a court filing last week. Later in the filing, the players state, "Given that the settlement would have permitted the NFL to spread its monetary award fund payments over 19 years … and 'not be subject to any interest obligation or inflation adjustment,' … the true net present value of the settlement is far less than $675 million."
The lawyer for the seven players, Steven Molo, declined to comment when asked whether he had his own figure for the settlement. There could, however, be several such estimates for a different calculation.
"Net present value" essentially tabulates what today's money is worth in the future when it is invested or bearing interest. It's why lottery winners can choose to receive a lump sum payment that is far less than what their total winnings would be if that sum were spread over years. How the calculation is done, though, involves several assumptions, like the rate of return.
The issue is hardly uncommon in settlements, said John Goldman, a sports lawyer with Herrick Feinstein. The judge could order the NFL to pay the money right away, he said, but this could carry risks if the money is invested unwisely.
Attorneys Chris Seeger and Sol Weiss, co-counsel for the class of players in the case, said in a statement, "We continue to work at the direction of the Court and Special Master as they review the settlement agreement and rightfully ensure that all members of the class are protected. We look forward to finalizing this agreement so that former players can soon begin taking advantage of its benefits."
The NFL said simply in an email, "We are continuing to work with the court."
The seven players, all recent retirees, criticize the settlement because it will not pay for new cases of chronic traumatic encephalopathy once the pact is approved by the court. Seeger has told SportsBusiness Journal that this is a non-issue because the symptoms of CTE are covered.


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Looking at the past is a chance for us to learn
Recent weeks have seen a plethora of anniversaries that have significance for the industry. Ben Colson argues that there is nothing wrong with looking back as long as we examine past mistakes and learn from them
Ben Colson
Nostalgia, they say, ain't what it used to be. I was going to write a heavyweight piece on the oppressive weight of regulation on the industry but I was struck by a
coincidence of anniversaries the other weekend, and so have changed my plan.
You probably picked up on three anniversaries over the recent holiday weekend. Without doubt the most important was the 30th anniversary of the last episode of Fawlty Towers, that monument of British television comedy. Probably better...
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22 Jun 2009
In the 1930's General Motors was behind the purchase of streetcar (LRT) systems and their replacement with bus services, which then withered to create a market for private cars.
Their involvement was exposed but the deed was done. However the wheel now seems to have come full circle and the economic bias which propped up the transport system making such inefficient use of resources has crumbled. Dow we see similar signs in the UK?


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English Department Scholarship
The English Department of Palomar College will be offering the Betty Webb and Richard Norlin Memorial Scholarship this spring. The details are as follows:
Amount: $750
Who: a current student at Palomar College.
Qualifications: an English major or someone with a strong interest in the major with plans to transfer to a four-year college/university; a GPA of 3.0 or better; completion of English 100.
How to Apply: apply directly to the English Department in P-2 (put in the mail tray of Gary Zacharias) and include the following:
Deadline: March 29, 2012 (no later than noon)
Questions? Contact Gary Zacharias (extension 2710)


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DURHAM, N.H. - UNH women's basketball head coach Sue Johnson, now in her eighth season with the Wildcat program, has announced that Danielle Flowers (Chalfont, Pa.) has signed a letter of intent to join the Wildcats beginning in the 2005-06 academic year.
Flowers is a 6'1" post player presently attending Central Bucks West High School in Doylestown, Pa. She is also a member of the Philly Belles A.A.U. team.
"We are excited to have Danielle joining the program," Johnson said. "Her versatility and athleticism will fit in well with our offensive and defensive systems. She is also a very hard worker both on the court and in the classroom."
The University of New Hampshire is a NCAA Division I school with membership in the America East Conference for basketball. The Wildcat women's basketball team is presently in its 30th season of varsity intercollegiate competition.


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COLUMBIA CITY — While Iotron Industries, USA may have been celebrating its grand opening, it was also playing host for the first time, with the guest of honor being the Whitley County Economic Development Corporation (EDC) and it's annual meeting.
This year's meeting was titled "Outlook 2012".
EDC President Alan Tio began by speaking about last year's meeting and how at the time, the EDC was just welcoming Iotron into the Whitley County fold.
Tio said it was only fitting a year later, the company was hosting the same event while also cutting the ribbon to open its doors.
"Iotron serves as a great case study of the work we do at the EDC," Tio said.
Tio said the EDC has spent the last year working with local businesses, referencing 80/20 and its 90,000 square-foot expansion in the Park 30 Business Center.
Whitley County Council, Whitley County Redevelopment Commission, Indiana Economic Development, WorkOne Northeast and Ivy Tech are just some of the entities the EDC has partnered with over the last few years, according to Tio.
"Over the last four or five years, we've worked very hard to use economic development to support the specific needs of our industry clients, wherever they may be throughout the county," said Tio.
[1] http://www.thepostandmail.com/sites/default/files/Tio.jpg


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MMA News
Matt Hughes Wants To Become A Judge, Possibly Open A Judging Academy
"When I'm a judge, I can only help the fighters that are right in front of me," Hughes explained. "I would rather have a piece of a school, or help these judges figure out the best way to judge. Of course, I wouldn't be the lead person. I wouldn't want any financial interest in it whatsoever. But by gosh, these judges need to have some knowledge. They can't go from a boxing atmosphere and think that [MMA] is going to be the same way. You just can't."
"I've judged a lot of matches and I've reffed a lot of matches, and so I think I could help out in figuring out what the best criteria is. My number one criteria when it comes to judging a mixed martial arts fight is damage. Whoever does the most damage probably ought to win the round. If you're on bottom, if you're on top, if you're on your feet, whoever does the cumulative most damage in a round, is probably going to win. And some of these judges think that because one guy was on top the whole five minutes, just because he was on top, they think he should have won the round. The bottom guy could have been throwing great elbows, creating a huge amount of damage, but they just don't see that."
During yesterday's session with "The MMA Hour" Matt Hughes discussed his departure from active competition and what he plans to do to stay active in Mixed Martial Arts.
Judging reform is a great calling, is it not?
15 Responses to "Matt Hughes Wants To Become A Judge, Possibly Open A Judging Academy"
This would be awesome. I really want to see former fighters judge fights! Imagine a fight being judged by Matt Hughes, Randy, and Royce Gracie. I think this is exactly what the future of the sport needs.
I'll say Hughes, Gracie & Liddell instead of Randy Couture. He sounds sometimes like Cecil Peoples
I can'T wait until all these ex fighters run off all the CROOKED on the "TAKE" judges like Cecil Peoples and Doc Hamilton. Both of those crooks have RUINED some of the best fighst in history. Both those idiots gave Bisping the win over Hamill after Hamill kicked Bisping ass NONSTOP for 15 minutes. Those same crooks gave Machida the decision in the first Shogun fight. Those crooks gave that iranian dude taht kicked varner in nuts time sin one fight a draw after Varner had beat his ass nonstop for 15 minutes. Can't think of his name the UFC just released him. He looks like he would cut your throat with a curved knife for looking at him wrong?????? NO 2 judges have screwed more fighters becausse of payoffs than these 2 crooks. Someday the ex fighters will take away the worst part of todays CURRENT MMA (JUDGING) another shi'ty judge is Jeff Blatnick who is the one taht wrote all the rules for MMA 15 year ago and of course he made all the rules favor wrestlers as he is gold medalist wrestler. Best rule in College wrestling is the NO STALLING rule and of course he left taht one out so now we fans are probably stuck with STALLING ie: LAY N PRAY (FOREVER) Fitch still holds to all time record for getting point deductions for stalling in college wrestling. Thats almost as much to be proud of as his 38-68 record. Ben Askren, Johny Hednricks had more PINS (PINFALLS) in one season than Fitch had wins in 5 years. you guys can have lay n pray its ruining MMA almost as much as horrible CORRUPT judging
U gotta put that in wikipedia for real, so everyone knows
yes! and refs should also study with judges and vice versa to help them understand more of the sport
Great idea
I think this would be great but I don't think former fighters being judges is necessarily the greatest thing….there will always be some bias…an academy for scoring would be the best…a system everyone goes by. Right now there's just too much self interpretation.
sometimes i feel like the refs could be better judges than the judges themselves
This sounds like a great idea. MMA needs more experienced judges.
Judging is a very precise discipline, and it matters less that one was a fighter than whether one is intelligent, focused, and has mastered the criteria for judging an MMA fight. Some of the best judges have never been MMA fighters (none of these are former boxing judges), and being a fighter does not necessarily mean that you possess the skills needed to be an excellent judge. One analogy might be in football, many great football players make terribel coaches. The former players that make good coaches have intelligence, patience, and the willingness to apprentice to learn the art of coaching. I feel it's the same with judging…some former fighters will become mediocre judges.
The problem with your argument is that you are comparing judging and coaching, which are nowhere near related. Former MMA fighters make good judges because they understand the sport inside and out from experience, they know the subtleties that are taking place that most current judges miss (which can typically only be picked up on from experience in the cage, which is why many new fans don't understand BJJ), they know when actual damage is being done as Matt said, and so much more. I would agree with you whole heartedly if you were saying that former MMA fighters could be bad coaches, as some have been great and some have been terrible. But as far as judging, the connection you are trying to make makes no sense at all. Sure, some will be bad, but we are talking about someone with a legacy such as Matt Hughes here. One last thought…a school can only teach so much. You can only fully grasp what is really going on in the cage from the experience of being there. Whether in the classroom setting, or as a judge himeslf, this is where the experience and expertise of someone such as Matt Hughes (and others as respected as he) would be a great addition!
well considering most of these mma fighters have high rank with multiple arts such as bjj, wrestling and stand up fighting of any kind, they would surely be able to judge fights because they know what they're looking at. and they'll probably be able to judge better than a guy who knows a thing or two.
I would be careful about letting him judge until Matt Hughes gets a little older. As of now he could potentially judge people he's fought before, which could give him some bias. Teaching others how to judge MMA better though? Definitely sounds like a good idea.
Go by way of these more mature items and look for your that tickle the fancy. Pull these individuals out and revel in them rather than the new solution you
Brilliant idea! Something needs to be done in this regard, ASAP. Erratic, irrational judging is one of the main issues the UFC and MMA at all levels face. There are a litany of questionalble UFC fights (Edgar vs Bendo I and II, Edgar vs Maynard II, etc) and it's even worse at the regional level. Not only do the unexpected results infuriate fans, but it can ruin a fighters's career and life, and that's not fair. How bad it must feel as a young up and comer to never get that shot because of a poor judging decision. A standard, a curriculum needs to be established globally, so as in many sports (soccer, tennis, pretty much any Olympic sport), we're all on the same page, and it's fair.
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Winter—June through September—is high season in the Pantanal. Temperatures are at their coolest, with averages in the low 80s, occasional peaks in the high 90s, and troughs in the low 50s during cold fronts. It's also when water levels are at their lowest and wildlife is easiest to see—usually concentrated along the remaining rivers and lakes, which have a high concentration of fish. Look out for caiman, herons, kingfishers, and other water birds. Anacondas can sometimes be seen crossing dirt roads in search of water. August and September are the best months to see jaguar, again near water, either at the far south of Transpantaneira road in Mato Grosso or along the Rio Vermelho River in Mato Grosso do Sul.
Temperatures and humidity rise in October and November. Visits are still possible, but there are frequent thunderstorms and animals begin to disperse. By December, the rains are fully underway, and many of the ranch-house lodges close up for low season. Sometime before Christmas, rivers in the north burst their banks and the flatland savannas of the northern Pantanal get completely submerged. The floods spread into the southern Pantanal a month or so later, when the few lodges that remain open offer tours only by boat, and animals and cattle crowd together on forested islands. The Pantanal is astonishingly beautiful at this time, but 100-plus-degree temperatures, 80 percent humidity, and clouds of mosquitoes make it uncomfortable.