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Purpose: Whether isocitrate dehydrogenase (IDH) gene aberrations affected prognosis of patients with acute myeloid leukemia (AML) was controversial. Here, we conducted a meta-analysis to evaluate their prognostic value.
Experimental Design: PubMed, Embase, Cochrane, and Chinese databases were searched to identify studies exploring how IDH gene aberrations affected AML outcome. Pooled HRs and relative risks (RR) were calculated, along with 95% confidence intervals (CI).
Results: Thirty-three reports were included. IDH mutations seemed not to affect overall survival (OS: HR, 1.05; 95% CI, 0.89–1.23) and event-free survival (EFS: HR, 0.97; 95% CI, 0.80–1.18) when considered as a single factor, but improved accumulative incidence of relapse (CIR: HR, 1.44; 95% CI, 1.18–1.76) in patients with intermediate-risk karyotypes (IR-AML). However, IDH1 mutation conferred worse OS (HR, 1.17; 95% CI, 1.05–1.31) and EFS (HR, 1.29; 95% CI, 1.07–1.56), especially in patients with normal cytogenetics (OS: HR, 1.21; 95% CI, 1.01–1.46; EFS: HR, 1.56; 95% CI, 1.23–1.98). Prognosis of the IDH1 single-nucleotide polymorphism rs11554137 was also poor (OS: HR, 1.34; 95% CI, 1.03–1.75). IDH2 mutation improved OS (HR, 0.78; 95% CI, 0.66–0.93), particularly in IR-AML patients (OS: HR, 0.65; 95% CI, 0.49–0.86). The IDH2 (R140) mutation was associated with better OS among younger cases (HR, 0.64; 95% CI, 0.49–0.82). Treatment outcome was poor [RR for complete remission rates in IDH1 mutation: 1.21; 95% CI, 1.02–1.44; IDH2 (R172) mutation: 2.14; 95% CI, 1.61–2.85].
Conclusions: Various subtypes of IDH mutations might contribute to different prognosis and be allowed to stratify IR-AML further. Clin Cancer Res; 23(15); 4511–22. ©2017 AACR.
Translational Relevance
With advent of prognostic heterogeneity in isocitrate dehydrogenase (IDH) gene aberrations in acute myeloid leukemia (AML) patients, it is necessary to determine what prognostic differences are between various subtypes of IDH aberrations, especially in cases with intermediate-risk karyotype who were harboring higher frequency of IDH mutations. In this meta-analysis including 33 reports, the authors eventually identified the diverged impact of IDH1 and IDH2 mutations on survival. Mutant IDH1 and IDH1 single-nucleotide polymorphism (SNP) rs11554137 might contribute to adverse prognosis, whereas IDH2 mutation should be related to better survival, particularly for IDH2 (R140) mutation among younger cohorts, all of which were allowed to perform more accurate molecular risk stratification of IR-AML in details and eventually direct personalized medicine in the future.
The development of effective therapies for most subtypes of acute myeloid leukemia (AML) has remained sluggish for decades. Among the many reasons, an essential one is the substantial heterogeneity of this malignancy (1). Prognosis of AML can be divided into three risk stratifications according to cytogenetic karyotypes reported in National Comprehensive Cancer Network (NCCN) guidelines: favorable, intermediate, and unfavorable risk. Although clinical outcome in most AML patients with favorable or poor karyotypes could be predicted (2), those with intermediate-risk karyotypes (IR-AML) need more molecular markers to determine their prognosis and guide personalized therapies. Fortunately, next-generation sequencing (NGS) techniques provided new opportunities for discovering more mutational profiles in AML genomes, such as the genes encoding DNA methyltransferase 3A (DNMT3A), isocitrate dehydrogenase 1 and 2 (IDH1/2), as well as Tet oncogene family member 2 (TET2;ref.3), which are the key for the modification of DNA methylation and involved in the pathogenesis of leukemia (4, 5).
Several studies and reviews have reported poor prognosis of patients with DNMT3A (6) and TET2 (7) mutation. However, prognostic assessment of IDH mutations was still controversial and needs to be further evaluated. Notably, a meta-analysis performed by Feng and colleagues (8) containing 15 studies indicated that mutant IDH1 was significantly related to shorter overall survival (OS), whereas in a study from Zhou and colleagues (9) including 13 studies, the IDH2 mutation was observed to improve OS. Besides, IDH mutations are particularly common in cytogenetically normal AML patients (CN-AML; ref. 9). For these reasons, prognostic availability of IDH mutations in IR-AML patients should be further explored. In addition, several studies, including the one by Wagner and colleagues (10), reported the association of the IDH1 single-nucleotide polymorphism (SNP) rs11554137 with noticeably poor prognosis in CN-AML patients. In addition, a large sample study by Papaemmanuil and colleagues (11) systematically perfected existing molecular classification system and especially pointed out that IDH2 (R172) but not IDH2 (R140) mutation was related to favorable prognosis in AML patients. Therefore, it is necessary to further assess IDH1 SNP rs11554137 and different subtypes of IDH2 mutation in AML.
In the other side, IDH mutations conferred a new enzymatic function, resulting in accumulation of 2-hydroxyglutarate (2-HG), which plays a vital role in changing DNA methylation of cells, impairing cell differentiation and probably contributing to aberrantly epigenetic mechanism of pathogenesis in AML (1). On the basis of the mechanism of IDH mutations, there have been 3 types of target drugs (IDH305 to IDH1R132 mutation, clinicaltrials.gov NCT02381886; AG-120 to IDH1 mutation, clinicaltrials.gov NCT02074839, NCT02632708, NCT02677922 and AG-221 to IDH2 mutation, clinicaltrials.gov NCT01915498, NCT02632708) generated and undergoing clinical trials (12–14). However, due to controversial prognosis of IDH mutations, it is crucial to determine a clear insight of prognostic value of each subtype in these mutations, which will contribute to more accurate and personalized medicine.
In this study, we identified whether each subtype of IDH mutations [IDH1, IDH2 (R140) and R (172)] could influence prognosis of AML patients.
Materials and Methods
Inclusion and exclusion criteria
Eligible studies have these criteria: (i) cohort studies published in English or Chinese, (ii) restricted to human studies mainly reporting the prognostic impact of IDH mutations on adult AML patients, (iii) included information in terms of survival and treatment outcome, and (iv) simultaneously described prognosis-related details comparing characteristics between patients harboring IDH mutations or not. Studies were excluded if they: (i) only emphasized on pediatric leukemia, (ii) reported data which were unavailable or insufficient, (iii) were reviews, case reports, editorials and letters, and (iv) had overlapping cohorts.
Literature review
We performed a literature search without limitation in regions. The primary sources were the electronic databases of PubMed, Embase, and Cochrane as well as Chinese databases including WanFang Database and China National Knowledge Internet (CNKI), with the publication date from January 1, 2010 to June 26, 2016. The terms included "AML," "acute myeloid leukemia," "IDH," "IDH1," "IDH2," "IDH1/2," " isocitrate dehydrogenase" and "IDH1 SNP." In addition, manual searches of reference list were also performed.
The titles and abstracts of all potential studies were initially browsed independently by two reviewers (Q.Y. Xu and Y. Li) to screen and narrow down the studies according to inclusion and exclusion criteria. Any discrepancy was resolved by discussion or consultation with another investigator not involved in the initial procedure. After candidate studies were selected, full-length articles were reviewed to identify eligible studies and the ultimately identified studies were determined by quality assessment.
Quality assessment of primary studies
The methodologic quality of primary manuscripts was evaluated separately by two reviewers (Q.Y. Xu and Y. Li), according to the Newcastle-Ottawa-Scale (NOS; ref. 15), which is used for quality assessment of cohort studies and case–control studies. Studies scoring six or more were considered to be with high quality. Any disparities between investigators were addressed by discussion.
Data extraction
Related information from the identified studies were extracted and summarized independently by two of the authors (Q.Y. Xu and Y. Li). Any disagreement was solved by discussion or consultation with a third reviewer.
The extracted data contained the first author, study characteristics (including NOS scores, publication year, journal, region, sample size, age, tumor types, incidence of different IDH gene aberrations, mutation detection therapies, therapeutic regimens and data types; Table 1) and participant characteristics [including sex ratio, laboratory examination results, French-American-British (FAB) classification, cytogenetic risk categories, sample size with normal karyotype, incidence of mutant nucleophosmin 1 gene (NPM1) and fms-like tyrosine kinase 3-internal tandem duplication gene (FLT3-ITD; Supplementary Table S1)].
Furthermore, survival and treatment outcome information was also incorporated into this meta-analysis, including relative risk (RR) for complete remission (CR) rates as defined according to recommended criteria (16) and HR for overall survival (OS, defined from diagnosis or the date of entry onto the studies to death or alive at last follow-up; refs. 10, 17), event-free survival (EFS, defined from diagnosis or the date of entry onto the studies to treatment failure, relapse, death or last follow-up in CR; refs. 17, 18), as well as cumulative incidence of risk (CIR; ref. 19). Data were preferentially extracted from multivariate analyses. However, in some studies without multivariate results provided, data were obtained from univariate analyses, or calculated from numeric reports or Kaplan–Meier survival curves using the methods previously proposed by Tierney and colleagues (20).
Statistical analysis
The Stata 12.0 statistical software was used for the meta-analysis. Pooled RRs or HRs less than 1.00 indicated a better therapeutic effect or prognosis in AML patients with IDH gene aberrations, compared with those harboring wild-type IDH gene, and it would be considered statistically significant that 95% CIs did not cover 1. A P value less than 0.05 also meant statistical significance.
The heterogeneity among primary studies was evaluated by using the Q test. A P value greater than 0.10 was considered to be without heterogeneity or with slight heterogeneity, whereas P < 0.10 indicated the existence of significant heterogeneity. Besides, I-square (I2) < 30%, 30%–50%, 50%–75%, and >75% were defined as low, moderate, substantial, and considerable heterogeneity, respectively (21). The random effect model, which was admitted to be more conservative, was chosen if significant heterogeneity was observed. Otherwise, the fixed-effect model was used. Moreover, to find the source of significant heterogeneity, sensitivity analyses were performed to determine whether an individual study affected the aggregate result. Subgroup analyses were also used for exploring the potential source of significant heterogeneity based on the following aspects: region of subjects, mean or median age, mutation detection therapy, data type, and therapeutic regimens.
Visual inspection of the funnel plot was initially done to assess publication bias. We next used the Egger (22) and Begg tests (23) to further evaluate it. A P value less than 0.05 indicates the existence of publication bias.
All analyses were based on published studies; therefore, no ethical approval and patient consent were required.
Study selection procedure
The procedure of selecting studies was shown in Figure 1. First, 502 studies were retrieved from PubMed, Embase, Cochrane, and Chinese databases (WanFang and CNKI), 197 of which were removed because of overlapping datasets. We screened the remaining 305 studies by browsing their titles and abstracts, excluded 225 studies for no association with our interest and chose 80 reports including articles and conference literatures for further evaluation. Of the 80 full-text studies, 47 were ruled out for the following reasons: 6 studies were only involved in pediatric leukemia; 3 reports were reviews; the data of 35 studies were incomplete or unavailable for analysis; the patient cohorts of 3 literatures overlapped with 3 other articles. The reviewers had perfect agreement in identifying the remaining 33 studies using the aforementioned eligibility criteria and all of identified manuscripts were with high quality (Table 1).
Study characteristics
The characteristics of 33 studies were summarized in Table 1 (6, 10, 11, 16–19, 24–49): 13 studies from Europe and Australia, 10 from Asia, 8 from America and 2 collaborated studies from Asia, Africa, and America as well as America, Japan, and Germany, respectively, with a total sample size of 12,747 cases. The frequency of IDH1 mutation was 2.02%–9.30% in AML patients and 10.91%–15.96 % in CN-AML patients, respectively, whereas the frequency of IDH2 mutation varied from 5.05% to 14.76% in AML subjects and from 5.85% to 19.27% in CN-AML cases, respectively.
As shown in Supplementary Table S1, IDH gene aberrations were closely associated with elderly patients in 12 studies (16, 18, 25, 26, 30, 32, 33, 38, 41–43, 47, 48) and with higher platelet count in 9 studies (16, 18, 26, 27, 29, 36, 38, 42, 43). In addition, in the aspect of FAB classification, patients with M1 harbored higher percentage of IDH mutations (6, 17, 18, 24, 25, 29, 30, 39, 42), whereas in cases with M4, lower percentage was observed (17, 24, 29, 47). Besides, the frequency of IDH mutations was higher in cases with normal karyotype in 9 studies (6, 16–18, 24, 25, 29, 30, 39, 40, 42, 48). Finally, higher percentage of mutant NPM1 was always correlated with higher frequency of IDH gene aberrations in 14 studies (6, 16–19, 24, 25, 30, 36, 38–40, 42, 43, 47, 48).
Prognosis of AML patients with IDH mutation
When mutant IDH1 and IDH2 were considered as a single factor - IDH mutation, pooled HRs for OS in AML patients were 1.05 (95% CI, 0.89–1.23; P = 0.5836; heterogeneity: I2= 65.1%, P = 0.000; Fig. 2A). Because of significant heterogeneity observed among the selected studies, we conducted a sensitivity test and found that omitting any single study did not influence the result of OS. Hence, subgroup analyses were proposed in Table 2. Among AML patients under 60 years of age, the combined HRs of OS were 0.99 (95% CI, 0.85–1.16, P = 0.9292; heterogeneity: I2= 0.0%, P = 0.662; Fig. 2B). Except for prognostic insignificance for OS, the summary HRs for EFS were 0.97 (95% CI, 0.80–1.18; P = 0.7713; heterogeneity: I2= 0.0%, P = 0.674; Fig. 2C).
For prognostic influence of IDH mutation on CN-AML patients, pooled HRs of OS and EFS were 1.09 (95% CI, 0.85–1.40, P = 0.4944; heterogeneity: I2= 52.3%, P = 0.078) and 1.14 (95% CI, 0.69–1.88; P = 0.6393; heterogeneity: I2= 67.5%, P = 0.027) (Supplementary Fig. S1A–S1C), respectively. As heterogeneity was observed, we also performed a similar sensitivity analysis. When the study by Nomdedéu and colleagues (34) was ruled out, the summary HRs of OS and EFS decreased to 1.03 (95% CI, 0.88–1.20, P = 0.7306; heterogeneity: I2= 0.0%, P = 0.568) and 0.91 (95% CI, 0.67–1.23, P = 0.5460; heterogeneity: I2= 0.0%, P = 0.795; Supplementary Fig. S1B and S1D), respectively. Therefore, this study might be the source of significant heterogeneity, which needs further discussion.
These pooled HRs of OS and EFS suggested that when IDH1 and IDH2 mutation were analyzed together rather than separately, prognostic impact of these mutations were insignificant in AML or CN-AML patients. Interestingly, among IR-AML patients, the combined HRs of CIR was 1.44 (95% CI, 1.18–1.76, P = 0.0003; heterogeneity: I2= 0.0%, P = 0.429; Fig. 2D).
Prognosis of AML patients with IDH1 mutation and SNP rs11554137
Becasue of prognostic ineffectiveness of IDH mutation, it was hypothesized that IDH1 and IDH2 mutations might be associated with different prognosis for AML patients. Indeed, patients with mutant IDH1 had a significant disadvantage of OS (HR: 1.17; 95% CI, 1.05–1.31, P = 0.0047; heterogeneity: I2= 0.0%, P = 0.570; Fig. 3A) and EFS (HR, 1.29; 95% CI 1.07–1.56, P = 0.0110; heterogeneity: I2= 2.8%, P = 0.391; Fig. 3B). Patients with IDH1 SNP rs11554137 also had shorter OS (HR, 1.34; 95% CI, 1.03–1.75, P = 0.0294; heterogeneity: I2= 0.0%, P = 0.396; Fig. 3C).
Among CN-AML patients, the summary HRs for OS and EFS were 1.21 (95% CI, 1.01–1.46, P = 0.0388; heterogeneity: I2= 4.4%, P = 0.393; Fig. 3D) and 1.56 (95% CI, 1.23–1.98, P = 0.0002; heterogeneity: I2= 22.2%, P = 0.273; Fig. 3E), respectively. Finally, for patients with IDH1 mutation, the CR rates were also lower (RR, 1.21; 95% CI, 1.02–1.44, P = 0.0289; heterogeneity: I2= 0.0%, P = 0.710; Fig. 3F).
Prognosis of AML patients with IDH2 mutation
Interestingly, the prognosis of patients with IDH2 mutation was significantly favorable in OS (HR, 0.78; 95% CI, 0.66–0.93, P = 0.0053; heterogeneity: I2= 28.7%, P = 0.199; Fig. 4A), especially in IR-AML patients (HR, 0.65; 95% CI 0.49–0.86, P = 0.0026; heterogeneity: I2= 0.0%, P = 0.950; Fig. 4B).
However, among CN-AML patients, the combined HRs for OS were 0.99 (95% CI, 0.70–1.42, P = 0.9867; heterogeneity: I2= 52.1%, P = 0.051; Supplementary Fig. S2A) and became 0.85 (95% CI, 0.65–1.10, P = 0.2114; heterogeneity: I2= 0.0%, P = 0.608; Supplementary Fig. S2bB) with the study by Boissel and colleagues (19) excluded. In addition, the summary HRs for EFS in CN-AML cases were 0.89 (95% CI, 0.66–1.21, P = 0.4671; heterogeneity: I2=0.00%, P = 0.933; Supplementary Fig. S2C).
For patients with the IDH2 (R140) mutation, the combined HRs for OS were 0.83 (95% CI 0.60–1.16, P = 0.2813; heterogeneity: I2= 69.0%, P = 0.006; Supplementary Fig. S3). As exclusion of any single study would not alter the aggregate result, subgroup analyses were also performed in Table 2.
For patients harboring the IDH2 (R172) mutation, the pooled HRs of OS were 0.72 (95% CI, 0.41–1.27, P = 0.2579; heterogeneity: I2= 64.3%, P = 0.024) and the sensitivity analysis showed that the study by Green and colleagues (30) brought great heterogeneity. After this study was removed, the pooled HRs for OS were 0.59 (95% CI, 0.35–0.99, P = 0.0457; heterogeneity: I2= 30.9%, P = 0.227; Supplementary Fig. S4A and S4B).
In the aspect of treatment outcome of patients with mutant IDH2, the pooled RRs of CR rates were 1.23 (95% CI, 0.96–1.59, P = 0.1004; heterogeneity: I2= 59.2%, P = 0.023) and were slightly lowered by excluding the study by Boissel and colleagues (ref.19; RR: 1.15; 95% CI, 0.94–1.40, P = 0.1767; heterogeneity: I2= 38.0%, P = 0.153; Supplementary Fig. S5A and S5B). Interestingly, the summary RRs of CR rates for the mutant IDH2 (R172) were 2.14 (95% CI, 1.61–2.85; P = 0.0000; heterogeneity: I2= 16.4%, P = 0.302; Supplementary Fig. S5C).
Sensitivity analyses
In CN-AML patients with IDH mutations, sensitivity analysis revealed that the study by Nomdedéu and colleagues (34) was the source of heterogeneity in pooled HRs for OS and EFS. The follow-up period in Nomdedéu and colleagues (34) (12–72 months) was significantly shorter than that of other studies (approximately 10 years), which brought relatively prolonged OS expectancy of patients with wild-type IDH gene, leading to outlier HR and generating great heterogeneity.
Among CN-AML cases with mutant IDH2, the great heterogeneity was derived from the study by Boissel and colleagues (19) in OS and CR rates analysis due to its lower percentage (5.85%) and fewer samples (12 cases) of IDH2 mutation than that in the remaining studies, which might be unrepresentative and bring randomness to HR for OS and RR for CR rates.
The prognostic value of IDH2 (R172) mutation was unclear due to significant heterogeneity, which might be from the study of Green and colleagues (30). In fact, the prognostic significance of IDH2 (R172) mutation in this manuscript was really different from four other studies. However, this study could not be excluded for the following two reasons: First, although the frequency of IDH2 (R172) mutation in Green and colleagues (30) was the lowest (2.01%) compared with other studies [Patel and colleagues (35), 2.30%; Koszarska and colleagues (38), 2.65%; Willander and colleagues (41), 2.64%; Papaemmanuil and colleagues (11), 2.53%], the sample size of cases with IDH2 (R172) mutation in this study was large, accounting for 32.22% of the total number of cases with mutant IDH2 (R172) in this analysis. Besides, the study by Green and colleagues (30) also had enough cases, accounting for 36.89% of the total. Therefore, the possibility of contingency derived from small samples might be low. Finally, the follow-up period of Green and colleagues (30) was 10 years, which was long enough to minimize bias from shorter duration of follow-up.
Subgroup analyses
With the advent of significant heterogeneity in OS for IDH and IDH2 (R140) mutations, we therefore performed subgroup analyses (Table 2). Although the most important source of heterogeneity might be from different prognostic value of subtypes of IDH mutations, we did not performed related subgroup analyses for clear prognosis of each mutation has been shown above.
As shown in Table 2, the original regions of samples, mutation direction methods, therapeutic schedules and data types had no effect on OS for mutant IDH and IDH2 (R140). However, in the aspect of mean/median age, younger people (mean/median age ≤ 50 years) with IDH mutations were with more consistency (HR, 0.91; 95% CI, 0.80–1.02, heterogeneity: I2= 0.0%, P = 0.553) than other age groups (> 50 years, HR, 1.00; 95% CI 0.73–1.37, heterogeneity: I2= 74.4%, P = 0.001, and unknown; HR, 1.36; 95% CI 1.10–1.68, heterogeneity: I2 = 0.0%, P = 0.635; P = 0.005). In addition, the IDH2 (R140) mutation was associated with prolonged OS among younger patients (mean/median age ≤ 50 years, HR, 0.64; 95% CI, 0.49–0.82, heterogeneity: I2= 0.0%, P = 0.906) when compared with older patients (mean/median age > 50 years, HR, 1.11; 95% CI, 0.37–3.33, heterogeneity: I2= 84.7%, P = 0.010).
Publication bias
Egger and Begg tests were performed to evaluate publication bias and funnel plot symmetry was examined. No evident publication bias was observed based on the visual distribution of funnel plot (Supplementary Fig. S6A–S6C) and P values in Egger and Begg tests (Supplementary Table S2).
Comparing results from random effect model with those from fixed effect model
As shown in Supplementary Table S3, the analyses without heterogeneity (I2 = 0.00%) had the same HRs or RRs and 95% CIs in random effect model and fixed effect model. Additionally, HRs, RRs and 95% CI from the analyses with heterogeneity (I2 > 0.00%) were slightly changed from random effect model to fixed effect model but it had no impact on prognostic analyses.
Major findings
In this study, IDH mutations showed obviously different prognostic significance because of various subtypes. When IDH1 and IDH2 mutation were analyzed together rather than separately, there was no prognostic availability and great heterogeneity was observed in our analysis, both of which could be explained by the diverged impact of IDH1 and IDH2 mutations on survival.
Cases with mutant IDH1 had reduced OS (HR, 1.17; P = 0.0047) and EFS (HR, 1.29; P = 0.0110) than those harboring wild type, especially in CN-AML patients (HR for OS: 1.21, P = 0.0388; EFS: 1.56, P = 0.0002). IDH1 SNP rs11554137 also conferred shorter OS (HR, 1.34; P = 0.0294). Therefore, these results suggested that mutant IDH1 and IDH1 SNP rs11554137 might contribute to adverse prognosis, similar to FLT3-ITD mutation (50), and would be allowed to perform more accurate molecular risk stratification of AML.
Likewise, mutant IDH2 might also be one of prognostic markers for its significant association with better prognosis (HR for OS: 0.78; P = 0.0053), especially in the subset of IR-AML cases (HR for OS: 0.65; P = 0.0026). Interestingly, among CN-AML patients, mutant IDH2 had no impact on OS (P = 0.2114) and EFS (P = 0.4671). The discrepancy of survival between CN-AML and IR-AML cases might originate from cytogenetically abnormal karyotype belonging to intermediate risk, such as isolated trisomy 8, t (9; 11) and some nondefined karyotypes. Abnormal karyotype frequencies were listed as follows: 24.44% versus 28.95% (mutant IDH2 vs. wild-type IDH2) in Chou and colleagues (29) and 31.58% versus 17.81% (mutant IDH2 vs. wild-type IDH2) in Ley and colleagues (6, 39). Notably, trisomy 8 alone was significantly associated with IDH mutations (24, 29). However, little is known about survival of patients with the combination of isolated trisomy 8 and IDH mutations, and more data are required to distinguish prognostic differences between IR-AML cases with normal and those with abnormal karyotypes when harboring mutant IDH. Furthermore, the IDH2 (R140) mutation could improve OS among younger patients (mean/median age ≤ 50 years, HR: 0.64, P = 0.0005) after conducting subgroup analyses. In addition, since several studies have reported favorable prognosis of IDH2 (R172) mutation, particularly in studies by Papaemmanuil and colleagues (11) and by Paschka and colleagues (European Hematology Association, 2016), we conducted a meta-analysis to evaluate prognostic value of this mutation. The impact of IDH2 (R172) mutation on survival had significant heterogeneity, showing it still remains controversial about its prognostic value and more studies are required to clarify its role.
Despite the diverged survival significance between IDH1 and IDH2 mutations, CR rates in patients with IDH mutations were consistently lower, particularly for those with mutant IDH1 (RR, 1.21; P = 0.0289) and IDH2 (R172; RR, 2.14; P = 0.0000). Interestingly, Green and colleagues (30) found that CR rates of the IDH2 (R140) mutation were relatively high (RR, 0.47; P = 0.0032). Except for declining CR rates, there was increasing CIR in IR-AML patients with IDH mutations (HR, 1.44; P = 0.0003).
Our results have identified the prognostic value of each subtype of IDH mutations in AML patients, which might contribute to the application and therapeutic evaluation of target drugs in clinic.
Prognosis when combining with other mutations
As mentioned in Supplementary Table S1, IDH mutations appear to be notably connected with mutant NPM1. Besides, FLT3-ITD and NPM1 mutations have been compiled into the NCCN guidelines. In this regard, it is worth discussing the prognosis of IDH mutations in consideration of the other two.
In cases with wild NPM1, IDH1 mutations were related to reduced OS (refs. 6, 39; P = 0.0030) and EFS (ref. 17; P = 0.044), whereas IDH2 mutation was associated with prolonged OS (ref. 30; P = 0.0206) and EFS (refs. 6, 39; P = 0.0283). In the study by Green and colleagues (30), patients with the IDH2 (R140) mutation showed a better OS (P = 0.0002) when limited to those with wild FLT3-ITD. Furthermore, for IR-AML cases with wild-type NPM1 and FLT3-ITD, IDH1 mutations were also related to remarkably shorter OS (P < 0.05) and EFS (P < 0.05; refs. 6, 18, 39).
Comparison with other analyses
Our results were consistent with two other studies published previously: a meta-analysis (8) including 15 studies involved in IDH1 mutation in AML and another one (9) covering 13 studies associated with IDH1 and IDH2 mutation in nonpromyelocytic AML. Both found that IDH1 mutation was correlated with poor prognosis, whereas opposite prognosis was observed in IDH2 mutation. Our meta-analysis contained 33 publications and included 12,747 cases in total, a larger scale study that could significantly increase the statistical power and accurately assess the prognostic impact of IDH mutations on AML patients.
Another significant feature of our research is that the populations included were broadly from Europe, Asia, Australia, and America. Hence, our meta-analysis promised an extensive utilization of IDH mutations in the prognosis of AML patients.
More importantly, we investigated more endpoints of survival and treatment outcome. IDH mutations had no impact on OS and EFS if integrated as a single factor. For mutant IDH1, we not only performed analyses about OS and EFS in AML and CN-AML cases, but also found that IDH1 SNP rs11554137 was correlated with poor prognosis for AML patients, a finding previously not reported in the two meta-analyses. We also noted that mutant IDH1 was more unfavorable for OS in CN-AML cases, which was not shown in the two previous analyses. We found that IDH2 mutation was not only associated with prolonged OS but more linked to favorable prognosis among IR-AML patients, which was also not shown in the two previous articles. We found that mutant IDH2 (R140) but not IDH2 (R172) was correlated with longer OS in subgroup analyses, a novel finding as well. In addition, we found that IDH mutations were related to CIR and treatment outcome. In particular, the CR rates were lower for patients with the IDH2 (R172) mutation, a finding not shown before.
We performed in-depth subgroup analyses according to different clinical and methodological features to synthetically estimate the prognostic influence of IDH and IDH2 (R140) mutations and investigated potential sources of heterogeneity. It was obvious that characteristics of patients (mean/median age ≤ 50 years) were more uniform than those older than 50 years and the IDH2 (R140) mutation in younger cases was notably related to better OS, reflecting that older age might be a more powerful factor in contributing to poor prognosis than the IDH2 (R140) mutation does.
Limitations of our study
Our meta-analysis has several limitations. First, although comprehensive studies were selected from three major databases and Chinese databases, other relevant studies, especially those published in non-English or non-Chinese language or not published in public might be overlooked. Second, our analyses were based on retrospective cohort studies. Therefore, it was difficult to precisely control selection, attrition, information, and confounding bias. Third, some data were obtained from univariate analyses or calculated from Kaplan–Meier survival curves and numeric reports, which might be in slight disparity with the fact. In addition, these results were from univariate analyses and might not be as stable as multifactor-derived data. Finally, although we extracted HRs or RRs from multivariate analyses as many as possible, various confounding factors existed and should be taken into account in different studies, thereby leading to heterogeneity of pooled HRs or RRs to some extent.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Authors' Contributions
Conception and design: Q. Xu, Y. Li, L. Yu
Development of methodology: Q. Xu, Y. Li
Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): Q. Xu, Y. Li, Y. Xu, Y.Y. Li, W. Li, Z. Yao, X. Chen, S. Huang
Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): Q. Xu, Y. Li
Writing, review, and/or revision of the manuscript: Q. Xu, Y. Li, Y.H. Li, L. Yu
Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): N. Lv, Y. Jing, L.L. Wang
Study supervision: L. Yu
Grant Support
This work was supported by the National Natural Science Foundation of China (81670162, 81370635, 81170518, 81270611, 81570137, 81470010 and 81400135), Capital Medical Development Scientific Research Fund (SF2001–5001-07), Beijing Natural Science Foundation (7151009), National Public Health Grant Research Foundation(No.201202017), the Capital of the Public Health Project (Z111107067311070).
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
- Received October 24, 2016.
- Revision received November 23, 2016.
- Accepted February 22, 2017.
- ©2017 American Association for Cancer Research.


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A Multi-Engine Rating equips you with the skills and knowledge required to fly a multi engine aircraft. Since most commercial planes are multi engine, you will require this rating to pursue a career in flying and aviation.
Course Description
- Minimum 17 years of age
- Ability to read, speak, write and understand the English language fluently.
- Should hold at least a Private Pilot License
- Pass tests (oral and flight) administered by an FAA inspector or another designated examiner
Classroom Instruction: 5 hours
Course Structure
- Preflight prep
- Performance and limitations
- Operations of systems
- Principle of flight- Engine Inoperative
Flight Training Requirements
There is no minimum requirement that is mandated for Multi Engine Rating.
Course Structure
- 10 hours of flight instruction
Course Syllabus
- Preflight Procedures
- Cockpit management
- Taxiing
- Before take-off check
- Take offs, landings and GO arounds
- Performance maneuver's
- Slow flight
- Stalls (power on/off)
- Spin awareness
- All Emergency procedures
- Multi Engine operations
- Maneuverings with one engine inoperative
- Vmc Demonstration
- Engine failure during flight in IMC
- Instrument approach with one engine inoperative
Duration : 1 week*
*Subject to flying weather conditions and student's ability and aptitude
Duration : 5 week
Professors : 1
Students : 10
Learning Outcomes
Course CurriculumCurriculum is empty
firstname.lastname@example.com +753 2547 7778
Related Courses
Instrument Rating
If you are looking to become a professional pilot or even a long distance flying private pilot, this course ...apply now

subset: commoncrawl


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With all of the excitement coming to New York City in 2019 with World Pride and the 50th Anniversary of Stonewall, we are pleased to announce that LGBT Week NYC will be held June 17-28, 2019, over a 2-week period, as an official partner of #WorldPride2019!
Stay tuned for our upcoming programming announcements. We look forward to continuing and expanding our partnerships with LGBTQ business organizations in NYC, including Rivendell Media, NGLCC, StartOut, Out Professionals, the Manhattan Chamber of Commerce, Spiire.org and more.
NOTE: The World Pride 2019 Parade and Festival are happening on Sunday, June 30, 2019.
Interested in hosting an LGBTQ business-focused event during LGBTQ Week NYC?
Please review our Event Hosting Page here for more information, and please contact us here for details.
Opportunities with our Conference Series:
You may also Contact Us Here to tell us more about your inquiry or opportunity.
How can you identify the best markets within LGBTQ to maximize ROI? Which mix of elements should be in your plans: Print ads? Websites? Mobile? Social? Influencers? Video? Sponsorships? How will you measure success? Who can you partner with to amplify your initiatives? We cover it all and much more with intriguing expert presentations and real-life case studies. Whether you are new to the LGBTQ market, or a long-time veteran, you can't afford to miss these comprehensive educational and networking programs.
LGBTQ Week® is an "open source" mosaic of events and activities, produced and hosted by various LGBTQ-dedicated organizations. Focusing on two weeks in New York City during World Pride facilitates a synergy among the events and organizers that isn't otherwise available. In year's past, we've worked with the NGLCC to produce a 1/2-day workshop regarding certification and business tools for success, as well as a joint networking reception. We've also worked with the IGLTA to produce a 1/2-day LGBT Travel Symposium, oSTEM and Credit Suisse to produce an evening panel on Talent in Modern FinTech, StartOut and their LGBT Women's Business Event, and Out Professionals with their LGBT Tech mixer event. These events are cross-promoted to all the other LGBTQ Week events, expanding awareness and participation. We're happy to consider all content contributors! Please review our Partner Page here for more information, and please contact us here for details.
CMI's 12th Annual LGBTQ Marketing & Advertising Symposium
8 am - 6 pm at Google NYC
Don't miss this comprehensive research, advertising, marketing, and communications forum, helping you better understand and serve LGBTQ consumers.
Audience: Marketing, advertising, PR and communications executives of all industries who want to successfully reach diverse LGBTQ communities, and initiate or update effective strategies. Perfect for newbies and veterans alike!
More Info Here
LGBTQ New Media Summit:
Symposium on the Blending of LGBTQ PR, Advertising, Social Media & Influencers
8:30 am - 11:30 am
These symposia will include LGBTQ influencers, as well as a focus on Facebook, Instagram, Twitter and LinkedIn, and how they fit into the LGBTQ online marketing environment. In conjunction with World Pride 2019, we will also be examining how some of the more innovative Pride Festivals are using a blend of these various marketing techniques when promoting their event, to both their local audience, and to those willing to drive or fly in. Events such as LGBTQ film festivals, circuit parties and Pride Festivals are unique in that they market themselves in advance of their event, and then use social media to display event coverage and user-generated content DURING their event as well. We'll take a deeper dive in exploring what has worked best for them, including leveraging Instagram Stories, video on social media and more.
More Info
1:30 pm - 4:00 pm
Debuting a new program designed for brands, advertising agencies, media planners & buyers, and anyone interested in learning about some of the latest in LGBTQ marketing opportunities from cutting-edge companies including #ILoveGay, Glitterbomb, Slay TV & Revry.TV. We'll also be including LGBTQ influencer presentations as well.
Designed as a series of fast-paced, 15-minute dynamic presentations on some of the latest trends & new opportunities in the LGBTQ media world... including new content, new talent & new capabilities for brands to consider partnering with when they are planning their strategies to reach their target LGBTQ demographic.
More Info
To see what we did in 2017 in NYC...
Our LGBTQ Week NYC 2017 Marketing & Advertising Program Guide (PDF)
Our LGBTQ Week NYC 2017 Tourism Program Guide (PDF)
Our LGBTQ Week NYC 2017 Marketing & Advertising Program Agenda
To see what we did in 2016 in NYC...
Influencers, Content Creators and LGBTQ New Media
Our LGBTQ Week NYC 2016 Marketing & Advertising Program Guide (PDF)
To see what we did in 2015 in NYC...
LGBTQ Week NYC Rings The Nasdaq Stock Market Closing Bell
Our LGBTQ Week NYC 2015 Program Guide (PDF)
To see what we did in 2014 in NYC...
Our 2014 LGBTQ Marketing Conference Summary & Schedule
Our 2014 LGBTQ Marketing Conference Wrap-Up


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It was inspiring to see local high school students make their voices heard in calling for the city to commit to reducing its carbon footprint. Along the way, they learned some valuable lessons about government.
The students were advocating for the city's Climate and Energy Action Plan. The plan, which was the result of more than a year of meetings, calls on the city to be carbon-neutral by 2030 and to reduce fossil fuel use 50 percent by 2030 and 100 percent by 2050.
Last spring, the City Council approved the goals, but stopped short of enacting an ordinance requiring the city to meet them. This frustrated not only the students but plenty of adults as well.
Over the summer, they kept up the pressure, attending council meetings and writing letters to the editor and guest opinions that were published on these pages.
Council members were sympathetic, but understandably reluctant to commit the city to specific reductions it might not be able to meet, which could expose it to the possibility of lawsuits for failing to comply with its own ordinance.
In the end, the council approved an ordinance rewritten to make the carbon reduction goals aspirational rather than mandatory. That's less than activists wanted, but more than they initially got.
Their work didn't stop with Tuesday's vote. In the end, it won't be what's in the ordinance that matters, but what the city accomplishes, and that will depend on continued vigilance from the students and their fellow activists.


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Get Today in Masonic History into your Inbox. Sign up today for one of our email lists!
Get Today in Masonic History into your Inbox. Sign up today for one of our email lists!
Today in Masonic History Archie Bleyer is born in 1909.
Archie Bleyer was an American musician and band leader.
Bleyer was born in New York City, New York. His father was a well known trumpet player of the time. His father would even play at the Metropolitan Opera. Bleyer himself would start playing piano at the age of 7. In 1927, Bleyer went to Columbia University. His original major was electrical engineering. In his sophomore year he would change his major to music. He would leave college without graduating to become an arranger.
In the 1930's Bleyer wrote a number of songs that would be recorded. He would also begin directing his own band. While directing his band he would work with a variety of people including Johnny Mercer who became better known as a songwriter and co-founder of Capitol Records.
In 1946, Bleyer would become musical director for Arthur Godfrey. Many attribute Godfrey's success to Bleyer who had a creativity and understanding of the music that Godfrey did not posses. In many ways Bleyer was the mentor to Godfrey despite Godfrey being the elder of the two.
In 1952, Bleyer started Cadence records. Within a year, Cadence, at least in part, would be the end of Godfrey and Bleyer's relationship. In 1953, Bleyer would record Don McNeil, a Chicago based radio personality. At the time McNeil was not a competitor of Godfrey, although he was once. Godfrey still saw him as a competitor and confronted Bleyer about it. According to Godfrey's account of the events, when Godfrey confronted Bleyer about the issue and threatened to fire him, Bleyer simply shrugged and said "do what he had to do". It is also believed that Godfrey, in part, fired Bleyer for dating another staff member, Janet Ertel, which Godfrey expressly forbade. Bleyer would later marry Ertel in 1954.
Cadence records would continue until 1963. During Bleyer's time with Cadence he would produce and work with many artists including Andy Williams and the Everly Brothers. Bleyer had an intense dislike for Rock and Roll. Despite his dislike he would sign pioneering garage-rock guitarist Link Wray. Cadence would put out one album from Wray and a second was recorded. Bleyer disliked the album so much that he broke his contract with Wray and sealed the album away. The album would not see the light of day for decades.
In 1964, Bleyer could not accept the changing pop music market with the coming British Invasion, so he sold Cadence to Andy Williams who would manage the Cadence catalog under Barnaby Records. Bleyer would hold on to the unreleased Wray album in the sale.
Bleyer would retire with his Janet to Sheboygan, Wisconsin. In Wisconsin on March 20th, 1989 Bleyer would pass away from the effects of Parkinson Disease.
Bleyer was a member of St. Cecile Lodge No. 568 in New York City, New York.


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In a little town in rural Ghana, thousands of miles away from my own farm and family, I have found a new home away from home, as Sistah Adwoa, the newest member of the Appiah family in Bipoa.
I don't think I have yet felt so close to home as I did driving to Mr. Appiah's farm last weekend. It was last Friday morning and I was riding down a small, washed out back road to an even smaller back, squished beside Mr. Appiah and two cousins in the front seat with a load of younger family members riding in the back. This ride brought me back to riding in the tractor or truck down the back lane to our own fields back home. The same sounds of an old diesel engine and branches scraping the windshield, the smells of diesel, dust and green growth, and the familiar steering around potholes that you've known forever. That lane back home is one of my favorite places to be, and what a treat to be getting a taste of it here in Bipoa.
Bipoa is a little community about an hour outside of Kumasi, where I spent part of last week learning more about the agricultural sector in Ghana. Bipoa was no exception to the outstanding hospitality that I have witnessed since coming to Ghana. I was introduced to the Appiah family from a friend that is a local extension agent. Right away the family took me in as their newest sister. My Ghanaian parents and siblings all called me Sistah Adwoa (my Ghanaian name – for being Monday born, pronounced Adjua) from the first morning. I learned so much about farming and rural livelihoods during my time in Bipoa, about how the extension system works and how farmers interact with the public sector.
Let me go back a minute and introduce you to Mr.Appiah. Mr. Appiah is a farmer. In fact, a very good farmer. Last year he was awarded the Famer of the Year award in his district and he also acts as a chief farmer. He explained to me that he farms on land that used to belong to his grandfather and is now parcelled between many cousins and uncles and brothers. As his farm has prospered, he's expanded to other plots of land, and I think he has at least 6 different plots now, with plans to continue expanding. He farms palm nut, plantain, banana, maize, oranges, cocoa yam and cassava and also has a few goats and sheep. However, his main crop, and his main source of income is farming cocoa. The other crops bring in a small profit, but also play an important role in subsistence for the family and intercropping with the cocoa (eg. plaintain and palm are used to shade cocoa seedlings until they are matured, then the plantain and palm will be cut down to let the cocoa take over).
Each day in Bipoa I went to the farm with Mr.Appiah and some of his labourers and kids. We harvested, maintained plants, weeded, applied chemicals and prepared food. It was hard work – all done by hand and cutlass. I was exhausted from just walking to the farm (walking is an understatement, it was a 40 minute hike through thick brush). This week cocoa farmers in Bipoa were participating in a training program to increase their business skills in order to have more profitable, sustainable and food secure farms. I attended the trainign on Monday with Mr.Appiah and learned a lot that will be useful for our own agribusiness training that we do! At home I played with by new sisters and brothers, ate amazing food and met many, many, many community members. The kids in the community were especially excited to see me. In church, one kid leaned over in his pew so far to see me that he fell over the in the middle of the service.
And what did I learn?
The main purpose of my stay in Bipoa was to spend some time learning more about agriculture and rural livelihoods, trying to understand the extension system better. Extension is how farmers access information, and it is the area in which my team works. One of the objectives of our work at the colleges is to ensure that students that will become extension agents graduate from agricultural colleges with the skills and attitudes required to give high quality advisory services to farmers.
So, what did I learn? Well, I was expecting to learn about how Mr. Appiah got his information on farming, and actually ended up finding out that he himself is a huge resource of information for other farmers! Let's back up, to say, December 2011, when Mr. Appiah was chosen as his district's Farmer of the Year! This is a huge honour and recognizes his excellence in farming and his contribution to the agricultural development of Ghana. Agricultural Extension Agents (AEAs) that I met this week all praised Mr. Appiah's farming, saying that he is an extremely innovative farmer and always the first to adopt any new technology that will improve his farms.
AEAs see him a key resource for their own efforts. They think that farmers trust information coming from other farmers more than from AEAs, so having role models like Mr.Appiah is a great incentive for other farmers to learn about and adopt new technologies. And I really saw this in action: other farmers really respect Mr.Appiah and often discuss farming best practices with him. Other farmers rely on him for advice, and even to help with inputs, such as cocoa seedlings.
The fact that Mr. Appiah is so hard working, innovative and generous allows him to play a role in strengthening the agricultural sector in Bipoa – leading farmers throughout his community to make good decisions for the growth and sustainability of their farms, the food security of their family and the development of their community.
So all in all, a pretty amazing week. Learning so much about extension and agriculture, learning lots of Twi, visiting farms and making myself at home with my new Ghanaian family as their newest Sistah Adwoa!


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Hi LEAD_NAME –
One of the first logical steps in the home search process is narrowing down your true wants and needs in a home. Doing this simple exercise early in the process will help save you time and frustration during the search process.
Some major things to consider:
- How many bedrooms/baths?
- What neighborhood or area?
- How close do you need/want to be to schools?
- What is your price range?
- How close to work?
- How much square footage do you need?
You should also consider which features of the home might be required vs. nice to have. Things like:
- Garage
- Yard
- Swimming Pool or hot tub
- Walk-in closets
- Fireplace
I_AM_WE_ARE sure you will find that spending a little time in advance thinking about these things is well worth it. I_WE would love to sit down with you and guide you through the exercise.
How else may I_WE_LC be of service in your home search? I_WE look forward to serving you in any way I_WE_LC can. Please don't hesitate to contact ME_US_LC.


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For starters I have to make this abundantly clear- I did NOT make this mesh or the map or anything else required to make this mug look so awesome. This is the work of Nysha, aka Whiterider, at MTS. So go and check out her creator page as she's got quite a few goodies up on there. =D All I did was make her object an accessory.
There are 4 packages zipped in the Accessory download. Two are rings, two are bracelets. Why bracelets and rings? Well, if your sim is wearing a bracelet or ring and you don't use a mod that allows for multiple accessories per location you can still use the mug accessory and they'll keep their bracelet or ring on. Also, they are for multiple hands just because sometimes I drink coffee left handed, sometimes right handed depending on what else I'm doing at the moment.
There are 3 presets included, each with a custom thum in CAS so you know what you're clicking on.
The mugs have three channels. The outside, the handle, and the inside.
So there are lots of CASting possibilities for you to use.


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120g dark cooking chocolate
60g butter
small bag of white chocolate buttons
2 tbsp white granulated sugar
drop of black food colouring
Prep time: 30 mins
Cook time: no cook, but does need at least 2-3 hours in the fridge to set
Makes 14-16 cigars
- Line a baking tray with cling film or greaseproof paper, and make some space for it in the fridge.
- Break the dark cooking chocolate into pieces in heatproof glass bowl and melt the chocolate. (This can be done either in the microwave by microwaving for 30 seconds on medium, stirring and continuing in 10 second bursts until fully melted, or if you prefer by melting over a pan of bowling water).
- Chop the butter into small cubes and mix into the melted chocolate until the butter is also melted. Leave the mixture to cool for 10 minutes before sifting in the icing sugar. Beat until combined.
- With very clean hands, scoop out a bit of the mixture and mould it into a cigar shape and place it onto the prepare baking tray. Repeat until all of the mixture has been used and then place the tray in the fridge to set for at least 2-hours. The cigars (truffles) should be solid and firm to touch.
- Meanwhile, put the sugar into a plastic food bag and add the black food colouring. Seal the bag and then rub the sugar between your hands until the sugar has absorbed the food colouring and is various shades of gray. (Don't worry if the colour is not even, I found that it looked more like ash having some granules darker than others!) Place the coloured sugar into a bowl.
- Once the truffles are set, melt the white chocolate buttons. Dip each truffle about 1cm into the chocolate at one end, and then immediately dip this into the grey sugar. Place back on the baking tray to set.
- Wrap a small piece of paper around the truffle and secure into place with some white chocolate. You can choose to fashion the paper to match any brand of cigar – just remember to tell people not to eat that part!
200ml Guinness beer
170g plain flour
2 medium eggs, beaten
290g soft brown sugar
60g cocoa powder
100g dark chocolate chips
115g margarine
¼ tsp bicarbonate of soda
¼ tsp baking powder
For the chocolate ganache covering:
300g dark chocolate
250ml double or whipping cream
125g cream cheese
250g icing sugar
90g unsalted butter
1 tsp vanilla essence
1 tsp lemon curd
Cook time: 1.5 hours
Serves: 14
Serves: 14
- Start by preparing the chocolate ganache, as this will need time to cool and set. Break the chocolate into small pieces into a large mixing bowl. Bring the cream to the boil in a small saucepan over a medium heat, then immediately pour over the chocolate. Mix until all of the chocolate has melted then put the bowl to one side and leave to set, uncovered, for 2 hours at room temperature. Whilst the ganache is setting, make the cake.
- Preheat the oven to gas mark and grease and line a 4 inch cake pan
- In a large mixing bowl, mix the butter and sugar together until smooth and creamy, then gradually beat in the eggs until combined.
- Sift the flour, bicarbonate of soda and baking powder into a second bowl, and in a third bowl, mix the cocoa and the Guinness.
- Fold a small amount of the Guinness mixture into the butter and sugar, followed by an equal amount of the flour mixture. Repeat this process until all three mixture are well combined (careful not to over beat as you don't want to loose the air!) Fold in the chocolate chips.
- Place ¼ of the mixture into the baking pan and bake for 25-30 minutes until a skewer inserted into the centre of the cake comes out clean. When the cake is done, place this on a wire wrack to cool. Repeat until all the cake mixture has been used, and you have 4 layers.
- Whilst the cake is cooling, prepare the cream cheese frosting. Note: The recipe I based this on said to put all ingredients in a food processor and blend until smooth. Not that I'm questioning Mr. Worrall-Thompson's authority on frosting, but clearly his food processor is far superior to mine, as whenever I try this I end up with tiny lumps of butter in a mixture that is anything but smooth. Therefore, the technique below is to make the frosting by hand. However, if you would prefer to try the professionals way, then pop all the ingredients into your food processor and blend until smooth ^_^
- Chop the butter into small cubes and place in a large mixing bowl. Beat until soft. Add the cream cheese, vanilla essence and lemon curd and mix until combined, then sift in the icing sugar and mix well. Keep in the fridge until you need to use it.
- Once the cakes are cool, begin to layer them, using the chocolate ganache between the layers. Tip: if your cake start to tilt then place a skewer straight down the middle as a support – just remember to remove this before serving!
- Use the remaining chocolate ganache to completely cover the sides of the cake.
- Roll up some greaseproof paper, and shape this into a handle, poking the ends into the chocolate ganache to secure it into place.
- Spoon half of the cream cheese frosting into the centre of the top of the cake. Allow this to run naturally to the edges. Save the other half of the cream cheese in the fridge for serving.
And there you have your very own Beer cake and chocolate cigars!! Now the beer cake is pretty tall, so to serve this I cut it in half to make two two layer cakes, and used the rest of the cream cheese frosting to top the cake which didn't have any, before cutting into slices.


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Frequently Asked Questions
What's this issue all about
Why does infertility matter to me in NY
What can be done to help families with infertility
These more effective treatments have made single births vastly more likely (and multiple births, twins, triplets less likely) and thereby help keep costs down.
Why do families need our help
How can I help
The New York Legislature needs to be urged to help our state's families by requiring health insurers to cover fertility medical treatments that are recommended by doctors based on the ages of the patients and the medical diagnosis. The additional cost to a health insurance policy would be very small and the need is very large.
Can my joining the Coalition really help the cause
What does fertility preservation have to do with cancer
Who else supports this and is signed onto the joint letter
RESOLVE: The National Infertility Association is a non-profit, charitable organization, who works to improve the lives of women and men living with infertility.
The largest charity that comprehensively addresses young adult cancer through advocacy, research, support, outreach, awareness, mobile health and social media, the non-profit, Stupid Cancer, also supports our effort


text:
Personal Checking
Whatever your needs, United Bank has a personal checking account for everyone!
United Bank offers interest-bearing and non interest-bearing personal checking accounts. Let us help you select the option best suited to your needs and lifestyle.LEARN MORE
Reward Checking offers you options to reduce or
eliminate the $8.00 monthy service change by utilizing
service each month that best fit your lifestyle.
Reward Plus Checking provides higher interest earnings
and offers options to reduce or eliminate the $10.00
monthly service charge.
Debit CardsLEARN MORE
Online ServicesLEARN MORE
Bill PayLEARN MORE
Over Draft ProtectionLEARN MORE
Auto PaymentLEARN MORE
MobileLEARN MORE
Credit Cards
United Bank offers business and personal credit cards, complete with a convenient online portal that will help you manage your activity and payments.VIEW SERVICE
CDs & IRAs
Maximize your interest earnings with United Bank's CDs and IRAs, perfect for long-term or larger sum savings.VIEW SERVICE
Online Services
Securely access your United Bank accounts from anywhere in the world with our online services.VIEW SERVICE
We offer a variety of personal savings options that offer you the right amount of flexibility and exclusive benefits.VIEW SERVICE


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Welcome to Big Thicket Veterinary Clinic!
Your local veterinarian in Cleveland. Call us today at 281 593 1876 to schedule your pet care appointment!
Veterinary Services Available
Our Veterinary Hospital in Cleveland, TX is pleased to provide a wide variety of veterinary services for animals in Cleveland & Surrounding Area. These services include dentistry, flea control, surgery & more!


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This morning I designed these two quote posters for our home. Two concepts I want before my eyes continually.
A home is a haven, a place of inspiration and learning. I feel like the art I hang in my home is important. Cheers to wise words. And cheers to Fifth and Hazel for my design inspiration. Mel is so talented.


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It's the self-styled 'Wikipedia for parking'. Through its website and native mobile apps, Parkopedia lets you see information on meters, spaces, parking lots and even private drives that are for hire. Much of this data is added to and updated by the Parkopedia community. Its data is also used by many of the major car makers, including Audi, BMW, Ford, Toyota, Volvo and Jaguar Land Rover, who can integrate the Parkopedia database into their dashboards.
The current database includes 150,000 off-street parking facilities in 6,300 cities, with information on more than 38 million parking spaces in 75 countries. With the global smart parking market forecast to grow at more than 30 per cent annually over the next four years, Parkopedia is in the driver's seat for growth.
For more information please visit www.parkopedia.co.uk


text:
So, I've been wanting to change my blog design up for a while now and finally got around to it. I LOVE the way it turned out. I'm really loving chevron these days and I just loved this colorful pattern!
What do you guys think?
I like it! For some reason the banners on your other background would come forwards sometimes so I could only read one line at a time. That probably doesn't make any sense, but I'm not sure how to explain it. Anyway this one is nice and crisp and clean
I love the chevron and the colors! :)
Looks awesome! You did a great job!
Love the colors and pattern! Looks great!
I absolutely LOVE your blog design! I wish I could figure out how to create my own. Any chance you'd want to give a tutorial sometime? :-)


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I was lucky to draw Lara Croft for a project I'm currently working on. For that particular purpose it's just a simple spot illustration on white background. After I finished it I couldn't resist doing a very quick experiment and work it a little bit further. Would be fun to something like this more often.
13 August 2011
A figure in the dust - Lara Croft
Posted by Petri Suni at 17:53
Labels: experimenting
2 comments:
Very nice! Simple and streamlined, very effective. This is awesome. If there was a comic book of Tomb Raider that looked exactly like this I would buy it in a heartbeat.ReplyDelete
Thanks Zee! Nice words, I'm flattered. Comics I haven't done that much, but recently I've felt some itch to do something like that. So I guess I'm waiting for the idea for a story... Gotta finish the gorilla first :)ReplyDelete
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No, you can leave this one: "Takers"December 11, 2010
Chris Brown deserves to be thrown off a bridge. He deserves to be blown up in a hyperbaric tank like that dude in License to Kill. He deserves to be fed to water monitors–small ones, adolescents—who will tear out his intestines and play tug-of-war with them, while the whole thing is broadcast internationally, so that all of us normal joes who work hard, pay our taxes, and don't beat the holy living fuck out of Rihanna can watch and raise a glass and discuss what a little bitch he is when set upon by hungry reptiles. Appearing in Takers isn't quite a comparable punishment, but it's not going to make anyone forget that he beat a gorgeous woman so badly she looked like last night's sirloin steak either. Call it a draw.
Okay, but before we get into Takers as a Chris Brown-rehabilitation project, let's talk about it as a movie. It's a crappy movie. More specifically, it's a crappy heist movie. Takers follows a crew of professional bank robbers who, apparently, met in a GQ ad for brandy or something. You got Jesse (Brown) the sensitive one; his brother Jake (Michael Ealy) who's the sensitive one with the hot girlfriend (Zoe Saldana); AJ (Hayden Christensen), a jazz pianist whose defining characteristic is his porkpie hat; John (Paul Walker), and Cozier (Idris Elba) who along with John are the groups nominal leaders by virtue of the fact they have more brains than your average ring-tailed lemur and are played by competent actors.
The movie begins with the crew knocking over a bank in an LA high-rise. Everything goes perfectly in the way that only a heist scripted by a screenwriter who knows nothing about actual bank robbers can go (they make off in a hijacked news helicopter, if you can swallow that). They then, as near as I can tell, spend the next couple days living out a high-end fashion commercial as they strut around in immaculate suits and hang out in Jake and Jesse's improbably well-appointed pad. Alas, trouble is a-brewing on two fronts.
One takes the form of cop-on-the-edge Jake (Matt Dillon), who takes a personal interest in this case for no discernible reason. The other cloud in their blue sky is the release of an old partner named Ghost (Tip "T.I." Harris, as he's credited…chose whatever name you want). Ghost took a bullet in a heist gone wrong six years earlier and spent the ensuing years in the joint. The Takers (yeah, I guess we'll call them that) have his money squirreled away for him, as per their agreement, but they're still hinked by the possibility that Ghost will rat them out the moment he gets his money (which doesn't make a lot of sense when you think about it, but neither does anything else in the movie). Further gumming things up is the fact that Ghost used to be involved with Zoe before he got popped.
Ghost, however, approaches them with a new plan—and armored car heist that will nab them a massive pile of money. The Takers mull it over, but decide to do it anyway. The middle chunk of the film follows them as they prepare for the big job. In the meantime, Jack is getting closer and closer. They also pad this part out with some largely unnecessary subplots concerning Cozier's junkie sister and Jack's IAD investigation. These nominally inform the rest of the story's action, but don't really pay dividends.
So, they pull off the armored car job, but it doesn't go precisely flawlessly (the second job in heist movies never do, do they?) Making matters worse, Ghost set them up with Russian gangsters, who descend upon the Takers, resulting in one of the most ludicrous shootouts 2010 has yet presented us with. AJ is killed in the melee (after magically surviving a close-range shotgun blast to the midriff), and the Takers are scattered. From this point, it's just a matter of everyone reaching the ends of their rope. Zoe is killed by Ghost, and Jake and Jesse go down in a blaze of…um…glory isn't quite the right word here…truly terrible cinematography is a bit closer to the mark. Ghost, Jack, and Cozier have a three-way standoff straight out of Reservoir Dogs that ends with Ghost dead, a wounded Cozier and unscathed John riding into the night, and Jack injured (shot in either the stomach or the leg, depending upon the scene) calling 911, saying over and over "I need help" (which we can probably safely take to refer to his career).
Takers could have been pulpy fun if director John Luessenhop and the stew of writers credited with the screenplay were at all good at their jobs. As it is, they're more interested in parading their characters in designer suits than telling a coherent story. There's no realism in the heists. The look cobbled together from Heat, The Italian Job, and whatever other, better heist films the guys could fit in their Netflix queue. There's no logic in them, though. Luessenhop just figures if he shows the guys using explosives and M4 rifles, we'll overlook niggling little facts like how they let the guy with the foreign accent do all the talking during the bank robbery. Sure, no one will remember that. Likewise, it's very convenient that the armored car's route over an empty bit of unused subway tunnel that the Takers can get into and drill out for three days without anyone noticing. It's also apparently dead simple to control LA traffic signals.
Luessenhop also doesn't have much of a sense of action sequences, either. Brown leads the cops on a seemingly-endless foot chase—complete with parkour—in which he his hit by no fewer than five cars, leaps six stories onto a car, and walks away without even a sprain. The idiotic gunfight with the Russians is shot all arty-style with the gunshots muted to dull thumps, and the dialogue clear and coherent (when in reality, small arms fire in an enclosed space would have left them all deaf).
The acting's pretty uneven. Elba is fine (nice to see him reigning it in after his regular overacting in the ludicrous Luther), and both Walker and Dillon are fine, but have so little to work with they don't leave much of an impression. The rest of the cast, however, pretty much sucks on toast. Really. The sheer depth of the acting incompetence is so vast that the actors are visibly struggling to remember their lines in some scenes. And someone should have told Tip "TI" Whatever-the-hell-else that acting does not mean delivering your dialogue in one uninterrupted sentence while swaying like a cobra charmer.
Also, it further deepens the mystery of what George Lucas saw in Hayden Christensen that made him put a huge chunk of his Star Wars franchise in the guy's hands. Not only does he have precisely two modes of acting (smarm and insufferably smug smarm), but he looks…well, he looks like The Joker whenever he wears his flesh-covered makeup. Precisely how many dudes did George audition anyway?
Finally, as part of Brown's rehabilitation project, it's a bust. Jesse is kind and quiet and sensitive, and the movie gives him what Luessenhop must have thought was a heroic death, but his character is otherwise a nonentity, and Brown is completely forgettable in the role. He doesn't wear a stupid bow-tie/sweater combo, but it's never far from the viewer's mind. Sorry, Chris, but no matter how hard you try you're always going to be the shitbag who beat the hell out of Rihanna. And that's the punishment you've earned.
At least until I finish training the local water monitors.


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The value of Idaho's 2014 agricultural production reached $8.8 billion, setting a new record high, according to the National Agricultural Statistics Service. This is an 8 percent increase from the 2013 revised figure.
Milk remained the leading agricultural commodity in the state with a 2014 value of $3.20 billion. Milk represented 36 percent of the total agricultural value compared with 32 percent in 2013.
Cattle, Calves
Cattle and calves remained in the second position and had value of production totaling $1.73 billion dollars in 2014. This was up 25 percent from 2013.
All hay, valued at $961 million, moved up one spot to number three. This represents a 2 percent increase from the previous year.
Potato value of production dropped 6 percent to $957 million, ranking fourth in the state.
Wheat rounds out the top five with value of production in 2014 totaling $582 million, down 20 percent from the previous year.
These five commodities had a combined value of $7.44 billion, or 85 percent of the 2014 value for all commodities (excluding government payments). The same five commodities in 2013 had a combined value of $6.65 billion, or 82 percent of the total value.
Record High Values
Record high values of production were established for three of the top 10 Idaho commodities: milk, cattle and calves, and trout. Two top 10 commodities that declined in value in 2014 were barley, down 29 percent to $264 million and corn for grain, down 34 percent to $67.2 million. Commodities outside the top 10 that showed significant increases included hops, up 24 percent from 2013; peaches, up 61 percent from the previous year; and honey, up 29 percent.
Dropping out of top 10
Dropping out of the top ten in 2014 were dry onions with a value of $44.1 million, down 38 percent from the previous year. A notable commodity that declined in value in 2014 was the apple crop, down 65 percent to $8.74 million.
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In Luke 11, when Jesus finished praying, one of His disciples asked, "Teach us to pray." Even His example in prayer accomplished something. It moved those disciples to want to learn more. I know the prayers of my parents did much for me. The same is true with my companions. One time it was going to be a busy day and therefore I did not spend much time in prayer, but rather left the bedroom and got busy with the day, but 15 minutes later I returned to the bedroom, and found my companion still on his knees! It was a rebuke to me!
One lady, in giving her testimony, said, "I find in the morning that if I pray first, there is always time to work afterwards, but if I work first, there is seldom time to pray!" Jesus began with, "Our Father which art in heaven." We can hardly take it in that our Father is the Creator of heaven and earth! He is the greatest power and the highest in the universe, and one who is so magnificent and beautiful! The one we have come to know as our Father, who is kind and loving and understanding! He has the power, and can use this power to meet the needs of His people, and defend them against their cruel enemy.
In John 14, Jesus encouraged His disciples to ask in His name. If Jesus had not come, we would not be able to approach God. So we want to be faithful in finishing our prayer in His name. There was once an explosion in a coal mine in England, and many miners were killed, affecting many families. One widow was left with several young children. There was no help from the mine, so she found it difficult to provide food for her children. The oldest boy was 12 years old. He began to wonder what he could do to help their family. He thought that if only he could talk to the Queen, she could help him! So he walked down to the Palace one day, and the guard asked him, "What are you doing here?" He answered, "I need to see Queen Victoria!" "You can't do this -- no one can enter the Palace without an invitation," the guard said. Broken hearted, he went away crying. Down the street he met a well dressed boy who asked him what had made him so sad, and he told him his story. The well dressed boy said, "Come with me," and they went back to the gate of the Palace, and the guards opened the door, and they walked in. Then they came to the door of the Palace itself, and it also was opened! Then the well dressed boy took the other one down a long hallway and came to a door and knocked, "Mother, are you in?" he asked, and Queen Victoria spoke from inside that room and said, "Come in," and he had the opportunity to pour out his heart unto the Queen. She put her arm around him to comfort him, and said, "You go home and tell your mother that help is on the way!" The only way he could have done this was through the son, and the only way we can ever come into the presence of the God of heaven is by His Son!
There are some keys that we can take with us into the place of prayer. Keys, open doors--doors that open right into God's presence. When the Pharisee and the publican went to pray in Luke 18, there were no doors that opened for the Pharisee, because of the way he prayed. But the publican had a key ring with three keys on it, and he used all three, which opened wonderful doors to him!
(1). He had the key of humility. Without this key we will never enter the King's presence. The Pharisee had the key of pride, which will never open the door into God's presence.
(2). The key of honesty. The publican was honest about his sin and his
need. He went away justified because he came with the consciousness
of sin. When he went away, his heart was right with God.
(3). The key of repentance. We can never be freed from our sin without
this key.
He took the key of complete submission to His Father's will
into the place of prayer in Gethsemane. He had used this key all His
life. When only twelve years old, He had used this key. Jesus went into that prayer with a struggle in His heart, but when He
used this key, He could leave with a complete peace. Whenever we are
having a struggle, it is good to check our key ring, to see if we have
this key of complete willingness
to the will of God.
Afterwards, an angel came to strengthen Him -- that key opened the door of strength coming to Him.
Jesus praying on the cross, "Father, forgive them," He had
been treated so cruelly, but He took the key of forgiveness into that prayer. In His sample prayer in
Luke 11, he mentioned the need of forgiveness. If we refuse to forgive
others, this will close the door to God forgiving us. It will open doors
to our own forgiveness if we take this key into the place of prayer.
He also brought the key of unworthiness into his request, and Jesus responded to these two keys. It also touches us when we come to the Lord in all a our unworthiness, and God is touched to help us!


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Another request - Jody Grind by Horace Silver
Some tricky moments in this one.... in bar 11 use side A#.
I have also transcribed bass and drums. Let me know if you would like them.
Welcome to the Get Jamming Blog Site
Welcome to the Get Jamming Books Blog SiteHere you will find latest information on the Get Jamming Books available in the Apple Book Store, resources, tips and general information related to saxophone playing.
Students of the Get Jamming method are able to request pieces which I will make available for downloading.
Visitors are more than welcome to download the files, but please pass on the word about the Get Jamming books to your friends.
Students, if you are enjoying the book please remember to leave a review in the Apple Book Store.
So enjoy and. ..
Get Jamming!
Saturday, 22 February 2014
Request - The Jody Grind
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Read this tip to make your life smarter, better, faster and wiser. LifeTips is the place to go when you need to know about Planning and Forecasting and other Business Intelligence topics.
Cognos.com Tip: Establish a higher priority for better planning tools and forecasting software. Such a planning process should focus on key economic and business drivers, the KPIs (key performance indicators) of performance planning. Try to make these improvements:
·Consistency across corporate planning and forecasting
·Plan from the top-down
·Streamline the process cycle time
·Forecast the future with both historical data and predicted key economic drivers
Furthermore, the ultimate goal from pursuing this approach is suggested to be a transition to rolling forecasts and a subsequent organizational planning revolution.
|Guru Spotlight
|Kristle Jones


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July 9, 2013
Downtown Eastside Neighbourhood Council Raises Concerns About Recent
Pedestrian Deaths
(Vancouver) The Downtown Eastside Neighbourhood Council (DNC) is
calling on Vancouver Police to step-up speed enforcement in the
Downtown Eastside after three pedestrians were killed in the past few
"We're pleased the city implemented a 30 kilometer zone along the
Hastings corridor but they must enforce it," commented Richard
Cunningham, Co-President of the DNC. " We also call on city officials
to carefully monitor traffic volumes and speed on other east-west
corridors now that Powell is closed."
Recently, Powell Street was closed for construction and has likely
resulted in heavier traffic on Hastings and Cordova – the two streets
where pedestrians were killed.
Several years ago, in response to the pedestrian safety initiative of
VANDU, the city created a 30 kilometer zone along Hastings for several
blocks on both sides of Main street.
For more information and interviews please contact:
Roland Clarke 778-323-5415
Jamie Richardson 778-707-8459
Bill Beauregarde 604-442-5808


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ANDOVER, Mass.--(BUSINESS WIRE)--DeuteRx LLC, a R&D-focused biotechnology company improving racemic small molecule marketed drugs and drug candidates, today announced an upcoming oral presentation at the AASLD Annual Meeting, being held in San Francisco, CA from November 13-17, 2015.
"Pioglitazone is one of the most widely studied drugs in NASH patients. Although clinical trial results are promising, pioglitazone's use for the treatment of NASH is limited due to the adverse side effects of weight gain and fluid retention. DeuteRx's preclinical data with the stabilized R-enantiomer of pioglitazone, DRX-065, offers the prospect of separating the undesired weight gain and fluid retention from the beneficial therapeutic properties for NASH," says Dr. Scott Friedman, consultant to DeuteRx. "DRX-065 represents a potentially significant therapeutic improvement over pioglitazone for NASH patients."
Oral Presentation Details
Presentation Date/Time: Monday, November 16, 2015; 4:00 – 4:15 p.m. PT
Title: DRX-065, the stabilized R-enantiomer of pioglitazone, is without PPARγ-agonist activity and exhibits the beneficial in vivo pharmacodynamic effects for the treatment of NASH
Authors: Sheila H. DeWitt, Vincent Jacques, Lex H.T. Van der Ploeg
About DRX-065 and Non-alcoholic Steatohepatitis (NASH)
In preclinical experiments, DeuteRx demonstrated that DRX-065 has pharmacological properties desirable for the treatment of NASH (mitochondrial function modulation, non-steroidal anti-inflammatory effects, and glucose lowering effects) without the undesired PPARγ-related weight gain side effect. DeuteRx's issued U.S. Patent #8,722,710 includes composition of matter claims to deuterium-enriched pioglitazone analogs, including DRX-065.
About DeuteRx LLC
DeuteRx is pioneering 'deuterium-enabled chiral switching' (DECS), a revolutionary approach to improve racemic (a mixture of two mirror-image compounds or enantiomers) small molecule marketed drugs and drug candidates intended for patients across multiple therapeutic indications. Numerous drugs are still developed and marketed as racemic mixtures because the enantiomers are chemically unstable and rapidly interconvert in vivo. To date, DeuteRx has demonstrated the use of DECS to stabilize the enantiomers of many racemic active ingredients. DeuteRx's prioritized single enantiomer product assets are DRX-065 for adrenoleukodystrophy and NASH, DRX-164 for multiple myeloma and combination therapy with immuno-oncology drugs, DRX-194 for pediatric sickle cell disease, and DRX-184 for CNS disorders.
DeuteRx is a Boston-based biotechnology company founded in December 2012 as a spin-out company from Deuteria Pharmaceuticals Inc. Deuteria was sold to a major biopharmaceutical company in December 2012.


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Superintendent and School Board Evaluation: A Three-State Study.
Superintendent and School Board Evaluation: A Three-State Study. - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.
This paper describes a study that explored superintendent and school-board evaluations. Specifically, it looked at some of the methods and uses of boards' evaluations of superintendents and some of the needs and methods of boards' evaluation of themselves. Data for the study were collected from 188 surveys of selected school superintendents in Indiana, Illinois, and Texas. Following are some of the findings on superintendent evaluation: A total of 83.5 percent of the superintendents said they had a formal written evaluation by their school boards. In addition to those, 13 percent of the superintendents said that their boards evaluated them in writing. A total of 77.5 percent stated that the evaluation was done annually. Texas used the self-evaluation for a majority of its superintendents (74.6 percent), while 28.2 percent in Indiana and 36.2 percent in Illinois used such an instrument as part of the evaluation process. Following are some of the findings on board self-evaluation: Overall, 13.8 percent of the superintendents stated that their board evaluated itself formally every year. Only 22.9 percent of the boards asked the superintendent to assist in this evaluation process, and 18.6 percent used an outside consultant. (WFA)
Descriptors: Accountability, Administrator Attitudes, Board Administrator Relationship, Board of Education Policy, Boards of Education, Elementary Secondary Education, Evaluation Criteria, Evaluation Utilization, Instructional Leadership, Occupational Information, Personnel Evaluation, School Administration, Self Evaluation (Groups), Self Evaluation (Individuals), State Surveys, Superintendents
Autor: Sharp, William L.; Malone, Bobby G.; Walter, James K.
Fuente: https://eric.ed.gov/?q=a&ft=on&ff1=dtySince_1992&pg=5304&id=ED481621


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priya, 27 Sep 2015worst phone i have ever used...nothng good...bad camera ...bad ram .....no front camera....old... morePlz escape from this phone. ....
I think it's high time I sell this phone
because I never found any good thing in it
touch sensitive very fake
battery consumption very fast
front camera areal dream
what a fake phone this is
thIs ph0ne reaLLY sucks, kEeps hanging, l0w ram, battery c0nsumes fast, heating, and 0thers.
reaLly d w0rzt ph0ne.. fake!
worst phone i have ever used...nothng good...bad camera ...bad ram .....no front camera....old android version....phn gangs tooooooooo much ....i hate dis phn.....plsss dont buy it otherwise u will cryy...like i m
Anonymous, 21 Sep 2015this is the wrost phone first it dosent support 3g second the battery backup is horrible anr h... morebst nt phn wst phn then i hve ever it dsnt support 3g no frnt camera old andrid version jelly bean oly 2mp camera low ram cheapest internal strage but high rte this company should be banned and closed in the world tey had copied apple iphone apps close
Vikram, 23 Aug 2015This phone is supeeerrrrrb flopp
camera very poor
if u reciving call its not working
if u s... moreBull shit phone worst phone ever and what a speed.... i can't play any game ...the keyboard doesn't come
No dialpad nothing...
Very poor phone ..
very very slow in speed, no 3G,no GPS,low battery,no front cammra, no flash,app to SD feature missing
worst phone ever
this is the wrost phone first it dosent support 3g second the battery backup is horrible anr hanging problem
to be freak this phone is OK is just that the do malfunction but anyway it is good
worst phone i ever experienced very very very slow plus awesome hanging problem i was using this phone for past 1 year & 3g is not supporting many of the app's are not working battery no words to express it while you are putting charge around 92% after unplugging fro charging you will see the charge percentage as 100% it true camera is worst and many problems.............................................. worst phone :(
after a year of usage i'd say this is the worst android phone ever hangs alot i mean ALOT and its camera and battery are so horrible i'd recommend microsoft lumia 430 for you its way better than this one
after 1 year my mob is automatically shut down and start and this process is continue while battray is empty


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Discussion in 'Android Devices' started by ifb-online, Jun 2, 2010.
Does the Desire support multitude rotate?
I'm not sure I understand exactly what you're asking. Can you explain it more?
No. Not too sure of any phone that does.
It only rotates one way
Rooted Nexus Ones can rotate every which way (yes Virginia, you can use your phone upside down). A Froyo'd N1 can rotate two ways.
Presumably a Desire can do the same.
If you are asking if you can have the display showing the right way in each of the four directions, on a standard HTC Desire you cannot. You can only have it displayed portrait with the buttons at the bottom and landscape with the buttons on the right.
Sorry for the confusion. I mean rotate the display by using two fingers, say when viewing a map. I'm not that familiar with iPhones, but I seem to be able to do this on my daughter's iPod Touch.
That's not rotation. That's pinch to zoom.
Well, not quite. I think he means you put two fingers on the screen and 'twist' them to rotate... there was an app on the iPoo that would let you do it to pictures which was fun. Don't think Android has anything yet.
Is this coming with froyo? You can do it already with google earth anyway.
I think you should make the distinction that this is an app feature, not a phone or ipod feature.
I know we have pinch to zoom. But the iPod Touch I have here has a rotate function too.


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This month Money Supermarket kindly donated £30 to spend on my chosen charity. So, I thought it would be fitting do spend the money for a place where I do voluntary art therapy. The Garage Art Group based in Evesham, the charity uses the medium of art to encourage health and well-being with individuals who are suffering from mental illness or learning difficulties.
First I went to the charity shops to see what I could find for the group. Sue Ryder have a great range of brand new art materials in all of their stores. The group was specifically in need of some acrylic paint and paintbrushes, I found this set which I thought was perfect.
Half price, and the money for the art supplies goes to another charity. YAY.
N.b. If you are in ever need of art materials check their range out, unfortunately I did not need any canvases today but the ones in store were of great quality and half price.
After exploring the art stores in town, I decided to make a trip to The Range. Which is the best valued store EVER especially for art supplies, it is a great place to buy affordable, high quality (this is the important part) art materials. Using cheap paints really does not do your painting any justice.
Which worked out at £2 a tube. I had been in an art store earlier that day where they were charging £4+ for each tube.
And finally with £2.50 left I brought a few paintbrushes.
I will deliver the materials to the group next week. My appreciation goes out to Sue Ryder and The Range for their great variety of art materials, and a big thanks to Money Supermarket for helping a great cause in my community.
Emma Dilemma
P.S. Quote of the day- "Art washes from the soul the dust of everyday life."
- Pablo Picasso


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MOND BUBBLE BATH 700ML SOFIA THE FIRSTBe the first one to write a review
$9.99 in stockSKU 476514
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Asia Today: Asia's Role in Obama's Address
As U.S. President Barack Obama discussed the future of the U.S., the changing economies of India and China loom in the background. WSJ's Jake Lee discusses the issue with Asia Heard on the Street Editor Mohammed Hadi.
This transcript has been automatically generated and may not be 100% accurate.
... I ... Asia speeches by ... the Obama thing ... yes ... this is Asia's today mine joint study by Mohammed Hadi at Asur up on the Street column ... low on it's it's can you take on a bomb is an speech contest ... as it sounds like that I'd take measures to counter the growing might of China and India ... War when you take away more of this ... while I think it's I think it's ... probably better to frame it as ... measures to make sure that the U S ... doesn't fall behind ... as China and India continue to change ... definitely China and India were mentioned specifically ... that the general tone of the conversation was ... about the changing world ... and about how the US is going to stay competitive in that world ... and that equals ... you know that's really about the rise of Asia ... the growth in Asia and into something that ... Americans have been very anxious about Lee shows a whistle more specifically as as Obama said that as can change down the US to keep up the mess with upon what he proposed I mean some very basic things he proposed improving the quality of education in math and science in the U S ... which is something for us students are through the notorious for ... being behind ... most Asian countries ... there was a there is a study that came out just in December at the North Sea


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Daily Voice accepts signed and original letters to the editor up to 350 words. To send a letter, e-mail firstname.lastname@example.com.
When, earlier this month, the Trump Administration announced its decision to scale back requirements that employer sponsored health plans include coverage for contraception, the message was clear: the Administration does not believe women have a right to make their own medical decisions, and medical evidence takes a back seat to political priorities.
Since the enactment of contraceptive coverage under the Affordable Care Act, more than 62 million American women have saved more than $1 billion each year. It has given women access to contraception regardless of their economic status as well as the power to determine when to start a family and how best to space pregnancies.
Contraception has been proven to improve women's health and save women's lives while reducing unintended pregnancies and abortions—a reality 188 of my colleagues and I stressed in a letter to President Trump calling for a reversal of his administration's contraception rules.
Women have a fundamental right to make decisions about their health, free from outside pressure or interference. Unless Congressional Republicans stand up to the Administration, they will be complicit in rolling back decades of progress on women's health.
Rep. Nita Lowey
Click here to sign up for Daily Voice's free daily emails and news alerts.


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When a Siberian husky took in a stray kitten as her own, the little cat grew up thinking she was part of the pack.
The scrawny stray ignited Lilo's maternal instincts and she began treating the little kitten as if it were her own puppy—and the cat grew up with the heart of a sled dog.
Seven months later, Rosie the cat goes everywhere that Lilo and the family's two other huskies go. The cat also features prominently in photos alongside Infinity and Miko on Lilo's Facebook, Twitter, and Instagram accounts.
(WATCH the kitten and surrogate mom at the start of the video below) –Photo: Lilo the Husky, Facebook
LOVE ANIMAL STORIES? … GET OUR GOOD NEWS APP—> Download FREE for Android and iOS
Share This With Your Pack…


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It was really funny to watch... I was still laughing changing his bath water a few minutes later.
Linking to Camera Critters, The Bird D'pot and Our World Tuesday
thanks for the smiles
HI Andrew Well that made me laugh. these shots are superb. Yes they need to get rid of the white powder so that they can replace it and then they are able to waterproof their outer feathers.
Super lindo!!! Amei essa série de fotos, com o movimento das gotinhas de água.
Ótimo mês de novembro!
Bom fim de semana!
Beijinhos do Brasil ❥°º•.¸
very cute!
Hahaha, It is so cute!
Greetings, RW & SK
That made me LOL, so very cute. You did great job at capturing these.
Now that was neat to watch!
Nice job getting the images!
You've made my day. What fabulous shots! This is why birdbaths are made and why people buy them, in hopes of such a sight. Few get to see such enthusiastic use of their birdbaths, but there's always hope.
Had to laugh at these pictures too :)
So dang cute~~~ He is lucky to have such a good bath attendant there, changing the water as needed ;>)....worth it for the laughs though; I'd be delighted to do it. Thanks for sharing.
This one cracked me up looking at the splashing and splashing. What a major bath that was...and the milky water. I have yet to have ever seen a bird in my little bath. There is always hope.
A wonderful show. I like the dirt bath water reference.
Ha ha haa ha
it looks so funny, cheers Andrew.
it's a good feeling to know how much the birds enjoy the offerings you give; great series Andrew
Nice set of pictures - makes me wonder what sort of muck it was washing off.
Cheers - Stewart M - Melbourne
This is a great serie!
Well done!
I loved these photos!!! What great timing. You did a marvelous job Andrew.
Bonjour Andrew! Again, a splendid serie of pictures.Delicious bath!
These made me smile! I love the shots with the water drops flying around.
I was going to say I bet you had to change the water again! LOL! He wasn't shy about his bath!
This is such a cool series of shots!
Je découvre ton blog, j'aime beaucoup ton travail. Des aventures et de très belles photos d'une beauté incroyable.
Je suis artiste peintre, photographe amateur; je me suis inscrite pour suivre tes publications!
Je t'invite à me rendre visite sur mes blogs, merci beaucoup et bonne soirée! Cath
Great shots, I love watching birds take a bath.
Oh, how funny and WILD!! I love it and what terrific captures, Andrew!! Thanks for sharing the fun -- and what a CLEAN bird!!!
Maybe had a hot date.
Marvellous shots!
Love these photos! Can't count how many times this has happened when I put fresh water in the birdbath but never been lucky enough to catch it in photos!
Wonderful series of shots - I'd have been laughing too. He was obviously just impressed you'd run a nice bath for him!
These are spectacular shots! Bravo!
That's wonderful!
So funny! I love watching birds take a bath.
That pigeon had a blast! :)
What fun Andrew, gave me a well needed giggle!


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I think I love Julie Bonello at Cataromance. She's just reviewed Propositioned by the Billionaire and given it 4.5 stars. The full review is here, but in the meantime here's a taster of what she thought:
Propositioned by the Billionaire is another first-rate contemporary romance from Lucy King! Sparkling with a bucket load of sassiness, freshness and feel-good charm, Lucy King's second novel has a fabulous heroine, a delectable hero, wonderful dialogue, sizzling chemistry, red-hot love scenes and a believable and plausible conflict.
Fast-paced, sexy, poignant and deliciously enjoyable, Propositioned by the Billionaire will go down a treat with fans of Modern Heat the world over – and readers would do well to remember Lucy King's name because she is a writer destined for greatness!
Oh my. While I think she might be a tad optimistic about my future, I need to go and have a lie down...


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Tunis, Tunisia (PANA) - The Executive Board of the World Bank is to give US$285 million to the three countries in West Africa badly affected by the Ebola virus disease, according to a statement issued by the bank on Tuesday.
This additional funding will help Guinea, Sierra Leone and Liberia deploy additional national and international workers, while expanding prevention and early detection of suspected cases of Ebola virus.
The assistance is also aimed at revitalizing and strengthening basic health services in recipient countries, the statement added.
Ebola has killed more than 5,100 people mainly in the three countries. There has been a huge international mobilization of money and logistics and personnel to help fight the virus.
-0- PANA AD/INBEH/IBA/JEN/MA 19Nov2014


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Forestry MB Weekend - Oct 7-9 2011
On Friday, October 7, 2011, ten scouts from Troop 314 and one scout from Troop 660, plus I and one other Troop 314 scouter, went to Schoepe Scout Reservation at Lost Valley (SSRLV) for a weekend of working and learning, to earn the Forestry Merit Badge. We had a lot of fun, and did a lot of work maintaining the trees of the camp. I think the best part was just being there when the weather was cool, and hardly anybody else was there. The boys also really enjoyed staying in the staff cabins, in spite of the mice that had taken up residence there.Read More