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Certain malignant B cells rely on B-cell receptor (BCR)–mediated survival signals. Spleen tyrosine kinase (Syk) initiates and amplifies the BCR signal. In in vivo analyses of B-cell lymphoma cell lines and primary tumors, Syk inhibition induces apoptosis. These data prompted a phase 1/2 clinical trial of fostamatinib disodium, the first clinically available oral Syk inhibitor, in patients with recurrent B-cell non-Hodgkin lymphoma (B-NHL). Dose-limiting toxicity in the phase 1 portion was neutropenia, diarrhea, and thrombocytopenia, and 200 mg twice daily was chosen for phase 2 testing. Sixty-eight patients with recurrent B-NHL were then enrolled in 3 cohorts: (1) diffuse large B-cell lymphoma (DLBCL), (2) follicular lymphoma (FL), and (3) other NHL, including mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), mucosa-associated lymphoid tissue lymphoma, lymphoplasmacytic lymphomas, and small lymphocytic leukemia/chronic lymphocytic leukemia (SLL/CLL). Common toxicities included diarrhea, fatigue, cytopenias, hypertension, and nausea. Objective response rates were 22% (5 of 23) for DLBCL, 10% (2 of 21) for FL, 55% (6 of 11) for SLL/CLL, and 11% (1/9) for MCL. Median progression-free survival was 4.2 months. Disrupting BCR-induced signaling by inhibiting Syk represents a novel and active therapeutic approach for NHL and SLL/CLL. This trial was registered at www.clinicaltrials.gov as #NCT00446095.
Despite intensive efforts to develop improved therapy in the past decade, mantle cell lymphomas (MCL) and the indolent non-Hodgkin lymphoma (NHL), including small lymphocytic leukemia/chronic lymphocytic leukemia (SLL/CLL), remain essentially incurable. In addition, despite the inclusion of rituximab in standard chemotherapy regimens, almost one-half of patients with clinical high-risk diffuse large B-cell lymphoma (DLBCL) are not cured.1 More effective and tolerable therapeutic agents are needed to improve the outcome for these patients.
Most B-cell malignancies express the B-cell receptor (BCR).2 BCR signaling induces receptor oligomerization, immunoglobulin (Ig) α and β phosphorylation and the recruitment and activation of the spleen tyrosine kinase (Syk). Thereafter, Syk initiates downstream events and amplifies the original BCR signal.3,4 In addition to ligand-induced BCR signaling, there are critical "tonic" (nonligand dependent) BCR maintenance or survival signals that occur in the absence of receptor engagement.4,5 The role of tonic BCR survival signals was first shown in murine models in which the inducible loss of murine BCR expression or Ig α function led to the death of mature B cells.6,7 Although the molecular mechanisms regulating tonic BCR signaling remain to be defined, several studies highlight the critical role of Syk.8,9
Studies that used small interfering RNA to inhibit BCR expression have shown that constitutive signaling by BCR is critical for the survival and proliferation of both murine and human B-cell lymphomas.10 The primary outcome of BCR signaling in these cells appeared to be the activation of Syk.11 Activation of Syk leads to several downstream events that promote cell survival, including activation of phosphatidylinositol 3-kinase and Akt,12 and the phosphorylation of multiple proliferation proteins, including RAS, PLC-γ, and MAPK kinases.
A subset of DLBCLs exhibits coordinate overexpression of components of the BCR signaling cascade and tonic BCR-dependent survival signals.8,13,14 In such primary DLBCLs and DLBCL cell lines, targeted inhibition of Syk abrogates BCR signaling and induces apoptosis. Additional evidence that Syk is a rational therapeutic target for DLBCL comes from a murine model of MYC overexpression in which BCR signaling drives lymphomagenesis; a model that was used to determine the role of Syk in the maintenance of aggressive B-cell lymphoma. This model integrates both tonic signaling and the signaling associated with antigen binding, both of which are mediated by Syk.15 Tumor cells deficient in Syk failed to expand in vivo, and the inhibition of Syk led to tumor regression in vivo.16
Evidence that BCR and Syk are valid targets for the therapy of indolent B-cell NHL comes from the comparison of the single-cell signaling profiles of follicular lymphoma (FL) cells to those of nonmalignant B cells within individual patient biopsies.17 BCR-mediated signaling through Syk occurred more rapidly, to a greater degree, and for a longer duration in FL cells compared with the tumor-infiltrating nonmalignant B cells. This suggests that enhanced signaling through BCR may contribute to the malignant phenotype of FL. Similarly, in a MCL line, Syk was found to be amplified at the DNA level and overexpressed at both the RNA and protein levels. After treatment with piceatannol (a Syk inhibitor), cell proliferation arrest and apoptosis were observed and were correlated to the degree of Syk overexpression.18
Taken together, these data provide rationale for inhibiting the BCR, and its downstream target Syk, as a therapeutic approach for a variety of B-cell NHLs.19
R406 is a potent and selective inhibitor of Syk.20 Fostamatinib disodium (R788; FosD) is a prodrug of R406 available in an oral formulation and is also under clinical development for the treatment of rheumatoid arthritis21 and immune thrombocytopenic purpura.22 Pharmacokinetic and pharmacodynamic data from several human clinical studies have shown that twice daily administration is sufficient to achieve a significant reduction in Syk activity, with no adverse effects on innate immunity or hemostasis.20 Herein, we present the results of the first phase 1/2 trial of FosD in the treatment of patients with relapsed and refractory B-cell NHL and CLL.
This study was registered at www.clinicaltrials.gov (NCT00446095). Patients with relapsed or refractory B-cell lymphoid malignancies were enrolled, and treatment was initiated between February 2007 and January 2008. Written informed consent was obtained in accordance with the Declaration of Helsinki, applicable federal regulations, and requirements of local institutional review boards, and all participating institutions approved this study. Eligibility criteria included relapsed/refractory B-cell malignancy (DLBCL, FL, MCL, mucosa-associated lymphoid tissue lymphoma, marginal zone lymphoma [MZL], and SLL/CLL), age of 18 years or older, measurable disease, Karnofsky performance status of at least 60, absolute neutrophil count (ANC) of at least 1.5 × 109/L (1500/μL), hemoglobin level of at least 90.0 g/L (9.0 g/dL), platelet count of at least 75.0 × 109/L (75 000/μL), aspartate aminotransferase and alanine aminotransferase less than 3 times upper limit of normal (up to 5 times upper limit of normal if tumor involvement), bilirubin level no greater than 25.7 μmol/L (1.5 mg/dL), creatinine level no greater than 176 800 μmol/L (2.0 mg/dL), no systemic steroids greater than the equivalent of 10 mg/d prednisone, no CYP3A4 inducer/inhibitor within 1 week before treatment, and no significant gastrointestinal disease, difficulty swallowing, or malabsorption.
Study design
This was a phase 1/2 study. Phase 1 consisted of 2 cohorts of 6 patients each who were sequentially assigned to receive 1 of 2 dose levels of FosD (provided by Rigel Pharmaceuticals) 200 mg by mouth twice daily or 250 mg by mouth twice daily. These doses were chosen on the basis of previous experience in rheumatoid arthritis.23 In the event of unacceptable toxicity in the first cohort, a dose deescalation was planned to be 150 mg by mouth twice daily. After the completion of 4 weeks of FosD administration in the first cohort, dose-limiting toxicities and adverse events were examined by a Data Safety Monitoring Board (DSMB), which determined it safe to accrue to the second dose cohort. On the completion of 4 weeks of treatment for the second cohort of patients, the DSMB reviewed the aggregate data from the 2 cohorts and recommended the dose level for the phase 2 portion of the study. Patients in the phase 1 portion could continue on therapy until unacceptable toxicity or disease progression occurred. Phase 1 dose-limiting toxicities were defined as absolute neutrophil count (ANC) of grade 3 or 4 plus fever; ANC of less than 0.5 × 109/L (500/μL) for 5 days or longer; platelet count less than 25 × 109/L (25 000/μL); grade 3 or 4 nausea, vomiting, diarrhea if persistent despite optimal antiemetic or antidiarrheal therapy; grade 3 elevation of transaminases if persistent for longer than 7 days; any other grade 3 or 4 toxicity except alopecia; need for delay or modification of dose.
In phase 2, patients were enrolled into 1 of 3 groups according to histology (DLBCL, FL, and other, which included MZL, MCL, SLL/CLL, and lymphoplasmacytic lymphoma). Patients in each group received FosD by mouth twice daily until unacceptable toxicity or progression. Common Toxicity Criteria grade 3 or 4 toxicity, including febrile neutropenia, ANC less than 0.5 × 109/L (500/μL) for 5 days, nausea or vomiting persistent despite optimal therapy, increase in alanine aminotransferase or aspartate aminotransferase persisting for longer than 7 days prompted interruption of the study drug. A dose reduction of 50 mg by mouth twice daily was instituted when the study drug was resumed. A reduction in dose to less than 100 mg by mouth twice daily was permitted only after discussion with the sponsor.
Supportive care
Patients were not permitted to receive any other antineoplastic therapy or immunosuppressive agents while on study. Use of growth factor was allowed per institution-specific guidelines. All other necessary supportive care was encouraged.
Response assessment
Initial tumor response, assessed per the Revised Response Criteria for Lymphoma,24 was determined after 8 weeks (56 days) of treatment; subsequent response assessments were performed at 12-week intervals. Patients with SLL/CLL were assessed according to lymphoma response criteria only.
Pharmacokinetic/pharmacodynamic evaluations
Samples were obtained for pharmacokinetic (PK) analysis on days 1, 8, 29, and 57 and every 12 weeks thereafter. Samples were drawn before the dose and at 1, 2, and 4 hours after the dose on days 1, 8, and 29. Additional samples were obtained on day 57 and at 12-week intervals thereafter. Pharmacodynamic assessments included analyses of normal circulating CD14+ cells as a measure of FosD activity, because CD14+ cell counts were inversely correlated with FosD in previous studies.25
Statistical methods
Sample size in phase 1 was based on a standard phase 1 design. The sample size for phase 2, allowed the exclusion of a response rate of 25% if no responses were seen within a treatment group.
The intent to treat population included all patients receiving any amount of the study drug. All efficacy and safety analyses were based on the intent to treat population. Best response was used for all response analyses. The number and percentage of patients achieving a response (complete response [CR] plus partial response [PR]) was calculated for each treatment group and overall. The 95% confidence intervals (95% CIs) for response were calculated by using the exact method. The number and percentage of patients achieving clinical benefit (defined as responding patients and those with stable disease) were also calculated. Progression-free survival (PFS) was determined by the Kaplan-Meier method.
Phase 1 component.
Thirteen patients were enrolled in 2 cohorts; 6 in cohort 1 (200 mg twice daily) and 7 in cohort 2 (250 mg twice daily; details in Table 1). The median age in the phase 1 component was 74 years (range, 52-91 years). Histologies included DLBCL (3 patients), MCL (3 patients), FL (5 patients), and SLL/CLL (2 patients). Most patients had received extensive prior therapy (median, 4 prior regimens; range, 1-6 prior regimens), including prior autologous stem cell transplantation (ASCT; n = 2) and prior radioimmunotherapy (n = 4).
Phase 2 component.
After review by the DSMB, the dose of 200 mg twice daily was chosen for phase 2 testing. Patients (median age, 63 years; range, 41-87 years) were enrolled in 3 cohorts; 23 with DLBCL (group 1: 17 de novo DLBCL, 6 transformed LBCL), 21 with FL (group 2), and 24 with other lymphomas (group 3), including 11 with SLL/CLL, 9 with MCL, 3 with MZL, and 1 with lymphoplasmacytic lymphoma. The median number of prior therapies was 4, 4, and 2 in groups 1, 2, and 3, respectively. There was no difference in the median number of prior therapies for patients with transformed LBCL compared with those with de novo DLBCL. In the DLBCL cohort, 12 patients (9 de novo and 3 transformed LBCL) had undergone prior ASCT. In the FL cohort, 9 patients had received prior radioimmunotherapy, and 5 had received prior ASCT. In the other cohort (group 3), prior therapies included aggressive fludarabine-containing combinations and the fractionated cyclophosphamide, vincristine, Adriamycin, and dexamethasone/methotrexate/cytarabine regimen for MCL. Approximately 33% of patients with DLBCL and 11% of patients with FL had an International Prognostic Index or FL-International Prognostic Index score indicative of poor prognosis at diagnosis. Additional details can be found in Table 1.
Adverse events
Adverse events in phase 1 included neutropenia, anemia, thrombocytopenia, fatigue/asthenia, and diarrhea. Severe events were infrequent; most events were grade 1 or 2 in severity; see details in Table 2. One patient with CLL in phase 1 was withdrawn because of leukocytosis after treatment with FosD. On the basis of the observation of dose-dependent toxicities, with an increased rate of adverse events at the 250-mg twice daily level, the DSMB determined that 200 mg twice daily would be the appropriate dose level for the phase 2 trial. The dose-limiting toxicity was felt to be a constellation of diarrhea, neutropenia, and thrombocytopenia.
Common related adverse events for the phase 2 study are detailed in Table 3; those occurring in greater than 20% of patients in phase 2 included diarrhea, fatigue, cytopenias, hypertension, and nausea. With the exception of hematologic toxicities, most of these adverse events were grade 1 and grade 2 according to the Common Toxicity Criteria for Adverse Events Version 3. Febrile neutropenia occurred in 8% of patients. There were a total of 9 instances when infection occurred in the setting of neutropenia. These infections included a viral process (n = 1), pneumonia/pneumonitis (n = 2), dental abscess/tooth infection (n = 2), upper respiratory infection (n = 2), vaginal yeast infection (n = 1), and possible colitis (n = 1). No grade 5 events were thought to be related to therapy; however, 2 patients died while on study because of sepsis (n = 1) and pneumonia after influenza A infection (n = 1). Serious adverse events related to therapy included 5 episodes of febrile neutropenia and 1 episode each of pancytopenia, abdominal pain, diarrhea, renal failure, and superior vena cava occlusion. Renal failure occurred in a patient with baseline renal insufficiency; there was no evidence of tumor lysis, and no clear cause for the renal failure was determined. Only 2 patients were withdrawn from the phase 2 portion of the study for adverse events. One patient developed influenza A, but there were no reported opportunistic infections considered related to the FosD therapy.
Eight patients in phase 2 required a dose adjustment (to 150 mg twice daily) per protocol; 3 for neutropenia, 2 for hypertension, and 1 each for elevated results of liver function tests, fever, and anemia. Two patients required 2 dose reductions (to 150 mg daily). Seventeen patients (25%) had dose interruptions during the course of therapy. These interruptions lasted a median of 20 days (range, 1-57 days).
Nineteen patients (6 with a prior history of hypertension) were reported to have new onset or worsening hypertension in the phase 2 portion of the study, including 6 with grade 3 hypertension (defined as requiring drug therapy or additional therapy if previously treated). Hypertension most commonly occurred within 1 month of initiation of FosD. Of the 13 patients who required a new antihypertensive regimen, the majority (n = 8) required a single oral medication to establish blood pressure control. Hypertension resolved quickly after discontinuation of FosD.
Interestingly, all patients with SLL/CLL initially had increases in circulating lymphocyte count observed during the first 29 days of therapy; in 9 of the 13 patients with SLL/CLL (phase 1 and phase 2) this increase exceeded 50% of baseline circulating lymphocytes. The first patient in phase 1 was withdrawn for this reason. In several subsequent patients, circulating lymphocytes peaked at day 15 or 29 and fell slowly during the remainder of the time on therapy.
Clinical response and patient outcome
In the phase 1 portion of the trial, all patients in cohort 1 had stable disease after treatment with FosD with a median duration of 5.3 months (range, 1.8-10.4 months). In cohort 2 of the phase 1 study, one patient with FL had a PR with a response duration of 13.3 months. Two additional patients (with FL and SLL/CLL) had stable disease, with a duration of 4.8 and 13.7 months, respectively.
Responses for the phase 2 portion of the trial are summarized in Table 4. One patient with de novo DLBCL had a CR, 4 patients (including 1 with transformed LBCL) had a PR, and 4 additional patients (2 with transformed LBCL) had stable disease; the overall response rate (CR + PR) in the DLBCL cohort was 22% (95% CI, 7.5%-43.7%), and the median PFS was 2.7 months (95% CI, 1.3-4.5 months). Two patients with FL had a best response of PR to therapy (overall response rate [ORR], 10%; 95% CI, 1.2%-30%), and 11 additional patients had stable disease after therapy; the median PFS was 6.4 months (95% CI, 2.0-8.3 months). Six of 11 patients with SLL/CLL had a PR to therapy (ORR, 55%; 95% CI, 23%-83%) assessed according to lymphoma response criteria26; 2 additional patients had stable disease after therapy. The median PFS for patients with SLL/CLL was 6.4 months (95% CI, 2.2-7.1 months). Of the 6 responding patients with CLL, Zap-70 was positive (n = 3), negative (n = 1), and unknown (n = 2); cytogenetic abnormalitiesincluded trisomy 12 (n = 1), del13 (n = 1), normal (n = 1), complex (n = 1), and unknown (n = 2). One patient with MCL had a PR (ORR, 11%; 95% CI, 0.3%-48%); 4 additional patients with MCL had stable disease after therapy.
For all patients in phase 2, the median time to response was 57 days because responses generally occurred at the time of first response evaluation. The median duration of response was 4.3 months (range, 1-13 months). The median PFS for all patients in phase 2 was 4.1 months (95% CI, 2.1-5.6 months). The median duration of therapy was 75 days (range, 3-511 days). PFS by cohort is shown in Figure 1A. PFS for patients with SLL/CLL is shown in Figure 1B. In addition, a waterfall plot of best responses by histology is shown in Figure 2.
As of July 1, 2009, 2 patients remain on study treatment, 1 with transformed LBCL and 1 with SLL/CLL. Nine deaths have been reported, 8 from complications of progressive lymphoma and 1 from influenza pneumonia.
PK studies
On day 1 of FosD administration in the phase 1 study, the maximum plasma concentrations were 668 plus or minus 258 ng/mL and 1020 plus or minus 781 ng/mL, and the estimates of the area under the curve at 0 to 4 hour were 1800 plus or minus 602 ng × h/mL and 2590 plus or minus 1900 ng × h/mL, at 200 mg and 250 mg twice daily, respectively. Plasma concentrations increased approximately 2-fold with continued administration, but beyond day 29 there was no apparent change in FosD concentrations over time. For comparison to in vitro data with R406, 1800 ng/mL is roughly 3.6mM. No correlation between PK and clinical outcome was detected.
Pharmacodynamic studies
In previous human studies involving FosD, a correlation was observed between FosD dose/R406 plasma levels and number of CD14+ circulating cells in peripheral blood.25 We therefore evaluated this pharmacodynamic marker before and after therapy in all patients with the use of conventional flow cytometric evaluation. The median percentage of decrease of CD14+ cells on day 29 of therapy compared with baseline was 35%. There was no correlation between the magnitude of decrease in CD14+ cells after therapy with FosD and tumor response or development of cytopenias or hypertension (P = NS). Moreover, there was no apparent correlation between changes in CD14+ counts and R406 area under the curve, suggesting this may not be an optimal pharmacodynamic marker in patients with lymphoma and CLL.
In this first phase 1/2 clinical trial of the specific Syk inhibitor FosD, we have demonstrated both safety and efficacy in the treatment of B-cell NHLs and SLL/CLL. Despite a heavily pretreated relapsed and refractory patient population, responses were observed in DLBCL, FL, MCL, and SLL/CLL. Common toxicities observed in our study included diarrhea, fatigue, and cytopenias, similar to toxicities observed in rheumatoid arthritis studies that used lower doses of FosD.21 Although neutropenia was frequently observed, febrile neutropenia was uncommon despite the heavily pretreated nature of the patient population. We observed mild-to-moderate hypertension in 22% of patients, generally occurring within the first month of initiation of therapy, and typically managed with the addition of a single oral agent. The onset of hypertension did not appear to correlate with a prior history of hypertension. The mechanism of this observed hypertension is not known, but it has been reported in rheumatoid arthritis trials with FosD and may be related to off-target inhibition of vascular endothelial growth factor receptor.21 FosD has also been reported to inhibit FLT-320 and Ret kinase27; however, it is unlikely these targets contributed to toxicity or lymphoma responses. Although grade 3 neutropenia was observed in a subset of patients, there were few severe infections and no opportunistic infections, even with extended treatment (longer than 1 year in some patients). These findings are consistent with earlier murine safety studies in which the reduction in lymphocytes and bone marrow cellularity after treatment with FosD had no adverse effects on the humoral immune response.28
More than 20% of the patients in our series with multiply relapsed/refractory DLBCL responded to therapy with FosD. In vitro evidence of DLBCL sensitivity to Syk inhibition, manifested by a dose-dependent reduction in basal proliferation, has been shown in a variety of cell lines treated with piceatannol (a less specific Syk inhibitor).10 Off-target effects are always possible, but these data support the notion that Syk inhibition is responsible for the clinical outcomes observed in our study. Chen et al8 recently published a comprehensive preclinical evaluation of R406 in DLBCL. In their study, DLBCL cell lines and primary tumors with an intact BCR signaling pathway were highly sensitive to R406-mediated apoptosis. Responses to R406 were detected in primary DLBCLs with evidence of both tonic and induced BCR signaling. Of interest, R406-sensitive, BCR-dependent DLBCLs were independently identified as BCR-type tumors by transcriptional profiling.8,13 In the preclinical evaluation of R406, only cell lines and primary tumors with absent surface IgG or IgM or lower levels of cell-surface IgG had ineffective BCR signaling. We were unable to determine IgG expression in DLBCLs from the current trial because of the lack of fresh tissue. Future trials in DLBCL that limit enrollment to patients expressing cell-surface IgM or high levels of cell-surface IgG are under development.
Although the response rates were lower in MCL and FL, prolonged stable disease was observed in several patients with FL. The mechanism by which Syk inhibition leads to clinical responses in these diseases may be different from that in DLBCL. It is not clear whether tonic signaling through BCR is required to maintain survival in subgroups of FL and MCL. However, in a study that used piceatannol or small interfering RNA plasmids to inhibit Syk in vitro, potent inhibition of mammalian target of rapamycin (mTOR) activity was shown in both FL and MCL cell lines.29 Syk therefore appears to also play a central role in mTOR activation; this is of particular relevance because targeting of mTOR signaling with temsirolimus has resulted in significant therapeutic activity in indolent lymphoma and MCL.30
The highest response rate in our trial, by conventional lymphoma response criteria,26 was observed in patients with SLL/CLL. Tonic signaling through BCR has been identified in a subset of patients with CLL, particularly in CLL with unmutated IgH.31,32 Mutation analysis was not performed in our patients; however, clinical responses were observed in patients with SLL/CLL who did and did not express Zap-70, a robust surrogate marker for IgH mutation status.33 This suggests that patients with both mutated and unmutated IgH responded to treatment with FosD in our trial. Additional rational for inhibiting Syk as therapy for SLL/CLL comes from a recent analysis of spontaneous regression in patients with SLL/CLL, which determined Syk was overexpressed and that functional BCR signaling was present in this subset of cases compared with normal B lymphocytes.34
In a laboratory model of CLL, induction of the chemoattractants CCL3 and CCL4 was abrogated by the inhibition of Syk, suggesting that cells within the CLL microenvironment induce these chemokines through BCR activation.35 Quiroga et al36 have found that BCR can trigger increased CLL cell migration toward the chemokines CXCL12 and CXCL13. Moreover, in their laboratory study, BCR activation also enhanced CLL cell migration beneath marrow stromal cells. Migration of CLL cells could be inhibited by R406, suggesting that the BCR-induced CLL survival signals in the tissue microenvironments can be disrupted by Syk inhibition. This laboratory finding is of particular interest, given our observation that several patients with CLL had rapid nodal responses in the setting of a transient worsening of lymphocytosis. We speculate that the inhibition of Syk in these patients may have disrupted the nodal microenvironment and increased the trafficking of CLL cells out of nodal tissues. Little is known about the equilibrium between the circulating state and the lymph node resident state in CLL, but nodal disease appears to be more resistant to other novel therapeutic agents.37 Additional studies are underway to identify how Syk inhibition leads to responses in CLL, including a detailed evaluation of the malignant microenvironment in nodal tissue.
The future development of FosD is likely to include rational combinations. Rituximab, an anti-CD20 monoclonal antibody with several mechanisms of action,38 confers a survival benefit in both indolent and aggressive lymphomas when combined with chemotherapy39,40 and improves PFS in CLL.41 The cytotoxic activity of another monoclonal antibody, gemtuzumab ozogamicin, in acute myelogenous leukemia correlates negatively with the expression of Syk,42 suggesting the possibility that the antibody-dependent cellular cytotoxicity activity of rituximab could be affected negatively by FosD. In vitro and in vivo studies are ongoing to determine whether FosD alters the response to rituximab. Other rational agents to combine with FosD may include mTOR inhibitors, because mTOR is a potential downstream target of Syk. In addition, there is evidence that a ubiquitin/proteasome-dependent mechanism contributes to Syk regulation,43 and proteasome inhibitors that have significant activity in NHL44 may be synergistic with FosD. Finally, because cAMP negatively regulates Syk, and inhibition of PDE4B expression significantly improved the efficacy of Syk inhibitors in several murine models of DLBCL, approaches that inhibit both Syk and PDE4B are under investigation.45
The inhibition of a critical B-cell lymphoma survival pathway with FosD results in tumor cell death and clinical responses in a significant proportion of heavily pretreated patients with SLL/CLL and DLBCL. The most common toxicities are hematologic and reversible; no B cell–specific toxicities were observed. Additional clinical trials are planned to identify lymphomas dependent on the BCR pathway and to further analyze this promising rational targeted therapy for B-cell lymphomas and leukemia.
Contribution: J.W.F., J.P.L., A.M.L., J.M.V., R.L., and M.A.S. designed the research; J.W.F., J. Sharman, J.S.-C., P.B.J., S.D.V., A.L., J.P.L., L.D.C., R.S., S.A.G., J. Sweetenham, and J.M.V. performed the research; J.W.F., J. Sharman, J.S.-C., M.P.S., A.M.L., R.L., and M.A.S. analyzed data; and J.W.F., A.L., R.L., and M.A.S. wrote the paper.
Conflict-of-interest disclosure: A.M.L. and M.P.S. are employees at Rigel. J.W.F., J. Sweetenham, P.B.J., J.M.V., S.D.V., R.S., J.P.L., L.D.C., S.A.G., and R.L. have received research support for this trial from Rigel. The remaining authors declare no competing financial interests.
Correspondence: Jonathan W. Friedberg, James P. Wilmot Cancer Center, University of Rochester, 601 Elmwood Ave, Box 704, Rochester, NY 14642; e-mail: jonathan_friedberg{at}urmc.rochester.edu.
This study was supported by Rigel Pharmaceuticals. J.W.F. is a Clinical Scholar of the Leukemia & Lymphoma Society and is supported in part by the University of Rochester Specialized Program of Research Excellence (SPORE) in Lymphoma (CA-130805).
An Inside Blood analysis of this article appears at the front of this issue.
Presented in part in oral form at the 50th annual meeting of the American Society of Hematology, San Francisco, CA, December 7, 2008.
The publication costs of this Article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734.
- Submitted August 7, 2009.
- Accepted October 26, 2009.
- © 2010 by The American Society of Hematology


text: Welcome to the Heritage Christian School elementary page of our website. Our professional teachers provide excellent educational opportunities for children in Pre Kindergarten through 6th grade students in the following subjects: Bible, Reading, English, Math, History, Science, Foreign Language, and Spelling. Children are challenged academically while being discipled in their relationship with Jesus Christ. They are taught academics while learning biblical truths everyday.

subset: commoncrawl


text:
I made a little guitar tuner, and from that spawned a pitch based audio oscillator orchestra that ingests mp3s or other chop audio. and spits out cheesy ultra low-fi Music! Yes!
https://www.youtube.com/playlist?list=P ... egjXORSW47
All of these songs are reproduced with audio oscillators inside Touchdesigner. 32 Oscillators of various types mimic the original stereo audio track by analyzing it's frequencies and volume levels.
It's pretty trippy I feel like I can make out lyrics in the Everclear one.


text:
How can I get involved?
1. STAY INFORMED: Receive updates and other news related to the leafy green guidelines, comment periods, web discussions and key LGMA meetings by joining our mailing list. To be added to this list, contact WG' Sonia Salas at firstname.lastname@example.com. Updates will also be posted on this website.
2. CHECK OUR MASTER CALENDAR: It includes timelines for upcoming events and discussions
3. SUBMIT COMMENTS:Unless otherwise specified, comments will be considered during established comment periods
4. PARTICIPATE: Provide input during upcoming web discussions and before any proposals are submitted to the LGMA groups in Arizona and California


text:
Brian Ritchie, the former bass player Violent Femmes now with Aussie band The break, will perform at benefit concert this weekend for the Sikh Temple in Oak Creek, Wisconsin.
Brian formed The Violent Femmes in Milwaukee in 1980 but after the band broke-up he moved to Hobart, Tasmania in 2008 and recently became an Australian citizen.
In 2010, Brian formed the instrument surf-band The Break with former members of Midnight Oil, Rob Hirst, Jim Moginie and Martin Rotsey. They released the album 'Church of the Open Sky' in 2010.
Brian is currently back in Wisconsin visiting the family.
Details for the benefit show this Sunday are as follows:
Shank Hall, Brian Ritchie and Ragani have joined together to create an impromptu benefit concert and tribute to the Sikh Temple in Oak Creek, Wisconsin, which was the site of a tragic and senseless act of violence. The Hindu based music of Kirtan Ragani and Zen derived jazz of Brian Ritchie Shakuhachi Club MKE will calm and uplift concertgoers. Musicians include Ragani, Brian, John Sparrow, Dave Gelting, Silas Ritchie, Michael Kashou and more. Doors open at 6:30 and music starts at 7:00. Shank Hall 1434 North Farwell Avenue Milwaukee, WI 53202 (414) 276-7288. All donations will go to the Sikh Temple of Wisconsin.


text:
Judging the Royals
Was it the Royals' hitting or the Brewers' pitching?
In St. Louis the Royals' bats were in a deep freeze; last night in Milwaukee the Royals' bats were smoking hot. On Monday night against the Brewers the Royals put up 13 hits and eight runs. Everyone in the starting lineup — with exception of pitcher Edinson Volquez — had at least one hit. Alex Rios and Omar Infante had two each.
When a team goes off like that someone is sure to say that hitting is contagious. I guess it's a theory, but it's a theory that doesn't make a lot of sense. It doesn't seem logical that one hitter sees another hitter get a hit and then thinks: "Hey, it hadn't occurred to me before, but I'd like to do that!"
When an entire team slumps or an entire team gets hot at the same time, what's the common factor? If you said the pitchers they face, give yourself a pat on the back.
The St. Louis Cardinals have the lowest team ERA in baseball; the Milwaukee Brewers are 28th in that category. The Cardinals have given up the fewest runs; only two teams have given up more runs than the Brewers. The Cardinals are third in quality starts; the Brewers are 27th. So it's not too hard to figure out why the Royals were cold in St. Louis but hot in Milwaukee.
And the same pattern continued over the nine innings of Monday night's game. Kyle Lohse started the game for the Brewers, threw five innings, gave up five runs and this morning has an ERA of 6.44. Lohse was followed by Neal Cotts, and he threw one inning, got whacked around to the tune of four hits and two more runs, and this morning Cotts' ERA is 4.61. In six innings with two scuffling pitchers on the mound, the Royals put nine hits, three walks and seven runs on the scoreboard.
But for the final three innings of Monday night's game, the Royals faced Michael Blazek (1.27 ERA) and former Royal Will Smith (1.59 ERA) and suddenly their bats cooled down. Four hits, no walks and one run over the final three innings.
This ain't rocket science; when you face good pitching you're going to look bad at the plate. When you face pitchers who aren't so good, you're going to get hot — or at least you better; that's where you pick up wins and build up your numbers.
So remember: Hitting probably isn't contagious, but bad pitching definitely is.
Why Holland got hit … maybe
According the website FanGraphs, Greg Holland has been throwing his fastball at an average speed of 93.3 mph this season, down from a career average of 95.6 mph. On Monday night Holland's fastball was thrown at a low of 92 and a high of 95, so at times he was throwing his fastball harder than his 2015 average velocity.
But to the untrained eye (and I've got two of them) Holland's command was off; he'd throw a couple of good sliders to get ahead and then hang one.
After the game Ned Yost said it was "rust" because Holland hadn't pitched in six days. So despite getting whacked around Monday night — five batters faced and zero outs — you will probably see Holland more, not less.
Omar Infante, Raul Mondesi Jr. and second base
Omar Infante is currently hitting .210, and despite the fact that he might actually start the All-Star Game (which shows you how badly MLB messed up that thing), the Royals appear to be thinking about who their second baseman of the future might be. So some people are putting 2 and 2 together after the Royals announced minor-league prospect Raul Mondesi Jr. will start playing some second base.
Mondesi has been playing shortstop, and I used to believe that if you had the range, glove and arm to play shortstop, you could handle just about any position on the field — with the exception of catcher.
And then I watched a whole lot of baseball.
Back when Mike Aviles was with the Royals they tried to put him at second base, and Mike had his problems, especially when turning double plays. During a double play, shortstops get to come across second base facing first base and they see the runner coming at them. They know when the runner will arrive and what they're going to have to do to keep from getting blown up.
Second basemen don't have that luxury; they've generally got their back to the runner and they have to rely on their inner clock to tell them when they should hang in there and try to turn two and when they should bail out to keep from being injured.
And you don't develop that inner clock overnight.
At times it appeared that Aviles was giving up on double plays that could have been turned, and at the major-league level you can't give away those outs. So maybe Mondesi is the answer at second base and maybe he isn't. Time — and his inner clock — will tell.
Downtown ballparks
I just got back from St. Louis, and if you haven't been there to see a ballgame, I can report that it's pretty cool to sit in Busch Stadium, look beyond the center-field fence and see a skyline that includes the Gateway Arch.
But then the game ends.
Downtown ballparks seem like a really good idea until you see 45,000 people try to leave downtown St. Louis at the same time. Traffic jams are everywhere and people are driving home a few inches at a time. I like downtown ballparks as much as anyone, but if I were in one of those massive traffic jams, I might have a different point of view. A downtown stadium would have some advantages, but ease of parking and traffic flow are not on that list.
Be happy with what you got, Kansas City.
To reach Lee Judge, call 816-234-4482 or send email to email@example.com. Follow him on Twitter: @leejudge8.


text:
He knew it long before she did. That they were going to be together. Cherise had just moved from North Carolina to the mountains of Virginia, smack into his life. She was beautiful, smart, and funny. Stu just knew.
But Cherise hadn't moved to Virginia for a relationship. He's not my really my type. Right? Even as she asked all her friends, she already knew that deep down, he had already stolen a piece of her heart. They were friends, good friends, and even when she said No to him. Even when he handed her a stuffed teddy bear named Scooby, smiled, and agreed to just be friends. She was smitten, and it was love from then on.
Thank you Cherise & Stu, for inviting me to Virginia. Inviting me to share in your life and love. I'm so honored to be your friend, and Brian and I cannot wait until your September wedding!
We started in the Jefferson Park where Stu proposed to Cherise.
I have a whole set of silly images like this one! These two had me laughing the entire session!!
This waterfall was simply breathtaking. Totally worth it even though we had to slide to our death rock climb down an embankment!
Okay, I know, technically it's out of focus... but I. LOVE. IT. Like hard.
After we left the Jefferson National Park, we headed to where they were going to have their reception. And it was Stun.Ning.
Oh the light!!! Gorge!
Cherise, goodness gracious you're gorgeous.
When I took this shot, I'm pretty sure I jumped up in the air. And clicked my heels.
And if a breathtaking mountain wasn't enough... throw in a TRAMPOLINE!
I'll end with my favorite, favorite, favorite shot. Because this shot is like Whoa. A lot like their love.


text:
RAC are a group of artists mainly from the US that have included other international members. THey re-interpret music, but we're not talking fist pumping or booty popping mixes. These artists recreate music by playing with the arrangements until they're barely recognizable. RAC tends to include original instrumentals from their own artists along with retro drum samples and laser-like synthesizers. Unlike most electronica mixes where you'd expect more technical precision and, their mixes are generally more casual, playful, and easy to dance to.
These guys are remix giants and GOD are they good, so here's a few of my favorites.
Check out the rest at their soundcloud page here
Love this track so fucking much! Gotta love how RAC in all their fame and excellence decides to remix a song by a considerably unknown Malaysian female vocalist's Zee Avi.
Here's one of their originals.


text:
Whole Foods has been fueling my kitchen creativity lately (hot pink apples, French bleu cheese) and my trip there on Sunday morning did not disappoint. I came home with fresh lavender, did some research on lavender baking (as to make sure I didn't end up with something that tasted like bath salts) and decided to make lavender cupcakes. I adapted this recipe by using brown sugar in place of white sugar, almond milk and half & half in place of milk, and a basic lemon buttercream icing instead of the lime glaze.
I was thrilled with the results; lavender cupcakes are light and refreshing, without being boring. The lemon icing was a good match for the lavender, although I've decided I want to make a dark chocolate icing next time (I can't help it, it's just who I am).


text:
Westboro Baptist Church planning Orlando demonstration
Westboro Baptist Church, a nationally known religious group from Topeka, Kansas, is planning a demonstration in Orlando this Saturday, according to the Orlando Police Department.
OPD posted on Twitter Thursday evening that the church sent them a letter "saying they intend to be here 6/18 to demonstrate."
In an announcement on their Twitter, Westboro Baptist Church said they plan on demonstrating outside the Cathedral Church of St. Luke on Magnolia Avenue. Since the shooting at a gay nightclub in Orlando that left 49 dead and 53 injured, the group has celebrated the killings on social media, saying that "God sent the shooter." The URL for the church's website is www.godhatesfags.com.
Westboro Baptist Church has received national media attention since 1998 when they picketed at the funeral of Matthew Shepard, who was killed in Colorado, allegedly for being gay.
The group also made headlines during the Iraq War for protesting at the funerals of Americans killed in action, carrying signs reading "Thank God for dead soldiers."
The church's visit is planned on the same day as a ceremony to commemorate the shooting victims, which will be held at Lake Eola Park. The church's demonstration will be held about two blocks away from the park.
As reported by the Washington Post, a "human chain" was organized at the funeral for Javier Jorge-Reyes, a victim of the shooting. The chain — which was organized in response to rumors that the Westboro Baptist Church would be there wrapped around the outside of the service as a show of solidarity and support for the victim's family and friends. An organized told the Washington Post that members of the chain plan on attending other memorial services.
Alex Storer is the Entertainment Editor of the Central Florida Future. You can reach him at firstname.lastname@example.com.


text:
On Tuesday 14th November at 10.30, at InPrint I will be hosting a special discussion at the InPrint Show with 4 leaders from the world of print technology about the growing opportunity for décor production. The discussion will centre on developments such as wallcoverings, the growing surface design revolution, and the opportunity that this provides for printers and manufacturers – we will also tackle the technical difficulties and why a flexible approach is important in order to find the sweet spot for this exciting and visually arresting industry.
Joining me areJohn Corrall or Industrial Inkjet, Frank Seemann of Erfurt, Jeremy Spencer of Global Graphics and Heidi-Jane Fowler of Sihl.
We would really welcome your attendance and participation.


text:
Switching Test IDs To Official IDs [CLOSED]
On 08/02/2015 at 06:33, xxxxxxxx wrote:
User Information:
Cinema 4D Version: 15
Platform: Windows ;
Language(s) : C++ ;
Hi PluginCafe,
when writing plugins one can use ids in the range 1000001 to 1000010. When I obtain official ids from the website, my old scenes alert errors, that some (or all) plugins are missing.
That behavior makes absolutely sense, but does anyone know a trick, to tell C4D that the plugins now have different ids? Is there any way so that I don't lose all the settings in my testing scenes. It would be a lot of work to recreate all settings/material/tags etc.
On 08/02/2015 at 10:12, xxxxxxxx wrote:
Well next time you know to use a Plugin ID immediately. ;)
I think your most feasable option is to write the BaseContainer to a
HyperFile, and then load it again in your plugin with the new Plugin ID.
On 08/02/2015 at 11:47, xxxxxxxx wrote:
Huh, I was afraid that it won't be easy.
Could you give me some hints what to write to the HyperFile? I guess I can write data from, for example, only a tag to a file. Let's say that I could simply write only the data of the most annoying one and do the rest by hand?
Are there really no scenarios where someone has to change an id after release or in such a situation? I feel really dumb, that I have underestimated the id problem^^
On 08/02/2015 at 18:08, xxxxxxxx wrote:
I only use test IDs for internal projects or tests. While it is something of a waste, for plugins that will be made public or when involving test documents, I immediately get all of my plugin IDs even if not all end up being used or the plugin is never released (happens once in a while). The ID is the association. Once it is saved into a document, you can't just tell C4D to look at a different ID.
On 09/02/2015 at 00:09, xxxxxxxx wrote:
Thanks for the replies, I set this to [CLOSED].
Happy coding!
On 09/02/2015 at 09:23, xxxxxxxx wrote:
at first I'd like to thank Niklas and Robert for doing my work
And then I wanted to let you know, that we'll add something to the docs and the PluginID request site, to make this matter more clear. Sorry, Andreas, you stepped into this trap. But at least we want to make sure, it doesn't happen again in future.
On 01/06/2015 at 08:22, xxxxxxxx wrote:
I know, this thread is closed for quite some time.
Nevertheless I want to propose a possible workaround.
Let's assume you have a NodeData plugin (or any one derived from NodeData) and you want to change the PluginID. You will register two Plugins, one with the old and one with the new IDs, for as long as you need a conversion/compatibility layer. Now, in the plugin with the old ID you can remove most of the code, but you will want to implement:
- Alloc(), Free() and Init()
- Write(), here simply return false to prevent the old nodes from being written
- Message(), this is where the magic happens. You need to implement MSG_DOCUMENTINFO -MSG_DOCUMENTINFO_TYPE_LOAD, only. That's where you get informed, that the scene got loaded. Then you walk over all nodes from your old plugin, allocate nodes of the new plugin, transfer the data properly from new to old, insert the new nodes and remove the old nodes from the scene.
@Andreas: I'm terribly sorry, that I come up with this solution only after it's probably too late for you.
On 01/06/2015 at 14:43, xxxxxxxx wrote:
Hi Andreas,
thanks for the response! Your solution is fine for reference. As you guessed correctly, we already have updated our scenes manually;-)


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An article written by the magnificent Peter Minkoff. For more of his work, please check out his social media.
From time to time, you have to clean your body and mind the same way you clean your house. And since spring seems to be the perfect time for a fresh start, we have prepared an ultimate body and mind detox guide with some useful advice on how to create healthy habits and get ready for new endeavors and adventures.
Drink a lot of water
The ground rule for a successful detoxification is that you drink a lot of water. Forget all other beverages, like coffee and beer, since they only poison your body making the process of detoxification much slower. Instead, stick to water, and as soon as you wake up, drink one glass of warm water in order to keep your body hydrated and accelerate your metabolism. Another great option is making ginger water since it's both healthy and useful for breaking the monotony of drinking plain water.
Turn off your phone
If you want to relax and unwind completely, you must turn off your phone. Instead of reading emails, text messages and stressing about all the deadlines, spend at least one hour a day far away from all that and do something you enjoy. For example, you and your beloved one can go for an amazing couples massage. This will help you relieve all the stress and thus detoxicate both your body and mind. On top of that, you should look at this as a way of saying "thank you" to yourself. Don't ever feel bad for doing something nice and treating yourself since you deserve it.
Learn to say "no"
One of the most important things, if you want to maintain good mental health and detoxicate your mind, is to learn how to say "no". It's noble to want to help everyone, but this doesn't mean you should let others use you and drain your energy. So, before you decide to make a sacrifice, make sure to find out whether a person really needs and deserves your help, or if it's just easier for them to let you do all the hard work. Remember that being able to focus on yourself and your own priorities is the key step to achieving a complete detoxification.
Eat healthy
Eating healthy is very important in the process of detoxification. However, keep in mind that this doesn't mean you should be hungry all the time since hunger only leads to stress, and stress is exactly what we're fighting here. Instead, stick to healthy meals which will give your body enough strength, but which won't harm it. For example, apples are perfect for a full body detoxification since they contain antioxidants and a lot of water. Furthermore, they are extremely rich in vitamin C, so you'll strengthen your body to be able to fight off any colds and flues.
Do yoga
Nothing can be more soothing both to your body and mind than regular yoga classes. They will give you an opportunity to get in touch with your inner self and detoxicate your body on a spiritual level as well. Furthermore, in the state of full relaxation, it will be easier for you to let go of all the negative feelings and embrace a more positive view of the world. On top of that, yoga is extremely healthy for your body as well since it increases blood circulation, stimulates the lymphatic system and helps the liver function properly so that your body can be properly cleansed.
As you can see, the process of full body and mind detoxification is not that hard after all. You just need to learn to stand up for yourself and fulfill your own desires. Finally, make sure to eat and drink healthy since all the mediation in the world won't help you if you poison your body.
Photos by pexels.com and unsplash.com


text:
With the hernia and the shoulder injury keeping me in check, I feel like I'm just kind of biding my time until my surgery. On one hand it really sucks, but on the other hand it feels good to know that soon I'll be back at 100%. The doctor said that I should be able to return to lifting about 6 weeks after the surgery, and by then my shoulder should also be ready to go. My shoulder, by the way, has felt great for the past week. I can't wait until I can start lifting again, even though I'll have to use light weights for a while.
My waist is down to an all-time low: 30 inches! That's 1/2″ I've lost off my problem area in the past 3 weeks. I've got to hand it to Ab-Solved and Tight. They seem to be working because the smallest my waist has ever been is 30.5″, even last summer when I was a 160 pounds.
This week's going to be a killer at work, so I may not be around on the forums as much as I'd like to.
I'm off to do my cardio. Have a great day!


text:
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I'd changed the WordPress theme to Andreas09 – which provides a 3-column layout, with sidebar widgets on the left and right of the main body.
Hope you like it – I think it gives more flexibility to exploit sidebar widgets.
Happy New Year.
Posted by Brian Kelly on 31 Dec 2006
I'd changed the WordPress theme to Andreas09 – which provides a 3-column layout, with sidebar widgets on the left and right of the main body.
Hope you like it – I think it gives more flexibility to exploit sidebar widgets.
Happy New Year.
Posted in Blog, General | 3 Comments »
Posted by Brian Kelly on 31 Dec 2006
My predictions for the forthcoming year:
Any comments on these predictions?
Posted in General, Web2.0 | 6 Comments »
Posted by Brian Kelly on 27 Dec 2006
It was nice to see that this Blog was featured as the number 1 in WordPress's list of Blogs of The Day for growing blogs:
I don't think this with drive much traffic to the blog, but at least one person noticed this and visited my blog.
Posted in Blog, General | Leave a Comment »
Posted by Brian Kelly on 22 Dec 2006
A colleague came in to my office yesterday clutching a book ("Wiki A New Wave in Web Collaboration") she had just received which, she informed me, had a contribution from me. Rather than a brief mention I was surprised to find that it included an 8 page article on "Experiences of Using a Wiki for Note-taking at a Workshop". I had to search for this title before finding that this was an article I'd written which had been published in Ariadne (Issue 42, January 2005). I then recalled that over a year ago we had received a request from someone in Indian working for ICFAI (Institute of Chartered Financial Analysis of India) for permission to include this article in a book he was editing. I was happy to give my permission – and was very pleased to receive a copy of the book just before Christmas.
Having a article published in a book produced in India reminded me that back in January 1995 I sent out an announcement about a handbook on "Running A WWW Service" which I had written and which was mirrored in the US, Sweden,Turkey and Slovenia (not Singapore, as I mistakenly announced, misinterpretting the .si country code). The handbook was also, at one stage, included in the SuSE Linux distribution pack.
I've always has an open attitude regarding materials I've written, and, for the past year, my slides have contained a Creative Commons logo. In June 2005 I gave a talk at the EUNIS 2005 conference on "Let's Free IT Support Materials!" in which I argued for support services in our institutions should be pro-active in allowing documents produced for internal use available for re-use by others.
Three days before Christmas it is timely to repeat this proposal. Remember, openness is about giving, not taking.
Merry Christmas
Posted in openness, publications | 2 Comments »
Posted by Brian Kelly on 20 Dec 2006
In the Christmas Quiz II posting I asked the question:
The current version of HTML is XHTML 1.1. What is the next version likely to be:
There were two responses to this question which I will discuss in more detail:
Posted in HTML | 2 Comments »
Posted by Brian Kelly on 20 Dec 2006
Phil Bradley's Blog describes how he has joined in the Blogtagging game and has Blog tagged me: he has posted 5 interesting facts about himself, and invited 5 people he knows to do likewise. It sounds like a pyramid chain but, rather than predicting ill-fortune on those who break the chain, I take a positive view that this can be useful in building a community by getting to know each other better (we normally have to wait for the social events at IWMW events to do this, so this is a useful approach in the run up to Christmas). Read the rest of this entry »
Posted in General | 3 Comments »
Posted by Brian Kelly on 20 Dec 2006
UKOLN hosted a workshop on "Exploring The Potential Of Wikis" in Birmingham on 3 November 2006. A summary of the workshop evaluation is now available; the comments on the workshop, the talks and the discussion groups give an indication of the interest there is in the institutional provision of Wikis.
However as usage of Wiki software grows, some of the limitations become more apparent. Here are some of the issues which I have identified, which may not have been discussed at the workshop:
Are these show-stoppers? Should we put on hold our plans to deploy Wiki software until such issues have been addressed? Are there other significant problems with Wikis? Or can such limitations be outweighed by the benefits which Wikis can provide?
Posted in Events, Wikis | 2 Comments »
Posted by Brian Kelly on 19 Dec 2006
It had been expected that the WCAG 2.0 guidelines would be released by W3C WAI this year, to replace WCAG 1.0 which came out way back in 1999. However the reviewing process for WCAG 2.0 seems to have slowed down (if not stopped) due, I suspect, to the huge influx of comments received after Joe Clark published his "To Hell With WCAG 2.0" article published in May on A List Apart. Joe's posting generated much debate from commentators such as The Pickards, Stephen Downes, Joe Dolson and contributors to Accessify Forum as well as follow up articles and discussions on Joe's own Blog. Read the rest of this entry »
Posted in Accessibility | 1 Comment »
Posted by Brian Kelly on 19 Dec 2006
In my Christmas Quiz posting I asked which of the following are open standards:
Flash PDF RSS 1.0 RSS 2.0 MS Word
Before giving my thoughts on this, I will comment on the responses.
James Brown felt that "first, my definition of an open standard: publicly available and able to be implemented such that two or more different uses of the standard will be compatible and accessible." He then went on to apply that rule to the examples I gave and felt that each of them had characteristics of openness but not completely so.
Phil Wilson felt gave his "definition of an open standard: publicly available and able to be implemented such that two or more different uses of the standard will be compatible and accessible."
Ravis Reddick thinks that "Flash itself isn't the standard, it's the official authoring tool and general brand name for the technology. Other authoring tools can author 'Flash'; the export format is various version of Shockwave Flash. I think this can now be authored in an open way using an intermediary format"
Kevin Ashley's view is that "Flash, PDF and more recent versions of MS Word are all open in the sense that the file format is published, and it is possible to create tools to read/render content in those formats using nothing except the published standards." He went on to add that "All of them are not open in the sense that new versions of the formats can be created at the whim of the company that owns them." Although he is "not so worried about that; if I don't like PDF 1.7 because of some new license twist, I won't use it. All the stuff I already have in PDF 1.x (x".
And finally Steve Nisbett feels that "PDF, FLASH and MS may well be seen as 'standard' – available all over the place, but they are certain not Open."
I can recall back in 1993-4 having similar discussions about open standards. Back then I can recall arguing that a system such as the Web because of the:
There were a number of other bullet points (which I have forgotten) but I do recall that my definition was used in a response to other systems which were competing with the Web (and in my opinion where inferior to the Web). These included such as the Guide hypertext system, developed at the University of Kent and Microcosm, an "Open Hypermedia Environment for Information Integration" developed by Professor Wendy Hall and colleagues at the University of Southampton. As these products were being pushed in 1992/3 as potential alternatives to the Web (and came from well-established Computer Science departments with good reputations for the quality of their research) I came up with my definition of openness, which I gave at a day's workshop on Hypertext Systems On Unix Platforms at the University of Kent back in 1993 (it was originally intended, I think, as a promotional events for Guide, and I was the token person describing at alternative approach!) However my definition of openness was clearly not an open definition – it was intended to embrace my preferred solution, at the expense of the competitors. I'm aware that others take a similar approach (which all too often seems to resolve to "an open standard is one that Microsoft have no involvement in, no matter how proprietary it may be!").
The respondents to this quiz take a more honest approach, I'm pleased to find.
So what are my thoughts?
The examples I used were taken from a presentation of a paper on A Contextual Framework For Standards which I gave at the "Workshop on E-Government: Barriers and Opportunities" which was held in Edinburgh in May 2006. The opening speaker at the workshop was Ivan Herman of the W3C (and currently the lead of the W34C's Semantic Web activity). In his presentation Ivan cited an EU definition of openness:
Shortly after Ivan's talk I delivered my slides, and, as can be seen, I asked the audience (which included not only Ivan Herman, but also Steve Bratt, CEO of W3C) which of the following were open standards:
XHTML Flash PDF Java RSS 1.0 RSS 2.0 MS Word
There was universal agreement that XHTML was an open standard and Flash, PDF, Java and MS Word weren't. But there was ambivalence over both versions of RSS – it may be based on XML – but there are uncertainties over the governance of the standards. As Phil Wilson commented:
RSS 2.0 is published but there is a strict copyright on the usage of the term, and no-one apart from Dave Winer may make changes to it ("Someone has to have the last word, and when it comes to the RSS 2.0 roadmap, that's me", "I am banging the gavel").
Related concerns have been raised over the future development of RSS 1.0. I would argue, therefore, that RSS 1.0 and RSS 2.0 fail the EU's definition according to the "will be maintained by a not-for-profit organization" – neither seems to being adequately maintained.
Tavis Reddick mentioned that "The question isn't clear about what is the standard: the interface, the file format, the information model…? I took it to mean something like the data binding format."
It should be noted that the EU's definition of a open standards relates to the openness and the governance of the standard itself – it is silent on issues such as the openness of tools to support its usage.
What does this mean to policy makers, developers, funders and users with digital library development programmes? One response is "nothing, this is just splitting hairs". But if our mantra is "Interoperability through open standards" then surely we need to have an agreed understanding and definition of 'open standards'? Oleg Liber, Director of CETIS touched on this issue in his talk at the recent JISC-CETIS Conference. His slides reviewed CETIS historical involvement with educational technology standards:
From the certainties we held at the start of the new century, we are now beginning to challenge some of our basic assumptions.
"Interoperability? Standards?" or "Interoperability! Standards!"? What is your view?
Merry Christmas
Posted in standards | Leave a Comment »
Posted by Brian Kelly on 19 Dec 2006
This year has seen UKOLN building on its work on ways in which standards can be used to support digital library development programmes. In the past a simplistic approach had been taken, which assumed that standards developed by trusted standards bodies (W3C, IETF, ISO, etc.) would become widely accepted within the market place. This approach, however, has failed in the past (Coloured Book software anyone?) and we currently are seeing a wide range of debates over standards across the Web development community (Web Services Considered Harmful; RSS vs RSS vs Atom debates; the Semantic Web vs the lower case semantic web and microformats and, more recently, a radical vision for the future based on XHTML 2.0 vs an evolutionary development towards HTML 5.0 – as described in Molly Holzschlag's Blog) .
UKOLN's contribution to the debate has been the development of a contextual three-layered approach, based on a neutral standards catalogue (containing details of standards, their governance; their maturity and a risk assessment) together with policy layers for selecting relevant standards and for managing non-compliance with the policies. This approach, which has been designed to provide a level of flexibility which is needed in a rapidly changing technical environment is supported by an advocacy strategy (which promotes the benefits of open standards) and an iterative feedback and development approach (in order to learn from patterns of best practices).
We have sought to develop our ideas and gain feedback by papers which have been submitted to a number of peer-reviewed conferences. In May a paper on A Contextual Framework For Standards was presented at the "Workshop on E-Government: Barriers and Opportunities" which was co-located with the International World Wide Web Conference held in Edinburgh.
My colleague Marieke Guy has been engaged in implementing the system which is based on our contextual model. It was pleasing when Marieke and I met with members of the eReSS project to discover that they had taken a similar approach in the area of e-science standards.
This contextual approach has been designed to be usable by the wider community. The information provided in the standards catalogue has a Creative Commons licence associated with the entries, so there should be no legal barriers to the reuse of the content. This will enable developers, policy makers, managers, etc. within institutions to make use of the resources to support institutional development activities. More importantly from a JISC perspective, the approach can be used by JISC's partners in the Strategic E-Content Alliance (SEA). The SEA is an alliance of bodies such as JISC, MLA. BBC and Becta, which aims to provide seamless access for the public to a wide range of scholarly, cultural and educational resource. The contextual approach to the selection and use of open standards is particularly relevance in this content as, though the bodies will seek agreement where possible on relevant standards, there will be areas in which organisational or political considerations may outweigh technical factors.
Next year will see UKOLN continuing to build on this work – and we are particularly pleased that a paper on Addressing the Limitations of Open Standards has been accepted at the Museums and the Web 2007 conference.
Posted in standards | 1 Comment »
Posted by Brian Kelly on 18 Dec 2006
This year the tenth in the series of UKOLN's annual Institutional Web Management Workshops was held here at the University of Bath. This was also the year in which I stepped down as chair of the Programme Committee and handed responsibility to my colleague Marieke Guy. The event, which took place on 14-16 June 2006 was also the largest we've held and, judging by the comments and scores on the evaluation forms, the best ever! Read the rest of this entry »
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Posted by Brian Kelly on 18 Dec 2006
This, my tenth year at UKOLN, has been the busiest year ever for giving presentations, with a total of 42 presentations given at conferences, seminars and workshops – I was invited to give another talk recently, but, like all fans of Douglas Adams, I knew when it was a good time to stop :-). Read the rest of this entry »
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Posted by Brian Kelly on 15 Dec 2006
UKOLN has hosted the Institutional Web Management Workshop every year since 1997, with this year's event being the tenth in the series.
At the workshop a number of participants commented that they felt themselves to be a member of the Institutional Web management community, with the event providing the main focal point for the community, with the web-support and website-info-mgt JISCMail lists providing additional mechanisms for community sharing and collaboration.
The IWMW 2006 event highlighted the importance of Web 2.0 to the community. Since the workshop a range of presentations and events have been held throughout the country. And on 1 November
29006 2006 (my tenth anniversary at UKOLN) this Blog was set up. The Blog has not been announced on mailing list in order to gain experience in Blogging and the time and effort needed to Blog in a sustainable fashion. However it is now timely for an official launch of the Blog, which has been announced on the web-support JISCMail list.
The Blog will cover areas related to the Web, especially areas of interest to our key communities (the higher and further education and cultural heritage sectors, the digital library development and research communities and the institutional Web management community).
In order to support the institutional Web management community, a well-established and thriving community of practice, posts on this Blog which are likely to be of interest to the community will be tagged with the 'IWMC' tag.
I would encourage members of the community who are setting up Blogs with similar roles to use the same tag, to help in finding and sharing posts.
I would also invite Bloggers from the IWMC community to contact me (using email or by commenting on this posting) with details of their Blog.
Posted in IWMC | 4 Comments »
Posted by Brian Kelly on 15 Dec 2006
I recently attended a joint JISC/UKOLN/CETIS awayday meeting. One of the issues which arose in the discussion group I participated in was the boundaries between personal services, institutional services and national services.
Scott Wilson (CETIS) suggested the acronym PING (personal, institutional, national and global).
In response I proposed PONG (personal, organisational, national and global).
An alternative would be DING and DONG (distributed institutional/organisational, national and global).
The PING PONG debate will, no doubt, be bounced between UKOLN and CETIS.
(Note UKOLN has its Christmas lunch yesterday, and I have probably been reading too many Christmas cracker jokes and puns).
Posted in General | 2 Comments »
Posted by Brian Kelly on 15 Dec 2006
Another quiz for Christmas.
The current version of HTML is XHTML 1.1. What is the next version likely to be:
Feel free to add your comments.
Posted in IWMC, standards | 4 Comments »
Posted by Brian Kelly on 12 Dec 2006
There has been some discussion on the JISC-Repositories JISCMail list (under the confusing subject line of "PLoS business models, global village") on the issue of file formats for depositing scholarly papers. Some people (including myself) feel that open formats such as XHTML should be the preferred format; others feel that the effort required in creating XHTML can be a barrier to populating digital repositories, and that use of PDF can provide a simple low-effort solution, especially if authors are expected to take responsibility for uploading their papers to an institutional repository.
An issue I raised was the accessibility of resources in digital repositories. There are well established guidelines developed by WAI which can help to ensure that HTML content can be accessible to people with disabilities. Myself and others have argued that the guidelines and the WAI model is flawed, but many of the guidelines are helpful and institutions should seek to implement them (indeed there are legal requirements to ensure that services do not discriminate against people with disabilities).
WCAG 1 has the following requirements:
3.2 Create documents that validate to published formal grammars. [Priority 2]
11.1 Use W3C technologies when they are available and appropriate for a task and use the latest versions when supported. [Priority 2]
11.4 If, after best efforts, you cannot create an accessible page, provide a link to an alternative page that uses W3C technologies, is accessible, has equivalent information (or functionality), and is updated as often as the inaccessible (original) page. [Priority 1].
This seems to be pretty unfriendly towards PDFs, I would argue. WCAG 2.0 (which is in draft form) is, however, neutral regarding file formats – a development I welcome (although the guidelines still have their limitations). However the guidelines still require that content is accessible; and as well as the requirement in the guidelines, there are also legal and ethical requirements to address such issues.
Proprietary formats such as PDF can be made accessible. However I am uncertain as to how alternative text for images and providing structure to PDF documents will happen in a distributed workflow environment.
Rather than dwelling on this (technical) issue, I would like to focus on the policy issues, which should be independent of particular file formats. UK legislation requirements organisations to take reasonable measures to ensure that people with disabilities are not discriminated against unfairly. One could argue that it would be unreasonable to expect hundreds in not thousands of legacy resources to have accessibility metadata and document structures applied to them, if this could be demonstrated to be an expensive exercise of only very limited potential benefit. However if we seek to explore what may be regarded as 'unreasonable' we then need to define 'reasonable' actions which institutions providing institutional repositories would be expected to take.
One approach would be for the institution to ensure that it provides appropriate training and staff development for authors who are expected to upload documents to repositories. Linked to this may be tools which can flag problem areas to the authors, as documents are being prepared for uploading. There may then be auditing tools which can alert institutions to potential problems.
Related to policies to support the authors, are policies which address specific problems which users with disabilities may have. Clearly many scientific papers (containing formulae, for example) may be difficult to be processed by traditional assistive technologies. Perhaps this is where there is a need for just-in-time accessibility (as opposed to the traditional just-in case approach) or blended accessibility (real world alternatives to digital accessibility barriers).
Posted in Accessibility, Repositories | 9 Comments »
Posted by Brian Kelly on 12 Dec 2006
A quiz for Christmas.
Which of the following are open standards:
Flash PDF RSS 1.0 RSS 2.0 MS Word
As a follow-up, give reasons why the opposite of what you said may be true.
Please use the comments box for your thoughts.
Posted in General, IWMC, standards | 11 Comments »
Posted by Brian Kelly on 10 Dec 2006
A LibraryThing Blog posting informs me that recently their database contained 8,388,608 records – apparently this is half of 224, the largest number you can store in three bytes. It's also the limit for MySQL's "signed medium integer" (111111111111111111111111). They have now rebuilt the database – and won't hit another barrier until they hold information on 8.4 billion books!
This is clearly a 'cool' service (it was also recently featured on Slashdot) . How did they succeed in being so popular? What lessons can the JISC development community learn from the popularity of the service? Any suggestions?
Posted in Web2.0 | 3 Comments »
Posted by Brian Kelly on 10 Dec 2006
I recently gave a talk on "Web 2.0: Implications For The Publisher" at a meeting organised by ALPSP. A fellow speaker was Terry Hulbert of IOPP. During lunch Terry and I discussed how we both enjoy seeing slides and demonstrations from fellow speakers who are advanced users of FireFox, as this can provide an opportunity to learn about cool new FireFox extensions. Terry noticed two of my extensions that he'd not come across. A few days after the meeting I received an email from Terry saying:
"Downloaded the Blogger Web Comments and RSS Panel Firefox plug-ins – they rock !"
Terry's right – these are my favourite FireFox extensions. They are illustrated below.
The RSS Panel Greasemonkey script (on the left) appears if a Web page contains an (autodiscovery) link to an RSS page. Initially it appears as a floating window simply containing the title of the RSS feed. On opening the window access to all of the RSS links is available, as illustrated.
The Google Web Comments extension provides an interface to Google's Blog Search service. If a blog entry has links to a page you are viewing (or pages below it) an indication of this is displayed in the bottom right hand corner of the browser status bar. Clicking on the icon results in the title of the posting appearing, as illustrated. It was using the tools that I came across David Rothman's comments about a recent talk of mine.
The FireFox extension that Terry uses which I hadn't come across was
Colorful Tabs – which I must get round to installing.
You've now heard about our cool FireFox extensions – what are yours?
Posted in IWMC, Web2.0 | Leave a Comment »
Posted by Brian Kelly on 10 Dec 2006
"Have you seen LibraryThing – it's cool!". "I agree. And I've written a cool XSLT script to take data from my OPAC and upload it to LibraryThing – and also to del.icio.us." "That's cool!" (see footnote).
A common response to hearing discussions such as this is to be dismissive – "It's just geeks being clever. We need to adopt a user-focused approach to development, and we must deploy formal user needs analysis. And we should be dispassionate about the services we're developing – so the 'cool' word is banned! "
Although there is a need to take a user-focused approach to development, I would argue that there's also a need to encourage a 'cool' approach to development, especially at a time of rapid technological development that we are currently seeing.
One reason for this is to build on the work of the early developers and bridge the 'chasm' in the Gartner hype curve.
For developers to be pleased with their work and wish to share their successes with others is, I would argue, an approach to be encouraged. And if the vocabulary includes the word, 'cool' then that's fine by me.
There is also a need to have a better understanding of the positive aspects of the term 'cool' in development circles. At the international World Wide Web conferences which I have attended, the word cool is often used to refer to development work based on simple and elegant implementations of new standards and technologies elegant; the emphasis in this community does not normally focus on fashionable user interfaces.
However I would argue that development of 'cool user interfaces' should also be encouraged. Andy Powell has commented on the differences between Slideshare.net and JORUM – and I would argue that Slideshare's cool interface has contributed to its popularity.
There is, however, a danger to being cool. Cool can be used to refer to innovation for its own sake or fashionable user interface features which may result in degraded experiences for some. Let our mantra be "Let's do cool cool stuff and avoid the bad cool development". If you're a manager and you hear your developers talking about cool applications, grill them to find out which meaning of cool they are using – if they are good developers, you may learn something; and if they're not you will need to make use of your management skills.
See Dave Pattern's blog entry about how he integrated data from the Library OPAC with LibraryThing and del.icio.us – and the first comment :-).
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Posted by Brian Kelly on 5 Dec 2006
I have given a number of Web 2.0 presentations to the library and information professional communities recently. It has been pleasing to note that responses to hearing about technologies such as Blogs and Wikis and Web 2.0 approaches such as trust and the importance of user-generated content has been very positive. The attitude seems to be "I can appreciate possible benefits, but I'm not sure what to do next".
In terms of Blogging, a good approach would be to observe what one's colleagues are doing, identify types of usage and examples of best practice and, if this fits in with local needs, to seek to emulate the best practices.
But where are the Blogging librarians in the UK? I recently heard about the Northampton University Library Blog (called Shush!), which is illustrated.
This is based on a WordPress Blog, which seems to be hosted locally. There are several contributors to the Blog (including HeatherD, Miggie, Chris, Fionna and Phil). Some observations on this Blog:
thanks for the support in using the harvard system it was useful and helpped me well i am beginning to understand it now and will put it into practices as much as i can
thanx alot
I am also aware of Univ of Bath Library Science News (which only covers the Faculty of Science). And quick Googling finds:
At this early stage in the development of library Blogs it does seem to be that it would be very timely to survey the approaches which are being taken to providing Blogs and to observe patterns of usage. A useful project for a Library and Information Science student perhaps?
If you provide a Library blog within the UK community, or are aware of links to such resources, perhaps you could provide details in a comment to this posting.
Posted in Blog | 17 Comments »
Posted by Brian Kelly on 4 Dec 2006
On Friday 1st December 2006 I gave a talk on "Web 2.0: An Introduction" at a seminar organised by the CILIP UCRG (Yorkshire and Humberside Region). As I've been doing for the past couple of years my opening slide gave explicit permission for attendees to exploit networked application during my talk – for example, to Blog my talk, to discuss the talk with others using chat software or to record or broadcast my talk.
I was pleased when Sheila Webber, during her talk on Blogs and Blogging in Libraries, brought up her Blog page which showed that she had Blogged my talk. More accurately, I should probably say that I was pleased but slightly apprehensive! Sheila, however, said nothing in her Blog for me to be apprehensive about – but it did make me wonder about the etiquette of Blogging at events, and how possible conflicts should be addressed. From one point of view, if a WiFi network is available during an event, an attendee with a laptop or PDA would be inclined to make use of it to make notes, to follow up examples given during a talk, etc. To make notes on a Blog is, surely, not fundamentally different from making notes in MS Word. But I suspect from a legal perspective there may be differences. More importantly, though, is whether there will be felt to be differences from a cultural perspective. How will lecturers feel about students Blogging their talk? Will this become a frowned-upon activity, similar to using a mobile phone at an event?
I think I will continue to explicitly encourage openness by stating my views on the title slide of my talks. Is this something others seek to emulate, or am I in a minority?
Posted in Blog, Events | 5 Comments »


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As the old saying goes, the game is to be sold and not to be told. But when it comes to hip-hop, the selling of the telling has become a game in itself. Ever since 50 Cent pocketed a fat advance and hit the New York Times bestseller list with his 2003 memoir From Pieces to Weight, rappers have been hiring ghostwriters and spilling their secrets for anybody with an Amazon Kindle.
Although celebrity autobiographies tend to be cumbersome (with subjects glossing over the more negative details of their lives), there's a renewed interest in the hip-hop memoir—and the realer, the better. Everybody wants to get into the game, although writing books is easier said than done: Both Diddy and Foxy Brown have been sued by publishers for cashing their advance checks ($325,000 for Puff; $75,000 for Foxy) and then failing to turn anything in.
Earlier this year Prodigy released his incredible book, My Infamous Life, which is filled with insane fights and cocaine use. More recently Common released his memoir One Day It'll All Make Sense, a treasure trove of groupie tales and Erykah Badu anecdotes. Now Nas seems to be following suit after he recently announced that he's planning to releases an autobiography next fall, It Ain't Hard To Tell.
But not all rap memoirs are created equal. Snoop's book The Doggfather strings the reader along for 240 pages before admitting that he's not going to give up any juicy details about the nitty-gritty inner workings of Death Row. So which rap autobiographies are really worth reading? Check out this of The 10 Most Shocking Revelations In Rap Memoirs and decide for yourself...
Written by Keenan Higgins


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Criminal Justice Graduate Student Association
The Criminal Justice Graduate Student Association will assist members with adjustment into the Criminal Justice Graduate Program, act as student-faculty liaisons for the purpose of addressing student body concerns, organize events designed to promote graduate research, encourage student involvement in academic and social events within the Department of Criminal Justice and Criminology, and assist graduating students in transitioning into graduate careers.
Faculty Advisor: Joshua Hinkle, email@example.com
President: Michelle Harris, firstname.lastname@example.com
Vice President: Kirsten Hill, firstname.lastname@example.com
Club meeting dates for the Fall semester will be forthcoming.
CJGSA correspondence occurs through OrgSync. Simply register here: https://orgsync.com/communities/georgia-state-university and then perform a search for CJGSA.


text:
Supply Demand Wyckoff Trading Mentor
Supply Demand Wyckoff Trading Mentor. Author. Cyclist. I share with you my Trading Experience.
Founder of > Profiting.Me
Past performance is not an indication of future results.
Nobody in this website is a Financial Advisor and nothing herein is intended to be or to be constructed as Financial Advice. It is for information and educational purposes only.
This website is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for website owners to earn advertising fees by advertising and linking to amazon(.com, .co.uk, .ca, .it etc) and any other website that may be affiliated with Amazon Service LLC Associates Program.


text:
New York-based importer National Console Support warns customers today that getting their hands on a Japanese version of the DualShock 3 might be tricky. It writes in its semi-daily news updates that offers from one overseas distributor has the following requirement: "In order to obtain 1 Dual Shock 3, we also have to buy 1 PlayStation 3 40GB console." That's a hefty tax.
NCSX urges caution to rumble-hungry games, warning them to wait until stock levels off or distributors offer more sane pricing schemes.
One of its biggest competitors, Play-Asia, is no longer soliciting pre-orders, asking customer to check in for potential restocks. With two of the bigger Japanese hardware and software importers unclear of their availability for the November 11 launch of the new controller, it's looking likely that latecomers will have to hold tight for a while longer.
General Updates [NCSX]


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b. Santa Fe, New Mexico, currently in San Francisco, California. Halley Roberts Strongwater is a fine art photographer from Santa Fe, New Mexico.
She is currently working on Circadian Rhythms, a series of low-light photographs of the world at dusk and dark.
for limited edition prints, photography and design inquires: email@example.com


text:
Kelly McVerry
Classroom Phone: 269-250-8982
School Phone: 269-250-8960
Welcome to Third Grade!
My name is Kelly McVerry! I've been teaching at Green Meadow Elementary for 6 years, and a total of 13 years at the elementary level.
I feel it's a privilege to be a child's teacher, as I know how much of a role my own children's teachers play in their lives.
Feel free to contact me anytime!


text:
A former South Korea national team goalkeeper has confessed to his involvement in fixing soccer matches in the growing K-League corruption scandal, according to local media.
A senior K-League official said that the Jeonbuk Motors goalkeeper has admitted to fixing games last season when playing for rival team Chunnam Dragons.
"The goalkeeper first informed his Jeonbuk head coach Choi Kang-hee last Friday night," K-League secretary Ahn Gi-heon told Yonhap news agency. "After speaking with Lee Chul-geun, general manager of Jeonbuk, we decided to hand the case over to prosecutors."
The goalkeeper, whose name was withheld, was briefly a member of the national squad in 2008.
He is the first known player to turn himself in for ties to match-fixing since the K-League launched a wide-reaching probe into the problem.
Players have until the end of this month to come forward in return for reduced penalties from the league as part of an amnesty.
The K-League's sting has already led to life bans for 10 players — eight from the Daejeon Citizen team alone — in the most embarrassing scandal since the country's professional league was established in 1983.


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Thursday 25 May / Dydd Iau Mai 25
7.30pm, Leisure Centre / Canolfan Hamdden
Tickets / Tocynnau: £15.00 / £12.00
First prize winners of the Val Tidone International Chamber Music Competition 2010 and the St Martin's Chamber Music Competition 2013, Second prize winners of the Karol Szymanowski International String Quartet Competition 2014, and third prize winners of the Trondheim International Chamber Music Competition 2013, the Jubilee Quartet was formed in 2006 at the Royal Academy of Music, London. They held a Leverhulme Chamber Music Fellowship at the Academy during 2012-13, and the Richard Carne Junior Fellowship at the Trinity Laban Conservatoire of Music and Dance during 2013-14.
The quartet are award winners of the Tillett Trust 'Young Artists' Platform'; the Park Lane Group 'Young Artists'; the Hattori Foundation; the Worshipful Company of Musicians 'Concordia Foundation Artists Fund'; and are recipients of the Philharmonia MMSF 'Charles Henderson Ensemble Award' and the Eaton Square 'St. Peter's Prize' 2014. In 2012 the quartet were finalists in the Joseph Joachim International Chamber Music Competition, Weimar, and in 2013 and 2015, in the Royal Over-Seas League.
Their studies have been overseen by professors such as Günter Pichler, Hatto Beyerle, Thomas Brandis, Jon Thorne, Garfield Jackson, and Martin Outram, and they have participated in masterclasses by the Skampa, Wihan and Chilingirian Quartets, Miguel da Silva and Sylvia Rosenberg. The group began their studies with Rainer Schmidt at the Musikhochschule Basel in October 2014, and this year are privileged to have the guidance of the Belcea Quartet, thanks to the support of the Belcea Charitable Trust.
The quartet has performed widely throughout the UK; in venues such as the Wigmore Hall and the Purcell Room, and their continental tours have included a performance in the presence of the former Czech president Vaclav Havel. They also enjoy a variety of outreach work as part of the Live Music Now! scheme, and have participated in the Lake District Summer Music and St Magnus Festivals. More recently the group was selected to attend the McGill International String Quartet Academy in Montreal, Canada.