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Stage IV and Recurrent Melanoma
Treatment Options for Patients With Stage IV and Recurrent Melanoma
Treatment option overview for patients with stage IV and recurrent melanoma
Signal transduction inhibitors
Palliative local therapy
Other Treatment Options Under Clinical Evaluation for Patients With Stage IV and Recurrent Melanoma
Current Clinical Trials
Stage IV melanoma is defined by the American Joint Committee on Cancer's TNM classification system:[1]
- Any T, any N, M1
- Immunotherapy.
- Signal transduction inhibitors.
- BRAF (V-raf murine sarcoma viral oncogene homolog B1) inhibitors (for patients who test positive for the BRAF V600 mutation).
- MEK inhibitors.
- Multikinase inhibitors.
- KIT inhibitors.
- Chemotherapy.
- Palliative local therapy.
- Clinical trials should be strongly considered because of the rapid advances in the development of novel agents and combinations of agents designed to reverse or interrupt aberrant molecular pathways that support tumor growth.
Although melanoma that has spread to distant sites is rarely curable, two approaches have demonstrated clinical benefit by prolonging overall survival (OS) in randomized trials: immunotherapy (e.g., ipilimumab) and inhibition of the mitogen-activated protein (MAP) kinase pathway (e.g., with vemurafenib in patients whose tumors have a V600 mutation in the BRAF gene). Both ipilimumab and vemurafenib were approved by the U.S. Food and Drug Administration (FDA) in 2011. Although neither appears to be curative when used as a single agent, clinical trials are currently testing combinations of these and similar agents to prevent the development of resistance. Ipilimumab and vemurafenib are available to newly diagnosed and previously treated patients.
IL-2 was approved by the FDA in 1998 on the basis of durable complete response (CR) rates in a minority of patients (0%–8%) with previously treated metastatic melanoma in eight phase I and II studies. No improvement in OS has been demonstrated in randomized trials.
Dacarbazine (DTIC) was approved in 1970 based on overall response rates. Phase III trials indicate an overall response rate of 10% to 20% with rare CRs observed. An impact on OS has not been demonstrated in randomized trials.[2-6] Temozolomide, an oral alkylating agent, appeared to be similar to DTIC (intravenous administration) in a randomized phase with a primary endpoint of OS; however, the trial was designed for superiority, and the sample size was inadequate to prove equivalency.[3]
Attempts to develop combination regimens that incorporate chemotherapy, for example, multiagent chemotherapy;[7,8] combinations of chemotherapy and tamoxifen;[9-11] and combinations of chemotherapy and immunotherapy [7,12-17] have not demonstrated an improvement of the combination on OS.
In smaller subsets of melanoma, activating mutations may occur in NRAS [neuroblastoma RAS viral (v-ras) oncogene homolog] (15%–20%), c-KIT (28%–39% of melanomas arising in chronically sun-damaged skin, or acral and mucosal melanomas), and CDK4 (cyclin-dependent kinase 4) (<5%), whereas GNAQ is frequently mutated in uveal melanomas. Drugs developed to target the pathways activated by these mutations are currently in clinical trials.
Malignant melanoma has been reported to spontaneously regress; however, the incidence of spontaneous complete regressions is less than 1%.[18]Immunotherapy
Checkpoint inhibitors
Anti-CTLA-4: ipilimumab
Ipilimumab is a human monoclonal antibody that blocks the activity of CTLA-4, blocking the function of CTLA-4 as a down regulator of T-cell activation. It is approved for the treatment of unresectable or metastatic melanoma and supported by two prospective, randomized, international trials, one each in previously untreated and treated patients.[6,19]
Previously treated patients. A total of 676 patients with previously treated, unresectable stage III or stage IV disease, who were HLA-A*0201-positive patients, were entered into a three-arm, multinational, randomized, double-blind trial comparing ipilimumab with or without glycoprotein 100 (gp100) peptide vaccine to the gp100 vaccine plus placebo.[19] Patients were stratified by baseline metastases and prior receipt or nonreceipt of IL-2 therapy. Of the patients, 82 had metastases to the brain at baseline. The median OS was 10 months and 10.1 months among patients receiving ipilimumab alone or with the gp100 vaccine, respectively, versus 6.4 months for patients receiving the vaccine alone (hazard ratio [HR], 0.68; P < .001; HR, 0.66; P < .003).
An analysis at 1 year showed that among those patients treated with ipilimumab, 44% and 45% of them were alive compared with 25% of the patients who received vaccine only. Grade 3 to grade 4 immune-related adverse events (AEs) occurred in 10% to 15% of patients treated with ipilimumab. These immune-related AEs most often included diarrhea or colitis, and endocrine-related events (i.e., inflammation of the pituitary) that required cessation of therapy and institution of anti-inflammatory agents, such as corticosteroids or in four cases, infliximab (i.e., an anti-tumor necrosis factor-alpha antibody). There were 14 deaths related to study drugs (2.1%), and seven were associated with immune-related AEs.[19][Level of evidence: 1iA]
Previously untreated patients. A multicenter, international trial randomly assigned 502 patients untreated for metastatic disease (adjuvant treatment was allowed) in a 1:1 ratio to ipilimumab (10 mg/kg) plus dacarbazine (850 mg/m2) or placebo plus dacarbazine (850 mg/m2) at weeks 1, 4, 7, and 10 followed by dacarbazine alone every 3 weeks through week 22.[6] Patients with stable disease or an objective response and no dose-limiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary endpoint was survival.
Patients were stratified according to Eastern Cooperative Oncology Group (ECOG) performance status (PS) and metastatic stage. Approximately 70% of the patients had an ECOG PS of 0, and the remainder of the patients had an ECOG PS of 1. Approximately 55% of the patients had stage M1c disease. The median OS was 11.2 months (95% confidence interval [CI], 9.4–13.6) versus 9.1 months (95% CI, 7.8–10.5). Estimated survival rates in the two groups respectively were 47.3% and 36.3% at 1 year; 28.5% and 17.9% at 2 years; and 20.9% and 12.2% at 3 years (HR for death with ipilimumab-dacarbazine, 0.72; P < .001). The most common study-drug–related AEs were those classified as immune related. Grade 3 to 4, immune-related AEs were seen in 38.1% of patients treated with ipilimumab plus dacarbazine versus 4.4% in patients treated with placebo plus dacarbazine, the most common being hepatitis and enterocolitis. No drug-related deaths occurred.[6][Level of evidence: 1iA]
Clinicians and patients should be aware that immune-mediated adverse reactions may be severe and fatal. Early identification and treatment, including potential administration of systemic glucocorticoids or other immunosuppressants according to the immune-mediated–adverse reaction management guide provided by the manufacturer, is necessary.[20]Anti-PD-1 and PD-L1
Anti-PD-1 and PD-L1 are immune checkpoint inhibitors; however, they inhibit different targets than ipilimumab. Promising early data have supported testing anti-PD-1 against DTIC in a phase III trial (NCT01721772).[21]IL-2
Response to high-dose IL-2 regimens generally ranges from 10% to 20%.[12,13,22] Approximately 4% to 6% of patients may obtain a durable complete remission and be long-term survivors; these results were the basis for approval by the FDA in 1998. Phase III confirmatory trials have not been conducted, and there are currently no predictive biomarkers to select who is likely to respond to treatment.
Attempts to improve on this therapy have included the addition of lymphokine-activated killer cells (i.e., autologous lymphocytes activated by IL-2 ex vivo) and tumor-infiltrating lymphocytes (TIL) (i.e., lymphocytes derived from tumor isolates cultured in the presence of IL-2). A single-institution trial reports that adoptive cell therapy (ACT) with lymphodepletion (using cyclophosphamide plus fludarabine with or without total-body irradiation) followed by autologous TIL transfer and high-dose IL-2 may improve durable response.[23][Level of evidence: 3iiiDiv] A multicenter, randomized trial of high-dose IL-2 with and without a peptide vaccine [gp100:209–217(210M)] in patients with locally advanced stage III or stage IV melanoma who were HLA*A0201-positive reported an increase in response rate with the combination.[24][Level of evidence:1iiDiv] Multicenter, phase III trials powered for an assessment on OS are needed for validation, because response rates are not known to be a surrogate for OS in melanoma.Signal transduction inhibitors
Studies to date indicate that both BRAF and MEK (mitogen-activated ERK-[extracellular signal-regulated kinase] activating kinase) inhibitors can significantly impact the natural history of melanoma, although as single agents, they do not appear to provide a cure.BRAF inhibitors
Vemurafenib is an orally available, small molecule, selective BRAF inhibitor that is approved by the FDA for patients with unresectable or metastatic melanoma that tests positive for the BRAF V600E mutation. Treatment with vemurafenib is discouraged in wild-type BRAF melanoma because data from preclinical models has demonstrated that BRAF inhibitors can enhance rather than downregulate the MAPK (mitogen-activated protein kinase) pathway in tumor cells with wild-type BRAF and upstream RAS mutations.[25-28]
Previously untreated patients. The approval of vemurafenib was supported by an international, multicenter trial (BRIM-3 [NCT01006980]) that screened 2,107 patients with previously untreated, stage IIIC or IV melanoma for the BRAF V600 mutation and identified 675 patients by the cobas® 4800 BRAF V600 Mutation Test.[5] Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m2 intravenously [ IV] every 3 weeks). Coprimary endpoints were rates of OS and PFS.[5][Levels of evidence: 1iiA and 1iiDiii]
At the planned interim analysis, the Data and Safety Monitoring Board determined that both the OS and PFS endpoints had met the prespecified criteria for statistical significance in favor of vemurafenib and recommended that patients in the dacarbazine group be allowed to cross over to receive vemurafenib. A total of 675 patients were evaluated for OS; although the median survival had not yet been reached for vemurafenib and the data were immature for reliable Kaplan-Meier estimates of survival curves, the OS in the vemurafenib arm was clearly superior to that in the dacarbazine arm. The HR for death in the vemurafenib group was 0.37 (95% CI, 0.26–0.55; P < .001). The survival benefit in the vemurafenib group was observed in each prespecified subgroup; for example, age, sex, ECOG PS, tumor-stage lactic dehydrogenase, and geographic region. The HR for tumor progression in the vemurafenib arm was 0.26 (95% CI, 0.20–0.33; P < .001). The estimated median PFS was 5.3 months versus 1.6 months in the vemurafenib and dacarbazine arms, respectively.
Twenty patients had non-V600E mutations: 19 with V600K and 1 with V600D. Four patients with a BRAF V600K mutation had a response to vemurafenib.
AEs required dose modification or interruption in 38% of patients receiving vemurafenib and 16% of those receiving dacarbazine. The most common AEs with vemurafenib were cutaneous events, arthralgia, and fatigue. Cutaneous squamous cell carcinoma (SCC), keratoacanthoma, or both, developed in 18% of patients and were treated by simple excision. The most common AEs with dacarbazine were fatigue, nausea, vomiting, and neutropenia.
Previously treated patients. A total of 132 patients with a BRAF V600E or BRAF V600K mutation were enrolled in a multicenter phase II trial of vemurafenib, which was administered as 960 mg orally twice daily.[29] Of the enrolled patients, 61% percent had stage M1c disease, and 49% had an elevated lactate dehydrogenase level. All patients had received one or more prior therapies for advanced disease. Median follow-up was 12.9 months. An Independent Review Committee (IRC) reported a 53% response rate (95% CI, 44–62) with eight patients (6%) achieving CR. Median duration of response per IRC assessment was 6.7 months (95% CI, 5.6–8.6). Most responses were evident at the first radiologic assessment at 6 weeks; however, some patients did not respond until they received therapy for more than 6 months.[29][Level of evidence: 3iiiDiv]Dabrafenib
Dabrafenib is an orally available, small molecule, selective BRAF inhibitor that has been compared with DTIC in an international, multicenter trial (BREAK-3 [NCT01227889]). A total of 250 patients with unresectable stage III or IV melanoma and BRAF V600E mutations were randomly assigned in a 3:1 ratio (dabrafenib 150 mg orally twice a day or DTIC 1000 mg/m2 IV every 3 weeks). IL-2 was allowed as prior treatment for advanced disease. The primary endpoint was PFS; patients could cross over at the time of progressive disease after confirmation by a blinded IRC.[30]
With 126 events, the HR for PFS was 0.30 (95% CI, 0.18–0.51; P < .0001). The estimated median PFS was 5.1 months versus 2.7 months for dabrafenib and DTIC, respectively. OS data are limited by the median duration of follow up and crossover. Partial response was 47% versus 5%, and CR was 3% versus 2% in patients receiving dabrafenib versus DTIC, respectively.[30][Level of Evidence: 1iiDiii]
The most frequent AEs in patients treated with dabrafenib were cutaneous (i.e., hyperkeratosis, papillomas, palmar-plantar erythrodysesthesia), pyrexia, fatigue, headache, and arthralgia. Cutaneous SCC or keratoacanthoma occurred in twelve patients, basal cell carcinoma occurred in four patients, mycosis fungoides occurred in one patient, and new melanoma occurred in two patients.[30]MEK inhibitors
Trametinib is an orally available, small molecule, selective inhibitor of MEK1 and MEK2. Preclinical data suggest that MEK inhibitors can restrain growth and induce cell death of some BRAF-mutated human melanoma tumors. BRAF activates MEK1 and MEK2 proteins, which, in turn, activate MAP kinases.
A total of 1,022 patients were screened for BRAF mutations, resulting in 322 eligible patients (281 with V600E, 40 with V600K and 1 with both mutations).[31] Patients were randomly assigned in a 2:1 ratio to receive trametinib (2 mg once daily) or IV chemotherapy (either DTIC 1000 mg/m2 every 3 weeks or paclitaxel 175 mg/m2 every 3 weeks). Crossover was allowed, and the primary endpoint was PFS. The investigator-assessed PFS was 4.8 months in patients receiving trametinib versus 1.5 months in the chemotherapy group (HR for PFS or death, 0.45; 95% CI, 0.33–0.63; P < .001). Median OS has not yet been reached.
AEs leading to dose interruptions occurred in 35% of patients in the trametinib group and 22% of those in the chemotherapy group. AEs leading to dose reductions occurred in 27% of patients receiving trametinib and 10% of those receiving chemotherapy. The most common AEs included rash, diarrhea, nausea, vomiting, fatigue, peripheral edema, alopecia, hypertension, and constipation. Central serous retinopathy and retinal-vein occlusion are uncommon, but serious, AEs associated with trametinib. On-study cutaneous SCCs were not observed.Combinatorial therapy with signal transduction inhibitors
Resistance to BRAF inhibitors, in patients with BRAF V600 mutations, may be associated with reactivation of the MAP kinase pathway. Early phase II data with combinations of BRAF and MEK inhibitors have supported testing this combination in phase III trials, such as NCT01584648, NCT01597908, and NCT01689519.[32] Combination therapy to address other mechanisms of resistance (e.g., via activation of the PI3K/Akt pathway) are in early-phase trials.Multikinase inhibitors
The multikinase inhibitor sorafenib has activity against both the vascular endothelial growth-factor signaling and the Raf/MEK/ERK pathway at the level of RAF kinase. This agent had minimal activity as a single agent in melanoma and two large, multicenter, placebo-controlled, randomized trials of carboplatin and taxol plus or minus sorafenib showed no improvement over chemotherapy alone as either first-line treatment or second-line treatment.[33,34]KIT inhibitors
Early data suggest that mucosal or acral melanomas with activating mutations or amplifications in c-KIT may be sensitive to a variety of c-KIT inhibitors.[35-37] Phase II and phase III trials are available for patients with unresectable stage III or stage IV melanoma harboring the c-KIT mutation.Chemotherapy
The objective response rate to DTIC and the nitrosoureas, carmustine and lomustine, is approximately 10% to 20%.[2,38-40] Responses are usually short-lived, ranging from 3 to 6 months, though long-term remissions can occur in a limited number of patients who attain a CR.[38,40] A randomized trial compared IV DTIC with temozolomide (TMZ), an oral agent that hydrolyzes to the same active moiety as DTIC; OS was 6.4 months versus 7.7 months, respectively (HR, 1.18; 95% CI, 0.92–1.52). While these data suggested similarity between DTIC and TMZ, no benefit in survival has been demonstrated for either DTIC or TMZ and therefore, demonstration of similarity did not result in approval from the FDA.[3][Level of evidence: 1iiA] An extended schedule and escalated dose of TMZ was compared with DTIC in a multicenter trial (NCT00091572) that randomly assigned 859 patients. No improvement was seen in OS or PFS for the TMZ group, and this dose and schedule resulted in more toxicity than standard dose, single-agent DTIC.[41][Level of evidence: 1iiA]
The design of two recent randomized, phase III trials in previously untreated patients with metastatic melanoma included DTIC as the standard therapy arm. Vemurafenib (in BRAF V600 mutant melanoma) and ipilimumab showed superior OS compared with DTIC in the two separate trials.
Other agents with modest, single-agent activity include vinca alkaloids, platinum compounds, and taxanes.[38,39]Palliative local therapy
Melanoma metastatic to distant, lymph node-bearing areas may be palliated by regional lymphadenectomy. Isolated metastases to the lung, gastrointestinal tract, bone, or sometimes the brain, may be palliated by resection with occasional long-term survival.[15-17]
Although melanoma is a relatively radiation-resistant tumor, palliative radiation therapy may alleviate symptoms. Retrospective studies have shown that patients with multiple brain metastases, bone metastases, and spinal cord compression may achieve symptom relief and some shrinkage of the tumor with radiation therapy.[42,43] (Refer to the PDQ summary on Pain for more information.) The most effective dose-fractionation schedule for palliation of melanoma metastatic to the bone or spinal cord is unclear, but high-dose-per-fraction schedules are sometimes used to overcome tumor resistance. A phase I and II clinical trial (MCC-11543 [NCT00005615]) evaluated adjuvant radiation therapy plus interferon in patients with recurrent melanoma and results are pending.Biochemotherapy
A published data meta-analysis of 18 randomized trials (15 of which had survival information) that compared chemotherapy with biochemotherapy (i.e., the same chemotherapy plus interferon alone or with IL-2) demonstrated no impact on OS.[44][Level of evidence:1iiA]Other Treatment Options Under Clinical Evaluation for Patients With Stage IV and Recurrent Melanoma
- Immunotherapy, including anti-PD-1 and vaccines.
- Signal transduction inhibitors, including P13K (phosphoinositide-3 kinase) and Akt (protein kinase B inhibitors).
- Antiangiogenesis agents. Preclinical data suggest that increased vascular endothelial growth factor production may be implicated in resistance to BRAF inhibitors.[45]
- Intralesional injections; for example, oncologic viruses.
- Complete surgical resection of all known disease versus best medical therapy.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV melanoma and recurrent melanoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.References
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- Chapman PB, Einhorn LH, Meyers ML, et al.: Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 17 (9): 2745-51, 1999. [PUBMED Abstract]
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- Avril MF, Aamdal S, Grob JJ, et al.: Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol 22 (6): 1118-25, 2004. [PUBMED Abstract]
- Chapman PB, Hauschild A, Robert C, et al.: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364 (26): 2507-16, 2011. [PUBMED Abstract]
- Robert C, Thomas L, Bondarenko I, et al.: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364 (26): 2517-26, 2011. [PUBMED Abstract]
- Kirkwood JM, Strawderman MH, Ernstoff MS, et al.: Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 14 (1): 7-17, 1996. [PUBMED Abstract]
- Kirkwood JM, Ibrahim JG, Sondak VK, et al.: High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 18 (12): 2444-58, 2000. [PUBMED Abstract]
- Kirkwood JM, Ibrahim J, Lawson DH, et al.: High-dose interferon alfa-2b does not diminish antibody response to GM2 vaccination in patients with resected melanoma: results of the Multicenter Eastern Cooperative Oncology Group Phase II Trial E2696. J Clin Oncol 19 (5): 1430-6, 2001. [PUBMED Abstract]
- Hancock BW, Wheatley K, Harris S, et al.: Adjuvant interferon in high-risk melanoma: the AIM HIGH Study--United Kingdom Coordinating Committee on Cancer Research randomized study of adjuvant low-dose extended-duration interferon Alfa-2a in high-risk resected malignant melanoma. J Clin Oncol 22 (1): 53-61, 2004. [PUBMED Abstract]
- Koops HS, Vaglini M, Suciu S, et al.: Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593. J Clin Oncol 16 (9): 2906-12, 1998. [PUBMED Abstract]
- Atkins MB, Lotze MT, Dutcher JP, et al.: High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 17 (7): 2105-16, 1999. [PUBMED Abstract]
- Atkins MB, Kunkel L, Sznol M, et al.: High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am 6 (Suppl 1): S11-4, 2000. [PUBMED Abstract]
- Lee ML, Tomsu K, Von Eschen KB: Duration of survival for disseminated malignant melanoma: results of a meta-analysis. Melanoma Res 10 (1): 81-92, 2000. [PUBMED Abstract]
- Leo F, Cagini L, Rocmans P, et al.: Lung metastases from melanoma: when is surgical treatment warranted? Br J Cancer 83 (5): 569-72, 2000. [PUBMED Abstract]
- Ollila DW, Hsueh EC, Stern SL, et al.: Metastasectomy for recurrent stage IV melanoma. J Surg Oncol 71 (4): 209-13, 1999. [PUBMED Abstract]
- Gutman H, Hess KR, Kokotsakis JA, et al.: Surgery for abdominal metastases of cutaneous melanoma. World J Surg 25 (6): 750-8, 2001. [PUBMED Abstract]
- Wang TS, Lowe L, Smith JW 2nd, et al.: Complete spontaneous regression of pulmonary metastatic melanoma. Dermatol Surg 24 (8): 915-9, 1998. [PUBMED Abstract]
- Hodi FS, O'Day SJ, McDermott DF, et al.: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363 (8): 711-23, 2010. [PUBMED Abstract]
- Yervoy (Ipilimumab): Serious and Fatal Immune-Mediated Adverse Reactions [Medication Guide]. Princeton, NJ: Bristol-Myers Squibb, 2011. Available online. Last accessed November 23, 2012.
- Topalian SL, Hodi FS, Brahmer JR, et al.: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366 (26): 2443-54, 2012. [PUBMED Abstract]
- Rosenberg SA, Yang JC, Topalian SL, et al.: Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA 271 (12): 907-13, 1994 Mar 23-30. [PUBMED Abstract]
- Dudley ME, Yang JC, Sherry R, et al.: Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol 26 (32): 5233-9, 2008. [PUBMED Abstract]
- Schwartzentruber DJ, Lawson DH, Richards JM, et al.: gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med 364 (22): 2119-27, 2011. [PUBMED Abstract]
- Heidorn SJ, Milagre C, Whittaker S, et al.: Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 140 (2): 209-21, 2010. [PUBMED Abstract]
- Hatzivassiliou G, Song K, Yen I, et al.: RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 464 (7287): 431-5, 2010. [PUBMED Abstract]
- Poulikakos PI, Zhang C, Bollag G, et al.: RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 464 (7287): 427-30, 2010. [PUBMED Abstract]
- Su F, Viros A, Milagre C, et al.: RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 366 (3): 207-15, 2012. [PUBMED Abstract]
- Sosman JA, Kim KB, Schuchter L, et al.: Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 366 (8): 707-14, 2012. [PUBMED Abstract]
- Hauschild A, Grob JJ, Demidov LV, et al.: Phase III, randomized, open-label, multicenter trial (BREAK-3) comparing the BRAF kinase inhibitor dabrafenib (GSK2118436) with dacarbazine in patients with BRAFV600E-mutated melanoma. [Abstract] J Clin Oncol 30 (Suppl 15): A-LBA8500, 2012.
- Flaherty KT, Robert C, Hersey P, et al.: Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 367 (2): 107-14, 2012. [PUBMED Abstract]
- Flaherty KT, Infante JR, Daud A, et al.: Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 367 (18): 1694-703, 2012. [PUBMED Abstract]
- Hauschild A, Grob JJ, Demidov LV, et al.: Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 380 (9839): 358-65, 2012. [PUBMED Abstract]
- Flaherty KT, Lee SJ, Zhao F, et al.: Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma. J Clin Oncol 31 (3): 373-9, 2013. [PUBMED Abstract]
- Hodi FS, Friedlander P, Corless CL, et al.: Major response to imatinib mesylate in KIT-mutated melanoma. J Clin Oncol 26 (12): 2046-51, 2008. [PUBMED Abstract]
- Guo J, Si L, Kong Y, et al.: Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol 29 (21): 2904-9, 2011. [PUBMED Abstract]
- Carvajal RD, Antonescu CR, Wolchok JD, et al.: KIT as a therapeutic target in metastatic melanoma. JAMA 305 (22): 2327-34, 2011. [PUBMED Abstract]
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- Patel PM, Suciu S, Mortier L, et al.: Extended schedule, escalated dose temozolomide versus dacarbazine in stage IV melanoma: final results of a randomised phase III study (EORTC 18032). Eur J Cancer 47 (10): 1476-83, 2011. [PUBMED Abstract]
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- Martin MJ, Hayward R, Viros A, et al.: Metformin accelerates the growth of BRAF V600E-driven melanoma by upregulating VEGF-A. Cancer Discov 2 (4): 344-55, 2012. [PUBMED Abstract]


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Kidney Cancer (Adult) Renal Cell Carcinoma Overview
Talking With Your Doctor TOPICS
What are some questions I can ask my doctor about kidney cancer?
As you cope with cancer and cancer treatment, we encourage you to have honest, open talks with your doctor. Feel free to ask any question that's on your mind, no matter how small it might seem. Here are some questions you might want to ask. Be sure to add your own questions as you think of them. Nurses, social workers, and other members of the treatment team may also be able to answer many of your questions.
- Would you please write down the exact kind of kidney cancer I have?
- Do you think my cancer spread?
- What is the stage of my cancer, and what does that mean in my case?
- What treatment choices do I have?
- What do you recommend and why?
- What is the goal of this treatment?
- What are the chances of the cancer coming back with the treatment you recommend?
- What are the risks or side effects of treatment?
- Based on what you've learned about my cancer, what is my long-term outlook?
- What should I do to be ready for treatment?
- How soon should I be treated?
- What kind of follow-up will I need after treatment?
- Are there any clinical trials I should think about?
Add your own questions below:
Last Medical Review: 11/27/2012
Last Revised: 04/01/2014


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Ensure Duty-of-Care for Workers Traveling, Living AbroadAs terror threats, diseases, natural disasters and other dangers mount, employers must establish detailed plans for ensuring traveling employees' well-being.Protect Against Winter Weather Hazards, Storm ThreatsWinter doesn't officially begin until Dec. 21, but employers and workers need to prepare for and protect themselves against cold-weather hazards now—before the freezing temperatures and blizzards arrive.Navy Yard Shooting: Resources to Help HR Deal with Violence at WorkThe active shooter situation at the Washington Navy Yard in Washington, D.C., reminds us once again of the problem of violence in the workplace. These SHRM resources can assist employers prevent and mitigate the risks of workplace violence.
Protecting Your Workplace in the Wake of the Navy Yard ShootingWhat can employers do to prevent people with valid access to their worksites from doing harm?Are You Prepared to Evacuate Your Workers with Disabilities?Although employers are not required to have emergency evacuation plans under the Americans with Disabilities Act, if employers covered by the ADA opt to have such plans they are required to include people with disabilities
Managing Through Emergency and DisasterWhether a natural disaster, such as the deadly floods in Colorado, or a manmade disaster, such as the shooting at the Navy Yard, it is critical that organizations have plans in place to manage operations during such times with minimal losses and disruptions in normal business flow.SHRM's Disaster Recovery ResourcesOSHA Tornado Recovery Guidelines
Keep Your Employees Safe During Disaster Cleanup
Business Continuity & Recovery After Disaster
Extreme Weather Blows Ill Wind for Small BusinessesSHRM Chapters, Members Quickly Moved to Tornado RecoveryEmergency Plans, Survival Instincts Kick In During Okla. TornadoHR Issues
Employee Leave Eligibility and Natural Disasters
When Workplace Emergencies Raise Wage and Hour Issues
When Disaster Strikes: Pay, Leave and Related Issues
Employee Assistance Programs
Crowdfunding Among Ways Employers Can Help After Disasters
Managing Employee Assistance Programs
Requiring the Use of an EAP
Terrorism in the Workplace
How Employers Can Aid Victims After Disasters
Workplace Violence
Violence in the Workplace
Securing Against Random Workplace Violence
Domestic Violence at Work
ASIS/SHRM Workplace Violence Prevention and Intervention Standard
First Aid
AEDs in the Workplace
Good Samaritan Laws in EmergenciesPreventing Workplace Fire CasualtiesSafety Guides Targeted to Small BusinessesSmall Businesses Lack Proper Safety Preparation
Crisis Management in Today's Business Environment: HR's Strategic RoleThis SHRM research paper discusses HR's strategic role in dealing with unexpected crises.
Planning for DisasterThis article describes a systematic plan for approaching emergencies, and preparations to keep employees safe and minimize disruptions to operations.
Time to Prepare for Hurricane SeasonWith hurricane season officially starting June 1, 2013, now is the time to make important decisions to help keep your family, business and property safe. GOVERNMENT RESOURCES
Redcross.org Get suggestions for a Personal Workplace Disaster Supplies Kit here.
FEMA.govLearn about federal, state and local resources to prepare for, prevent or recover from disasters.
CDC.govThe Centers for Disease Control offers resources on emergency response to natural disasters and severe weather.
Weather.govStay up-to-date on the latest weather news.
Create, evaluate and test your disaster prep plan with these resources:
When Disasters Strike: Pay, Leave and Related IssuesWhen business is suspended or employees can't get to work, numerous employment laws are implicated including the Fair Labor Standards Act (FLSA) and the Family and Medical Leave Act (FMLA).
Pandemic ResponsePreparing for a pandemic at work.
Disaster Assistance.govDetails the kinds of assistance available and reduces the number of forms to file to receive assistance.State Offices and Agencies of Emergency ManagementDirect contact information for emergency management offices in your state.Tax Relief in Disaster Situations--IRS.govThe latest information on which localities can apply for tax relief following a disaster in their area.Redcross.org Has a "safe and well" list where employees can let family, supervisors and co-workers know where they are.
Flood RecoveryVisit this page for flood preparedness and response advice.Hurricane PreparednessVisit this page for hurricane preparedness and response advice.
Click here to view resources on employee leave, wage and hour issues, disaster recovery, more.


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Recent Comments
Aww, I want to be there when you hang out. That would be super fun times! Make sure there are photos.
Definitely hand it in! I'm sorry if you lost your money :(
I once found £20 on the supermarket floor, no idea who dropped it so I gave it to a member of staff and asked them to hand it to lost property/a manager. If she kept it, that's her choice - I did my part.
I also once found £5 in a bar and when I handed it to the security guy he looked at me like I was mad and said to keep it. I didn't want to benefit from it so I bought him a drink with it.
i'm basically a saint.
Also, easiest meal of all time that I love for a quick supper: slices of halloumi cooked on a griddle pan with salad and roasted vegetables.
Hot chillies - chilli peppers.
The Flavo(u)r Thesaurus is a great book for understanding how to combine ingredients rather than following a recipe.
Prawn linguine with chilli and cherry tomatoes (sort of via Jamie Oliver, but minus 90% of the olive oil) is A+ easy and tasty.
Cook the prawns in a little oil with a chopped chilli or two (depending how spicy you like things), some chopped basil stalks and some garlic. Cook the pasta as per packet instructions. Add chopped tomatoes (~500g) to prawns and smoosh them a bit. Stir in pasta once it is done, sprinkle with some chopped basil leaves. Eat.


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-noun: a person who has an unusual ability in the field of placing or leaving (a vehicle) in a certain place for a period of time for low cost and with the help of others.
- Refined Experience
- More Platforms
- More Incentives
- More Cities
- Richer Ecosystem
- Made by You
- Available Late 2011
ParkShark v1.7.0 for iPhone/iPad is Available Now!
ParkShark for iPad is Here!
Recent ParkShark features:
- San Francisco Street Cleaning Regulations
- More Parking Garages
- Parking rule street spans (NYC only)
- Twitter integration
AlThomson7 : If you're a driver and have a iphone this looks brilliant. .........iPhone app http://bit.ly/7JTiYK (View Tweet)
rboyd : awesome, it's like a secret society for parking http://bit.ly/8sgp09 (View Tweet)


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Photo by Karen Quincy Loberg, Ventura County Star
Eric Rogers, a wide receiver on the California Lutheran University football team, poses for a portrait at practice on Monday.
Buy this photo
Eric Rogers has always been a good listener. It's a trait that has served him well and guided him in the right direction. If he didn't listen to his first-grade teacher, Rogers may not have learned to set goals. If he didn't listen to his mother, Rogers may not have avoided the gang life that sidetracked some of his friends.
Feels Like: 64°
Humidity: 76%
Precip: 12%
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Humidity: 93%
Precip: 28%
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Precip: 7%
Deepening the coverage, widening the conversation about education.
Seating is limited at May 1 workshop. Register now to attend.
Your resource for Ventura County outdoor news and information.
Exploring the true cost of living in Ventura County.
Watch up to the minute changes in local weather with vcstar.com's new tech.
Learn more about the new academic standards.
Find places to explore, from solo adventures to family-friendly hikes.


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UK breakdown coverGet a quote
– buy online
Arrange cover over the phone
Call us on 0800 085 2721
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We can help – call us now
0800 88 77 66
There are 11 results - Show results on a map Print this page
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A friendly welcome waits at this hotel which occupies a prime position in the centre of the historic market town, and is a popular meeting place for the local community. Bedrooms are mostly well propo...More about The Golf Hotel


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These fellow med students turned fiancés knew exactly what they wanted when it came to their wedding: simple romance kissed by elegance every step of the way. And while Steve Steinhardt's gorgeous photos make feel oh so effortless, it was pretty-makers like The Wedding Company and ...
The Wedding Company
The Wedding Company offers wedding planning services to discerning couples planning luxury weddings in Hong Kong, China and the rest of Southeast Asia.Contact This Member
Social Mediatheweddingco.hk/blog
We had worked with the Bride in a professional capacity over 8 years ago and needless to say, we were flattered when she rang up one day asking us to organise her wedding in two short months time.
On the big day, after a hectic morning of games and Chinese Tea ceremony for the couple and their families, hundreds of friends and well wishers crowded into St...
Calling all Brides and Grooms to be! The Luxury Wedding Showcase 2014 is a 'must-do' for anyone planning a wedding in the next 12-18 months! Held at the InterContinental Hong Kong Ballroom this Sunday, March 9, (12 noon – 6:30 pm) and organized by yours truly, its your one-stop destination for wedding planning, with 35 of the city's top wedding specialists, from...
Kung Hei Fat Choy! We wish all of our clients past and present, their families and all of our dedicated vendors a very happy and prosperous year of the Horse!


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Albertsons Grocery Deals Week 4/16 – Save on Chicken, Strawberries, Triscuits, Sugar and More!
Albertsons frugal living Groceries
Albertsons Weekly Coupons Deals Week 4/16-4/22. You may only use one manufactures coupon per item. All coupon options are listed. Great resources to use: Northwest Coupon Database to see if you received the coupon Current Catalina List Meat DeptCure 81 Smoked Spiral Ham – Read More


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Master of the Met
General manager Joseph Volpe calls the shots at New York City's Metropolitan Opera.
Mervyn Rothstein
From the Print Edition:
Michael Douglas, May/Jun 98
(continued from page 5)
Whether or not he loves opera, he certainly loves cigars. He began smoking them about 10 years ago, he says, and there was an instant ardor. "One of our tenors, Frank Lopardo, came over to me after a performance," Volpe recalls. "He told me he was going to give me a cigar because it would be good for my hypertension. He said I would have to sit still for 45 minutes and try it. He gave me two Macanudos, and they were interesting. And of course what happens is that I'm a screwball, and when I do anything I get very serious about it, very passionate. So I started collecting cigars--Cuban cigars in particular. I guess it's a decent-sized collection. The thing is, I keep smoking them."
He also gives them away. Wolfgang Schmidt, a German tenor, is arriving in the next few days to sing Tannhauser. "Schmidt smokes cigars," Volpe says. "I want to give him a few to get things off to a good start."
Volpe's favorite cigars are Cohibas--"of course"--but he also loves the Hoyo de Monterrey Epicure No. 2. "It's a great cigar," he says. "I'll also smoke some torpedos, especially Bolivars. I'm not a big fan of the Montecristo No. 2. I've always liked the La Gloria Cubana Wavell. And I've just bought a box of Bauzá robustos. It's a good cigar." Among his other favorites are Cohiba Esplendidos, Hoyo de Monterrey Churchills and double coronas, and Romeo y Julietas.
He smokes three or four cigars a day. "I get up early in the morning, no matter what time I get to sleep," he says. "For example, when we opened Turandot with Luciano, there was a party afterward. So we rolled in at 2 or 2:30 a.m. But I was up at 7. I had a cup of coffee, I read the newspaper and I had a cigar. Then, depending on my schedule, I might have another cigar in the office before I go home. What I try to do is to go home at about 5 or 6 o'clock--I live just across the street from the opera house--and have another cigar. Then I'm back in the theater for the performance, and afterward I'll have another cigar. And every once in a while I'll throw in yet another for good measure."
Volpe's passion for cigars does not abate during performance hours. One of his guests for Turandot is George Vasquez of the well-known De La Concha tobacconist on Sixth Avenue in Manhattan, who shows up in Volpe's office after Act One with a gift: a Fuente Fuente OpusX and two Fuente Don Carlos robustos--"the best non-Cuban robustos," Volpe says. After Act Two, Volpe proudly removes a cigar-store catalogue from his desk drawer. It's from Mom's Cigars, on lower Fifth Avenue. "Look at this," he says. "A box of 25 Bauzá robustos for $100. They'll cost you $140 anywhere else. And I know they have them in stock. We get all the cigars we use for Carmen there."
As for the reasons he smokes cigars, they're simple: "It relaxes me," he says. "And I get great enjoyment from it. What's not relaxing, of course, is that there are many people who dislike cigars. When I smoke a cigar in my office, I had better keep my door closed, or else I hear from my staff. But the other side of it is that cigar smokers are very friendly with each other, so you have this relationship, this camaraderie that develops. Some of our donors, for example, smoke cigars. We have this group called the Golden Horseshoe. If you give $150,000 [within three years] to the Metropolitan Opera, you become a member of the Golden Horseshoe. Every year we have a dinner for them on the Grand Tier, and some members and I will start talking about cigars. They'll come over and say, 'Joe, try one of these.' And it will always be good."
Volpe met his wife, Jean, at the Met, where she was a dancer. They were married in 1989 and have a daughter, Anna, 6--"It's pronounced like Anna Magnani, the Italian actress," he says. He has seven other children from two previous marriages. His oldest is in his mid-30s--"Michael Joseph Volpe, a lawyer, named for my father."
He hopes to stay at the Met for many more years, he says. And what then? "I haven't come up with anything," he says. "Something in the performing arts? After the Met, probably not. But I've sometimes thought, given my expertise in labor relations, maybe something in sports, like football or baseball. And maybe something--I haven't thought this through, and I'll probably regret saying it--but if there was some position, given my love for this city.... I don't want to be a political creature, but if there was a way I could accomplish something in government, I wouldn't mind doing that."
But there is one thing, he says, of which he is sure. "I'll never retire," he says. "There's no such thing. Luciano says that if you retire for six months, you're dead. And even if I leave this kind of full-time position I'll always live in New York. I'm not going to live in the country and watch the grass grow. I want to be where the action is, and New York is where the action is." He smiles.
"I'm not going to go off and sit at the end of the dock with my fishing pole," he says. "I'd last about one good cigar." *
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Grant helps Norman County West upgrade technologyHalstad, MN (WDAY TV) - A small town school has gone Hi-Tech. Norman County West in Halstad got almost $200,000 in grant money to transform its school.
A small town school has gone Hi-Tech. Norman County West in Halstad got almost $200,000 in grant money to transform its school.
As Nathan McCraven teaches his 7th grade math class from this tiny hand held computer, never did he imagine he would be able to rid himself of traditional teaching supplies.
Nathan McCraven – Math Teacher: "When I came here four years ago all I had were my white boards, I didn't even have a smart board."
With the grant money the school was able to put a smart board in every classroom along with 60 new iPads. This new technology not only excites students about learning, but it helps them stay up to date so they are better prepared for the future.
Nathan McCraven: "When these kids are in the real work force they are going to be using technology like this every day."
The students can not only take a picture and show their work, they can also record their voice as they work through the problem.
Nathan McCraven: "Being one teacher I can only listen to one kid or help one kid at a time going through a problem, when they are talking into the iPad and recording their voice then I can go back and see exactly how every single kid was looking at the problem."
The school's curriculum coordinator Mary Niklaus helped push for the grant money. Niklaus saw the importance technology played in learning.
Mary Nicklaus – Curriculum Coordinator: "They can really apply themselves they can actually say that it is just not just what I find in a book, I can not only search the internet, I can Skype or face time with people across the whole United States."
Educators aren't the only ones excited about the new state of the art improvements. The ones benefiting most, may be the most excited.
Quinn Merkens – 7th Grade: "You get more attached to using the iPad so it is a lot funner and you learn while you're having fun."
Gracie Schilling – 7th Grade: "More better to use iPads because you have it right there, and he can come help you and he can just erase it if you mess up."
School officials hope to seek more grant money to incorporate more iPads.
Tags: k-12 education, danielle miller, news, halstad, minnesota, technology, reporters, updates


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So you extend your data and services as APIs to power features like social, personalization, analytics, more. But it's not just about having an API! What makes a great API that developers will be successful building against? What's the best architecture? How do you build clients that use APIs? How is making an API call different than request/response?
To win in the app economy, it is necessary to choose ROI criteria that drive smart decisions about digital investments. But according to an Apigee Institute survey of IT and Marketing executives, there is a wide gap between what corporate leaders believe are the best ROI metrics and what are actually used in most enterprises today. In this webcast, Bryan Kirschner and Sam Ramji took a deep dive into patterns and practices for digital ROI that drive more confident decision making and stronger results.
Analytics play a crucial role in ensuring the success of API programs. But analytics to glean insights and improve an API product don't happen by accident. Are you designing for analytics? We joined Brian Pagano & Kumar Srivastava of Apigee recently for a discussion of designing for analytics.
In June, we offered a 100% revamped version of our mobile app training for Objective-C (Native) development with XCode & Cocoa Touch. View the video recording, slides, and code from the live session here. For developers, who have always wanted to dive into native (non-HTML5) mobile apps but didn't know where to start, this webcast has everything you need to get started - Objective-C syntax and its quirks, iOS UI Design patterns, an API backend to store & retrieve your mobile app data, etc.
How do you keep app users engaged in the app economy? Only 12% of emails are opened, according to recent study by Mogreet, and social media channels are not too far behind, with only 15% of Facebook updates read. This webcast shows how Push Notifications can help you connect with the right people, avoid missed engagement opportunities, and establish deeper relationships with app users.
In this webcast, @timanglade demonstrated how to build a mobile app from scratch using HTML5, jQuery, Apigee and PhoneGap. The video, slides, and a link to the source code on github are posted here.
The app revolution has turned consumer expectations upside down in all areas of our lives, including in the cars we drive. Our connected cars are already filled with computing power and experiences influenced by consumer electronics. Forward-looking car makers have the pedal to the metal on further innovation. There's an undeniable conceptual shift from the connected car to the programmable car.


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This 5mm 4 1/2 inch reach truss rod tool is a must if you have a Martin guitar that adjusts thru the sound hole. It fits perfectly and with the soft grip handle it makes adjusting a truss rod a snap. Buy one you need this for your Martin guitar. Mine was for a DX1 model Martin.
The wrench I needed wasn't a complicated item, but it was an item I could not live without here in Wisconsin. It has been a harsh winter, causing heaters to run more than normal, causing problems with guitar necks. I have a Martin d45 that is my pride and joy. The neck has not warped in almost 17 years, it warped slightly, but enough that I had to correct it, so I looked in my StewMac catalog and found this wrench. it is easy to find anything you could ever want for guitars in there, it has become like a guitar survival book for me. The wrench was the perfect length, it fit easily through the hole, so there was no danger on scuffing the finish, that was very important to me! To order off the website, was the easiest, most user friendly site I have ever used. They gave me an estimated time of arrival at the confirmation of my purchase, and also offered tracking info on my order, and to my surprise the order was I think three days earlier than estimated. That was an important thing in these cold winter days, when you develop cabin fever. I also enjoy the repair tips they email me, I have learned valuable information that keeps my guitars in the optimal playing condition, improving my playing, and my enjoyment. THANK YOU STEWMAC
I had good luck with the 4-1/2" soundhole wrench. However, I was a little suspicious that the 5-3/4" would be too big, and I was right. The reach is too long to fit through the soundhole AND fit into the truss rod of my Ibanez OOO guitar. (#6212, 4mm, triple bend, wrench).
Going at your $4k fine instrument with something not quite right kept me up at night. Alternatively, I just didn't make the adjustment and hated playing my 000-042. Not any more. The right tool makes all the difference. This is it for Martins.
When I needed a truss rod tool for my 90s Martin 000C16-RGTE, Stew-Mac recommended exactly the right model. Works great!
When you need to adjust the truss rod on a newer Martin, this is the perfect size! Not a bad price either, when they make 4mm with a 4 1/2" reach i'll buy it in a heartbeat.
Arrived fast and in good condition. Works great and is comfortable to use.
Needed to tweak the truss rod on my Martin 00-18V, but no standard allen wrench was going to handle the task without serious compromise and risk of damage. A quick Google search and I found the perfect solution at Stewmac.com! This wrench is custom-fit and purposed for this job, and allowed me to make the adjustment and quickly eliminate the buzzing that had crept into my setup.
I know I can count on STEWMAC in the future for any specialty tool needs that should arise. Thanks!
Got the #6110 for a 2000 Martin. Perfect fit. Very high quality tool; an excellent value. Don't hesitate to get one.
The 6114 works perfect on my Martin 000-28EC. Great tool.
To add items to your order, select the check box next to the item you want. You can edit the quantity you wish to purchase here, or in Your Order.
To add items to your saved list, select the check boxes next to the items you want. You can edit the quantity you wish to save here, or in your Saved List.


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These boots can take some hard knocks and not miss a step. Milwaukee®'s Jackhammer Boots have a full lace front and a padded collar for comfort.
Their non-marking, non-skid, oil-resistant rubber outsoles give you sure footing on the job or around town. I cut a special deal that spells big savings!
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State Size, as available in the Shopping Cart below. Medium width. Order ONLINE Today!
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Men's Milwaukee® Jackhammer Boots, Black
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Press Room
No results
February 6, 2014
uTest Announces Winners of 5th Annual "2013 uTester of the Year" Awards
January 31, 2014
readwrite: Applause Analytics shows that Android reviewers were much more active than iOS reviewers—and they liked their apps more, too.
January 23, 2014
crowdsourcing.org: uTest's Plans Following its $43M Funding Round
January 22, 2014
Forbes: America's Most Promising Companies: The Top 25 Of 2014
January 22, 2014
Forbes: Goldman Sachs Bets Millions on uTest
January 22, 2014
Forbes: 20 Amazing Companies Founded During the Financial Crisis
January 22, 2014
Forbes: uTest #7 on Forbes' 2014 list of America's Most Promising Companies
January 22, 2014
Boston.com: uTest leads 7 Massachusetts businesses on Forbes list of most promising companies
January 22, 2014
uTest Named 7th Most Promising Company in America by Forbes Magazine
January 22, 2014
CNBC: Cornering the App Testing Market and Focusing on App Quality
January 14, 2014
Xconomy: UTest Adds $43M for App Testing, Gets Ready for Future as Applause
January 14, 2014
Forbes: App Tracker uTest Raises $43M From Goldman Sachs For Future Acquisitions And IPO
January 14, 2014
Wall Street Journal: Applause Raises $43M to Test Apps, Hardware 'In the Wild'
January 14, 2014
Re/code: uTest Raises $43 Million for Crowdsourced Testing
January 14, 2014
TechCrunch: Utest, Now Called Applause, Secures $43M Series E Round Led By Goldman Sachs, To Roll Up App Testing Market
January 14, 2014
VentureBeat: Utest gets $43M to test your apps in the real world
January 14, 2014
Geektime: uTest raises $43M and changes name to Applause
January 14, 2014
VentureFizz: uTest/ Applause Announces a $43M Series E
January 14, 2014
uTest Closes $43 Million Series E Round Led by Goldman Sachs
December 11, 2013
uTest Announces Launch of uTest University
December 4, 2013
uTest Adds Chief Financial Officer To Executive Team
November 22, 2013
Forbes: Essential Apps for Black Friday And Cyber Monday Shopping Deals
November 21, 2013
uTest Partners with BlazeMeter to Provide Full-Service Load Testing Solutions for Web & Mobile Apps
November 17, 2013
Business Insider: The 17 Hottest Enterprise Mobile Startups Right Now
November 05, 2013
Forbes: Targeting Bigger Market, uTest To Change Name To Applause Along With Strategy
September 18, 2013
LA Times: Apple iOS 7 could be a bigger change than iPhone 5s and 5c
September 17, 2013
uTest Honored with Gold and Silver Stevie® Awards at 2013 American Business AwardsSM
September 17, 2013
Internet Retailer: Will Apple's new iOS 7 wreak havoc with mobile apps?
September 13, 2013
uTest Wins Mass Technology Leadership Council's Award for Private Company of the Year
September 11, 2013
VentureBeat: Developer wake-up call: Shift from iOS 6 to iOS 7 is 'biggest since the original iPhone'
August 21, 2013
Harvard Business Review: Setting Up a Crowdsourcing Effort? Read This First.
August 20, 2013
uTest Celebrates 5th Birthday with Second Straight Appearance on Inc. 500 List
August 19, 2013
The Boston Globe: Inside uTest, which puts apps in the hands of testers around the world
We've written a lot about uTest the past year, but now you can take an inside look yourself...
June 10, 2013
Huffington Post: Six Tools to Market Your New Mobile App
June 3, 2013
USA TODAY: How to find the best travel apps (and avoid the worst)
The top travel apps according to Applause.
May 16, 2013
Gartner Names Applause as a "Cool Vendor" in Mobile Marketing, 2013
May 2, 2013
NBC Press Here: Don't Fight in the iOS Playground
April 25, 2013
uTest Named #1 on the Boston Business Journal's 2013 Pacesetters
April 16, 2013
TIME: Who's Winning, iOS or Android? All the Numbers, All in One Place
April 10, 2013
Bloomberg TV: Software 'Appification' Is Next Frontier
March 13, 2013
Mashable: SXSWi 2013: A Great Show About Nothing
February 6, 2013
uTest Named 8th Most Promising Company in America by Forbes Magazine
January 31, 2013
Forbes: uTest's Mobile App Genome Project
January 30, 2013
The Boston Globe: Want to know how your app is doing? Just listen to uTest's Applause
January 30, 2013
ReadWrite: New Analytics Service Applause Ranks App Quality
uTest has accomplished the seemingly impossible: It can now quantify the quality of the apps for iOS and Android.
January 30, 2013
TechCrunch: uTest Launches Applause, An iOS And Android Mobile App Analytics Dashboard
January 30, 2013
uTest Labs Debuts to Develop Solutions to the App Quality Challenges Posed By the Apps Economy
October 23, 2012
Forbes: uTest's 60,000 Testers Debug Your Software
August 21, 2012
Inc 500: uTest Named America's 16th Fastest Growing Private Company on 2012 Inc. 500 List
August 21, 2012
uTest Named America's 16th Fastest Growing Private Company on 2012 Inc. 500 List
August 17, 2012
ZDNet: uTest snaps up Poland's Apphance in seven-figure mobile apps deal
US testing company uTest has acquired Polish mobile app testing tools provider Apphance in a deal that's thought to be the biggest of its kind in the country.
August 16, 2012
Bloomberg TV: How to test a new mobile app
Bloomberg Television's Deirdre Bolton interviews uTest CEO Doron Reuveni live on "Money Moves" about the company's acquisition of Apphance, it's rapid growth and the current state of the mobile app market.
August 15, 2012
TechCrunch: uTest Acquires Apphance In 7-Figure Deal As Mobile Developer Tools Consolidate
August 15, 2012
Boston Business Journal: uTest makes 1st acquisition, approaches $40M run rate
August 15, 2012
uTest Acquires Mobile App Tool Company, Apphance, in Seven-Figure Deal
July 30, 2012
Metrowest Daily News: Southborough's uTest makes sure apps work 'in the wild'
June 7, 2012
Wireless Week: uTest, provider of in-the-wild software testing, announces partnership with Appcelerator
May 14, 2012
Telecom Lead: Amdocs inks reseller agreement with uTest
May 7, 2012
TechCrunch: AppGrader Scores Mobile Apps, Helps Developers Squash Bugs
May 3, 2012
uTest Announces AppGrader for Android to Benchmark App Performance
February 27, 2012
uTest Expands Its Footprint in EMEA by Partnering with Tesnet As A Reseller
February 7, 2012
The Street: Angry Birds Crashing? There's a Test for That
January 23, 2012
WIRED: Expertsourcing (Or, How to Test a Product Without Losing It in a Bar)
December 5, 2011
Fortune: Venture capital deals: uTest Closes $17 Million Series D
December 5, 2011
uTest Closes $17 Million Series D Financing Led by QuestMark Partners
August 15, 2011
uTest Expands into Localization & Security Testing, Creates the First End-to-End Suite of Crowdsourced Software Testing Services
June 21, 2011
uTest Wins "Most Innovative Small Company of 2011" at the American Business Awards
May 4, 2011
uTest A Back-To-Back Winner Of Boston Business Journal's Best Places To Work
March 21, 2011


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|Amount in $M
Long-term development assistance
Malawi is a small land-locked country of approximately 15 million people in Southern Africa. It is one of the world's poorest countries, and ranks 170 out of 187 countries on the United Nations Development Programme's 2012 human development index. Three out of four Malawians live on less than US$1.25/day. Almost half of the population— 46 percent—is under 15 years old.
Most Malawians are subsistence farmers, with women producing 75 percent of the nation's food supply. Agricultural productivity in Malawi is low. In 2010, maternal mortality stood at 675 per 100,000 births and 47 percent of under-five children suffered from stunting.
Although the country experienced high economic growth between 2004 and 2010, it remains vulnerable to external economic shocks such as reduced global demand for its primary exports—tobacco, tea and sugar.
Progress toward the Millennium Development Goals in Malawi is uneven. The country has exceeded its water and sanitation targets and has made significant strides in strengthening food security nationally. It is on track to achieving the targets for reducing infant and child mortality and combatting HIV/AIDS.
Challenges remain, however, in achieving the goals for poverty reduction, maternal health, universal primary education and gender equality. Only 55 percent of children who enter Grade 1 actually complete the full eight years of primary school. Some 22 percent of primary school-aged girls do not attend school, while 60 percent of those enrolled do not attend regularly.
Canada's international development program in Malawi is closely aligned with the goals of the Government of Malawi's Growth and Development strategy II for 2011-2016. Its main objectives are to reduce poverty and achieve the Millennium Development Goals.
The goal of Canada's international development program in Malawi is to help the country secure a future for children and youth by reducing the primary school dropout rate and improving the nutritional status of young children and pregnant/nursing women.
Canada supports efforts to improve the quality of basic education to reduce dropout rates. With support from Canada to the Malawi's Ministry of Education is strengthening primary school teacher training and ensuring that new teachers have the skills to help girls stay in school. Canada is also supporting efforts to help increase the Ministry of Education's capacity to manage and monitor the national education sector plan, including strengthening government systems that handle the purchase of education materials such as textbooks.
Canada also provides support to reduce malnutrition in young children and pregnant/nursing women. Canada continues to help Malawi train health workers and educate parents and community leaders about appropriate feeding practices. Canada supports the Government of Malawi's community-based therapeutic care program, which treats acute malnutrition of children and mothers at the community level. This outreach includes support to provide locally produced ready-to-use therapeutic foods to those suffering from malnutrition.
Malawi adheres to the Paris Declaration on Aid Effectiveness (PDF, 317 KB, 23 pages). Donor harmonization and alignment is steadily improving. The Government of Malawi encourages all donors to work with its priorities and monitors aid flows. Program-based approaches are used in the health, HIV/AIDS, education, and water sectors.
Canada participates in the annual Joint Education Sector Review process and also participates in donor-government working groups related to education and nutrition.
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Away from Home: Orcas IslandOrcas Island, Puget Sound, Wash.
What: Orcas Island, Puget Sound, Wash.
When: September 2012
Distance from Fargo: 1,224 miles
Comments: This photo was taken on Orcas Island, part of the San Juan Islands in the Puget Sound. We were on our one-year anniversary vacation.
Angella and Brandon Popinga, Fargo
Send us your snapshots: This is a regular feature that runs in The Forum's Travel section, where readers give us a taste of their vacation.
Send us your best vacation photographs from this year's trip, and we'll publish the best shots.
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Brian Lease is like most other graziers in that he depends on a hefty charge to maintain the electric fences that outline his paddocks. But he also finds that springtime in Missouri is a great time to charge up the paddocks themselves by no-tilling in some legumes.
New data from West Texas adds to the proof higher stock densities can improve soil and forage health.
Plant an annual forage crop in your grazing rotation this summer to help delay feeding hay this fall and to save money.
The science about grazing just keeps getting better.
Fred Greer says it is cheaper and easier to use Max-Q fescue instead of winter wheat for protein supplement on his northern Georgia ranch.
Water deserves a lot more respect when it comes to laying out grazing systems.
Some Nebraska Panhandle ranchers now raise more grass, cattle and wildlife by taking part in the Environmental Quality Incentives Program. EQIP is a voluntary conservation program available from the USDA Natural Resources Conservation Service to private landowners and operators.
Paul Brown is a young man who could be making big bucks in North Dakota's oil fields. But he figures he's making more per hour mob-grazing yearling beef cattle on his family's Bismarck, N.D., ranch.
John Majerus of Cedar Rapids worked on his first prescribed burn this spring as a new member of the 3-year-old Central Nebraska Prescribed Burn Association. He and eight other members conducted the burn on a 30-acre native pasture owned by Pete Berthelsen of St. Paul.
David Fischer was tired of hauling nutrients off of his land. The farmer from Fordyce in Cedar County wanted to put something back, so he converted irrigated alfalfa to certified organic pasture. On 800 acres of land that he now manages, he allows the cattle to spread the nutrients for him and do much of his harvesting.
How would you like someone on the farm that is always ready to go, eager to work and never complains? For livestock owners, a good stock dog may be the answer — and more.
According to the 2007 U.S. Ag Census, more than 11,000 Wisconsin dairy and livestock farms utilize some form of rotational or managed grazing. For dairy herds of all sizes, managed grazing is a flexible practice that can fit into current feed management and forage production strategies. Pasture resources can be managed to provide forage needs of individual groups of lactating cows, dry cows, heifers or the entire herd during the grazing season.
A GPS, or global positioning system, is a device used to help navigate from one location to another — essentially, it helps you find your way.
You want to have good range and pasture, but where do you start?
After being forgotten in the wake of developing tall fescues, meadow fescue is staging a comeback for pasture grazing. "The grass has great potential for grazing-based livestock operations, where it's adapted," says Geoffrey Brink, research agronomist at the U.S. Dairy Forage Research Center in Madison, Wis.
Much like he does during the day at his UPS package job, Mitch Baltz delivers — with feed his cattle can use.
The buffet of grasses on Mitch Baltz's place is a work in progress, but the Powhatan, Ark., cattle producer sees a day coming when his cows and calves will spend most of the year grazing in pastures of plenty.
For openers, Craig Roberts tells farmers that toxic endophyte in fescue costs the Missouri beef industry $160 million each year.
When it comes to growing winter wheat, some aim for grain, other producers seek livestock forage, while others want both.
Located near Estherville in northern Iowa, Gordon Garrison is a do-it-yourself kind of farmer. But the conservation-minded sheep producer didn't flinch at getting some assistance from the sun to help keep his steep land in grass.
Tansy ragwort, common groundsel and fiddleneck, weeds commonly found in California, are extremely toxic to cattle and horses due to their content of toxins called pyrrolizidine alkaloids, or PAs, and can cause significant economic loss to cattle producers and horse owners. The warning comes from the California Animal Health and Food Safety Laboratory System at the University of California, Davis.
A lot can change on a farm in five years, and it has at Sawyer Beef near Princeton. Since Neal Sawyer joined his dad, Norm, in the operation in 2005, the two have transformed the way they're grazing their rolling hills near the Mississippi River in eastern Iowa, and they're expanding a niche market they found for grass-fed beef.
Some 300 visitors filled six large buses for the Dow AgroSciences Heritage Tour of the Antilley Ranch this spring at Wingate, Texas, just outside Abilene.
Hit by drought, cattle producers are asking how to stretch their pastures. Two major techniques may be pursued, according to Iowa State University Extension beef specialist Denise Schwab. One is to reduce the grazing pressure from the animal side, and the other is to supplement the amount of feed available.
The first thing you see when you drive down the lane toward Mike Hoopengardner's livestock barns is a sign proclaiming the family as local soil conservation honorees. That's not bad once you learn the family just began to convert their acreage from cropland into all forages about four years ago.
Fire has been a part of the prairie landscape for centuries, but virtually disappeared after more than a century of settlement. The U.S. Forestry Service is trying to reverse that trend at the Black Kettle National Grassland in western Oklahoma with a prescribed burn program that is slowly reverting the landscape back to its natural state.
Droughts are an act of Mother Nature and cannot be controlled. However, proper management can help maintain pastureland during a period of drought by following this advice:
Jim Randall is one of those rare individuals who actually can see the forest through the trees. And if a tree does not fit into his overall farm plan, he cuts it down.
Mob grazing — heavy stocking on small paddocks of forage — intrigues livestock producers. Promised benefits of increased soil organic matter, even distribution of manure, and more diverse forage species are talking points of promoters.
Native grasses that have proven themselves suitable to the Shackelford County, Texas, environment are the backbone for cattle and wildlife on the Merrick Davis Ranch, operated by H&M Cattle Co.
Gabe Brown and son Paul have a breakeven cost on corn of $1.18 per bushel — thanks to their innovative use of no-till, cover crops and cattle."Cattle so improve cropland that we want to get cattle on every acre we farm," Gabe says.
When the price of fuel, fertilizer and feed went through the roof three years ago, a group of University of Arkansas Division of Agriculture experts went back to basics to help struggling cattle producers manage their costs.
Dan Specht is as concerned about making a profit as any other farmer. But the organic grassland farmer in northeast Iowa believes he can manage his pastures in a way that maximizes profit and still offers good habitat for birds and other wildlife.
Feeding a seasonal herd of 300 cows, pastured and milked three times a day, isn't as challenging as you might think. Rob Hunt of Vergennes, Vt., ought to know. He's been doing it successfully for years.
As a conventional dairy producer, Justin Burbrink, Brandt Farm, Bartholomew County, had a goal of maximizing milk production. Under organic dairy production for three years, his goals became maintaining herd health and focusing on moving toward totally grass-based, self-sufficient production.
Texas cattle raisers have another way to get weed control in pastures — in one step.
Mitch Baltz loves to see his cows on grass, but he can't stand to see them standing in ponds loafing.So, in one sloping pasture, the Powhatan, Ark., cattle producer built two successive stair-step ponds.
Monty and Bobbie Jo Williams — and a silent partner who does not want to be identified — have made many improvements in recent years to the ranch that they operate together, and have increased its carrying capacity by 40%.
One of the greatest advantages of Management-intensive Grazing, or MiG, is summer grazing in order to give producers the opportunity to grow more forages for winter grazing, says Jim Gerrish, a nationally recognized grazing specialist. Winter grazing can save money and time, allowing farmers and ranchers to graze standing forages and stalks instead of feeding hay.
You may have more choices than you think in how you graze your land. Changes in technology for flexible fencing and watering systems make concentrated, high-density rotational grazing with long rest periods for the pasture or forage more attractive now. And there are more benefits for livestock owners who develop a successful grazing system and commit to closely managing and moving their animals.
The 2011 record drought and merciless heat hammered rangeland. More than 30,000 fires burned 4 million acres. Hundreds of thousands of cattle were impacted.
Jim Carr, Atkinson, has been a rangeland manager in the making since his days on the high school FFA range-judging team, and he's determined to help the next generation of farmers and ranchers become successful grass managers.
Three Nebraska cattle producers who have adopted winter grazing programs for their operations are realizing benefits from the practice.
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January 2013
Monthly Horoscope for VirgoPresented by Horoscope.com
Planets in Capricorn will help you feel secure and grounded, especially regarding love and romance. You'll know that your partner or love interest is committed and trustworthy. Intense feelings will increase your bond and you'll be able to show your partner how you feel. Venus will be in Sagittarius during the first part of the month. You may visit a female relative, but there could be tension. Jupiter in Gemini will bring opportunities to realize your ambitions, but you might have to sacrifice some of your other activities. You'll think a lot about your career path.
Don't know your sign? Enter your birthday:
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NEW - 2014 Love TarotWill 2014 be hot or not?More
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Cork Jewelry Organizer
Material List
- Opening Collectible Case, 14"x18"
- Creatology™ Roll of Cork, Adhesive-backed Ribbon – Burlap
- Martha Stewart Crafts™ Laser-cut Stencils – Geometric
- Martha Stewart Crafts™ Acrylic Paint – Sea Lavender, Summer Haze and Summer Linen
- Martha Stewart Crafts™ Stencil Tape
- Recollections™ Adhesive Tape, ¼"
- E-6000® Glue
- Push Pins
- Spouncer™
- Sandpaper
- Scissors
Project Instructions
Cut cork to fit inside case. Remove backing and place in case.
Use stencil tape to tape off 5" along bottom. Paint with desired color and let dry.
Remove tape.
Use Spouncer™ and desired paint and stencil your design onto cork.
Use adhesive tape to adhere burlap ribbon along bottom of case, overlapping in back.
Use E-6000® glue to adhere embellishments to push pins. Let glue dry.


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Information contained on this page is provided by an independent third-party content provider. WorldNow and this Station make no warranties or representations in connection therewith. If you have any questions or comments about this page please contact firstname.lastname@example.com.
SOURCE Research and Markets
DUBLIN, Feb. 21, 2014 /PRNewswire/ --
Research and Markets
) has announced the addition of the
"Concise Analysis of the International Nanomedicine Market - Forecast to 2019"
report to their offering.
(Logo: http://photos.prnewswire.com/prnh/20130307/600769)
The emergence of nanomedicine and the application of nanomaterials in the healthcare industry will bring about groundbreaking improvements to the current therapeutic and diagnostic scenario.Some of thedrivers of this market include increasing research funding, rising government support, improved regulatory framework, technological know-how and rising prevalence of chronic diseases such as diabetes, cancers, obesity, kidney disorders, orthopedic diseases and others.
The global nanomedicine market is categorized into six segments on the basis of application, namely neurology, cardiovascular, anti-inflammatory, anti-infective, oncology and others.
Oncology held majority of the market share in 2012 on account of following factors:
However, the global market for cardiovascular segment is expected to grow at the fastest pace owing to increasing prevalence of cardiovascular diseases demanding drugs with improved efficacy and therapeutic properties. Furthermore, realizing the importance and benefits of nanomedicine, researchers and manufacturers are striving to develop products with improved therapeutic properties in the cardiovascular segment.
The North American nanomedicine market held the majority of global market share in 2012 because of the rapidly growing nanomedicine market in the Asia-Pacific, Latin American and African region, presence of large number of patented nanomedicine products and favorable regulatory framework in the region.In addition, the presence of sophisticated healthcare infrastructure supports development of advanced products such as nano probes, nanorobots, monoclonal antibody based immunoassays and nanoparticle based imaging agents for early detection of diseases.
Key Topics Covered:
1 Preface
2 Executive Summary
3 Global Nanomedicine Market Overview
4 Global Nanomedicine Market, by Applications
5 Global Nanomedicine Market, by Geography
6 Recommendations
7 Company Profiles
Companies Mentioned:
For more information visit http://www.researchandmarkets.com/research/v92vqz/nanomedicine
Media Contact: Laura Wood , +353-1-481-1716, firstname.lastname@example.com
©2012 PR Newswire. All Rights Reserved.


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Slideshow posted in Entertainment News | Sunday, February 27, 2011
5 of 15:
Kim Kardashian has her own 'va-va-vanilla' cupcake mix, available at the Famous Cupcakes store in Beverly Hills. Pictured: Kim Kardashian appears in a photo with her "va-va-vanilla" cupcake from the Famous Cupcakes web site.
( Photo / facebook.com/pages/Famous-Cupcakes)


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The Wilderness Systems Tsunami 140 Kayak is the most paddler friendly, comfortable, versatile and high performance light touring kayak ever designed. The Tsunami series melds the stability and quickness of a recreational touring kayak with the speed, storage and efficiency of a sea kayak. The Phase 3 AirPro Tour seating system adds comfort and easy adjustability.
|I recently bought this kayak from Austin Kayak from their Austin store out of their rental fleet (I guess they swap out the boats yearly with newer models). I bought the boat at a nearly 50% discount, and other than a few scratches the boat is in great condition (and I got the factory warranty). I have added a rudder (installed by ACK for free because I bought the boat from them), I could not be happier with the money spent and how much value I am getting out of it. Now on to the review: Pros: 1. The boat is very fast and easy to handle. Even without the rudder, it tracks very very well, (compared to cheap "recreational" kayaks or my Ocean Kayak Torque/Trident 13). 2. The boat is quite well-made. This model is the polyethylene, lesser cost version (Wilderness makes the same boat out of composite materials at a greater cost/weight) version. Both the fore and aft compartments are large and watertight (tested by filling the cockpit with water). Everything is conveniently placed as with most sea kayaks with all the appropriate lines (for paddle float re- entry/safety) and deck bungees. 3. The seat is simply amazing! It is the "phase 3 pro air" made by Wilderness systems and is fully adjustable and positioned well to keep puddling water from soaking your posterior. The seat alone is probably worth what I paid for the boat. If you have the opportunity, sit in one of these in the showroom, and you will feel the difference. The seat also "breathes" to allow air flow under and behind so the experience is not a sticky, sweaty mess in warmer weather as is common with neoprene style seats. 4. This boat is a real touring sea kayak evidenced by the sealed compartments. Granted, it is on the lower end of the spectrum in terms of cost, but i would feel as comfortable in this kayak far from shore (ocean) as any kayak costing many time the price. 5. The boat is very light (about 40lbs) and easy to load ,especially compared with my angling kayak. 6. Stable. This kayak is difficult to turn over. This stability probably comes at a price in performance, but as this is my first seak kayak, this is a desirable thing. WIlderness makes two more expensive series (Focus and Zephyr) of sea kayaks that presumably have faster hull speeds, but are less stable. Cons (not big things, but worth noting): 1. The hatch seals can be difficult to close completely. They are press on, and care must be taken to fully seal all 360 degrees of the circular covers. Also, for cartop or trailer travel you will want these completely sealed. The hatch covers are leashed to the boat, but it seems possible that these could break loose in a strong wind (such as 70 mph driving down the road) if not properly sealed. 2. As noted above, this is not the fastest hull type, but I opted for stability vs speed.
|I just purchased a Wilderness Systems Tsunami 140. While I havent used it yet and probably wont until the spring, I am very impressed with the quality of the kayak. I also was very satisfied with Austin Canoe & Kayak..their sales people, the price, shipping cost and delivery time. My kayak arrived in perfect shape. I will definitely buy from them in the future
|We finally got the kayaks wet last weekend and they handled very well. We paddled for the better part of two hours on a calm lake and the boats were pretty darn fast and easy to steer. It took about 30 minutes of use before we had the seats trimmed correctly and after that they were very comfortable for each of us, despite a significant difference in posterior size. These are the first kayaks weve actually owned and Im looking forward to next weekend. Were actually thinking of buying two more for company to use. I almost gave a 5-Star Rating but I didnt have a lot of experience in other boats to compare to.
|I bought this kayak for a 7 day 100+ mile trip down the Buffalo River Arkansas in January. I'm 6'3" and 220 lbs, and the kayak fit me perfectly. I didn't get the rudder, and was glad as it did a great job of tracking straight. There was plenty of space in the boat for me and my gear. The bow had enough room for a weeks worth of food, a spare paddle, and fishing gear. The rear hatch had my tent, sleeping bag, air matress, clothes, and kitchen items. I bought a deck bag for the camera gear and little stuff. The seat was amazingly comfortable. Due to winter, I wore a wetsuit, and was plenty warm. The boat handled great in the mild white water, and could get up to some pretty decent speeds with not too much effort. The staff at the Houston ACK was amazing. They spend a great deal of time with me making sure I had the right gear and that everything fit properly before the trip. The only reason for the 4/5 stars, is that the height adjustable seat broke on the second day. It didn't affect the trip, but that seems like a weak design. I'm going to take the boat in this weekend to get it fixed.


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The previous entry was more of a general explanation about YUM speed and that if used in it's normal environment how current YUM is often more than fast enough, this entry is going to be a companion to it but focus on specific things that might make YUM appear slow but would better be described as using it suboptimally.
Note that I'm still not going to directly compare to other tools as I'm not as familiar with them and, as I said in the previous article, the tools are designed so differently that they don't lend themselves to comparisons. Also, as I also said before, if something is fine if it takes less than 10 seconds if two tools take 6 seconds and 4 seconds it doesn't really matter if yum is the faster (again, see the previous post, this should not be the end goal IMO).( Read more...Collapse )


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Filippo Tommaso Marinetti
From Wikiquote
Filippo Tommaso Emilio Marinetti (December 22, 1876 – December 2, 1944) was an Italian ideologue, poet, editor, and main founder of the futurist movement of the early 20th century.
- We love the indomitable bellicose patriotism that sets you apart; we love the national pride that guides your muscularly courageous race; we love the potent individualism that doesn't prevent you from opening your arms to individualists of every land, whether libertarians or anarchists.
- Speech, 1910, Lyceum Club, London. Futurist Speech to the English, published in Marinetti: Selected Writings (1972)
- There is no longer beauty except in the struggle. No more masterpieces without an aggressive character. Poetry must be a violent assault against the unknown forces in order to overcome them and prostrate them before men.
- The Founding and Manifesto of Futurism, Figaro (Paris, Feb. 20, 1909)
- The past is necessarily inferior to the future. That is how we wish it to be. How could we acknowledge any merit in our most dangerous enemy: the past, gloomy prevaricator, execrable tutor?
- We Abjure Our Symbolist Masters..., from War, the World's Only Hygiene (1911-1915)
- A new beauty has been added to the splendor of the world—the beauty of speed.
- The Founding and Manifesto of Futurism, Figaro (Paris, Feb. 20, 1909)
- A Race car is more beautiful than the Victory of Samotracia
External links[edit]
- Works by Filippo Tommaso Marinetti at Project Gutenberg
- MP3 of Marinetti performing one of his poems: 'Battaglia, Peso + Odore' (1912)
- MP3 of Marinetti performing one of his poems: 'Dune, parole in libertà' (1914) Score to this poem
- MP3 of Marinetti performing one of his poems: 'La Battaglia di Adrianopoli' (1926) recorded by Marinetti (1935)


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CHARLESTON (AP) - A Kanawha County judge has dismissed a lawsuit that claimed new vaccination requirements for schoolchildren are illegal.
Circuit Judge Tod Kaufman says in a ruling issued today that the Department of Health and Human Resources' rule is consistent with state law and doesn't exceed the Legislature's limits on interpretive rules.
Delegate Patrick Lane filed the lawsuit on behalf of six families. The lawsuit argued that the DHHR can't require additional vaccines without the Legislature's approval.
Lane didn't immediately return a telephone message Wednesday.
A Pickens School student and her father filed a complaint in Randolph County Circuit Court that also dealt with the new vaccine requirement. The student has been barred from the classroom over her refusal to get mandatory immunizations.
Circuit Judge Jaymie Godwin Wilfong ruled Sept. 28 that the Randolph County School System provide home-bound educational services to the student until there is a final resolution in Kanawha County Circuit Court.
Copyright 2012 The Associated Press.


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That's a decent base plot; however, it might be good to add some conflict in there--something to overshadow your heroes and heroines throughout their adventures.
Ah so now that I've done some thinking (and some growing up) I think I can finally say I have a steady base plot...
Please give me feedback,like what important questions would the reader have, stuff like that.
It's in the future, where humans have advanced far into technology and have met other races. It is called the Technological Revolution(Like the Industrial Revolution) So humans have evolved over time too right? Now the humans live on the planet of Atari and on this planet is the Universal Academy. Here comes people from all other galaxy's to become Galaxy Defenders, like the universe's police. It centers on one class The Dangerous and Strange Abilities Class 3, and their adventures. ^^
That's a decent base plot; however, it might be good to add some conflict in there--something to overshadow your heroes and heroines throughout their adventures.
Well many of the people in the class are treated like political objects because they have such dangerous powers.
The main charachter is also supposed to suffer from amnesia and have an evil twin brother. Kinda like.. Star Wars? I AM YOUR FATHER.
So it's like a sci-fi transhumanism story? That sounds interesting. Yet Matt's point stands--this isn't a plot; it's a premise. What's missing is conflict, but it seems like you've got a few sources to draw from for that. The conflict could be the amnesiac trying to regain his identity whilst his twin tries to destroy it. Or maybe there's a power struggle in the team? Or a traitor?
It's all up to you, really.
But in all honesty, it sounds really, really interesting, and I'd definitely give it a read. (D'aww, how cute and alliterative I am. XD)
I already had all of those in, I just didn't type the whole plot out because I thought someone wouldn't read it.
Ok I decided to suck it up and put up the three plotways I decided to go with.
A) The main charachter Ace is kicked out of basically every school because he cannot control his powers. Whenever he sneezes, holds his breath, or is surprised he time travels.(which causes for some extermley strange situations) His father, who is good friends with the Dean of the Universal Academy let's him join the Academy so he can learn how to control his powers
B)After defeating a bunch of Bank Robbers Ace decides to join the academy and become a Universal Defender, the highest level of ... fighting justice? Think of Naruto wanting to become Hokage
C) Ace suffers from amnesia and is unaware of his powers. His "father" helps him get into the Academy. There he slowly learns secrets about who he really is....
D) An action comedy about kids who are universal police. Think Gintama. No real plot but so wierd and bendy it works.
Why are people saying this is unique? It's a high school story in a science-fiction setting.
"The main character is also supposed to suffer from amnesia and have an evil twin brother."
That's two overdone clichés in a single sentence. In addition the whole 'academy for SPECIAL PEOPLE' premise has been done to death over the last few decades. I'm not saying it can't be done well, just that from the premise it seems absurdly unlikely that it's going to be anything other than a massive orgy of overblown tropes.
Originally Posted by Fenn
People have been saying this is unique? Huh.
How do you make a cliche special is basically what you're saying, right?
Yeah. I'm not saying an overdone concept like this can't be done well, but without massive subversion of what the audience expects and some sort of deconstruction (see: GAINAX), it's going to turn into X-Men in space, which is neither interesting nor original at this point. Unless you explicitly plan on attacking the underlying assumptions of the concept ("policemen are good", "powers are desirable", "with great power comes great responsibility", etc.) then it's probably safer to leave this to get lost in space.
Originally Posted by Fenn
I need something that sets this story out from the rest. But by Gainax does that mean that you want me to troll my audience? I know Gainax takes some pretty overused plots but I'm not seeing what that has to do with this.