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Journal of Cancer Therapy
Vol.05 No.13(2014), Article ID:51257,11 pages
10.4236/jct.2014.513122
Current Possible Drug Therapies for Ovarian Cancer
Jungyeob Seoung, Young-Han Park*, Chaechun Rhim, Sungju Kim
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Hallym University Sacred Heart Hospital, Anyang, South Korea
Email: *drparkyh@yahoo.co.kr
Ovarian cancer is the most aggressive gynecologic cancer of the heterogenous phenotypes. Development of the new chemotherapeutic agents and drug delivery mode makes better outcomes for patient treatments. Optimal cytoreductive therapy followed by molecular targeting therapy, intra- peritoneal chemotherapy and dose dense chemotherapy is a hot therapeutic concept in ovarian cancers. In our review, we will introduce recent therapeutic advances in epithelial ovarian cancer patients.
Ovarian Cancer, Intraperitoneal Chemotherapy, Targeting Therapy
Epithelial ovarian cancer (EOC) is the most lethal malignancy in gynecologic cancer. It is estimated that 22,240 cases were diagnosed with EOC and 14,030 deaths from EOC occurred in the US in 2013. The cure rate of this disease is less than 40% [1] . At the time of diagnosis, most patients have the advanced stage disease. The standard treatment of newly diagnosed EOC is the optimal cytoreductive surgery and followed platinum-based chemotherapy. Despite advances in surgical and chemotherapeutic strategies, the majority will experience disease recurrence requiring further treatment. Over 70% of the patients with advanced stage EOC experience recurrence within 2 years after initial treatment.
Resistance to chemotherapy is a major clinical problem. Multiple signaling pathways have been implicated in the resistance to chemotherapy. To overcome the resistance to therapy, innovative therapeutic strategies are needed. In this review, we will summarize current treatment strategy with conventional cytotoxic agents including intraperitoneal (IP) chemotherapy and dose dense chemotherapy schedule. We also focused our attention on reviewing current phase 3 trials with promising target agents to overcome conventional cytotoxic agents and improve outcome of EOC (Table 1).
2. Cytotoxic Chemotherapy
2.1. Finding Optimal Regimen of Conventional Cytotoxic Agent; Dose Dense Chemotherapy
Currently, the combination of paclitaxel and carboplatin is the standard chemotherapy regimen for EOC. This consists 175 mg/m2 of paclitaxel given intravenously over 3 hours, followed by carboplatin intravenous (IV) infusion over 30 - 60 min at a dose of AUC 5 - 6. This is repeated every 3 weeks for six cycles. Dose dense therapy is strategy to enhance antitumor activity to focus on rapid regrowth of tumor between treatment cycles. Increasing the dose density of chemotherapy is expected to increase efficacy by minimizing the opportunity for regrowth of tumor cells [2] . The Japanese Gynecologic Oncology Group (JGOG) conducted a randomized phase 3 trial of dose-dense weekly paclitaxel in combination with 3-weekly carboplatin for advanced EOC (JGOG 3016, NOVEL trial) [3] . In this study, Median PFS was longer in the dose-dense treatment group (28.0 months, 95% CI 22.3 - 35.4) than in the conventional treatment group (17.2 months, 15.7 - 21.1; HR0.71; 95% CI 0.58 - 0.88; p = 0.0015). Overall survival (OS) at 3 years was higher in the dose-dense regimen group (72.1%) than in the conventional treatment group (65.1%; HR 0.75, 0.57 - 0.98; p = 0.03). Patient treated with dose dense therapy had a significantly higher frequency of hematologic toxicity, and a lower treatment completion rate (63% vs. 48%). In long term follow-up data of this trial, median PFS was significantly longer in the dose-dense treatment group than in the conventional treatment group (28.2 months vs. 17.5 months, HR 0.76, 95% CI 0.62 - 0.91, p = 0.0037). Median OS was 100.5 months in the dose-dense treatment group and 62.2 months in the conventional treatment group (HR 0.79, 95% CI 0.63 - 0.99, p = 0.039) [4] .
Confirmatory studies are ongoing in western countries. In the United States, a Gynecologic Oncology Group (GOG) 0262 trial was conducted for suboptimally operated patients. It is randomized phase III trial of every 3 weeks paclitaxel versus dose dense weekly paclitaxel in combination with carboplatin with or without concurrent and consolidation bevacizumab in the treatment of primary stage III or IV epithelial ovarian, peritoneal or fallopian tube cancer. The primary analysis demonstrated no significant difference in PFS in the patients who received the dose dense paclitaxel/carboplatin regimen compared to those who received the standard paclitaxel/carboplatin regimen (14.8 vs. 14.3 months, HR 0.97). However, there was a significant difference in PFS in the dose dense paclitaxel group (14.2 vs 10.3 months, HR 0.586) in a subset analysis of the small fraction of patients who did not receive bevacizumab.
The Multicentre Italian Trials in Ovarian Cancer (MITO-7) have launched in Italy, 2008. This randomized, multicenter, open-label, phase 3 trial assessed whether a weekly schedule of carboplatin (AUC 2) plus paclitaxel (60 mg/m2) is more effective than the same drug given every 3 weeks (AUC 6 of carboplatin plus 175 mg/m2 of paclitaxel) [5] . Unlike Japanese "NOVEL" trial, number of cases reporting grade 3-4 neutropenia was fewer in dose dense group than those allocated treatment every 3 weeks (42% vs. 50%). Another ongoing trial is ICON-8 trial which began in June, 2011 and whose estimated primary completion date is June, 2017. This trial is three-armed randomized trial comparing carboplatin AUC 5 plus 175 mg/m2 paclitaxel with carboplatin AUC 5 plus weekly 80 mg/m2 paclitaxel and with weekly carboplatin AUC 1.67 plus weekly 80 mg/m2 paclitaxel for stage IC to IV EOC.
2.2. Route of Administration-IP Chemotherapy
In addition to chemotherapeutic regimen, the route of administration chemoptherpeutic agents is important. Peritoneal seeding is the most frequent type of metastasis of advanced EOC, which results in a poor prognosis, with 5-year survival of around <25% [6] . The potential advantage of IP chemotherapy is that administration of chemotherapeutic agents into intra-peritoneal cavity could increase the dose and exposure time of intra-abdo- minal cancer cells to anticancer drugs, with minimal systemic toxic effects [7] . IP chemotherapy has been attempted since 1980s. Multicenter randomized phase 3 trials and meta-analysis of IP chemotherapy have been performed and demonstrated that IP administrated regimens are superior to standard IV administrated regimens in patient with optimally debulked EOC. The representative study is GOG 172 trial; a phase III randomized
Table 1. Clinical trials of currently accruing in ovarian cancer.
trial of intravenous paclitaxel and cisplatin versus intravenous paclitaxel, intraperitonealcisplatin and intraperitoneal paclitaxel in patients with optimal stage III epithelial ovarian carcinoma or primary peritoneal carcinoma [8] . In this trial, IV paclitaxel plus cisplatin administration regimen was compared to IV paclitaxel plus IP cisplatin and paclitaxel administration regimen. The patients with stage 3 ovarian carcinoma or primary peritoneal carcinoma with no residual mass greater than 1.0 cm were randomly assigned to receive IV paclitaxel (135 mg/m2) over a 24-hour period followed by either 75 mg/m2 of IV cisplatin on day 2 (IV-therapy group) or 100 mg of IP cisplatin per square meter on day 2 and 60 mg of IP paclitaxel per square meter on day 8 (IP-therapy group). Treatment was given every three weeks for six cycles. It is reported that the adverse events were more common in the IP-therapy group than in the IV-therapy group (p ≤ 0.001) and only 42 percent of the patients in the IP-therapy group completed six cycles of the assigned therapy. However, the median duration of progression-free survival (PFS) in the IV-therapy group and IP-therapy group were 18.3 and 23.8 months, respectively (p = 0.05 by the log-rank test). And the median duration of OS in the IV-therapy group and IP-therapy group was 49.7 and 65.6 months, respectively (p = 0.03). Based on these studies, The National Comprehensive Cancer Network guidelines now recommend IP chemotherapy for patients with optimal cytoreductive surgery [9] . The recommended IP chemotherapy regimen is paclitaxel, 135 mg/m2 continuous infusion over 3 to 24 hours on day 1. Cisplatin 75 to 100 mg/m2 IP on day 2 after IV paclitaxel, paclitaxel 60 mg/m2 IP on day 8 and repeat every 3weeks times 6 cycles [9] . However, adjuvant IP chemotherapy has not been widely accepted and underused despite its survival benefits. Possible reasons are toxicities and inconvenience of IP therapy. IP chemotherapy has known to cause more gastrointestinal toxicity, pain, fever and infection than IV chemotherapy [10] . And there is additional risk of catheter-related complication [11] . In GOG 172 trial, only 42% of patients completed all 6 cycles of IP chemotherapy due to these toxicities and catheter related complications [8] . Though only 42% of women were able to complete all 6 treatment cycles in GOG 172 trial, this percentage has been improved in the major cancer centers. Modification of regimen enables improved compliance to IP chemotherapy, and various chemotherapeutic agents and doses were tested to find optimal regimens. Using a lower IP cisplatin dose of 75 mg/m2 or splitting the dose may help to decrease toxicity [12] . Though it has not been proven to be equivalent to a 24-hour infusion, 3-hour infusion of paclitaxel has been reported to be more convenient with less toxicity profile [13] [14] . Based on inspiring result of dose dense chemotherapy, a randomized phase 2/3 trial is currently underway comparing IV dose dense paclitaxel plus IV carboplatin every 3 weeks to IV dose dense paclitaxel plus IP carboplatin every 3 weeks.
Pharmacokinetics after IP administration are important and are affected by a variety of biophysical parameters, including molecular weight, electric charge of drugs, temperature, pH, and other conditions of the solution [7] . Some clinicians use hyper-thermic condition (HIPEC) to promote absorption of agents from the surface of peritoneal tumors, with minimal systemic toxic effects. However, to date, there is no prospective randomized trial and HIPEC is considered to be associated with high morbidity and mortality. Instead of conventional drug, nanodrugs are considered. Nanodrugs are significantly smaller than conventional drugs and are effectively accumulated in tumor tissue with enhanced permeability and retention [15] . Though there is no study with EOC, this nanodrug demonstrated antitumor effect in peritoneal metastatic cancer of esophageal cancer, gastric cancer and breast cancer [7] .
Another new approach in IP chemotherapy is adoption of target agents [7] . The representative agents are catumaxomab and bevacizumab. Catumaxomab is a trifunctional monoclonal antibody and it binds to human EpCAM-positive cancer cells and activating a complex antitumor immune reaction such as antibody-dependent cellular cytotoxicity, phagocytosis and T-cell mediated cytotoxicity [16] . A randomized phase 2/3 trial of catumaxomab in patients with malignant ascites due to epithelial cancer, including ovarian, gastric, breast, pancreatic, colorectal, and endometrial cancers had been conducted in 2012. In this study, 258 patients with malignant ascites were randomized and treatment with catumaxomab enabled those patients to benefit from better quality of life for prolonged survival period [17] . Another possible agent is bevacizumab. Bevacizumabhas shown significant efficacy in combination with chemotherapy. However there is no clinical trial addressing the use of bevacizumab by IP administration.
2.3. Targeted Therapies
Despite various efforts to overcome recurrence of EOC, drug resistance is major problem and leading the highest mortality of disease entity to recurrent disease. For patients with platinum refractory and resistant disease, conventional cytotoxic agents showed limited responses and clinical insignificant survival gains despite therapy related toxicities. Targeted agents hold the promise of greater selectivity with lower toxicity than conventional cytotoxic chemotherapy. The most important advanced included the introduction of anti-angiogenic therapy and the assessment of PARP inhibitors.
2.4. Anti-Angiogenic Therapy-Bevacizumab
Angiogenesis is essential for tumor invasion and metastasis, and is required for tumor growth beyond 1 - 2 mm [18] [19] . The vascular endothelial growth factor (VEGF) pathway is the most widely studied angiogenic pathway in carcinogenesis. The bevacizumab was the first anti-angiogenesis agent to be advanced in to the phase 3 randomized trial for advanced EOC. Recently, Gynecologic Oncology Groupconducted three-arm phase 3 randomized controlled trial, (GOG-0218 trial) to assessed bevacizumab combined with carboplatin/paclitaxel in the upfront setting compared to carboplatin/paclitaxel alone [20] . In the first experimental arm, patients were treated with concurrent bevacizumab (15 mg/kg) followed by placebo maintenance (bevacizumab-initiation), while in the second experimental arm, patients received concurrent and maintenance bevacizumab every 21 days for up to 16 doses (bevacizumab-throughout). A total of 1873 women with previously untreated, advanced stage, epithelial ovarian, primary peritoneal and fallopian tube cancer were enrolled at 336 institutions in 4 countries. The median PFS was significantly prolonged in patients receiving prolonged bevacizumab-throughout arm when compared to chemotherapy alone (14.1 months vs. 10.3 months, p < 0.0001). Relative to control, the hazard ratio (HR) for progression or death was 0.717 (95% CI 0.625 to 0.824; p < 0.001) with bevacizumab throughout. However PFS was not significantly increased in patients who did not receive maintenance bevacizumab versus chemotherapy alone and no significant difference in OS among the three groups was identified. The rates of other adverse events including gastrointestinal fistula/perforation, proteinuria (≥grade 3), neutropenia, thromboembolism, and wound disruptions were similar among the 3 treatment arms. Another phase 3 randomized controlled trial is ICON (International Cooperative Group for Ovarian Neoplasia)-7 trial. This trial is a two- armed trial comparing carboplatin plus paclitaxel (six cycles) against carboplatin plus paclitaxel with bevacizumab every 3 weeks for 6 cycles, followed by 12 cycles of maintenance bevacizumab. The dose of bevacizumab (7.5 mg/kg) was half of that used in former (GOG 218) trial [21] . The PFS was significantly improved in the bevacizumab arm relative to control (19 vs. 17.3 months; HR 0.81, 95% CI 0.7 - 0.94, p = 0.0041). In patients at high risk of recurrence (stage 4, stage 3 with residual disease less than 1 cm), the benefits of bevacizumab were magnified, with a 5.4 month improvement in PFS. Mature OS data for ICON-7 was recently presented at the 2013 ESMO Annual Meeting in Amsterdam [22] . There was no significant difference in OS between control and the bevacizumab containing arm (58.6 vs. 58.0 months respectively, HR 0.99, p = 0.85). Interestingly, the beneficial effects of bevacizumab in the subset of patients at high risk for progression (stage 4, stage 3 with residual disease less than 1 cm) continued, with bevacizumab treatment resulting in a 9.4 month improvement in median OS (30.3 vs. 39.7 months; p = 0.0072).
Bevacizumab therapy is mentioned as primary chemotherapy/primary adjuvant therapy regimens for stage II-IV EOC. However this therapy is belonged to category 3 (based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate). Because data from these two studies have not shown a statistically significant increase in OS and/or improved quality of life.
Bevacizumab also is tested in recurrent EOC. The OCEANS; a randomized, double blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer; showed the efficacy and safety of bevacizumab in the treatment of patients with recurrent, platinum sensitive EOC [23] . Overall, 484 platinum sensitive (disease progression ≥6 months after completion of front-line platinum based chemotherapy) patients were enrolled. These were randomly assigned to carboplatin/gemcitabine + bevacizumab vs. carboplatin/gemcitabine + placebo for 6 to 10 cycles. Bevacizumab or placebo was then continued until disease progression. Median PFS for the bevacizumab arm was superior to that for the control arm, 12.4 vs. 8.4 months, respectively (HR 0.484, 95% CI 0.388 - 0.605; p < 0.0001). Addition of bevacizumab significantly improved the objective response rate (ORR) (78.5% vs. 57.4%; p = 0.0001), with the majority being partial responses. The OS data is immature yet.
In patients with platinum resistant recurrent EOC, the AURELIA: a randomized phase III tiral evaluating bevacizumab plus chemoptherapy for platinum-resistant recurrent ovarian cancer; was conducted [24] . In this study, platinum resistant (disease progressed <6 months after completing platinum based therapy) patient were randomly assigned to single agent chemotherapy alone or with bevacizumab (10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks). The PFS hazard ratio (HR) after PFS events in 301 of 361 patients was 0.48 (95% CI, 0.38 to 0.60, p < 0.001). Median PFS was 3.4 months with chemotherapy alone versus 6.7 months with bevacizumab-containing therapy. ORR was 11.8% versus 27.3%, respectively (p = 0.001). Although addition of bevacizumab treatment showed longer PFS and higher ORR, there was no significant difference in OS.
2.5. Other Anti-Angiogenesis Agents
Besides bevacizumab, other anti-angiogenetic agents, including pazopanib, cediranib and trebananib, are under clinical trials. The Arbeitsgemeinschaft Gynaekologische Onkologie (AGO)-OVAR 16 study is phase 3 randomized trial of maintenance daily pazopanib vs. placebo following primary platinum-based combination chemotherapy. Pazopanib is a tyrosine kinase inhibitor showing anti-angiogenic effect by inhibiting VEFGR, PDGFR and c-Kit signaling. In this study, pazopanib maintenance is associated with a significantly increased median PFS (17.9 months vs 12.3 months; HR 0.766, p = 0.0021) [25] . OS data is immature yet.
Another tyrosine kinase inhibitor, Cediranib, also showed activity in recurrent EOC as single agent [26] . In the ICON-6 trial, randomized, double blind, phase 3 trial in platinum sensitive recurrent EOC, cediranib maintenance showed significant improvement in PFS in the relative to control (12.5 vs. 9.4 months; HR 0.57, 95% CI 0.45 - 0.74, p = 0.00001). Additionally, a 2.7 month improvement in OS was identified in the cediranib plus platinum based chemotherapy followed by maintenance cediranib arm. ICON-6 is the first trial to demonstrate a significant improvement in OS anti-angiogenic agent. Other antiangiogenic agents included trebananib and nintedanib. Trebananib (AMG 386) targets the angiopoietin axis and inhibit angiogenic pathway. Inn TRINOVA-1: a phase 3 randomized, double blind trial, weekly paclitaxel in combination with trebananib (15 mg/kg) given weekly or placebo in women were compared in recurrent EOC [27] . There was a significant improvement in PFS in the trebananib arm relative to control (7.2 vs. 5.4 months; HR 0.66, 95% CI 0.57 - 0.77, p < 0.001). OS data is immature. Major adverse events were edema, ascites and pleural effusions though common toxicities of VEGF were not common. TRINOVA-3: A prospective, phase 3, randomized, double blind placebo controlled trial, is evaluating in up front treatment of advanced EOC treatment with paclitaxel and carboplatin. Nintedanib (Vargatef) is an angiokinase inhibitor against VEGFR, fibroblast growth factor receptor and platelet derived growth factor receptor. In phase 3 randomized placebo-controlled trial (AGO-OVAR12/LUME-Ovar 1), administering nintedanib with paclitaxel and carboplatin significantly increasing PFS (HR 0.84; 95% CI 0.72 - 0.98; p = 0.0239) in up front therapy [28] .
2.6. PARP Inhibitors-Olaparib
PARP inhibitors are the first biologic agents to be used to treat EOC based upon pre-selection characteristics of the patient's cancer [29] . PARP inhibitors are most active in cancers with defects or aberrations in DNA repair. As DNA repair defects present in about half of high grade serous cancers (HGSC), PARP inhibitor has been of particular interest in this subset of patients [30] .
Olaparib (AZD2281) is most actively investigated agent in EOC. As a single agent, olaparib has demonstrated anti-cancer activity in germline BRCA-mutated recurrent germline BRCA mutated EOC [31] . In another phase 2 study, single-agent olaparib (400 mg BID dose) demonstrated efficacy in both germline BRCA as well as sporadic EOC without a known BRCA mutation [32] . Responses seen in the non-BRCA-associated cancers were associated with platinum sensitivity. The response rate was 50% in patients with platinum sensitive cancer while only 4% patients with platinum resistant and non-BRCA-associated cancer had a response. Several randomized phase 2 studies testing olaparib in recurrent EOC have been conducted against pegylated liposomal doxorubicin (PLD) for treatment of recurrent EOC [33] . In this study, recurrent EOC patients with known germline BRCA1 or BRCA2 mutation were randomized 1:1:1 to PLD 50 mg/m2 IV every 4 weeks, olaparib capsules 200 mg BID continuously or olaparib capsules 400 mg BID continuously. Though this was a small study of only 97 patients, this study demonstrated that a PARP inhibitor has activity comparable to PLD in recurrent BRCA-associated EOC and that the 200 mg BID dose of olaparib has comparable activity to 400 mg BID. As maintenance therapy, Ledermann et al. tested olaparib for platinum sensitive recurrent high grade serous carcinoma (HGSC) in a double-blinded study against placebo [34] . This study included both germline BRCA-associated and sporadic HGSC. Following platinum-based chemotherapy, 265 patients were randomized to placebo or olaparib 400 mg BID daily. The PFS was 8.4 months in olaparib maintenance group while 4.8 months in placebo group. (HR 0.35, 95% CI 0.25 - 0.49, p < 0.00001) and median PFS for the olaparib group was 11.2 months compared to 4.3 months for the placebo group (HR = 0.18, 95% CI 0.11 - 0.31, p < 0.00001). Based on these Phase 2 trials, phase 3 studies testing olaparib versus placebo as maintenance therapy for BRCA-associated EOC in both newly diagnosed and platinum-sensitive recurrent settings are on-going.
Combinations of PARP inhibitors with conventional chemotherapy agents have been evaluated. Because myelosupression is common in both treatments, use of full dose chemotherapy is difficult in combination setting. The dose-limiting toxicity (DLT) was myelosuppression in a phase 1 studies of olaparib combining with carboplatin or paclitaxel. Other toxicities included neutropenia, thrombocytopenia, anemia, fatigue and carboplatin hypersensitivity [29] .
2.7. Other PARP Inhibitors
The other PARP inhibitors including veliparib, niraparib, rucaparib and BMN 673 [29] . Veliparib inhibits both PARP-1 and PARP-2 and has undergone testing as a single agents and combination with other chemotherapy agents. Phase 1 studies have been performed using veliparib in combination with topotecan, irinotecan, doxorubicin and cyclophosphamide. In the phase 1 study of veliparib (40 mg daily) and oral cyclophosphamide (50 mg once per day for 21 days), seven of thirty five patients with BRCA mutations had partial responses [35] . In phase 2 trial of single-agent veliparib in recurrent BRCA-related EOC, preliminary results as 8 of 31 patients experienced a PR [36] . Myelosupression was major toxicities as olaparib.
Niraparib (MK4827), a selective PARP-1 and PARP-2 inhibitor, has been discovered in 2009 [37] . In phase 1 trial in BRCA mutation carriers and patients with sporadic BRCA cancer, eight (40%, 95% CI 19 - 64) of twenty BRCA1 or BRCA2 mutation carriers with EOC had RECIST partial responses [38] . Antitumor activity was also reported in sporadic high-grade serous ovarian cancer. Myelosupression, fatigue and pneumonitis were dose- limiting toxicities. Currently, a phase 3 study of niraparib versus placebo as maintenance therapy in patients with platinum sensitive, recurrent EOC, is accruing patients. Another PARP-1 and PARP-2 oral inhibitor, rucaparib (CO338 and AGO14699) has demonstrated anti-cancer responses for both platinum resistant and sensitive EOC patients in phase 1 study [39] . Rucaparib is currently undergoing further phase 2 and 3 trials in patients with HGSC.
3. Combination Strategies
In addition to, as single agents, novel target agents were tried as combination manner with other cytotoxic agents or target agents. The OCTAVIA: a phase II study evaluated front line bevacizumab plus weekly paclitaxel and tri-weekly carboplatin [40] . Patients received a median of six chemotherapy and seventeen bevacizumab cycles. For 189 enrolled patients, median PFS was 23.7 months (95% CI, 19.8 - 26.4 months), 1-year PFS rate was 85.6%, Response Evaluation Criteria in Solid Tumors (RECIST) response rate was 84.6% and median response duration was 14.7 months. Adverse events were no more common than in phase 3 bevacizumab trials. A combined with IP chemotherapy, GOG 252: phase III clinical trial of bevacizumab with IV versus IP chemotherapy in ovarian, fallopian tube and primary peritoneal carcinoma is underway to evaluated efficacy of bevacizumab for optimally cytoreduced patients. Evaluation of combination therapies between target agents is also underway. Phase 1 study of olaparib and combined with bevacizumab has conducted and olaparib 400 mg BID with bevacizumab 10 mg/kg IV every 2 weeks were tolerable [41] . An ongoing randomized phase 2 study is testing the combination of cediranib plus olaparib in patients with platinum sensitive recurrent EOC. PARP inhibitors are also tried with inhibitors of other signaling pathways including PI3 kinase inhibitors. As the activation of the PI3K pathway occurs in as much as 70% of all EOC, these strategies could increase the patients who may benefit from PARP inhibitors beyond BRCA-associated and/or HR-deficient cancers.
Ascorbic Acid as Alternative Cancer Treatments
Ascorbic acid has been known as antioxidant and helps prevent oxidative stress. Ascorbic acid has long been implicated in preventing and treating cancers [42] . Among the most enduring of alternative medical treatments, ascorbic acid is also one of the most popular. A survey published in 2010 evaluating the use of ascorbic acid among health care practitioners attending annual complementary medicine conferences found that 84% of complementary medicine practitioners reported using ascorbic acid for various conditions including cancer [43] . There are several mechanisms which intake of ascorbic acid may influence mortality among women with cancer. In preclinical studies, ascorbic acid can induce apoptosis in tumor cells and enhance antitumor effects of chemotherapy in vitro and in vivo [44] [45] . Ascorbic acid also exhibits antioxidant actions including neutralization of free radicals which may impact cancer progression [46] . And help protect and repair normal cells that are damaged by chemotherapy or radiation therapy, which can result in fewer or less severe adverse effects and improve compliance to cancer therapy [47] . Conversely, evidence from some laboratory studies and randomized trials suggested that use of antioxidant supplements, including ascorbic acid, during chemotherapy or radiation therapy may actually protect tumor cells and decrease the efficacy of treatment [48] .
Although there are some reports of anti-cancer effect of ascorbic acid in animal study and in vivo study, in vivo and animal study, there are little studies in the literature regarding the effect of ascorbic acid to ovarian cancer patients. In sub-analysis of Women's Health Initiative (WHI) study, dietary intake and supplemental antioxidant nutrients including ascorbic acid were not associated with a reduction in ovarian cancer risk [49] .
Recently, Harris, H.R., et al. conducted meta-analysis about the association between ascorbic acid supplement and survival in breast cancer patients. The summary RR for a 100 mg per day increase in dietary ascorbic acid intake was 0.73 (95% CI 0.59 - 0.89) for total mortality and 0.78 (95% CI 0.64 - 0.94) for breast cancer-specific mortality [50] . This study has limitations as meta-analysis of observation studies. The dosage, formula and schedule of ascorbic acid differed between studies and the studies did not provide a rationale for them. Although this meta analysis could not control confounders that were not adjusted for in individual studies, they resulted post-diagnosis ascorbic acid supplement use may be associated with a reduced risk of mortality. Besides dietary supplement, high dose ascorbic acid treatment is also performed as alternative treatment. Owing to bioavailability and renal excretion, it is hard to get high concentration by current ascorbic acid dietary formula. However by IV administration, studies suggest that higher levels of ascorbic acid may cause the death of cancer cells in the laboratory. The mechanism of high dose ascorbic acid is not fully understood, and anti-tumor activity via generation of hydrogen peroxide and metabolite have been proposed [51] -[53] . Current clinical evidence for effect of high dose ascorbic acid are inconsistent.
4. Conclusion and Perspectives
Dose dense chemotherapy and IP chemotherapy are an effective treatment with improved PFS in patients with advanced EOC. Current ongoing trials would be critical to determine optimal dose and administration route. However conventional cytotoxic agents showed limited responses for patients with platinum resistance. To overcome limitation of conventional cytotoxic agents, various targeting agents have been developed and are under-development. Anti-angiogenesis and PARP inhibition are the most promising with positive randomized trial results. These agents demonstrate improvements in PFS with tolerable adverse events compared to cytotoxic agents. As PARP inhibitor demonstrates response in limited patients with BRCA mutation or homologous recombination (HR) deficient tumor, to select these patients is another challenge. Currently there is neither prospectively validated biomarker of HR-deficient EOC nor predicts responsiveness to PARP inhibitors. Genomic studies of cancer and miRNA studies could be meaningful in this aspect. The Cancer Genome Atlas (TCGA) project divided EOC into four groups based on gene expression patterns and provided the basis for an integrated view of miRNA and mRNA expression [54] . Mutations including TP53, NF1, BRCA1, BRCA2, RB1 and CDK12 were evaluated and pathway analyses suggested that HR was defective in about half of the EOC analised. Though further research is required, miRNA levels are promising as a diagnostic tool and miRNAs are evaluated as predictor of chemotherapy response and prognostic marker [55] . With these efforts improved outcomes would be fulfilled with less toxicity and better cost effectiveness in EOC.
Siegel, R., Naishadham, D. and Jemal, A. (2013) Cancer Statistics, 2013. CA: A Cancer Journal for Clinicians, 63, 11-30. http://dx.doi.org/10.3322/caac.21166
Norton, L. (2001) Theoretical Concepts and the Emerging Role of Taxanes in Adjuvant Therapy. The Oncologist, 6, 30-35. http://dx.doi.org/10.1634/theoncologist.6-suppl_3-30
Katsumata, N., Yasuda, M., Takahashi, F., Isonishi, S., Jobo, T., Aoki, D., et al. (2009) Dose-Dense Paclitaxel Once a Week in Combination with Carboplatin Every 3 Weeks for Advanced Ovarian Cancer: A Phase 3, Open-Label, Randomised Controlled Trial. Lancet, 374, 1331-1338. http://dx.doi.org/10.1016/S0140-6736(09)61157-0
Katsumata, N., Yasuda, M., Isonishi, S., Takahashi, F., Michimae, H., Kimura, E., et al. (2013) Long-Term Results of Dose-Dense Paclitaxel and Carboplatin versus Conventional Paclitaxel and Carboplatin for Treatment of Advanced Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer (JGOG 3016): A Randomised, Controlled, Open- Label Trial. The Lancet Oncology, 14, 1020-1026. http://dx.doi.org/10.1016/S1470-2045(13)70363-2
Pignata, S., Scambia, G., Katsaros, D., Gallo, C., Pujade-Lauraine, E., De Placido, S., et al. (2014) Carboplatin plus Paclitaxel Once a Week versus Every 3 Weeks in Patients with Advanced Ovarian Cancer (MITO-7): A Randomised, Multicentre, Open-Label, Phase 3 Trial. The Lancet Oncology, 15, 396-405. http://dx.doi.org/10.1016/S1470-2045(14)70049-X
Ozols, R.F. (2005) Treatment Goals in Ovarian Cancer. International Journal of Gynecological Cancer: Official Journal of the International Gynecological Cancer Society, 15, 3-11. http://dx.doi.org/10.1111/j.1525-1438.2005.15351.x
Kitayama, J. (2014) Intraperitoneal Chemotherapy against Peritoneal Carcinomatosis: Current Status and Future Perspective. Surgical Oncology, 23, 99-106. http://dx.doi.org/10.1016/j.suronc.2014.03.004
Armstrong, D.K., Bundy, B., Wenzel, L., Huang, H.Q., Baergen, R., Lele, S., et al. (2006) Intraperitoneal Cisplatin and Paclitaxel in Ovarian Cancer. The New England Journal of Medicine, 354, 34-43. http://dx.doi.org/10.1056/NEJMoa052985
Morgan Jr., R.J., Alvarez, R.D., Armstrong, D.K., Boston, B., Burger, R.A., Chen, L.M., et al. (2011) Epithelial Ovarian Cancer. Journal of the National Comprehensive Cancer Network, 9, 82-113.
Welfare Aloha. Australian Cancer Incidence and Mortality (ACIM) Books.
Jaaback, K., Johnson, N. and Lawrie, T.A. (2011) Intraperitoneal Chemotherapy for the Initial Management of Primary Epithelial Ovarian Cancer. The Cochrane Database of Systematic Reviews, 2011, Article ID: CD005340. http://dx.doi.org/10.1002/14651858.CD005340.pub3
Markman, M. (2009) An Update on the Use of Intraperitoneal Chemotherapy in the Management of Ovarian Cancer. Cancer Journal, 15, 105-109. http://dx.doi.org/10.1097/PPO.0b013e31819e31f2
Barlin, J.N., Dao, F., Zgheib, N.B., Ferguson, S.E., Sabbatini, P.J., Hensley, M.L., et al. (2012) Progression-Free and Overall Survival of a Modified Outpatient Regimen of Primary Intravenous/Intraperitoneal Paclitaxel and Intraperitoneal Cisplatin in Ovarian, Fallopian Tube and Primary Peritoneal Cancer. Gynecologic Oncology, 125, 621-624. http://dx.doi.org/10.1016/j.ygyno.2012.03.027
Blinman, P., Gainford, C., Donoghoe, M., Martyn, J., Blomfield, P., Grant, P., et al. (2013) Feasibility, Acceptability and Preferences for Intraperitoneal Chemotherapy with Paclitaxel and Cisplatin after Optimal Debulking Surgery for Ovarian and Related Cancers: An ANZGOG Study. Journal of Gynecologic Oncology, 24, 359-366.
Matsumura, Y. and Maeda, H. (1986) A New Concept for Macromolecular Therapeutics in Cancer Chemotherapy: Mechanism of Tumoritropic Accumulation of Proteins and the Antitumor Agent Smancs. Cancer Research, 46, 6387- 6392.
Bokemeyer, C. (2010) Catumaxomab—Trifunctional Anti-EpCAM Antibody Used to Treat Malignant Ascites. Expert Opinion on Biological Therapy, 10, 1259-1269. http://dx.doi.org/10.1517/14712598.2010.504706
Wimberger, P., Gilet, H., Gonschior, A.K., Heiss, M.M., Moehler, M., Oskay-Oezcelik, G., et al. (2012) Deterioration in Quality of Life (QoL) in Patients with Malignant Ascites: Results from a Phase II/III Study Comparing Paracentesis plus Catumaxomab with Paracentesis Alone. Annals of Oncology: Official Journal of the European Society for Medical Oncology, 23, 1979-1985.
Eskander, R.N. and Randall, L.M. (2011) Bevacizumab in the Treatment of Ovarian Cancer. Biologics: Targets & Therapy, 5, 1-5.
Folkman, J. (1971) Tumor Angiogenesis: Therapeutic Implications. The New England Journal of Medicine, 285, 1182- 1186. http://dx.doi.org/10.1056/NEJM197111182852108
Burger, R.A., Brady, M.F., Bookman, M.A., Fleming, G.F., Monk, B.J., Huang, H., et al. (2011) Incorporation of Bevacizumab in the Primary Treatment of Ovarian Cancer. The New England Journal of Medicine, 365, 2473-2483. http://dx.doi.org/10.1056/NEJMoa1104390
Perren, T.J., Swart, A.M., Pfisterer, J., Ledermann, J.A., Pujade-Lauraine, E., Kristensen, G., et al. (2011) A Phase 3 Trial of Bevacizumab in Ovarian Cancer. The New England Journal of Medicine, 365, 2484-2496. http://dx.doi.org/10.1056/NEJMoa1103799
Wagner, U., Marth, C., Largillier, R., Kaern, J., Brown, C., Heywood, M., et al. (2012) Final Overall Survival Results of Phase III GCIG CALYPSO Trial of Pegylated Liposomal Doxorubicin and Carboplatin vs Paclitaxel and Carboplatin in Platinum-Sensitive Ovarian Cancer Patients. British Journal of Cancer, 107, 588-591. http://dx.doi.org/10.1038/bjc.2012.307
Aghajanian, C., Blank, S.V., Goff, B.A., Judson, P.L., Teneriello, M.G., Husain, A., et al. (2012) OCEANS: A Randomized, Double-Blind, Placebo-Controlled Phase III Trial of Chemotherapy with or without Bevacizumab in Patients with Platinum-Sensitive Recurrent Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 30, 2039-2045.
Pujade-Lauraine, E., Hilpert, F., Weber, B., Reuss, A., Poveda, A., Kristensen, G., et al. (2014) Bevacizumab Combined with Chemotherapy for Platinum-Resistant Recurrent Ovarian Cancer: The AURELIA Open-Label Randomized Phase III Trial. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, Published Online.
Du Bois, A., Floquet, A., Kim, J.W., Rau, J., Maria Del Campo, J., Friedlander, M., Pignata, S., et al. (2013) Randomized, Double-Blind, Phase III Trial of Pazopanib versus Placebo in Women Who Have Not Progressed after First- Line Chemotherapy for Advanced Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer (AEOC): Results of an International Intergroup Trial (AGO-OVAR16). Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 31, Article ID: LBA5503.
Matulonis, U.A., Berlin, S., Ivy, P., Tyburski, K., Krasner, C., Zarwan, C., et al. (2009) Cediranib, an Oral Inhibitor of Vascular Endothelial Growth Factor Receptor Kinases, Is an Active Drug in Recurrent Epithelial Ovarian, Fallopian Tube and Peritoneal Cancer. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 27, 5601-5606.
Monk, B.J., Poveda, A., Vergote, I., Raspagliesi, F., Fujiwara, K., Bae, D.S. and Oaknin, A. (2013) A Phase III, Randomized, Double-Blind Trial of Weekly Paclitaxel plus the Angiopoietin 1 and 2 Inhibitor, Trebananib or Placebo in Women with Recurrent Ovarian Cancer: TRINOVA-1. European Journal of Cancer, 49.
DuBois, A., Kristensen, G., Ray-Coquard, I., Reuss, A., Pignata, S., Colombo, N. and Denison, U. (2013) AGO-OVAR 12: A Randomized Placebo-Controlled GCIG/ENGOT-Intergroup Phase III Trial of Standard Frontline Chemotherapy +/− Nintedanib for Advanced Ovarian Cancer. International Journal of Gynecological Cancer: Official Journal of the International Gynecological Cancer Society, 23, Oral Abstract.
Liu, J.F., Konstantinopoulos, P.A. and Matulonis, U.A. (2014) PARP Inhibitors in Ovarian Cancer: Current Status and Future Promise. Gynecologic Oncology, 133, 362-369. http://dx.doi.org/10.1016/j.ygyno.2014.02.039
Weberpals, J.I., Clark-Knowles, K.V. and Vanderhyden, B.C. (2008) Sporadic Epithelial Ovarian Cancer: Clinical Relevance of BRCA1 Inhibition in the DNA Damage and Repair Pathway. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 26, 3259-3267.
Audeh, M.W., Carmichael, J., Penson, R.T., Friedlander, M., Powell, B., Bell-McGuinn, K.M., et al. (2010) Oral Poly(ADP-ribose) Polymerase Inhibitor Olaparib in Patients with BRCA1 or BRCA2 Mutations and Recurrent Ovarian Cancer: A Proof-of-Concept Trial. The Lancet, 376, 245-251. http://dx.doi.org/10.1016/S0140-6736(10)60893-8
Gelmon, K.A., Tischkowitz, M., Mackay, H., Swenerton, K., Robidoux, A., Tonkin, K., et al. (2011) Olaparib in Patients with Recurrent High-Grade Serous or Poorly Differentiated Ovarian Carcinoma or Triple-Negative Breast Cancer: A Phase 2, Multicentre, Open-Label, Non-Randomised Study. The Lancet Oncology, 12, 852-861. http://dx.doi.org/10.1016/S1470-2045(11)70214-5
Kaye, S.B., Lubinski, J., Matulonis, U., Ang, J.E., Gourley, C., Karlan, B.Y., et al. (2012) Phase II, Open-Label, Randomized, Multicenter Study Comparing the Efficacy and Safety of Olaparib, a Poly(ADP-Ribose) Polymerase Inhibitor, and Pegylated Liposomal Doxorubicin in Patients with BRCA1 or BRCA2 Mutations and Recurrent Ovarian Cancer. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 30, 372-379.
Ledermann, J., Harter, P., Gourley, C., Friedlander, M., Vergote, I., Rustin, G., et al. (2012) Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer. The New England Journal of Medicine, 366, 1382-1392. http://dx.doi.org/10.1056/NEJMoa1105535
Kummar, S., Ji, J., Morgan, R., Lenz, H.J., Puhalla, S.L., Belani, C.P., et al. (2012) A Phase I Study of Veliparib in Combination with Metronomic Cyclophosphamide in Adults with Refractory Solid Tumors and Lymphomas. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 18, 1726-1734.
Coleman, R.L., Sill, M. and Aghajanian, C. (2013) A Phase II Evaluation of the Potent, Highly Selective PARP Inhibitor Veliparib in the Treatment of Persistent or Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer in Patients Who Carry a Germline BRCA1 or BRCA2 Mutation—A Gynecologic Oncology Group Study. Proceedings of Society of Gynecologic Oncology 45th Annual Meeting on Women's Cancer, Tampa, 22-25 March 2014, Abstract 136.
Jones, P., Altamura, S., Boueres, J., Ferrigno, F., Fonsi, M., Giomini, C., et al. (2009) Discovery of 2-{4-[(3S)-Piperidin- 3-yl]Phenyl}-2H-Indazole-7-Carboxamide (MK-4827): A Novel Oral Poly(ADP-Ribose)Polymerase (PARP) Inhibitor Efficacious in BRCA-1 and -2 Mutant Tumors. Journal of Medicinal Chemistry, 52, 7170-7185. http://dx.doi.org/10.1021/jm901188v
Sandhu, S.K., Schelman, W.R., Wilding, G., Moreno, V., Baird, R.D., Miranda, S., et al. (2013) The Poly(ADP-Ribose) Polymerase Inhibitor Niraparib (MK4827) in BRCA Mutation Carriers and Patients with Sporadic Cancer: A Phase 1 Dose-Escalation Trial. The Lancet Oncology, 14, 882-892. http://dx.doi.org/10.1016/S1470-2045(13)70240-7
Kristeleit, R.B.H., LoRusso, P., Patel, M., Giordano, H. and Evans, J. (2013) Phase I Study of Continuous Oral Rucaparib: Analysis of Patient Subgroup with Ovarian/Peritoneal Cancer. International Journal of Gynecological Cancer, 23, S564.
Gonzalez-Martin, A., Gladieff, L., Tholander, B., Stroyakovsky, D., Gore, M., Scambia, G., et al. (2013) Efficacy and Safety Results from OCTAVIA, a Single-Arm Phase II Study Evaluating Front-Line Bevacizumab, Carboplatin and Weekly Paclitaxel for Ovarian Cancer. European Journal of Cancer, 49, 3831-3838.
Dean, E., Middleton, M.R., Pwint, T., Swaisland, H., Carmichael, J., Goodege-Kunwar, P., et al. (2012) Phase I Study to Assess the Safety and Tolerability of Olaparib in Combination with Bevacizumab in Patients with Advanced Solid Tumors. British Journal of Cancer, 106, 468-474. http://dx.doi.org/10.1038/bjc.2011.555
Cameron, E. and Pauling, L. (1976) Supplemental Ascorbate in the Supportive Treatment of Cancer: Prolongation of Survival Times in Terminal Human Cancer. Proceedings of the National Academy of Sciences of the United States of America, 73, 3685-3689. http://dx.doi.org/10.1073/pnas.73.10.3685
Padayatty, S.J., Sun, A.Y., Chen, Q., Espey, M.G., Drisko, J. and Levine, M. (2010) Vitamin C: Intravenous Use by Complementary and Alternative Medicine Practitioners and Adverse Effects. PLoS ONE, 5, e11414. http://dx.doi.org/10.1371/journal.pone.0011414
Drisko, J.A., Chapman, J. and Hunter, V.J. (2003) The Use of Antioxidant Therapies during Chemotherapy. Gynecologic Oncology, 88, 434-439. http://dx.doi.org/10.1016/S0090-8258(02)00067-7
Prasad, K.N., Cole, W.C., Kumar, B. and Che Prasad, K. (2002) Pros and Cons of Antioxidant Use during Radiation Therapy. Cancer Treatment Reviews, 28, 79-91. http://dx.doi.org/10.1053/ctrv.2002.0260
Frei, B. (1994) Reactive Oxygen Species and Antioxidant Vitamins: Mechanisms of Action. The American Journal of Medicine, 97, 5S-13S.
Nakayama, A., Alladin, K.P., Igbokwe, O. and White, J.D. (2011) Systematic Review: Generating Evidence-Based Guidelines on the Concurrent Use of Dietary Antioxidants and Chemotherapy or Radiotherapy. Cancer Investigation, 29, 655-667. http://dx.doi.org/10.3109/07357907.2011.626479
Lawenda, B.D., Kelly, K.M., Ladas, E.J., Sagar, S.M., Vickers, A. and Blumberg, J.B. (2008) Should Supplemental Antioxidant Administration Be Avoided during Chemotherapy and Radiation Therapy? Journal of the National Cancer Institute, 100, 773-783. http://dx.doi.org/10.1093/jnci/djn148
Thomson, C.A., Neuhouser, M.L., Shikany, J.M., Caan, B.J., Monk, B.J., Mossavar-Rahmani, Y., et al. (2008) The Role of Antioxidants and Vitamin A in Ovarian Cancer: Results from the Women's Health Initiative. Nutrition and Cancer, 60, 710-719.
Harris, H.R., Orsini, N. and Wolk, A. (2014) Vitamin C and Survival among Women with Breast Cancer: A Meta- Analysis. European Journal of Cancer, 50, 1223-1231. http://dx.doi.org/10.1016/j.ejca.2014.02.013
Vance, T.M., Su, J., Fontham, E.T., Koo, S.I. and Chun, O.K. (2013) Dietary Antioxidants and Prostate Cancer: A Review. Nutrition and Cancer, 65, 793-801. http://dx.doi.org/10.1080/01635581.2013.806672
Mamede, A.C., Pires, A.S., Abrantes, A.M., Tavares, S.D., Goncalves, A.C., Casalta-Lopes, J.E., et al. (2012) Cytotoxicity of Ascorbic Acid in a Human Colorectal Adenocarcinoma Cell Line (WiDr): In Vitro and in Vivo Studies. Nutrition and Cancer, 64, 1049-1057. http://dx.doi.org/10.1080/01635581.2012.713539
Chen, Q., Espey, M.G., Sun, A.Y., Lee, J.H., Krishna, M.C., Shacter, E., et al. (2007) Ascorbate in Pharmacologic Concentrations Selectively Generates Ascorbate Radical and Hydrogen Peroxide in Extracellular Fluid in Vivo. Proceedings of the National Academy of Sciences of the United States of America, 104, 8749-8754. http://dx.doi.org/10.1073/pnas.0702854104
Cancer Genome Atlas Research Network (2011) Integrated Genomic Analyses of Ovarian Carcinoma. Nature, 474, 609-615. http://dx.doi.org/10.1038/nature10166
Davidson, B., Trope, C.G. and Reich, R. (2014) The Clinical and Diagnostic Role of microRNAs in Ovarian Carcinoma. Gynecologic Oncology, 133, 640-646. http://dx.doi.org/10.1016/j.ygyno.2014.03.575
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text:
Off Your Radar
Issue #109: Grief Pedigree by Ka
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Grief Pedigree by Ka
Released By Iron Works Records
This Week's Selection Chosen By Kellen "J. Clyde" Ford
"The loudest one in the room is the weakest one in the room."
Denzel Washington as Frank Lucas. American Gangster, 2007
One huge thing that I think everyone misses about the legacy of The RZA is that he made hip hop so intimate. He took it out of the club, and brought it to your headphones by making audio-movies that were seemingly best enjoyed one person at a time — on your headphones. I grew up in apartments for most of my life. I always wanted to play drums, but my living situation made that an impossibility. That, and my father is an extremely cautious man. I was banned from even having my bedroom speakers at a reasonable volume, so my headphones became my world. I digested every morsel of music on headphones. I learned to DJ on headphones. I learned to make beats on headphones. And to this very day, I still make and mix all of my own music on headphones (note: I also still live in an apartment). For records like Only Built 4 Cuban Linx or Ironman or Supreme Clientele, the absolute best way to enjoy them is on headphones, laying in bed with the lights off, pillow over my face to prevent any distractions or additional sensory stimulation. Ka's Grief Pedigree is one of those albums.
The overall sound of the record is vintage New York. It's the exact minimalist sound that made me fall in love with hip hop in the first place. In fact, when I first heard Grief Pedigree, I called several friends and recommended it by saying "it's exactly like the first time you heard the classic Wu stuff." What I meant with that statement was that there is a cohesive, grimy, continuously guttural vibe that carries us through Ka's life on the streets of Brownsville. Part of the reason I admire this record so much is that not only did Ka deliver a masterful performance on the mic, with only one feature, mind you, but he also produced the entire record himself! Some of the records have drums. Some of them don't. There's no hiding behind massive 808 bass drums or extra instrumentation. The music is raw, and, by its minimal nature, makes you pay attention to the lyrics in ways that you normally wouldn't. That, and you're already listening to the record with your full attention on headphones. And then there's Ka's voice. His gravely bars hold that much more weight for the simple fact that he doesn't have to raise his voice. It's kind of like when Sonny in Bronx Tale calmly told the biker gang "now you's can't leave." His production style accommodates his delivery perfectly, or is it the other way around?
PSA: You know you're knee deep in graduate-level-rap-nerd-talk when anyone quotes or makes reference to any Gravediggaz record.
Remember that line in Gravediggaz' "Diary Of A Madman" where RZA says "about to die from thirst, that's when the minister / quenched my jaws with a cold glass of vinegar"? Well, that's what Grief Pedigree is — rap's cold glass of vinegar.
The entire album is haunting. Even the clever "Decisions," which is by far the lightest moment on the album, refrains that "a simple right or left could mean life or death." Ka works in pain and angst the way other artists might work in oils or clay (boom, A Christmas Story reference). I swear, he talks about the hood and the accompanying drug trade in the simplest, yet slickest ways I've ever heard. The metaphors at play here are extraordinary. For instance, there's "Cold Facts" where he talks about "pyrotechnics with no alarms / I blew up the block, and I sold the bombs." Even better, on "Up Against Goliath," he proclaims that he's "up against Goliath, to bring butter home / I'm David on the pavement, sling another stone." There's even a few bits of dark humor along the way, like on "Every…" where he pines "from amazin' days, and nights excitin' / where you get played for playin', and learn how to fight by fightin'." The point is, where his voice is short on volume, he's a giant with the lyrics.
I appreciate this record so much because it's uncompromising. While all of his peers were making New York City sound like Atlanta, Ka stood strong, and put together a masterpiece without having to venture outside of his own neighborhood. And he put together this masterpiece fully aware that it would go under the radar, completely unappreciated by the masses, but he did it anyway. For the art. If that isn't the prototype for what we do here at OYR, then I don't know what is.
Kellen "J. Clyde" Ford (@jclyde757)
Steadfast Hip-Hop Historian & Creator
http://jclydebeats.com
Kaseem Ryan — Brownsville FDNY firefighter by day, hip-hop dignitary by night.
Blonde, tall, crystalline blue eyes… my first mentor taught me so much about art, presenting yourself, and grace. A former advertising executive for Coca-Cola, she had somehow landed back in Auburn, Alabama, running an art gallery where I learned to be a photographer. Once, in expressing frustration that one of the older white male English professors I had would never listen to me in class, choosing instead to relentlessly call on the few lower-classman men in the room, she told me to speak lower, not louder. "If you're quieter than they are and just keep talking, eventually they'll shut up, lean in, and listen," she said, matching frame samples to a watercolor. That seemingly contrary advice played in my mind all week alongside Grief Pedigree, a surprisingly calm hip-hop album from Ka. Overwhelmingly subdued, the album plays best in one listen, a flowing, hypnotic expression. Ka has said in the past he felt beaten by the talent in the field when comparing himself to other rappers, even in his previous group Natural Elements. On this album, though, his sophomore solo attempt, the juxtaposition of those quietly compelling beats against socially aware lyrical content doesn't measure up to his self-evaluation. Perhaps his unaffected vocals could be viewed as less than by some, but there is power in that voice you have to lean in to hear.
Laura Burroughs (@_thetwors)
Jestful Musical Erudite
If you haven't been listening to the I Only Listen To The Mountain Goats podcast, I highly recommend jumping in, whether or not you're a fan of John Darnielle and company. The discussions typically veer into territory related to the creative process, and the "Jenny" episode includes a deep dive on form and the benefits of creative restrictions. Well worth a listen. It's a tried-and-true paradox — the idea that challenging yourself to draw between certain lines can result in a renewed sense of freedom. Ka got me thinking about that paradoxical approach when I was listening to "Decisions." The strict lyrical structure reminds me of two of my all-time favorite hip-hop performances: the nimble, homonym-happy track from Jay-Z's Reasonable Doubt album, "22 Two's," and Big L's "Ebonics," which serves as a dictionary for hip hop neophytes, with a "X is Y" structure (my favorite iteration: "If you got the dragon you got bad breath") that serves as a close parallel to the "X or Y" equation you hear on Ka's "Decisions." Like those other brilliant pieces of writing, the themes "Decisions" touches on are serious ("A simple right or left could mean life or death"), but the formal backdrop sets the stage for an exhibition of structural inventiveness that uplifts. And "Decisions" gets a warm, nostalgic boost via looping production that makes masterful use of a sampled Hammond B-3 organ, just as Kanye West did at the start of his undeniable Jay-Z collaboration "Otis." It's a formal sense of fun balanced with a palpable sense of command — and it sounds masterful.
Davy Jones (@youhearthat)
Idealistic Seeker Of Neoteric Sounds
http://youhearthat.wordpress.com
My favorite sentence on Ka's website is on a page called Guidelines: "Please have patience with your order, I don't go to the post office everyday." Talk about keeping it real! I first came across that line back in 2016 when I was grooving hard to the spare beats and smart rhymes on his album Honor Killed The Samurai and thought I would order a copy to give to a young cousin of mine. Unfortunately, my gifting schedule was too tight for such vague promises and I ended up going with something else. But that doesn't mean I don't think every hip hop fan, especially of the east coast gritty variety, should be up on Ka. I connect to his deep New York roots and the "grief pedigree" he has from growing up in a tough neighborhood where you always had to be on high alert. While Manhattan Valley (now part of the Upper West Side) was never as brutal as Brownsville where he's from, it was no joke having people constantly angling to get something of yours away from you — and often succeeding. While Ka doesn't quite achieve the heights of some other NYC legends (Prodigy, for example — a definite influence here) at their best, there's an admirable consistency to his work, perhaps due to the complete lack of commercial striving behind his music. He makes it clear in interviews that he doesn't need to make any money off of his records thanks to his job as a Fire Captain in the FDNY, so everything he does is for the love of it and the pursuit of excellence. All that said, I came to his story via a dim awareness of Natural Elements, the '90s collective he was a part of, and then The Knight's Gambit, the 2013 follow-up to Grief Pedigree, so many thanks to J. Clyde for giving me the impetus to look back a little further in Ka's career. And I found a number of new favorite tracks from him. Take your pick from "No Downtime," "Decisions," "Up Against Goliath," or "Born King N.Y. to hear him at his hypnotic best. But enough of my yakkin', let Ka tell you who he is: "The gifted narrator /Gunmetal gray rhymes, your scripts is lavender / Poor all my life, but rich in character / Wise civilized, don't make me flip to savage ya / The proven wizard that move deliberate / Way of tools exhibit the rules are rigid / Reside and abide, or lose your gizzards."
Jeremy Shatan (@anearful)
Prescient & Appreciative Musical Omnivore
http://anearful.blogspot.com
Click here to watch the minimally expressive video for "Cold Facts."
Interestingly enough, every track on Grief Pedigree has a video as sly as this.
I don't listen to hip hop all the time but it's a genre that has a lot of aspects I enjoy, so I'm always happy when a hip hop album comes up on Off Your Radar — if nothing else, it forces me to spend a little more time with the genre in a particular week than I might have otherwise. Ka's Grief Pedigree is pretty much exactly what I want when that happens, too. As with the Ka album I was previously familiar with (The Night's Gambit, his 2013 follow-up to Grief Pedigree), this album has an unrelentingly dark mood that emphasizes the dead-serious intensity of Ka's lyrics and delivery. The persistently ominous musical backing tracks, produced in minimal, repetitive fashion by Ka himself, only further underscore the mood he's attempting to create. While standout tracks are relatively rare — the foreboding funk of "No Downtime" is most noteworthy — Ka's ability to paint a musical and lyrical picture of desperate living in a world of desperation, crime, and neglect is all but unparalleled. Songs like "Vessel" juxtapose stark, hollow beats with harsh lyrical tales of street-level survival in a world with no mercy. It's not glorified or romanticized, just described in an unflinching manner that makes it hit much harder than the cartoonish gangsta tales that are always most popular in the hip hop world. This isn't a fun album, by any means, but it's an incredibly worthwhile listen, one that will suck you into its world if you let it.
Drew Necci (@buzzorhowl)
Insightful Scholar Of The Underground
http://gayrva.com
As a music fanatic, I'm pretty sure I'm not alone in saying that there are some albums that, for one reason or another, are slow burners, requiring several listens before I begin to recognize how wonderful it is. Ka's Grief Pedigree falls squarely into this category for me. When I first listened to it, I was on my way to work and, frankly, this album deserves to be more than a soundtrack to a commute. Because I was focused on not missing my stop and ignoring the loud group of teenagers next to me, the music was largely relegated to background noise which is not a great way to make a first impression. My second listen to Grief Pedigree didn't fare much better: I was sitting at home and reading a book, once again putting my focus elsewhere. It wasn't until my third listen when I understood that I was going about it all wrong: this is a highly lyrical album and by putting it on in situations where I either couldn't hear the lyrics or I wasn't actively listening to them, I couldn't fully appreciate it. Ka is a sharp lyricist, using homonyms and double meanings to his advantage, painting images in a matter of seconds that it might take some entire paragraphs. "No Downtime," a song about Ka's experiences growing up and hustling in the city, has a lot of clever lines that highlight not only how important Ka's lyrics are, but Ka's mastery of using language as an art form. "In the city eatin' til the apple was a core" is a line that stuck out to me, and after browsing Genius to see what else I was missing, I came across "I'm the hustle, you the running man," an insult that both illustrates Ka's abilities on the streets, and compares two dances from different eras. There's a lot of unpack in that one song alone, so I'm positive that there are hundreds more couplets and one-liners scattered throughout each track that I haven't caught yet. I know I said that it wasn't a smart idea for me to read while listening to this album, but with the sheer number of lyrical references and double entendres on Grief Pedigree, I could make an exception if what I'm reading is a lyric sheet.
Dustin Gates (@cmoncheermeup)
Relapsed Pop Culture Junkie
http://dustinhatesmusic.blogspot.com
I'm a big fan of succinctness, and I imagine that's glaringly obvious. Still, it's worth mentioning explicitly in light of Ka's Grief Pedigree: 11 songs, 36 minutes, one feature, no skits. The no-bullshit-ness of it all it noble. Hell, I wish more rap albums would study Illmatic. But even with a lean runtime, there's still much to explore (including a Fight Club clip!) — particularly Ka's concise fatalism, the album's main throughline. He makes pithy, matter-of-fact observations like, "A simple right or left could be life or death." He also uses clever and darkly comical wordplay to advance his position: "Waltz up with the nina, no dance lesson." And when he states that he celebrates all of his blessings, it's no great leap to assume he includes a MAC-10—described as "reliable" — in that list. His cold and calculated delivery, reminiscent of an assassin, tells you he's speaking from experience. His slick, languid flow matches the album's August-humid production, too. The heat is suffocating like the Everglades throughout, mirroring the inescapability of Ka's worldview. So of course the album's sunniest song is also its bleakest. Honestly, it wouldn't make sense any other way. Four years prior to this album, Ka made an appearance on GZA's Pro Tools where he declared, "I tour with toast 'cause drama's always close." Given Grief Pedigree's content, I don't doubt that.
Steve Lampiris (@stevenlampiris)
Sure, Let's Go With That
http://stevelampiris.com
Over relaxed but florid beats, Ka's cursive flow swells around reflective detections & empathetic admissions.
Much of the time, when faced with a straight up hip-hop / rap based pick for the newsletter, what ends up being my main takeaway is the lyrical depth. This week's 2012 selection by J. Clyde lands within this same ball park. However, Grief Pedigree isn't all about making listeners lean on the narrative for an enjoyable experience. Sure, there are electronic strings and repeated melodic motifs that help to hold up the eleven track record. Nevertheless, the way the sounds are shaped and paired (sounds of vintage vinyl cracks and pops, organ that seems filtered to a mono-like quality of sound, and quiet studio piano that could easily fit into any modern dub or ambient track,) make the musical framing of Ka's narrative's entertaining and fascinating as well. This bit of sonic texture and stylistic diversity gives the album a default level of good replay value, if for no other reason than listeners would need to give the music and lyrical sides of the album undivided attention respectively. Add to this the use of historical spoken samples — and one's referencing a New York City of the past at that — and some listening to Grief Pedigree can come away with fun conceptual bonuses that perpetuate a connective listening experience, should you happen to be from, or frequently visit, the Big Apple. Then of course, it's interesting to dissect and really take in what each track has to say verbally but admittedly, that takes some dedicated energy and if you're not partial to hearing n***** (regardless of the grey social complexities of the term's inclusion on rap tracks of different artists), it might take extra patience to get to the end. Hopefully thought, this one element won't be a full deterrent for anyone out there curious to hear non-run-of-the-mill hip hop.
Kira Grunenberg (@shadowmelody1)
Prolific Sonic Scribe & Unifier
http://throwthediceandplaynice.com
While I like a lot of music, and a lot of different genres, rap has never really been a favourite of mine. That being said, I do like to give everything a chance and I found that this album had a very nice laid back vibe to it, which is a nice contrast to some other rap albums that almost excel at being "in your face." The backing tracks have a great flow and I like how each track kind of just blends in to the next, making it more of an overall listening experience as opposed to listening song by song. Ka's vocals also have very nice rhythm and his lyrics are more varied and in depth. He raps about life experiences rather than money, sexy women, and how famous he is, and this just makes it more relatable even if his life experience is vastly different than yours or mine. I also really enjoyed that some of the songs had a spoken word intro / outro. Just an unique twist and adds something extra to this very special hip hop album.
Chelsea Kostrey (@chelseakostrey)
Retrophile & Festival Enthusiast
http://ckostrey.wixsite.com/chelseakostrey
"Magician this scripture, flame on paper, no pages smokin' / Feel this realness, I ain't on stage just boastin'" — that line pops up in the opening track to Grief Pedigree. Along with mentions of drugs, crime, and violence, it puts Ka's lyricism within the catch-all topics of hip hop culture that most sadly recognize. It's braggadocious, but in a tangible way that you can feel throughout his record, and by putting it in the forefront of the record, he allows himself about a half-hour to prove that it's not bluster — it's truth. A few songs later, on "No Downtime," he opens up in a very subtle manner that reinforces that bold claim by showing off his insatiable work ethic and the anxiety that certainly must come with it: "We, never at ease no downtime / I'm sick with it, y'all niggas sound fine / From where it's hard, a man stressin / Either starve or pull a transgression." It's this ability to couple real observations and vulnerable admissions with the familiar topics and guideposts that give you a sense of who he truly is, and I don't just mean where he's been and what he's seen. The Brownsville neighborhoodof Brooklyn shaped who he is and he's proud of it — according to his own annotation, the song "Born King N.Y." is in reference to BKNY (Brooklyn, New York) — but it's also clear he's not defined by it as this crucial line in album stand-out "Vessel" states: "Everybody all over the fucking world man/ If you're a live nigga, it's just your music, it's for you." You'll find empowering lines like this throughout Grief Pedigree which all add to Ka's ridiculously impressive DIY ethos. Not only did Ka produce, write, and record this record himself, but he also directed and edited all eleven music videos that accompany the songs here, but what else should you expect from someone who's a full-time New York firefighter and part-time hip-hop luminary? The double-life must weight on him to some degree though. In "Decisions," he casually asks: "Is this lust or do I love this shit?" You only need to listen to one song off of this imposing album to know the true answer to that ridiculous question.
Doug Nunnally (@musicdoug)
Garrulous Aural Braggart
http://sound-gaze.com
Next Week's Selection:
The End Of History by Fionn Regan
Chosen By Guest Contributor Jess Abbott (Tancred)
Off Your Radar Newsletter
Editor: Doug Nunnally
Contributors: James Anderson, Laura Burroughs, Erin Calvert, Catherine Dempsey, Kellen "J. Clyde" Ford, Dustin Gates, Kira Grunenberg, Davy Jones, Chelsea Kostrey, Steve Lampiris, David Munro, Drew Necci, & Jeremy Shatan
Logo By Matt Klimas
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John Grosvenor is the artist behind GrosvenorDesign. John graduated from the Columbus College of Art & Design with a BFA in Illustration in 1996 and he has been freelancing in the Ohio area for many years now.
John established GrosvenorDesign in 2000 and has been focusing his energies on the illustration field and is constantly refining his skills and technical knowledge to keep pace with the demands of the digital age. In creating his digital illustrations, John integrates traditional techniques and media with digital creative software.
The driving theme behind GrosvenorDesign is to give each of our clients an experience in Illustration that quickly and effectively meets their design needs. GrosvenorDesign gives your project professional execution without leaving you feeling as if you had to settle for sub par artwork. Whether it is in books, magazines, film, or the internet, GrosvenorDesign has the skill-set to successfully fulfill your illustration and design project.
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Cliff Brunt
Published: April 7, 2020, 8:47 pm Updated: April 7, 2020, 9:06 pm
Tags: Sports, Mike Holder, Mike Gundy
Florida police, National Guard prepare for 'most secure inauguration ever'
City vaccine sites at senior centers could close soon
Oklahoma State's Gundy targets May 1 return to football
In this Nov. 30, 2019 file photo Oklahoma State head coach Mike Gundy walks on the sidelines during an NCAA college football game against Oklahoma in Stillwater, Okla. Gundy said Tuesday, April 7, 2020 he hopes to have his team return to its facilities on May 1, a proposed timetable that would defy federal social-distancing guidelines and was quickly disputed by the university and its athletic director. (AP Photo/Sue Ogrocki) (Copyright 2019 The Associated Press. All rights reserved.)
Oklahoma State coach Mike Gundy said Tuesday he hopes to have his team return to its facilities on May 1, a proposed timetable that would defy federal social-distancing guidelines and was quickly disputed by the university and its athletic director.
The Centers for Disease Control and Prevention has recommended against gatherings of 50 or more people through May 11 to prevent the spread of the new coronavirus, which as of Tuesday had infected more than 380,000 people in the United States — more than any other country in the world — and killed 81,000 worldwide, including at least 11,000 in the U.S.
Gundy, who has been outspoken about his right-wing politics, also said in a conference call with reporters that the media has been too negative in its coverage of what he called the "Chinese virus."
Most Americans are living under stay-at-home orders, many of which extend past May 1, although Oklahoma Gov. Kevin Stitt, a Republican, has only urged people under 65 to stay home while banning gatherings of more than 10 people through April 30.
Gundy said he hopes there will be enough tests available in a few weeks that he could get his assistant coaches and support personnel tested for the virus, followed by the players, so his program can get back to business.
"I can't say right now, but that's the plan," Gundy said. "We have to have a plan, and the plan right now is for them to start on May 1."
Like many Division I football programs, Oklahoma State has more than 100 players on its roster along with a coaching staff of 35 people. The university has canceled in-person classes for the spring semester and moved its May graduation ceremonies to December.
Following Gundy's comments, OSU issued a statement saying, essentially, that the decision about when to bring the football team back together wouldn't be up to the coach.
"We will adhere to the advice of public health experts who are making informed decisions in the best interest of the citizens of our nation and state based on sound scientific data," the university statement said. "We will also abide by the federal and state mandates as well as Big 12 guidelines. We will not compromise the health and well-being of our campus community. This virus is deadly and we will do our part at Oklahoma State to help blunt the spread."
Athletic director Mike Holder also declined to back Gundy's timeline, saying in a statement: "May 1 seems a little ambitious."
Gundy said he was interested in hearing more positive news about the COVID-19 pandemic, which has crippled economies and forced restrictions on the movement of people around the world in an effort to stop the virus from spreading further and overwhelming health care systems.
"I'm seeing total number of cases, but what I'm not seeing is how many number of those cases that are now back to a normal life," Gundy said, adding: "It's really interesting to me to see with the mainstream media, sadly enough, just how negative everybody can be. Let's just report the news. Let's start putting some things in there that are positive, because I know there's positive out there."
The NCAA has canceled all spring sports, and there is no date in place for college teams to return to practice. Gundy said if his target date doesn't work, he'd be willing to push things back — but not too far.
"It might get backed up two weeks," Gundy said. "I don't know, I can't make that call. But if it does, we'll start with the employees of this company — the ones that come in this building. Then we'll bring the players in, and slowly but surely. We test them all in. Is it 100 percent? No, it's not 100 percent."
Gundy said he isn't trying to be insensitive to those who are sick, but he believes things need to get back to normal sooner rather than later. Oklahoma State is scheduled to begin its season on Sept. 3, hosting Oregon State.
"The curve's going to flatten so we can get our state back to work," Gundy said. "So we just continue with our safety measures to give us the best chance to get back to work and get back to a normal daily operation as soon as possible."


The Novel Construction Fall Session took place in Geneva, Switzerland on Wednesday and Thursday, 24 - 25 October 2018. We would like to thank everyone for their active participation and collaboration.
In order to review the agenda including the Novel Initiatives presented, please click here.
The meetings were held at the Crowne Plaza Hotel where people from different companies gathered for a productive session to discuss new construction technologies.
For the second time, IPLOCA offered a webcast for part of the H&S Workshop and the Novel Construction Session. We hope you were able to take advantage of this offer if you were unable to attend the session.
Can we still innovate in the Onshore Lines Protections?


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Home > Cases > Gibson et al.
Ministerio Fiscal v. Shawn "Thomas" Gibson, Philip Wolford and Philip De Camp
This case summary is being revised and will be updated soon
Court Audiencia Nacional / National Court (High Court), Spain
Case number 144/2009
Decision title Auto
Decision date 14 July 2009
Ministerio Fiscal (Public Prosecutor)
Shawn "Thomas" Gibson
Philip Wolford
Philip DeCamp
José Couso Case
Auto ordenando la conclusión sumario del caso (in Spanish)
Judicial investigations into the incident were initiated in 2005 by Judge Santiago Gomez (Audiencia nacional), who ordered the arrest of three US soldiers, Sgt. Shawn Gibson, Capt. Philip Wolford and Lt. Col. Philip De Camp, in October of the same year.
However, this detention order was overturned in 2006 on issues of jurisdiction, before the Supreme Court of Spain decided to reissue arrest warrants in December 2006. The soldiers were then indicted in April 2007, but the charges were dropped due to lack of evidence.
See also: 18-05-2007 - Recurso del Fiscal, 18 May 2007; Auto del Juez Santiago Pedráz, 24 May 2007; Auto de la sala de lo penal de la Audiencia nacional, 16 May 2008)
In 2009, Judge Gomez issued a new indictment against the same soldiers, for the same charges, stating that the testimony of three journalists provided evidence sufficient to support the initial homicide allegations.
In July 2010, the Spanish Supreme Court ordered a lower court to reopen the investigation. Subsequently, an arrest warrant was issued on 29 July 2010 by Judge Santiago Pedraz.
José Couso was a Spanish cameraman who died in Iraq in 2003, when US soldiers allegedly opened fire on a Baghdad hotel frequented by journalists.
On 14 July 2009, the Spanish Audiencia Nacional dismissed the charges, ruling that Judge Gomez had produced no new evidence against the soldiers.
TRIAL Fact Sheet: Shawn Gibson.
TRIAL Fact Sheet: Philip Wolford.
TRIAL Fact Sheet: Philip DeCamp.


Farmers are being urged not to be April fools when it comes to electricity, following a surge in the number of agricultural accidents involving overhead lines.
Fortunately, the driver of this vehicle at Flawborough in Nottinghamshire escaped unhurt when his tractor crashed into a pylon while using autosteer.
As the country's largest electricity network operator, we are warning that accidents involving electricity are endangering life and costing farmers thousands of pounds a year.
Every year, we respond to hundreds of incidents in which farm workers and/ or vehicles have come into contact with electricity, usually overhead lines. In one incident in Nottinghamshire, 1,300 homes were left without power when a tractor crashed into a pylon while using auto-steer.
The latest figures show that at least one agricultural accident involving overhead lines is reported every day – up by more than 100 a year, from 263 in 2013 to 378 in 2018. In the last five years, there have been more than 1,140 near misses involving electricity on farmland.
Most accidents involve farm vehicles fitted with Sat Nav or other automated steering systems, which do not take into account poles, pylons and overhead lines nearby.
Dave added: "This campaign is all about working together. We want to give farmers the information and advice they need to be aware of the dangers and do their jobs safely so that we, in turn, can operate the network safely." Additional risks are posed by objects, such as straw bales or even new buildings, being placed too close to overhead lines.
In an electricity emergency, farm workers should call 105, the national emergency number. If contact is made with a power line, they are advised to stay in the cab and try to drive clear. If that is not possible, the driver should stay in the cab and contact 105, only leaving the machine in an emergency. When leaving the vehicle, they should take care not to hold the machine and touch the ground at the same time; they should take leaping strides or 'bunny hop' away so that one foot is off the floor at all times.
You cannot see electricity – the area around a fallen line, including the soil, equipment and other objects, could be live - so stay away.


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Once more into the breach: The "Bitlicense" battles continue
Posted on May 12, 2017 May 12, 2017 by Babu Kumaran
Guest post by Colin Gallagher, Advisory Board Member at Lifeboat Foundation (https://lifeboat.com/ex/bios.colin.gallagher)/Chair of Education Committee, Bitcoin Foundation/Visionary for ABIS (http://abis.io )
California's third try at passing a bad bill
Once again, the California legislature is attempting to pass "Bitlicense," an effort by the state to require you to obtain an expensive permit, audits, and background check, merely to express yourself and choose how you wish to transact with others. The Electronic Frontier Foundation, a nonprofit that defends the rights of people in California and beyond, recently sent a letter to the legislature opposing AB 1123 (California's latest "Bitlicense" attempt).
AB 1123, authored by Dababneh, is California's third try at passing bad legislation on the subject of usage of what now are over 700 distributed, decentralized virtual systems, which have applications that cannot be simply described as "money," since they are actually decentralized ledgers and a form of public expression.
As with AB 1326 (the previous "Bitlicense" bill that failed to pass in California – twice) AB 1123 fails to focus on security of exchanges. Some of the best minds in bitcoin, including Andreas Antonopoulos and others, have already designed some security standards that can could be made applicable to exchanges. However, AB 1123 doesn't attempt to set a minimum security standard for exchanges. (As I've asserted before, people should not rely upon exchanges, and should not store funds in them for long periods, in part due to persistent security issues.) Instead, in a fatal flaw, AB 1123 tries to regulate the behavior of all individuals who might ever use any of the over 700 distributed, decentralized virtual systems – bitcoin or any other.
Are you a merchant who would use bitcoin for anything other than receiving it in exchange for your product? Make donations? Sending it to your friend's startup without permission of the state? In each case, you'd be a criminal under AB 1123!
Feel like applying for a permit to make donations to someone in this state? Get ready: Depending on the whim of a commissioner, you would have to fork out 500 dollars — initially. Don't forget your nonrefundable "application fee" — $3,500. Renewals? They've got that covered. $2,500 annually. Branch office fees? $125 to each branch office involved. Oh, and $75 dollars per hour would be billed to you for the benefit of the state examiners who would scrutinize your application to express yourself, innovate, and choose the medium of exchange that you personally prefer. If AB 1123 passes, companies will absolutely flee California at rates previously unseen. (Although this article deals specifically with crypto related issues, it's worth a mention that California's enactment of SB 1 (increase in gas tax and registration) and its proposal to enact SB 640 (tax on all services) will also force more people out of the state.)
AB 1123 would, if passed and signed into law, necessitate surveillance and monitoring that would conflict with laws of CA, such as CalECPA (SB-178), which was designed specifically to limit surveillance in California and require warrants. The implementation of AB 1123 would involve state regulators attempting to identify whoever uses decentralized, distributed systems and then sending them warrants, creating a chilling effect for anyone considering doing anything online. It would transform California's digital landscape into a system reminiscent of East Germany and California's regulators into the Stasi.
If you live in California, contact your state legislators and urge them to oppose AB 1123, the third attempt by the legislature to license innovation and free expression. Contact the Governor and ask him to veto AB 1123 if it arrives at his desk (you can do this from anywhere in the world, regardless of whether or not you live in California). Remind them that AB 1123 is merely a renumbered version of AB 1326, which the people of the state have successfully defeated twice before.
Sending California's bitlicense to defeat when it first emerged was a victory worth celebrating — and we must do it again. California should not be allowed to fall prey to the same blunders that have cast New York (and some other states) in a financial stone age, and we deserve the freedom to be innovators (without state sanction) both in the making of new decentralized systems as well as in our daily actions and explorations of new systems.
What happened with the New York bitlicense?
AB 1123 is similar to the approach that New York took when it adopted a bitlicense. Many companies ceased to operate in New York as a result of it.
A partial list of companies that immediately left NY were: BitQuick, Eobot, Genesis Mining, GoCoin, Kraken, LocalBitcoins, Paxful, and Poloniex. Kraken, an exchange headquartered in San Francisco, CA, said the license "comes at a price that exceeds the market opportunity of servicing New York residents. Therefore, we have no option but to withdraw our service from the state." The price of bitlicense in New York was, in many instances, well beyond the $5,000 license fee, often requiring as much as $50,000 in compliance costs. These companies, which stopped serving NY customers, are likely to make an exodus from CA if AB 1123 is adopted.
The New York bitlicense has been challenged in court by Theo Chino. The Bitcoin Foundation and various persons who support innovation, freedom of expression, and decentralized or distributed systems are supporting Theo Chino's case against New York's bitlicense. The case will be heard next at the New York Supreme Court on June 8, 2017, and it is likely other legal challenges will be launched against the New York bitlicense, in addition to the increasing availability of technological (software-based) means of circumvention.
The North Carolina bitlicense
In North Carolina, due to the enactment of bill H289 on June 30, 2016, the sale or issuance of any payment instruments or stored value primarily for personal, family, or household purposes, or even receiving of money or monetary value primarily for personal, family, or household purposes (including bitcoin or any cryptocurrency) is considered a crime unless you have a permit from the state or you fall under one of very limited exemptions. As such, H289 in North Carolina was very similar to California's proposed bitlicense (originally proposed as AB 1326), but the difference was that California's bill failed twice due to overwhelming opposition from both residents of the state and EFF, whereas H289 (North Carolina's bill) slipped through the cracks and got passed by the Governor despite that the content of the bill makes it just horrible (not to mention unenforceable).
North Carolina residents, under H289, are unable to put up a website and advertise that they are accepting bitcoin as payment for goods or services, without running the risk of having someone from the State demand they get a license for money transmission (the cost of which in North Carolina is $1,500 just to get started for the application, and there are numerous other requirements). Altogether, H289 is a horrible bill, yet it managed to get enacted. It arguably should be contested (and overturned) in court, much as New York's bitlicense is being subjected to court challenge.
Recently, the State of California got handed a defeat as (another) of its anti-1st Amendment laws were struck down in the case of Doe Publius and Derek Hoskins v. California Legislative Counsel Diane Boyer-Vine. In the decision in that case, it was stated that "the Court finds that Plaintiffs are likely to succeed on their claims that § 6254.21(c) violates the First Amendment as applied to them, and also violates the dormant Commerce Clause as applied to Hoskins. The Court further finds that the remaining preliminary injunction factors weigh in Plaintiffs' favor. The Court therefore preliminarily restrains and enjoins Defendant from applying or enforcing § 6254.21(c) against Plaintiffs." And in the Hassell v. Bird case at the California Supreme Court, the Electronic Frontier Foundation filed an amicus brief asking the court to overturn the lower court's dangerous holding. In their brief, the Electronic Frontier Foundation emphasized that website owners have a 1st Amendment right to defend content on their platform. Although these cases are specific to California, the same issues (1st Amendment and Commerce Clause, for example) will no doubt be applicable in any future challenges to North Carolina's H289.
To be sure, there are bills in other states which propose similarly awful ideas, but the above examples are provided as just a few examples of bills which either need to be challenged in court (in the case of the New York's and North Carolina's bitlicense) or simply defeated so that they cannot ever take hold in the first place (in the case of California). Some states, however, have seen the light and are moving in the right direction: New Hampshire's legislature has just passed a repeal of its anti-bitcoin legislation, and Hawaii, one of the worst states to do business in for people interested in bitcoin, is now considering legislation (with its Senate Bill 949) to change that, just as New Hampshire did.
The legislatures of Washington, Georgia, Connecticut, New Mexico, North Carolina, and New York — the highly bitcoin-hostile and anti-innovation states – should take note of these recent efforts in New Hampshire and Hawaii, and these legislatures (and the people of those states) should work to repeal laws that attempt to force licensing requirements upon people who choose to innovate and engage in free expression by using bitcoin or any of the many newer systems now emerging.
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Earlham College marked the 25th anniversary of Ford/Knight research during a convocation that featured presentations and displays from current and past projects.
Earlham College's Annie Bandy is the Indiana Foreign Language Teachers Association's Teacher of the Year for post-secondary language. The Professor of French describes her teaching style as purposeful eclecticism.
Alicia Kees, a senior Bonner Scholar, has refined her ideas of teaching through a variety of experiences, most recently through her work at the Boys and Girls Club and at Westview Elementary in Richmond.
A junior International Studies major, Sara Amina Adem (left) recently gave testimony before the Special Political and Decolonization Committee of the United Nations about issues of self-determination for the Sahrawi people of Western Sahara.
A video version of the Earlham College Podcast takes a look behind the scenes of the College Archives in the basement of Lilly Library. Assistant Archivist Anne Thomason gives a tour of the archives' cold storage area.
Can't find what you're looking for? Check the site index.


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Asylum from Rape
For almost four decades we have been providing self-help services for women seeking asylum from rape, domestic abuse and other sexist/racist violence. Over third have been detained in Yarl's Wood immigration Removal Centre. Many are mothers, some who were forced to leave their children behind when they fled for safety and some who have children born in the UK including as a result of rape. Others are lesbian/bi who would face violence, persecution and even death .
We campaign for the rights of asylum seekers to safety and justice, and an end to detention, deportation and destitution. Rape and torture are grounds for asylum and there must be an end to the systemic sexism and structural racism women face when applying to the immigration authorities.
Together with our partners, the All African Women's Group, we are campaigning to highlight and end the injustices women face in the asylum system, and government imposed destitution they suffer as a result.
Refuge from Rape & Destitution - Blog
We started our campaign because destitution is the most hidden of these experiences and has particularly devastating consequences for women who are forced into dangerous and exploitative situations. Women are less likely to sleep rough and instead have to exchange housework, childcare, and even sexual favours to survive. Thirty-five percent of destitute homeless women asylum seekers report being raped in the UK. Children are increasingly taken away from destitute mothers and families.
End Destitution!
Page being updated . . .
Close Down Detention Centres