text: Jqq$ In!. J. Cancer: 68,452-456 (1996) C 1996 Wiley-Liss, Inc. -'s;-: Publication ofthe International Union Against Cancer Publication de I'Union InternationaleConrre le Cancer TUMORAL PLATINUM CONCENTRATIONS IN PATIENTS TREATED WITH REPEATED LOW-DOSE CISPLATIN AS A RADIOSENSITIZER Jean-Leon LAG RANG^:^, Pierre-Yves BONDIAU', Eric TESSIER', Pierre CHACVEL', Nicole RENEE', and Gerard MII.ANO~.~ Marie-Christine ETIEN!W* Departments of 'Radiation Oncology and *OncopharmacoIogy, Centre Antoine-Lacassape,Nice, France. The aim of the present study was to check whether platinum (Pt) concentrations achieved in tumors with a daily low-dose schedule were close to those promoting radiosensitization. Fifteen previously untreated patients with histologically proven advanced uterine cervix tumors were studied. They received a daily irradiation30 min after a short infusion of 5 mg cisplatin for 5 consecutive days every week. A biopsy was taken from the accessible tumor mass, 4 to 6 hr after the daily injection. Blood samples were obtained once a week, just before the daily injection (HO) and 30 min after (H30). Quantificative analysis of Pt concentrationswas performedby atomic absorption spectrophotometty. Plasma and tumoral Pt concentrations exhibited a marked intersubject variability. The median tumoral Pt concentration was 1,710 mg/g. Median total and ultrafiltrable Pt concentrations in plasmataken at HO and H30 were 23 I and 360 ng/ml. and 7 and 90 ng/ml respectively. Tumoral and total plasma Pt concentrations significantly increased during the course of treatment. Present data show that tumoral Pt concentrations achieved with this CDDP schedule are in the range of tumoral Pt concentrations previously shown to promote radiosensitization(2,000 ng/g). These results suggest that this CDDP radiosensitization regimen might be started with higher CDDP doses in order to reach earlier radiosensitizing Pt tumoral concentrations. 01996 Wiley-Liss, Inc. Cisplatin (CDDP) is one of the most active chemotherapeutic agents presently available. Apart from its direct anti-tumor effect, CDDP exhibits interesting and apparently complex interactions with radiation (Kallman, 1994). Experimental data are scanty and have suggested that platinum (Pt) concentrations around 2,000 ng/ml (i.e., 10 pM) are necessary to induce radiosensitization and inhibition of DNA repair processes (Douple and Richmond, 1978; Fu et al., 1988). Additional work by Douple et al. (1991) pointed to a threshold for tissular Pt concentration allowing radiosensitization; according to these authors, this threshold value should be located around 2,000 ng/g. There is currently no general consensus for the optimal CDDP dose and optimal timing in the sequence of administration of the drug and irradiation. However, data obtained both in vitro (Lagrange et al., 1993) and in vivo (Kallman, 1994) have suggested that CDDP is more effective when given a short time before irradiation. Van Harskamp et al. (1987) have previously reported interesting therapeutic efficacy obtained with a combination of daily low-dose CDDP quickly followed by radiotherapy for inoperable, non-smallcell lung cancer. In our institute, a pilot study was previously initiated based on the same principle of daily, low-dose CDDP plus radiotherapy in patients with inoperable cervical cancer. According to this protocol, the daily CDDP dose ( 5 mg) is given 30 min before irradiation (1.8-2 Gy) for 2-5 weeks, depending on the patient's disease stage. In order to better understand this treatment strategy, we initially investigated both plasma and tumor pharmacokinetics in these patients (Milano et al., 1990). The present study concerns the analysis of tumoral Pt concentrations during the course of treatment aiming specificallyto check whether Pt concentrations achieved in tumors with this daily low-dose protocol were close to those known to promote radiosensitization. The data presented herein are complementary to those which we published prcviously (Milanoet al., 1990). PATIENTS AND METHODS Fifteen previously untreated women (mean age 58 years, range 46-76) with histologically proven advanced uterine cervix tumors were entered into this study. All patients were treated with daily irradiation (1.8-2 Gy) 30 rnin after a short infusion ( 5 min) of CDDP ( 5 mg in 50 ml 0.9% NaCI) for 5 consecutive days every week. This treatment was applied for 2 weeks to patients with stage-I1 diseasc (cumulative dose: 50 mg CDDP, 20 Gy) and for 4 to 6 weeks to patients with stage 111-IV disease (cumulative dose: 100-150 mg CDDP, 40-60 Gy). Before starting treatment, all patients had normal renal function (blood creatinine value below 150 +mol/l), a Karnofsky performance status of at least 60% and a life expectancy of at least 12 weeks. Renal function (blood electrolytes, urea and creatinine) and hematological function (RBC, WBC, platelet count) were evaluated every week during treatment. Response to treatment was evaluated at the end of the treatment period. Complete response (CR) Corresponded to the disappearance of all clinically visible or palpable lesions; partial response (PR) was defined as tumor regression of >50% and was stratified between major PR ( > 75%) and minor PR (> 50% and <75%); no response (NR) corresponded to tumor regression of s50'%,stable disease, or progressive disease. Pharmacokinetic investigations Tiirnors Every week, a clinical examination was planned to check on changes in the tumor. At this time and whenever possible a biopsy was taken from the accessible tumor mass 4 to 6 hr after the daily injection once a week on the first or second day of treatment. In total, 27 tumor biopsies were performed during the treatment: 7 in the 1st week, 6 in the 2nd week, 7 in the 3rd week. 4 in the 4th week, 2 in the 5th week and one in the 6th week. Repeated tumor sampling (2 to 4) was performed for 6 patients. In addition, for 4 patients, biopsies were performed at a certain distance after the end of treatment. Blood samples In addition to tumor biopsies, blood samples were obtained once a week on the first or second day of treatment, just before a daily injection (HO) and 30 min after the end of the injection (H30). HO and H30 samples were taken whenever possible on the same day and from the same patients. In case of practical difficulties (patient's status), only the HO sample was taken. A total of 57 blood samples were thus analyzed. Only these 2 blood samples per patient and per week were requested in order to limit the weight of pharmacological investigations for patients. 3T0whom correspondence and reprint requests should be addressed, at the Centre Antoine-Lacassagne, Oncopharmaculogy Laboratory, 33 avenuc Valombrose, 06050 Nice, France. Pax:33 04 93 81 71 31. Received: April 25,1996 and in revised form August 12, 1996. 'TUMORAL PLATINUM CONCENTRATIONS IN LOW-DOSE CISPI.ATIN TREATMENT For 8 patients it was possible to obtain both a tumoral biopsy and blood samples on the same day. 453 RESULTS Considering all available data, tumoral and plasma Pt concentrations exhibited a marked variability between subjects. Tumoral Pt concentrations were comprised between 0 Treatment of samples and 12,600 ng/g (median 1,710, mean 2,200). At HO, total Pt varied between 0 and 507 ng/ml (median 231, mean 227, Blood n = 34) and U F Pt varied between 0 and 80 ng/ml (mcdian 0, Blood samples (3 ml) obtained in ethylenediaminetetraace- mean 7.1, n = 34). At H30, total Pt varied between 120 and 579 tic acid (EDTA) tubes were immediately placed in a water ng/ml (median 360, mcan 346, n = 23) and U F Pt varied bath containing ice for transport to the laboratory (within between 10 and 160 ng/ml (mcdian 90, mean 85, n = 21). 10-15 min) and were then centrifuged at 4°C. A 500-pIaliquot Table I illustrates the variations in tumoral and plasma Pt of the resulting plasma was centrifugcd for 30 min at 2,000 g concentrations according to duration of treatment course. (4°C) in a Centrifree micropartition unit (Amicon, Denvers, Interestingly, tumoral Pt concentrations significantly increased MA). The resulting ultrafiltrate fraction was used to determine during the course of treatment and this pattern was particuultrafilterable (UF) Pt. Total Pt was measured in the whole larly pronounced between the 1st and 4th weeks of therapy. plasma fraction. Samples were stored at -20°C until analysis. Also, total Pt concentrations in plasma significantly increased during the treatment course. The accumulation in total Pt concentration was observed in plasma samples taken both at Biopsies Biopsies (10-15 mg) were taken from the accessible tumor HO and at H30 min. In contrast, U F Pt concentrations mass. Excess blood was removed and the tissue sample was mcasurcd in plasma at HO and H30 did not reveal any accumulation pattern during treatmcnt course. placed in a screw-top plastic tube that was stored at -20°C until analysis. Biopsies were then weighed (wet weight) and Tumor biopsies were obtained from 8 patients on the same digested overnight with 500 FI 50% nitric acid, then homog- day as blood samples (H30). These 8 paired samples showed enized in a glass-glass potter. The homogenate was dried no correlation (Spearman rank correlation) between tumoral under a nitrogen strcam (50°C) and the dried residue was Pt Concentration and either plasma total Pt concentration at dissolved in 200 pI H 2 0 . H30 (p = 0.23) or plasma U F Pt concentration at H30 ( p = 0.17). In 6 patients, serial tumoral biopsies were obtained. Figure 1 Pt assay Quantificative analysis of Pt in samples was performed by illustrates the intra-patient accumulation of tumoral Pt concenatomic absorption spectrophotometry (AAS) using a Pcrkin- tration during the treatment course for these 6 patients. For 4 Elmer model 3030 atomic absorption spcctrophotometer with patients, biopsies were performed at distance, between 7 and background correction by the Zeeman effect for trace analysis. 21 days after the end of treatment. Figure 2 shows the decrease Ultrafiltrates and biopsy extracts were measured without in Pt tumoral concentrations for these 4 patients. In the limited set of 8 patients available for both tumoral dilution. Before analysis, plasma was diluted 1:2 in a 0.2% H N 0 3 solution containing 0.01% Triton X-100. The injected pharmacokinetics and clinical response, tumoral Pt concentravolume was 20 ~ 1 A. standard curve (0, 162,325,650 ng/ml of tions were not significantly different between patients with NR Pt) was automatically performed with an auto-sampler using a (<SO%) or P R <75% and those with P R > 7 5 % or C R standard Pt solution. Analysis included the following steps: (Mann-Whitney test). drying at 110°C for 40 sec; ashing at 1,400"C for 20 scc and atomization at 2,650"C with a 3-scc stop flow and tube cleaning at 2,650"C for 4 scc. The limit of sensitivity (2 times the noise) DISCUSSION was 5 ng/ml for plasma and 2.5 ng/ml for U F and biopsies. A review of published data concerning Pt tumoral concentraIntcr-assay reproducibility calculated from 25 successive series of analyses was 12.2%, 9.6% and 5.5% for Pt concentrations of tions is presented in Table 11. A feature common to all studies is the marked interpatient variability in Pt tumoral levels for a 30,300 and 900 ng/ml, respectively. TABLE I - DESCRIPTION OF TUMOHAL 1'1, PLASMA TOTAI. Pt AND PIASMA U F Pt CON('ESTRATlONS ACCORDING TO TREATMENT COURSE (WEEKS) . 1 2 230 (0-3100) n=7 1830 (20-2500) n=6 3 4 5 6 Link between increase in Pt concentrations (blood, tumor) and the duration of treatment (Spearman rank correlation) HO? ~ ~~ 1710 (350-5500) n=7 5525 (920-12600) n=4 2005(410-3600) n=2 600 n=l r = 0.41 p = 0.034 UF Pt concentration in plasma' (ng/ml) Total Pt concentration in plasma' (ngiml) Tumoral PI concentrationi (ntYg) Week ~. 106 (0-210) n=9 289 (134-410) n = 11 270 (224-507) n=6 252 (10-434) n=S 311 (304-363) n=3 n=O r = 0.59 p = 0.0007 1?3IS 197 (12M18) n=7 384 (190-520) n=6 400 (321493) n=4 360 (210-579) n=3 378(363-392) n=2 45 1 n=l r = 0.49 p = 0.021 .~ tIW H302 0 (0-9) n=9 90 (10-110) n=7 85 (20-160) n=6 112 (105-140) n=3 80 (54-100) n=3 58 n = l 90 10 (0-30) n = 11 0 (0-80) n=6 0 (0-11) n=5 12(6-13) n=3 n=O NS n = l NS 'Median and extreme values, n = number of patients.-?HO means just before the daily CDDP injection; H30 means 30 min after the end of the injection. LAGKANGE ETAL. 454 I I 8 I I 8 I I I I I I 0 7 14 21 26 35 100000 c w \ -m C 10000 E 2 L .r( U m 1000 I+ a. I+ m L 0 100 E 3 F I0 42 Days o f t h e r a p y RGURE 1 - Plot of the evolution of tumoral Pt concentrations for 6 patients undergoing serial tumoral biopsies (each symbol depicts a different patient). 10000 I I I 1 I I 8 I 0 7 14 21 -I5 \ m c Y E 1 1000 c .d I+ m 100 L 0 E 3 I- 10 Days a f t e r c e s s a t i o n o f t h e r a p y F~GURE 2 - Plot of decrease in tumoral Pt concentrations for 4 patients undergoing a biopsy on the last day of treatment along with a biopsy at distance after cessation of treatment (each symbol depicts a different patient). given dose, for instance at 100 mg/m2. When differcnccs between mean values are considered, it appears that data are quite well grouped, with values varying between 1,000 and 4,000 ng/ml when determined within 48 hr after drug adminis&ration,an exception being [he study of Pujol el al. (1990) where concentrations 10 timcs higher were reported. The fact that, in this later study, tumor samples were obtained shortly after the end of cisplatin administration is not sufficient to explain this markcd difference in Pt concentration as compared to other studics. Our data concerning low daily CDDP doses concur well with those published by Stewart et al. (1995) at a dose of 10 mg/m2. Furthermore, our results obtained after 3 and 4 wceks of rcpeated daily low-dose cisplatin, giving a cumulated dose of 75-100 mg, are within thc range of TUMORAI. PLATINUM CONCENTRATIONS I N LOW-DOSE CISPI.ATIN TREATMENT 455 TABLE I1 - PLATINUM COSCENTRAIIONS I N TUMORS-A KEVIEW OF THE LITERATURE ,r;:zs Author (reference) time after Tumor localization Cisplatin dose (protocol)' cisplatin injection -. 'Troger et al. (1991) Hecquet et al. (1985) Pujol et al. (1990) Hecquet et al. (1986) Gouyette er af. (1986) 14 22 8 8 9 Esophagus Cervix (9) Head and neck (10) Breast (3) ., Lung Cervix 24 Head and neck Mattox et a/. (1983) 5 Head and neck Vennin et al. (1985) 10 Cervix Holdinget al. (1991) 27 Head and neck Stewart et al. (1995) Los et al. (1995) Lagrange et al. (present study) 20 23 Different tumors Head and neck Cervix 15 24-36 hr 48 hr 48 hr 48 hr 30 min 30 min 100 me/m2 hr (i.v.) - (i.v. . + i.a.) 24 24 hr (La.) day 21 (i.v.) day 3 (72 hr) i.a. 1 hr 50 mg/m2day 1 i.a. 6 hr 50 mg/m2day 2 (i.v. + i.a.) i.v. 1 hr i.v. 6 hr 100 rng/m?,4 patients (i.v.) 2 hr 50 mg/m', 1 patient (i.v.) 6 hr 24 hr 50 mg, 2 patients (i.v.) 2 hr 100 mg, 8 patients (i.v.) 4 hr 24 hr 48 hr 100 mgim? (i.v.) 0 hr 24 hr 41-64 hr 500 hr 700 hr 10 mg/m2 (i.v.) 1.25 hr ( 5 min to 6 hr) 150 mg/m? (La.) 24 hr 5 mg/day (i.v.) 4-6 hr week 1 week 2 week 3 week 4 Platinum concentrations mean t SD and/or range W g ) 3,750 ? 2,300 1,800 f 1,000 1,600 f 800 4,200 f 1,400 51,130 f 65,500 22,490 f 53,900 1.OOO-5.Y00 '900-5;YOO 200-500 2.760 f 2.590 1;930 -t 11250 1.270 k 350 11320 f 410 1,800 1,100-2,800) 2,700 6004,400) 1,300 1,200-1,300) 500-7,250 4,970 f 8,750 2,610 f 1,930 1.830 f 1.060 3;800 l;500 3,700 ? 1,500 2,800 (8004,300) 300 15.000 380 f 140 60040,700 680 k 1,120 1,720 k 880 2.160 f 1.800 6,140 f $230 i * 'I.V., intravenous administration; i.a., intra-arterial administration. concentrations found after a single dose of cisplatin at 100 mg/m2. The constant accumulation of tumoral Pt we found during the treatment period is in agreement with experimental data showing that cisplatin uptake is not saturable (Gately and Howell, 1993). After treatment cessation, a diminution in tumoral Pt levels was obscrvcd in samples obtained 6 to 21 days after the end of the treatment period. This is consistent with the data reported by Holding et al. (1991) and Hecquet et al. (1986, 1987). There arc few data which describe CDDP efflux from cells. We recently undertook an in v i m study to analyze more thoroughly relative influx and efflux of CDDP from human cancer cells in culture (Troger et af., 1992). We observed that C D D P can leave the cells following a 2-slope kinetic pattern with an a half-life of 1.29 hr and a p half-life of 94.4 hr. The slow release of platinum from tissues has recently been emphasized by Schicrl et al. (1995). These authors examined urinary platinum concentrations in 23 men at 150-3,022 days after C D D P treatment for testicular neoplasm. Regression analysis showed 2 phases of long-term renal platinum excretion, one occurring between 150 and 900 days of follow-up and the other beginning at 900 days after cisplatin administration. Onc can spcculate on the possible cytotoxicity exhibited by the long-term circulating Pt species. We recently reported data concerning the in vitro cytotoxic effects of a serum aliquot taken 3 weeks after cisplatin administration in a patient with renal insufficiency (Lagrange et a/., 1994). Interestingly, this serum sample induced marked in vitro cytotoxic effects on cancer cells in culture which were much greater that those which could have been anticipated considering the Pt concentration of this serum sample. Thus, the release of Pt from tissues, as stressed in the present study, may lead to Pt circulating species which can play a role in the pharmacological effects of the drug. Troger et al. (1992) have shown that the cytotoxicity of C D D P in vitro is directly related to intracellular concentrations of the drug. O n the other hand, decreased Pt accumulation develops early during the selection of resistant cclls both in vitro and in vivo (Gately and Howell, 1993). Our knowledgc concerning the hypothetical link between tumoral Pt concentrations and clinical response is limited. So far, both Bielack et al. (1989) and ourselves (Troger et al., 1991) have failed to demonstrate any relationship between tumor Pt concentration and treatment efficacy. Here again, based on a small number of cases, we reached the same conclusions. Pujol et al. (1990) found a weak correlation between simultaneous plasma and tumoral Pt concentrations. In the present study, based on a limited number of paired samples, we failed to find a relationship between these 2 parameters. Thus, the variability in plasma pharmacokinetics does not seem to account for the differences in tumor Pt concentrations. It must be emphasized that, according t o the work of Fu et al. (1988), low-dose-rate irradiation probably had no influence on the pharmacokinetics of plasma and tumor Pt. Stewart et al. (1995) recently reported on factors affecting Pt concentrations in human tumor specimens. They found, by multiple stepwise regression analysis, that the patient characteristics most closely associated with tumor Pt concentrations were tumor type, serum calcium and chloride and bilirubin levels. Some studies indicate that the radiosensitizing capability of C D D P is highly time-dependent (Lagrange et a/., 1993; Kallman, 1994). C D D P would be more effective when given a short time before irradiation. This suggests that C D D P in tissues does not remain in a radiosensitizing form (not identified) for more than a limited period of time. However, some authors have reported the attainment of tumoral Pt concentrations around 2,000 ng/g which induced radiosensitization (Carde 456 LAGRANGE E T A L and Laval, 1981; Douple et a/., 1991). Table I shows that, on average, these optimal concentrations were obtained by the 2nd week of treatment. In addition to enhancing our understanding of Pt concentrations in tumors, the present results, in the light of the pharmacokinetic data, point to several practical consequences. The main one could involve shortening the total duration of the cycle and starting the protocol with higher daily doses in order to reach potentially radiosensitizing Pt tumor concentrations carlier in the treatment course. This approach was recently used by Los et al. (1995) who demonstrated that intra-arterial administration of high-dose CDDP led to high tumor Pt concentrations and CDDP-DNA adducts, which resulted in high rcsponse rates when combined with daily irradiation. REFERENCES BIELACK, S.S., EKTAMNN, R. and Loon, G., Platinum disposition after haemodialysis in clcaring them. Europ. J. Cancer, 14, 2057-2060 intratumoral and intravenous infusion of cisplatin for osteosarcoma. (1994). Cancer Cheniother. Pharmacol., 24,376-380 ( 1989). LAG RANG^, J.L., FISCHEL, J.L., GALLIANI, S., FORMENTO, P., GUILLOT. M. and MILASO,G., Importance of the irradiation timing CARDE,P. and LAVAI.,F., Effect of cis-dichlorodiamine platinum I1 T., BAKDON, and X rays and mammalian cell survival. Inr. J. Radial. Oncol., 7, within a chemotherapy sequence including cisplatin and 5FU folinic acid. Experimental results. Europ. J. Cancer, 29,1531-1535 (1993). 929-933 (1981). F.A., BARTON, R., HEAI'H.D.D., DES ENGELSE, DOUPLE, E.B. and RICHMOND, D.R.C., Platinum complexes a s radio- Los, G . , BLOMMAERT, L., I~ASCHFIT, C., VICARIO, D., WEISMAN,R., ROBBINS, K.T., and sensitizers of hypoxic mammalian cells. Brit. J. Cancer, 37, 98-102 HowIi.~.,S.B., Selective intra-arterial infusion of high-dose cis latin in (1978). with advanced head-and-neck cancer results in hi& tumor DOUPLE.E.B., WILLS,M.L. and JONES,E.L., Radiopotentiation in a patients platinum concentrations and cisplatin-DNA adduct formation. Cancer murine tumor (MTG-B) by continuous infusion platinum. In: M. Cheniother. Pharmacol., 37,150-154 (1995). Rotman and J.C. Rosenthal (eds.), Concomitant continuous infusion chemotherapy and radiation, pp. 191-196. Springer, New York (1991). MAITOX, D.E., STEKSSON,L.A., VANHOFF, D.D., KUHN,J.G. and REPI'A, A.J., Tumor concentrations of latinum in patients with Fu. K.K., DE GKEOOKIO, M.W. and PHILLIPS. J.W., Plasma and tumor head-and-neck cancer. Otolatyngol. H e a l Neck Surg., 91, 271-275 concentrations of cisplatin following intraperitoneal infusion o r bolus (1983). injection with or without continuous low-dose rate irradiation. Nat. MILANO, G., TROGER, V., COURDI, A.. FON~ANA, X.. CHAUVEL, P. and Cancer Inst. Monogr., 6, 123-127 (1988). LAGRANGE, J.L., Pharmacokinetics of cisplatin given at a daily low GATELY,D.P. and HOWELL,S.B., Cellular accumulation of the dose as a radiosensitizer. Cancer Chernother. fhannacol., 27, 55-59 anticancer agent cisplatin. A review. Brit. J. Cancer, 67, 1171-1176 ( 1990). (1993). PUJOL,J.L., Curissoi., D., GESTIS-BOYER, C., BRES,J. and MICHEL, GOUYETTE, A,, Apaiis, A., FOKA, M. and RICHARD, J.M., Pharmaco- F.B., Tumor-tissue and plasma concentration of platinum during kinetics of intra-arterial and intravenous cisplatin in head-and-neck chemotherapy of non-small-cell lung canccr patients. Cancer Checancer patients. Europ. J. Cancerrlin. Oncol., 22,257-263 (1986). mother. Pharmacol., 27,72-75 (1990). HECOUET, B., LEROY,A.. LEFEBVRE, J.L., PEYRA'~, J.P. and ADENIS, S C H I ~ KR., I . , ROHKER,B. and HOHNLOSER, J., Long-term platinum L., Uptake of platinum corn ounds in human tumors: in vitro study. excretion in patients treated with cisplatin. Cancer Chrmother.fharmaBrill. Cancer, 73,535-541 (1916). Col., 36,75-78 (1995). HECOUET, B., VENNIN, P., FOIJRNIER, C., LEFEBVRI, J L , C A n , A., STEWAKT.D.J., MOI.EPO,J.M., GREEN,R.M., MONTPETIT, V.A.J., BONNETERKE, J., ADENIS, L. and DEMAILLE, A,, Platinum concentra- HUGENHOLTZ, M.D., H., LAMOTHE, A., MIKHAEI.,N.Z., REDMOND, tion in human tumors of head and neck. uterine cervix and breast GADIA,M. and GOEL,R., Factors affecting platinum concentrations in following treatment with cisplatin. Cancer Chettiother. fhannacol., 15, human surgical tumor specimens after cisplatin. Brit. J. Cancer, 71, 310-312 (1985). 598-604 (1995). HECOUET, B., VENNIN, P., FOURNIEK, C. and POISSOSXIER, B., Eval- TROGEK, V., FISCHEL, J.L., FORMENTO, P., GIOANSI, J. and MILANO, uation of the pharmacological benefit and determination of the G.. Effects of prolonged exposure to cisplatin on cytotoxicity and influencing factors of intra-arterial cis-diamminedichloroplatinum ad- intra-cellular drug concentration. Europ. J. Cancer, 28,82-86 (1992). ministration in atients with uterine cervical cancer. Cancer Res., 47, TROGER, V., FRANCOIS, E., FRENAY, M., NAMEK, M. and MILAKO,G., 6134-6137 (1987). Analysis of tissue platinum distribution in atients with cancer of the HOLDING, J.D., LININJP, W.E., BOWDLER, D.A., SIODLAK,M.Z. and oesophagus. Europ. J. Cancer, 27,256-259 8991). STELI..P.M., Disposition and tumor concentrations of latinum in VAN€IAKSKAMP, G., BOVEN,E., VERMORKEN, J.B., VANDEUTEKOM, hypoalbuminaemic patients after treatment with cisplatin E r cancer of E , GOLDING, H., STAM,J., NJO, K.H., KAKIM,A.B.D.M.F., T I ~ R I AH.. the head and neck. Brir. J. din. fharnicrcol., 32, 173-179 (1991). R.P. and PINEDO. H.M., P h a s e 4 trial of combined radiotherapy and KALLMAN,R.F., The importance of schedule and drug dose intensity in daily low-dose cisplatin for inoperable locally advanced non-small-cell combination modalities. Int. 1. Radiat. Oncol., 28,761-771 (1994). lung cancer. lnt. J. Radiut. Oncol.. 13, 1735-1738 (1987). c . , DEMAILLE, M.C. and ADENIS, LAGRANGE, J.L., CASSUTO-VIGUIER, E., BARBE,V., FISCHEL. J.L., VENNIN, L., lIECOUET, B., FOURNIER, MOSDAIN, J.R.,EIIE , M.C., FERRERO. J.M., CREISSON-DUCRAY, L., Sequential mcasurement of intratumoral platinum concentrations P. and MILASO,G . , Cytotoxic effects of long-term in cervix uterine tumors after cisdichlorodiammineplatinum (CDDP) A., FORW.NTO. circulating ultrafilterable platinum species and limited efficacy of administration. Anticancer Res., 5,369-370 (1985).

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As you may already have noticed from the header next to the headline, today is not your typical Thursday.
In fact, every Thursday from here on out will be focusing on the whole complicated world of relationships.
That being said, our newly revamped Thursday column will feature everything you could possibly think of when the word relationship enters your mind: Is it right for me? (You didn’t think we were going to get rid of everything sex related, did you?
You should not have any limitations when it comes to matters of the heart.
What service are we doing to our society as a whole if in the 21st century we are still looking down on two people of different races dating each other?
Throughout my four years in college, I’ve learned that this stigma that was very present in my parents’ generation is unfortunately still around today.
Disclosure: I am a pure blooded Armenian woman with MAJOR issues with the way I was raised.


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domain: artistic


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The ongoing privatisation of the power sector is facing a threat as winners of the 11 distribution companies of the Power Holding Company of Nigeria, PHCN, have issued the Federal Government fresh conditions before completing the balance of 75 percent of the bid’s value.
One of the conditions given by the bid winners was that the federal government must meet up with established “condition precedent.”
They also requested for additional one month extension to the payment deadline with just about two weeks to the expiration of deadline set by the National Council on Privatisation, NCP, for payment of the outstanding 75 percent bid price. Ten out of the 11 distribution companies with the exclusion of Kaduna Distribution Company, which met with Minister of Power, Chinedu Nebo, said the deadline of August 21 was not feasible.
Other demands of the bidders represented under the auspices of the Roundtable of Distribution Companies, the Disco Roundtable, are that the government must hand over the assets free of all legacy liabilities. It thus asked the government to quicken its payment of severance benefits to employees of the defunct PHCN companies to allow the bidders access finances to pay up its 75 percent balance.
Chairman of the Disco Roundtable, Dr. Ransome Owan, who led the group told the minister that government’s interactions with labour unions of PHCN have remained a source of concern to financial institutions willing to lend monies to the preferred bidders.
He explained that it was necessary for government to finalise payment of severance benefits of the workers before the stipulated August 21, 2013 long stop date, adding that lenders indeed expect evidence of these payments before funds for completion of the payments can be drawn down.
According to him, considering this situation, government should consider an extension of the payment deadline to September 21, 2013, perhaps, to allow for government’s completion of payment of the severance benefits.
He said: “By March 21, 2013, all the 10 bidders paid the 25 percent down payment and the balance is to be made by August 21, 2013. It is a condition precedent that the DISCOS would be handed over free from all legacy liabilities.
“Our lenders are mindful of this and are reluctant to approve loans and condition draw-down. Therefore, it is vital for full payment obligations to the current PHCN employees be finalised before the long stop date of August 21. Lenders expect evidence of these payments before we can draw down on funds to complete our payments.
“As at now, the discos operate at a loss and buyers would quickly deploy their respective turnaround plans. Therefore, we pray the minister to convene a stakeholders meeting before August 21 to check the progress before the long stop date.
“In addition, the minister should kindly consider the following: Conclude all labour issues and meet all conditions precedent before August 21, 2013, assistance in the release of the subsidy contained in the Multi Year Tariff Order (MYTO) model for each of the discos and adequate funding of the TCN”, he stated. The group also requested for “Extended five to10 years special tax holidays for electricity distribution companies akin to the telecom start-up assistance to mitigate tariff increases and high cost and consider extending the long stop date to September 21, 2013 to allow for the full satisfaction of all condition precedent items of the government.”
Nebo in his remarks acknowledged that government was aware of the challenges of the preferred bidders and has mulled on the issues before now to allow for a smooth privatisation transition.

domain: news


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Just when we thought that Covid-19 has taught us how important it is to be in harmony with nature; Himachal Pradesh is bearing the brunt of tourists returning to the state after Government opened up the state's alleys for people. A Twitter user posted his concern on the social media platform with pictures showing garbage strewn all over, which was left by tourists.
He echoed the concern and highlighted the condition of Himachal Pradesh for which a lot of support poured in from Himachal residents and others. Other residents of the state responded with their own photographs citing callousness shown by tourists.
Bollywood actress Yami Gautam also came out in support of this and called for stricter laws and penalties. She posted, "Hoping for stricter laws & such people need to be seriously penalized for doing this. It's high time, tourists need to start respecting the very State they resort to for seeking leisure. I urge the localities also to pull up such 'tourists' if they spot anyone doing the same."
As a Himachali I am disgusted and as an Indian, I am ashamed
A user wrote, "As a Himachali I am disgusted and as an Indian, I am ashamed that my fellow citizens can't even do the bare minimum."
It should be noted that in order to revive tourism in the state, restrictions were eased for tourists by the Himachal Pradesh government recently. Tourism is the backbone of the state's economy. Due to the pandemic, the tourism sector had come to a standstill.
In the Cabinet meeting, which was presided by Chief Minister Jai Ram Thakur, it was decided that minimum stay for tourists can be reduced to two days from five days.
There has been a significant relaxation in the existing norms in regard to Covid-19 negative reports/certificates. Due to this step, there has been a notable influx of tourists from nearby places and it has added up to several problems in the state.
A Twitter user pitched in while supporting more responsibility for tourists, "This is what tourists do to Himachal Pradesh, Uttarakhand and most other hill stations. Why act so foolish, uneducated and dumb?"


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Add to Cart
Southern Campeche State with its ruins of Becan, Xpujil and the Calakmul Biosphere Reserve offers unrivaled opportunities for nature lovers to enjoy birds, orchids and mammals in an unspoiled corner of the planet.
Swing your hammock under the high canopy of the verdant tropical forest as you listen for the calls of some of the 354 species of birds found in the Calakmul Biosphere Reserve, Mexico s largest protected area.
Along with the chorus of feathered creatures, Calakmul is host to 45 species of amphibians and reptiles, 95 different mammals including 5 of the 6 felines found in Mesoamerica, 36 kinds of orchids, and 8 bromeliads making the area a magnet for nature lovers who treasure the, as yet, unspoiled corners of our planet.
Day 1) MERIDA
Let us welcome you at your arrival at the Mérida airport and transfer to your hotel the Maison Lafitte.
Day 2) MERIDA - CALAKMUL
After an early breakfast departure from Merida, 6 hrs.driving toward Calakmul.We will spend the next 2 nights in a tented camp in Calakmul Biosphere Reserve in hopes of seeing a Jaguar. Jaguar tracking is done at night so there will be a variety of activities offered during the day. Jaguars are one of the most elusive animals in the world so sightings in the wild are very rare, but our experienced trackers will do their best to provide an exciting experience. Our camp is set in the jungle. The facilities in the camp are quite comfortable given its remote location.This first day we stop at the village of Xpuhil for an introduction of the area and conduct to our camping where after arriving we will take you to meet some of the local flora and fauna of the area into paths in the jungle or to a bath cave. (B and At the camp: D)
Today´s excursion is to the archeological site of Calakmul. This site was declared a few months ago, a world heritage site by the Onu. Calakmul was one of the biggest Mayan capitals in the classical period, it rivaled Guatemala´s Tikal, located mere 100 kilometers south. After visiting this site we will return to camp and by night will participate on a night walk in the jungle. (At the camp: B,L,D)
Day 4) CALAKMUL
We will spend the morning birdwatching in the area near the camp. The rest of the day will be devoted to walking in the jungle for the observation of the local flora & Fauna. Calakmul counts with 354 species of birds, 45 species of amphibians and reptiles, 95 different mammals, 36 kind of orchids and 8 bromeliad making the area a treasure for the nature lovers. Return to the camp for the chance to observe a jaguar in the night. (At the camp: B,L,D)
Day 5)CALAKMUL -BECAN - CHICANNA - XPUHIL - UXMAL.
Visit to the archaeological site of Becan, Chicanna and Xpujil.
Becan represented an important political and military control place, and is the only one that was walled. One of the most important attractions in Chicanna is a Mayan building reconstructed on a platform characteristics of the Rio Bec Style. The style of the Chenes shows baroque characteristics in the facade of the buildings. The entrances of these resemble the mouth of a monster, the principal gate represents a great mouth of the Chac God with large canine teeth which project over the lintel. You will see also the main building in Xpuhil has three enormous towers constructed in the architectural style of Rio Bec, with twelve rooms and platforms in whose center is a recess surrounded by a head of a serpent. In addition, there is a beautiful mask like a tiger which faces Becan. Transfer back to to the civilization. After lunch transfer to archeological site of Uxmal. Overnight at Hotel Hacienda Uxmal. (At the camp: B)
Day 6. UXMAL
After breakfast visit the archeological site of Uxmal and afterwards transfer to Mérdia to catch your flight back home (normally the itinerary ends here or with an extra overnight in Uxmal and transfer next morning to the Mérida airport). (B)
This Tour Includes:
*Accommodatios: 2 Hotel nights and 3 night at camping
*Tour guide with knowledge of archaeology and natural history for the sites,
*Biologist guide for exploration in the jungle
*Private transportation in A/C vehicles during all the tour.
*Meals as listed on the itinerary (5 Breakfast, 3 Lunches, 3 Dinners. Drinks included in camping)
*All camping equipment.
Does Not Include:
B= American breakfast included.
L= lunch included.
D= Dinner included.

domain: geography


The UK Space Agency is taking one giant leap for mankind by asking the general public, yes, the same people that came up with Boaty McBoatface, to name an incredibly complex piece of machinery that will explore the Mars surface.
Expected to launch in August 2020, the rover is a collaboration with the European Space Agency’s ExoMars mission. The journey to the alien planet aims to investigate how Mars evolved and explore whether the planet could be colonised by humans in the future.
“The ExoMars rover will be the first of its kind to travel across the martian surface and drill down to determine if evidence of life is buried underground,” the ESA explains.
But even before the arduous journey to the Red Planet, creators of the rover – which has six independently steered wheels and a whole host of gadgets like camera systems and ground penetrating radar – could be facing their biggest challenge, the power of the people.
The UK Space Agency has begun a competition to name the robot that scientists are pinning their exploration hopes. It means the machine could get the same treatment as Boaty McBoatface – a British Antarctic Survey submarine that was officially named after the surprise outcome of public poll.
The poll was originally to name a British polar research ship, but after the ridiculous name won a landslide victory officials named the vessel RRS Sir David Attenborough. Hilariously, a submersible onboard the ship is instead titled Boaty McBoatface.
Launching the competition, British ESA astronaut Tim Peake described the opportunity as a chance for people to put their mark on a new era of space exploration. But depending on the outcome, it might also lead organisers to utter the famed NASA phrase: “Houston, we have a problem”.
“Mars is a fascinating destination, a place where humans will one day work alongside robots to gather new knowledge and search for life in our solar system,” Peake said.
“The ExoMars rover is a vital part of this journey of exploration and we’re asking you to become part of this exciting mission and name the rover that will scout the Martian surface.”
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APPLE VALLEY, MN — Uponor North America (Uponor) recently announced Jon Sillerud, Vice President, Operations, has agreed to accept the additional responsibilities of leading the Supply Chain function for the company, effective immediately. He has been filling the Supply Chain leadership role on an interim basis for several months, proving his experience and extensive knowledge make him the ideal person to lead both functions. His new title is Vice President, Integrated Supply Chain, Uponor North America.
“Under Jon’s leadership, our business will accelerate its lean manufacturing journey and ensure we continue to drive our growth trajectory under the priorities of safety, quality, delivery, productivity, and continuous improvement,” says Andres Caballero, President, Uponor North America. “I am thrilled to have Jon expand his leadership role and look forward to the success he will bring for the Integrated Supply Chain functions in North America.”
For information about Uponor products, systems, services, and solutions, visit uponor.com.


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Creature Magic is a single switch program designed to introduce early language and cognitive concepts, cause and effect, turn-taking and use of a single switch for individuals with developmental, physical or visual disabilities or autism. This program is designed to introduce early language concepts, provide exposure to word combinations, reinforce critical cognitive concepts and offer recreational enjoyment. There are four games which show the concept of non-existence where things disappear and reappear; demonstrate the difference between one and more than one object; introduce prepositions; and show the importance of word order in simple sentences. COMPATIBILITY: For use with Macintosh and IBM and compatible computers. SYSTEM REQUIREMENTS: The IBM and compatible version requires a Pentium 133 megaHertz (MHz) or faster processor; hard drive with Windows 95, 98, ME, NT, 2000, XP or later; 16 megabytes (MB) RAM; a Windows compatible sound card; and a 4x speed CD drive. The Macintosh version requires a 68040 pocessor or PowerPC; System 7.5 or later; 8 MB application RAM; and a 4x speed CD-ROM.
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Half of SMEs still ineligible for financing in 2018
Poor cash flow and low annual revenue stall their opportunities.
Although SMEs had better access to the necessary capital to finance their business in 2018, there is little to low improvement amongst the number of SMEs who remain ineligible for financing. Business consultancy firm Linkflow Capital found that only 34% of SMEs were eligible indicatively for financing last year although this marks an improvement from 19% in 2017.
Also read: 4 in 5 SMEs fail in financing assessments
The firm’s findings attributed SMEs’ improved eligibility to financing schemes, such as the SME Working Capital Loan, and healthy domestic economic growth in 2018. The report also noted that alternative lending options, such as P2P crowdfunding platforms, gave credit-short SMEs access to the necessary loans.
However, more than half of SMEs may be unable to secure financing due to poor cash flow and small annual revenue. In 2018, half of SMEs declared an annual revenue of less than $300,000 and less than $10,000 average cash balances. There is little improvement from the 52% of SMEs who declared the same amount of revenue in 2017.
A separate survey by Experian notes that 34% of SMEs admitted to facing external finance-related challenges and 44% admitted to facing internal difficulties in managing their finances.
On the other hand, SMEs’ profitability improved with only 19% of users indicating financial loss during the survey period, lower than the 55% of users indicating loss-making in 2017.
Linkflow Capital also noted a rise in startups seeking financing. Around 26% of users are businesses less than a year old, compared to 21% in 2017.
The report used data from 2,771 unique users of the firm’s SME loan comparison portal, retrieved from January to December 2018.


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domain: entertainment


text:
Wendy Lohmann has always loved Vivaldi’s Four Seasons and has had a dream of a string quartet playing for her.
With her B&B and retreat, the Old Laravale School, offering the perfect setting for just such an event, she has organised her dream concert and invites everyone for an afternoon of jazz and classical music – Four Seasons in an Afternoon.
Music will be provided by Brisbane based string quartet Angel Strings.
Angel Strings was born in 2004 of a passion for bringing beautiful music to as many contexts as possible.
Regular performers of a broad classical repertoire, Angel Strings have also developed a reputation for their edgy renditions of modern works and pop/rock arrangements.
They have a unique ability to connect with a wide audience, having played on the Brisbane City Hall main stage, for Musica Viva CountryWide, at the Spark Bar of the Brisbane Powerhouse and at the Melbourne Crown Casino.
Professionally trained musicians with national and international experience, individual ‘Angels’ have performed with the Queensland Symphony and Pops Orchestras, Queensland Theatre and Opera Queensland.
They have shared the stage with Nigel Kennedy, Andrea Bocelli, Kanye West, Eminem, Il Divo, Archie Roach and William Barton.
Tickets to the event include a picnic box provided by That Platter Company.
Wines from Bunjurgen Estate Winery can be purchased on the day and Wendy advises guests to bring warm layers, especially if they want to stay on for a telescope viewing of the night sky with members of the Scenic Rim Astronomy Association.
“Even if they are not staying into the evening, the afternoons can cool down very quickly,” said Wendy.
Tickets are $87.50 which includes fees and a picnic box per person.
Ticket sales will close on Wednesday 22 June at midnight.


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Microsoft launched a new program in India to encourage more girls to take up careers in technology, the Times of India reports. "India DigiGirlz" aims to drive high school girls towards science and engineering fields by giving them the opportunity to participate in workshops and connect with Microsoft's employees. Microsoft's DigiGirlz program was founded in 2000 to address the issue of girls and science in the United States.
"The students are aware of technology more than ever before. Almost 100% of them have Facebook accounts, but the idea is to make them think of technology as a career," Jacky Wright, Vice President of Microsoft IT, said. She added that the company is focusing on increasing awareness about the lack of girls in the technology field.
Girls make up less than 20% of students at the Indian Institute of Technology, and about 30% of employees in the IT Business Processing Outsourcing Sectors. Microsoft plans to expand the programs across India and Brazil, the company's two focus countries.
"These economies are growing and we need the program in these countries," said Wright. "Girls need to see role models. If they see it can be done, they will do it."
Media Resources: Times of India 2/26/2013; Microsoft News Center 5/4/2010
1/23/2015 #HeForShe Campaign Launches Pilot Effort Aimed at Institutional Equality - The United Nations' gender equality campaign #HeForShe has launched a new program called IMPACT 10X10X10.
United Nations Goodwill Ambassador Emma Watson, together with UN Women Executive DirectorPhumzile Mlambo-Ngcuka, introduced the one-year pilot effort aimed at encouraging corporations, universities, and governments to play an active role in enhancing women's empowerment and equality in Davos, Switzerland today at the World Economic Forum.
"Women need to be equal participants in our homes, societies, in our governments, and in our workplaces," Watson said.
First introduced in September, HeForShe is a solidarity movement that calls on men and boys to confront gender inequalities that face women and girls globally. . . .
1/22/2015 BREAKING: House to Vote on Abortion Coverage Ban - After they were forced to scrap plans for a 20-week abortion ban, House Republican leaders decided late last night to instead ram through a vote today on a different extreme anti-abortion bill.
House Republicans are now pushing HR 7, a bill promoted as a ban on federal funding of abortion that would actually prevent women from using their own money to purchase health insurance that includes abortion care. . . .
1/22/2015 House Cancels Abortion Ban After GOP Congresswomen Drop Support - House Republicans cancelled plans to vote on a 20-week ban on abortion after Republican Congresswomen removed their names publicly as co-sponsors of the bill.
The vote on the unconstitutional 20-week ban had originally been scheduled for today, the anniversary of Roe v. . . .


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The Kashmir Great Lakes Trek is unusual and divine in many aspects, and it takes place in Kashmir, a paradise on earth. KGL is known for having some of the most magnificent vistas of any trip, and it entails climbing three mountain passes to access a plethora of high altitude lakes, making it physically demanding but well worth the effort. This journey is dominated by the lovely blue colour of the lakes.
This article explains why KGL should be your next adventure.
1. Learn About Kashmiri Culture:
What better way to learn about a place’s history and culture than to engage with the locals? Enjoy bonding with the local guides, who have a wealth of stories to share about how Kashmir was dominated by Buddhists, Hindus, and then Mughals, leading up to its current Mughal influence. On the route, stop to chat with the locals and enjoy the hospitality of the shepherds. I’m sure the mountain discussions will be much different from what you’ll encounter while sightseeing in the city.
2. Take a walk around the Scented Pine Tree Forest:
Do you prefer descents to ascents? I am, but it took a toll on my knees and feet with this one. Although the descent from Gangbal to Naranag appears to be an unending walk, the view you receive along the way is one of the reasons to do Kashmir Great Lakes. In any of my previous journeys, I have never encountered such fragrant pine tree forests. The scent of the pine trees is so invigorating, and the valley is so serene, that your mind will be forced to return to its own thoughts. Things that are difficult to express and indescribable to experience are rare. This is one of them, believe me.
3. Physically and mentally demanding:
Everyone thinks the Great Lakes of Kashmir hike is easy. I’d call it a moderate-altitude hike, but the physical and emotional challenges it presents are entirely different. Normally, on other treks, you may look forward to three to four days of climbing followed by a descent, but Kashmir Great Lakes tests your mental strength by requiring you to ascend and descend a significant amount of altitude virtually every day. It’s as though one day you’re celebrating the pass crossing and the next day you’re fighting the climb to the next pass. KGL completion is something you may be proud of for the rest of your life.
4. From Gadsar Pass, look for the Five Lakes:
Yes, it is correct! When you get a bit further up on the Gadsar Pass, you can see the Vishansar and Kishansar Lakes on the left side, and three of the Gadsar Lakes on the right. Wildflowers against a contrasting background of snow-covered mountains are a sight to behold, but that’s not all. Many of these little lakes may be found on the approach to Satsar camp site. How many do you think you can count? Take a stop for lunch at Gadsar Lake, which is just over the glacier.
5. Dal Lake, also known as ‘Srinagar’s Jewel,’ is a must-see attraction in Kashmir. On the final day of the journey, arrive in Srinagar in the afternoon and retire to your boathouse to watch the sunset. Enjoy local cuisine at floating restaurants, taste ‘Wazwan,’ a multicourse dinner for non-vegetarians, and shop for gifts at the floating market.
These things are enough to inspire me to start this journey all over again, and hopefully they will inspire you as well. So, while you’re planning your trip to the Kashmir Great Lakes, you’ll know it’ll be much more than that.

domain: hobby


text:
Mayfield-Graves Co. YLC tours courthouse, county jail | Politics
MAYFIELD, KY (KFVS) - The 2011 Mayfield-Graves County Youth Leadership Class learned about their local government recently.'
The YLC students participated in a mock city council meeting with Mayfield Mayor Teresa Cantrell presiding where each student played a role, from city council member to city attorney to concerned citizen.
Former Police Chief and Sheriff John Davis then showed a video talked about the history of Mayfield and Graves County. Students then went to the Graves County Courthouse where they watched Judge Deborah Crooks preside over district court.
Before lunch the group heard from elected officials about the county government. Speaking at the courthouse were Judge/Executive Tony Smith, Lana Thomas of pre-trial services, Sheriff Dewayne Redmon, County Attorney John Cunningham, Susan Jackson of juvenile justice, and County Clerk Barry Kennemore.
Students ended their visit with a tour through the Graves County Jail.
The YLC travelled to Frankfort in February to learn about the state government.
Copyright 2011 KFVS. All rights reserved.

domain: politics


text:
Today Forex earned 480 points
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domain: economics


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The Daily Bag combines the quality of custom-made bags with a contemporary vision of saddlery. The leather is soft, carnal and timeless. It adapts wonderfully to new ways of living and travelling.
Dimensions : 40×30 cm
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domain: design


text:
Clear Channel Inks SVP/Chief Accounting Officer Scott Hamilton To New Deal
June 26, 2014 at 3:57 AM (PT)
CLEAR CHANNEL parent CC MEDIA HOLDINGS, INC. has inked SVP/Chief Accounting Officer and Assistant Secretary SCOTT D. HAMILTON to a new contract, the company informed the SEC in a Form 8-K filing WEDNESDAY (6/25).
The deal runs from this past MAY 1st through APRIL 30th, 2018, with automatic two-year extensions absent notice of termination by either party. HAMILTON will get a base salary of $375,000 per year with eligibility for additional annual raises and an annual performance bonus targeted at 60% of his annual base salary.

domain: finance


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The EURUSD currency pair is in the spotlight this week as concerns about economic growth in the US and EU cloud the outlook.
Markets prepare for FOMC minutes
On the US dollar side, the FOMC Minutes will be released later today and will provide additional information on the economic outlook and the central bank’s monetary policy stance. In December, the Federal Reserve slowed the pace of interest rate hikes, but that should not mean an easing of monetary policy. Depending on the rhetoric in the minutes, the dollar may react.
The Fed relies on economic data to decide interest rates, and the evolution of the manufacturing sector should be a source of concern.
US manufacturing health
The ISM Purchasing Managers’ Index (PMI) will be released today and should provide some insight into the health of the US manufacturing sector.
December’s manufacturing PMI is expected to fall to 48.5 from 49 in November, indicating further contraction in this key sector. The November figures showed the first decline in manufacturing output since May 2020, with broad-based declines in new orders, supplier deliveries, order books and employment.
If something unexpected happens in the results, USD currency pairs can be affected.
On Friday, a series of data will be released with a possible impact on the EUR side of the world’s most traded currency pair.
European inflation decreased in December
The flash inflation level for December was 9.7% compared to 10.1% in the corresponding period of the previous year, and 0.1% compared to negative 0.1% in November. The base inflation rate is estimated at 5% per year.
Decline in retail sales
EU retail sales fell by -1.8% month-on-month and -2.7% year-on-year in October, as inflation weighed on consumer spending that could save for Christmas shopping in November and December. Updated retail sales figures for November are expected to be down 0.5% month-on-month and minus 3.3% year-on-year.
October’s weakening scenario showed the biggest drop in trade since December 2021, with sales of non-food items, online shopping, beverages and tobacco falling.
Consumer confidence in Europe is falling sharply
The final reading of consumer confidence for December will be released on Friday and is expected at minus 22.2, versus minus 23.9 previously.
Inflationary pressures appear to be easing in the EU, but have left behind shaken consumer confidence and an impact on the retail sector, which will weigh on economic performance.
Will the EURUSD pair be volatile? Traders and investors should be aware of the jitters surrounding fears of a global recession and factor this into their scenarios while keeping abreast of recent developments.
Interested in news trading? Learn how this approach works with our free webinars. Connect with professional traders. Attend live trading sessions and learn more.
INFORMATION ABOUT ANALYTICAL MATERIALS:
This content does not constitute investment advice or recommendations, an offer or solicitation to trade in financial instruments and should not be construed in any way. Please note that this marketing communication is not a reliable indicator of any current or future performance as conditions may change over time. Before making any investment decision, you should seek advice from independent financial advisors to ensure you fully understand the risks involved.


Gigabyte, well-known amongst enthusiasts for its performance motherboards and graphic cards, has announced the GM-M7800S wireless mouse, further expanding its product portfolio. The black stylish mouse, clad in black leather and CRYSTALLIZED – Swarovski elements, features a 1600 DPI laser sensor, adjustable DPI (800/ 1600 DPI), a 4-way scrolling wheel, gold plated center and side
Taipei, Taiwan, 9 November, 2010 – GIGABYTE, a leading manufacturer of motherboards and graphics cards, is pleased to present the latest premium graphics card – GV-N580D5-15I-B. Built with next-generation NVIDIA® GeForce® GTX 580 GPU and GDDR5 memory technology, GV-N580D5-15I-B runs every blockbuster games with amazing performance. Full press release inside.
If AMD does not have an answer to the NVIDIA GeForce GTX 580, GIGABYTE is ready to fight it out with its latest implementation of the NVDIA GeForce GTX 480. The GTX 480 Super Overclock Edition pops out of the box overclocked, and ready to be further overclocked. We also see the mention of a
GIGABYTE is back with more competitions for the hardware enthusiasts. For the next 6 weeks (Nov 1 ~ Dec 18), submit your top Core Wprime scores to HWBOT for your chance to win a GIGABYTE X58A-UD7, GIGABYTE X58A-UD3R, or GIGABYTE H55N-USB3.
The Intel P67 Express and Intel H67 Express chipsets are designed for Intel’s next generation of Core processors, codenamed Sandy Bridge. More details of GIGABYTE’s upcoming motherboards based on these chipsets inside.
GIGABYTE, well-known amongst enthusiasts for its motherboards and graphic cards, has announced the Sumo 5112 full tower enclosure, further expanding its product portfolio.
Notice that the GIGABYTE GA-H55N-USB3 becomes a better CPU overclocking platform when Load Line Calibration is disabled? We investigate why, and show you how to maximise your overclocks with a simple modification, or two.
GIGABYTE’s latest M1425 notebook and T1125 tablet sport Creative’s THX TruStudio Pro suite of audio enhancement technologies, enabling users to enjoy superior multimedia entertainment experiences complete with true-to-life audio.
15 competitors from 13 different countries duke it out to be crowned World GIGABYTE Open Overclocking Champion at the GIGABYTE Open Overclocking Championship 2010: World Wide Finals in Taipei, Taiwan on 25 September 2010. Head right in for a dose of extreme overclocking and liquid nitrogen!
The GIGABYTE Open Overclocking Championship 2010: World Wide Finals will be held on 25 September 2010, at Huashan Creative Park, Taipei, Taiwan. VR-Zone.com is at the competition venue to bring our dear readers a sneak peek!
Guess this is what most people are waiting for: a sneak preview of Cougar Point motherboards for Sandy Bridge processors. GIGABYTE has showcased their next generation Intel P67 Express chipset motherboards, the P67A-UD5 and P67A-UD7 at the Intel Developer Forum 2010. Looks like GIGABYTE has dropped its trademark blue for a cool jet black color
CDL Trading Pte. Ltd., distributor for GIGABYTE TECHNOLOGY CO., LTD. products in Singapore, invited GIGABYTE’s Technical Marketing Manager to showcase GIGABYTE’s latest technology focus and demonstrate the recently-launched Cloud OC to our local PC hardware enthusiasts. Food and drinks included, of course.
GIGABYTE has unveiled its PowerRock series of affordable PSUs, targeting mainstream users on a budget.
GIGABYTE TECHNOLOGY Co., Ltd, today announced a new overclocking competition in conjunction with HWBOT.org called the H55 Mini-ITX Contest. Press Release, links, and details inside.
GIGABYTE TECHNOLOGY Co., Ltd, a leading manufacturer of motherboards, graphics cards and other computing hardware solutions today announced support for USB Attached SCSI Protocol (UASP) on their entire range of USB 3.0 motherboards.
GIGABYTE is proud to announce that GIGABYTE On/Off Charge technology also works on the Apple iPhone 4. GIGABYTE first announced On/Off Charge in April this year by demonstrating how it speeds up iPhone, iPad and iPod Touch charging from a PC’s USB port whether the PC is operational or shut down.
GIGABYTE has launched two free real-time overclocking applications for their motherboards – the GIGABYTE Hotkey OC and the GIGABYTE Cloud OC. How can enthusiasts and extreme overclockers benefit from these two utilities?
GIGABYTE is again throwing out Super Overclock Edition graphics cards to overclockers who dare to fight it out on hwbot.org. This time round, overclockers will need to run their benchmarks on GIGABYTE AMD 8xx series chipset mainboards to qualify for the competition.
In Jakarta, 19 contestants from 16 countries get together to fight it out in the GIGABYTE Open Overclocking Championship 2010: Asia & Africa Regional Finals. More overclocking action, inside!
VR-Zone.com makes a trip to Jakarta, to experience the joy of overclocking with the folks at the GIGABYTE Open Overclocking Championship 2010. Indonesia Qualifier coverage inside, and more!


Two African elephants on the plains of South Africa at sunset. I was lucky enough to capture these two elephants walking through the bush at sunset when I was on safari in South Africa.
A pair of gannets sitting on the cliff edge on the island of Noss in the Shetland Isles, which is one of the largest breeding colonies for gannets in the UK. These birds are renowned for their spectacular diving skills.
Close up image of a cheeky young Robin redbreast, one of many that feed in my garden.
A close up shot of an European Eagle Owl.
Close up of an European Eagle Owl, in black and white with coloured eyes
The red squirrel is one of Britain's most endearing wildlife species. This endagered animal visits me regularly.
Close up imae of a Golden Eagle with a feather in it's beak. On a textured background
Red squirrel feeding. This rare native animal was photographed by Loch Awe, Argyll, in the Scottish Highlands. The Red Squirrel is on the endangered list in the British Isles. I am lucky enough to have them in my garden and they feed regularly on my bird feeder.
An adut and a juvenile gannet against a colourful sky. An original photograph of mine with added chalk effect.
Green macaw eating a peanut. I removed the background and used a green textured background. Close up image
This puffin was taken on Sumburgh Head in the Shetland Isles, UK. This is one of the largest breeding areas for puffins in the country. The Shetland name for these birds is 'tammie norrie'.
A young puffin on the side of a cliff stretching its wings.
The cute and comical Atlantic Puffin, sitting on its own on the cliffs in Shetland.
A pair of Gannets sitting on a rock silhouetted against the sky. Gannets are great diving seabrids.
The Artic Tern is a welcome visitor to Shetland as it heralds the arrival of summer. This one is sitting on a mooring rope at the harbour in Lerwick. The Shetland name is Tirrick.


The Vision on Fifteenth, Pittsburgh, PA 15222 - Office Space for rent
The Vision on Fifteenth is located at SEC of Interstate 579 and U.S. Route 28 in the Strip District neighborhood, PA, Pittsburgh, 15222. The Class A Office building was completed in 2021 and features a total of 260,400 Sqft. There is 1 Office space available for lease at SEC of Interstate 579 and U.S. Route 28, Pittsburgh, PA, 15222, totaling 250,000 Sqft. The largest space available has 250,000 Sqft.
There are 49 office spaces for lease in the Strip District neighborhood, totaling 1,510,756 Sqft of available office space. The office space availability for the 15222 zip code is 3,590,263 Sqft, in 320 office spaces. The average asking office rent per sq. ft. in Strip District is $24.21/sqft/year. For Class A office buildings the average office rate is $29.5/sqft/year, for Class B office buildings the average office rate is $26.25/sqft/year, for Class C office buildings the average office rate is $30/sqft/year.
In Strip District, there are 8 class A office buildings. In Strip District, there are a total of 3 LEED certified office buildings. In 2021, the same year The Vision on Fifteenth was built, 35 more commercial properties (office, industrial, retail) over 50,000 square feet were built in Pittsburgh, featuring 1,199,853 square feet of commercial space. At zip code level, there are 77 commercial properties, of which 73 are office buildings over 50,000 square feet.


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High-Powered LED Wash Zoom Moving Head Light with RGBWA+UV 4IN1, Touch Screen, and 16 Channel DMX Control
This High-Powered LED Wash Zoom Moving Head Light is designed to elevate your stage lighting experience to a new level. With its impressive specifications and versatile features, this lighting effect is a must-have for professional stages and DJ setups.
- Power: 400W
- Voltage: AC100V-240V, 50/60Hz
- Light source: 36pcs 10W four-in-one lamp beads
- Control: DMX512/master-slave/voice-controlled/self-propelled
- Channel: 16CH
- Strobe: 1-25 times/sec
RGBWA+UV 4IN1: The unlimited RGBW color mixing system and rainbow effect allow for stunning visual displays.
Touch Screen: Easily control and adjust settings with the intuitive touch screen interface.
DMX Control: Take full command of the lighting effects with 16 channel DMX control, offering extensive customization options.
Focus Function: Precision control with a focus function for directing the light exactly where it's needed.
Versatile Operation: Run automatically or take control using an external console to harness the power of 36 full-color lamp beads.
Elevate your stage presence and create captivating lighting displays with this high-powered LED wash zoom moving head light. It's a professional-grade lighting effect that offers exceptional performance and flexibility.


Oct 19, 2012, 1:00 PM EDT
Having witnessed owners reject the NHLPA’s three CBA proposals, Shawn Horcoff now fears for the fate of the 2012-13 season.
“I am worried for the season, I’m really worried,” the Oilers captain told the Edmonton Sun. “Especially after today, seeing what I saw. I think the next step is cancelling another big chunk of games, probably into the middle of November.”
Horcoff was one of 18 players in Toronto for Thursday’s meeting and, from what he saw, the negotiations went nowhere.
“There was no talk whatsoever, not even any communication among their own people in the room, among the owners. It was that quick,” he explained. “It didn’t really matter what we had to say. Unless we totally accepted their deal, they weren’t going to take it. ”
Horcoff also shared his disdain for commissioner Gary Bettman, re-iterating a common refrain heard throughout the work stoppage:
Players don’t trust Bettman. Nor do they like him.
Horcoff said the players huddled to watch Bettman’s post-meeting presser and were “going crazy” at what the commissioner told the media.
Things have gotten to the point where the players’ emotions have made the union almost defiant in its stance, something Horcoff shared with the Sun.
“We’re willing to sit the year out if it means getting the right deal,” he said.
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- Discuss: Penguins knock off the Senators in Game 5, headed to conference final 42
- Video: Morrow’s goal off the foot stands after review 5
- Maloney signs long-term contract as Coyotes GM 7
- Playoffs Tonight: Penguins aim to finish off Senators 20
- Kings’ Quick ‘didn’t have to work hard’ in shutout win over Sharks 7
- Discuss: Kings dominate Game 5, one win away from Western Conference final 22
- Discuss: Red Wings take 3-1 series lead 65
- Report: NHLPA director Fehr wants to address issue of fighting (113)
- Question for commenters: What, if anything, needs to be done about the officiating? (101)
- Discuss: Bruins rally in third, take 3-0 series lead (99)
- Discuss: Detroit takes 2-1 series lead vs. Chicago (95)
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- Watch LIVE: Pens-Sens, Game 5
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- Play Video: I was there: Bruins stun Maple Leafs in Game 7
- Play Video: Top-seeded Blackhawks on brink of elimination


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Lena has fled back to the place where she grew up hard, careening back through the shadows of her past and into a shocking underground world of bigotry and rage. The man who raised her is slowly killing himself with drugs. The man who beguiled - and beat - her is reaching out from prison. And now only Jeffrey and Sara can free Lena from the web of lies, betrayal, and brutality that has trapped her - as this powerhouse of a novel races toward its shattering climax...and a final, unforgettable twist.
©2007 Karin Slaughter; (P)2007 Brilliance Audio, Inc.
I regret giving this such a low rating, but the writing had serious problems. The worst is that the timeline skitters all over the place, way over the line of comprehensibility. You never know whether something is happening now or happened weeks ago. There are also odd grammatical errors that aren't enough to ruin the story, but mildly annoy -- given that she's among the rare few who know not to say "firstly" or "importantly," it seems strange she'd then misuse "comprise." The story is miserable, too. All of the major female characters have been savaged and brutalized. And the sex scenes are gratuitous rather than contributing to the meaning of the story.
AUDIO: Adequate, but there are noticeable misemphases and her low voices lose expression.
Karin Slaughter's books are fantastic and always a great read/listen. I didn't love the reading of the male characters' voices compared to past readers.
All 3 main characters are great.
I didn't love her performance overall, but Sarah was the best.
Wouldn't listen to performance by Joyce Bean again of Karin S's books.
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By Maung Shwe / The Stateless
Maungdaw : Myanmar government allowed Media consisting of local & international medias and a team of EU delegation to visit northern Maungdaw separately on Thursday, March 30, 2017. The teams were accompanied by Borders Guard Police (BGP).
The media teams visited some of affected areas to interview Rohingya but Myanmar didn’t allow the victims to talk with the teams. People were strictly refrained from gathering in two or three and crowd gathering was strictly monitored and prohibited. Rohingya villagers report they were not allowed to talk the visiting teams because of the heavy presence of BGP in many places where the delegation and media teams made their visit. In several places, unable to talk directly and express their concerns, Rohingya villagers tried to submit their statements though letters. Here too they failed.
The media teams reportedly visited Rabailla (Kyar Gaung Taung) at around 12 pm where few Rohingyas did manage to talk and submit their letters. One letter was a list showing damages suffered and lives lost by Rohingyas during Genocidal campaign by Myanmar armed forces in their village alone. The list includes crimes committed by Myanmar armed forces alone or together with Rakhine extremists against the Rohingya in that village as mentioned below:
Killed 10 Rohingya by shooting, beating and burnt alive, raped 40 girls and women, burnt 70 houses, 2 mosques and 2 shops, broken 14 houses and looted 250+ cows, 150+ goats, 350+ solar panels and with batteries, 32 motorbikes, 40 bicycles and looted others household from almost all the houses in the village.
After two hours of interviewing, the team went to Nga Kura BGP camp where BGP forcefully took the three rape victims who testified to the team earlier at the village. They were detained for hours and around 9:15 pm the three women returned to their homes, a villager reports.
The villager also reported that tomorrow all the three victims are asked to go to Maungdaw. The victims are now fearing for their lives as they don’t know what may happen to them tomorrow.
The media teams are also expected to visit some more villages tomorrow onwards.


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A galvanizing critique of the forces vying for our attention—and our personal information—that redefines what we think of as productivity, reconnects us with the environment, and reveals all that we’ve been too distracted to see about ourselves and our world
Nothing is harder to do these days than nothing. But in a world where our value is determined by our 24/7 data productivity . . . doing nothing may be our most important form of resistance.
So argues artist and critic Jenny Odell in this field guide to doing nothing (at least as capitalism defines it). Odell sees our attention as the most precious—and overdrawn—resource we have. Once we can start paying a new kind of attention, she writes, we can undertake bolder forms of political action, reimagine humankind’s role in the environment, and arrive at more meaningful understandings of happiness and progress.
Far from the simple anti-technology screed, or the back-to-nature meditation we read so often, How to do Nothing is an action plan for thinking outside of capitalist narratives of efficiency and techno-determinism. Provocative, timely, and utterly persuasive, this book is a four-course meal in the age of Soylent.
”How to Do Nothing” is genuinely instructive, elaborating a practical philosophy to help us slow down and temporarily sidestep the forces aligned against both our mental health and long-term human survival. You can knock the hustle—and you should.” —Los Angeles Times
”Jenny Odell’s brilliant How to Do Nothing is the book we all need to read now. With wonderful precision, passion, and artfulness, Odell finds the language to meet this cultural moment. She has written a joyful manifesto about resistance that is also an eccentric and practical handbook on how to reclaim your colonized and monetized attention. She then suggests how we can attend what really matters: our communities, ourselves in a specific context, and, ultimately, our responsibilities to one another.”
—Dana Spiotta, author of Innocents and Others
”Your chaotic, fraught internal weather isn’t an accident, it’s a business-model, and while ’thoughtful resistance’ isn’t ’productive,’ Odell proves that it is utterly necessary.” —Cory Doctorow, author of Radicalized and Walkaway
”Self-help for the collectively minded, How to Do Nothing is as thoughtful and morally serious as it is fun to read. This book will change how you see the world.” —Malcolm Harris, author of Kids These Days
“In a media and tech ecosystem simultaneously obsessed with ”digital detox” and building personal brands, How to Do Nothing is a breath of fresh air grounding readers in the complex, interdependent actual ecosystems of the physical world. Jenny Odell writes with remarkable clarity and compassion. Each chapter reads like going on a fascinating walk through a park in conversation with an old friend (who happens to also be able to tell you about every single bird in the park, which is awesome). It’s a book I already know I’ll be returning to and referencing for a long time.” —Ingrid Burrington, author of Networks of New York
“In How to do Nothing Jenny Odell breaks through the invisible yoke that binds 21st century first-worlders to our app-driven devices. With a thoughtful look at the attention economy, Odell’s book is a self-help guide for re-learning how to look at the world. The book braids threads of ancient philosophy together with contemporary visual and technological culture, and weaves an original route to re-wilding the mind. Wide-ranging and erudite, this book is also entertaining, and brings the reader along with enthusiasm to Odell’s philosophy of “manifest dismantling.” —Megan Prelinger, author of Inside the Machine: Art and Invention in the Electronic Age

domain: library


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17. "lol i'm just saying. if it's comic material reduced to a soap opera..." In response to In response to 15
... like Heroes, than I won't watch it. But if this actually turns out to be a decent action series where things happen and characters develop somewhat rationally, then I will give it AT LEAST as much of a chance as I did Heroes.


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To the average person, Nelson Mandela is remembered as a political leader who eventually was president of his homeland of South Africa. However, behind his seemingly ever smiling face, lied a life of struggles and injustice. Before Mandela could become the great leader that he was, he endured numerous trials and tribulations. Mandela was born in 1918, at Mvezo, and into a royal family of the Thembu people of the Xhosa nation. His father was a chief of Mvezo, however his untimely death when Mandela was 9, left Mandela to be greatly influenced by the regent. Growing up as part of a tribe, it greatly affected Mandela’s views which were shaped by custom, ritual and taboo. Mandela was in and out of schools, jobs and homes all throughout his childhood and even into his early adult life. Because of this nomad type of living in his young years, he got to know many different types of people from different tribes, who possible had different social and/or political views. This in turn would shape Mandela’s social and political views, as well as his view on the world. This paper argues that Mandela’s experiences at Healdtown helped to shape his cultural and moral values and his time at Fort Hare helped to shape his political values, all aiding to the development of the great political leader that he one day would become.
When Mandela was about 19 years old, following his rigorous experiences at Clarkebury Mandela enrolled in the Wesleyan College in Fort Beaufort, Healdtown. His time here certainly influenced his cultural view of his own tribe as well as other’s tribes. The first instance occurs when Mandela made [his] first Sotho-speaking friend, Zachariah Molete and he remembered feeling quite bold having a friend who was not Xhosa (37). Mandela never knew that the possibility of making not friendships outside of his own tribe even existed before attending Healdtown. However, by interacting with people outside of his native tribe, Mandela began to sense his identity as an African, not just a Thembu or even a Xhosa (38). These examples show how Mandela’s time at Healdtown led him to broaden his cultural horizons and shape his new cultural views and which in turn would contribute the great political leader he became.
In addition to making a friend outside of his tribe at Healdtown, Mandela also witnessed a black man stand up to Dr. Wellington, a white, important figure in the school, which further developing his cultural views. Reverend Mokitimi, a black man, refused to report to Dr. Wellington of the infraction that occurred between two prefects at the school. Dr. Wellington asked again, however Reverend Mokitimi refused once again to give away any information to him at the time, but he would inform him the next day. Through this Mandela realized then that a black man did not have to defer automatically to a white man, however senior he was (38). Similarly, to how Mandela would never have considered having a friend across tribe lines, he also would have never considered a black man standing up to a whit man across color lines. Previously, Mandela would have considered all black men to be below white, however through this experience, he understands that it is not necessarily that way. At Healdtown, Mandela witnesses the notion of double consciousness as he was a balck man trying to navigate the British style education during this time. He has empowerment and can achieve massive amounts throughout his time there, but he still has restrictions on him due to his color. As Reverend Mokitimi stood up to Dr. Wellington, Mandela’s cultural views were again shaped and molded to aid him in his ideals as a great political leader.
In addition to Mandela’s cultural views being shaped at Healdtown, his moral values were also put to the test. In his second year at the school Mandela was appointed a prefect by Reverend Mokitimi and Dr. Wellington. He had many responsibilities, but one specifically tested his moral values. He was assigned night duty and caught another prefect urinating in the bushes. Such behaviors were to be reported immediately, however instead of following the strict rules at Healdtown, Mandela did not report one of his own kind and he simply tore up [his list] and charged no one (40). Despite this being a minor event, it still demonstrates how Mandela would stick up for those of his own kind and not turn on them, showing loyalty. This instance shaped and even reinforced Mandela’s moral values, which helped him when becoming a major political leader.
During Mandela’s time at Fort Hare, there were many clear events that shaped his political viewpoints and strength. However, arguably the most defining and controversial moment in his time there was the student government election and the events surrounding it. Mandela was appointed for highest student organization at the school, the Student Representative Council. However, during the election time, many students believed that their voices were not heard. The students unanimously felt that the diet at Fort Hare was unsatisfactory and that the powers of the SRC needed to be increased (51). To change the issue that they were facing, the majority of the student body decided to boycott the upcoming election and Mandela also boycotted. Even though the majority of the students boycotted, approximately 25 students still voted in the Student Representative Council election. Mandela was elected with six other students all of whom wrote a letter of resignation to the principal, Dr. Kerr. Dr. Kerr accepted their resignation, and arranged for another election, this time however with all students voting at the dining hall during dinner. Mandela was once again elected, with the original five others. Despite the other five finding it acceptable to accept their Student Representative Council positions, Mandela did not and this resigned again. However, the principal told him that he either had to accept his position on the Student Representative Council or he would be forced to leave Fort Hare. Mandela had to make another moral decision, similar to the one made at Healdtown, and once again decides to stand up for what he believes in, thus leaving Fort Hare and its education behind. When describing this event in his autobiography, Mandela states that he simply could not [compromise]. Something inside me simply would not let me resented his absolute power over my fate (52-53).
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