text:
S- Editor Liu Y L- Editor Alpini GD E- Editor Wang HF
Published online Nov 28, 2007. doi: 10.3748/wjg.v13.i44.5867
Revised: August 8, 2007
Accepted: October 19, 2007
Published online: November 28, 2007
Colorectal cancer remains one of the major causes of cancer death worldwide. During the past years, the development of new effective treatment options has led to a considerable improvement in the outcome of this disease. The advent of agents such as capecitabine, irinotecan, oxaliplatin, cetuximab and bevacizumab has translated into median survival times in the range of 2 years. Intense efforts have focused on identifying novel agents targeting specific growth factor receptors, critical signal transduction pathways or mediators of angiogenesis. In addition, several clinical trials have suggested that some of these molecularly targeted drugs can be safely and effectively used in combination with conventional chemotherapy. In this article we review various treatment options combining cytotoxic and targeted therapies currently available for patients with metastatic colorectal cancer.
Citation: Rodriguez J, Zarate R, Bandres E, Viudez A, Chopitea A, García-Foncillas J, Gil-Bazo I. Combining chemotherapy and targeted therapies in metastatic colorectal cancer. World J Gastroenterol 2007; 13(44): 5867-5876
Chemotherapy remains the cornerstone of treatment of metastatic colorectal cancer (mCRC) and, with the exception of a minority of patients (pts) who are candidates for salvage surgery, the goal of chemotherapy is palliation. Remarkable and clinically relevant advances have been made in the last 5 years in the treatment of this disease, essentially owing to the introduction of combination chemotherapy regimens containing oxaliplatin and irinotecan (CPT-11)[1]. The addition of either drug to 5-fluorouracil/leucovorin (5-FU/LV) proved to significantly increase overall response rates and survival times. Indeed, median overall survival is highly correlated with the percentage of patients who receive the three cytotoxic agents in the course of their disease. Results from a Phase III study by Falcone et al[2] suggested that the up-front use of a triplet combination of irinotecan, oxaliplatin and 5-FU/LV significantly improved the outcome in terms of response rate (RR) and survival times compared to a standard doublet of irinotecan and 5-FU/LV.
Interestingly, with the more recent incorporation of bevacizumab and cetuximab into the treatment armamentarium, the median overall survival (OS) has doubled from 12 mo to approximately 2 years in Phase III trials. In fact, most recent trials that attempt to expose patients to all five drug classes (fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab and anti-EGFR antibody) target an OS well over 2 years. In this review we will summarize some of the available therapeutic repertoire based on targeted therapies in combination with chemotherapy for patients with mCRC.
The epidermal growth factor receptor (EGFR), a transmembrane tyrosine kinase, is one of four members of the HER receptor family. This receptor is overexpressed in a number of solid tumors of ectodermal origin, including colon adenocarcinoma[3]. EGFR over expression has been correlated with disease progression, poor prognosis and reduced sensitivity to chemotherapy[4]. Therefore, several strategies have been developed to target EGFR, including small molecule tyrosine kinase inhibitors and monoclonal antibodies[5].
Cetuximab is the most advanced monoclonal antibody against EGFR in clinical development. Since preclinical and early clinical studies suggested that Cetuximab might revert irinotecan resistance in CRC both in vitro and in vivo, a phase II trial of cetuximab with irinotecan was performed in patients with EGFR positive colorectal cancer that was refractory to both 5-fluorouracil (5-FU) and Irinotecan. Among the 120 patients treated with this regimen, overall response rate was 22.5%[6].
To confirm these clinical findings, 329 EGFR-positive, irinotecan-refractory mCRC patients were randomized in a 2:1 ratio to receive cetuximab plus irinotecan (arm A; n = 218) or cetuximab alone (arm B; n = 111) with the option to switch to the combination of cetuximab with irinotecan after failure of cetuximab as a single agent. Both the response rate (22.9% vs 10.8%, P = 0.007) and the median time to progression (4.1 vs 1.5, P < 0.001) favored the combination arm. Although no survival benefit was observed for arm A, cetuxibab was demonstrated to have clinically significant activity when given alone or in combination with irinotecan and consequently received FDA approval[7].
More recently, MABEL trial[8] investigated the combination of cetuximab and CPT-11 at a dose and schedule as pre-study in an uncontrolled, multicenter study including 1123 mCRC pts with detectable EGFR. 64% of the patients had received ≥ 2 lines of chemotherapy. 76% had also been pretreated with cetuximab. The estimated median survival was 9.2 mo at as expense of an acceptable toxicity profile, including grade 3-4 diarrhea (20%) acne-like rash (19%), neutropenia (9%) and asthenia (8%). MABEL clearly confirmed in a wider setting the efficacy and safety or C225 plus CPT-11 seen in previous studies. Similarly, EPIC trial is a randomized phase III trial comparing cetuximab plus irinotecan to irinotecan as second line therapy in patients with EGFR-expressing mCRC who have failed first line oxaliplatin in combination with a fluorpyrimidine. Accrual is currently ongoing[9].
Cetuximab-based combinations as salvage therapy: Several trials have addressed the potential of cetuximab-based combinations in heavily pretreated patients. Vincenzi et al[10] evaluated the efficacy of cetuximab plus oxaliplatin in patients previously failed on an oxaliplatin-based regimen in first line, irinotecan-based regimen in second line, and cetuximab plus irinotecan in third line. No objective clinical response was identified after the interim analysis planned according to the two-staged Simon accrual design. The same group[11] evaluated the activity of cetuximab and weekly irinotecan (90 mg/m2) in patients refractory to one oxaliplatin-based chemotherapy regimen (Capecitabine + Oxaliplatin or FOLFOX IV regimen, as first line) and one Irinotecan-based based-chemotherapy (FOLFIRI regimen, as second-line chemotherapy) for at least 2 mo. Overall response rate was 25.4% (95% CI: 21.7%-39.6%); 38.2% (95 CI: 18.6%-39.8%) of patients showed a disease stability as the best response. The median time to progression was 4.7 mo (95% CI: 2.5-7.1 mo) and the median survival time was 9.8 mo (95% CI: 3.9-10.1 mo). The most common G3-4 noncutaneous side toxicities were diarrhoea (16.4%), fatigue (12.7%), stomatitis (7.3%) and skin toxicity (32.6%). A statistically significant (P = 0.006) association between the cutaneous toxicity and both tumour response and time to progression was observed. The authors also identified a borderline significant difference in terms of overall survival.
The combination of Cetuximab plus FOLFIRI has been prospectively evaluated in 41 EGFR expressing mCRC pts refractory to prior FOLFIRI for metastatic disease[12]. Most of the patients were treated in third line. A 20% overall response rate was recorded, with a median PFS of 4.3 mo and a median overall survival of 5 mo.
Cetuximab-based combinations in front-line therapy: Cetuximab established activity in the salvage setting prompted its incorporation to first-line combination therapy. Available preliminary data from Phase II trials combining cetuximab with either irinotecan or oxaliplatin-based chemotherapy have shown very encouraging activity. CALGB 80203[13] randomized untreated mCRC patients to FOLFOX or FOLFIRI with or without C225 independent of EGFR status. ORR was similar in the FOLFIRI or FOLFOX arms, while C225 containing arms had a higher ORR (49% vs 33%, P = 0.014) when compared to non cetuximab containing arms. No significant differences in grade 3 diarrhea or any grade 4 toxicity were seen with the addition of C225. Preliminary results of the combination of C225, capecitabine (800 g/m2 bid po on d 1 to 14) and Irinotecan (200 g/m2 i.v on d 1) vs C225 combined with capecitabine (1000 mg/m2 bid in d 1-14) and oxaliplatin (130 g/m2 on d 1) reported an overall response rate of 41% (95%; 22% to 61%) and 71% (95%; 48% to 89%) respectively, with both arms showing a manageable toxicity profile[14].
Promising results have also been reported[15] combining cetuximab with (AIO) infusional 5-FU/FA plus irinotecan regimen in EGFR-expressing mCRC.Grade 3 or 4 toxicities were acne-like rash (38%), diarrhea (29%), cardiovascular events (20%) and nausea/vomiting (5%). Objective responses were observed in 67% of the patients. The median time to progression was 9.9 mo and the median survival time was 33 mo.
The combination of cetuximab with modified FOLFOX 6 in 83 chemo-naive mCRC pts with positive or undetectable EGFR expression show a preliminary ORR of 53%[16]. Main grade 3-4 toxicities included neutropenia (38%), diarrhea (10%), rash (10%) and neurotoxicity (7%). The combination of FOLFOX-4 plus C225[17] has also been evaluated in 47 EGFR-expressing mCRC, with a reported ORR of 68%. Grade 3-4 adverse events included acne-like rash (18%) diarrhea (7%), nausea and vomiting (4%) and anemia (4%).
Preliminary results of the OPUS trial[18], a randomized phase II study in the first line treatment of mCRC, confirmed the superiority of FOLFOX plus cetuximab vs FOLFOX in terms of overall response rate (45.6% vs 36.8%).
These small trials supported the conduct of a multicenter Phase III clinical trial that compared FOLFIRI plus Cetuximab with FOLFIRI alone in 1217 EGFR-expressing chemotherapy-naive patients. Cetuximab plus FOLFIRI significantly increased response rate and progression-free survival, reducing the relative risk of progression by approximately 15%[19].
Panitumumab is a fully human IgG2 monoclonal antibody directed against the epidermal growth factor receptor. Its use in combination with IFL and FOLFIRI in first line treatment of metastatic CRC has been evaluated in a multicenter, single arm, phase 2 trial[20]. Panitumumab was given at a weekly dose of 2.5 mg/kg i.v. over 60-90 min followed by chemotherapy. The combination with IFL was considered too toxic, with grade 3-4 diarrhea in 47% of the patients. The FOLFIRI plus panitumumab combination was associated with a more manageable side effect profile with grade 3-4 diarrhea in 25% of the pts and grade 3-4 hypomagnesemia in 8%. Skin and nail toxicities occurred in at least 20% of patients but were rarely severe (grade 3 in 2 out of 24 pts). The objective response rate with FOLFIRI plus panitumumab was 66%, with a disease control rate of 79%. Median progression free survival was 10.9 mo. Further investigation of FOLFIRI with an every two weeks schedule of panitumumab is ongoing in randomized phase 3 trials.
Cetuximab-induced papulopustular skin rash is thought to be mechanism- and dose-related, and may be a surrogate indicator of an adequate degree of receptor saturation by cetuximab. The possibility of increasing Cetuximab efficacy by inducing skin rash has been recently confirmed. Cetuximab dose escalation up to 500 mg/m2 improves response rate in patients with absent or slight skin reaction on standard dose treatment[21].
Large studies validating molecular predictive markers are needed in order to identify the subset of patients more likely to respond to EGFR-targeted therapies. Candidate markers include total and phosphorylated EGFR, total and phosphorylated forms of AKT, mitogen-activated protein kinase (MAPK), mitogen-activated protein/ERK (MEK), ERK, signal transducers and activators of transcription (STAT), PTEN and mTOR[22] Although EGFR gene copy number has also been proposed[23], EGFR amplification, measured by FISH is a rare event (4%) in colorectal cancer[24]. Other potential predictive markers are k-ras[25] cyclin D1 A870G polymorphisms[26], HER-2 expression[27] or higher gene expression levels of VEGF[28]. More recently, a combination of various predictive biomarkers has retrospectively been able to identify subsets of patients more likely to benefit from cetuximab therapy[29]. In addition, several polymorphisms in genes involved in the EGFR and angiogenesis pathway have been associated with clinical outcome[30]. Prospective studies are clearly needed to confirm these preliminary findings.
Gefitinib: Gefitinib (ZD1839) selectively inhibits the EGFR tyrosine kinase and has approximately 100-fold greater potency against EGFR compared with other tyrosine or serine/threonine kinases. Unlike cetuximab, gefitinib does not induce EGFR internalization or degradation in CRC cells, nor does it reduce EGF binding sites or EGFR protein content. Both in vitro and in vivo studies indicated that gefitinib monotherapy had antitumor activity in some CRC cell lines[31]. However, phaseI/II clinical studies in patients with mCRC indicated that gefitinib had negligible activity[32,33]. Preclinical suggestions of a supra-additive, growth-inhibitory effect of gefitinib and a wide variety of cytotoxic drugs with different mechanism(s) of action[34] prompted several trials of gefitinib in combination with chemotherapy in mCRC patients.
Gefitinib plus fluoropyrimidines: In preclinical models a strong synergistic interaction between gefitinib and 5'-deoxy-fluorouridine (5'-DFUR) was demonstrated when ZD1839 was applied before or concurrently with 5'-DFUR[35]. Subsequently, the combination of intermittent gefitinib (250-500 mg/d on d 1-14) plus 5-FU/LV administered as a bolus in a dose-reduced Mayo Clinic regimen (370/20 mg/m2) on d 8-12 with 5-FU and leucovorin as first-line therapy in mCRC was tested, with no evidence of cumulative toxicity or major drug-drug pharmacokinetic interactions[36]. In the second part of the study, gefitinib was administered continuously at 500 mg/d, and 5-FU/LV was added to the schedule on d 8-12 and 36-40. Overall response rate was 23%, with the most common toxicities being rash and diarrhea.
Preliminary results from a small phaseI/II trial combining gefitinib 250-mg daily with capecitabine 1000-1250 mg twice daily after failure of first-line therapy[37] also suggest some evidence of activity .
Gefitinib plus irinotecan-based therapy: A dose-finding trial of irinotecan plus gefitinib in mCRC patients pretreated with fluoropyrimidine-based chemotherapy defined irinotecan given at a dose of 225 mg/m2 every 3 wk plus gefitinib at a dose of 250 mg/d as the maximun tolerated dose (MTD) of this regimen[38]. Dose-limiting toxicities (DLTs), such as neutropenia and diarrhea, occurred at unexpectedly low doses of irinotecan. Disease stabilization was achieved in 21% of the patients.
The combination of gefitinib plus FOLFIRI in both chemotherapy-naive mCRC patients[39] and as salvage therapy[40] was considered too toxic despite reduced weekly doses of 5-FU, LV, and irinotecan.
Gefitinib plus oxaliplatin-based therapy: Gefitinib plus FOLFOX has been tested in both the first line and the salvage setting. Kuo et al[41] reported data on a phase II study of one cycle of FOLFOX-4, and then additional cycles of FOLFOX-4 with 500 mg/d of gefitinib in 27 patients with documented progressive colorectal cancer after at least one chemotherapeutic regimen (usually irinotecan based). 33% of the patients achieved objective responses, whereas 48% had stable disease for a prolonged period. Response rates did not differ depending on number of prior regimens. Median event-free survival was 5.4 mo, and overall survival was 12 mo. Another feasibility study assessed the combination of gefitinib (250 mg/d) plus capecitabine (2000 mg/m2 per day, d 1-15) plus oxaliplatin (120 mg/m2 every 3 wk for six courses) as first-line treatment in patients with mCRC[42]. The most common grade 3 adverse events were diarrhea and neutropenia. A clinical benefit rate of 58% has been noted. Overall, toxicity rates with the addition of gefitinib to an oxaliplatin-fluoropyrimidine combination are markedly more favorable than with the irinotecan-based regimens, although higher incidences of grade III or IV diarrhea, nausea, and vomiting than with FOLFOX alone are noted. Further studies of TKI-based therapy for CRC are planned or recruiting.
Erlotinib: Erlotinib, an orally reversible TKI reduces intratumoral EGFR autophosphorylation[43] with no effect on EGFR expression or surface receptor density. Evidence of single agent erlotinib activity in mCRC patients derived from disease-specific phase II studies[44] led to the design of several trials in combination with chemotherapy.
Tarceva plus fluoropyrimidines: Additive activity of capecitabine and erlotinib in tumor models[45] supported a phase 2 trial evaluating the combination of erlotinib 150 mg daily with capecitabine 1000 mg/m2 bid. for 14 d every 3 wk in chemotherapy-naive mCRC patients. Grade 3 diarrhea (30%) grade 3 renal insufficiency (10%) and grade 3 hiperbilirrubinemia (10%) were the most troublesome toxicities. Regarding efficacy, no complete responses were achieved whereas disease control rate was 34%[46].
Tarceva plus oxaliplatin: Meyerhardt et al[47] reported on the results of a triplet regimen of erlotinib, 100 mg/d, capecitabine, 1650 mg/m2 per day (d 1-14), and oxaliplatin, 130 mg/m2 every 3 wk in 32 patients mostly pretreated with an irinotecan-containing regimen. By intent-to-treat analysis, 25% of the patients experienced a partial response and 44% had stable disease for at least 12 wk. 29% of the patients discontinued study therapy due to toxicity.
EKB-569, an irreversible dual inhibitor of the EGFR and HER-2 tyrosine kinases, inhibits the growth of tumor cells that overexpress EGFR or HER-2 in vitro and in vivo[48]. Dose-limiting toxicities with EKB-569 plus FOLFIRI in 47 chemotherapy-naive mCRC patients[49] were grade 3 diarrhea and grade 3 fatigue. The MTD was selected as 25 mg EKB-569. The response rate was 38% and the clinical benefit rate was 85%. EKB-569 treatment resulted in complete inhibition of pEGFR and significant inhibition of pMAPK in both skin samples (11 patients) and tumor samples (three patients) with no change in pAkt activity.
In a dose-escalation study[50] with FOLFOX-4 plus EKB-569, 25-75 mg/d, starting from d 3, DLTs were observed with EKB-569 at a dose of 35 mg/d (grade III diarrhea and febrile neutropenia), leaving an MTD of 25 mg/d. The most common grade III or IV adverse events were neutropenia (32%; 9 of 29 patients) and diarrhea (8%; 2 of 29 patients).
Clinical development of Bevacizumab (BV) has rapidly progressed to Phase III trials after a preliminary randomized Phase II trial in which 104 previously untreated mCRC patients were randomized to two doses of BV (5 and 10 mg/kg) in addition to bolus 5-FU/LV (high dose, Rosewell-Park regimen) or to 5-FU/LV alone[51]. The combination of 5-FU/LV with low-dose BV (5 mg/kg every 2 wk) demonstrated superiority compared with the control monotherapy arm and to the BV-containing arm at a higher dose. These results provided the rationale for the key front-line Phase III study by Hurwitz et al[52] which demonstrated superiority of IFL plus BV over IFL plus placebo in terms of RR (45% vs 35%), PFS(10.6 mo vs 6.2 mo) and OS(20.3 mo vs 15.6 mo). A subanalysis of this trial has recently stablished the benefit of Bevacizumab in mCCR patients with poor conditions[53].
The second trial (E3200) was a second-line Phase III study, designed for patients who already failed an irinotecan-containing therapy and did not receive BV in first-line treatment[54]. Initially, the study included three randomization arms: FOLFOX4 plus BV 10 mg/kg, FOLFOX4 alone or BV 10 mg/kg alone. The BV single-agent arm was closed ahead of time since it was clearly inferior to both other arms (RR 3% and PFS 2.7 mo). The results again largely favored the BV-containing arm, especially in terms of RR (21.8% vs 9.2%, P < 0.0001) and PFS (7.2 mo vs 4.8 mo, P < 0.0001). The primary end point of the study was reached, since a statistically significant increase in median survival was obtained in the experimental arm (12.5 mo vs 10.7 mo, P < 0.0024).
Finally, updated results of N016966, a randomized phase III trial evaluating the addition of bevacizumab to oxaliplatin-based first line chemotherapy have been reported. Bevacizumab-containing arms demonstrated a significant benefit in terms of progression-free survival, although overall response rate did not significantly differ[55].
More recently, several phase II trials have addressed the feasibility and activity of bevacizumab when combined with various cytotoxic regimens. The First BEATrial[56] enrolled 1927 chemotherapy-naïve patients treated with a combination of bevacizumab and several first-line chemotherapies, including FOLFOX, FOLFIRI and XELOX. Median PFS was 10.4 mo. Combinations of XELOX or XELIRI plus bevacizumab have yielded tumor control rates in the range of 80% as front-line therapy for mCRC[57].
In contrast to its efficacy when used in combination with first- and second-line chemotherapy, activity of bevacizumab in chemoresistant disease has been disappointing. Chen et al[58] developed a treatment referral center (TRC) protocol (TRC-0301) for patients with mCRC in the third-line setting with the aim of evaluating the safety and activity of BV plus FU/LV in patients progressed after treatment with both irinotecan-based and oxaliplatin-based chemotherapy regimens. Independent review confirmed one PR (1%; 95% CI, 0% to 5.5%). Median PFS in this cohort was 3.5 mo (95% CI, 2.1 mo to 4.7 mo) and median OS was 9.0 mo (95% CI, 7.2 mo to 10.2 mo). The authors conclude that BV, alone or in combination with an ineffective chemotherapy in the third-line setting, is likely to be of minimal, if any, clinical benefit.
An important question that remains unresolved is whether to continue bevacizumab with second-line therapy following failure of a bevacizumab-containing first-line regimen. Although retrospective data from the BRiTE trial suggest that the use of bevacizumab beyond first progression correlate with an improved survival, more mature data are required to draw any firm conclusion[59].
Tyrosine kinase inhibitors of vascular endothelial growth factor receptors (VEGFRs) are low molecular weight, ATP-mimetic proteins that bind to the ATP-binding catalytic site of the tyrosine kinase domain of VEGFRs, resulting in a blockade of intracellular signaling. Several of these molecules have entered clinical evaluation.
Semaxanib: Semaxanib is a small, lipophilic, synthetic molecule that inhibits VEGFR-1, and -2 tyrosine kinases[60]. A promising response of 31.6% was observed with semaxanib at two different dose levels, 85 and 145 mg/m2 twice weekly in combination with fluorouracil plus leucovorin as first-line therapy for 28 patients with mCRC[61]. However, a randomized, multicenter, phase III trial failed to show any improvement in clinical outcome with semaxanib in combination with fluorouracil and leucovorin (Roswell Park regimen) versus fluorouracil and leucovorin alone as first-line therapy for 737 mCRC patients; moreover, worse toxicity in the semaxanib arm (in terms of diarrhea, cardiovascular events, vomiting, dehydration, and sepsis) was observed[62].
Vatalanib: Valatanib is a synthetic, low molecular weight, orally bio-available agent that inhibits all known VEGFR tyrosine kinases, platelet-derived growth factor receptor beta (PDGFR-β) and c-Kit tyrosine kinase[63].
Vatalanib was evaluated in two phaseI/II studies as a single daily dose in combination with FOLFOX-4 or FOLFIRI. In the first study, the pharmacokinetics and toxicity profiles of both vatalanib and FOLFOX-4 were unaffected by co-administration[64]. The reported response rate was 54%, with a median PFS of 11 mo and an estimated median OS time of 16.6 mo . In the second study[65], co-administration of vatalanib at 1250 mg/d with FOLFIRI had minor effects on irinotecan exposure but lowered by 40% the AUC of SN-38 in patients' serum. The response rate was 41%, with a median PFS duration of 7.1 mo and a median OS time of 24.3 mo. Two large, randomized, double-blinded, placebo-controlled, phase III trials compared the efficacy of oral vatalanib in combination with FOLFOX-4 with FOLFOX-4 alone in patients with mCRC, and none of them met the primary end points. In the CONFIRM-2 trial, the addition of PTK/ZK to FOLFOX-4 in previously treated mCRC did not meet the primary end points of the study. OS was 12.1 mo in the PTK/ZK arm and 11.8 mo in the placebo arm. The overall response rate was, respectively, 18.5 and 17.5%. PFS was significantly longer in the PSK/ZK arm (5.5 mo vs 3.8, P = 0.026) As in confirm 1 trial, patients with pretreatment high LDH showed a strong improvement in PFS[66]. Adverse events were similar to those of the CONFIRM-1 trial. Thrombotic and embolic events of all grades occurred in 6% of the patients treated with PTK/ZK vs 1% in the placebo arm. Trying to further analyze the relation between LDH levels and clinical outcome with PTK/ZK, Fixed paraffin embedded tumor samples from 36 mCRC not included in the CONFIRM trials were analyzed and tumor gene expression correlated with serum levels of LDH in the same group of patients. Intratumoral levels of LAMA, hipoxia inducible factor 1 (HIF-1), Glut-1 and VEGFA were significantly correlated. Moreover, patients with high serum LDH showed increased intratumoral gene expression of VEGFA, supporting the hypothesis of serum LDH levels as a surrogate maker for activation of the hypoxia inducible factor related genes in the tumor[66].
AZD2171: Preliminary data of a phase I evaluation of AZD2171, a highly potent and selective inhibitor of VEGFR signaling, in combination with several chemotherapy regimens including FOLFOX-6 and CPT-11, has shown some evidence of activity[67].
Vandetalib: Vandetalib, a once-daily oral inhibitor of VEGFR-dependent tumor angiogenesis, EGFR- and RET-dependent tumor proliferation, in combination with FOLFOX6[68] or FOLFIRI[69] has also shown some evidence of activity in mCRC, with diarrhea and neutropenia being the most frequent grade 3 toxicities.
So far, clinical, biochemical, and molecular markers have failed to discriminate which patients are more likely to benefit from bevacizumab-containing regimens. An analysis of predictive markers showed indeed that bevacizumab increased the activity of irinotecan plus FU/LV regardless of the level of VEGF expression, thrombospondin expression, and microvessel density[70]. Mutations of k-ras, b-raf, and p53 could not predict for a prolonged survival on bevacizumab plus irinotecan plus bolus FU/LV[71]. Recently, Shaye et al evaluated functionally significant polymorphisms of genes involved in the angiogenesis pathway in mCRC patients who receive bevacizumab as part of their front-line therapy. There were statistically significant associations between genomic polymorphisms of KDR, CXCR2, MMP7, leptin and both progression-free survival and response rate. Hopefully, prospectively collected samples from patients enrolled onto cooperative group studies and the development of selective micro arrays to define the angiogenesis-related genes in individual tumors, and at different stages of therapy and tumor progression may allow improved therapeutic efficacy.
The assumption that most advanced solid tumors derive their growth advantage from more than a signaling pathway and the significant level of compensatory cross talk among receptors within a signaling network as well as with heterologous receptor systems has provided the basis of a combined molecular targeting approach, in which more than one class of inhibitor is applied simultaneously.
A phase II study with the combination of FOLFOX, bevacizumab (5 mg/kg) and erlotinib (150 mg/d) every two weeks in 31 chemotherapy naive mCRC patients has been recently conducted. Grade 3-4 adverse events included diarrhea (29%) neutropenia (29%) rash (18%), fatigue (14%) and neuropathy (11%) 78% of the patients had at least one grade 3-4 toxicity. Remarkably, as much as 42% of the patients came off for toxicity. Similar results have been reported in the DREAM-OPTIMOX3 study, with a 70% incidence of grade 3-4 toxicity when adding erlotinib to a combination of bevacizumab and XELOX[73].
A phase II trial of FOLFOX plus bevacizumab and cetuximab in 67 chemotherapy-naïve mCRC patients yielded a 55% response rate, with a median PFS of 9.6 mo and 71% of the patients progression-free for at least 8 mo[74].
The combination of FOLFOX or FOLFIRI with panitumumab and AMG706, an oral multikinase inhibitor targeting VEGF, PDGF and Kit receptors has been tested in 45 mCRC patients, with no apparent PK/PD interactions and an overall response rate in the range of 50%[75].
Based on these results, combinations of monoclonal antibodies are currently being actively tested in first-line therapy of mCRC. The Cancer and Leukemia Group B (CALGB)/South West Oncology Group (SWOG) Intergroup 80405 Phase III trial randomizes patients to either cetuximab or bevacizumab, or both antibodies in combination, with the oncologist's choice of FOLFOX or FOLFIRI. In addition, the Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) trial is currently evaluating the efficacy of FOLFOX or FOLFIRI (depending on the investigator choice) plus BV, versus the same combination plus panitumumab.
Kortmansky et al[76] reported the results of the combi-nation of 5-FU and UCN-01, a selective inhibitor of a number of serine-threonine kinases, including calcium and phospholipid-dependent protein kinase C and cell cycle specific kinases, among 35 patients with advanced solid tumors, the majority of them with a diagnosis of mCRC. No objective responses were observed, although eight patients had stable disease. Most of the patients with stable disease had previously received and progressed on 5-fluorouracil. There was minimal toxicity attributed to the combination, although expected toxicities associated with UCN-01 were observed.
Bcl-2 plays a pivotal role in the regulation of caspase activation and apoptosis. Its overexpression is found in 30%-94% of clinocopathological colorectal carcinoma specimens and confers a multidrug resistant phenotype in several cell lines. In support of this data, antisense oligonucleotide therapy directed against bcl-2 was shown to significantly enhance the chemosensitivity in several cancer cell lines compared with controls in vitro. A recently published phaseItrial assessed the feasibility and pharmacokinetic behaviour of the combination of oblimersen sodium, a phosphorothioate antisense oligonucleotide that hybridizes to the first six codons of the bcl-2 open reading frame mRNA, with CPT-11 in 20 pts with mCRC. Among them, 1 pt experienced a PR while 10 additional patients had stable disease lasting 2.5-10 mo. The authors recommend oblimersen at 7 g/kg/d, d 1-8 with CPT-11 280 mg/m2 on d 6 once every 3 wk was the RD for further development in phase II trials[77].
The proteasome inhibitor Bortezomib (PS-341), at a dose of 1.3 mg/m2 administered twice weekly every 21 d in pretreated patients with mCRC did not prove to have clinical activity[78].
The main nonhematologic toxicities were elevation of alkaline phosphatase, constipation, fatigue, nausea, and sensory neuropathy. A phamacokinetic and phamacodynamic analysis of topotecan plus PS-341 in 22 patients with advanced solid malignancies found that, with the addition of PS-341, peripheral blood mononuclear cells (PBMC) topoisomeraseIlevels got stabilised or increased. These findings suggest that PS-341 may overcome resistance to topoisomeraseIinhibitors, since in vitro exposure to campothecin results in down-regulation of the target enzyme. Preliminary data of the combination of FOLFOX4 plus bortezomib in mCRC patients[79] show evidence of clinical activity, with bortezomib at a dose of 1 mg/m2 being the RD for phase II trials.
Numerous clinical trials are ongoing to test the efficacy of nonsteroidal anti-inflammatory COX-2 inhibitors in combination regimens for therapy of advanced solid tumors[80]. Preliminary data on the combination of rofecoxib (50 mg/d) with weekly irinotecan and infusional fluorouracil demonstrated a good tolerability up to the irinotecan dose of 125 mg/m2/wk. The phase II study showed a 36.7% objective response rate, a clinical benefit of 76.7% and a median TTP and overall survival of 4 and 9 mo, respectively. The combination was feasible and safe, with a reduced rate of mucositis and diarrhea[81].
However, in the BICC-C trial[82], addition of celecoxib to several Irinotecan/fluorpyrimidine combinations did not impact safety or efficacy. Results of larger studies seem warranted.
Histone acetylation by histone acetyltransferases is important for promoting the action of several transcription factors. Acetylation facilitates binding of transcription factors to specific target DNA sequences by destabilizing nucleosomes bound to the promoter region of the target genes[83].
Vorinostat, a novel histone deacetylase inhibitor that potentiates 5-FU through a decrease in thymidylate synthase (TS) expression has been tested in combination with FOLFOX, in a phaseIstudy that enrolled mCRC patients who had failed prior FOLFOX, irinotecan and cetuximab therapy. Tolerance was acceptable, and some evidence of both, clinical activity (SD in some patients) and biological activity (down regulation of TS) are suggested[84].
Rapamycin displays potent antimicrobial and immuno-suppressant effects as well as antitumor properties. Rapamycin's antiproliferative actions are due to it's ability to modulate key signal transduction pathways that link mitogenic stimuli to the synthesis of proteins necessary for the cell cycle to progress from the G1 to S phase[85].
Rapamycin clinical development has been hampered due to the poor aqueous solubility and chemical stability of the macrolide. CCI-779, a rapamycin ester derived from 2, 2-bis (hydroxymethyl) propionic acid, is one analog that was selected for further development due to its promising pharmacological, toxicological and antitumor profiles[86].
A phaseIstudy of escalating doses of CCI-779 in combination with 5-FU/leucovorin in patients with advanced solid tumors, including mCRC reported preliminary evidence of activity including 1 complete response in a patient with mCRC receiving the 15 mg/m2
dose and several patients with stable disease of a maximum duration of 12 mo. Further studies are required to determine appropriate regimens with this combination treatment[87].
In conclusion, the biological agents have clearly increased the therapeutic armamentarium of patients with metastatic CRC and offer also prospects for an increased chance of a longer survival. Eventually, the availability of more predictive biological factors may allow oncologists to tailor individualized targeted combination therapy to a specific patient with a specific tumor. However, the cost of novel therapies for mCRC is particularly high. Such a heavy economical burden may be counterbalanced either by a very significant breakthrough in treatment efficacy or by selection of patients with a higher chance of responding to a specific treatment.
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Spicy Subscriptions is my very favorite box to review, and it's not even makeup! I was a leeeeeeeeeetle nervous when they contacted me to see if I wanted to review another box, because I knew the September box was the "Screaming O" box. This sounded quite a bit racier than the boxes I was sent last September and February. Then I did some googling to see what they had been giving out lately and SWEET BABY JESUS there was a butt plug! My mom reads this blog! Granted, I have the kind of family who will sit around playing Cards Against Humanity or reading Urban Dictionary aloud for kicks, but even so, moms and butt plugs don't mix. (That should totally be a t-shirt).
Hey, Mom, if you're still here? Go away. LOVE YOU! xoxo, your daughter who only had sex twice ever to make your sweet grandbabies.
The deets: Spicy Subscriptions changed up the products a bit since last time. It looks like they ditched the smaller premium spice box and only the deluxe box remains. They added a new toy of the month option too, so I'm guessing people liked it when SS started offering the big toys. I think the 5% off diniwilks code should still work - I'll double check ASAP.
Get the Spice Box: $34.95/month
Get the Deluxe Toy Of The Month: $37.95/month
Date of arrival: September 26, 2013.
Packaging: It came in a discreet priority mail envelope with the box below inside. It's a really nice, sturdy box, but it's a shade less fancy than the one I received in February. I still love the design.
Looks like Spicy Subscriptions has a great referral program and bonus for doing reviews. Nice!!
I knew from the very first product in the box that this whole review is going to read like a giant game of "I never". I'll start. I have never had sex with someone wearing a cock ring before. And I never thought I'd say cock ring on my blog. I am, however, delighted to have one. It looked a little small (you're welcome, hubs), but it says it's super stretchy so we'll see how it goes. Also, I am DYING LAUGHING over that picture on the back (middle right of the image below). I have always said I wanted to be the graphic designer who made the warning image of the vending machine tipping on a person, but I think this one takes the cake. Or cock. Whatever.
|This cock ring is brought to you by the brand "Screaming O"
YAY, some Dona products!!! Dona makes my very favorite sexy time product ever, the linen spray. I talked about my love of the sexy spray in both of my past reviews, and I am still a huge fan. I am super duper excited to have some bath essences because it's nice to pamper yourself before some nookie.
I was also sent some Lingerie Wash, which I believe is a bonus gift. You are supposed to soak your lingerie in it before hand washing them, but let's get real. Ain't nobody got time for that!! I plan to throw some in when I'm washing our sheets and then spraying the sheets in more sexy spray as I roll around in them with my sexy bath essenced up body. It will be a sexy time triple threat.
For real, get yourself some sexy spray. You will NOT regret it. The scent I adore is mangosteen and they appear to be out but you really can't go wrong.
|Notice the runaway lube in the background
Okay, now for Screaming O product #2. This one is a bullet with 4 speeds. I love that it is disguised as a compact, because I can totally picture someone's friend going to borrow the mirror, and the owner sitting there horrified as the bullet falls out and clatters to the floor. But this is coming from someone whose vibrator is literally sitting out on the nightstand. I mean, it would be if I owned one. (You're not still here, Mom, are you?)
Side note: I had to use my hubby's laptop to post this because it seemed a little unwise to post such scandalous material from my work laptop. WTF - the icon for me is a freaking DOG. SOMEONE is not getting a cool, tingly blowie tonight.
So what do you think? Is this box too spicy, not spicy enough, or just right?

subset: commoncrawl


text:
For many people, the thought of converting an electric appliance to gas, changing your wood fireplace to gas, or installing a gas firepit or grill is at the top of your to-do list. Yet before you undergo a major change to your home that involves a gas line, there are a few things to consider first.
1. What is the benefit of using gas?
Natural gas appliances can be cheaper to run and more efficient to use. But you may incur upfront costs that can run into the thousands of dollars to make the replacement. To replace an electric appliance with a gas appliance, the gas line will need to be run from source to where the appliance is located. Because it is gas, only a certified plumber should work with the installation process to make sure it is done correctly. Also add in the costs of the new appliance to determine if this is the right upgrade for you.
2. What maintenance should I be prepared for?
Because natural gas can be deadly, it should always be left to the professionals. Natural gas appliances, equipment and connectors should always be installed and used in accordance with manufacturers guidelines. You should also watch for any product recalls or hazardous situations that can occur with the items installed in your home.
If your home has been using natural gas for years, some older uncoated brass connectors can crack or break apart, causing a gas leak. Have a licensed plumber perform regular checks on your gas lines to make sure all is connected and operating correctly. Do not try and move appliances or check them yourself; even slight movement can cause complete failure of these connectors, putting your family at risk.
If you will be planning a project that involves digging, trenching, drilling or excavating, be sure to connect with the local authorities to have underground lines clearly marked before work begins.
3. What should I know about natural gas to protect my family?
Natural gas is colorless and odorless, yet can be deadly for human consumption. That is why all gas providers must add a harmless, non-toxic odorant to make it detectable should problems occur. It usually has a gassy smell that resembles rotten eggs. If you detect a strong smell, leave the premises immediately and call your local gas company for immediate service.
Carbon monoxide is a colorless, odorless and potentially dangerous gas that is produced when fuel such as natural gas is burned without enough air for complete combustion. If inhaled, it can cause unconsciousness, brain damage, or even death. A carbon monoxide detector should be placed in every home, and in multiple locations if you have a large home.


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CORNWALL ART BIENNALE – Wednesday 7th August, 2013
Among the artists who contributed:
Robert Curgenven (1974) draws on the physicality of sound, not just the physical impact on the body but how it can shape our perception of space and the flow of time.
"Behind the music lurks such [disparate] presences as Alvin Lucier, King Tubby, Murray Schafer and Eliane Radigue." – The Wire (UK)
Beatrice Brown is a young talented artist who sees art as a revolutionary act, a means out of the solipsist trap to connect with others, and at times also a political commentary on how she experiences the strain of the British class-system, world injustice and capitalist nonsense at large.
ATOI (Amy Thomas and Oliver Irvine) have worked in collaboration over the past six years. The duo formed from a shared passion in using sculpture as a means of creating psychological situations, installations, performances and sculptural environments. In their time collaborating they have exhibited extensively throughout Europe, with solo shows in China at CEAC and large scale immersive installations and events at the Tate Modern Tanks, Tate Britain and the Garage Centre For Contemporary Culture in Moscow. They have also instigated many projects, and two galleries in the UK.
Roger Thorp is a film-artist based at CAST in Helston. His recent shows include Dwell 18.5:1 for The Dark Rooms and The Fountain Project for the James Turrell Skyspace at Tremenheere Sculpture Gardens.
For over 20 years Tony Plant has made ethereal, time based works to be washed away. His works are as simple as coloured water, a track through snow, or a group of painted rocks – left for nature to absorb and passersby to discover.
Peter Kirby is an artist and writer living at the end of a dirt track in Cornwall with his wife and daughters. His work has appeared in galleries, books, museums, festivals and streets around the world, including Tate St Ives in collaboration with Richard Long and the first 2 London Architectural Biennales. His most recent show, 'Abridged Sentences for Sol LeWitt', at LA-based Material Press Project Space, can be seen here
The Barefoot Amphitheatre was created early in 2012. Tom Baxter was the first artist to perform here on September 1st.
The Amphitheatre is available for humanist weddings and dry hire.


text:
VideoHive Quick Particular Titles Package 4383768
After Effects Project \ Titles \ Abstract
Reveal \ Include \ Particular \ Collection \ Included \ Audiojungle \ Please
After Effects Project - Quick Particular Titles Package 4383768 by zhenjueyimen @ VideoHive
After Effects Project \ Titles \ Abstract
HI! guys this time I present several elegant particular title reveals, the collection include 8 title reveals. feel free to edit and choose you want to render.!
Collection features
- Full HD (1920×1080)
- 4-6 seconds each reveal and all with alpha channel
- NO 3-rd plug-ins must be request(include particular 2.1 version)
- HD video tutorial is included
- BG audio not include can be download here http://audiojungle.net/item/inspire/2561637
- please note that the open logo reveal with hands is my own logo ident so not included but if you interesting click here
Don't know After Effect ?please don't hesitate to contact me I will help you with low price!
Any other questions send email to me if you like don't forget to rate!
good luck for you work!
Cinematic titles here
MY Popular Items
Requires Plugins: No; After Effects Version: CS5, CS5.5, CS6; Resolution: 1920x1080; File Size: 314mb.
12 Kinetic Typography Package; Your Film & Game Trailer; Flower Flow Preset (Showcase Tool); Cinematic Particular Title/Logo Package; Flow Ink Opener; Magic Show II; Magic Show I.
Keywords: elegance, flare, identity, intro, light, line, opener, particle reveal, particles, particular, reveal, title.


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Results 1 to 3 of 3
Thread: Code to update values from table
01-16-04, 15:19 #1Registered User
- Join Date
- Jan 2004
- Location
- Toronto, Canada
- Posts
- 259
Unanswered: Code to update values from table
I have two tables; one called Data Info, and another called FileTable
Data Info has two fields, one of which is empty. The non empty field contains ID No.s of two different kinds; one kind is a straight up number, like 233, while the other has the type FFF234, where FFF can mean any type of 3 letter combo.
I want to update the first empty field with values from another table, FileTable whenever i come across an ID no. of type FFF***; the code will automatically look up the corresponding value for *** in the File table and then refresh the empty field with that no.
I know only ADO, so could the code be written in ADO instead of DAO?
thx for the help
01-16-04, 15:51 #2Grand Poobah
- Join Date
- Sep 2003
- Location
- Posts
- 3,713
Yes it can ...
SELECT * FROM [Data Info] WHERE (Left(2ndFieldName,3)='FFF');
01-16-04, 15:55 #3Registered User
- Join Date
- Jan 2004
- Location
- Toronto, Canada
- Posts
- 259
Unfortunately, the FFF is not the same for each value; some have different values, like POO, or DCA
i just wanna know the code to update a recordset, so if left(.....) NOT an int, then do you update the field as, rec.Update "Fiedlname" value?


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What We Do:
The First Tee has at its very foundation our NINE CORE VALUES. What is so great is how the game of golf allows our participants to EXPERIENCE these Values: CONFIDENCE, COURTESY, HONESTY, INTEGRITY, JUDGMENT, PERSEVERANCE, RESPECT, RESPONSIBILITY and SPORTSMANSHIP. In addition to learning a lifetime sport and values that will last forever, our programming seamlessly integrates our teaching of golf skills with our Life Skills Experience program. The Life Skills Experience programming will provide our participants with methods to help manage emotions, set goals, resolve conflicts and interact with others. To be clear, we are serious about teaching golf skills. But, we want our participants to have fun and to enrich their lives along the way. It is our goal to prioritize each of these equally.
How We Do It:
We offer our programming at two locations: The First Tee Learning Center in Lowell (main site) and in Bella Vista at the Tanyard Creek Driving Range and Brittany Golf Course facilities.
Our regular programming offers seven monthly sessions, beginning in April and ending in October. Each session features four classes, in a group setting, for the participant to attend – one each week. The sessions are not progressive, meaning that missing a session and coming back the next month does not put you behind. You will register for a class on a given day and time for each session you wish to attend. Classes are available by age group: PLAYer (seven and eight year olds), PAR 9-11 (nine to 11 year olds) and PAR 12-18 (12 years and older). We also offer Girls Only classes in each age group, as well as a special Girls on Course program for girls ages 11-17, made up of five special events.
In addition to our regular programming, we offer competitive golf experiences (High School Development Class, Let's Go Golfing, DASANI Summer Tour), Summer Golf Camps and Individual Golf Lessons.
For those participants striving for excellence, we offer The First Tee Certification Program. Beginning at nine years old, all participants are classified at the PAR Level. Through hard work, a PAR Level participant can achieve the BIRDIE Level by completing the PAR Level Life Skills component and passing his/her PAR golf skills
The First Tee Learning Center 715 E. Monroe Ave. Lowell, AR 72745 479-419-5807 thefirstteeNWA.org
testing. Once at the BIRDIE Level, the participant becomes eligible for several The First Tee national opportunities and becomes eligible to move up in age classification within our programming. The Certification program continues to the EAGLE and ACE Levels, with each creating more opportunities at the national level and the awareness of advancing their golf and life skills.
How Do YOU Get Involved?
The process to get involved is easy and available online 24/7. You begin the process from this page by clicking on the Register Now button on our website.
The first step in the process is to complete an Annual Membership for your participant(s). A 2017 Annual Membership (for $50.00) will provide your participant with the ability to register for classes, receive a The First Tee ID card, become eligible for Participant Discounts at The First Tee Learning Center ($2 for a bucket of balls and $1 for up to nine holes) and discounts through our Get Them Playing Program at area golf courses.
Once your participant has an Annual Membership, you can immediately take advantage of our discount programs and all family members are eligible for discounts at The First Tee Learning Center.
Beginning March 1, registration for classes will begin for our April Classes. Prior to March 1, our website will provide a schedule of classes so that you will be able to determine a day/time/place that best fits your schedule and will help the class registration process go smoother.
We certainly hope this answered most of your questions about our program. If it did not answer ALL your questions, please do not hesitate to call us at 479-419-5807, or email us at email@example.com.
We hope to see you and your participant VERY SOON!


text:
Production at Volkswagen AG's subsidiary in Slovakia has increased by 45 percent in the first six months of 2011 compared to the same period the previous year, thanks to the increasing demand for sports utility vehicles.
Volkswagen Slovakia has disclosed in an email last Thursday from Bratislava, Slovakia, that it had assembled 94,600 units from January to June. The automaker manufactures Audi-brand Q7 and Touareg SUVs at its Bratislava factory.
The company also produces the Porsche Cayenne bodies at the plant. The company further stated that from July to December this year, production will be "positively influenced" by the commencement of the serial assembly of the New Small Family compact cars.
VW intends to launch the Up minicar, the first vehicle in this lineup, at the Frankfurt car show in September. Within the next years, the New Small Family range of vehicle models, which varies from a coupe to a minivan, will be revealed.
A decontented version is also planned for rising markets, and VW's sister brands Seat and Skoda will get their own variants. The new vehicle lineup will be tactically significant to VW, which is aiming to be the bestselling vehicle manufacturer in the world by 2018.
Last year, the group sold 7.14 million vehicles, coming in at third place after GM with 8.39 million and Toyota with 8.42 million. Last Friday, the group recorded an increase in retail sales to 4.75 million in the first seven months.


text:
Angel was adopted on 1/16/2010
A Home For An Angel!
Sanctuary resident Angel, a whippet mix, met her special person today. Birgit Fowler Burke of Laramie, Wyoming saw Angel's picture online and fell in love. From this day forward, Birgit says, Angel's life is going to be filled with cuddles, couch time, and music. After six years in teaching and research, Angel is starting a whole new life with a very special person.
As Birgit is a musician and university library employee, Angel will now enjoy a comfy couch while listening to Birgit play the mandolin, guitar, and mountain dulcimer. Her new friends will be two cats, some birds, and the dogs of Birgit's musician friends. She has a fenced yard to enjoy at her leisure.
The match appears to Birgit to be a perfect one. From the way Angel relaxed on the couch next to her, it seems she would agree. Birgit is a devoted animal lover who has helped out many animals in the past. She is looking forward to introducing Angel to new activities and giving her lots of love.


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Lay people's Europe: A Critical Assessment of the First EU Citizens' Conferences
Citizens' conferences attempt to include citizens in the decisional and political process. Created to foster deliberation and public debate on disputed issues, they place ordinary citizens in the spotlight and ask them to express their views, after having debated the issues with specialists. Whereas the conferences conducted in a domestic context have been well analyzed, little attention has been given so far to the first attempts to replicate the experience at the European level, and to the specific problems that may be encountered in so doing. Two main reasons have prompted the EU to pay interest to this participatory mechanism: functional reasons (the need to take position on a socio-technological controversy whose stakes are controversial) and political legitimacy (the absence of a strong democratic legitimacy at the EU level). Based on an analysis of the first two experiments organized in the EU, devoted to "the city of tomorrow" and to brain sciences respectively, this article argues that achieving such citizen deliberation is not without problems. In many respects, these problems point to the difficulty entailed in the creation of a European public space: the elusive quest for a "European people"; the question of representation according to the size of the countries; the issue of languages. At the same time, the main potential of this instrument may lie in its cognitive impact, since the interpretations and knowledge surrounding the issues which are debate may influence both the agenda-setting and the decision-making process.
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|Date of creation:
|21 Jul 2008
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| Web page: http://www.connex-network.org/
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text:
Medical research using primates
Sir, Voices calling for a ban on medical research using primates (Body & Soul, October 25) must be resisted or British science and the ability to find treatments for a range of severe illnesses will be jeopardised.
In the past few weeks we have read how research with monkeys is progressing medicine. Paralysed people may be able to use their limbs again (report, October 16); young women made infertile by cancer treatment have the prospect of becoming mothers (report, October 17). Neurosurgeons can interpret patient scans obtained from the Nobel-prize winning MRI technology (report, October 7) because research in primates showed how brain activity relates to blood flow and metabolism changes.
Yet, at the same time, some MPs have signed a parliamentary motion to ban…


text:
The BMW Group will showcase its BMW ConnectedDrive technology and disclose its future plans for highly automated driving at the 2014 Consumer Electronics Show that will be held at the Las Vegas Convention Center from 10:00 a.m. PST on January 7, 2014, until 12:00p.m. PST on January 9, 2014. BMW will also showcase the BMW i3 at the show.
BMW ConnectedDrive links the driver, the vehicle and the outside world via a range of assistance systems, as well as infotainment and entertainment features. BMW ConnectedDrive's Driver Assistance systems include navigation and traffic assistance and concierge services. The BMW i Remote app, meanwhile, allows drivers to share information with the vehicle any time, even the amount of charge on a BMW vehicle.
The Apps for Automotive technology by BMW allows drivers to employ smartphone applications to link with the car while being able to send text messages via voice or text. BMW ConnectedDrive also allows easier control of entertainment options without losing focus on the road.
BMW Group will also unveil at 2014 CES the details of its current research and development project for highly automated driving, which is meant to increase safety, comfort and efficiency for the driver and traffic system. The carmaker will also disclose a collaboration with a consumer electronics company at the CES. [source: BMW Group]


text:
Headbanga : Headbanga Da Don
- Artist: Headbanga
- Format: CD
- Release Date: 2/25/2003
|your cart is empty
Headbanga speaks for itself. A young rapper who has been through the struggle that life has givin him so rappin put's him in a place were it's alright to be yourself and to always keep it real. Headbanga da DON from VA.


text:
Wow. Jaguar Car buffs discuss all and customarily determine on nothing. But on one matter there is consensus: The Jaguar E-Type is the most pleasing automobile ever crafted by human hands on Earth. The elegant, sporty Jag was constructed for a surprisingly long time, from 1961 to 1975. Seeing one in the strength is as showstopping now as it was... Read more »
Sir Richard Branson on Necker Island in 2014. Virgin Limited Virgin Group founder Sir Richard Branson stared down Hurricane Irma and survived. Even though the billionaire's private island sustained complicated damage, Branson and his organisation are protected and sound. "Virgin Limited Edition can endorse that on the 6th September 2017 Necker Island sustained endless repairs as a outcome of Hurricane... Read more »
Former Navy SEAL Brandon Webb reveals since a high-powered flashlight is one of the many critical things you can carry. Following is a twin of the video. BRANDON WEBB: My friends and family are always asking me how to be better prepared. The biggest thing we consider — advice we can give women generally is to lift a high-power flashlight. A thousand... Read more »
Richard Branson and his group rode out Hurricane Irma on Necker Island.Courtesy of Virgin Limited Edition/Necker Island Hurricane Irma has brought poignant repairs to much of the Caribbean as it's barreled towards South Florida. One of the islands in the trail of the "potentially catastrophic" Category 5 hurricane was Necker Island, the British Virgin Island shelter belonging to billionaire businessman Richard Branson. ... Read more »
Life in NYC was a lot opposite back in the 1940s.Charles W. Cushman Photography Collection / Indiana University Archives Amateur photographer Charles W. Cushman trafficked extensively in the US and abroad from 1938 to 1969, capturing pleasing portraits of bland life. His archive has been donated to and confirmed by Cushman's alma mater, Indiana University, which has pleasantly given us permission to... Read more »
Eric Schneiderman speaks at a news discussion with other U.S. State Attorney's General to announce a state-based bid to fight meridian changeMike Segar/Reuters New York Attorney General Eric Schneiderman pronounced Friday that he's questioning the Equifax hack, in which 143 million people's personal information was compromised. Equifax, a company that provides credit scores, on Thursday pronounced the sum potentially accessed... Read more »
AP Air traffic in Florida is reaching new levels as people in the state try to shun before Hurricane Irma hits. Airports in the state, including Fort Lauderdale-Hollywood International Airport and Key West International Airport, will start shutting down on Friday afternoon and sojourn sealed on Saturday and Sunday. Orlando International Airport plans to cease operations by 5 p.m. on... Read more »
Not electric. Mazda Mazda has grown a new gas engine that's distant more fit than existent motors. The Skyactiv-X engine uses application rather than hint to light the fuel-air mixture. It can be used quick and simply in existent Mazda car designs but adding costs. There's a widespread arrogance that all-electric vehicles are over the next two decades going to... Read more »
Brad Katsuyama, President and CEO of IEX Group, Inc. speaks at the Sandler O'Neill + Partners, L.P. Global Exchange and Brokerage Conference in New YorkThomson Reuters IEX, the pretender exchange, is going after the NYSE and Nasdaq for their listed companies. IEX is charity companies which switch $250,000 in price credits, homogeneous to 5 years of inventory fees. The NYSE and... Read more »
GARY SHILLING: Stocks are expensive, and a 'shock' could send them plunging Read more »


text:
Teachers Trailer (1984)
"They fall asleep in class. Throw ink on each other. Never come in Mondays. And they're just the teachers." 05 October 1984 Drama 107 mins
A teacher tries to overcome his frustration teaching a high-school that seems to be full of flunkies.
Watch the official Teachers 1984 trailer in HD below or find more Teachers videos on Vidimovie.


text:
Yorick Build Guide by rafiqofmany
Not Updated For Current Season
This guide has not yet been updated for the current season. Please keep this in mind while reading. You can see the most recently updated guides on the browse guides page.
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Your votes and comments encourage our guide authors to continue
creating helpful guides for the League of Legends community.
Yorick Build
Ability Sequence
Not Updated For Current Season
The masteries shown here are not yet updated for the current season, the guide author needs to set up the new masteries. As such, they will be different than the masteries you see in-game.
Alright, when Yorick first came out, i bought him just as i promised. Within the first 2 games i noticed he was trash, his abilities were quite cool, ****py ultimate, but all his stats were WAY too low. Still, i played him and was able to at least stay even on my k/d ratios. THEN, he got buff.. HARD. So here it is, the most efficient build i have seen so far.
You normally don't see a rune build that splits the 9 into 2 types but i did with the seals. The reason being that i notice with the dodge mastery, 9 runes were not neccesary; and with getting only mana regen to start off, the hp regen in 4 seals of vigor AND one quint of vigor, he can solo top lane extremely efficiently.
1. Tear of Goddess WILL make it possible to lane and not suffer the rest of the game, especially since it builds into manamune.
2. Warmogs WILL make you be able to solo 2 champions once it is at full stacks. Your ghouls will be strong enough to hit 3-5 times each while you have enough hp to initiate team fights.
3. Trinity Force is... Trinity Force.. soo.. get it.
4. I rarely get a game drawn out longer than me getting trinity. I usually win and keep it until game is over. If i never get items, well that means their team is fed and we lost.
Skill Sequence
1. Getting Omen of Pestilence(w) first makes life a ton easier, especially when soloing top lane vs 2.(which is how i play) The reason being that dropping it in brush will give you vision, is there is a champion there, not only will you see him, the ghoul WILL chase them, giving you extended vision, and they will be slowed. That vision from a range and the slow help you avoid face-checking a bush, which often kills you level 1.
2. Depending on how aggressive your opponents are in the lane, the second skill is totally up to you. If they are harassing you to no end, get E with lifesteal; try to use it on the enemy champion, many times they will either back away from the minion wave or ignore the ghouls, granting you advantage either way. IF you get the aggressor, getting Q, Omen of War, you can beat them pretty good, shall they attack you, AND last hit minions better.
3. DO NOT MAX OUT YOUR ULTI. it is not worth it, the cooldown doesn't matter because it won't TOTALLY save you, you don't come back for very long and the extra hp on the copy isn't very purposeful. Get it at level 6 and don't worry about it until level 16
Summoner Spells
Teleport, especially when soloing top lane, will get you the items you need when you need them. Once my Teleport is off cooldown, that is usually the exact time i need to go to base to buy tear of goddess, warmogs, then boots/manamune.
Exhaust WILL get you kills. your E ability slows then, Exhaust slows them more, and your Q gives you movement speed. They will seem to stand still while you wreck them.
DO IT. last hit minions like it's your job, especially easy with 3 ghouls fighting for you and Omen of War dealing wonderful damage when you need it. ALSO, once you get warmogs, clear as many jungle minions and last hit EVER lane minion to get max-stacks as quickly as possible.


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First class all the way. A lot of people will get second hand smoke other than that every thing was wonderful. I think that a person should not have to pay for using the bar or the robe. The room cost enough money for one night.
- Official Description (provided by the hotel):
- While in Detroit, get down to business at the ultimate entertainment destination, MGM Grand Detroit. Surround yourself in timeless design in our ultra-chic hotel. Dream big on king-size beds with 300 thread count sheets, relax in our oversized marble baths with dual rain shower heads. Or indulge yourself in a garden of earthly delights within our signature restaurants, or nightlife options. Last, lavish yourself within Immerse, Detroit's only resort style Spa. Immerse Spa. ... more less
- Reservation Options:
- TripAdvisor is proud to partner with Travelocity, Hotels.com, Expedia, Priceline, Orbitz, Hotwire, Booking.com, Cancelon, Cheap Tickets and getaroom.com so you can book your MGM Grand Detroit reservations with confidence. We help millions of travelers each month to find the perfect hotel for both vacation and business trips, always with the best discounts and special offers.
- Also Known As:
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