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Fig. 3 ; . Inhibitor insensitive kinase mutants. 2004 by Elsevier ; . Schematic representation of the technology, mutating a small residue in the active site of the kinase into a larger residue and thereby preventing inhibitor binding while preserving kinase activity A ; . The EGF-R and the EGF-RT766M were chosen as representative examples for the technology. Upon mutation of the gatekeeper residue, the threonine 766 into a methionine, the mutant EGF-RT766M no longer binds gefitinib nor does gefitinib inhibit the autophosphorylation of the receptor B ; . Experimental details are found in reference [138]. Fig. 3B is adapted also from reference [138], with permission from Elsevier.
Correct answers in bold ; 1. The criteria for diagnoses of diabetes mellitus includes: a ; b ; c ; Fasting blood glucose 126 mg dl Casual plasma glucose 200 mg dl and diabetes symptoms 2 hr plasma glucose 200 mg dl during OGTT All of the above.
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Unfortunately, gefitinib did not have statistically significant efficacy, as compared with a placebo, in a recent phase iii survival trial isel ; in patients with advanced nsclc.
Eective Time. If David R. Bethune resigns his seat on the Board of Directors of Parent within four months following the Eective Time, the vacancy resulting from his resignation shall be lled promptly by an individual identied prior to the Eective Time who shall have been selected by the Board of Directors of the Company from among its members and who shall be reasonably acceptable to the Board of Directors of Parent consistent with the policies of its Corporate Governance and Nominating Committee as notied by Parent to the Company prior to the Eective Time. David R. Bethune shall be appointed Vice Chairman of the Board of Directors of Parent for a term of three months commencing at the Eective Time. Parent's chief executive ocer, in consultation with such Vice Chairman of the Board of Directors of Parent, shall be directly responsible for the oversight and direction of the integration of the businesses of the Company and Parent including with respect to the orderly transition of the Company. SECTION 6.16 Benet Matters.
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Hypoglycemia or insulin reaction ; is a common side effect of insulin therapy, although patients taking insulin secretagogues can also be affected. Autonomic symptoms are often the first signs of mild hypoglycemia and include shakiness, sweating, palpitations, and hunger. Neuroglycopenic symptoms can also occur at similar glucose levels as autonomic symptoms but with different manifestations. The earliest signs of neuroglycopenia include a slowing down in performance and difficulty concentrating and reading. As blood glucose levels drop further, the following symptoms occur: frank mental confusion and gemcitabine.
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Sufficient information about unapproved drugs to make informed decisions about their use. Increased access to new products before approval is never ethical unless full information including animal toxicity studies and clinical trial results are disclosed. It is time to debate whether `compassionate use' is ethical, even if full information is disclosed. It is our opinion that the efficacy and safety of gefitinib and the regulatory approval process should be completely re-examined using data accumulated through clinical trials, expanded access programs and the postmarketing experience in Japan. In the meantime gefitinib should be withdrawn, both in Japan and in Western countries where it is available through expanded access programs and gemifloxacin.
Establish policy commitment and responsibility for health-care waste management Before an action plan is implemented there must be commitment to the development of a national policy, and responsibility must be delegated to the appropriate government authority. The ministry of health or the ministry of environment will usually serve as the principal authority, and should work closely with other relevant ministries. The designated authority will cooperate with other ministries, the private sector, nongovernmental organizations NGOs ; , and professional organizations, as necessary, to ensure implementation of the action plan. Policy commitment should be reflected in appropriate budgetary allocations at different government levels. Guidance from central government should lead to maximum efficiency in the use of available resources from health-care establishments.
Angiotensin type 1 receptor. Biochem Biophys Res Commun 1994; 204: 10391046. Guo DF, Furuta H, Mizukoshi M, Inagami T. The genomic organization of human angiotensin II type 1 receptor. Biochem Biophys Res Commun 1994; 200: 313319. Curnow KM, Pascoe L, Davies E, White PC, Corvol P, Clauser E. Alternatively spliced human type 1 angiotensin II receptor mRNAs are translated at different efficiencies and encode two receptor isoforms. Mol Endocrinol 1994; 9: 12501262. Rosenfeld CR, Gant NF. The chronically instrumented ewe. A model for studying vascular reactivity to angiotensin II in pregnancy. J Clin Invest 1981; 67: 486492. Sasaki K, Yamano Y, Bardham S, Iwai N, Murray JJ, Hasegawa M, Matsuda Y, Inagami T. Cloning and expression of a complementary DNA encoding a bovine angiotensin II type-1 receptor. Nature 1991; 351: 230232. Magness RR, Shaw CE, Phernetton TM, Zheng J, Bird IM. Endothelial vasodilator production by uterine and systemic arteries II. Pregnancy effects on NO synthase expression. J Physiol 1997; 272: H1730-H1740. Voyta JC, Netland PA, Via DP, Zetter BR. Specific labelling of endothelial cells using fluorescent acetylated low density lipoprotein. J Cell Biol 1984; 99: 81A. Millican DS, Bird IM. A general method for single stranded DNA probe generation. Anal Biochem 1997; 249: 114117. Carnegie JA, Robertson HA. Conjugated and unconjugated estrogens in fetal and maternal fluids of the pregnant ewe: a possible role for estrone sulfate during early pregnancy. Biol Reprod 1978; 19: 202 Magness RR, Cox K, Rosenfeld CR, Gant NF. Angiotensin II metabolic clearance rate and pressor responses in nonpregnant and pregnant women. J Obstet Gynecol 1994; 171: 668679. Naden RP, Coultrup S, Arant BS Jr, Rosenfeld CR. Metabolic clearance of angiotensin II in pregnant and nonpregnant sheep. J Physiol 1985; 249: E49-E55. Guo DF, Inagami T. Epidermal growth factor-enhanced human angiotensin II type 1 receptor. Hypertension 1994; 23: 10321035. Zheng J, Vagnoni KE, Bird IM, Magness RR. Expression of basic fibroblast growth factor, endothelial mitogenic activity and angiotensin II type-1 receptors in the ovine placenta during the third trimester of pregnancy. Biol Reprod 1997; 56: 11891197. Varner MW, Dildy GA, Hunter C, Dudley DJ, Clark SL, Mitchell MD. Amniotic fluid epidermal growth factor levels in normal and abnormal pregnancies. J Soc Gynecol Invest 1996; 3: 1219. Cheung CY, Singh M, Ebaugh MJ, Brace RA. Vascular endothelial growth factor gene expression in ovine placenta and fetal membranes. J Obstet Gynecol 1995; 173: 753759. Alshihabi SN, Chang YS, Frangos JA, Tarbell JM. Shear stress-induced release of PGE2 and PGI2 by vascular smooth muscle cells. Biochem Biophys Res Commun 1996; 224: 808814. Magness RR, Mitchell MD, Rosenfeld CR. Uteroplacental production of eicosanoids in ovine pregnancy. Prostaglandins 1990; 39: 7588. Curtis SW, Washburn T, Sewall C, DiAugustine R, Lindzy J, Couse JF, Korach KS. Physiological coupling of growth factor and steroid receptor signaling pathways: estrogen receptor knockout mice lack estrogen-like response to epidermal growth factor. Proc Natl Acad Sci USA 1996; 93: 1262612630. Bunone G, Briand PA, Miksicek RJ, Picard D. Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. EMBO J 1996; 15: 21742183 and gemtuzumab.
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Being combined. First data were raised in phase I or II breast cancer trials by combining trastuzumab with small molecule inhibitors of EGFR such as gefitinib or erlotinib indicating that this combination provided a well tolerated targeted therapy with preliminary evidence of antitumor activity [68, 69] . As activation of the EGF receptor may induce vessel formation by cellular liberation of VEGF, approaches blocking both pathways possess certain attractiveness. In conditions of limiting VEGF, EGF plays an important role in endothelial cell proliferation, survival, and sprouting of small vessels. Animal data suggest that combined inhibition of EGFR and VEGFR pathways may produce synergistic results and that resistance to EGFR inhibition may be overcome by inhibition of VEGFR tyrosine kinase[70, 71]. In an in vivo model, the combination of anti-VEGF-R and anti-EGF-R therapies was effective in inhibiting gastric cancer growth whereas the decrease in tumor growth in mice treated with DC101 an antiVEGF-R antibody ; or cetuximab alone did not reach statistical significance[72]. As mentioned above, the addition of an inhibitor of the hepatocyte growth factor was able to overcome resistance against gefitinib resulting from the interaction of stromal and cancer cells in an animal model of scirrhous gastric cancer[34]. Inhibitors not selective for a single pathway: Agents targeting multiple RTKs are currently undergoing preclinical testing or phase I studies. These include AEE788 directed against EGFR, erbB2, VEGFR2; Novartis ; , BAY 43-9006 Sorafenib; Raf kinase, VEGFR2, PDGF-R beta; Bayer ; , SU11248 PDGF-R, VEGFR, c-kit-R, FLT3-R; SUGEN ; , and ZD6474 VEGFR and EGFR, AstraZeneca ; , all designed to inhibit multiple mechanisms of tumor growth in addition to conventional chemotherapy[73-76]. Similar to the combination of anti-EGFR and anti-VEGFR antibodies mentioned above, McCarthy et al[77] tested the inhibitor of both tyrosine kinases, ZD6474, in an orthotopic model of gastric cancer. The agent led to marked.
Dose, or other reasons. NCIC CTG has conducted studies with both erlotinib and gefitinib at varying doses using the same centres, investigators and methods of toxicity assessment. Methods: One published NCIC CTG phase I and 3 phase II studies of gefitinib or erlotinib were selected and common drug related toxicity rates compared across studies. Results: See table. MTT assay it was evident that the docetaxel-induced antiproliferative effects 1-h exposure, IC50 ; could be increased by a 2-h pretreatment with 5 mg ml Cetuximab relative gain in cell growth inhibition + 22% in OVCAR-3, + 13% in IGROV-1, + 18% in SKOV-3 ; , 20 nM Herceptin + 6%, + 10%, + 18% ; or 20 mg ml Omnitarg + 23%, + 14%, + 9% ; . Antiproliferative effects of docetaxel further increased upon pretreatment with Cetuximab combined with Herceptin + 22%, + 24%, + 25% ; or Omnitarg + 19%, + 31%, + 34% ; . The caspase-3 activity assay, as a measure of apoptosis, reflected the data of the MTT assay: docetaxel-induced caspase-3 activity was further increased by pretreatment with Cetuximab combined with Herceptin or Omnitarg resulting in a relative gain of, respectively, + 32% and + 31% in OVCAR3, + 33% and + 60% in IGROV-1, + 17% and + 29% in SKOV-3. To further examine the molecular consequences of EGFR HER2 inhibition, cells were stimulated with EGF or Heregulin after they were treated or not with either of the mAbs or a combination. Upon stimulation with EGF, increased protein levels of phosphorylated EGFR and ERK1 2 in all three cell lines could almost completely be inhibited by Cetuximab, but were not affected by Herceptin or Omnitarg. Early immunoprecipitation studies in IGROV-1 and SKOV-3 revealed that EGF could induce HER2 phosphorylation, which could be inhibited by Omnitarg. In conclusion, 1 ; human ovarian cancer cells frequently express EGFR, HER2 and HER3, 2 ; pretreatment of OVCAR-3, IGROV-1 and SKOV-3 cells with a combination of Cetuximab plus either Herceptin or Omnitarg resulted in increased antitumor effects of docetaxel, 3 ; although Omnitarg could inhibit EGF-induced HER2 phosphorylation, it was not able to downregulate EGF-induced ERK1 2 phosphorylation. Current studies are running to reveal the importance of HER2 as the prefered dimerization partner of HER3 after stimulation with Heregulin. P.508 CETUXIMAB PLUS CAPECITABINE CAP ; AND OXALIPLATIN LOHP ; AS SALVAGE TREATMENT FOR PATIENTS WITH METASTATIC COLORECTAL CANCER CRC ; RELAPSING AFTER COMBINATION CHEMOTHERAPY INCLUDING OXALIPLATIN, IRINOTECAN CPT-11 ; , AND 5-FLUOROURACIL 5-FU ; OR CAPECITABINE J. Souglakos, N. Androulakis, A. Kalykaki, Z. Saridaki, N. Vardakis, K. Kalbakis, S. Agelaki, L. Vamvakas, N. Kentepozidis, S. Giassas, D. Mavroudis, V. Georgoulias University General Hospital of Heraklion, Heraklion, Greece Background: Cetuximab is an IG1 monoclonal antibody targeting EGFR which has shown to be active in irinotecan-refractory metastatic CRC. This phase II trial evaluated the safety and efficacy of cetuximab combined with CAP and LOHP XELOX ; as salvage treatment for patients with metastatic CRC. Methods: Patients with metastatic CRC who had progressed on prior treatment including CPT-11, LOHP, 5-FU and CAP, with ECOG PS 2 were enrolled into the study. Cetuximab was given at an initial dose of 400 mg m2, then 250 mg m2 iv weekly; LOHP was administered on d1 at the dose of 85 mg m2 and CAP on d1-7 at the dose of 2000 mg m2 d in a two week cycle. Results: Until December 2004 22 patients have been enrolled into the study. Median age was 65 years, and median PS ECOG ; was 1. For two patients it was 2nd line treatment while for the 20 it was 3rd. Sixty-seven cycles have been administered with a median of 3 cycles patient. Twenty-one patients are evaluable for toxicity and 11 for response. No grade 3 4 hematologic toxicity has occurred while non-hematologic toxicity included grade 3 vomiting in 5% of the patients, grade 3 diarrhea in 5%, grade 3 fatigue in 5%, grade 2 neurotoxicity in 5% and grade 2 allergy in 9%. Among the 11 patients evaluable for response one experienced a PR and two SD. The median TTP was 2 months. Conclusions: Salvage treatment with cetuximab plus XELOX of patients with metastatic CRC is safe and feasible. More data are needed in order to further evaluate its efficacy in patients with LOPH 5FU or Xeloda-resistant CRC and gemzar.
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38 ; . Clinical trials testing the combinations of HDAC inhibitors and EGFR TKIs are planned. Acquired resistance to EGFR TKIs. Acquired mutations in exon 20 of the EGFR gene would change conformation of the receptor and block binding of gefitinib and erlotinib to the active site creating resistance to these EGFR TKIs 43, 44 ; . Irreversibly binding EGFR TKIs were shown to maintain activity in tumors with these exon 20 mutations and are being tested in clinical trials 45!
Two combination trials with gefitinib, intact 1 and 2, counting over 2, 000 enrolled patients, failed to demonstrate any improvement in overall survival os ; , time to disease progression ttp ; , and response rates rr ; with the gefitinib combination compared to standard chemotherapy and genotropin.
Cell lung cancer NSCLC ; continues to be a disease characterized by late stage of presentation coupled with intrinsic resistance to cytotoxic chemotherapy. The epidermal growth factor receptor EGFR ; is frequently overexpressed in NSCLC and can regulate NSCLC growth and survival. Gefitinib and erlotinib are small molecule inhibitors of EGFR tyrosine kinase activity that act by inhibiting EGFR autophosphorylation and subsequently inhibit NSCLC tumor growth 1, 2 ; . Gefitinib or erlotinib monotherapy in patients who received.
Gefitinib Iressa, ZD1839 ; is a potent high-affinity competitive tyrosine kinase inhibitor aimed primarily at epidermal growth factor receptor EGFR ; . Inhibitors in this class have recently been approved for clinical use in the treatment of advanced non small cell lung cancer as monotherapy following failure of chemotherapy. We examined the efficacy of gefitinib on lung tumorigenesis in mouse models using both postinitiation and progression protocols. Gefitinib was given at a dose of 200 mg kg body weight i.g. ; beginning either 2 or 12 weeks following carcinogen initiation. In the postinitiation protocol, gefitinib significantly inhibited both tumor multiplicity f70% ; and tumor load f90% ; in A J or p53-mutant mice P 0.0001 ; . Interestingly, gefitinib was also highly effective against lung carcinogenesis in the progression protocol when individual animals already have multiple preinvasive lesions in the lung. Gefitinib exhibited f60% inhibition of tumor multiplicity and f80% inhibition of tumor load when compared with control mice both P 0.0001 ; . These data show that gefitinib is a potent chemopreventive agent in both wild-type and p53-mutant mice and that a delayed administration was still highly effective. Analyses of mutations in the EGFR and K-ras genes in lung tumors from either control or treatment groups showed no mutations in EGFR and consistent mutation in K-ras. Using an oligonucleotide array on control and gefitinib-treated lesions showed that gefitinib treatment failed to alter the activity or the expression level of EGFR. In contrast, gefitinib treatment significantly altered the expression of a series of genes involved in cell cycle, cell proliferation, cell transformation, angiogenesis, DNA synthesis, cell and gentamicin.
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Beyond the maximally tolerated dose ; and repeated dosing, to decrease or shut off promitotic cis-signaling from the receptor. Our data demonstrate that inhibition of receptor phosphorylation of mutant EGFRvIII may not be the only issue influencing mutant EGFRvIII-promoted growth and resistance. We have shown that despite significantly decreased or ablated phosphorylation of EGFRvIII, there remains undiminished signaling through Akt and possibly other promitotic signaling moieties. Phosphorylation of Akt, a promitotic kinase involved in signal transduction through the phosphatidylinositol-3 kinase signaling pathway 21, 36, 40 ; as well as increased cellular invasion 37 ; , was down-regulated in a dose-dependent manner in cells expressing wild-type EGFR, including U87MG.wtEGFR. We find this observation of particular interest because the U87MG parental cell line is known to have mutated and dysfunctional PTEN 45 ; , suggesting that gefitinib may inhibit wild-type EGFR-induced signaling through Akt via PTEN-independent mechanisms. Nevertheless, phosphorylated Akt expression was unaffected always and concentrations of gefitinib tested in cells expressing mutant EGFRvIII. Consistent with the observations that gefitinib did not decrease phosphorylation of Akt in cells expressing mutant EGFRvIII, daily treatment with gefitinib did not inhibit DNA synthesis or growth of mutant EGFRvIIIexpressing cells. We find these results particularly noteworthy because we have used a `pure' model system with NR6, in which NR6W only expresses wild-type EGFR and the fully tumorigenic NR6M only expresses mutant EGFRvIII, which is required for its neoplastic phenotype 12 ; . Thus, the only difference between cell types should be the receptor and its corresponding influence on intracellular signaling, i.e., phosphorylated Akt in these studies. Further to this point, Rosen et al. have demonstrated in a panel of human breast cancer and other epithelial tumor cell lines that growth inhibition was associated with dephosphorylation of EGFR and down- regulation of Akt activity 40 ; . In consideration of this, our findings would lend support to the idea that a fundamental difference between wildtype EGFR sensitivity to gefitinib and mutant EGFRvIII resistance is due to the differential regulation and activity of Akt, and possibly other functionally redundant promitotic signaling pathways, in cells expressing mutant EGFRvIII. Alternatively, mutant EGFRvIII-mediated resistance could be due to a potential trans-phosphorylation or trans-signaling event by other signaling pathways involving Akt. To this end, others have reported that the Akt-dependent antiapoptotic pathway and the mitogenactivated kinase MAPK ; cascade are alternatively activated in human glioblastoma multiforme in response to different stimuli 36, 46 ; . There are several potential arguments to explain why EGFRvIII responds differently to gefitinib, despite having the same nucleotide and amino acid sequence as EGFR in the COOH-terminal intracellular domain. The simplest explanation rests in the possibility that the deleted extracellular domain of EGFRvIII sterically affects the transmembrane and intracellular domain, thereby structurally altering its intracellular configuration. Precedence for this argument comes from Huang et al. 18 ; and others 4750 ; who demonstrated that EGFRvIII does not traffic intracellularly as well as EGFR. They argued that altered intracellular conformations of EGFRvIII did not result in the exposure of receptor sequence motifs required for endocytosis and gefitinib.
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1Q07A Revenues Cost of sales Gross Margin Operating expenses R&D SG&A Amortization - intangibles Total Operating income loss ; Interest income Net loss Avg. shares out. - diluted Earnings per share diluted ; 3, 243 2, ; 86 5, 840 ; 34, 362 0.17 ; 309 247 63 and gentian
Suneeta Kochhar London Medical and dental students do not prefer learning anatomy with prosections compared to dissection, say researchers from Guy's, King's, and St Thomas's School of Medicine, London, in a study published in Clinical Anatomy 2003; 16: 165-172 ; . Dental students, however, find prosection more useful than medical students. Above all, both groups of students found the use of tutorials and textbooks most beneficial in their learning. In recent times there has been a trend towards using prosection over traditional undergraduate dissecting programmes because of costs, the shortage of skilled staff, and time constraints. James Snelling and colleagues looked at how attitudes towards dissection varied with.
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Were randomized to receive chemotherapy with either placebo or two different doses of gefitinib 250 or 500 mg ; . In the Iressa NSCLC Trial Assessing Combination Treatment 2 INTACT2 ; trial, chemotherapy consisted of carboplatinpaclitaxel, which is standard in North America, and in the INTACT1 trial, chemotherapy consisted of cisplatin-gemcitabine, which is more frequently employed in Europe. Unfortunately, both studies failed to reach the major end point, which was improvement in survival by the addition of gefitinib, or any of the other end points, which included progression-free survival time, time to worsening of symptoms, objective tumor response, and quality of life. As the studies were robust and well designed, it should be concluded that these efficacy results are definitive. However, the studies did confirm the safety and tolerability of gefitinib, with comparable toxicity profiles in the control and the gefitinib treatment arms, with the exceptions of an expected dose-dependent skin toxicity and diarrhea in patients treated with gefitinib and two- to threefold more drug-related withdrawals in the 500 mg day gefitinib arm in both studies. Although the results are disappointing, the high expectations may have been too optimistic for several reasons. One of these reasons may be the lack of patient selection, which may have diluted a possible beneficial effect of the addition of gefinitib to combination chemotherapy. The impact of EGFR expression levels on sensitivity is still an issue, even though preclinical data point to the lack of an effect. Other markers that may be used for selection are activated forms of EGFR and downstream effectors. Recently, the expression of EGFR HER-2 Neu ; was tested in 43 patients with advanced NSCLC who received 250 mg day of gefinitib. No correlation with response or survival was observed [81]. Similarly, there was no correlation between response and the EGFR immunohistochemical results in patients who were entered in the IDEAL phase II studies [82]. It is theoretically possible that tumors pretreated with chemotherapy are more sensitive to EGFR-TKIs than chemotherapy-nave tumors, which would be consistent with the positive results seen in the IDEAL1 and IDEAL2 trials. This hypothesis, together with the results of the INTACT studies, suggests that sequential administration of chemotherapy followed by gefinitib may be a more effective approach. Although no phase II studies have so far been performed for the first-line therapy of advanced NSCLC with gefinitib alone, data reported from the extended access program seem to indicate definite activity in that setting. Provocative results have been reported in the treatment of bronchioalveolar carcinoma [83]. This tumor type has a definitively different biology than the common adenocarcinomas of the lung, as it is more frequently observed in women and nonsmokers. Female gender and no smoking history and Japanese race in the IDEAL1 study ; were, in fact, identified in phase II studies as and gemcitabine.
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Noma and never-smoked. In view of the higher probability of a response in patients with adenocarcinoma who never smoked, an adenocarcinoma that developed in nonsmoking patients is more likely to have different characteristics in the EGFR gene or its expression. Two recent studies 9, 10 ; found mutations in the EGFR gene only in responders to gefitinib. Most of the responders had a deletion in exon 19 or point mutations in exon 18 or 21 the EGFR gene, whereas none of the nonresponders had these mutations. Moreover, these mutations of EGFR doubled or tripled the EGF signal and prolonged the activation compared with the wild-type receptor. The mutations are thought to be correlated with gefitinib sensitivity because the mutant receptors on tumor cells are significantly more sensitive to gefitinib and play a significant role and ginkgo.
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