1、 preclinical antitumor activity. Int J Cancer, 2011, 129(1), 245-255. J Med Chem. 2015 Apr 9;58(7):2958-66. Br J Cancer. 2017 Sep 26;117(7):974-983. J Exp Clin Cancer Res. 2018 Jan 22;37(1):11. Cell Physiol Biochem. 2016;38(1):160-72. Oncol Rep. 2018 Aug;40(2):635-646.www.MedChemE22. Heng DY, et al.
2、 Targeted therapy for metastatic renal cell carcinoma: current treatment and future directions. Ther Adv Med Oncol, 2010, 2(1), 39-49.3. Carr BI, et al. Fluoro-Sorafenib (Regorafenib) effects on hepatoma cells: growth inhibition, quiescence, and recovery. J Cell Physiol, 2013, 228(2), 292-297.4. Wag
3、ner J, et al. Anti-tumor effects of ONC201 in combination with VEGF-inhibitors significantly impacts colorectal cancer growth and survival in vivo through complementary non-overlapping mechanisms. J Exp Clin Cancer Res. 2018 Jan 22;37(1):11.Caution: Product has not been fully validated for medical a
4、pplications. For research use only.Tel: 609-228-6898 Fax: 609-228-5909 E-mail: techMedChemEAddress: 1 Deer Park Dr, Suite Q, Monmouth Junction, NJ 08852, USAwww.MedChemE3tumor activity. Int J Cancer, 2011, 129(1), 245-255. J Med Chem. 2015 Apr 9;58(7):2958-66. Br J Cancer. 2017 Sep 26;117(7):974-983
5、. J Exp Clin Cancer Res. 2018 Jan 22;37(1):11. Cell Physiol Biochem. 2016;38(1):160-72. Oncol Rep. 2018 Aug;40(2):635-646.www.MedChemE22. Heng DY, et al. Targeted therapy for metastatic renal cell carcinoma: current treatment and future directions. Ther Adv Med Oncol, 2010, 2(1), 39-49.3. Carr BI, e
6、t al. Fluoro-Sorafenib (Regorafenib) effects on hepatoma cells: growth inhibition, quiescence, and recovery. J Cell Physiol, 2013, 228(2), 292-297.Caution: Product has not been fully validated for medical applications. For research use only.Tel: 609-228-6898 Fax: 609-228-5909 E-mail: techMedChemEAdd
7、ress: 1 Deer Park Dr, Suite Q, Monmouth Junction, NJ 08852, USAwww.MedChemE3栀栀rest (ROI) using Living-Image analysis software2.MCE has not independently confirmed the accuracy of these methods. They are for reference only.REFERENCES1. Bibian M, et al. Development of highly selective casein kinase 1/
8、1 (CK1/) inhibitors with potent antiproliferative properties. Bioorg Med Chem Lett. 2013 Aug 1;23(15):4374-80.2. Rosenberg LH, et al. Therapeutic targeting of casein kinase 1 in breast cancer. Sci Transl Med. 2015 Dec 16;7(318):318ra202.www.MedChemE2Caution: Product has not been fully validated for
9、medical applications. For research use only.Tel: 609-228-6898 Fax: 609-228-5909 E-mail: techMedChemEAddress: 1 Deer Park Dr, Suite Q, Monmouth Junction, NJ 08852, USAwww.MedChemE3 Fax: 609-228-5909 E-mail: techMedChemEAddress: 1 Deer Park Dr, Suite Q, Monmouth Junction, NJ 08852, USAwww.MedChemE2樕樕上
10、市公司正常信息披露受到影响之间的因果关系往往显而易见。上市公司之澄清公告与虚假信息多存在对应关系，且多将虚假信息内容列于公告之中，明确正是因虚假信瘳瘳事責任 12 至 24三、未遂犯 25 至 27四、正犯與共犯 28 至 31六、累犯 47 至 49七、數罪併罰 50 至 56五、刑 32 至 46刑罰論八、刑之酌科與加減 57 至 73九、緩刑 74 至 76十、假釋 77 至 79 之 1十一、時效 80 至 85十二、保安處分 86 至 99 保安處分論二、分則第一章至第十章 100 至 172侵害國家法益之犯罪第十一章至第十五章、第十六章之一至第二十一章 173 至 220、 230
11、 至 270侵害社會法益之犯罪第十六章、第二十二章至第三十六章 221至 229之 1、 271 至 363侵害個人法益之犯罪（三）刑法的功能1. 保護法益的功能這是依據憲法的精神及規定而來，所有刑罰規定的背後，都是為了保護一個或數個法益，此即法益保護原則。2. 抑制犯罪的功能透過刑罰的威嚇，使犯罪行為人不敢犯罪，而這也同時達到了保護法益的目的。11 Regorafenib monohydrateCat. No.: HY-10331ACAS No.: 1019206-88-2Molecular Formula: CHClFNOMolecular Weight: 500.83Target: VE
12、GFR; Autophagy; PDGFR; RafPathway: Protein Tyrosine Kinase/RTK; Autophagy; MAPK/ERK PathwayStorage: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 monthSolvent VEGFR2, IC50: 4.2 nM; VEGFR3, IC50: 46 nM; PDGFR, IC50: 22 nM; Raf-1, IC50: 2.5 nM; Braf, IC50: 28 nM; BRafV600E, IC50: 19 nMIn
13、 Vitro Regorafenib potently inhibits VEGFR2 autophosphorylation in NIH-3T3/VEGFR2 cells with an IC50 of 3 nM. In HAoSMCs, regorafenib inhibits PDGFR- autophosphorylation after stimulation with PDGF-BB, with an IC50 of 90 nM. Regorafenib inhibits the proliferation of VEGF165-stimulated HUVECs, with a
14、n IC50 of 3 nM1. Regorafenib causes a concentration-dependent decrease in Hep3B cell growth, having an IC50 of 5 M. Regorafenib subsequently increases the levels of phospho-c-Jun, a JNK target, but not total c-Jun in Hep3B cells3.Regorafenib effectively inhibits growth of the Colo-205 xenografts in
15、the dose range of 10-100 mg/kg reaching a TGI of 75% at day 14 at the 10 mg/kg dose. In the MDA-MB-231 model, regorafenib is highly efficacious at a dose as low In VivoProduct Data Sheet InhibitorsAgonistsScreening Librarieswww.MedChemE1as 3 mg/kg, resulting in a significant TGI of 81%, which increa
16、ses to 93% at doses of 10 and 30 mg/kg, where tumor stasis is reached1.PROTOCOLKinase Assay 1 Initial in vitro kinase inhibition profiling is performed at Millipore Corporation at a fixed 1 M compound concentration under Millipore standard conditions 10 M adenosine-5-triphosphate (ATP) concentration
17、. Inhibitory concentration of 50% (IC50) values are determined from selected responding kinases,e.g., VEGFR1 and RET. TIE2 kinase inhibition is measured with a homogeneous time-resolved fluorescence (HTRF) assay using a recombinant fusion protein of glutathione-S-transferase, the intracellular domai
18、n of TIE2 and the peptide biotin-Ahx-EPKDDAYPLYSDFG as substrate1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Cell Assay 1 For proliferation assays, GIST 882 and TT cells are grown in RPMI medium containing L-glutamine, and MDA-MB-231, HepG2 and A37
19、5 cells in DMEM always containing 10% hiFBS. Cells are trypsinized, plated at 5104 cells/well in 96-well plates in complete media containing 10% FBS and grown overnight at 37C. The next day, vehicle or Regorafenib serially diluted in complete growth media to between 10 M and 5 nM final concentration
20、s, and 0.2% DMSO, is added and incubation is continued for 96 hr. Cell proliferation is quantified using CellTitre-GloTM1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Administration 1Mice1 Female athymic NCr nu/nu mice are subcutaneously inocu
21、lated with 5106 Colo-205 or MDA-MB-231 cells or implanted with 1 mm3 786-O tumor fragments. When tumors reach a volume of 100 mm3, Regorafenib or vehicle control is administered orally qd21 in the 786-O model, and qd9 in the Colo-205 and MDA-MB-231 models, respectively, at doses of 100, 30, 10, and
22、3 mg/kg. Paclitaxel is administered intravenously at 10 mg/kg in ethanol/Cremophor EL/saline (12.5%/12.5%/75%) every 2 days5. Tumor size (volume) is estimated twice weekly (lw2)/2, and the percentage of tumor growth inhibition (TGI) is obtained from terminal tumor weights (1-T/C100). Mice are weighe
23、d every other day starting from the first day of treatment. The general health status of the mice is monitored daily.MCE has not independently confirmed the accuracy of these methods. They are for reference only.CUSTOMER VALIDATIONSee more customer validations on www.MedChemEREFERENCES1. Wilhelm SM,
24、 et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antiRetaspimycin HydrochlorideCat. No.: HY-10210CAS No.: 857402-63-2Molecular Formula: CHClNOMolecular Weight: 624.17Target: HSPPathway: Cell Cyc
25、le/DNA Damage; Metabolic Enzyme/ProteaseStorage: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 monthSolvent GRP94, EC50: 119 nMRetaspimycin (IPI-504) is a novel and highly soluble analog of 17AAG, an inhibitor of Hsp90. Retaspimycin can abrogate both the unfolded protein response eleme
26、nt (UPRE) and ERSE-driven luciferase activity in non-treated U266 and MM.1s cells as well as in Tunicamycin (Tm)-treated cells. The IC50s for the inhibition of reporter gene activity by Retaspimycin are 19656 nM in U266 and 472177 nM in MM.1s for UPRE-luc activity and 213140 nM for the ERSE-driven a
27、ctivity in MM.1s cells. Retaspimycin treatment leads to a dose-dependent decrease of p50ATF6 with EC50 of 237 nM, consistent with the reporter-gene assay. The level of sXBP1 is decreased in the presence of Retaspimycin with an apparent EC50 between 300 nM and 1 M1. Incubation of Retaspimycin (IPI-50
28、4) potently suppresses both Akt and MAPKs phosphorylation in both sensitive and Trastuzumab-resistant cells. Total levels of Akt In VitroProduct Data Sheet InhibitorsAgonistsScreening Librarieswww.MedChemE1decreased in all 4 cell lines (BT474, SKBR-3, HCC1569, and HCC1569) in a dose-dependent manner
29、. However, levels of total MAPKs are not significantly altered with Retaspimycin treatment2.In Vivo Retaspimycin (IPI-504) and Trastuzumab independently induce tumor regression of Trastuzumab-sensitive BT474 cell-derived xenografts. Xenografts derived from BT474R cells continue to grow in the presen
30、ce of Trastuzumab but are still sensitive to Retaspimycin. When used in combination, Retaspimycin and Trastuzumab add only marginal benefits to Retaspimycin monotherapy. Retaspimycin (100 mg/kg) as a single agent is more efficacious than Trastuzumab in inhibiting tumor growth in HCC1569 xenografts.
31、The combination is not significantly superior to Retaspimycin used as a single agent2.PROTOCOLCell Assay 1 Hela cells are grown in Dulbeccos modified Eagles medium containing 10% fetal bovine serum, 1 ug/mL streptomycin and 1 ug/mL penicillin. U266 and MM.1s are cultured in RPMI 1640 medium containi
32、ng 15% fetal bovine serum, 1 mM pyruvate, 1 ug/mL streptomycin, and 1 ug/mL penicillin. All the cell lines are maintained at 37C in a humidified 5% CO2 atmosphere. Viability studies are performed using the vital mitochondrial function stain Alamar Blue. After cells are incubated in 96-well plates (2
33、00 L) Retaspimycin, 20 L of Alamar Blue is added and incubated for 4-6 h at 37C. The Alamar Blue reduction is monitored using an Envision plate reader at EM=544 nm and EM=590 nm. The ratios obtained from drug-treated cells versus vehicle treated cells are quantified and plotted against drug concentr
34、ation to give EC50 values. Caspase-3 and 7 activities are detected using the Caspase Glow kit1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Administration 2Mice2 For all the experiments, 2107 cells are injected into the right flanks of 10 mice
35、 for each experimental condition. Established tumors are treated with Trastuzumab, Retaspimycin, or the combination as following: Trastuzumab (10 mg/kg in sterile PBS) or sterile PBS (control) is given intraperitoneally twice weekly. Retaspimyci (100 mg/kg) is administered intraperitoneally thrice w
36、eekly. Retaspimyci, Trastuzumab, and the combination treatments are tolerable. No significant toxicity is noticed among the treatment arms. Tumor growth is measured with digital calipers as indicated and tumor volume is determined using the formula: (lengthwidth2)(/6). At the end of the experiments,
37、 the animals are anesthetized with 1.5% isofluorane-air mixture and killed by cervical dislocation. Results are depicted as means of tumor volumeSE.MCE has not independently confirmed the accuracy of these methods. They are for reference only.REFERENCES1. Patterson J, et al. IPI-504, a novel and sol
38、uble HSP-90 inhibitor, blocks the unfolded protein response in multiple myeloma cells. Cancer Chemother Pharmacol. 2008 May;61(6):923-32.2. Scaltriti M, et al. Antitumor Activity of the Hsp90 Inhibitor IPI-504 in HER2-Positive Trastuzumab-Resistant Breast Cancer. Mol Cancer Ther. 2011 May;10(5):817-
39、24.3. Sydor JR, et al. Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90. Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17408-13. Epub 2006 Nov 7.www.MedChemE2Caution: Product has not been fully validated for medic
40、al applications. For research use only.Tel: 609-228-6898 Fax: 609-228-5909 E-mail: techMedChemEAddress: 1 Deer Park Dr, Suite Q, Monmouth Junction, NJ 08852, USAwww.MedChemE3 vehicle alone is injected IP. After 30 min for the Rapamycin-treated mouse or 10 min for the PP 242 and vehicle-treated mice,
41、 250 mU of insulin in 100 L of saline is injected IP. 15 min after the insulin injection, the mice are killed by CO2 asphyxiation followed by cervical dislocation. Tissues are harvested and frozen on liquid nitrogen in 200 L of cap lysis buffer. The frozen tissue is thawed on ice, manually disrupted
42、 with a mortar and pestle, and then further processed with a micro tissue-homogenizer. Protein concentration of the cleared lysate is measured by Bradford assay and 5-10 g of protein is analyzed by Western blot2. MCE has not independently confirmed the accuracy of these methods. They are for referen
43、ce only.CUSTOMER VALIDATIONSee more customer validations on www.MedChemE Cancer Res. 2013 Apr 15;73(8):2574-86. ACS Chem Biol. 2012 Jun 15;7(6):982-7.www.MedChemE2REFERENCES1. Apsel B, et al. Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nat Chem B
44、iol. 2008 Nov;4(11):691-9.2. Feldman ME, et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol. 2009 Feb 10;7(2):e38.Caution: Product has not been fully validated for medical applications. For research use only.Tel: 609-228-6898 Fax: 609-228-5909 E-
45、mail: techMedChemEAddress: 1 Deer Park Dr, Suite Q, Monmouth Junction, NJ 08852, USAwww.MedChemE30.1018 年用水量 立方米 14142.8119 总能耗 吨标准煤 101.6520 节能率 21.67%21 节能量 吨标准煤 30.3622 员工数量 人 544第二章 建设背景及必要性分析泓域咨询MACRO/ 气辅系统项目投资备案报告一、项目建设背景1、到2020年，战略性新兴产业发展要实现以下目标：产业规模持续壮大，成为经济社会发展的新动力。战略性新兴产业增加值占国内生产总值比重达到15%，形成新一代信息技术、高端制造、生物、绿色低碳、数字创意等5个产值规模10万亿元级的新支柱，并在更广领域形成大批跨界融合的新增长点，平均每年带动新增就业100万人以上。2、项目建成投产后，可以大幅度提高企业的经济效益，为公司进一步发展创造条件；更为重要的是，项目承办单位在多年的生产服务承包中，积累了大量的生产经验和管理经验，自主研发的项目产品技术含量高、性能优良、节能环境保护，在整个相关行业中市场潜力
