大豆提取物提高小鼠免疫功能及抑制裸鼠的人肝癌原位移植瘤
|
摘要
本工作旨在探讨大豆提取物(soybean extract,简称SBE)对免疫低下小鼠免疫功能的影响以及从整体、细胞、分子水平研究SBE对裸鼠的人肝癌原位移植瘤的抑制作用,并探讨其细胞周期的调节机制,深层次揭示SBE的抗肿瘤作用,并为其临床应用提供科学依据。在第一部分中,采用在体实验,通过给小鼠腹腔注射环磷酰胺(Cyclophosphamide,CTX),建立免疫功能低下模型,观察SBE对免疫低下小鼠免疫功能的影响。结果表明,SBE能提高免疫低下小鼠的脾指数和血清IgG2a的水平,增加外周血的白细胞数、中性粒细胞和单核细胞百分率,增强NK细胞杀伤活性和腹腔巨噬细胞的吞噬功能,显著提高CTX造成的免疫低下小鼠的固有免疫和适应性免疫的作用,增强免疫功能。在第二部分中,建立裸鼠的人肝癌原位移植瘤的动物模型,研究SBE对肝癌的抑制作用,及其对肝癌细胞周期的调节机制。结果表明,SBE能够抑制裸鼠的人肝癌原位移植瘤的生长,提高荷瘤裸鼠的外周血白细胞数,增强免疫功能,降低血清AFP的水平,改善荷瘤裸鼠的肝功能;其部分机制可能是提高荷瘤裸鼠的免疫功能,同时,通过对p21、Cyclin D1/CDK4、CyclinE/CDK2、P-pRb蛋白表达的影响,引起肝癌细胞的G1期阻滞,抑制肿瘤细胞的增殖,从而抑制人肝癌裸鼠原位移植瘤的生长。
The influence of soybean extract (SBE) on immune function of immunosuppressive micewas investigated in present study. The inhibitory effects of SBE on human orthotopictransplanted hepatocellular carcinoma (HCC) of nude mice and the mechanisms ofregulating the cell cycle were also investigated. In part I, immunosuppressive mice wasestablished by intraperitoneal injection of cyclophosphamide (CTX) to investigate theeffect of SBE on immune function of immunosuppressive mice. The data indicated thatspleen index and IgG2a level were significantly increased. The peripheral leucocytecount and the percentage of mononuclear leucocytes and neutrophils were markedlyraised. The activity of NK cell and peritoneal macrophage was remarkably stimulated.SBE significantly increased the immune function of CTX-induced immunosuppressivemice. Since SBE was shown to increase the immune function of CTX-inducedimmunosuppressive mice, we examined whether SBE would inhibt the growth of HCC.In part II, to combine our previous findings of HCC, the experimental model of humanorthotopic transplanted HCC of nude mice in vivo was used to investigated inhibitoryeffects of SBE on bearing cancer nude mice. We focused mainly on the cell cyclechanges of hepatocellular carcinoma cell. It was found that the growth of humanorthotopic transplanted HCC was inhibited by SBE. The peripheral leucocyte count ofnude mice was increased and AFP level of blood serum was decreased. Hepatic functionof bearing cancer nude mice was ameliorated by SBE. The hepatocellular carcinoma cellcount of G1 phase was significantly increased in SBE 30mg/kg group. The principalmechanism may relate with the changes in the expression of p21, Cyclin D1/CDK4,Cyclin E/CDK2 and P-pRb. The upregulation of p21 and downregulation of CyclinD1/CDK4, Cyclin E/CDK2 and P-pRb were related with G1 cell arrest and influencedthe G1/S transition.
The influence of soybean extract (SBE) on immune function of immunosuppressive micewas investigated in present study. The inhibitory effects of SBE on human orthotopictransplanted hepatocellular carcinoma (HCC) of nude mice and the mechanisms ofregulating the cell cycle were also investigated. In part I, immunosuppressive mice wasestablished by intraperitoneal injection of cyclophosphamide (CTX) to investigate theeffect of SBE on immune function of immunosuppressive mice. The data indicated thatspleen index and IgG2a level were significantly increased. The peripheral leucocytecount and the percentage of mononuclear leucocytes and neutrophils were markedlyraised. The activity of NK cell and peritoneal macrophage was remarkably stimulated.SBE significantly increased the immune function of CTX-induced immunosuppressivemice. Since SBE was shown to increase the immune function of CTX-inducedimmunosuppressive mice, we examined whether SBE would inhibt the growth of HCC.In part II, to combine our previous findings of HCC, the experimental model of humanorthotopic transplanted HCC of nude mice in vivo was used to investigated inhibitoryeffects of SBE on bearing cancer nude mice. We focused mainly on the cell cyclechanges of hepatocellular carcinoma cell. It was found that the growth of humanorthotopic transplanted HCC was inhibited by SBE. The peripheral leucocyte count ofnude mice was increased and AFP level of blood serum was decreased. Hepatic functionof bearing cancer nude mice was ameliorated by SBE. The hepatocellular carcinoma cellcount of G1 phase was significantly increased in SBE 30mg/kg group. The principalmechanism may relate with the changes in the expression of p21, Cyclin D1/CDK4,Cyclin E/CDK2 and P-pRb. The upregulation of p21 and downregulation of CyclinD1/CDK4, Cyclin E/CDK2 and P-pRb were related with G1 cell arrest and influencedthe G1/S transition.
引文
[1]何维.医学免疫学[M].北京:人民卫生出版社,2005,145-149.
[2]Starke I,Donnelly P.Antimicrobial therapy in the immunocompromised patients a guide to retional therapy[M].London:Current Medical Literature,1992,1-89
[3]汪复.免疫功能低下者的感染与抗菌药物应用[J].中华医学杂志,1996,76(4):244
[4]Marcos MA,Alvarez-Martinez MJ,Niubo J,Pumarola T.Infections in immunosuppressed patients[J].Enferm Infecc Microbiol Clin.2008,26 Suppl 9:58-65.
[5]von Wagner M,Zeuzem S.Prevention and therapy of reactivation of hepatitis B in immunosuppressed patients[J].Dtsch Med Wochenschr.2009,134(6):255-8.
[6]Vento S,Cainelli F,Temesgen Z.Lung infections after cancer chemotherapy[J].Lancet Oncol.2008,9(10):982-92
[7]Connolly JE Jr,McAdams HP,Erasmus J J,Rosado-de-Christenson ML.Opportunistic fungal pneumonia[J].J Thorac Imaging.1999,14(1):51-62.
[8]Cebular S,Lee S,Tolaney P,Lutwick L.Community-acquired pneumonia in immunocompromised patients.Opportunistic infections to consider in differential diagnosis[J].Postgrad Med.2003,113(1):65-6,69-70,73-4 passim.
[9]Cohn J,Blumberg EA.Immunizations for renal transplant candidates and recipients [J].Nat Clin Pract Nephrol.2009,5(1):46-53.
[10]Johnson RW,Wasner G,Saddler P,Baron R.Herpes zoster and postherpetic neuralgia:optimizing management in the elderly patient[J].Drugs Aging.2008,25(12):991-1006.
[11]Hlava N,Niemann CU,Gropper MA,Melcher ML.Postoperative infectious complications of abdominal solid organ transplantation[J].J Intensive Care Med.2009,24(1):3-17
[12]Echavarria M.Adenoviruses in immunocompromised hosts[J].Clin Microbiol Rev. 2008, 21(4): 704-15.
[13]Littlewood KE. The immunocompromised adult patient and surgery [J]. Best Pract Res Clin Anaesthesiol. 2008, 22(3): 585-609.
[14] Sullivan RJ, Pantanowitz L, Casper C, Stebbing J, Dezube BJ. HIV/AIDS: epidemiology, pathophysiology, and treatment of Kaposi sarcoma-associated herpesvirus disease: Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman disease [J]. Clin Infect Dis. 2008, 1, 47(9): 1209-15.
[15]Mrsic M. The treatment of febrile immunosuppressed patient [J]. Reumatizam. 2007, 54(2): 63-6
[16]Patel RV, Weinberg JM. The patient with human immunodeficiency virus, Part 2: Review of treatment [J]. Cutis. 2008, 82(3): 202-10
[17]Solari R, Corti M, Cangelosi D, Escudero M, Negroni R, Saccheri C, Schtirbu R. Disseminated histoplasmosis with lesions restricted to the larynx in a patient with AIDS. Report of a case and review of the literature [J]. Rev Iberoam Micol. 2007, 24(2): 164-6.
[18] Li Yumin, Chen Hao, Li Xun, Zhou Wence, He Minyan, Chiriva-Internati M, Wachtel MS, Frezza EE. A new immunomodulatory therapy for severe sepsis: Ulinastatin Plus Thymosin {alpha} 1 [J]. J Intensive Care Med. 2009, 24(1): 47-53.
[19]Kellici S, Burazeri G. Thymosin alphal: a promising molecule for important clinical applications [J]. Med Arh. 2009, 63(1): 48-50.
[20]Zhang Peijun; Hu Rui; Chen Dekun. Effects of swine transfer factor on the quantity and phagocytic activities of canine peripheral blood neutrophil [J]. Chinese Journal of Preventive Veterinary Medicine, 2007, 29 (3): 208-211
[21]Pekmezci D, Cakiroglu D. Investigation of Immunmodulatory effects of levamisole and vitamin E on Immunity and some blood parameters in newborn Jersey calves [J]. Vet Res Commun. 2009, 23. [Epub ahead of print]
[22] Chen LY, Lin YL, Chiang BL. Levamisole enhances immune response by affecting the activation and maturation of human monocyte-derived dendritic cells [J]. Clin Exp Immunol. 2008, 151(1): 174-81
[23]Gao S, Liu C, Qu S, Song J, Li J, Zhang P, Wang Q, Guo C, Gao F, Zhang L. Non-cell Corynebacterium parvum generated by nanotechnology:a promising immunomodulator with less side effects[J].Int Immunopharmacol.2007,7(10):1334-42.
[24]Lue P,Li L,Lue S,Zhang L.Study on the effects of Corynebacterium parvum onsolid tumor and immue system in mice[J].Chinese Journal of Microecology,2007,19(6):529-530
[25]罗若荣,林旭凯,蔡文德,陈文玲,李盛鹏,柯跃斌.香菇多糖对大鼠免疫调节作用的研究[J].现代预防医学,2007,34(21):53-54
[26]宁安红,曹婧,黄敏,张伟.灵芝多糖对小鼠肿瘤的抑制作用及免疫指标的观察[J].肿瘤研究与临床,2004,16(3):31-33
[27]袁学千,王淑梅,高权国.刺五加多糖增强小鼠免疫功能的实验研究[J].中医药学报,2004,32(4):44-45
[28]王统一,赵兵,王玉春.多糖免疫调节和抗肿瘤研究进展[J].过程工程学报,2006,6f4):34-42
[29]Anderson JW,Smith BM,Washnock CS.Cardiovascular and renal benefits of dry bean and soybean intake[J].Am J Clin Nutr 1999;70:464-474.
[30]Messina MJ.Legumes and soybeans:overview of their nutritional profiles and health effects[J].Am J Clin Nutr 1999;70:439-450.
[31]Liu KS.Chemistry and nutritional value of soybean components[M].In Soybeans:Chemistry,Technology and Utilization.Aspen Publ.Inc.:Gaithersburg,Maryland,USA,1999,25-113.
[32]Xiao CW.Health effects of soy protein and isoflavones in humans[J].J Nutr.2008,138(6):1244S-9S
[33]Michelfelder AJ.Soy:a complete source of protein[J].Am Fam Physician.2009,79(1):43-7.
[34]Sakai T,Kogiso M,Soy isoflavones and immunity[J].J Med Invest.2008,55(3-4):167-73
[35]徐超斗,梁爱君,祝业,等.大豆低聚糖对免疫功能的促进作用[J].解放军药学学报,2005,21(1):37-39
[36]Kushi LH,Meyer KM,Jacobs DR.Cereals,legumes,and chronic disease risk reduction:evidence from epidemiologic studies[J].Am J Clin Nutr 1999,70:451-458
[37]邵传森,朱胜禾.临床疾病与免疫[M].北京,科学出版社,2002,80-90
[38]高晓明.医学免疫学基础[M].北京,北京大学医学出版社,2003,13-23
[39]龚非力.医学免疫学[M].北京,科学出版社,2003,113-116
[40]周光炎.免疫学原理[M].上海.上海科学技术出版社,2007,40-49.
[41]Rodriguez-Pinto D.B cells as antigen presenting cells[J].Cell Immunol.2005,238(2):67-75.
[42]Batista FD,Harwood NE.The who,how and where of antigen presentation to B cells[J].Nat Rev Immunol.2009,9(1):15-27.
[43]Khatib R,Rabah R,Sarnaik SA.The spleen in the sickling disorders:an update[J].Pediatr Radiol.2009,39(1):17-22.
[44]Ozturk E,Mutlu H,S(o|¨)nmez G,Sildiroglu HO.Primary angiosarcoma of the spleen.Turk J Gastroenterol[J].2007,18(4):272-5
[45]Cheng S,Evans WK,Stys-Norman D,Shepherd FA.Lung Cancer Disease Site Group of Cancer Care Ontario's Program in Evidence-based Care[J].Chemotherapy for relapsed small cell lung cancer:a systematic review and practice guideline.J Thorac Oncol.2007,2(4):348-54.
[46]Parking DM,Bary F,Ferlay J,et al.Global cancer statistics,2002[J].CA Cancer J Clin,2005,55:74-108.
[47]骆抗先.乙型肝炎基础和临床[M].北京:人民卫生出版社,2003:583.
[48]Dillon P.Lymphatic and venous disorders[A].In:Oldham KT,Colombani PM,Foglia RP,eds.Surgery of infants and children[M].Philadelphia:Lippincott-Raven,1997.1727-1736
[49]Llovet JM,Burroughs A,Bruix J.Hepatocellular carcinoma[J].Lancet.2003,362(9399):1907-17
[50]Park NH,Chung YH.Molecular mechanisms of hepatitis B virus-associated hepatocellular carcinoma[J].Korean J Hepatol,2007,13(3):320-40.
[51]Laurent-Puig P, Zucman-Rossi J. Genetics of hepatocellular tumors [J]. Oncogene. 2006, 25(27): 3778-86.
[52] Kudo M. Hepatocellular carcinoma 2009 and beyond: from the surveillance to molecular targeted therapy. Oncology [J]. 2008, 75 Suppl 1:1-12.
[53]Robinson P. Hepatocellular carcinoma: development and early detection [J]. Cancer Imaging. 2008, 8 Suppl A: S128-31.
[54]Debruyne EN, Delanghe JR. Diagnosing and monitoring hepatocellular carcinoma with alpha-fetoprotein: new aspects and applications [J]. Clin Chim Acta. 2008, 395(1-2): 19-26.
[55] Aljabiri MR, Lodato F, Burroughs AK. Surveillance and diagnosis for hepatocellular carcinoma [J]. Liver Transpl. 2007,13(11 Suppl 2): S2-12.
[56]Giannelli G, Antonaci S. New frontiers in biomarkers for hepatocellular carcinoma [J]. Dig Liver Dis. 2006, 38(11): 854-9.
[57] Zhou L, Liu J, Luo F. Serum tumor markers for detection of hepatocellular carcinoma [J]. World J Gastroenterol. 2006,12(8): 1175-81.
[58] Yuen MF, Lai CL. Serological markers of liver cancer [J]. Best Pract Res Clin Gastroenterol. 2005, 19(1): 91-9.
[59] Yao DF, Dong ZZ, Yao M. Specific molecular markers in hepatocellular carcinoma [J]. Hepatobiliary Pancreat Dis Int. 2007, 6(3): 241-7.
[60]Blum HE, Spangenberg HC. Hepatocellular carcinoma: an update [J]. Arch Iran Med. 2007,10(3): 361-71.
[61] Spangenberg HC, Thimme R, Blum HE. Advances in prevention and diagnosis of hepatocellular carcinoma. [J]. Expert Rev Gastroenterol Hepatol. 2008,2(3): 425-33.
[62] Wong CH, Chan SK, Chan HL, Tsui SK, Feitelson M. The molecular diagnosis of hepatitis B virus-associated hepatocellular carcinoma [J]. Crit Rev Clin Lab Sci. 2006,43(1): 69-101.
[63] Ju LX, Chen Z, Ren RZ. Progress in research on the treatment of primary liver cancer with traditional Chinese medicine for activating blood to resolve stasis [J]. Zhong Xi Yi Jie He Xue Bao. 2005, 3(6): 491-4.
[64] Mu XY, Zhao AG. Progress in research of traditional Chinese medicine in inducing differentiation of human hepatoma cells [J]. Zhong Xi Yi Jie He Xue Bao. 2007, 5(1): 92-6.
[65]Meng MB, Cui YL, Guan YS, Ying Z, Zheng MH, Yuan CK, Zhang RM. Traditional Chinese medicine plus transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma [J]. J Altern Complement Med. 2008, 14(8): 1027-42.
[66]Luk JM, Wang X, Liu P, Wong KF, Chan KL, Tong Y, Hui CK, Lau GK, Fan ST. Traditional Chinese herbal medicines for treatment of liver fibrosis and cancer: from laboratory discovery to clinical evaluation [J]. Liver Int. 2007, 27(7): 879-90.
[67] Jones RG, Thompson CB. Tumor suppressors and cell metabolism: a recipe for cancer growth [J]. Genes Dev. 2009, 23(5): 537-48.
[68] Jones E, Pu H, Kyprianou N. Targeting TGF-beta in prostate cancer: therapeutic possibilities during tumor progression [J]. Expert Opin Ther Targets. 2009, 13(2): 227-34.
[69] Fan D, Ma C, Zhang H. The molecular mechanisms that underlie the tumor suppressor function of LKB1 [J]. Acta Biochim Biophys Sin (Shanghai). 2009, 41(2): 97-107.
[70]Golubovskaya VM, Kweh FA, Cance WG. Focal adhesion kinase and cancer [J]. Histol Histopathol. 2009, 24(4): 503-10.
[71] Liu W, Zhou Y, Reske SN, Shen C. PTEN mutation: many birds with one stone in tumorigenesis [J]. Anticancer Res. 2008, 28(6A): 3613-9.
[72]Mizuno M, Yamada J, Terai H, et al. Differences in immunomodulating effects between wild and cultured Panax ginseng [J]. Biochem Biophys Res Commun. 1994, 200(3): 1672-1678
[73]Fong WF, Tse AK, Poon KH, et al. Magnolol and honokiol enhance HL-60 human leukemia cell differentiation induced by 1, 25-dihydroxyvitamin D3 and retinoic acid [J]. Int J Biochem Cell Biol. 2005, 37(2): 427-441
[74] Wadsworth TL, McDonald TL, Koop DR. Effects of Ginkgo biloba extract (EGb 761) and quercetin on lipopolysaccharide-induced signaling pathways involved in the release of tumor necrosis factor [J]. Biochem Pharmacol. 2001, 62(7): 963-974
[75]林科,张太平,朱顺,等.山楂熊果酸的制备及对小鼠免疫功能和肝癌细胞凋亡的影响[J].中国生化药物杂志,2007,28(5):308-311.
[76]Aiken C,Chen CH.Betulinic acid derivatives as HIV-1 antivirals[J].Trends Mol Med.2005,11(1):31-36
[77]Watanabe S,Uesugi S,Kikuchi Y.Isoflavones for prevention of cancer,cardiovascular diseases,gynecological problems and possible immune potentiation [J].Biomed Pharmacother.2002,56(6):302-312.
[78]Lee JN,Lee DY,Ji IH,et al.Purification of Soluble β-Glucan with Immune-enhancing Activity from the Cell Wall of Yeast[J].Bioscience,Biotechnology,and Biochemistry.2001,65(4):837-841.
[79]Guo Y M,Ali R A,Qureshi M A.The influence ofβ-glucan on immune response in broiler chicks[J].Immunopharmaeology and Immunotoxicology,2003,25(3):461-472.
[80]Hanif R,Qiao L,Shift S J,et al.Curcumin,a natural plant phenolic food additive,inhibits cell proliferation and induces cell cycle changes in colon adenocarcinoma cell lines by a prostaglandin-independent pathway[J].J Lab Clin Med,1997,130:576-584.
[81]Batth BK,Tripathi R,Srinivas UK.Curcumin-induced differentiation of mouse embryonal carcinoma PCC4 cells[J].Differentiation,2001,68:133-140.
[82]Alberts,B Bray,D Lewis,et al.Molecular Biology of the Cell[M].New York:Garland Publishing Inc,1994.
[83]Gerald Karp.Cell and Molecular Biology:concepts and ecperiments[M].New York:John Wiley & Sons,Inc,1999.
[84]Evan G I,Vousden K H.Proliferation,cell cycle and apoptosis in cancer[J].Nature,2001,411(6835):342-348.
[85]Nurse P.A long twentieth century of the cell cycle and beyond[J].Cell,2000,100(1):71-78
[86]Sherr CJ.Cancer cell cycle[J].Science,1996,274:1672-1677
[87]Pines J.Cyclins and cyclin-dependent kinases:a biochemical view[J].Biochem J,1995,308:697-711.
[88] Clarke B, Chetty R, Cell cycle aberrations in the pathygenesis of squamous cell carcinoma of the uterine cervix [J]. Gynecol Oncol, 2001, 82: 238-246.
[89] Milde-Langosch K, Riethdorf S. Role of cell-cycle regulatory proteins in gynecological cancer [J]. Cell physiol, 2003, 196: 224-244.
[90]Funk JO. Cancer cell cycle control [J]. Anticancer Res, 1999, 19: 4772-4780.
[91]Lew DJ, Reed S I. A proliferation of cyclins [J]. Trends in Cell Biology, 1992, 2: 77-81.
[92] Serrano M, Harmon GJ, Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4 [J]. Nature, 1993, 366: 704-707.
[93]Polyak K, Lee MH, Erdjument-Bromage h, koff A, Roberts JM, Tempst P, Massague J. Cloning of p27~(kip1), a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals [J]. Cell, 1994, 78: 59-66.
[94]Xiong Y, Harmon GJ, Zhang H, Casso D, Kobayashi R, Beach D. p21 is a universal inhibitor of cyclin kinases [J]. Nature, 1993, 366: 701-704.
[95]Hutchison C J, Glover D D. Cell Cycle Control [M]. Oxford: IRL Oxford University Press, 1995.
[96]Kastan M B. Check Point Controls and Cancer [M]. New York: Cold Spring Harbor Laboratory Press, 1997.
[97] Zhou BB, Elledge SJ. The DNA damage response: putting checkpoints in perspective [J]. Nature, 2000, 408(23): 433-439.
[98]Norbury CJ, Zhivotovsky B. DNA damage-induced apoptosis [J]. Oncogene, 2004, 23: 2797-2808.
[99]Sherr CJ. Mammalian G1 cyclins [J]. Cell, 1993, 73: 1059-1065.
[100] Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression [J]. Genes Dev, 1999, 13: 1501-1512.
[101] Mittnacht S. Control of pRB phosphorylation [J]. Curr Opin Genet Dev. 1998, 8(1): 21-7.
[102] Seville LL, Shah N, Westwell AD, Chan WC. Modulation of pRB/E2F functions in the regulation of cell cycle and in cancer [J]. Curr Cancer Drug Targets. 2005, 5(3): 159-70.
[103]Sherr C J,Roberts JM.Inhibitors of mammalian G1 cyclin-dependent kinases[J].Genes Dev,1995,9:1149-1163.
[104]Roberta W.C.Pang,Jae Won Joh,Philip J.Johnson,Morito Monden,Timothy M.Pawlik,Ronnie T.P.Poon,Biology of Hepatocellular Carcinoma[J],Annals of Surgical Oncology,2008,14(4):962-971
[105]Kobayashi H,Fukuda Y,Yoshida R,Kanada Y,Nishiyama S,Suzuki M,Kanayama N,Terao T,Suppressing effects of dietary supplementation of soybean trypsin inhibitor on spontaneous,experimental and peritoneal disseminated metastasis in mouse model[J].Int J Cancer.2004,112(3):519-24.
[106]Hayakawa K,Mizutani J,Wada K,Masai T,Yoshihara I,Mitsuoka T.Effects of soybean oligosaccharides on human faecal flora[J].MICROB ECOL HEALTH DIS.1990,6(3):293-303
[107]Steiner C,Amould S,Scalbert A,et al.Isoflavones and the prevention of breast and prostate cancer:new perspectives opened by nutrigenomics[J].Br J Nutr.2008,99:ES78-108
[108]Watanabe S,Uesugi S,Kikuchi Y.Isoflavones for prevention of cancer,cardiovascular diseases,gynecological problems and possible immune potentiation [J].Biomed Pharmacother.2002,56(6):302-312.
[109]Lakshman M,Xu L,Ananthanarayanan V,et al.Dietary genistein inhibits metastasis of human prostate cancer in mice[J].Cancer Res.2008,68(6):2024-32.
[110]Park JH,Oh EJ,Choi YH,Kang CD,Kang HS,Kim DK,Kang KI,Yoo MA.Synergistic effects of dexamethasone and genistein on the expression of Cdk inhibitor p21WAF1/CIP1 in human hepatocellular and colorectal carcinoma cells[J].Int J Oncol.2001,18(5):997-1002
[111]张绪霞,陈卫梅,董海洲.大豆膳食纤维的营养功能特性及开发前景[J].中国食物与营养.2007,13(2):49-51
[112]Liu ES,Luk SC,Leung ET,Lee WH,Yuen WF,Kwok KM,Siu SW,Kwok NS,Xing HT,Wu M,Pang SF.Effect of CKBM on prostate cancer cell growth in vitro and in vivo[J].J Chemother.2008,20(2):246-252
[113]Chan A.S.,E.C.Yip,L.Y.Yung,H.Pang,S.C.Luk,S.F.Pang,Y.H.Wong.CKBM stimulates MAPKs but inhibits LPS-induced IFN-gamma in lymphocytes[J].Phytother Res.2006,20(9):725-731
[114]Zhang W,E.S.Liu,J.Fu,H.M.Tian,Y.J.Wu,S.F.Pang.Suppression of primary breast,colon,gastric and bladder cancers cell growth in vitro by CKBM,a natural product.Invest New Drugs[J].Invest New Drugs.2006,24(3):181-187
[115]Chan A.S.,E.C.Yip,L.Y.Yung,H.Pang,S.C.Luk,S.F.Pang,Y.H.Wong.Immuno-regulatory effects of CKBM on the activities of mitogen-activated protein kinases and the release of cytokines in THP-1 monocytic cells[J].Biol Pharm Bull.2005,28(9):1645-1650
[116]刘鲁明,杨宇飞.肝癌中西医综合治疗[M].北京:人民卫生出版社,2002,5
[117]于尔辛.中医治疗肝癌的科学基础[A].见:汤钊猷,杨秉辉主编.原发性肝癌的研究与进展[M].上海:上海医科大学出版社,1990,302.
[118]Luk S.C.,S.W.Siu,C.K.Lai,Y.J.Wu,S.F.Pang.Cell Cycle Arrest by a Natural Product via G2/M Checkpoint[J].Int J Med Sci.2005,2(2):64-69
[119]Chan,B.P.,W.F.Yuen,W.H.Lee,S.N.Wong,T.Y.Chung,Y.J.Wu,S.E Pang Immunomodulating effects of CKBM on the cytokine production in peripheral blood mononuclear cells(PBMCs) from healthy volunteers[J].Immunopharmacol Immunotoxicol.2004a,26(2):177-92
[120]Chan,J.Y.,J.Y.Cheung,S.C.Luk,Y.J.Wu,S.F.Pang,K.R Fung Anti-cancer and pro-apoptotic effects of an herbal medicine and Saccharomyces cerevisiae product(CKBM) on human hepatocellular carcinoma HepG2 cells in vitro and in vivo[J].Immunopharmacol Immunotoxicol.2004b,26:597-609
[121]Shin V.Y.,W.H.Leung So,E.S.Liu,Y.J.Wu,S.F.Pang C.H.Cho.Anti-tumorigenic and Pro-apoptotic effects of CKBM on gastric cancer growth in nude mice[J].Int J Med Sci.2004,1:137-145
[122]Field KM,Dow C,Michael M.Liver function in oncology:biochemistry and beyond[J].Lancet Oncol.2008,9(11):1092-101.
[123]Evdokimova VN,Butterfield LH.Alpha-fetoprotein and other tumour-associated antigens for immunotherapy of hepatocellular cancer[J].Expert Opin Biol Ther.2008,8(3):325-36.
[124]Schacherer D,Schoelmerich J,Zuber-Jerger I.The diagnostic approach to hepatocellular carcinoma[J].Z Gastroenterol.2007,45(10):1067-74.
[125]Pang RW,Joh JW,Johnson PJ,Monden M,Pawlik TM,Poon RT.Biology of hepatocellular carcinoma[J].Ann Surg Oncol.2008,15(4):962-71.
[126]Spangenberg HC,Thimme R,Blum HE.Serum markers of hepatocellular carcinoma[J].Semin Liver Dis.2006,26(4):385-90.
[127]Taketa K.α-fetoprotein:Reevaluation in hepatology[J].Hepatology,1990,12(6):1420-1432.
[128]王红阳,付静.肝癌研究现状与进展[J].中华肝脏病杂志2007,15(8):561-562
[129]汤钊猷.现代肿瘤学[M].上海:复旦大学出版社,2003,745-746
[130]刘鲁明,杨宇飞.肝癌中西医综合治疗[M].北京:人民卫生出版社,2002,241
[131]Sherr CJ.Cancer cell cycles[J].Science,1996,274:1672-7.
[132]Ward TH,Cummings J,Dean E,Greystoke A,Hou JM,Backen A,Ranson M,Dive C.Biomarkers of apoptosis[J].Br J Cancer.2008,16,99(6):841-6.
[133]Malumbres M,Barbacid M.Cell cycle,CDKs and cancer:a changing paradigm [J].Nat Rev Cancer.2009,9(3):153-66.
[134]Vermeulen K,Bememan ZN,Van Bockstaele DR.Cell cycle and apoptosis[J].Cell Prolif.2003,36(3):165-75.
[135]Bartkova J,Rajpert-De Meyts E,Skakkebaek NE,Lukas J,Bartek J.Deregulation of the G1/S-phase control in human testicular germ cell tumours[J].APMIS.2003,111(1):252-65,discussion 265-6.
[136]Abukhdeir AM,Park BH.P21 and p27:roles in carcinogenesis and drug resistance[J].Expert Rev Mol Med.2008,1,10:e19
[137]Ortega S,Malumbres M,Barbacid M.Cyclin D-dependent kinases,INK4inhibitors and cancer[J].Biochim Biophys Acta.2002,14,1602(1):73-87.
[138]Gerland LM,Ffrench M,Magaud JP.Cyclin dependent kinase inhibitors and replicative senescence[J].Pathol Biol(Paris).2001,49(10):830-9.
[139] Viallard JF, Lacombe F, Belloc F, Pellegrin JL, Reiffers J. Molecular mechanisms controlling the cell cycle: fundamental aspects and implications for oncology [J]. Cancer Radiother. 2001, 5(2): 109-29.
[140] Pines J. The cell cycle kinases [J]. Semin Cancer Biol, 1994, 5: 305-313.
[141] Garner E, Raj K. Protective mechanisms of p53-p21-pRb proteins against DNA damage-induced cell death [J]. Cell Cycle. 2008, 7(3): 277-82
[142] Spugnini EP, Campioni M, D'Avino A, Caruso G, Citro G, Baldi A. Cell-cycle molecules in mesothelioma: an overview [J]. J Exp Clin Cancer Res. 2007, 26(4): 443-9.
[143] Pines J. Cyclins: wheels within wheels [J]. Cell Growth Differ, 1991, 2: 305-310
[144] Melk A. Senescence of renal cells: molecular basis and clinical implications [J]. Nephrol Dial Transplant, 2003, 18: 2474-2478.
[1].Lovet JM,Bruix J.Novel advancements in themanagement of hepatocellular carcinoma in 2008[J].J Hepatol 2008,48 Suppl 1:S20-S37
[2].骆抗先.乙型肝炎基础和临床[M].北京:人民卫生出版社,2003:583.
[3].Jones RG,Thompson CB.Tumor suppressors and cell metabolism:a recipe for cancer growth[J].Genes Dev.2009,23(5):537-48.
[4].Pines J.Cyclins and cyclin-dependent kinases:a biochemical view[J].Biochem J,1995,308:697-711.
[5].Clarke B,Chetty R,Cell cycle aberrations in the pathygenesis of squamous cell carcinoma of the uterine cervix[J].Gynecol Oncol,2001,82:238-246.
[6].Milde-Langosch K,Riethdorf S.Role of cell-cycle regulatory proteins in gynecological cancer[J].Cell physiol,2003,196:224-244.
[7].Funk JO.Cancer cell cycle control[J].Anticancer Res,1999,19:4772-4780.
[8].Pines J.The cell cycle kinases[J].Semin Cancer Biol,1994,5:305-313.
[9].Mittnacht S.Control of pRB phosphorylation[J].Curr Opin Genet Dev.1998,8(1):21-7.
[10].Seville LL,Shah N,Westwell AD,Chan WC.Modulation of pRB/E2F functions in the regulation of cell cycle and in cancer[J].Curt Cancer Drug Targets.2005,5(3):159-70.
[11].Fei P,E1-Deiry WS.P53 and radiation responses[J].Oncogene,2003,1,22(37):5774-83
[12].Zhou BB,Elledge SJ.The DNA damage response:putting checkpoints in perspective[J].Nature,2000,408(23):433-439.
[13].Norbury CJ,Zhivotovsky B.DNA damage-induced apoptosis[J].Oncogene,2004,23:2797-2808.
[14].Sherr CJ.Mammalian G1 cyclins[J].Cell,1993,73:1059-1065.
[15]. Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression [J]. Genes Dev, 1999, 13: 1501-1512.
[16]. Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm [J]. Nat Rev Cancer. 2009 Mar, 9(3): 153-66.
[17]. Laiho M, Latonen L. Cell cycle control, DNA damage checkpoints and cancer [J]. Ann Med, 2003, 35(6): 391-397.
[18]. Hutchison C J, Glover D D. Cell Cycle Control [M]. Oxford: IRL Oxford University Press, 1995.
[19]. Lew DJ, Reed S I.A proliferation of cyclins [J]. Trends in Cell Biology, 1992, 2: 77-81.
[20]. Serrano M, Harmon GJ, Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4 [J]. Nature, 1993, 366: 704-707.
[21]. Polyak K, Lee MH, Erdjument-Bromage h, koff A, Roberts JM, Tempst P, Massague J. Cloning of p27~(kip1), a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals [J]. Cell, 1994, 78: 59-66.
[22]. Xiong Y, Harmon GJ, Zhang H, Casso D, Kobayashi R, Beach D. p21 is a universal inhibitor of cyclin kinases [J]. Nature, 1993, 366: 701-704.
[23]. Samuel T, Weber HO, Funk JO. Linking DNA damage to cell cycle checkpoints [J]. Cell Cycle, 2002, 1(3): 162-168.
[24]. Latif C, Harvey SH, O'Connell J. Ensuring the Stability of the Genome: DNA Damage Checkpoints [J]. Scientific World Journal, 2001, 1(11): 684-702.
[25]. Iliakis G, Wang Y, Guan J, Wang H. DNA damage checkpoint control in cells exposed to ionizing radiation [J]. Oncogene, 2003, 22(37): 5834-5847.
[26]. Bartek J, Lukas J. Chk 1 and Chk 2 kinases in checkpoint control and cancer [J]. Cancer Cell, 2003, 3(5): 421-429.
[27]. McGowan CH. Checking in on Cds1 (Chk2): A checkpoint kinase and tumor suppressor [J]. Bioessays, 2002, 24(6): 502-511.
[28]. Melo J, Toczyski D. A unified view of the DNA-damage checkpoint [J]. Curr Opin Cell Biol, 2002, 14(2): 237-245.
[29].Abraham RT.Cell cycle checkpoint signaling through the ATM and ATR kinases [J].Genes Develop,2001,15:2177-2196.
[30].Donjerkovic D,Scott DW.Regulation of the G1 phase of the mammalian cell cycle[J].Cell Res,2000,10(1):1-16.
[31].Bartek J,Lukas J.Mammalian G 1-and S-phase checkpoints in response to DNA damage[J].Curr Opin Cell Biol,2001,13(6):738-747.
[32].Funk JO,Kino P.Cell cycle control[J].Genetic instability and cancer.Hautarzt,2002,48:157-159.
[33].韦伟,龚建平,裘法祖.细胞周期调控与肿瘤的发生发展[J].癌症,2004,18:95-97.
[34].Bartek J,Lukas J.Pathways goveming G1/S transition and their response to DNA damage[J].FEB S Left,2001,490(3):117-122.
[35].Smits VA,Medema RH.Checking out the G(2)/M transition[J].Biochim Biophys Acta,2001,1519(1-2):1-12.
[36].Taylor WR,Stark GR.Regulation of the G2/M transition by p53[J].Oncogene,2001,5,20(15):1803-1815.
[37].Bartek J,Falck J,Lukas J.CHK2 kinase-a busy messenger[J].Nat Rev Mol Cell Biol,2001,2(12):877-886.
[38].Bartek J,Lukas J.Chkl and Chk2 kinases in checkpoint control and cancer[J].Cancer Cell,2003,3(5):421-429.
[39].江国春.细胞周期蛋白D[J].国外医学·遗传学分册,1998,21:173一177
[40].王辉云,严瑞琪,龙江斌,吴秋良.肝癌中cyclin D1扩增与HBV感染及病理学的关系[J].世界华人消化杂志,1999,7:98-100
[41].孙宝华,武忠弼,阮幼冰,杨木兰.肝细胞癌mdm2基因表达及其与p53基因突变的关系[J].世界华人消化杂志,1999,7:291-294
[42].Iolascon A,Giordani L,Moretti A,Basso G,Borriello A,Della Ragione F.Analysis of CDKN2A,CDKN2B,CDKN2C,and cyclin D's gene status in hepatoblastoma[J].Hepatology,1998,27:989-995.
[43].Mnoeo V,del Valle Guijarro M,Link W,et al.Overexpression of Cyclin D1 inhibits TNF-induced growth arrest[J].J Cell Biochem,2003,89(3):484-449.
[44].Yu Q,Geng Y,Sicinski P.Specific protection against breast cancers by Cyclin D1 ABLation[J].Nature,2001,411:1017-1021
[45].朱斌,姚晓平,杨甲梅,丛文铭.原发性肝细胞癌中细胞周期G1期相关基因Cyclin D1的表达及其临床病理学意义[J].肝胆外科杂志,1999,7:214.216
[46].O' connor PM,Ferris DK,White GA,Pines J,Hunter T,Longo DL.Relationships between cdc2 kinase,DNA cross-linking and cell cycle perturbations induced by nitrogen mustard[J].Cell Growth Diff,1992,3:43-52
[47].Wang J,Zindy F,Chenivesse.Modification of cyclinA expression by hepatocellular carcinoma[J].Oncogene,1992,7:1653-1656
[48].Ito Y,Takeda T,Sakon M et al.Expression and prognostic role of cyclin-dependent kinase 1(cdc2) in hepatocellular carcinoma[J].Oncology,2000,59(1):68-74
[49].HX Xia,PhD,MD,Series Editor.Molecular mechanism underlying the functional loss of cyclindependent kinase inhibitors p16 and p27 in hepatocellular carcinomaHarry.World J Gastroenterol 2008 March 21,14(11):1734-1740
[50].Hui AM,Sakamoto M,Kanai Y,Ino Y,Gotoh M,Yokota J,Hirohashi S.Inactivation of p16~(INK4) in hepatocellular carcinoma[J].Hepatology,1996,24:575-579
[51].Juliette M,Jean-Francois D.Tumor suppressor and hepatocellular carcinoma[J].World J Gastroenterol 2008,14(11 ):1720-1733
[52].He H,Baldwin GS.Rho GTPases and p21-activated kinase in the regulation of proliferation and apoptosis by gastrins[J].Int J Biochem Cell Biol.2008,40(10):2018-22.
[53].Ching YP,Leong VY,Lee MF,Xu HT,Jin DY,Ng IO.P21-activated protein kinase is overexpressed in hepatocellular carcinoma and enhances cancer metastasis involving c-Jun NH2-terminal kinase activation and paxillin phosphorylation[J].Cancer Res.2007,67(8):3601-8.
[54].Hui AM,Kanai Y,Sakamoto M,Tsuda H,Hirohashi S.Reduced p21(WAF1/CIP1) expression and p53 mutation in hepatocellular carcinomas[J]. Hepatology,2002,25:575-579
[55].Sun BH,Zhang J,Wang B J,Zhao XP,Wang YK,Yu ZQ,Yang DL,Hao LJ.Analysis of in vivo patterns of caspase 3 gene expression in primary hepatocellular carcinoma and its relationship to P21~(WAF1) expression and hepatic apoptosis[J].World J Gastroenterol,2002,6:356-360
[56].叶晟,冯懿正,刘友富,袁政洪.P53,P21,nm23和PCNA在原发性肝癌中的表达与预后的关系[J].世界华人消化杂志,2004,7:160
[57].Qin LF,Ng IO,Fan ST,Ng M.P21/WAF1,P53 and PCNA expression and P53mutation status in hepatocellular carcinoma[J].Int J Cancer,2003,79:424-428
[58].Polyak K,Lee MH,Erdjument-Bromage H,Koff A,Roberts JM,Tempst P,Massague J.Cloning of p27~(kip1),a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals[J].Cell,2000,78:59-66
[59].Kawamata N,Morosetti R,Miller CW,Park D,Spirin KS,Nakamaki T,Takeuchi S,Hatta Y,Simpson J,Wilczynski S,Lee YY,Bartram CR,Koeffier HE Molecular analysis of the cyclin-dependent kinase inhibitor gene P27~(kip1) in human malignancies[J].Cancer Res,2000,55:2266-2269
[60].Ponce-Casta eda MV,Lee MH,Latres E,Polyak K,Lacombe L,Montgomery K,Mathew S,Krauter K,Sheinfeld J,Massague J,Cordon-Cardo C.P27~(kip1):chromosomal mapping to 12p 12-12p 13.1 and absence of mutations in human tumors [J].Cancer Res,2000,55:1211-1214
[61].Nourse J,Firpo E,Flanagan WM,Coats S,Polyak K,Lee MH,Massague J,Crabtree GR,Roberts JM.Interleukin-2-mediated elimination of the p27~(kip1)cyclin-dependent kinase inhibitor prevented by rapamycin[J].Nature,2000,372:570-573
[62].Mal A,Poon RYC,Howe PH,Toyoshima H,Hunter T,Harter ML.Inactivation of P27~(kip1) by the viral EIA oncoprotein in TGFβ-treated cells[J].Nature,2001,380:262-265
[63].Tannapfel A,Grund D,Katalinic A,Uhlmann D,Kockerling F,Haugwitz U,Wasner M,Hauss J,Engeland K,Wittekind C.Decreased expression of p27 protein is associated with advanced tumor stage in hepatocellular carcinoma[J].Int J Cancer,2002,89:350-355
[64]. Ito Y, Matsuura N, Sakon M, Miyoshi E, Noda K, Takeda T, Umeshita K, Nagano H, Nakamori S, Dono K, Tsujimoto M, Nakahara M, Nakao K, Taniguchi N, Monden M. Expression and prognostic roles of the G1-S modulators in hepatocellular carcinoma: p27 independently predicts the recurrence [J]. Hepatology, 2004, 30: 90-99
[65]. Millard SS, Yan JS, Nguyen H, Pagano M, Kiyokawa H, Koff A. Enhanced ribosomal association of p27~(kip1) mRNA is a mechanism contributing to accumulation during growth arrest [J]. J Biol Chem, 2002, 272: 7093-7098
[66]. Cheng J, Williag ham T, Shuford M. Tumor suppression and inhibition of aneuploid cell accumaulation in human brain tumor cells by eltopic overexpression of cyclin-dependent kinase inhibitor p27~(kip1) [J]. J Clin Invest, 2001, 97: 1983-1988
[67]． 王华,王靖华．p27~(kip1)与肿瘤[J]．中华病理学杂志,2004,28：140-142
[68]. Loda M, Gukor B, Tarn SW. Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas [J]. Nat Med, 2002, 3:231-234
[69]. Yasui W, Kudo Y, Semba S. Reduced expression of cyclin-dependent kinase inhibitor p27~(kip1) is associated with advanced stage and invasiveness of gastric carcinomas [J]. Jpn J Cancer Res, 2002, 88: 625-629
[70]. Hui AM, Sun L, Kanai Y, Sakamoto M, Hirohashi S. Reduced p27~(kip1) expression in hepatocellular carcinomas [J]. Cancer Lett, 2003, 132: 67-73
[71]. Esposito V, Baldi A, DeLuca A. Prognostic role of the cyclin dependent kinase inhibitor p27 in non-small cell lung cancer. Cancer Res, 2002, 57: 3381-3387
[72]. Ravitz MJ, Wenner CE. Cyclin-dependent kinase regulation during G1 phase and cell cycle regulation by TGF-beta [J]. Adv Cancer Res, 2002, 71: 165-170
[73]. Greenblatt MS, Bennett WP, Hollstein M, Harris CC. Mutations in the P53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis [J]. Cancer Res, 2000, 54: 4855-4878
[74]. Teramoto T, Satonaka K, Kitazawa S, Fujimori T, Hayashi K, Maeda S. P53 gene abnormalities are closely related to hepatoviral infections and occur at a late stage of hepatocarcinogenesis [J]. Cancer Res, 2000, 54: 231-235
[75].Fujimoto Y,Hampton LL,Wirth PJ,Wang N J,Xie JP,Thorgeirsson SS.Alterations of tumor suppressor genes and allelic losses in human hepatocellular carcinomas in China[J].Cancer Res,2000,54:281-285
[76].Ueda H,Ullrich S J,Gangemi JD,Kappel CA,Ngo L.Functional inactivation but not structural mutation of p53 causes liver cancer[J].Nat Genet,2000,9:41-47
[77].孟照华,何振平.肝癌抑制基因治疗的研究现状[J].世界华人消化杂志,2004.7:350-352
[78].Martins C,Kedda MA,Kew MC.Characterization of six tumor suppressor genes and microsatellite instability in hepatocellular carcinoma in southern African blacks[J].World J Gastroenterol,2004,5:470-476
[79].郑建勇,李开宗,窦科峰,李江.肝细胞癌p53及nm23-H1 mRNA表达的意义[J].世界华人消化杂志,2004,7:40-42
[80].肖文华,刘为纹,吕有勇,高崇峰.肝细胞癌Rb基因缺失的研究[J].肿瘤防治研究,2002,24:210-211
[81].Lane DP.p53,guardian of the genome[J].Nature,1992,358:15-16
[82].Gao Y,Lin LP,Zhu CH,Chen Y,Hou YT,Ding J.Growth arrest induced by C75,A fatty acid synthase inhibitor,was partially modulated by p38 MAPK but not by p53 in human hepatocellular carcinoma[J].Cancer Biol Yher.2006,5(8):978-85
[83].张松平,戴益民,王能进.p53蛋白产物在肝细胞癌及其癌周组织中的表达[J].中华病理学杂志,1995,24:51-53
[84].Grana X,Reddy EE Cell cycle control in mammalian cell.Role of cyclins,cyclin dependent kinase,growth suppressor gene and cyclin dependent kidnase inhibitors[J].Oncogene,2000,11:2 01-217
[85].Terada T,Rakanuma Y.Expression of apoptosis,proliferating cell nuclear antigen,and apoptosis-related antigen(bcl-2,c-myc,Fas,lewisy,and p53) in human cholangiocarcinomas and hepatocellular carcinomas[J].Pathol Int,2001,46:764-770
[86].Fan G,Ma X,Kren BT.The retioblastoma gene product inhibits TGF-beta induced apoptosis in primary rat hepatocytes and human HUH-7 hepatoma cells[J].Oncogene,2001,12:1909-1919
[87].Kuroki T,Fujiwara Y,Nakamori S.Evidence for the presence of two tumor-suppressor genes for hepatocellular carcinoma on chromosome[J].Br J Cancer,2000,72:383-386
[88].Marakmi Y,Hoyashi K,Hironashi S.A beration of tumor suppressor p53 and retinoblastoma genes in human hepatocellular carcinomas[J].Cancer Res,1991,51:5520
[89].Pang R,Tse E,Poon RT.Molecular pathways in hepatocellular carcinoma[J].Cancer Lett.2006,240(2):157-69
[90].Hamilton SR.Targeted therapy of cancer:new rolesfor pathologists in colorectal cancer[J].Mod Pathol,2008,21 Suppl 2:S23-S30
[91].Daveau M,Scotte M,Francois A,Coulouarn C,Ros G,Tallet Y,Hiron M,Hellot MF,Salier JP.Hepatocyte growth factor,transforming growth factor alpha,and their receptors as combined markers of prognosis in hepatocellular carcinoma[J].Mol Carcinog 2003,36:130-141
[92].Scharf JG,Braulke T.The role of the IGF axis in hepatocarcinogenesis[J].Horm Metab Res 2003,35:685-693
[93].Breuhahn K,Schirmacher P.Reactivation of the insulin-like growth factor-Ⅱsignaling pathway in human hepatocellular carcinoma[J].World J Gastroenterol 2008,14:1690-1698
[94].Buolamwini JK.Cell cycle molecular targets in novel anticancer drug discovery [J].Curr Pharm Des,2000,6(4):379-92
[95].马凌娣,张彦,文世宏,何於娟,刘小珊,康格非.蒋纪恺苦参碱对荷瘤小鼠抑瘤作用的实验研究[J].Chin J Oncol,2005,27(6):339-341.
[96].李立新,叶胜龙,王艳红,孙瑞霞,薛琼,陈洁,高东梅汤钊猷.槐耳浸膏诱导肝癌细胞凋亡的实验研究[J].Clinical Medical Journal of China,2005.12(6):1152-1153.
[97].Park JH,Oh E J,Choi YH,Kang CD,Kang HS,Kim DK,Kang KI,Yoo MA.Synergistic effects of dexamethasone and genistein on the expression of Cdk inhibitor p21WAF 1/CIP 1 in human hepatocellular and colorectal carcinoma cells[J].Int J Oncol.2001,18(5):997-1002
[98]. Flatt PM, Pietenpol JA. Mechanisms of cell-cycle checkpoints: at the crossroads of carcinogenesis and drug discovery [J]. Drug Metab Rev, 2000, 32(3-4): 283-305
[99]. Gali-Muhtasib H, Bakkar N. Modulating cell cycle: current applications and prospects for future drug development [J]. Curr Cancer Drug Targets, 2002, 2(4): 309-36
[100]. Kohn KW, Shao RG, Pommier Y. How do drug-induced topoisomerase I-DNA lesions signal to the molecular interaction network that regulates cell cycle checkpoints, DNA replication, and DNA repair? [J] Cell Biochem Biophys, 2000,33(2): 175-80
[101]. Pommier Y, Yu Q and Kohn KW. Novel targets in the cell cycle and cell cycle checkpoints. In: Anticancer Drug Development, Edited by: Bagyley BC and Kerr DJ [J]. Academic Press, San Diego, 2002: 13-30
[2]Starke I,Donnelly P.Antimicrobial therapy in the immunocompromised patients a guide to retional therapy[M].London:Current Medical Literature,1992,1-89
[3]汪复.免疫功能低下者的感染与抗菌药物应用[J].中华医学杂志,1996,76(4):244
[4]Marcos MA,Alvarez-Martinez MJ,Niubo J,Pumarola T.Infections in immunosuppressed patients[J].Enferm Infecc Microbiol Clin.2008,26 Suppl 9:58-65.
[5]von Wagner M,Zeuzem S.Prevention and therapy of reactivation of hepatitis B in immunosuppressed patients[J].Dtsch Med Wochenschr.2009,134(6):255-8.
[6]Vento S,Cainelli F,Temesgen Z.Lung infections after cancer chemotherapy[J].Lancet Oncol.2008,9(10):982-92
[7]Connolly JE Jr,McAdams HP,Erasmus J J,Rosado-de-Christenson ML.Opportunistic fungal pneumonia[J].J Thorac Imaging.1999,14(1):51-62.
[8]Cebular S,Lee S,Tolaney P,Lutwick L.Community-acquired pneumonia in immunocompromised patients.Opportunistic infections to consider in differential diagnosis[J].Postgrad Med.2003,113(1):65-6,69-70,73-4 passim.
[9]Cohn J,Blumberg EA.Immunizations for renal transplant candidates and recipients [J].Nat Clin Pract Nephrol.2009,5(1):46-53.
[10]Johnson RW,Wasner G,Saddler P,Baron R.Herpes zoster and postherpetic neuralgia:optimizing management in the elderly patient[J].Drugs Aging.2008,25(12):991-1006.
[11]Hlava N,Niemann CU,Gropper MA,Melcher ML.Postoperative infectious complications of abdominal solid organ transplantation[J].J Intensive Care Med.2009,24(1):3-17
[12]Echavarria M.Adenoviruses in immunocompromised hosts[J].Clin Microbiol Rev. 2008, 21(4): 704-15.
[13]Littlewood KE. The immunocompromised adult patient and surgery [J]. Best Pract Res Clin Anaesthesiol. 2008, 22(3): 585-609.
[14] Sullivan RJ, Pantanowitz L, Casper C, Stebbing J, Dezube BJ. HIV/AIDS: epidemiology, pathophysiology, and treatment of Kaposi sarcoma-associated herpesvirus disease: Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman disease [J]. Clin Infect Dis. 2008, 1, 47(9): 1209-15.
[15]Mrsic M. The treatment of febrile immunosuppressed patient [J]. Reumatizam. 2007, 54(2): 63-6
[16]Patel RV, Weinberg JM. The patient with human immunodeficiency virus, Part 2: Review of treatment [J]. Cutis. 2008, 82(3): 202-10
[17]Solari R, Corti M, Cangelosi D, Escudero M, Negroni R, Saccheri C, Schtirbu R. Disseminated histoplasmosis with lesions restricted to the larynx in a patient with AIDS. Report of a case and review of the literature [J]. Rev Iberoam Micol. 2007, 24(2): 164-6.
[18] Li Yumin, Chen Hao, Li Xun, Zhou Wence, He Minyan, Chiriva-Internati M, Wachtel MS, Frezza EE. A new immunomodulatory therapy for severe sepsis: Ulinastatin Plus Thymosin {alpha} 1 [J]. J Intensive Care Med. 2009, 24(1): 47-53.
[19]Kellici S, Burazeri G. Thymosin alphal: a promising molecule for important clinical applications [J]. Med Arh. 2009, 63(1): 48-50.
[20]Zhang Peijun; Hu Rui; Chen Dekun. Effects of swine transfer factor on the quantity and phagocytic activities of canine peripheral blood neutrophil [J]. Chinese Journal of Preventive Veterinary Medicine, 2007, 29 (3): 208-211
[21]Pekmezci D, Cakiroglu D. Investigation of Immunmodulatory effects of levamisole and vitamin E on Immunity and some blood parameters in newborn Jersey calves [J]. Vet Res Commun. 2009, 23. [Epub ahead of print]
[22] Chen LY, Lin YL, Chiang BL. Levamisole enhances immune response by affecting the activation and maturation of human monocyte-derived dendritic cells [J]. Clin Exp Immunol. 2008, 151(1): 174-81
[23]Gao S, Liu C, Qu S, Song J, Li J, Zhang P, Wang Q, Guo C, Gao F, Zhang L. Non-cell Corynebacterium parvum generated by nanotechnology:a promising immunomodulator with less side effects[J].Int Immunopharmacol.2007,7(10):1334-42.
[24]Lue P,Li L,Lue S,Zhang L.Study on the effects of Corynebacterium parvum onsolid tumor and immue system in mice[J].Chinese Journal of Microecology,2007,19(6):529-530
[25]罗若荣,林旭凯,蔡文德,陈文玲,李盛鹏,柯跃斌.香菇多糖对大鼠免疫调节作用的研究[J].现代预防医学,2007,34(21):53-54
[26]宁安红,曹婧,黄敏,张伟.灵芝多糖对小鼠肿瘤的抑制作用及免疫指标的观察[J].肿瘤研究与临床,2004,16(3):31-33
[27]袁学千,王淑梅,高权国.刺五加多糖增强小鼠免疫功能的实验研究[J].中医药学报,2004,32(4):44-45
[28]王统一,赵兵,王玉春.多糖免疫调节和抗肿瘤研究进展[J].过程工程学报,2006,6f4):34-42
[29]Anderson JW,Smith BM,Washnock CS.Cardiovascular and renal benefits of dry bean and soybean intake[J].Am J Clin Nutr 1999;70:464-474.
[30]Messina MJ.Legumes and soybeans:overview of their nutritional profiles and health effects[J].Am J Clin Nutr 1999;70:439-450.
[31]Liu KS.Chemistry and nutritional value of soybean components[M].In Soybeans:Chemistry,Technology and Utilization.Aspen Publ.Inc.:Gaithersburg,Maryland,USA,1999,25-113.
[32]Xiao CW.Health effects of soy protein and isoflavones in humans[J].J Nutr.2008,138(6):1244S-9S
[33]Michelfelder AJ.Soy:a complete source of protein[J].Am Fam Physician.2009,79(1):43-7.
[34]Sakai T,Kogiso M,Soy isoflavones and immunity[J].J Med Invest.2008,55(3-4):167-73
[35]徐超斗,梁爱君,祝业,等.大豆低聚糖对免疫功能的促进作用[J].解放军药学学报,2005,21(1):37-39
[36]Kushi LH,Meyer KM,Jacobs DR.Cereals,legumes,and chronic disease risk reduction:evidence from epidemiologic studies[J].Am J Clin Nutr 1999,70:451-458
[37]邵传森,朱胜禾.临床疾病与免疫[M].北京,科学出版社,2002,80-90
[38]高晓明.医学免疫学基础[M].北京,北京大学医学出版社,2003,13-23
[39]龚非力.医学免疫学[M].北京,科学出版社,2003,113-116
[40]周光炎.免疫学原理[M].上海.上海科学技术出版社,2007,40-49.
[41]Rodriguez-Pinto D.B cells as antigen presenting cells[J].Cell Immunol.2005,238(2):67-75.
[42]Batista FD,Harwood NE.The who,how and where of antigen presentation to B cells[J].Nat Rev Immunol.2009,9(1):15-27.
[43]Khatib R,Rabah R,Sarnaik SA.The spleen in the sickling disorders:an update[J].Pediatr Radiol.2009,39(1):17-22.
[44]Ozturk E,Mutlu H,S(o|¨)nmez G,Sildiroglu HO.Primary angiosarcoma of the spleen.Turk J Gastroenterol[J].2007,18(4):272-5
[45]Cheng S,Evans WK,Stys-Norman D,Shepherd FA.Lung Cancer Disease Site Group of Cancer Care Ontario's Program in Evidence-based Care[J].Chemotherapy for relapsed small cell lung cancer:a systematic review and practice guideline.J Thorac Oncol.2007,2(4):348-54.
[46]Parking DM,Bary F,Ferlay J,et al.Global cancer statistics,2002[J].CA Cancer J Clin,2005,55:74-108.
[47]骆抗先.乙型肝炎基础和临床[M].北京:人民卫生出版社,2003:583.
[48]Dillon P.Lymphatic and venous disorders[A].In:Oldham KT,Colombani PM,Foglia RP,eds.Surgery of infants and children[M].Philadelphia:Lippincott-Raven,1997.1727-1736
[49]Llovet JM,Burroughs A,Bruix J.Hepatocellular carcinoma[J].Lancet.2003,362(9399):1907-17
[50]Park NH,Chung YH.Molecular mechanisms of hepatitis B virus-associated hepatocellular carcinoma[J].Korean J Hepatol,2007,13(3):320-40.
[51]Laurent-Puig P, Zucman-Rossi J. Genetics of hepatocellular tumors [J]. Oncogene. 2006, 25(27): 3778-86.
[52] Kudo M. Hepatocellular carcinoma 2009 and beyond: from the surveillance to molecular targeted therapy. Oncology [J]. 2008, 75 Suppl 1:1-12.
[53]Robinson P. Hepatocellular carcinoma: development and early detection [J]. Cancer Imaging. 2008, 8 Suppl A: S128-31.
[54]Debruyne EN, Delanghe JR. Diagnosing and monitoring hepatocellular carcinoma with alpha-fetoprotein: new aspects and applications [J]. Clin Chim Acta. 2008, 395(1-2): 19-26.
[55] Aljabiri MR, Lodato F, Burroughs AK. Surveillance and diagnosis for hepatocellular carcinoma [J]. Liver Transpl. 2007,13(11 Suppl 2): S2-12.
[56]Giannelli G, Antonaci S. New frontiers in biomarkers for hepatocellular carcinoma [J]. Dig Liver Dis. 2006, 38(11): 854-9.
[57] Zhou L, Liu J, Luo F. Serum tumor markers for detection of hepatocellular carcinoma [J]. World J Gastroenterol. 2006,12(8): 1175-81.
[58] Yuen MF, Lai CL. Serological markers of liver cancer [J]. Best Pract Res Clin Gastroenterol. 2005, 19(1): 91-9.
[59] Yao DF, Dong ZZ, Yao M. Specific molecular markers in hepatocellular carcinoma [J]. Hepatobiliary Pancreat Dis Int. 2007, 6(3): 241-7.
[60]Blum HE, Spangenberg HC. Hepatocellular carcinoma: an update [J]. Arch Iran Med. 2007,10(3): 361-71.
[61] Spangenberg HC, Thimme R, Blum HE. Advances in prevention and diagnosis of hepatocellular carcinoma. [J]. Expert Rev Gastroenterol Hepatol. 2008,2(3): 425-33.
[62] Wong CH, Chan SK, Chan HL, Tsui SK, Feitelson M. The molecular diagnosis of hepatitis B virus-associated hepatocellular carcinoma [J]. Crit Rev Clin Lab Sci. 2006,43(1): 69-101.
[63] Ju LX, Chen Z, Ren RZ. Progress in research on the treatment of primary liver cancer with traditional Chinese medicine for activating blood to resolve stasis [J]. Zhong Xi Yi Jie He Xue Bao. 2005, 3(6): 491-4.
[64] Mu XY, Zhao AG. Progress in research of traditional Chinese medicine in inducing differentiation of human hepatoma cells [J]. Zhong Xi Yi Jie He Xue Bao. 2007, 5(1): 92-6.
[65]Meng MB, Cui YL, Guan YS, Ying Z, Zheng MH, Yuan CK, Zhang RM. Traditional Chinese medicine plus transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma [J]. J Altern Complement Med. 2008, 14(8): 1027-42.
[66]Luk JM, Wang X, Liu P, Wong KF, Chan KL, Tong Y, Hui CK, Lau GK, Fan ST. Traditional Chinese herbal medicines for treatment of liver fibrosis and cancer: from laboratory discovery to clinical evaluation [J]. Liver Int. 2007, 27(7): 879-90.
[67] Jones RG, Thompson CB. Tumor suppressors and cell metabolism: a recipe for cancer growth [J]. Genes Dev. 2009, 23(5): 537-48.
[68] Jones E, Pu H, Kyprianou N. Targeting TGF-beta in prostate cancer: therapeutic possibilities during tumor progression [J]. Expert Opin Ther Targets. 2009, 13(2): 227-34.
[69] Fan D, Ma C, Zhang H. The molecular mechanisms that underlie the tumor suppressor function of LKB1 [J]. Acta Biochim Biophys Sin (Shanghai). 2009, 41(2): 97-107.
[70]Golubovskaya VM, Kweh FA, Cance WG. Focal adhesion kinase and cancer [J]. Histol Histopathol. 2009, 24(4): 503-10.
[71] Liu W, Zhou Y, Reske SN, Shen C. PTEN mutation: many birds with one stone in tumorigenesis [J]. Anticancer Res. 2008, 28(6A): 3613-9.
[72]Mizuno M, Yamada J, Terai H, et al. Differences in immunomodulating effects between wild and cultured Panax ginseng [J]. Biochem Biophys Res Commun. 1994, 200(3): 1672-1678
[73]Fong WF, Tse AK, Poon KH, et al. Magnolol and honokiol enhance HL-60 human leukemia cell differentiation induced by 1, 25-dihydroxyvitamin D3 and retinoic acid [J]. Int J Biochem Cell Biol. 2005, 37(2): 427-441
[74] Wadsworth TL, McDonald TL, Koop DR. Effects of Ginkgo biloba extract (EGb 761) and quercetin on lipopolysaccharide-induced signaling pathways involved in the release of tumor necrosis factor [J]. Biochem Pharmacol. 2001, 62(7): 963-974
[75]林科,张太平,朱顺,等.山楂熊果酸的制备及对小鼠免疫功能和肝癌细胞凋亡的影响[J].中国生化药物杂志,2007,28(5):308-311.
[76]Aiken C,Chen CH.Betulinic acid derivatives as HIV-1 antivirals[J].Trends Mol Med.2005,11(1):31-36
[77]Watanabe S,Uesugi S,Kikuchi Y.Isoflavones for prevention of cancer,cardiovascular diseases,gynecological problems and possible immune potentiation [J].Biomed Pharmacother.2002,56(6):302-312.
[78]Lee JN,Lee DY,Ji IH,et al.Purification of Soluble β-Glucan with Immune-enhancing Activity from the Cell Wall of Yeast[J].Bioscience,Biotechnology,and Biochemistry.2001,65(4):837-841.
[79]Guo Y M,Ali R A,Qureshi M A.The influence ofβ-glucan on immune response in broiler chicks[J].Immunopharmaeology and Immunotoxicology,2003,25(3):461-472.
[80]Hanif R,Qiao L,Shift S J,et al.Curcumin,a natural plant phenolic food additive,inhibits cell proliferation and induces cell cycle changes in colon adenocarcinoma cell lines by a prostaglandin-independent pathway[J].J Lab Clin Med,1997,130:576-584.
[81]Batth BK,Tripathi R,Srinivas UK.Curcumin-induced differentiation of mouse embryonal carcinoma PCC4 cells[J].Differentiation,2001,68:133-140.
[82]Alberts,B Bray,D Lewis,et al.Molecular Biology of the Cell[M].New York:Garland Publishing Inc,1994.
[83]Gerald Karp.Cell and Molecular Biology:concepts and ecperiments[M].New York:John Wiley & Sons,Inc,1999.
[84]Evan G I,Vousden K H.Proliferation,cell cycle and apoptosis in cancer[J].Nature,2001,411(6835):342-348.
[85]Nurse P.A long twentieth century of the cell cycle and beyond[J].Cell,2000,100(1):71-78
[86]Sherr CJ.Cancer cell cycle[J].Science,1996,274:1672-1677
[87]Pines J.Cyclins and cyclin-dependent kinases:a biochemical view[J].Biochem J,1995,308:697-711.
[88] Clarke B, Chetty R, Cell cycle aberrations in the pathygenesis of squamous cell carcinoma of the uterine cervix [J]. Gynecol Oncol, 2001, 82: 238-246.
[89] Milde-Langosch K, Riethdorf S. Role of cell-cycle regulatory proteins in gynecological cancer [J]. Cell physiol, 2003, 196: 224-244.
[90]Funk JO. Cancer cell cycle control [J]. Anticancer Res, 1999, 19: 4772-4780.
[91]Lew DJ, Reed S I. A proliferation of cyclins [J]. Trends in Cell Biology, 1992, 2: 77-81.
[92] Serrano M, Harmon GJ, Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4 [J]. Nature, 1993, 366: 704-707.
[93]Polyak K, Lee MH, Erdjument-Bromage h, koff A, Roberts JM, Tempst P, Massague J. Cloning of p27~(kip1), a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals [J]. Cell, 1994, 78: 59-66.
[94]Xiong Y, Harmon GJ, Zhang H, Casso D, Kobayashi R, Beach D. p21 is a universal inhibitor of cyclin kinases [J]. Nature, 1993, 366: 701-704.
[95]Hutchison C J, Glover D D. Cell Cycle Control [M]. Oxford: IRL Oxford University Press, 1995.
[96]Kastan M B. Check Point Controls and Cancer [M]. New York: Cold Spring Harbor Laboratory Press, 1997.
[97] Zhou BB, Elledge SJ. The DNA damage response: putting checkpoints in perspective [J]. Nature, 2000, 408(23): 433-439.
[98]Norbury CJ, Zhivotovsky B. DNA damage-induced apoptosis [J]. Oncogene, 2004, 23: 2797-2808.
[99]Sherr CJ. Mammalian G1 cyclins [J]. Cell, 1993, 73: 1059-1065.
[100] Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression [J]. Genes Dev, 1999, 13: 1501-1512.
[101] Mittnacht S. Control of pRB phosphorylation [J]. Curr Opin Genet Dev. 1998, 8(1): 21-7.
[102] Seville LL, Shah N, Westwell AD, Chan WC. Modulation of pRB/E2F functions in the regulation of cell cycle and in cancer [J]. Curr Cancer Drug Targets. 2005, 5(3): 159-70.
[103]Sherr C J,Roberts JM.Inhibitors of mammalian G1 cyclin-dependent kinases[J].Genes Dev,1995,9:1149-1163.
[104]Roberta W.C.Pang,Jae Won Joh,Philip J.Johnson,Morito Monden,Timothy M.Pawlik,Ronnie T.P.Poon,Biology of Hepatocellular Carcinoma[J],Annals of Surgical Oncology,2008,14(4):962-971
[105]Kobayashi H,Fukuda Y,Yoshida R,Kanada Y,Nishiyama S,Suzuki M,Kanayama N,Terao T,Suppressing effects of dietary supplementation of soybean trypsin inhibitor on spontaneous,experimental and peritoneal disseminated metastasis in mouse model[J].Int J Cancer.2004,112(3):519-24.
[106]Hayakawa K,Mizutani J,Wada K,Masai T,Yoshihara I,Mitsuoka T.Effects of soybean oligosaccharides on human faecal flora[J].MICROB ECOL HEALTH DIS.1990,6(3):293-303
[107]Steiner C,Amould S,Scalbert A,et al.Isoflavones and the prevention of breast and prostate cancer:new perspectives opened by nutrigenomics[J].Br J Nutr.2008,99:ES78-108
[108]Watanabe S,Uesugi S,Kikuchi Y.Isoflavones for prevention of cancer,cardiovascular diseases,gynecological problems and possible immune potentiation [J].Biomed Pharmacother.2002,56(6):302-312.
[109]Lakshman M,Xu L,Ananthanarayanan V,et al.Dietary genistein inhibits metastasis of human prostate cancer in mice[J].Cancer Res.2008,68(6):2024-32.
[110]Park JH,Oh EJ,Choi YH,Kang CD,Kang HS,Kim DK,Kang KI,Yoo MA.Synergistic effects of dexamethasone and genistein on the expression of Cdk inhibitor p21WAF1/CIP1 in human hepatocellular and colorectal carcinoma cells[J].Int J Oncol.2001,18(5):997-1002
[111]张绪霞,陈卫梅,董海洲.大豆膳食纤维的营养功能特性及开发前景[J].中国食物与营养.2007,13(2):49-51
[112]Liu ES,Luk SC,Leung ET,Lee WH,Yuen WF,Kwok KM,Siu SW,Kwok NS,Xing HT,Wu M,Pang SF.Effect of CKBM on prostate cancer cell growth in vitro and in vivo[J].J Chemother.2008,20(2):246-252
[113]Chan A.S.,E.C.Yip,L.Y.Yung,H.Pang,S.C.Luk,S.F.Pang,Y.H.Wong.CKBM stimulates MAPKs but inhibits LPS-induced IFN-gamma in lymphocytes[J].Phytother Res.2006,20(9):725-731
[114]Zhang W,E.S.Liu,J.Fu,H.M.Tian,Y.J.Wu,S.F.Pang.Suppression of primary breast,colon,gastric and bladder cancers cell growth in vitro by CKBM,a natural product.Invest New Drugs[J].Invest New Drugs.2006,24(3):181-187
[115]Chan A.S.,E.C.Yip,L.Y.Yung,H.Pang,S.C.Luk,S.F.Pang,Y.H.Wong.Immuno-regulatory effects of CKBM on the activities of mitogen-activated protein kinases and the release of cytokines in THP-1 monocytic cells[J].Biol Pharm Bull.2005,28(9):1645-1650
[116]刘鲁明,杨宇飞.肝癌中西医综合治疗[M].北京:人民卫生出版社,2002,5
[117]于尔辛.中医治疗肝癌的科学基础[A].见:汤钊猷,杨秉辉主编.原发性肝癌的研究与进展[M].上海:上海医科大学出版社,1990,302.
[118]Luk S.C.,S.W.Siu,C.K.Lai,Y.J.Wu,S.F.Pang.Cell Cycle Arrest by a Natural Product via G2/M Checkpoint[J].Int J Med Sci.2005,2(2):64-69
[119]Chan,B.P.,W.F.Yuen,W.H.Lee,S.N.Wong,T.Y.Chung,Y.J.Wu,S.E Pang Immunomodulating effects of CKBM on the cytokine production in peripheral blood mononuclear cells(PBMCs) from healthy volunteers[J].Immunopharmacol Immunotoxicol.2004a,26(2):177-92
[120]Chan,J.Y.,J.Y.Cheung,S.C.Luk,Y.J.Wu,S.F.Pang,K.R Fung Anti-cancer and pro-apoptotic effects of an herbal medicine and Saccharomyces cerevisiae product(CKBM) on human hepatocellular carcinoma HepG2 cells in vitro and in vivo[J].Immunopharmacol Immunotoxicol.2004b,26:597-609
[121]Shin V.Y.,W.H.Leung So,E.S.Liu,Y.J.Wu,S.F.Pang C.H.Cho.Anti-tumorigenic and Pro-apoptotic effects of CKBM on gastric cancer growth in nude mice[J].Int J Med Sci.2004,1:137-145
[122]Field KM,Dow C,Michael M.Liver function in oncology:biochemistry and beyond[J].Lancet Oncol.2008,9(11):1092-101.
[123]Evdokimova VN,Butterfield LH.Alpha-fetoprotein and other tumour-associated antigens for immunotherapy of hepatocellular cancer[J].Expert Opin Biol Ther.2008,8(3):325-36.
[124]Schacherer D,Schoelmerich J,Zuber-Jerger I.The diagnostic approach to hepatocellular carcinoma[J].Z Gastroenterol.2007,45(10):1067-74.
[125]Pang RW,Joh JW,Johnson PJ,Monden M,Pawlik TM,Poon RT.Biology of hepatocellular carcinoma[J].Ann Surg Oncol.2008,15(4):962-71.
[126]Spangenberg HC,Thimme R,Blum HE.Serum markers of hepatocellular carcinoma[J].Semin Liver Dis.2006,26(4):385-90.
[127]Taketa K.α-fetoprotein:Reevaluation in hepatology[J].Hepatology,1990,12(6):1420-1432.
[128]王红阳,付静.肝癌研究现状与进展[J].中华肝脏病杂志2007,15(8):561-562
[129]汤钊猷.现代肿瘤学[M].上海:复旦大学出版社,2003,745-746
[130]刘鲁明,杨宇飞.肝癌中西医综合治疗[M].北京:人民卫生出版社,2002,241
[131]Sherr CJ.Cancer cell cycles[J].Science,1996,274:1672-7.
[132]Ward TH,Cummings J,Dean E,Greystoke A,Hou JM,Backen A,Ranson M,Dive C.Biomarkers of apoptosis[J].Br J Cancer.2008,16,99(6):841-6.
[133]Malumbres M,Barbacid M.Cell cycle,CDKs and cancer:a changing paradigm [J].Nat Rev Cancer.2009,9(3):153-66.
[134]Vermeulen K,Bememan ZN,Van Bockstaele DR.Cell cycle and apoptosis[J].Cell Prolif.2003,36(3):165-75.
[135]Bartkova J,Rajpert-De Meyts E,Skakkebaek NE,Lukas J,Bartek J.Deregulation of the G1/S-phase control in human testicular germ cell tumours[J].APMIS.2003,111(1):252-65,discussion 265-6.
[136]Abukhdeir AM,Park BH.P21 and p27:roles in carcinogenesis and drug resistance[J].Expert Rev Mol Med.2008,1,10:e19
[137]Ortega S,Malumbres M,Barbacid M.Cyclin D-dependent kinases,INK4inhibitors and cancer[J].Biochim Biophys Acta.2002,14,1602(1):73-87.
[138]Gerland LM,Ffrench M,Magaud JP.Cyclin dependent kinase inhibitors and replicative senescence[J].Pathol Biol(Paris).2001,49(10):830-9.
[139] Viallard JF, Lacombe F, Belloc F, Pellegrin JL, Reiffers J. Molecular mechanisms controlling the cell cycle: fundamental aspects and implications for oncology [J]. Cancer Radiother. 2001, 5(2): 109-29.
[140] Pines J. The cell cycle kinases [J]. Semin Cancer Biol, 1994, 5: 305-313.
[141] Garner E, Raj K. Protective mechanisms of p53-p21-pRb proteins against DNA damage-induced cell death [J]. Cell Cycle. 2008, 7(3): 277-82
[142] Spugnini EP, Campioni M, D'Avino A, Caruso G, Citro G, Baldi A. Cell-cycle molecules in mesothelioma: an overview [J]. J Exp Clin Cancer Res. 2007, 26(4): 443-9.
[143] Pines J. Cyclins: wheels within wheels [J]. Cell Growth Differ, 1991, 2: 305-310
[144] Melk A. Senescence of renal cells: molecular basis and clinical implications [J]. Nephrol Dial Transplant, 2003, 18: 2474-2478.
[1].Lovet JM,Bruix J.Novel advancements in themanagement of hepatocellular carcinoma in 2008[J].J Hepatol 2008,48 Suppl 1:S20-S37
[2].骆抗先.乙型肝炎基础和临床[M].北京:人民卫生出版社,2003:583.
[3].Jones RG,Thompson CB.Tumor suppressors and cell metabolism:a recipe for cancer growth[J].Genes Dev.2009,23(5):537-48.
[4].Pines J.Cyclins and cyclin-dependent kinases:a biochemical view[J].Biochem J,1995,308:697-711.
[5].Clarke B,Chetty R,Cell cycle aberrations in the pathygenesis of squamous cell carcinoma of the uterine cervix[J].Gynecol Oncol,2001,82:238-246.
[6].Milde-Langosch K,Riethdorf S.Role of cell-cycle regulatory proteins in gynecological cancer[J].Cell physiol,2003,196:224-244.
[7].Funk JO.Cancer cell cycle control[J].Anticancer Res,1999,19:4772-4780.
[8].Pines J.The cell cycle kinases[J].Semin Cancer Biol,1994,5:305-313.
[9].Mittnacht S.Control of pRB phosphorylation[J].Curr Opin Genet Dev.1998,8(1):21-7.
[10].Seville LL,Shah N,Westwell AD,Chan WC.Modulation of pRB/E2F functions in the regulation of cell cycle and in cancer[J].Curt Cancer Drug Targets.2005,5(3):159-70.
[11].Fei P,E1-Deiry WS.P53 and radiation responses[J].Oncogene,2003,1,22(37):5774-83
[12].Zhou BB,Elledge SJ.The DNA damage response:putting checkpoints in perspective[J].Nature,2000,408(23):433-439.
[13].Norbury CJ,Zhivotovsky B.DNA damage-induced apoptosis[J].Oncogene,2004,23:2797-2808.
[14].Sherr CJ.Mammalian G1 cyclins[J].Cell,1993,73:1059-1065.
[15]. Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression [J]. Genes Dev, 1999, 13: 1501-1512.
[16]. Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm [J]. Nat Rev Cancer. 2009 Mar, 9(3): 153-66.
[17]. Laiho M, Latonen L. Cell cycle control, DNA damage checkpoints and cancer [J]. Ann Med, 2003, 35(6): 391-397.
[18]. Hutchison C J, Glover D D. Cell Cycle Control [M]. Oxford: IRL Oxford University Press, 1995.
[19]. Lew DJ, Reed S I.A proliferation of cyclins [J]. Trends in Cell Biology, 1992, 2: 77-81.
[20]. Serrano M, Harmon GJ, Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4 [J]. Nature, 1993, 366: 704-707.
[21]. Polyak K, Lee MH, Erdjument-Bromage h, koff A, Roberts JM, Tempst P, Massague J. Cloning of p27~(kip1), a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals [J]. Cell, 1994, 78: 59-66.
[22]. Xiong Y, Harmon GJ, Zhang H, Casso D, Kobayashi R, Beach D. p21 is a universal inhibitor of cyclin kinases [J]. Nature, 1993, 366: 701-704.
[23]. Samuel T, Weber HO, Funk JO. Linking DNA damage to cell cycle checkpoints [J]. Cell Cycle, 2002, 1(3): 162-168.
[24]. Latif C, Harvey SH, O'Connell J. Ensuring the Stability of the Genome: DNA Damage Checkpoints [J]. Scientific World Journal, 2001, 1(11): 684-702.
[25]. Iliakis G, Wang Y, Guan J, Wang H. DNA damage checkpoint control in cells exposed to ionizing radiation [J]. Oncogene, 2003, 22(37): 5834-5847.
[26]. Bartek J, Lukas J. Chk 1 and Chk 2 kinases in checkpoint control and cancer [J]. Cancer Cell, 2003, 3(5): 421-429.
[27]. McGowan CH. Checking in on Cds1 (Chk2): A checkpoint kinase and tumor suppressor [J]. Bioessays, 2002, 24(6): 502-511.
[28]. Melo J, Toczyski D. A unified view of the DNA-damage checkpoint [J]. Curr Opin Cell Biol, 2002, 14(2): 237-245.
[29].Abraham RT.Cell cycle checkpoint signaling through the ATM and ATR kinases [J].Genes Develop,2001,15:2177-2196.
[30].Donjerkovic D,Scott DW.Regulation of the G1 phase of the mammalian cell cycle[J].Cell Res,2000,10(1):1-16.
[31].Bartek J,Lukas J.Mammalian G 1-and S-phase checkpoints in response to DNA damage[J].Curr Opin Cell Biol,2001,13(6):738-747.
[32].Funk JO,Kino P.Cell cycle control[J].Genetic instability and cancer.Hautarzt,2002,48:157-159.
[33].韦伟,龚建平,裘法祖.细胞周期调控与肿瘤的发生发展[J].癌症,2004,18:95-97.
[34].Bartek J,Lukas J.Pathways goveming G1/S transition and their response to DNA damage[J].FEB S Left,2001,490(3):117-122.
[35].Smits VA,Medema RH.Checking out the G(2)/M transition[J].Biochim Biophys Acta,2001,1519(1-2):1-12.
[36].Taylor WR,Stark GR.Regulation of the G2/M transition by p53[J].Oncogene,2001,5,20(15):1803-1815.
[37].Bartek J,Falck J,Lukas J.CHK2 kinase-a busy messenger[J].Nat Rev Mol Cell Biol,2001,2(12):877-886.
[38].Bartek J,Lukas J.Chkl and Chk2 kinases in checkpoint control and cancer[J].Cancer Cell,2003,3(5):421-429.
[39].江国春.细胞周期蛋白D[J].国外医学·遗传学分册,1998,21:173一177
[40].王辉云,严瑞琪,龙江斌,吴秋良.肝癌中cyclin D1扩增与HBV感染及病理学的关系[J].世界华人消化杂志,1999,7:98-100
[41].孙宝华,武忠弼,阮幼冰,杨木兰.肝细胞癌mdm2基因表达及其与p53基因突变的关系[J].世界华人消化杂志,1999,7:291-294
[42].Iolascon A,Giordani L,Moretti A,Basso G,Borriello A,Della Ragione F.Analysis of CDKN2A,CDKN2B,CDKN2C,and cyclin D's gene status in hepatoblastoma[J].Hepatology,1998,27:989-995.
[43].Mnoeo V,del Valle Guijarro M,Link W,et al.Overexpression of Cyclin D1 inhibits TNF-induced growth arrest[J].J Cell Biochem,2003,89(3):484-449.
[44].Yu Q,Geng Y,Sicinski P.Specific protection against breast cancers by Cyclin D1 ABLation[J].Nature,2001,411:1017-1021
[45].朱斌,姚晓平,杨甲梅,丛文铭.原发性肝细胞癌中细胞周期G1期相关基因Cyclin D1的表达及其临床病理学意义[J].肝胆外科杂志,1999,7:214.216
[46].O' connor PM,Ferris DK,White GA,Pines J,Hunter T,Longo DL.Relationships between cdc2 kinase,DNA cross-linking and cell cycle perturbations induced by nitrogen mustard[J].Cell Growth Diff,1992,3:43-52
[47].Wang J,Zindy F,Chenivesse.Modification of cyclinA expression by hepatocellular carcinoma[J].Oncogene,1992,7:1653-1656
[48].Ito Y,Takeda T,Sakon M et al.Expression and prognostic role of cyclin-dependent kinase 1(cdc2) in hepatocellular carcinoma[J].Oncology,2000,59(1):68-74
[49].HX Xia,PhD,MD,Series Editor.Molecular mechanism underlying the functional loss of cyclindependent kinase inhibitors p16 and p27 in hepatocellular carcinomaHarry.World J Gastroenterol 2008 March 21,14(11):1734-1740
[50].Hui AM,Sakamoto M,Kanai Y,Ino Y,Gotoh M,Yokota J,Hirohashi S.Inactivation of p16~(INK4) in hepatocellular carcinoma[J].Hepatology,1996,24:575-579
[51].Juliette M,Jean-Francois D.Tumor suppressor and hepatocellular carcinoma[J].World J Gastroenterol 2008,14(11 ):1720-1733
[52].He H,Baldwin GS.Rho GTPases and p21-activated kinase in the regulation of proliferation and apoptosis by gastrins[J].Int J Biochem Cell Biol.2008,40(10):2018-22.
[53].Ching YP,Leong VY,Lee MF,Xu HT,Jin DY,Ng IO.P21-activated protein kinase is overexpressed in hepatocellular carcinoma and enhances cancer metastasis involving c-Jun NH2-terminal kinase activation and paxillin phosphorylation[J].Cancer Res.2007,67(8):3601-8.
[54].Hui AM,Kanai Y,Sakamoto M,Tsuda H,Hirohashi S.Reduced p21(WAF1/CIP1) expression and p53 mutation in hepatocellular carcinomas[J]. Hepatology,2002,25:575-579
[55].Sun BH,Zhang J,Wang B J,Zhao XP,Wang YK,Yu ZQ,Yang DL,Hao LJ.Analysis of in vivo patterns of caspase 3 gene expression in primary hepatocellular carcinoma and its relationship to P21~(WAF1) expression and hepatic apoptosis[J].World J Gastroenterol,2002,6:356-360
[56].叶晟,冯懿正,刘友富,袁政洪.P53,P21,nm23和PCNA在原发性肝癌中的表达与预后的关系[J].世界华人消化杂志,2004,7:160
[57].Qin LF,Ng IO,Fan ST,Ng M.P21/WAF1,P53 and PCNA expression and P53mutation status in hepatocellular carcinoma[J].Int J Cancer,2003,79:424-428
[58].Polyak K,Lee MH,Erdjument-Bromage H,Koff A,Roberts JM,Tempst P,Massague J.Cloning of p27~(kip1),a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals[J].Cell,2000,78:59-66
[59].Kawamata N,Morosetti R,Miller CW,Park D,Spirin KS,Nakamaki T,Takeuchi S,Hatta Y,Simpson J,Wilczynski S,Lee YY,Bartram CR,Koeffier HE Molecular analysis of the cyclin-dependent kinase inhibitor gene P27~(kip1) in human malignancies[J].Cancer Res,2000,55:2266-2269
[60].Ponce-Casta eda MV,Lee MH,Latres E,Polyak K,Lacombe L,Montgomery K,Mathew S,Krauter K,Sheinfeld J,Massague J,Cordon-Cardo C.P27~(kip1):chromosomal mapping to 12p 12-12p 13.1 and absence of mutations in human tumors [J].Cancer Res,2000,55:1211-1214
[61].Nourse J,Firpo E,Flanagan WM,Coats S,Polyak K,Lee MH,Massague J,Crabtree GR,Roberts JM.Interleukin-2-mediated elimination of the p27~(kip1)cyclin-dependent kinase inhibitor prevented by rapamycin[J].Nature,2000,372:570-573
[62].Mal A,Poon RYC,Howe PH,Toyoshima H,Hunter T,Harter ML.Inactivation of P27~(kip1) by the viral EIA oncoprotein in TGFβ-treated cells[J].Nature,2001,380:262-265
[63].Tannapfel A,Grund D,Katalinic A,Uhlmann D,Kockerling F,Haugwitz U,Wasner M,Hauss J,Engeland K,Wittekind C.Decreased expression of p27 protein is associated with advanced tumor stage in hepatocellular carcinoma[J].Int J Cancer,2002,89:350-355
[64]. Ito Y, Matsuura N, Sakon M, Miyoshi E, Noda K, Takeda T, Umeshita K, Nagano H, Nakamori S, Dono K, Tsujimoto M, Nakahara M, Nakao K, Taniguchi N, Monden M. Expression and prognostic roles of the G1-S modulators in hepatocellular carcinoma: p27 independently predicts the recurrence [J]. Hepatology, 2004, 30: 90-99
[65]. Millard SS, Yan JS, Nguyen H, Pagano M, Kiyokawa H, Koff A. Enhanced ribosomal association of p27~(kip1) mRNA is a mechanism contributing to accumulation during growth arrest [J]. J Biol Chem, 2002, 272: 7093-7098
[66]. Cheng J, Williag ham T, Shuford M. Tumor suppression and inhibition of aneuploid cell accumaulation in human brain tumor cells by eltopic overexpression of cyclin-dependent kinase inhibitor p27~(kip1) [J]. J Clin Invest, 2001, 97: 1983-1988
[67]． 王华,王靖华．p27~(kip1)与肿瘤[J]．中华病理学杂志,2004,28：140-142
[68]. Loda M, Gukor B, Tarn SW. Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas [J]. Nat Med, 2002, 3:231-234
[69]. Yasui W, Kudo Y, Semba S. Reduced expression of cyclin-dependent kinase inhibitor p27~(kip1) is associated with advanced stage and invasiveness of gastric carcinomas [J]. Jpn J Cancer Res, 2002, 88: 625-629
[70]. Hui AM, Sun L, Kanai Y, Sakamoto M, Hirohashi S. Reduced p27~(kip1) expression in hepatocellular carcinomas [J]. Cancer Lett, 2003, 132: 67-73
[71]. Esposito V, Baldi A, DeLuca A. Prognostic role of the cyclin dependent kinase inhibitor p27 in non-small cell lung cancer. Cancer Res, 2002, 57: 3381-3387
[72]. Ravitz MJ, Wenner CE. Cyclin-dependent kinase regulation during G1 phase and cell cycle regulation by TGF-beta [J]. Adv Cancer Res, 2002, 71: 165-170
[73]. Greenblatt MS, Bennett WP, Hollstein M, Harris CC. Mutations in the P53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis [J]. Cancer Res, 2000, 54: 4855-4878
[74]. Teramoto T, Satonaka K, Kitazawa S, Fujimori T, Hayashi K, Maeda S. P53 gene abnormalities are closely related to hepatoviral infections and occur at a late stage of hepatocarcinogenesis [J]. Cancer Res, 2000, 54: 231-235
[75].Fujimoto Y,Hampton LL,Wirth PJ,Wang N J,Xie JP,Thorgeirsson SS.Alterations of tumor suppressor genes and allelic losses in human hepatocellular carcinomas in China[J].Cancer Res,2000,54:281-285
[76].Ueda H,Ullrich S J,Gangemi JD,Kappel CA,Ngo L.Functional inactivation but not structural mutation of p53 causes liver cancer[J].Nat Genet,2000,9:41-47
[77].孟照华,何振平.肝癌抑制基因治疗的研究现状[J].世界华人消化杂志,2004.7:350-352
[78].Martins C,Kedda MA,Kew MC.Characterization of six tumor suppressor genes and microsatellite instability in hepatocellular carcinoma in southern African blacks[J].World J Gastroenterol,2004,5:470-476
[79].郑建勇,李开宗,窦科峰,李江.肝细胞癌p53及nm23-H1 mRNA表达的意义[J].世界华人消化杂志,2004,7:40-42
[80].肖文华,刘为纹,吕有勇,高崇峰.肝细胞癌Rb基因缺失的研究[J].肿瘤防治研究,2002,24:210-211
[81].Lane DP.p53,guardian of the genome[J].Nature,1992,358:15-16
[82].Gao Y,Lin LP,Zhu CH,Chen Y,Hou YT,Ding J.Growth arrest induced by C75,A fatty acid synthase inhibitor,was partially modulated by p38 MAPK but not by p53 in human hepatocellular carcinoma[J].Cancer Biol Yher.2006,5(8):978-85
[83].张松平,戴益民,王能进.p53蛋白产物在肝细胞癌及其癌周组织中的表达[J].中华病理学杂志,1995,24:51-53
[84].Grana X,Reddy EE Cell cycle control in mammalian cell.Role of cyclins,cyclin dependent kinase,growth suppressor gene and cyclin dependent kidnase inhibitors[J].Oncogene,2000,11:2 01-217
[85].Terada T,Rakanuma Y.Expression of apoptosis,proliferating cell nuclear antigen,and apoptosis-related antigen(bcl-2,c-myc,Fas,lewisy,and p53) in human cholangiocarcinomas and hepatocellular carcinomas[J].Pathol Int,2001,46:764-770
[86].Fan G,Ma X,Kren BT.The retioblastoma gene product inhibits TGF-beta induced apoptosis in primary rat hepatocytes and human HUH-7 hepatoma cells[J].Oncogene,2001,12:1909-1919
[87].Kuroki T,Fujiwara Y,Nakamori S.Evidence for the presence of two tumor-suppressor genes for hepatocellular carcinoma on chromosome[J].Br J Cancer,2000,72:383-386
[88].Marakmi Y,Hoyashi K,Hironashi S.A beration of tumor suppressor p53 and retinoblastoma genes in human hepatocellular carcinomas[J].Cancer Res,1991,51:5520
[89].Pang R,Tse E,Poon RT.Molecular pathways in hepatocellular carcinoma[J].Cancer Lett.2006,240(2):157-69
[90].Hamilton SR.Targeted therapy of cancer:new rolesfor pathologists in colorectal cancer[J].Mod Pathol,2008,21 Suppl 2:S23-S30
[91].Daveau M,Scotte M,Francois A,Coulouarn C,Ros G,Tallet Y,Hiron M,Hellot MF,Salier JP.Hepatocyte growth factor,transforming growth factor alpha,and their receptors as combined markers of prognosis in hepatocellular carcinoma[J].Mol Carcinog 2003,36:130-141
[92].Scharf JG,Braulke T.The role of the IGF axis in hepatocarcinogenesis[J].Horm Metab Res 2003,35:685-693
[93].Breuhahn K,Schirmacher P.Reactivation of the insulin-like growth factor-Ⅱsignaling pathway in human hepatocellular carcinoma[J].World J Gastroenterol 2008,14:1690-1698
[94].Buolamwini JK.Cell cycle molecular targets in novel anticancer drug discovery [J].Curr Pharm Des,2000,6(4):379-92
[95].马凌娣,张彦,文世宏,何於娟,刘小珊,康格非.蒋纪恺苦参碱对荷瘤小鼠抑瘤作用的实验研究[J].Chin J Oncol,2005,27(6):339-341.
[96].李立新,叶胜龙,王艳红,孙瑞霞,薛琼,陈洁,高东梅汤钊猷.槐耳浸膏诱导肝癌细胞凋亡的实验研究[J].Clinical Medical Journal of China,2005.12(6):1152-1153.
[97].Park JH,Oh E J,Choi YH,Kang CD,Kang HS,Kim DK,Kang KI,Yoo MA.Synergistic effects of dexamethasone and genistein on the expression of Cdk inhibitor p21WAF 1/CIP 1 in human hepatocellular and colorectal carcinoma cells[J].Int J Oncol.2001,18(5):997-1002
[98]. Flatt PM, Pietenpol JA. Mechanisms of cell-cycle checkpoints: at the crossroads of carcinogenesis and drug discovery [J]. Drug Metab Rev, 2000, 32(3-4): 283-305
[99]. Gali-Muhtasib H, Bakkar N. Modulating cell cycle: current applications and prospects for future drug development [J]. Curr Cancer Drug Targets, 2002, 2(4): 309-36
[100]. Kohn KW, Shao RG, Pommier Y. How do drug-induced topoisomerase I-DNA lesions signal to the molecular interaction network that regulates cell cycle checkpoints, DNA replication, and DNA repair? [J] Cell Biochem Biophys, 2000,33(2): 175-80
[101]. Pommier Y, Yu Q and Kohn KW. Novel targets in the cell cycle and cell cycle checkpoints. In: Anticancer Drug Development, Edited by: Bagyley BC and Kerr DJ [J]. Academic Press, San Diego, 2002: 13-30