摘要
研究背景
甲状旁腺作为人体重要的内分泌腺体,其分泌的甲状旁腺激素(PTH)是人体内调节血钙水平的最重要激素。甲状旁腺肿瘤多数有典型的原发性甲状旁腺机能亢进症状,临床表现复杂,如表现为骨关节病变,泌尿系结石,或表现胃肠道症状,如恶心、反酸、食欲不振、消瘦等。本病临床较少见,且早期常缺乏典型的临床表现,往往造成误诊,延误治疗,造成严重后果,因此,早期诊断和早期治疗对甲状旁腺肿瘤有着重要意义。随着各种肿瘤分子致病机理研究的深入,甲状旁腺肿瘤的研究也有所进展。转化生长因子β1(Transfoming growth factor-β1,TGF-β1)是内源性细胞生长抑制因子,与肿瘤的关系较为复杂。TGF-β1能抑制早期肿瘤的发生,对中晚期肿瘤的发展、转移却又起促进作用。细胞周期蛋白D1(CyclinD1)是G1期细胞增殖信号的关键蛋白,是细胞周期的启动因子,其过表达可促进细胞从G1—S期的转化,从而使细胞过快生长,从而造成细胞恶性增殖。细胞周期蛋白与肿瘤的发生发展乃至预后都有密切的关系。为了进一步研究TGF-β1和CyclinD1在甲状旁腺肿瘤中的作用及相互关系,本实验拟用免疫组化的方法研究TGF-β1和CyclinD1在正常甲状旁腺组织、甲状旁腺腺瘤组织、甲状旁腺癌组织中的表达以及二者的关系。TGF-β1与CyclinD1的研究有助于我们了解甲状旁腺肿瘤的发生发展机制,为甲状旁腺肿瘤的临床诊断、治疗提供重要的理论依据。
目的
研究TGF-β1和CyclinD1在正常甲状旁腺组织、甲状旁腺腺瘤组织、甲状旁腺癌组织中的表达以及二者的关系；根据TGF-β1和CyclinD1在上述组织中表达及与病理类型的关系,研究二者在甲状旁腺肿瘤的发生过程中的作用。
方法
收集郑州大学第一附属医院甲状腺外科1997～2009年外科手术切除并经病理科医生诊断明确的甲状旁腺肿瘤组织标本共49例,其中甲状旁腺腺瘤组织43例,甲状旁腺癌组织6例,此外还包括10例正常甲状旁腺组织。通过SP免疫组化法检测了TGF-β1和CyclinD1的表达,并进行分组比较和统计学分析。
结果
10例正常组织中4例TGF-β1阳性,43例腺瘤组织中21例阳性,6例癌组织中4例阳性。10例正常组织中1例CyclinD1阳性,43例腺瘤组织中24例阳性,6例癌组织中5例阳性。TGF-β1蛋白的表达,甲状旁腺癌组织中TGF-β1阳性表达率高于甲状旁腺腺瘤组,甲状旁腺腺瘤组TGF-β1阳性表达率高于甲状旁腺正常组织,正常组、腺瘤组、癌组比较差异无统计学意义(P>0.05)；甲状旁腺癌组织中CyclinD1阳性表达率高于甲状旁腺腺瘤组,但差异无统计学意义(P>0.05)；甲状旁腺腺瘤组CyclinD1阳性表达率及甲状旁腺癌组织阳性表达率均高于甲状旁腺正常组织,差异有统计学意义(P<0.05),TGF-β1和CyclinD1在甲状旁腺腺瘤中的表达存在相关性(P<0.05)。
结论
CyclinD1的过度表达在甲状旁腺肿瘤发生中起重要作用,而TGF-β1则可能是参与了CyclinD1蛋白失活导致甲状旁腺肿瘤发生的关键环节。
Background
Parathyroid is the important endocrine gland in human, the secretion of parathyroid hormone (PTH) is the the most important hormones in human body which adjust blood calcium level. Parathyroid tumors most have the typical symptoms of primary hyperparathyroidism, the main clinical type is bone and bone-kidney mixed type, some of them show other symptoms, such as nausea, gastrointestinal symptoms, inappetence, emaciation, etc. It is often a lack of typical clinical manifestations in early stages.The main principle is detecting and treating in time.With the research of all kinds of tumor molecular pathogenesis,the research of parathyroid tumors also made some progress. Being a potent negative regulator of cell proliferation, transforming growth factor-β1(TGF-β1) plays an important role in inhibiting normal epithelial cell growth,and it has a complicated relationship with tumors. CyclinD1 is a key protein in G1 phage of the cell cycle. Its over expression can shorten the proeess from G1 to S phage, thus accelerate cell proliferation. In order to investigate the possible mechanism of parathyroid tumors and the clinicoPathologic significance of TGF-β1 and CyclinDl,the exression in parathyroid tumors, an Immunohistochemical SP method was used to examine the expression of the two kinds of proteins.
Objective
To investigate both the function of TGF-β1、CyclinD1 and the relationship between the two protein in parathyroid tumors and normal parathyroid tissues. It was helpful in learning the relationship between TGF-β1 signaling pathway and emergence development through study the TGF-β1 and CyclinD1 in parathyroid tumors. It also would provide the basis for diagnosis, judging to stage ofparathyroid tumors' invasion and predicting the prognosis, finding new methods of therapy.
Methods
Tissues specimens were collected from the First Affiliated Hospital of Zhengzhou University from 1997 to 2009,10 cases of normal parathyroid tissues,43 cases of parathyroid adnoma tissues and 6 cases of parathyroid carcinoma tissues. SP Immunohistochemical technique was used to determine the expression of TGF-β1 and CyclinD1 in normal parathyroid tissues、parathyroid adenoma tissues and parathyroid carcinoma tissues. The data was analyzed by software SPSS 16.0.
Results
There are 4 positive TGF-β1 expression (40%) and 1 overexpression of CyclinD1 (10%) in 10 normal parathyroid tissuess. There are 21 positive TGF-β1 expression (48.8%) and 24 overexpression of CyclinD1 (55.8%) in 43 parathyroid adenoma tissuess. There are 4 positive TGF-β1 expression (66.7%) and 5 overexpression of CyclinDl (83.3%) in 6 parathyroid carcinoma tissuess.The expression of TGF-β1 was not significantly different among the three groups.The expression of CyclinD1 protein was significantly different between normal parathyroid tissuess and parathyroid adnoma tissuess (P<0.05),and it was significantly different between normal parathyroid tissuess and parathyroid carcinoma tissuess(P<0.05),but it was not significantly different between parathyroid adnoma tissuess and parathyroid carcinoma tissuess (P>0.05). The expression of TGF-β1 was significantly related to the overexpression of CyclinD1 in the parathyroid adnoma tissuess, but it was not significantly related to the overexpression of CyclinD1 in the parathyroid carcinoma tissues.
Conclusions
Derangements of the TGF-β1 pathyway due to CyclinD1 would be also implicated in the development of parathyroid tumors, the overexpression of CyclinD1 plays an important role in parathyroid tumors.
引文
[1]Carling T,Udelsman R.Parathyroid tumors[J].Curr Treat Options Oncol,2003,4(4):319-328
[2]Blobe GC,Schiemann WP and Lodish HF.Role of transforming growth factor β in human diseases.N Engl J Med,2000,342(18):1350-1358
[3]Tanaka S, Mori M, Mafune K, et al. A dominant negative mutation of transforming growth factor-beta receptor typell gene in microsatellite stable oesophageal carcinoma.Br J Cancer, 2000,82(9):1557-1560
[4]Shao J,Teraishi F,Katsuda K, et al. p53 inhibits adriamycin-induced down-regulation of cyclin Dl expression in human cancer cells[J].Biochem Biophys Res Commun,2002, 290(3):1101-1107
[5]Schw andner O, Bruch HP, BrollR. p21, p27, cyclin D1, and p53 in rectal cancer: immunohistology with prognostic significance [J]. Int JColorectalDis,2005,17(1):11-19
[6]Yu Z, Weinberger PM, Haffty BG, et al. Cyclin dl is a valuable prognostic marker in oropharyngeal squamous cell carcinoma [J].Clin Cancer Res,2005,11(3):1160-1166
[7]Temmim L, Ebraheem AK, Baker H, Sinowatz F. CyciinD1 protein expression in human thyroid gland and thyroid cancer[J]. Anat Histol Embryol 2006;35(2):125-129
[8]Yu J,Miehlke S, Ebert MP, et al.Expression of cyclin genes in human gastric cancer and in first degree relatives [J].Chin Med J (Engl),2002,115(5):710-715
[9]姚欣,刘岩雪,张莉,等.人膀胱移形细胞癌TGF-β1及其受体的表达意义[J].中华肿瘤杂志.2002,24(2)：158
[10]Motokura T, Bloom T, Kim HG, et al.A novel cyclin encoded by a bell-linked candidate oncogene [J].Nature,1991,350(6318):512-515.
[11]Heldin CH,Miyazono K,ten Dijke P.TGF-beta signaling from cell membrane to nueleus through SMAD Proteins.Nature,1997:390(6659):465-471
[12]唐正严,杨罗艳,张永琎,等Smad4与TGF-β1在膀胱移行细胞癌中的表达及临床意义[J].中南大学学报,2006,31(3)：363-366.
[13]Su E, Han X, Jiang G The transforming growth factor beta 1/SMAD signaling pathway involved in human chronic myeloid leukemia. Tumori.2010,96(5):659-666
[14]Cavallaro G, Cucina A, Coluccia P,et al. Role of Growth Factors on Human Parathyroid Adenoma Cell Proliferation World J Surg.2010;34(1):48-54
[15]Battegay EJ, Raines EW, Seifet RA,et al.TGF-β induces bimodal proliferation of connective tissue cells via complex control of an autocrine PDGF loop. Cell.1990,63(3): 515-524
[16]Lin JK, ChouCK. In vitro apoptosis in the human hepatoma cell line induced by transforming growth factor beta 1.Cancer Res,1992,52(2):385-388
[17]Massague J, Blain SW, Lo RS.TGF- beta signaling ingrowth control,cancer,and heritable disorders.Cell.2000,103(2):295-309
[18]Biswas S, Chytil A, Washington K.et al. Transforming growth factor beta receptor type II inactivation promotes the establishment and progression of colon cancer. Cancer Res. 2004,64(14):4687-4692
[19]Suardet L.Gaide AC,Calmes JM,et al.ResPonsiveness of three newly established human colorectal cancer cell lines to transforming growth factors betal and beta2.Cancer Res 1992,52(13):3705-3712
[20]Goldstein D, O'Leary M,et al Effects of interferon beta ser and transforming growth factor beta on prostatic cell lines. J Urol.1991,146(4):1173-1177.
[21]Marth C, Lang T, Koza A.et alTransforming growth factor-beta and ovarian carcinoma cells: regulation of proliferation and surface antigen expression.Cancer Letters 1990,51(3): 221-225
[22]Tang B. Bottinger E.P, Jakowlew S.B Transforming growth factor b1 is a new form of tumor suppressor with true haploid in sufficiency.Nat med 1998,4(7):802-807
[23]Cui W Fowlis DJ,Bryson S,et al.TGF betal inhibits the formation of Benign skin tumors,but enhances progression to invasive spindle Carcinomas in transgenic mice.Cell 1996,86 (4):531-542
[24]Hirayama D, Fujimori T, Arao M, et al. Immunohistochemical study of epidermal growth factor and transforming growth factor-beta in the penetrating type of early gastric cancers. Human Pathol,1992,23(6):681-685
[25]Shim KS, Kim KH, Han WS,et al Elevated serum levels of transforming growth factor-betal in patients with colorectal carcinoma:its association with tumor progression and its significant decrease after curative surgical resection. Cancer.1999,85(3):554-61.
[26]Wang SF, Lai LC. The role of TGF-β1 in human cancer. Pathology,2001,33(1):85-92
[27]Kaklamani VG, Pasche B. Role of TGF-beta in cancer and the potential for therapy and prevention, Expert Rev Anticancer Ther.2004,4(4):649-661
[28]Teicher BA.Malignant cells, directors of the malignant process:role of transforming growth factor-beta. Cancer Metastasis Rev.2001,20(1-2):133-143
[29]Bierie B,Moses HL. TGF-beta and cancer. Cytokine Growth Factor Rev.2006,17(1-2):29-40
[30]Derynck R, Akhurst RJ, Balmain A.TGF-β signaling in tumor suppression and cancer progression. Nat Genet 2001,29(2):117-129
[31]Siegel PM, Shu W, Cardiff RD,et al. Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Proc Natl Acad Sci USA 2003,100(14):8430-8435.
[32]Wei Y-S, Zhu Y-H, Du B,et al. Association of transforming growth factor-betal gene polymorphisms with genetic susceptibility to nasopharyngeal carcinoma. Clin Chim Acta 2007,380(1-2):165-169
[33]Kang HG, Chae MH, Park JM,et al. Polymorphisms in TGF-betal gene and the risk of lung cancer. Lung Cancer 2006,52(1):1-7
[34]Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 2003,15(6):740-746
[35]Lu SL, Kawabata M, Imamura T, Miyazono K, Yuasa Y. Two divergent signaling pathways for TGF-beta separated by a mutation of its type II receptor gene. Biochem Biophys Res Commun 1999,259(2):385-390
[36]Ellenrieder V, Hendler SF, Ruhland C, et al.Tgf-beta-induced invasiveness of pancreatic cancer cells is mediated by matrix metalloprotein-2 and the urokinase plasminogen acticator system. Int J Cancer,2001,93(2):204-214
[37]Heldin CH,Miyazono K,Dijke PT. TGF-β signaling from cell membrane to nucleus through SMAD proteins.Nature,1997,390(6659):465-471
[38]Reiss M. TGF-β and cancer.Microbes Infect,1999,1(15):1327-1347
[39]Pasehe B.Role of transforming growth factor beta in cancer.J Cell Physiol,2001,186(2): 153-168
[40]Motkura T, Bloom T, Kim HG, et a.l A novel cyclin encodedby a bell-linked candidate oncogene[J]. Nature,1991,350(6318):512.
[41]Udhayakumar G, Jayanthi V,Devaraj N, etal. Interaction of MUC1 with beta-caten in modulates the Wnt target gene CyclinD1 in H.pylori-induced gastric cancer[J].Mol Carcinog,2007,46(9):807-817
[42]Huang GX, Cheng RX, Feng DY. p16 and CyclinDl protein expression and p16 gene mutation in primary human hepatocellular carcinoma. Hunan Yi Ke Da Xue Xue Bao,2001, 26(6):527-530
[43]Wang X, Zou S. The relationship of CyclinDl and estrogen receptor expression in the process of proliferation and metastasis in breast neoplasm. Tongji Med Univ, 2001,21(3):231-232
[44]Gugger M, Kappeler A, Vonlanthen S, et al.Alterations of cell cycle regulators are less frequent in advanced non-small cell lung cancer than in resectable tumours.Lung Cancer, 2001,33(2-3):229-239
[45]Zhang L, Xu Y, Ge Y, et al. Expression of p27 protein and CyclinDl in laryngeal carcinoma. Lin Chuang Er Bi Yan Hou Ke Za Zhi,2002,16(12):646-647
[46]Oda K,Okabayashi T,Kataoka M,et al.Evaluation of CyclinD1 mRNA expression in gastric and coloreetal cancers.Res Commun Mol Pathol Pharmaeol,1999,105(3):237-252
[47]Zwijsen RML,Wientjiens E,KiomPmaker R,et al.CDK-Independent activation of estrogen receptor by CyclinD1.Cell,1997,88(3):405-415
[48]Dibrov A, Kashour T, Amara FM.The role of transforming growth factor beta signaling in messenger RNA stability. Growth Factors.2006,24(1):1-11.
[49]Sowa H, Kaji H, Kitazawa R,et al. Menin inactivation leads to loss of transforming growth factor b inhibition of parathyroid cell proliferation and parathyroid hormone secretion, Cancer Res.2004,64(6) 2222-2228.
[50]Jung B, Doctolero RT, Tajima A,,et al. Loss of activin receptor type 2 protein expression in microsatellite unstable colon cancers, Gastroenterology.2004,126(3):654-659
[51]Li TF, Chen D, Wu Q, et al.Transforming growth factor-beta stimulates cyclin D1 expression through activation of beta-catenin signaling in chondrocytes, J. Biol.Chem. 2006,281 (30)21296-21304.
[52]Matsuo SE, Fiore AP, Siguematu SM et al. Expression of SMAD proteins, TGF-beta/ activin signaling mediators, in human thyroid tissues. Arq Bras Endocrinol Metabol. 2010,54(4):406-412
[53]Watanabe Y, Itoh S, Goto T,et al.TMEPAI, a transmembrane TGF-beta-inducible protein, sequesters Smad proteins from active participation in TGF-beta signaling. Mol Cell. 2010,15;37(1):123-134
[54]Wang H, Rajan S, Liu GT,et al.ransfonning growth factor beta suppresses beta-catenin/Wnt signaling and stimulates an adhesion response in human colon carcinoma cells in a Smad4/DPC4 independent manner Cancer Lett.2008,18;264(2):281-287
[1]Elaraj DM, Clark OH.Current Status and Treatment of Primary Hyperparathyroidism Perm J.2008 Winter; 12(1):32-37
[2]Carling T.Udelsman R.Parathyroid tumors [J].Curr Treat Options Oncol,2003,4(4): 319-328
[3]Mark LA,Pasieka JL.Asymptomatic primary hyperparathyroidism:a surgical perspective [J]. Surg Clin North Am,2004,84(3):803-816
[4]Heath H 3rd, Hodgson SF, Kennedy MA. Primary hyperparathyroidism. Incidence, morbidity, and potential economic impact in a community. N Engl J Med 1980,24; 302(4):189-193
[5]Silverberg SJ, Bilezikian JP. Evaluation and management of primary hyperparathyroidism. J Clin Endocrinol Metab 1996; 81(6):2036-2040
[6]Bilezikian JP,Rubin M,Silverberg SJ. Asymptomatic primary hyperparathyroidism. Arq Bras Endocrinol Metabol.2006,50(4):647-656.
[7]Siperstein AE, Shen W, Chan AK, et al. Normocalcemic hyperparathyroidism. Biochemical and symptom profiles before and after surgery. Arch Surg 1992; 127(10):1157-1163
[8]Richard BF, Demay MB, Kronenberg A, et al.Hormones and disorders of mineral metabolim.Endocrinology,1998:50:1172-1175
[9]Proceedings of the NIH Consensus Development Conference on diagnosis and management of asymptomatic primary hyperparathyroidism. Bethesda, Maryland,1990; 29-31
[10]Heath H 3rd, Hodgson SF, Kennedy MA. Primary hyperparathyroidism. Incidence, morbidity, and potential economic impact in a community. N Engl J Med 1980,24; 302(4):189-93
[11]Black W C.The surgical pathology of parathyroid chief cell hyperplasia.Am J Clin Pathol, 1970;53(5):565-579
[12]Agarwal SK, Schrock E, KesterMB, et al·[J]·CancerGenetCytogenet,1998,106(1):30-36
[13]Kytola S, Farnebo F, Obara T, et al·[J]·Am J Patho,l 2000,157(2):579-586·
[14]Arnold A, Shattuck TM, Mallya SM, et al. Molecular pathogenesis of primary hyperparathyroidism. J Bone Miner Res,2002,17 (12):30-36.
[15]Krebs LJ, Arnold A. Molecular basis of hyperparathyroidism and potential targets for drug development. Curr Drug Targets Immune Endocr Metabol Disord,2002,2(2):167-179
[16]Motkura T, Bloom T, Kim HG, et a.l A novel cyclin encodedby a bell-linked candidate oncogene[J]. Nature,1991,350(6318):512-515
[17]Hendy GN. Molecular mechanisms of primary hyperparathyroidism [J].Endocrine & Metabolid Disorders,2000,1:297-305.
[18]DeGregori J. The Rb network [J]. Journal of Cell Science,2004,117:3411-3413.
[19]Zukerburg LR, Benedict WF, Arnold A, et al. Expression of retinoblastoma protein in low-grade B-cell lymphoma:relationship to CyclinD1.[J].Blood,1996,88:268-276.
[20]Mittendorf EA,McHenry CR.Parathyroid carcinoma.J 2005,89:136-142
[21]Imanishi Y, Hosokawa Y, Yoshimoto, K, et al. Primary hyperparathyroi-dism caused by parathyroid-targeted overexpression of cyclin D1 in transgenic mice. J Clin Invest, 2001,107:1093-1102
[22]Hemmer S, Wasenius VM, Haglund C,et al. Deletion of 11q23 and CyclinDl OverexpressionAreFrequent Aberrations in Parathyroid Adenomas. American Journal of Pathology,2001,158(4):1355-1362
[23]胡慧,薛新波.甲状旁腺组织中细胞周期素D1过度表达与Rb肿瘤抑制基因的表达和临床意义.临床外科杂志,2006,14(4)：224-225
[24]Larsson C, Skogsied B, Oberg K, et al. Multiple endocrine neoplasia type 1 genemaps to chromosome 11 and is lost in insulinoma[J]. Nature,1988,332:85-87
[25]Chandrasekharappa S, Teh BT. Clinical and molecular aspects of multiple endocrine neoplasia type1-for the book "Genetic Disoders of Endocrine Neoplasia"[J]. Front Horm Rea,2001,28:50-80,
[26]Uchino S, Noguchi S, Sato M, et al. Screening of the MEN1 gene and discovery of germ-line and somatic mutations in apparently sporadic parathyroid tumors [J]. Cancer research, 2000,60:5553-5557.
[27]Howell VM, Haven CJ, Kahnoski K, et al. HRPT2 mutations are associated with malignancy in sporadic parathyroid tumor [J]. J.Med.Genet,2003,40:(9):657-63.
[28]Knudson, AG. Hereditary cancer:tow hits revisited[J]. Cancer Res Clin Oncol,1996,22, 134-140
[29]Adami S. Marcoci C, Gatti D. Epidemiology of primary hyperparathyroidism in Europe. J Bone Miner Res,2002,17 (12):18-23.
[30]Brown EM.The pathophysiology of primary hyperparathyroidism. [J] J Bone Miner Res, 2002,17(12):24-29
[31]龚龙,薛新波,王从俊Menin蛋白和TGF_在甲状旁腺肿瘤中的表达及临床意义.临床外科杂志,2005,13(11)：698-699
[32]Crabtree JS, Scacheri PC, Ward JM, et al. A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors. Proc Natl Acad Sci USA,2001, 98:1118-1123
[33]Brown EM, Cambs G, Riccardl D, et al. Cloning and characterization Of an extracelluar Ca2+ -sensing receptor from bovine parathyroid[J]. Nature,1993,366(6455):575-580
[34]Brown EM, MacLeod RJ. Extracellular calcium sensing and extracellular calciu -m signaling. Physiol Rev,2001,81:239-297
[35]Hansen JT, Brown EM. The calcium sensing receptor in normal physiology and pathohysiology[J]. A review Crit Revin Clin Lab Sciences,2005,42(1):35-70.
[36]Rodriguez M, Nemeth E, Martin D. The calcium-sensing receptor:a key factor in the pathogenesis Of secondary hyperparathyroidism[J].Am J Physiol Renal Physiol,2005, 288(2):253-264.
[37]Nagano N, Nemeth EF. Functional proteins involved in regulation of intracellula -rCa2+ for drug development:the extracellular calcium receptor and an innovative medical approach to control secondary hyperparathyroidism by calcinumetics. J Phan -nacol Sci, 2005,97:355-360
[38]Crabtree JS, Scacheri PC, Ward JM, et al. A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors. Proc Natl Acad Sci USA,2001,98:1118-1123.
[39]Cowin P, Rowlands TM, Hatsell SJ. Cadherins and catenins in breast cancer J. Curr Opin Cell Biol,2005,17:499-508
[40]Kohn AD, Moon RT. Wnt and calcium signaling:β-catenin-independent pathways J. Cell Calcium,2005,38(3):439-446
[41]Verras M, Sun Z. Roles and regulation of Wnt signaling and beta-catenin in prostate cancer J. Cancer Lett,2006,237(1):22-32.
[42]Yoshida R, Kimura N, Harada Y, et al. The loss of E-cadherin, alpha-and beta-catenin expression is associated with metastasis and poor prognosis in invasive breast cancer J. Int J Oncol,2001,18(3):513-20.
[43]Lustig B, Behrens J. TheWnt signaling pathway and its role in tumor development J. Cancer Res Clin Oncol,2003,129:199-221.
[44]Martinez Diaz-Guerra G, Hawkins Carranza FConcept, etiology and epidemiology of primary hyperparathyroidism Endocrinol Nutr.2009,56(1):2-7
[45]Westin G, Bjorklund P, Akerstrom G. Molecular Genetics of Parathyroid Disease. World J Surg.2009;33(11):2224-33.
[46]Rogers SE, Perrier ND.Parathyroid carcinoma. Curr Opin Oncol,2006,18:16-22
[47]Rawat N, Khetan N, Williams DW et al. Parathyroid carcinoma. Br J Surg 2005,92:1345-1353
[48]Shatruck TM, Va "lima "ki S, Obara T et al. Somatic and germ-line mutations of the HRTP2 gene in sporadic parathyroid carcinoma. N Engl J Med,2003,349:1722-1729
[49]Howell VM, Haven CJ, Kahnoski K et al HRPT2 mutations are associated with malignancy in sporadic parathyroid tumors. J Med Genet,2003,40:657-663
[50]Gill AJ, Clarkson A, Gimm O et al.Loss of nuclear expression of parafibromin distinguishes parathyroid carcinomas and hyperparathyroidism jaw tumor (HPT-JT) syndrome-related adenomas from sporadic parathyroid adenomas and hyperplasias. Am J Surg Pathol,2006,30:1140-1149
[51]Cetani F, Ambrogini E, Viacava P et al.Should parafibromin staining replace HRPT2 gene analysis as an additional tool for histological diagnosis of parathyroid carcinoma? Eur J Endocrinol,2007,156:547-554
[52]Haven CJ, van Puijenbroek M, Tan MH et al.Identification of MEN1 and HRPT2 somatic mutations in paraffinembedded (sporadic) parathyroid carcinomas. Clin Endocrinol(Oxf) 2007,67:370-376
[53]Hewitt KM, Sharma PK, Samowitz W,et al.Aberrant methylation of the HRPT2 gene in parathyroid carcinoma.Ann Otol Rhinol Laryngol,2007,116:928-933
[54]Hahn MA, Marsh DJ. Identif ication of a functional bipartite nuclear localization signal in the tum or suppress or parafibro min [J].On cogene,2005,24(41):6241-6248
[55]Frank-Raue K, Rondot S, Hoeppner W,et al. Coincidence of multiple endocrine neoplasia types 1 and 2:mutations in the RET proto-oncogene and MEN1 tumor suppressor gene in a family presenting with recurrent primary hyperparathyroidism. J Clin Endocrinol Metab, 2005,90:4063-4067.
[56]Yart A, Gstaiger M, Wirbelauer C, et al.The HRPT2 tumor suppressor gene product parafibromin associates with human PAF1 and RNA polymerase Ⅱ. Mol Cell Biol,2005, 25:5052-5060.
[57]Bradley KJ, Cavaco BM, Bowl MR, et al. Parafibromin mutations in hereditary hyperparathyroidism syndromes and parathyroid tumours. Clin Endocrinol,2006,64: 299-306.
[58]Shattuck TM, Valimaki S, Obara T, et al. Somatic and germ li ke mutations of the HRPT2 gene in sporadic parathyroid carcino ma[J]. N Engl JMed,2003,349(18):1722-1729.
[59]Howell VM, Haven CJ, Kahnosk iK, et al. HRPT2 mutations are associated with malignancy in sporadic parathyroid tumours [J]. JMed Genet,2003,40(9):657-663.
[60]Cetani F, Pardi E, Borsari S, et al. Genetic analyses of the HRPT2 gene in primary hyperparathyroidism:germline and somatic mutations in familial and sporadic parathyroid tumors J Clin Endocrinol Metab.2004;89(11):5583-5591
[61]Krebs LJ, Shattuck TM, Arnold A. HRPT2 mutational analysis of typical sporadic parathyroid adenomas [J].J Clin Endocrinol Metab.2005 Sep;90(9):5015-5017.
[62]Dwight T, Twigg S, Delbridge L,et al. Loss of heterozygosity in sporadic parathyroid tumours:involvement of chromosome 1 and the MEN1 gene locus in 11q13.Clin Endocrinol (Oxf).2000,3(1):85-92
[63]Shattuck TM, Valimaki S, Obara T,et al.Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. N Engl J Med,2003,349:1722-1729.
[64]Cetani F, Pardi E, Borsari S,et al.Genetic analyses of the HRPT2 gene in primary hyperparathyroidism:germline and somatic mutations in familial and sporadic parathyroid tumors. J Clin Endocrinol Metab,2004,89:5583-5591.
[65]Hodgson SF, Watts NB, Bilezikian JP, et al.American Association of Clinical Endocrinologists medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporosis:2001 edition, with selected updates for 2003. Endocr Pract,2003,9(6):544-564.
[66]Pasieka JL, Parsons LL. Prospective surgical outcome study of relief of symptoms following surgery in patients with primary hyperparathyroidism. World J Surg.1998,22: 513-519.
[67]Sheldon DG, Lee FT, Neil NJ, et al. Surgical treatment of hyperparathyroidism improves health-related quality of life. Arch Surg.2002,137:1022-1028.
[68]Joborn C, Hetta J, Johansson H, et al. Psychiatric morbidity in primary hyperparathyroidism. World J Surg.1988,12:476-481.
[69]Prager G, Kalaschek A, Kaczirek K, et al. Parathyroidectomy improves concentration and retentiveness in patients with primary hyperparathyroidism. Surgery,2002,132:930-936.
[70]Doherty GM. Parathyroid glands. In:Greenfield LJ, Mulholland MW, Oldham KT, et al, eds. Surgery:Scientific Principles and Practice. Philadelphia:Lippincott, Williams & Wilkins,2001,1284-1306.
[71]Stewart AF. Clinical practice.Hypercalccmia associated with cancer. N Engl J Med. 2005,352(4):373-379
[72]Bilezikian JP, Silverberg SJ.Clinical practice. Asymptomatic primary hyperparathyroidism. N Engl J Med.2004,350(17):1746-1751.
[73]杨哗,干维力,当代内科学[M].北京：李庆棣,2002,3885-3896
[74]Babar-CraigBabar-Craig H, Quaglia A, Steams M.Parathyroid carcinoma:a report of two cases and a concise review and update of the literature[J].J Laryngol Otol,2005,119(7): 577-580
[75]蔡伟耀.有关原发性甲状旁腺功能亢进诊治的若干问题[J].外科理论与实践,2005,10(6)：503-504
[76]Moka D,Voth E,Dietlein M,et al. Technetium 99m-MIBI SPECT:a highly sensitive diagnostic tool for localization of parathyroid adenomas [J].Surgery,2000,128(1):29-35.
[77]Civelek AC, Ozalp E, Donovan P, et al.Prospective evaluation of delayed technetium 99m sestamibi SPECT seintigraphy for preoperative localization of Primary hyperparathy roidism.Surgery,2002,131(2):149-157.
[78]付利军,闫红印,邱新光等.原发性甲状腺功能亢进的诊治分析[J].中华内分泌外科杂志,2010,4(6)：396-398
[79]Civelek AC, Ozalp E, Donovan P et al Prospective evaluation of delayed techne -tium-99m sestamibi SPECT scintigraphy for preoperative localization of primary hyperparathyroidism, Surgery.2002,131(2):149-57,
[80]Pasieka JL, Parsons LL. Prospective surgical outcome study of relief of symptoms following surgery in patients with primary hyperparathyroidism. World J Surg.1998,22:513-519
[81]Sheldon DG, Lee FT, Neil NJ, et al. Surgical treatment of hyperparathyroidism improves health-related quality of life. Arch Surg.2002,137:1022-1028
[82]Burney RE, Jones KR, Wilson Coon J, et al. Assessment of patient outcomes after operation for primary hyperparathyroidism. Surgery.1996,120:1013-1019,
[83]Minisola S, Rosso R, Romagnoli E, et al. Trabecular bone mineral density in primary hyperparathyroidism:relationship to clinical presentation and biomarkers of skeletal turnover. Bone Miner.1993,20:113-123
[84]Joborn C, Hetta J, Johansson H, et al. Psychiatric morbidity in primary hyperparathyroidism. World J Surg.1988,12:476-481
[85]Numann PJ, Torppa AJ, Blumetti AE. Neuropsychologic deficits associated with primary hyperparathyroidism. Surgery.1984,96:1119-1123.
[86]Prager G, Kalaschek A, Kaczirek K, et al. Parathyroidectomy improves concentration and retentiveness in patients with primary hyperparathyroidism. Surgery.2002,132:930-936
[87]Burney RE, Jones KR, Wilson Coon J, et al. Assessment of patient outcomes after operation for primary hyperparathyroidism. Surgery.1996,120:1013-1019
[88]Burney RE, Jones KR, Christy B, et al. Health status improvement after surgical correction of primary hyperparathyroidism in patients with high and low preoperative calcium levels. Surgery.1999,125:608-614.
[89]Sywak MS, Knowlton ST, Pasieka JL, et al. Do the National Institutes of Health consensus guidelines for parathyroidectomy predict symptom severity and surgical outcome in patients with primary hyperparathyroidism? Surgery.2002,132:1013-1020.
[90]Quiros RM, Alef MJ, Wilhelm SM, et al. Health-related quality of life in hyperparathyroidism measurably improves after parathyroidectomy. Surgery.2003,134: 675-681
[91]Wang CA. Surgical management of primary hyperparathyroidism. Curr Probl Surg 1985, 22(11):1-50.
[92]Goldstein RE, Carter WM,Fleming M,et al.Unilateral cervical surgical exploration aided by intraoperative parathyroid hormone monitoring in patients with primary hyperparathyroidism and equivocal sestamibi scan results[J].Arch Surg,2006,141(6): 552-557.
[93]Udelsman R. Six hundred fifty-six consecutive explorations for primary hyperparathyroidism. Ann Surg.2002,235:665-670.
[94]Goss JC, Landerholm R. A changing experience with primary hyperparathyroi- dism at Group Health Cooperative, Seattle. Am J Surg.2001,181:445-448.
[95]Goldstein RE, Blevins L, Delbeke D, Martin WH. Effect of minimally invasive radioguided parathy- roide ctomy on efficacy, length of stay, and costs in the manage- ment of primary hyperparathyroidism. Ann Surg.2000,231:732-742.
[96]Perrier ND, Ituarte PH, Morita E, Hamill T, Gielow R, Duh QY, Clark OH. Parathyroid surgery:separating promise from reality. J Clin Endocrinol Metab.2002,87:1024-1029.
[97]Rolighed L, Heickendorff L, Hessov Let alPrimary hyperparathyroidism:intrao- perative PTH-measurements. Scand J Surg.2004,93(1):43-47.
[98]G.Ippolito,F.F.Palazzo,et al.Intraoperative diagnosis and treatment of parathyroid cancer and atypical parathyroid adenoma[J]. British Journal of Surgery,2007,94(5):566-570
[99]Senchenkov A, Staren ED. Ultrasound in head and neck surgery:thyroid, parathyr -oid, and cervical lymph nodes [J]. Surg Clin North Am,2004,84(4):973-1000
[100]Lee NC, Norton JA. Multiple-gland disease in primary hyperparathyroidism:a function of operative approach?. Arch Surg.2002,137:896-899
[101]Udelsman R. Six hundred fifty-six consecutive explorations for primary hyperparathyroidism. Ann Surg.2002,235:665-670
[102]Goss JC, Landerholm R. A changing experience with primary hyperparath -yroidism at Group Health Cooperative, Seattle. Am J Surg.2001,181:445-448
[103]Bilezikian JP, Potts JT Jr, Fuleihan Gel-H, Kleerekoper M, Neer R, Peacock M, et al. Summary statement from a workshop on asymptomatic primary hyperparathyroidism:a perspective for the 21st century. J Bone Miner Res.2002,17(2):2-11
[104]Wells SA Jr, Debenedetti MK, Doherty GM. Recurrent or persistent hyperparathyroidism. J Bone Miner Res.2002,17(2):158-162
[105]Lorin M. Henrich, Alan D.et alPersistent Hypercalcemia After Parathyroidectomy in an Adolescent and Effect of Treatment With Cinacalcet HCl Clinical Chemistry. 2006,52:2286-2293
[106]Nemeth EF. Summary--calcium receptors:potential targets for novel treatments for skeletal disease. J Musculoskelet Neuronal Interact,2004,4:416-417
[107]Peacock M, Bilezikian JP, Klassen PS,et al.Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism. J Clin Endocrinol Metab. 2005,90(1):135-141
[108]Bilezikian JP,Potts Jr JT,E1-Hajj Fuleihan G,et al.2002 Summary statement from a workshop on asymptomatic primary hyperparathyroidism:a perspective for the 21st century.J.J Bone Miner Res,2002,17(2):2-11
[109]Bilezikian JP,Potts JT. Asymptomatic primary hyperparathyroidism:new issues and new questions--bridging the past with the future.J.J Bone Miner Res,2002,17:57-67
[110]Melton LJ.The epidemiology of primary hyperparathyroidism in North America J.Bone Miner Res,2002,17:12-17
[111]Bilezikian JP, Silverberg SJ. Normocalcemic primary hyperparathyroidism. Arq Bras Endocrinol Metabol,2010,54(2):106-109
[112]Wells SA Jr, Debenedetti MK, Doherty GM. Recurrent or persistent hyperparathyroidism. J Bone Miner Res.2002,17(2):158-162