本文選題：Rg3 + 黑色素瘤�。� 參考：《大連醫(yī)科大學(xué)》2015年博士論文

【摘要】：一、目的與意義黑色素瘤是全世界皮膚腫瘤相關(guān)性死亡的主要原因(80%)。它是一種惡性程度較高,臨床預(yù)后較差的惡性腫瘤。IV期黑色素瘤患者的中位生存時(shí)間少于1年,而5年生存期少于10%。黑色素瘤的發(fā)病率在世界范圍內(nèi)逐年增加,它的致死率的增長(zhǎng)速度高于其他任何形式的惡性腫瘤。傳統(tǒng)的晚期轉(zhuǎn)移性惡性黑色素瘤的治療包括:化療(達(dá)卡巴嗪、替莫唑胺)、生物治療(干擾素α-2b)及藥物靶向治療(vemurafenib和ipilimumab)等。由于這些治療的腫瘤反應(yīng)率低,腫瘤耐藥的產(chǎn)生及嚴(yán)重的毒副作用而限制了它們的應(yīng)用。因此,對(duì)于黑色素瘤的治療仍然需要尋找新的治療策略,新的靶點(diǎn)及新的治療藥物。人參是一個(gè)古老的中草藥,它具有滋補(bǔ)、強(qiáng)心、抗炎、抗腫瘤和免疫刺激的作用。20(R)-人參皂苷Rg3是從人參中提取的單體成分,具有廣泛的藥理學(xué)活性和治療作用。報(bào)道顯示Rg3在結(jié)腸癌、胃癌、乳腺癌及肝癌中具有抑制腫瘤生長(zhǎng)的作用;Rg3在前列腺癌和結(jié)腸癌中具有增加多西他賽和順鉑化療敏感性的作用;Rg3在肝癌細(xì)胞中具有抗腫瘤血管形成和誘導(dǎo)凋亡的作用。目前,參一膠囊(其主要成分為Rg3)已經(jīng)在中國(guó)被批準(zhǔn)為治療臨床晚期非小細(xì)胞肺癌的輔助藥物。蛋白質(zhì)轉(zhuǎn)錄后的修飾與腫瘤發(fā)生發(fā)展密切相關(guān),其中乙�；吞腔渤蔀榭箰盒院谏亓龅难芯繜狳c(diǎn)。然而Rg3抗黑色素瘤的作用機(jī)制是否與調(diào)控蛋白質(zhì)的乙酰化和糖基化目前還不清楚。乙�；腿ヒ阴；钦{(diào)控基因表達(dá)的表觀遺傳學(xué)過(guò)程。異常的去乙酰化酶(HDACs)的表達(dá)與腫瘤的生長(zhǎng)、侵襲和轉(zhuǎn)移密切相關(guān)。例如,HDAC6在人類乳腺癌和前列腺癌中過(guò)表達(dá),HDAC2在宮頸癌和胃癌中過(guò)表達(dá),HDAC8在兒童神經(jīng)母細(xì)胞瘤中過(guò)表達(dá)。HDAC3的過(guò)表達(dá)也在許多惡性腫瘤中被報(bào)導(dǎo),如肺癌、結(jié)腸癌、胃癌和前列腺癌。有研究認(rèn)為HDAC3的表達(dá)與p53的乙�；c腫瘤的生長(zhǎng)有關(guān)。然而Rg3抗惡性黑色素瘤生長(zhǎng)的機(jī)制是否與調(diào)節(jié)HDAC3和p53乙�；谋磉_(dá)需要進(jìn)一步探索。蛋白的糖基化在腫瘤病理生理過(guò)程中發(fā)揮重要的作用,包括腫瘤增殖、侵襲、血源性轉(zhuǎn)移和血管形成。巖藻糖基化是蛋白糖基化的一種重要形式。巖藻糖基轉(zhuǎn)移酶(FUTs)是催化合成巖藻糖的關(guān)鍵酶。其中FUT4是FUTs家族的成員之一,是催化合成α1,3-巖藻糖Le Y的關(guān)鍵酶。文獻(xiàn)報(bào)道顯示FUT4在很多腫瘤中過(guò)表達(dá),例如在結(jié)腸癌、胃癌和肺癌中。過(guò)表達(dá)FUT4能夠促進(jìn)細(xì)胞的增殖、轉(zhuǎn)移和抗凋亡。然而Rg3在惡性黑色素瘤生長(zhǎng)誘導(dǎo)凋亡中的作用與潛在的調(diào)節(jié)FUT4表達(dá)與EGFR/MAPK和NF-κB信號(hào)通路目前仍不清楚。本研究通過(guò)Rg3對(duì)HDAC3和FUT4表達(dá)調(diào)控的研究,分析Rg3在黑色素瘤中抑制腫瘤生長(zhǎng)誘導(dǎo)凋亡及其調(diào)控的相關(guān)信號(hào)通路,進(jìn)一步探討Rg3介導(dǎo)的抗黑色素瘤作用的分子機(jī)制,以期為臨床治療黑色素瘤提供科學(xué)依據(jù)。二、實(shí)驗(yàn)方法1、收集2003至2010年在大連醫(yī)科大學(xué)附屬第一醫(yī)院病理科存檔的石蠟組織標(biāo)本且臨床資料完整的惡性黑色素瘤患者32例。采用免疫組化法測(cè)定所有病理標(biāo)本中HDAC3的表達(dá)情況,并對(duì)所有病例進(jìn)行隨訪。分析HDAC3與患者臨床病理特征和預(yù)后的相關(guān)性。應(yīng)用SPSS16.0統(tǒng)計(jì)軟件進(jìn)行數(shù)據(jù)分析,以P0.05為顯著性標(biāo)準(zhǔn)。表達(dá)的組間差異比較采用χ2檢驗(yàn);2、利用CCK-8、MTT法及細(xì)胞克隆形成實(shí)驗(yàn)分析黑色素瘤細(xì)胞的增殖能力;3、利用脂質(zhì)體瞬時(shí)轉(zhuǎn)染技術(shù)將HDAC3 si RNA、FUT4 si RNA轉(zhuǎn)染至人黑色素瘤細(xì)胞中,下調(diào)HDAC3和FUT4的表達(dá);4、采用Real-time PCR的方法檢測(cè)HDAC3、PCNA、FUT4和p65基因的表達(dá);5、采用Western blot的方法檢測(cè)HDAC3、FUT4、Le Y、Caspase-3、-8、-9、Bcl-2、Bax、Survivn、NF-κB和EGFR/MAPK信號(hào)通路等相關(guān)蛋白的表達(dá);6、利用免疫}D化和免疫熒光檢測(cè)HDAC3、FUT4、PCNA和p65的表達(dá);7、采用流式細(xì)胞儀分析細(xì)胞周期及細(xì)胞凋亡;8、采用凝膠電泳遷移率(EMSA)方法檢測(cè)NF-κB與DNA的結(jié)合情況;9、使用熒光素酶報(bào)告基因檢測(cè)p53和NF-κB的活性情況;10、使用染色質(zhì)免疫共沉淀(Ch IP)方法檢測(cè)NF-κB與FUT4啟動(dòng)子區(qū)的結(jié)合情況。三、結(jié)果(一)人參皂苷Rg3抑制黑色素瘤的增殖與下調(diào)HDAC3,增加p53乙�；南嚓P(guān)性研究1、HDAC3過(guò)表達(dá)與淋巴結(jié)轉(zhuǎn)移及腫瘤分期有關(guān);2、Rg3抑制黑色素瘤的生長(zhǎng);3、Rg3降低HDAC3的表達(dá);4、下調(diào)HDAC3表達(dá)抑制細(xì)胞的增殖;5、Rg3和下調(diào)HDAC3的表達(dá)增加p53的乙�；娃D(zhuǎn)錄活性;6、Rg3下調(diào)HDAC3改變細(xì)胞周期相關(guān)蛋白的表達(dá);7、Rg3在體內(nèi)抑制裸鼠腫瘤的生長(zhǎng)。(二)人參皂苷Rg3抑制黑色素瘤增殖與下調(diào)FUT4/Le Y介導(dǎo)的EGFR/MAPK通路的失活的相關(guān)性研究1、Rg3抑制A375黑色素瘤細(xì)胞的生長(zhǎng);2、Rg3降低FUT4和Le Y的表達(dá);3、下調(diào)FUT4的表達(dá)抑制A375細(xì)胞的增殖和減少Le Y的表達(dá);4、下調(diào)FUT4的表達(dá)減少EGFR/MAPK通路的磷酸化;5、Rg3在體內(nèi)抑制裸鼠腫瘤的生長(zhǎng)。(三)人參皂苷Rg3誘導(dǎo)黑色素瘤凋亡與抑制FUT4表達(dá)通過(guò)靶向調(diào)節(jié)NF-κB/p65信號(hào)通路機(jī)制的研究1、Rg3抑制人黑色素瘤細(xì)胞的增殖;2、Rg3誘導(dǎo)黑色素瘤細(xì)胞的凋亡;3、Rg3抑制NF-κB信號(hào)通路的活性;4、Rg3下調(diào)FUT4的表達(dá)抑制NF-κB連接到FUT4啟動(dòng)子區(qū);5、Rg3誘導(dǎo)凋亡通過(guò)抑制NF-κB信號(hào)通路及FUT4的下調(diào);6、Rg3抑制黑色素瘤裸鼠腫瘤生長(zhǎng)誘導(dǎo)凋亡。四、結(jié)論(一)人參皂苷Rg3抑制黑色素瘤的增殖與下調(diào)HDAC3,增加p53乙�；南嚓P(guān)性研究1、Rg3具有抑制黑色素瘤裸鼠動(dòng)物模型和黑色素瘤細(xì)胞生長(zhǎng)的作用;2、Rg3下調(diào)HDAC3表達(dá)具有劑量和時(shí)間的依賴性;3、使用si RNA或HDAC3潛在的抑制劑(MS-275),下調(diào)HDAC3表達(dá)抑制黑色素瘤細(xì)胞的增殖;4、Rg3抑制黑色素瘤增殖通過(guò)抑制HDAC3的表達(dá)增加p53的乙�；娃D(zhuǎn)錄活性。(二)人參皂苷Rg3抑制黑色素瘤增殖與下調(diào)FUT4/Le Y介導(dǎo)的EGFR/MAPK通路失活的相關(guān)性研究1、Rg3抑制黑色素瘤的生長(zhǎng)與下調(diào)FUT4/Le Y有關(guān);2、巖藻糖基轉(zhuǎn)移酶FUT4與調(diào)控的糖抗原Le Y表達(dá)有關(guān);3、Rg3抑制黑色素瘤增殖通過(guò)抑制FUT4/Le Y表達(dá)及其下游的EGFR/MAPK信號(hào)通路。(三)人參皂苷Rg3誘導(dǎo)黑色素瘤凋亡與抑制FUT4表達(dá)通過(guò)靶向調(diào)節(jié)NF-κB/p65信號(hào)通路機(jī)制的研究1、Rg3具有抑制黑色素瘤裸鼠動(dòng)物模型和黑色素瘤細(xì)胞生長(zhǎng),誘導(dǎo)凋亡的作用;2、Rg3誘導(dǎo)細(xì)胞凋亡通過(guò)下調(diào)NF-κB信號(hào)通路蛋白的表達(dá)及NF-κB DNA連接/轉(zhuǎn)錄活性;3、NF-κB直接調(diào)控FUT4的啟動(dòng)子區(qū),影響FUT4的表達(dá);4、Rg3誘導(dǎo)凋亡通過(guò)抑制NF-κB信號(hào)通路介導(dǎo)的下調(diào)FUT4的表達(dá)。
[Abstract]:Objective and significance melanoma is the main cause of death associated with skin tumor in the world (80%). It is a high malignant and clinically poor malignant tumor of.IV melanoma with a median survival time of less than 1 years, while the incidence of less than 10%. melanoma in the 5 year survival period increases year by year in the world. The rate of death is higher than any other form of malignant tumor. The treatment of traditional advanced metastatic malignant melanoma includes chemotherapy (Dhaka basazine, temozolomide), biological therapy (interferon alpha -2b) and drug targeting therapy (vemurafenib and ipilimumab). Serious toxic and side effects restrict their application. Therefore, the treatment of melanoma still needs to find new therapeutic strategies, new targets and new therapeutic drugs. Ginseng is an ancient Chinese herbal medicine, which has the effects of nourishing, heart, anti-inflammatory, anti-tumor and immune stimulation,.20 (R) - ginsenoside Rg3 is extracted from ginseng It has been reported that Rg3 plays a role in inhibiting tumor growth in colon, gastric, breast and liver cancers; Rg3 has the effect of increasing the chemosensitivity of docetaxel and cisplatin in prostate and colon cancer; Rg3 has antitumor angiogenesis and induction in liver cancer cells. The effect of apoptosis. Currently, Shen Yi capsule (its main component is Rg3) has been approved as an auxiliary drug in the treatment of advanced non small cell lung cancer in China. The posttranscriptional modification of protein is closely related to the development of tumor. Acetylation and glycosylation also become a hot spot in the study of malignant melanoma. However, Rg3 is anti melanoma. It is not clear whether the mechanism of action and the regulation of acetylation and glycosylation of proteins is still unclear. Acetylation and deacetylation are epigenetic processes regulating gene expression. The expression of abnormal deacetylase (HDACs) is closely related to tumor growth, invasion and metastasis. For example, HDAC6 is overexpressed in human breast and prostate cancer, HDAC2 Overexpression of HDAC8 in children with cervical cancer and gastric cancer, overexpression of.HDAC3 in children with neuroblastoma is also reported in many malignant tumors, such as lung cancer, colon cancer, gastric cancer, and prostate cancer. Studies have suggested that the expression of HDAC3 and the acetylation of p53 are related to the growth of the tumor. However, the mechanism of Rg3 for the growth of malignant melanoma is whether or not. The expression of HDAC3 and p53 acetylation needs further exploration. Protein glycosylation plays an important role in the pathophysiological process of tumor, including tumor proliferation, invasion, hematogenous metastasis and angiogenesis. Fucoylation is an important form of protein glycosylation. Fucose transferase (FUTs) is the key to catalyze the synthesis of fucose. FUT4 is one of the members of the FUTs family and is the key enzyme to catalyze the synthesis of alpha 1,3- fucose Le Y. The literature has reported that FUT4 is overexpressed in many tumors, such as colon, gastric and lung cancer. Over expressed FUT4 can promote cell proliferation, metastasis and anti apoptosis. However, Rg3 is in the growth induced apoptosis of malignant melanoma. The expression of EGFR/MAPK and NF- kappa B signaling pathway with potential regulatory FUT4 is still unclear. Through the study of the regulation of the expression of HDAC3 and FUT4 in Rg3, this study analyzed the signaling pathway of Rg3 in the inhibition of tumor growth induced apoptosis and its regulation in melanoma, and further explored the molecular mechanism of Rg3 mediated anti melanoma. In order to provide a scientific basis for clinical treatment of melanoma. Two, method 1, 32 cases of malignant melanoma were collected from 2003 to 2010 in the pathology department of the first hospital of the First Affiliated Hospital of Dalian Medical University and 32 cases with complete malignant melanoma. The expression of HDAC3 in all the diseased specimens was measured by immunohistochemistry and all the diseases were detected. Follow up. Analyze the correlation between HDAC3 and the patient's clinicopathological features and prognosis. Using the SPSS16.0 statistical software to analyze the data with P0.05 as the significant standard. The difference of the expression between the groups was compared with the x 2 test; 2, the proliferation ability of melanoma cells was analyzed by CCK-8, MTT and cell clone formation; 3, using liposome transient. HDAC3 Si RNA and FUT4 Si RNA were transfected into human melanoma cells to reduce the expression of HDAC3 and FUT4. 4, Real-time PCR method was used to detect HDAC3, PCNA, and expressions. Expression of the protein; 6, the expression of HDAC3, FUT4, PCNA and p65 by immunization}D and immunofluorescence; 7, the cell cycle and apoptosis were analyzed by flow cytometry; 8, the binding of NF- kappa B and DNA was detected by gel electrophoresis mobility (EMSA) method; 9, the activity of p53 and NF- kappa B was detected by luciferase reporter gene; 10, use Chromatin immunoprecipitation (Ch IP) method was used to detect the combination of NF- kappa B and FUT4 promoter region. Three. Results (1) ginsenoside Rg3 inhibits melanoma proliferation and down-regulation of HDAC3, increases the correlation of p53 acetylation, 1, HDAC3 overexpression is related to lymph node metastasis and tumor staging; 2, Rg3 inhibits the growth of melanoma; 3, Rg3 reduces HDAC3 4, down regulated the proliferation of HDAC3 expression inhibition cells; 5, Rg3 and down regulated HDAC3 increased the acetylation and transcriptional activity of p53; 6, Rg3 reduced HDAC3 to change the expression of cell cycle related proteins; 7, Rg3 inhibits the growth of nude mice in vivo. (two) ginsenoside Rg3 inhibits melanoma proliferation and down-regulation of FUT4/Le Y mediated EGFR/MAPK passage Correlation study of inactivation of the road 1, Rg3 inhibits the growth of A375 melanoma cells; 2, Rg3 reduces the expression of FUT4 and Le Y; 3, down regulation of FUT4 inhibits the proliferation of A375 cells and reduces the expression of Le Y; 4, down-regulation of FUT4 expression reduces the phosphorylation of EGFR/MAPK pathway; (three) induction of ginsenoside induction in vivo Melanoma apoptosis and inhibition of FUT4 expression through targeted regulation of NF- kappa B/p65 signaling pathway mechanism 1, Rg3 inhibits the proliferation of human melanoma cells; 2, Rg3 induces apoptosis of melanoma cells; 3, Rg3 inhibits the activity of NF- kappa B signaling pathway; 4, Rg3 downregulation FUT4 expression inhibits NF- kappa B to connect to the promoter region; 5, induces apoptosis passing through Inhibition of NF- kappa B signaling pathway and down regulation of FUT4; 6, Rg3 inhibits the growth of melanoma tumor growth induced apoptosis. Four. Conclusion (1) ginsenoside Rg3 inhibits the proliferation of melanoma and down regulated HDAC3, and increases the correlation of p53 acetylation 1. Rg3 has the effect of inhibiting the growth of melanoma model and melanoma cells in melanoma, and 2, Rg3 downregulation H DAC3 expression has a dose and time dependence; 3, the use of Si RNA or HDAC3 potential inhibitor (MS-275), down regulation of HDAC3 expression to inhibit the proliferation of melanoma cells; 4, Rg3 inhibits the proliferation of melanoma by inhibiting the expression of HDAC3 and increases p53 acetylation and transcriptional activity. (two) ginsenoside Rg3 inhibits melanoma proliferation and downregulation FUT4/Le Y Correlation study mediated inactivation of EGFR/MAPK pathway 1, Rg3 inhibition of melanoma growth is related to down-regulation of FUT4/Le Y; 2, fucose transferase FUT4 is associated with the regulated sugar antigen Le Y expression; 3, Rg3 inhibits the proliferation of melanoma by inhibiting FUT4/Le Y expression and downstream EGFR /MAPK signal pathway. (three) ginsenoside induces melanin Apoptosis and inhibition of FUT4 expression through the targeting mechanism of targeting NF- kappa B/p65 signaling pathway 1, Rg3 can inhibit the growth of melanoma nude mice and melanoma cell growth and induce apoptosis; 2, Rg3 induced apoptosis by down-regulation of NF- kappa B signaling pathway protein and NF- kappa B DNA connection / transcriptional activity; 3, NF- kappa B The promoter region of FUT4 controls the expression of FUT4. 4, Rg3 induces apoptosis to inhibit FUT4 expression through inhibition of NF- kappa B signaling pathway.

【學(xué)位授予單位】：大連醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R739.5

【相似文獻(xiàn)】

相關(guān)期刊論文 前10條

1 陳世文,張榮偉,袁紹紀(jì),司永兵;椎管內(nèi)原發(fā)性黑色素瘤1例[J];中國(guó)誤診學(xué)雜志;2001年10期

2 高紅,焦健;原發(fā)于骶骨部黑色素瘤1例[J];中國(guó)醫(yī)學(xué)影像學(xué)雜志;2001年03期

3 ;白介素-2加組織胺可改善晚期黑色素瘤的存活率[J];中華醫(yī)學(xué)信息導(dǎo)報(bào);2002年04期

4 祝紅輝,魏銳利,蔡季平;原發(fā)性淚囊黑色素瘤1例[J];中國(guó)實(shí)用眼科雜志;2003年11期

5 楊潔;黑色素瘤的治療新進(jìn)展[J];激光生物學(xué)報(bào);2003年03期

6 肖文斌,劉玉蘭;原發(fā)性消化道黑色素瘤的臨床分析[J];中華胃腸外科雜志;2003年01期

7 李建國(guó),陳善紅,孫桂明;變異型黑色素瘤1例[J];中國(guó)誤診學(xué)雜志;2003年02期

8 楊甫文;趙敏;余英豪;;喉部黑色素瘤2例報(bào)告[J];福州總醫(yī)院學(xué)報(bào);2004年04期

9 高金明,陳勇,張志庸,李力,周煒?shù)?發(fā)生于肺部的黑色素瘤一例[J];中華內(nèi)科雜志;2005年04期

10 傅濤,魏文斌,王陽(yáng),劉小超;血清黑色素瘤活性抑制蛋白與葡萄膜黑色素瘤[J];中華眼底病雜志;2005年03期

相關(guān)會(huì)議論文 前10條

1 李東;謝遵江;賀業(yè)春;劉穎;劉麗;;在黑色素瘤組織中免疫細(xì)胞的形態(tài)學(xué)觀察[A];中國(guó)解剖學(xué)會(huì)第八屆組織學(xué)與胚胎學(xué)專業(yè)青年研討會(huì)論文集[C];2004年

2 安菊生;吳令英;李寧;俞高志;劉麗影;;原發(fā)女性生殖道黑色素瘤42例臨床分析[A];中華醫(yī)學(xué)會(huì)第九次全國(guó)婦科腫瘤學(xué)術(shù)會(huì)議論文匯編[C];2006年

3 陳陸霞;孫保存;張?jiān)娢?賀忠江;;眼內(nèi)移植性黑色素瘤微循環(huán)模式的初步研究[A];中華醫(yī)學(xué)會(huì)第十二屆全國(guó)眼科學(xué)術(shù)大會(huì)論文匯編[C];2007年

4 楊志濤;陸洪光;;死亡受體和黑色素瘤的抗凋亡作用[A];中華醫(yī)學(xué)會(huì)第14次全國(guó)皮膚性病學(xué)術(shù)年會(huì)論文匯編[C];2008年

5 鐘傳華;楊文治;王曉蘭;;黑色素瘤與痔診治失誤的啟迪[A];2012醫(yī)學(xué)前沿——中華中醫(yī)藥學(xué)會(huì)肛腸分會(huì)第十四次全國(guó)肛腸學(xué)術(shù)交流大會(huì)論文精選[C];2012年

6 郭軍;;黑色素瘤最新進(jìn)展和未來(lái)趨勢(shì)[A];中國(guó)腫瘤內(nèi)科進(jìn)展 中國(guó)腫瘤醫(yī)師教育（2014）[C];2014年

7 孫保存;張?jiān)娢?劉志勇;張丹芳;郭華;;多西環(huán)素影響黑色素瘤微循環(huán)模式的形成[A];第四屆中國(guó)腫瘤學(xué)術(shù)大會(huì)暨第五屆海峽兩岸腫瘤學(xué)術(shù)會(huì)議論文集[C];2006年

8 郭偉;;口腔頜面-頭頸黏膜黑色素瘤的個(gè)體化診治與思考[A];中國(guó)腫瘤內(nèi)科進(jìn)展 中國(guó)腫瘤醫(yī)師教育（2014）[C];2014年

9 孫保存;張丹芳;張?jiān)娢?郭華;張文治;趙秀蘭;;缺血缺氧對(duì)黑色素瘤局部浸潤(rùn)的相關(guān)分子機(jī)制影響的初步研究[A];中華醫(yī)學(xué)會(huì)病理學(xué)分會(huì)2006年學(xué)術(shù)年會(huì)論文匯編[C];2006年

10 唐亮;;手術(shù)治療足跟底部皮膚黑色素瘤6例臨床分析[A];2013年全國(guó)激光醫(yī)學(xué)學(xué)術(shù)聯(lián)合會(huì)議暨2013年浙江省醫(yī)學(xué)會(huì)整形美容學(xué)術(shù)年會(huì)論文匯編[C];2013年

相關(guān)重要報(bào)紙文章 前10條

1 王倫邋王晨;早期發(fā)現(xiàn)黑色素瘤可挽救生命[N];科技日?qǐng)?bào);2007年

2 倪方;黑色素瘤早治療可痊愈（三）[N];醫(yī)藥養(yǎng)生保健報(bào);2008年

3 健康時(shí)報(bào)特約記者 管九蘋(píng);澳大利亞免費(fèi)普查黑色素瘤[N];健康時(shí)報(bào);2010年

4 實(shí)習(xí)生 易立;黑色素瘤,是否無(wú)藥可治？[N];科技日?qǐng)?bào);2011年

5 記者 張e，

本文編號(hào)：1786111