【摘要】：目的:肺癌的發(fā)病率和死亡率居高不下。此外一些不健康的飲食生活習(xí)慣、外界大氣環(huán)境的污染、職業(yè)粉塵及化學(xué)元素的接觸等危險(xiǎn)因素及煙草行業(yè)的流行帶給我們的影響,都促成著肺癌的發(fā)生與形成,時(shí)刻威脅著人類的健康。由于肺癌的惡性程度較高,且在疾病早期缺乏特異性的臨床癥狀,不能夠做到早發(fā)現(xiàn)、早治療,從而使得病情延誤,大部分患者確診肺癌時(shí)已處于晚期階段,僅以姑息對(duì)癥治療為主,從而大大縮短了生存期。因此,肺癌的診斷,甚至是早期篩查診斷就顯得尤為重要,為延長患者生存時(shí)間、改善患者生活質(zhì)量提供了重要前提。病理學(xué)診斷仍是診斷肺癌的金標(biāo)準(zhǔn)。低劑量CT是目前主要的肺癌篩查手段,但由于其過高的假陽性率、射線輻射效應(yīng)、過度診斷及高昂的檢查費(fèi)用等一系列問題,能否使患者真正受益還存在爭議。近年來,血清肺癌自身抗體的檢測(cè)手段在肺癌的診斷與篩查中顯示出較好的敏感性和特異性,其簡便、無創(chuàng)、便于推廣的特點(diǎn)提高了受試者的依從性,為肺癌的診斷與篩查提供了新思路。p53基因突變導(dǎo)致的p53蛋白失活是癌癥產(chǎn)生的一個(gè)重要步驟。p53自身抗體通常針對(duì)發(fā)生突變的p53基因產(chǎn)物而產(chǎn)生。PGP9.5是表達(dá)在神經(jīng)組織中的一種泛素水解酶,在原發(fā)性肺癌和肺癌細(xì)胞系中有大量表達(dá)。SOX2是一個(gè)轉(zhuǎn)錄因子,誘導(dǎo)腫瘤癌信號(hào)EGFR及BCL2L1,促進(jìn)肺癌細(xì)胞的增殖、存活。GAGE 7屬于腫瘤/睪丸抗原,只表達(dá)于惡性腫瘤和睪丸組織,具有抗細(xì)胞凋亡活性。GBU4-5屬于ATP結(jié)合RNA解旋酶,在癌變過程中發(fā)揮重要作用,同時(shí)有腫瘤特異性和免疫原性。MAGE A1屬人黑色素瘤抗原家族,只表達(dá)于惡性腫瘤和睪丸組織,可能與基因轉(zhuǎn)錄調(diào)節(jié)和癌癥的轉(zhuǎn)化或進(jìn)展有關(guān)。CAGE屬于DEAD box解旋酶家族,它的表達(dá)量與細(xì)胞周期有關(guān),在癌細(xì)胞中激活ERK和p38蛋白并增加腫瘤細(xì)胞的擴(kuò)散。本文收集了不同類型患者的血清標(biāo)本,并應(yīng)用酶聯(lián)免疫法(ELISA)分組進(jìn)行血清七種自身抗體(p53、PGP9.5、SOX2、GAGE7、GBU4-5、MAGEA1、CAGE)水平的檢測(cè),觀察此檢測(cè)方法對(duì)肺癌診斷與篩查的靈敏度和特異度,并對(duì)比組間抗體水平的差異性,探討肺癌自身抗體檢測(cè)方法在肺癌診斷與篩查中的作用。方法:納入2016年11月-2017年2月就診于河北醫(yī)科大學(xué)第四醫(yī)院的患者共140例,經(jīng)病理學(xué)檢查明確組織分型及TNM分期的肺癌,且排除其它臟器惡性腫瘤者88例,設(shè)為肺癌組,經(jīng)影像學(xué)或病理學(xué)檢查排除肺癌及其它臟器惡性腫瘤者47例(包括良性肺部疾病患者34例,健康受試者13例),設(shè)為對(duì)照組,經(jīng)病理證實(shí)為血管免疫母性T細(xì)胞淋巴瘤患者1例、錯(cuò)構(gòu)瘤患者2例、畸胎瘤患者1例、肉瘤患者1例。全血采集后經(jīng)過離心收集血清標(biāo)本,并對(duì)其進(jìn)行分組、編號(hào),用ELISA方法對(duì)血清七種自身抗體進(jìn)行檢測(cè):本實(shí)驗(yàn)采用的試劑盒將純化的七個(gè)抗原包被到固相板表面。向包被抗原的微孔中分別加入稀釋好的血清樣本,經(jīng)孵育使血清樣本中的自身抗體與固相載體上的抗原發(fā)生特異性結(jié)合。洗掉沒有結(jié)合的樣本,加入酶標(biāo)記抗人IgG抗體(酶結(jié)合物)。第二次孵育使酶標(biāo)記抗人IgG抗體與吸附到固相載體上的自身抗體結(jié)合,形成抗原-抗體-酶標(biāo)抗體復(fù)合物,洗掉沒有結(jié)合的酶標(biāo)記抗人IgG抗體,加入顯色劑底物反應(yīng)后用酶標(biāo)儀在450nm波長下測(cè)定其吸光度,通過標(biāo)準(zhǔn)曲線計(jì)算出自身抗體的相對(duì)濃度,并根據(jù)“陽性判斷值”對(duì)檢測(cè)的抗體濃度做出“陰性”、“陽性”的結(jié)果判斷,七種自身抗體的正常上限值如下:p53:13.1U/ml;PGP9.5:11.1U/ml;SOX2:10.3U/ml;GAGE7:14.4U/ml;GBU4-5:7.0U/ml;MAGEA1:11.9U/ml;CAGE:7.2U/ml。(注:本數(shù)據(jù)經(jīng)過2008例大樣本多中心臨床試驗(yàn)驗(yàn)證),從而得出此方法的靈敏度和特異度,并對(duì)比組間檢測(cè)陽性率及組間抗體水平的差異性。非正態(tài)計(jì)量資料組間差異采用Mann-Whitney U檢驗(yàn)。組間檢測(cè)陽性率的比較采用卡方檢驗(yàn)。所有檢驗(yàn)都為雙側(cè)檢驗(yàn),P0.05為差異具有統(tǒng)計(jì)學(xué)意義。結(jié)果:1研究對(duì)象的臨床特征肺癌組納入88例肺癌患者作為研究對(duì)象。其中男性患者56例,占63.6%,年齡范圍分布在35-80歲,平均年齡為61.2±9.4歲,年齡≥60歲者55例,占62.5%;腺癌患者54例,占61.4%,鱗癌患者18例,占20.4%,其它類型肺癌患者16例,占18.2%;有吸煙史者42例,占47.7%;Ⅰ、Ⅱ期肺癌患者53例,占60.2%,Ⅲ、Ⅳ期肺癌患者35例,占39.8%。良性肺部疾病組納入34例良性肺部疾病患者作為研究對(duì)象。其中男性患者18例,占52.9%;年齡范圍分布在25-86歲,平均年齡為54.8±16.2歲,年齡≥60歲者11例,占32.4%;有吸煙史者10例,占29.4%;肺炎患者16例,占47.0%,肺結(jié)核患者9例,占26.5%,慢性阻塞性肺疾病患者5例,占14.7%,其它類型患者4例,占11.8%。健康人群組納入13例健康受試者作為研究對(duì)象。其中男性患者6例,占46.2%;年齡范圍分布在39-76歲,平均年齡為56.5±11.5歲,年齡≥60歲者4例,占30.8%。另有血管免疫母性T細(xì)胞淋巴瘤患者1例、錯(cuò)構(gòu)瘤患者2例、畸胎瘤患者1例、肉瘤患者1例。2肺癌組與對(duì)照組七種自身抗體檢測(cè)陽性率的比較:肺癌組的p53和GBU4-5抗體檢測(cè)的陽性率均高于對(duì)照組(p53:17.0%vs4.3%,P0.05;GBU4-5:15.9%vs0%,P0.05)。其余五種自身抗體在肺癌組與對(duì)照組之間的檢測(cè)陽性率均無統(tǒng)計(jì)學(xué)差異(P0.05)。3七種自身抗體單獨(dú)檢測(cè)對(duì)肺癌篩查的靈敏度、特異度、診斷符合率、正確指數(shù):靈敏度:9.1%-17%;特異度:89.4%-100%;診斷符合率:38.5%-45.2%;正確指數(shù):0.03-0.16。4自身抗體聯(lián)合檢測(cè)對(duì)肺癌篩查的靈敏度、特異度、診斷符合率、正確指數(shù):p53與GBU4-5抗體聯(lián)合檢測(cè)的靈敏度為27.2%,特異度為95.7%,診斷符合率為51.1%,正確指數(shù)為0.23;p53、GBU4-5與MAGEA1抗體聯(lián)合檢測(cè)的靈敏度為34.1%,特異度為91.5%,診斷符合率為54.1%,正確指數(shù)為0.26;七種自身抗體聯(lián)合檢測(cè)的靈敏度為46.6%,特異度為70.2%,診斷符合率為54.8%,正確指數(shù)為0.17。5七種抗體聯(lián)合檢測(cè)對(duì)不同類型肺癌篩查的靈敏度及特異度:七種抗體聯(lián)合檢測(cè)對(duì)肺腺癌診斷的靈敏度為35.2%,特異度為70.2%;對(duì)肺鱗癌診斷的靈敏度為72.2%,特異度為70.2%。6肺癌組與對(duì)照組七種自身抗體表達(dá)水平的比較:肺癌組p53抗體表達(dá)水平高于對(duì)照組(2.30(0.83,7.18)vs1.60(0.20,2.80),P0.05)。其余六種自身抗體在肺癌組與對(duì)照組之間的表達(dá)水平無統(tǒng)計(jì)學(xué)差異(P0.05)。7不同病理類型肺癌與對(duì)照組七種自身抗體表達(dá)水平的比較:7.1肺腺癌與肺鱗癌患者血清七種自身抗體表達(dá)水平的比較:肺鱗癌患者PGP9.5抗體表達(dá)水平高于肺腺癌患者(5.05(2.13,19.85)vs2.45(1.60,3.73),P0.05)。其余六種自身抗體在肺腺癌與肺鱗癌患者之間的表達(dá)水平均無統(tǒng)計(jì)學(xué)差異(P0.05)。7.2肺腺癌患者與對(duì)照組血清七種自身抗體表達(dá)水平的比較:七種自身抗體在肺腺癌患者與對(duì)照組之間的表達(dá)水平均無統(tǒng)計(jì)學(xué)差異(P0.05)。7.3肺鱗癌患者與對(duì)照組血清七種自身抗體表達(dá)水平的比較:肺鱗癌患者血清p53、PGP9.5、MAGEA1抗體的表達(dá)水平均高于對(duì)照組,差異具有統(tǒng)計(jì)學(xué)意義(p53:2.95(1.63,19.70)vs1.60(0.20,2.80),P0.05;PGP9.5:5.05(2.13,19.85)vs2.60(1.90,4.00),P0.05;MAGEA1:2.15(0.20,13.58)vs0.50(0.10,1.70),P0.05)。其余四種自身抗體在肺鱗癌患者與對(duì)照組之間的表達(dá)水平均無統(tǒng)計(jì)學(xué)差異(P0.05)。8Ⅰ、Ⅱ期肺癌患者與Ⅲ、Ⅳ期肺癌患者血清自身抗體表達(dá)水平的比較:Ⅲ、Ⅳ期肺癌患者血清PGP9.5、GBU4-5、CAGE抗體的表達(dá)水平均高于Ⅰ、Ⅱ期肺癌患者,差異具有統(tǒng)計(jì)學(xué)意義(PGP9.5:3.10(2.30,18.10)vs2.30(1.55,3.75),P0.05;GBU4-5:1.50(0.20,22.00)vs0.40(0.00,1.15),P0.05;CAGE:1.70(1.20,8.10)vs1.40(0.20,2.05),P0.05)。其余四種自身抗體在Ⅰ、Ⅱ期與Ⅲ、Ⅳ期患者之間的表達(dá)水平均無統(tǒng)計(jì)學(xué)差異(P0.05)。結(jié)論:1單一抗體檢測(cè)(p53、PGP9.5、SOX2、GAGE7、GBU4-5、MAGEA1、CAGE)對(duì)肺癌篩查的特異度較高(89.4%-100%),靈敏度較低(9.1%-17.0%),尚不能滿足作為肺癌篩查的指標(biāo)。2兩個(gè)(p53與GBU4-5)或三個(gè)(p53、GBU4-5與MAGEA1)肺癌自身抗體聯(lián)合檢測(cè)較單一抗體檢測(cè)可以提高檢測(cè)的靈敏度。3七種血清自身抗體聯(lián)合檢測(cè)對(duì)肺癌篩查的靈敏度為46.6%,特異度為70.2%,推薦七種自身抗體聯(lián)合檢測(cè)技術(shù)應(yīng)用于肺癌的臨床篩查工作中。4 p53、PGP9.5、MAGEA1抗體可作為肺鱗癌與良性肺疾病的鑒別指標(biāo)。5 PGP9.5、GBU4-5、CAGE抗體的表達(dá)水平與腫瘤負(fù)荷相關(guān)。
[Abstract]:Objective: the incidence and mortality of lung cancer are high. In addition, some unhealthy dietary habits, ambient air pollution, occupational dust and chemical elements contact and other dangerous factors, as well as the impact of the tobacco industry, have contributed to the occurrence and formation of lung cancer and threaten human health at all times. Due to lung cancer It has a high degree of malignancy and lack of specific clinical symptoms in the early stage of the disease. It can not be found early, early treatment, so that the disease is delayed, most patients are in the late stage of diagnosis of lung cancer, only with palliative treatment, thus greatly shortening the life period. Therefore, the diagnosis of lung cancer, even early screening and diagnosis, It is particularly important to provide an important prerequisite for prolonging the patient's survival time and improving the quality of life of the patients. The pathological diagnosis is still the gold standard for the diagnosis of lung cancer. Low dose CT is the main screening method for lung cancer at present, but it has a series of problems due to its high false positive rate, radiation effect, diagnosis and high cost of examination. In recent years, the detection of serum lung cancer autoantibodies has shown good sensitivity and specificity in the diagnosis and screening of lung cancer. It is simple, noninvasive and easy to spread, which improves the compliance of the subjects, and provides a new idea for the diagnosis and screening of lung cancer.P53 gene mutation caused by P 53 protein inactivation is an important step in cancer production.P53 autoantibodies usually produce.PGP9.5, a ubiquitin hydrolase expressed in nerve tissue, in response to the mutation of the p53 gene product. In the primary lung cancer and lung cancer cell lines, a large number of.SOX2 are expressed as a transcription factor, inducing cancer signal EGFR and BCL2L1, promoting the tumor cancer signal. The proliferation of lung cancer cells, survival.GAGE 7 belongs to tumor / testicular antigen, only expressed in malignant tumor and testis tissue, with anti apoptotic activity.GBU4-5, which belongs to ATP combined with RNA helicase, plays an important role in the process of carcinogenesis, and there are tumor specific and immunogenic.MAGE A1 human melanoma antigen family, only expressed in malignant swelling. Tumor and testicular tissue may be related to gene transcription regulation and cancer transformation or progression..CAGE belongs to the DEAD box helicase family. Its expression is related to cell cycle, activates ERK and p38 protein in cancer cells and increases the proliferation of tumor cells. This article collected serum specimens of different types of patients and applied enzyme linked immunoassay (ELISA). The serum levels of seven serum autoantibodies (p53, PGP9.5, SOX2, GAGE7, GBU4-5, MAGEA1, CAGE) were detected in the group. The sensitivity and specificity of this detection method to the diagnosis and screening of lung cancer were observed and the difference of the level of antibody between the groups was compared. The role of the self anti examination method of lung cancer in the diagnosis and screening of lung cancer was discussed. Method: 11 in 2016. In February, -2017, 140 cases were diagnosed at the fourth hospital of Hebei Medical University. The lung cancer was identified by pathological examination and TNM staging, and 88 cases of other malignant tumors were excluded. 47 cases of lung cancer and other organ malignant tumors were excluded by imaging or pathological examination (including 34 patients with benign lung disease, 34 For example, 13 healthy subjects were set as control group, 1 cases of vascular immune maternal T cell lymphoma, 2 cases of angiomyolipoma, 2 cases of hamartoma, 1 cases of teratoma and 1 cases of sarcoma. The serum samples were collected by centrifugation after the whole blood collection, and they were grouped and numbered by ELISA method. The purified seven antigen packages were coated on the surface of the solid phase plate. The diluted serum samples were added to the micropores of the coated antigen, and the autoantibodies in the serum samples were specifically combined with the antigen on the solid carrier. The non binding samples were washed away and the anti human IgG antibody (enzyme binding) was added to the enzyme labelled. The second incubation made the enzyme labeled anti human IgG antibody combined with the autoantibody adsorbed on the solid phase carrier, formed an antigen antibody enzyme antibody complex, washed out the anti human IgG antibody with the non binding enzyme label, and then used the enzyme labeled instrument to determine the absorbance at the 450nm wavelength after adding the chromogenic agent substrate and calculated the autoantibody by the standard curve. Relative concentration, and according to the "positive judgement value" to the antibody concentration of the detected "negative", "positive" results to judge the normal upper limit of the seven kinds of autoantibodies as follows: p53:13.1U/ml; PGP9.5:11.1U/ml; SOX2:10.3U/ml; GAGE7:14.4U/ml; GBU4-5:7.0U/ml; MAGEA1: 11.9U/ml; CAGE:7.2U/ml. (Note: this data passes 2008 large samples more. In the central clinical trial, the sensitivity and specificity of this method were obtained, and the difference between the positive rate and the level of intergroup antibody was compared. The difference between the non normal measurement data groups was tested by Mann-Whitney U test. The comparison of the positive rates between groups was checked by chi square test. All the tests were bilateral test, and P0.05 was a differential system. Results: 1 the clinical features of the lung cancer group were included in 88 cases of lung cancer in 56 cases, accounting for 63.6%, the age range was 35-80 years old, the average age was 61.2 + 9.4 years, the age was 60 years old, 55 cases, 62.5%, 54 cases of adenocarcinoma, 61.4%, squamous carcinoma 18, other types of lung cancer. 16 cases, accounting for 18.2%, 42 cases of smoking history, accounting for 47.7%, 53 cases of lung cancer in stage II, 60.2%, III and stage IV lung cancer in 35 cases, which accounted for 34 cases of benign lung disease in 39.8%. benign lung disease group as the research object. Among them, the male patients were 18 cases, accounting for 52.9%, the age range was 25-86 years old, the average age was 54.8 + 16.2 years, the age was more than 6. There were 11 cases of 0 years old, accounting for 32.4%, 10 cases of smoking history, 16 cases of pneumonia, 47%, 9 cases of pulmonary tuberculosis, 26.5%, 5 cases of chronic obstructive pulmonary disease, 14.7%, and other types of patients, which accounted for the healthy subjects of 11.8%. healthy subjects as research subjects. -76 years old, the average age was 56.5 + 11.5 years old, 4 cases aged more than 60 years old, accounting for 1 cases of 30.8%. and 1 cases of vascular immune maternal T cell lymphoma, 2 cases of hamartomas, 1 cases of teratoma, 1 cases of sarcoma patients with.2 lung cancer and the control group. The positive rate of p53 and GBU4-5 antibody in lung cancer group was higher than that of p53 and GBU4-5 antibody. The control group (p53:17.0%vs4.3%, P0.05; GBU4-5:15.9%vs0%, P0.05). The positive rates of the other five kinds of autoantibodies in the lung cancer group and the control group were not statistically different (P0.05).3 seven autoantibodies for lung cancer screening sensitivity, specificity, diagnostic coincidence rate, correct index: sensitivity: 9.1%-17%; specificity: 89.4%-100%; diagnosis. Fracture coincidence rate: 38.5%-45.2%; correct index: sensitivity, specificity, diagnostic coincidence rate and correct index of 0.03-0.16.4 autoantibody combined detection of lung cancer screening: the sensitivity of combined detection of p53 and GBU4-5 antibody was 27.2%, specificity was 95.7%, diagnostic coincidence rate was 51.1%, correct index was 0.23; p53, GBU4-5 and MAGEA1 antibody were sensitive combined detection. The degree is 34.1%, the specificity is 91.5%, the diagnostic coincidence rate is 54.1%, the correct index is 0.26; the sensitivity of the combined detection of seven kinds of autoantibodies is 46.6%, the specificity is 70.2%, the diagnostic coincidence rate is 54.8%, the correct index is the sensitivity and specificity of the combined detection of 0.17.5 seven antibodies against different types of lung cancer screening. Seven kinds of antibodies are combined to detect the lung gland. The sensitivity of the cancer diagnosis was 35.2%, the specificity was 70.2%, the sensitivity of the diagnosis of lung squamous cell carcinoma was 72.2%, the specificity was the comparison of the expression level of seven kinds of autoantibodies in the 70.2%.6 lung cancer group and the control group: the expression level of p53 antibody in the lung cancer group was higher than that of the control group (2.30 (0.83,7.18) vs1.60 (0.20,2.80), P0.05). The other six kinds of autoantibodies were in the lung cancer group and the control There was no statistical difference between the groups (P0.05) the comparison of the expression levels of seven kinds of autoantibodies in different pathological types of lung cancer and control group: 7.1 comparison of the level of serum seven autoantibodies in 7.1 lung adenocarcinoma and squamous cell carcinoma: the expression level of PGP9.5 antibody in lung squamous cell carcinoma was higher than that of lung adenocarcinoma (5.05 (2.13,19.85) vs2.45 (1.60,3.73), P 0.05) the expression level of the other six kinds of autoantibodies in lung adenocarcinoma and lung squamous cell carcinoma was not statistically significant (P0.05) the comparison of the level of seven kinds of autoantibodies in the patients with.7.2 lung adenocarcinoma and the control group: the level of the seven kinds of autoantibodies in the patients with lung adenocarcinoma and the control group had no statistical difference (P0.05).7.3 lung squamous cell carcinoma The expression level of seven kinds of autoantibodies in the serum of the patients and the control group: the levels of serum p53, PGP9.5 and MAGEA1 antibodies in the patients with lung squamous cell carcinoma were higher than those in the control group, and the difference was statistically significant (p53:2.95 (1.63,19.70) vs1.60 (0.20,2.80), P0.05; PGP9.5:5.05 (2.13,19.85) vs2.60 (1.90,4.00)), P0.05). The expression levels of the other four kinds of autoantibodies in the lung squamous cell carcinoma patients and the control group were not statistically different (P0.05).8 I, stage II lung cancer patients and stage III and IV lung cancer patients' serum autoantibody expression levels: III, stage IV lung cancer patients' serum PGP9.5, GBU4-5, CAGE antibody levels were higher than that of stage I, stage II lung cancer patients, The differences were statistically significant (PGP9.5:3.10 (2.30,18.10) vs2.30 (1.55,3.75), P0.05; GBU4-5:1.50 (0.20,22.00) vs0.40 (0.00,1.15), P0.05; CAGE:1.70 (1.20,8.10)). There was no significant difference in the expression level between the other four kinds of autoantibodies in stage I, stage II and stage IV patients. Conclusion: 1 single antibody detection (p53, PGP9.5, SOX2, GAGE7, GBU4-5, MAGEA1, CAGE) with higher specificity (89.4%-100%) for lung cancer screening (89.4%-100%) and low sensitivity (9.1%-17.0%), it is not yet able to meet the two (p53 and GBU4-5) or three of the lung cancer screening indicators (p53 and GBU4-5) or the single antibody detection can improve the sensitivity of seven kinds of detection. The sensitivity of combined detection of serum autoantibodies to lung cancer screening is 46.6% and the specificity is 70.2%. Seven kinds of autoantibody combined detection techniques are recommended for the clinical screening of lung cancer,.4 p53, PGP9.5, MAGEA1 antibody can be used as a differential indicator of lung squamous cell carcinoma and benign lung disease.5 PGP9.5, GBU4-5, CAGE antibody expression and tumor load Relevant.
【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R734.2

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