顺铂注射液联合卡铂注射液对喉癌患者临床疗效的研究

目的 观察顺铂注射液联合卡铂注射液在喉癌患者中的临床疗效。方法 选择2017年4月~2018年1月入院治疗的喉癌患者110例,采用随机数字法分为对照组和观察组,每组55例。对照组采用顺铂注射液治疗,观察组采用顺铂注射液联合卡铂注射液治疗,两组均连续治疗4个疗程,治疗后对两组患者有效率、毒副反应发生率进行评估。结果 观察组顺铂注射液联合卡铂注射液治疗4个疗程疗效率为38.18%,高于对照组23.64%,差异有统计学意义（P＜0.05）;治疗4个疗程后,观察组恶心呕吐、白细胞下降、腹泻、发热、神经毒性及皮疹发生率与对照组相比,差异无统计学意义（P＞0.05）。结论 顺铂注射液联合卡铂注射液用于喉癌患者能提高临床疗效,未增加毒副反应发生率。     

伊立替康联合卡铂辅助化疗对宫颈癌患者血清叶酸、SCC-Ag水平及临床疗效的影响

目的 探讨宫颈癌患者利用伊立替康联合卡铂辅助化疗时,患者血清叶酸、SCC-Ag水平及临床疗效的变化情况.方法 选取2015年7月至2016年4月间于我院确诊的126例宫颈癌患者,随机分为两组,对照组60例患者直接进行广泛全子宫切除及盆腔淋巴结清扫术;实验组患者66 例于术前进行卡铂与伊立替康的联合化疗,再行全子宫切除及盆腔淋巴结清扫术.治疗结束后,对两组患者的血清叶酸、SCC-Ag水平及临床治疗效果进行对比分析,并注意辅助化疗期间进行定期复查,记录毒副反应并给予相应治疗.结果 实验组临床治疗有效率显著优于对照组,两组对比差异具有统计学意义 (P<0.05);两组患者经治疗后血清叶酸水平均增高(P<0.05),实验组的SCC-Ag 水平显著下降,且SCC-Ag 水平低于对照组(P<0.05),实验组中发生骨髓抑制5例,胃肠道反应4例,脱发11例,切口感染2例,不良反应发生率为33.3%,对照组中发生切口感染4例,不良反应发生率为6.1%,两组的不良反应发生率比较差异有统计学意义(P<0.05).结果 对宫颈癌患者实施伊立替康联合卡铂辅助化疗能显著改善患者血清叶酸及SCC-Ag水平,虽然化疗会增加不良反应的发生率,但仍不失为提高临床疗效的重要手段.     

不同紫杉醇剂型联合卡铂治疗卵巢癌的疗效研究

目的 观察卵巢癌（OC）患者中应用不同紫杉醇剂型联合卡铂的临床疗效。方法 收集我院2014年10月~2016年10月收治的70例OC患者的临床资料,随机分为甲组（38例）和乙组（32例）,甲组患者采用注射用紫杉醇脂质体+卡铂治疗,乙组患者采用紫杉醇注射液+卡铂治疗,比较两组近期疗效、远期疗效、副作用、医疗费用。结果 甲组、乙组治疗总有效率分别为68.42%、65.63%,疾病控制率分别为81.58%、78.13%,差异均无统计学意义（P＞0.05）;甲组无进展生存期大于乙组[（15.79±3.02）个月 vs （13.42±2.13）个月],差异有统计学意义（P＜0.05）;两组总生存期比较,差异无统计学意义（P＞0.05）;甲组副作用发生率为10.53%,低于乙组的31.25%,差异有统计学意义（P＜0.05）;甲组医疗费用高于乙组,差异有统计学意义（P＜0.05）。结论 OC治疗中紫杉醇脂质体联合卡铂与紫杉醇注射液联合卡铂近期疗效相当,前者可延长患者无进展生存期,且安全性更高,但医疗费用较高。     

Thalidomide delayed the ability of 4T1 cells to amass into tumors in Balb/c mice

Thalidomide (Thal) can suppress the growth of established, as well as explanted tumors in mice. We wanted to determine if it could suppress the ability of tumor cells to assemble and establish a primary tumor at the injection site. Using the mouse 4T1 mammary tumor model, we fed Thal to mice for 4 days, then injected 10⁵ 4T1 cells into the interscapular region of Balb/c mice. After 20 days on treatment with Thal, all seven control mice, fed with meal had tumors ranging from 3 to 93?mm³ (median 20). Two of the eight mice fed with meal + Thal had no tumors, and the remaining mice had tumors ranging from 2 to 22?mm³ (median 5). The median volume of the tumors in the control group was significantly more than that of mice treated with Thal (p?=?0.03, Mann–Whitney test). In vitro treatment of the 4T1cells with Thal did not inhibit their ability to proliferate, to adhere to plastic, or to bind to Concanavalin-A. Thal caused a marked reduction in the ability of the 4T1 cells to assemble into palpable tumors.     

31P magnetic resonance spectroscopy is sensitive to tumor hypoxia: perfusion and oxygenation of rat 9L gliosarcoma after treatment with BCNU

The mechanism behind the relative increase in high-energy phosphates observed by MRS in many tumors following chemotherapy is poorly understood. To test the hypothesis that this metabolic activation is associated with a decrease in tumor hypoxia, tumor blood flow and oxygenation were measured in tumors that were also analyzed by MRS. 31P MR spectra were acquired with a GE 2T CSI spectrometer from subcutaneous 9L tumors in rats 4 days following treatment with BCNU (10 mg/kg) and from age-matched sham-treated control tumors. BCNU-treated tumors (n = 13) underwent a significant improvement in bioenergetic state compared to control tumors (n = 14), showing a relative increase in high-energy phosphate (Pi/phosphocreatine) (p less than 0.01), and a relative decrease in Pi (Pi/alpha nucleoside biphosphate) (p less than 0.01). Gamma camera imaging of 133Xe washout, following injection of 133Xe in saline into control and treated 9L tumors 4 days after treatment, was used to measure tumor perfusion. Sham-treated control tumors (n = 21) were perfused at a rate of 35.4 (+/- 6.4 SE) mL/100 g/min, while BCNU-treated tumors (n = 20) were perfused at a rate of 55.1 (+/- 7.5 SE) mL/100 g/min (T = 1.96; p less than 0.05). The partial pressure of oxygen (pO2), measured with a polarographic electrode was found to be significantly higher in treated 9L than in sham-treated controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Simple and rapid determination of carboplatin in plasma by high-performance liquid chromatography. Error pattern and application to clinical pharmacokinetic studies

Carboplatin is an antitumor agent widely employed in cancer chemotherapy. A specific and selective method for the determination of carboplatin in human plasma and its applications to pharmacokinetic investigations is described. One ultrafiltration step, through a Centrifree micropartition system (Amicon) at 2000 g for 10 min, is the only requirement as sample treatment. The resulting solution is injected into an Inertsil ODS-2 (5 microm, 25 cm x 4.6 mm I.D.) analytical column. The mobile phase consisted of 0.1 M potassium dihydrogenphosphate with 1 mM dipotassium edetate adjusted to a pH between 3 and 3.5. The limit of quantitation was 1 mg/l. The method showed good recovery (100.68+/-5.49%) and precision: the within-day relative standard deviation (RSD) for carboplatin (3-350 mg/l) was 2.07% and the between-day RSD for carboplatin, in the previously described range, was 1.31%. We determined the assay error pattern for proper weighting of serum level data in pharmacokinetic models. The selectivity (discrimination between the parent drug and platinum-containing species such as carboplatin metabolites), simplicity and speed of this assay for free carboplatin quantitation should facilitate pharmacokinetic investigations and therapeutic drug monitoring.     

Thalidomide delayed the ability of 4T1 cells to amass into tumors in Balb/c mice

Thalidomide (Thal) can suppress the growth of established, as well as explanted tumors in mice. We wanted to determine if it could suppress the ability of tumor cells to assemble and establish a primary tumor at the injection site. Using the mouse 4T1 mammary tumor model, we fed Thal to mice for 4 days, then injected 10(5) 4T1 cells into the interscapular region of Balb/c mice. After 20 days on treatment with Thal, all seven control mice, fed with meal had tumors ranging from 3 to 93?mm(3) (median 20). Two of the eight mice fed with meal + Thal had no tumors, and the remaining mice had tumors ranging from 2 to 22?mm(3) (median 5). The median volume of the tumors in the control group was significantly more than that of mice treated with Thal (p?=?0.03, Mann-Whitney test). In vitro treatment of the 4T1cells with Thal did not inhibit their ability to proliferate, to adhere to plastic, or to bind to Concanavalin-A. Thal caused a marked reduction in the ability of the 4T1 cells to assemble into palpable tumors.     

多发性硬化症患者APL特异性T细胞系免疫生物学特性分析

本文报告采用髓鞘碱性蛋白 (MBP )的修饰性肽段配体 (APL )对多发性硬化症 (MS )患者治疗 1年后 ,在细胞克隆水平分析T细胞免疫应答的结果。从 5例患者外周血淋巴细胞中建立了 31个APL特异性T细胞系。首先测定患者和健康人体内APL特异性T细胞的反应频率 ,发现患者中平均为 31 6%± 2 3 7% ,而 10例对照者中仅为 5 %± 2 %。 31株APL反应性T细胞系对APL抗原表现出高度的增殖特异性。同时发现 ,APL特异性T细胞系与MBP优势肽段 (氨基酸 83 99)发生交叉反应的比例 ,患者中为 19 4% (6/ 31) ,而对照组中仅有 4 3% (1/ 2 3)。未发现与MBP优势肽段 83 99有交叉反应。来自MS治疗组的APL特异性T细胞系中 ,67%分泌IL 5和 /或IL 13,表明这些T细胞系具有Th2细胞特性。以上结果提示 ,这一修饰性MBP多肽作为一种治疗性疫苗 ,有可能在体内通过诱导Th2调节细胞 ,下调自身反应性T细胞介导的免疫损伤 ,发挥治疗作用。     

Outcome of surgical treatment for early adenocarcinoma of the esophagus or gastro-esophageal junction

Adenocarcinoma of the esophagus, or GEJ, has a poor prognosis. Early lesions [i.e. high grade dysplasia (HGD) or T1-carcinoma] are potentially curable. Local endoscopic therapies are promising treatment options for superficial lesions; however, for deeper lesions, surgical resection is considered to be the treatment of choice. To contribute to therapeutic decision-making, we retrospectively analysed the outcome of transhiatal esophagectomy in 120 patients with pathologically proven HGD (n=13) or T1-adenocarcinoma (n=107) of the distal esophagus or gastro-esophageal junction (GEJ). Tumors were subdivided into six different depths of invasion (T1-mucosal m1-m3, T1-submucosal sm1-sm3), and the frequency of lymphatic dissemination and time to locoregional and/or distant recurrence were analysed. Only one of the 79 T1m1-3/sm1 tumors (1%) showed lymph node metastases as compared with 18 out of 41 T1sm2-3 tumors (44%). There was a significant difference in recurrence-free period between T1m1-m3/sm1 versus T1sm2-sm3 tumor patients (P log rank <0.0001), with 5-year recurrence-free percentages of 97% and 57%, respectively. In multivariate analysis including age, gender, tumor differentiation grade, N-stage and depth of invasion, only N-stage was an independent prognostic factor for recurrence-free period (hazard rate=5.9, 95% CI 1.7–20.7). However, if N-stage was excluded from analysis, only depth of invasion (T1sm2-3 versus T1m1-m3/sm1) was an independent prognostic factor for recurrence-free period (hazard rate=7.5, 95% CI 2.0–27.7). These data indicate that T1m1-m3/sm1 adenocarcinomas of esophagus or GEJ show a very low risk of lymphatic dissemination and are therefore eligible for local endoscopic therapy. After transhiatal surgical resection, almost half of the patients with T1sm2-sm3 lesions develop recurrent disease within 5 years, and therefore need additional therapy to improve survival.     

ATR 抑制剂联合卡铂对裸鼠乳腺癌移植瘤的作用及其对组织 BRG1、 RAD51、 PALB2 的影响

目的 探究 ATR 抑制剂联合卡铂对裸鼠乳腺癌移植瘤的作用及其对组织 BRG1、 RAD51、 PALB2 的影响。 方法 将 40 只乳腺癌移植瘤模型裸鼠随机分为对照组、 卡铂组、 ATR 抑制剂 M6620 组和卡铂 + M6620 组 (n = 10)。 记录肿瘤体积和质量, RT-qPCR 和 Western 印迹检测肿瘤组织中 Ki67、 MMP2、 N-cadherin、 E-cadherin mRNA 和蛋白表达量, 免疫组化检测 Brahma 相关基因 1 (Brahma related gene 1, BRG1)、 重组酶 51 (recombinase 51, RAD51)、 乳腺癌易感基因 2 定位协作蛋白 ( breast cancer susceptibility gene 2 localization collaboration protein, PALB2) 蛋白水平。 结果 卡铂组和 M6620 组的肿瘤质量、 体积、 Ki67、 MMP2、 N-cadherin mRNA 和蛋白水平, 以及 BRG1、 RAD51、 PALB2 蛋白水平显著低于对照组, E-cadherin mRNA 和蛋白显著高于对照组 (P< 0. 05)。 卡铂 + M6620 组的肿瘤质量、 体积、 Ki67、 MMP2、 N-cadherin mRNA 和蛋白水平, 以及 BRG1、 RAD51、 PALB2 蛋白水平显著低于卡铂组和 M6620 组, 而 E-cadherin mRNA 和蛋白显著高于卡铂组和 M6620 组 (P< 0. 05)。 结论 ATR 抑制剂联合卡铂可抑制裸鼠乳腺癌移植瘤 的生长和组织中 BRG1、 RAD51、 PALB2 的表达。     

Monitoring response to chemotherapy of non-Hodgkin's lymphoma xenografts by T(2)-weighted and diffusion-weighted MRI

An effective method for in vivo detection of early therapeutic response of patients with non-Hodgkin's lymphoma would enable personalized clinical management of cancer therapy and facilitate the design of optimal treatment regimens. This study evaluates the feasibility of T(2)-weighted MRI (T2WI) and diffusion-weighted MRI (DWI) for in vivo detection of response of human diffuse large B-cell lymphoma xenografts in severe combined immunodeficient mice to chemotherapy. Each cycle of combination chemotherapy with cyclophosphamide, hydroxydoxorubicin, Oncovin, prednisone, and bryostatin 1 (CHOPB) was administered to tumor-carrying mice weekly for up to four cycles. T2WI and DWI were performed before the initiation of CHOPB and after each cycle of CHOPB. In order to corroborate the MRI results, histological analyses were carried out on control tumors and treated tumors after completion of all MRI studies. DWI revealed a significant (P < 0.03) increase in the mean apparent diffusion coefficient in CHOPB-treated tumors as early as 1 week after initiation of CHOPB. However, a significant (P < 0.03) decrease in mean T(2) was observed only after two cycles of CHOPB. Both MRI methods produced high-resolution (0.1 x 0.1 x 1.0 mm(3)) maps of regional therapeutic response in the treated tumors based on local apparent diffusion coefficient and T(2). Only a specific region of the tumors (in 3 of the 5 tumors) corresponding to about one third of the tumor volume exhibited a response-associate increase in ADC and decrease in T(2). An adjacent region exhibited an increase in T(2) and no change in ADC. The rest of the tumor was indistinguishable from sham-treated controls by MRI criteria. The therapeutic response of the treated tumors detected by MRI was accompanied by changes in tumor cell density, proliferation and apoptosis revealed by histological studies performed upon completion of the longitudinal study. The mechanism producing the regional response of the tumor remains to be elucidated.     

Effects of estradiol,cyproterone acetate,tibolone and raloxifene on uterus and aorta atherosclerosis in oophorectomized cholesterol-fed rabbits

BACKGROUND: Different hormonal replacement regimens are used for treating climacteric complaints; however, not all of them have the same clinical profile. Cardiovascular disease (CVD) is a major health problem and tibolone, raloxifene, estradiol (alone or with cyproterone acetate) have been added to cholesterol-fed rabbits to study atherosclerosis. METHODS: A total of 48 cholesterol-fed New Zealand white rabbits were studied for 4 months. Forty rabbits underwent bilateral ovariectomy and the other eight were sham operated (group S). The ovariectomized rabbits were allocated to five groups of eight animals each receiving tibolone (Group T, 6 mg/day), raloxifene (R, 35 mg/day), estradiol valerate (E, 3 mg/day), estradiol valerate plus cyproterone acetate (EC, 3+0.5 mg/day, respectively), and no treatment for the control group (C). The sham group received no treatment too. RESULTS: After 4 months the percentage of the extent of atherosclerosis in the aorta was 30.4% in C group, 24.5% in S group, 10.2% in T group, 30.3% in R group, 17.9% in E group and 28.1% in EC group (P<0.05 T vs. C, R, EC). The aortic cholesterol content compared with aortic weight was 8.55 microg/mg in C group, 11.97 microg/mg in S group, 1.86 microg/mg in T group, 3.82 microg/mg in R group, 2.86 microg/mg in E group and 5.24 microg/mg in EC group (P<0.05 T vs. EC, C, S; R vs. C, S; E vs. C, S). Uterine weights in grams were: 1.89 (C group), 2.24 (S), 7.38 (T), 1.94 (R), 9.92 (E), and 5.94 (EC); P<0.05 (C, S, R, vs. T, E, EC; T vs. E; EC vs. T, E). CONCLUSION: Our study showed a decrease in the extent of aortic atherosclerosis in oophorectomized cholesterol-fed rabbits treated with tibolone or estradiol, and a decrease in aortic cholesterol content in rabbits treated with tibolone, raloxifene and estradiol. However, rabbits treated with tibolone showed an increased uterine weight, which is contrary to that observed in humans.     

Effects of Z-100, a Mycobacterium-tuberculosis-derived arabinomannan, on the LP-BM5 murine leukemia virus infection in mice.

OBJECTIVE: To investigate the effects of Z-100, an arabinomannan extracted from Mycobacterium tuberculosis, on the LP-BM5 murine leukemia virus (LP-BM5 MuLV) infection in mice. METHODS: C57BL/6 mice infected intraperitoneally with 4.5 x 10(2) PFU/mouse of LP-BM5 MuLV (MAIDS mice) were treated intraperitoneally with a 10-mg/kg dose of Z-100 every other day beginning 1 day after the viral infection. MAIDS mice treated with Z-100 were compared with control mice (MAIDS mice treated with saline) for their survival and splenomegaly after LP-BM5 infection. Cytokine-producing profiles of splenic T cells from these two groups of mice were also compared. RESULTS: When MAIDS mice treated with Z-100 were compared with those of control mice, a decrease in splenomegaly and lymphadenopathy was observed. Splenomegaly was markedly enhanced in MAIDS mice treated intraperitoneally with IL-4 or IL-10. When MAIDS mice were treated with Z-100, their survival rates were significantly increased compared to those of controls. Splenic T cells from control mice produced type-2 cytokines (IL-4 and IL-10). However, a decreased production of type-2 cytokines by splenic T cells from MAIDS mice treated with Z-100 was demonstrated. CONCLUSION: Z-100 could decrease the severity of the LP-BM5 MuLV infection through the regulation of MAIDS-associated type-2 T-cell responses.     

Induction of pancreatic islet cell tumors in rats by repeated intravenous administration of 4-hydroxyaminoquinoline 1-oxide.

The inducibility of pancreatic islet cell tumors by administration of 4-hydroxyaminoquinoline 1-oxide (4HAQO) was investigated in male 6-week-old Sprague-Dawley rats. Rats were given 4HAQO intravenously at a weekly dose of 5 mg/kg 4 times (group 1) or a single dose of 10 mg/kg (group 2). Control rats received the vehicle alone (group 3). Fifty-six weeks after the first 4HAQO administration, all surviving animals were killed and the pancreas was examined histopathologically, immunohistochemically and ultrastructurally. The incidences and multiplicities of islet cell tumors in groups 1, 2, and 3 were 52.3% (p < 0.05 vs group 2, p < 0.01 vs group 3), 19.2% and 0%, and 0.70/animal (p < 0.05 vs group 2, p < 0.01 vs group 3), 0.23 and 0, respectively. Islet cell carcinomas were induced only in group 1, accounting for 6/44 (26%) tumors. Islet cell hyperplasias were found in 61.4% (p < 0.05 vs group 3), 42.3% and 10.0% of groups 1, 2, and 3, with multiplicities of 0.95 (p < 0.05 vs groups 2 and 3), 0.54 and 0.20, respectively. As compared with normal islets from control subjects, islet cell tumors showed an increase in the number of insulin positive cells associated with cytological features indicative of enhanced insulin synthesis and secretion, and a decrease in the number of glucagon positive cells without ultrastructural signs of modified secretory activity. Thus our results indicate that repeated intravenous administration of 4HAQO to rats is useful for the induction of islet cell tumors at high incidence.     

流式细胞术检测调节性T细胞方法的建立

目的建立流式细胞术（FCM）检测外周血CD4＋CD25＋调节性T细胞（Tregs）的方法，并观察紫杉醇联合卡铂治疗对晚期肺癌和乳腺癌患者外周血CD4＋CD25＋Tregs数量的影响。 方法19例晚期肺癌和10例乳腺癌患者均给予紫杉醇联合卡铂方案化疗，于化疗前1d和化疗后第7天采集患者外周血，分别加入鼠抗人CD4-FITC（异硫氰酸荧光素）/CD8-PE（藻红蛋白）/CD3-PerCP（多甲藻叶绿素蛋白）、CD25-FITC/CD127-PE/CD4-PerCP、CD3-FITC/CD（16＋56）-PE/CD45-PerCP单抗，并以分别加入同型鼠抗人IgG1-FITC、IgG1-PE、IgG1-PerCP抗体作为阴性对照。采用流式细胞术（FCM）检测化疗前后外周血CD3＋、CD4＋、CD8＋T细胞和CD4＋CD25＋Tregs、NK细胞所占比例并进行数据分析。实验重复3次。 结果与化疗前比较，晚期肺癌和乳腺癌患者化疗后外周血CD4＋CD25＋Tregs的比例均明显降低（6.82%±3.11%vs.5.48%±2.13%，P=0.045；6.38%±1.84%vs.3.88%±1.69%，P=0.007）；晚期肺癌患者化疗后外周血CD4＋T细胞的比例升高（48.84%±16.44%vs.56.35%±14.50%，P=0.006），CD8＋T细胞的比例降低（51.18%±16.44%vs.43.65%±14.50%，P=0.006），CD4＋/CD8＋T细胞比值升高（1.12±0.60vs.1.57±0.88，P=0.008），而CD3＋T细胞和NK细胞的比例均无明显变化；乳腺癌患者化疗后外周血CD3＋、CD4＋、CD8＋T细胞、NK细胞的比例和CD4＋/CD8＋T细胞比值均无明显变化。 结论成功建立了FCM检测CD4＋CD25＋Tregs的方法，联合应用CD4、CD25、CD127检测CD4＋CD25＋Tregs简便可行、重复性好，检测结果可靠、准确，比较适用于临床检验。紫杉醇联合卡铂能够降低晚期肺癌和乳腺癌患者外周血CD4＋CD25＋Tregs的数量。     

Toxicity profiles in rats treated with tumorigenic and nontumorigenic triazole conazole fungicides: Propiconazole, triadimefon, and myclobutanil

Conazoles are a class of azole based fungicides used in agriculture and as pharmaceutical products. They have a common mode of antifungal action through inhibition of ergosterol biosynthesis. Some members of this class have been shown to be hepatotoxic and will induce mouse hepatocellular tumors and/or rat thyroid follicular cell tumors. The particular mode of toxic and tumorigenic action for these compounds is not known, however it has been proposed that triadimefon-induced rat thyroid tumors arise through the specific mechanism of increased TSH. The present study was designed to identify commonalities of effects across the different conazoles and to determine unique features of the tissue responses that suggest a toxicity pathway and a mode of action for the observed thyroid response for triadimefon. Male Wistar/Han rats were treated with triadimefon (100, 500, 1800 ppm), propiconazole (100, 500, 2500 ppm), or myclobutanil (100, 500, 2000 ppm) in feed for 4, 30, or 90 days. The rats were evaluated for clinical signs, body and liver weight, histopathology of thyroid and liver, hepatic metabolizing enzyme activity, and serum T3, T4, TSH, and cholesterol levels. There was a dose-dependent increase in liver weight but not body weight for all treatments. The indication of cytochrome induction, pentoxyresorufin O-dealkylation (PROD) activity, had a dose-related increase at all time points for all conazoles. Uridine diphopho-glucuronosyl transferase (UDPGT), the T4 metabolizing enzyme measured as glucuronidation of 1-naphthol, was induced to the same extent after 30 and 90 days for all three conazoles. Livers from all high dose treated rats had centrilobular hepatocyte hypertrophy after 4 days, while only triadimefon and propiconazole treated rats had hepatocyte hypertrophy after 30 days, and only triadimefon treated rats had hepatocyte hypertrophy after 90 days. Thyroid follicular cell hypertrophy, increased follicular cell proliferation, and colloid depletion were present only after 30 days in rats treated with the high dose of triadimefon. A dose-dependent decrease in T4 was present after 4 days with all 3 compounds but only the high doses of propiconazole and triadimefon produced decreased T4 after 30 days. T3 was decreased after high-dose triadimefon after 4 days and in a dose-dependent manner for all compounds after 30 days. Thyroid hormone levels did not differ from control values after 90 days and TSH was not increased in any exposure group. A unique pattern of toxic responses was not identified for each conazole and the hypothesized mode of action for triadimefon-induced thyroid gland tumors was not supported by the data.     

CTLA4Ig可诱导T淋巴细胞对氧化修饰低密度脂蛋白的免疫无反应性

 目的 研究融合蛋白CTLA4Ig对氧化修饰低密度脂蛋白（ox-LDL）诱导的T淋巴细胞特异性免疫反应的作用，探索预防和延缓动脉粥样硬化发生和发展的新途径。方法 从健康成人外周血分离单核细胞，加入500 IU/ml的重组人粒单细胞集落刺激因子（rhGM-CSF）和500 IU/ml的重组人白细胞介素4（rhIL-4），培养6 d。取 1×106个细胞以流式细胞仪检测CD14的表达，其余细胞分为4组，分别加入细菌脂多糖（LPS）30 ng/ml（LPS 组）、LDL 10 μg/ml（LDL 组）、ox-LDL 10 μg/ml（ox-LDL组）和相同体积的PBS（PBS组），作用48 h，以流式细胞仪检测CD86和HLA-DR的阳性表达率和平均荧光强度（MFI）。将各组DC与同种异体T淋巴细胞以1:5和1:10的比例混合进行同种异体混合淋巴细胞增殖反应（MLR），其中ox-LDL 组在1:5的试验中分为4个亚组，分别给予加入1.25、0.62、0.31 μg/ml的CTLA4Ig和不加CTLA4Ig的处理，各组细胞继续培养 4 d，以噻唑蓝（MTT）比色法检测T淋巴细胞增殖活性，结果以刺激指数（SI）表示。结果 细胞培养6 d后CD14的阳性表达率为2.9%，证实已由单核细胞转化为DC。LPS组、ox-LDL组CD86阳性表达率（96.0%±8.8%，97.7%±11.4%）和HLA-DR阳性表达率（90.3%±8.8%，90.9%±7.0%）均明显高于LDL组（90.0%±10.2%，84.4%±9.6%）和PBS组（87.3%±8.4%，83.6%±7.0%）（均P<0.05），ox-LDL组CD86 MFI（73.4±6.6）和HLA-DR MFI（87.0±7.1）均明显高于LDL组（40.0±7.4，55.0±7.7，均P<0.01）和PBS组（54.6±8.2，P<0.01；70.2±6.7，P<0.05）。在MLR中，DC:T细胞=1:5和1:10两种条件下，LPS组、ox-LDL组SI均明显高于LDL组和PBS组（均P<0.05）。在ox-LDL组的MLR中，以1.25、0.62、0.31和0 μg/ml的CTLA4Ig处理的各亚组SI分别为0.96±0.30，1.12±0.33，1.29±0.28和1.64±0.37，CTLA4Ig 浓度为1.25 μg/ml时，ox-LDL激发的同种异体MLR已被完全抑制。结论 ox-LDL可作为抗原被DC递呈，激发同种异体MLR；CTLA4 Ig能明显抑制该作用，诱导T细胞对ox-LDL的免疫无反应。这一结果为动脉粥样硬化防治的研究提示了新的思路。     

Chromosomal imbalances in brain metastases of solid tumors

Metastases account for approximately 50% of the malignant tumors in the brain. In order to identify structural alterations that are associated with tumor dissemination into the central nervous system we used Comparative Genomic Hybridization (CGH) to investigate 42 brain metastases and 3 primary tumors of 40 patients. The metastases originated from lung cancer (14 cases), melanomas (7), carcinomas of breast (5), colon (5), kidney (5), adrenal gland (1) and thyroid (1). In addition, tumors of initially unknown primaries were assessed in 3 cases. The highest incidence of DNA gains were observed for the chromosomal regions 1q23, 8q24, 17q24-q25, 20q13 (>80% of cases) followed by the gain on 7p12 (77%). DNA losses were slightly less frequent with 4q22, 4q26, 5q21, 9p21 being affected in at least 70% of the cases followed by deletions at 17p12, 4q32q34, 10q21, 10q23-q24 and 18q21-q22 in 67.5% of cases. Two unusual narrow regional peaks were observed for the gain on 17q24-q25 and loss on 17p12. The incidence at individual loci can be viewed at our CGH online tumor database at http:// amba.charite.de/cgh/. The metastases of each tumor type showed a recurrent pattern of changes. In those cases with primary tumor and metastases available, the CGH pattern exhibited a high degree of conformity. In conclusion, our data suggests that specific genetic lesions are associated with tumor dissemination into the nervous system and that CGH analysis may be a useful supplementary tool for classification of metastases with unknown origin.     

新生大鼠高胆红素血症及脑病模型的建立与评价

 目的：建立新生SD大鼠高胆红素血症和胆红素脑病模型并评价其效果。方法：将3 日龄 SD新生大鼠按窝系和体重随机均分为7组,分别经腹腔注射生理盐水（Con）以及胆红素6.25 μg/g（T1）、12.5 μg/g（T2）、25 μg/g（T3）、50 μg/g（T4）、100 μg/g（T5）和200 μg/g（T6）,每天2次,共3 d。末次注射12 h后拍照、称重、取材,称量胃内容物重量,计算胃内容物指数和肝/体重比,测定血清总胆红素和游离胆红素浓度,检测脑组织的含水量、胆红素含量和ATP含量,HE和尼氏染色进行形态学检测。结果：随着注射次数和剂量的增加,新生鼠的一般表现逐渐变差,皮肤和黏膜黄染加重,活动次数逐渐减少,体重增长被抑制,T6组出现体重负增长;死亡率逐渐升高,T6 组72 h死亡率接近100%,停止注射后观察1周,T4和T5组死亡率继续升高;与Con和T1组相比,T3~T5组胃内容物重量及其指数显著降低（P<0.05）;T5 组肝/体重比显著升高（P<0.05）;血清总胆红素、游离胆红素和脑组织总胆红素的浓度在T1~T5组逐渐递增;各组大鼠脑组织的含水量没有差异;脑组织ATP含量在T1~T5组先升高后降低,T3组达高峰,与Con 组相比,T4 组和T5 组显著降低(P<0.05)。HE染色结果显示：随着胆红素浓度升高,各组大鼠大脑皮层神经元数量逐渐减少,T4和T5组神经元结构紊乱,细胞肿胀,部分细胞核染色质致密浓缩。尼氏染色显示,随着胆红素浓度增多,神经元胞体逐渐变小,尼氏小体减少、染色逐渐变浅,T4和T5组部分神经元溶解甚至消失。结论：新生3 日龄SD大鼠腹腔注射胆红素12.5、25、50和100 μg/g,每天2次,注射3 d可致高胆红素血症,50和100 μg/g可引起胆红素脑病的发生。     

氧控制性再灌注抗犬体外循环肺缺血再灌注早期损伤过程中高迁移族蛋白1的表达

目的 探讨氧控制性再灌注抗犬体外循环肺缺血再灌注早期损伤过程中高迁移族蛋白1(HMGB1)的表达.方法 健康犬14只按完全随机法分为对照组(n=7)和实验组(n=7),均进行体外循环肺缺血再灌注.对照组全程吸入氧浓度(FiO2)80%;实验组在主动脉开放即刻调整FiO2至40%,随后每5 min依次上调10%,最后达80%,其余时段均维持FiO2 80%.观察2组犬在麻醉后、主动脉开放前、主动脉开放后5、10、15、20、25 min以及停机前动脉血氧分压(PaO2)的变化.在开胸后即刻(T1)、主动脉开放25 min(T2)、主动脉开放90min(T3)分别留取血液标本及肺组织标本,检测肺组织HMGB1及NF-κB的表达,酶联免疫吸附法(ELISA)检测血清IL-6和TNF-α含量;检测肺组织湿干质量比及肺组织髓过氧化物酶(MPO)活性、丙二醛(MDA)含量;观察肺组织病理学变化.结果 实验组PaO2在主动脉开放后5、10、15、20min均显著低于对照组(均P＜0.05).与对照组比较,在T2和T3时点实验组HMGB1 mRNA表达(T2:0.9260±0.013 9比1.0496±0.0306;T3:0.832 5±0.0154比0.9894±0.0144,均P＜0.05)和蛋白表达(T2:0.434 5±0.074 8比0.551 2±0.047 4;T3:0.449 0±0.054 1比0.545 5±0.040 6,均P＜0.05)均降低.实验组肺组织NF-κB蛋白表达在T2和T3时点低于对照组(均P＜0.05).实验组血清IL-6和TNF-α含量在T2和T3时点低于对照组(均P＜0.05).实验组肺组织湿干质量比、MPO活性、MDA含量在T2和T3时点均低于对照组(均P＜0.05).实验组肺损伤评分在T2和T3时点均低于对照组[T2:(2.0±0.7)分比(3.8±0.5)分;T3:(2.6±0.6)分比(4.2±0.8)分,均P＜0.05].结论 氧控制性再灌注对体外循环肺缺血再灌注早期损伤具有保护作用,其机制可能与下调HMGB1表达有关.