细胞周期调控因子在分化型甲状腺癌中的表达及相关性研究

目的：研究细胞周期调控因子p16、p27和CyclinD1在分化型甲状腺癌中的蛋白表达情况，及其在分化型甲状腺癌发生发展中的作用。方法：应用免疫组化S—P法对40例分化型甲状腺癌包括甲状腺乳头状癌和滤泡癌以及30例甲状腺腺瘤组织中p16、p27和CyclinD1的蛋白表达情况进行检测。结果：p16、p27和cyclinD1三种蛋白在40例分化型甲状腺癌的阳性表达率分别为57．5％、70．0％和62．5％；p16蛋白的阳性表达量与分化型甲状腺癌的颈淋巴结转移之间具有相关性（P〈0．05）；p27蛋白的阳性表达量与分化型甲状腺癌的颈淋巴结转移和原发灶的大小及包膜侵犯之间具有相关性（P〈0．05）；CyclinD1蛋白的阳性表达量与分化型甲状腺癌的颈淋巴结转移和原发灶的包膜侵犯之间具有相关性（P〈0．05）；p16的阳性表达与CyclinD1的阳性表达之间具有相关性（P〈0．05），且呈负相关关系（rs=-0．283）；p27的阳性表达与CyclinD1的阳性表达之间具有相关性（P〈0．05），且呈负相关关系（rs=-0．279）。结论：p16、p27和CyclinD1三种蛋白的异常表达共同参与了分化型甲状腺癌的发生发展，可能成为判断分化型甲状腺癌恶性程度、转移及预后的指标。     

细胞周期调控因子与下咽癌生物学行为相关性初步研究

目的：探讨细胞周期调控因子与下咽癌临床生物学行为之间的关系。方法：取下咽鳞状细胞癌手术标本53例，癌旁正常粘膜标本11例，应用免疫组化SP法检测P27^Kipl、Cyelin D1、CDK4在下咽癌组织及正常粘膜中的表达。结果：P27^Kipl、CyclinD1、CDK4均为弥漫性细胞核表达。P27^Kipl。在下咽癌中的表达低于正常粘膜．且表达与N分级明显相关（P〈0．05）；CyclinD1在下咽癌中的表达高于正常粘膜，且表达与T分级明显正相关（P〈0．05）：CDK4在下咽癌中的表达高于正常粘膜，且表达与T分级、N分级明显正相关（P〈0．01、P〈0．05）P27^Kipl与CyclinD1．P27^Kipl与CDK4在下咽癌组织中多呈反向表达，CyclinD1与CDK4多呈同向表达。结论：CyclinD1、CDK4与P27^Kipl在下咽癌发病机制中共同作用．对预后有一定的参考价值。     

MCM7、CDK2及 Ki-67蛋白在甲状腺癌中表达的临床意义

目的探讨甲状腺癌中MCM7、CDK2及Ki-67蛋白表达的临床意义。方法收集甲状腺乳头状癌、甲状腺腺瘤、结节性甲状腺肿及正常甲状腺标本各30例,然后用免疫组织化学SP法来检测所选甲状腺组织标本中MCM7、CDK2及Ki-67蛋白的表达。结果 MCM7、CDK2及Ki-67蛋白在甲状腺癌中表达的阳性率分别为100.00%(30/30)、80.00%(24/30)及83.33%(25/30),三者在甲状腺乳头状癌中的阳性率均明显高于甲状腺腺瘤、结节性甲状腺肿及正常甲状腺。甲状腺癌中MCM7、CDK2及Ki-67蛋白的表达呈正相关。结论 MCM7、CDK2及Ki-67蛋白的高表达与甲状腺乳头状癌存在一定的关联,三者表达的检测可为临床上早期诊断及评价甲状腺乳头状癌的预后提供重要的参考依据。     

甲状腺乳头状癌组织中DAPK1与RARβ的表达及临床意义

目的：通过检测新疆地区甲状腺乳头状癌组织及甲状腺良性病变组织中DAPK1和RARβ的蛋白表达特点,探讨其在甲状腺乳头状癌发生发展中的意义。方法：采用免疫组织化学S-P法,检测DAPK1与RARβ在新疆地区38例甲状腺乳头癌、21例甲状腺良性腺瘤、13例桥本氏甲状腺炎、6例结节性甲状腺肿和6例癌旁正常甲状腺组织中的蛋白表达,并分析其与临床病理因素间的关系。结果：DAPK1在甲状腺乳头状癌中的阳性表达明显低于甲状腺腺瘤、桥本氏甲状腺炎、结节性甲状腺肿和癌旁正常甲状腺组织（P〈0.01）;RARβ在甲状腺乳头状癌中的阳性表达明显高于在甲状腺良性腺瘤、桥本氏甲状腺炎、结节性甲状腺肿和癌旁正常甲状腺组织（P〈0.01）;DAPK1与RARβ在甲状腺乳头状癌中的表达与患者的年龄、性别、民族无明显相关关系（P〉0.05）。结论：DAPK1可能参与了甲状腺乳头状癌的发生发展过程。检测DAPK1和RARβ的表达水平可作为判断甲状腺乳头状癌转移和预后的参考指标。     

甲状腺肿瘤细胞DNA含量及Cyclin D1与p27和Rb基因表达的定量检测

目的：探讨DNA含量(D1值)、细胞增殖活性(PI值)、Cyclin D1、p27及Rb基因表达在不同甲状腺肿瘤中的变化，为甲状腺癌的癌变机制及甲状腺肿瘤的鉴别诊断提供实验依据。方法：采用流式细胞术(FCM)和免疫荧光技术对甲状腺癌(40例)、结节性甲状腺肿(21例)、甲状腺腺瘤(16例)、正常甲状隙组织(10例)的DNA含量、细胞增殖活性及Cyclin D1、p27、Rb基因蛋白的表达进行定量检测结果：甲状腺癌组的D1值明显增高，异倍体细胞明显增多，异倍体率为80．0％，PI值明显增高Cyclin D1蛋白在甲状腺癌组表达显著增高，p27蛋白表达量在结节性甲状腺肿、甲状腺腺瘤和甲状腺腺癌组中依次减少，均明显低于正常甲状腺组织。结论：甲状腺癌发展过程中，DNA含量及异倍体率增加，细胞增殖活性增高Cyclin D1蛋白高表达，p27蛋白低表达，Cyclin D1、p27与甲状腺肿瘤的发生密切相关。     

甲状腺滤泡癌P—AKT表达异常与血管生成的关系

目的探讨P—AKT异常表达与甲状腺滤泡癌血管生成之间的关系。方法采用免疫组织化学PV-6000两步法检测甲状腺滤泡癌、甲状腺腺瘤及结节性甲状腺肿标本中P—AKT、VEGF及CD34的表达。结果P—AKT在甲状腺滤泡癌中的表达较甲状腺腺瘤和结节性甲状腺肿中显著增高（P〈0．001）。甲状腺滤泡癌组织中,P—AKT、VEGF蛋白表达均与微血管密度（MVD）相关（P〈0．05）,P—AKT阳性标本的MVD值高于P—AKT阴性标本（P〈0．05）,VEGF阳性标本的MVD值亦高于VEGF阴性标本（P〈0．05）。P-AKT表达与VEGF表达的相关性有统计学意义（P〈0．05）。结论P-AKT在甲状腺滤泡癌中的高表达在甲状腺滤泡癌的发生发展及继发转移过程中发挥着重要作用。甲状腺滤泡癌中可能存在AKT／VEGF通路,AKT是调控VEGF表达通路的关键因子。     

甲状腺乳头状癌组织HMGB1表达与临床病理特征相关性分析

目的：通过检测高迁移率族蛋白B1（high mobility group boxl,HMGBl）在甲状腺乳头状癌组织中的表达情况,并分析与临床病理特征之间的相关性,探讨其在甲状腺乳头状癌中发生、发展及转移等的意义。方法：选取2010—01—18—2012-11-23潍坊医学院附属医院50例临床确诊的甲状腺乳头状癌组织及20例结节性甲状腺肿组织病理蜡块标本,采用免疫组织化学和免疫荧光检测HMGBl的表达,并分析其与甲状腺乳头状癌临床病理特征的关系。结果：HMGBl蛋白主要表达于细胞质和细胞核中。甲状腺癌组织和结节性甲状腺肿组织中HMGBl阳性表达率分别为74．0％（37／50）和15．0％（3／20）,P〈0．05。甲状腺乳头状癌组织中HMGBl蛋白阳性表达与年龄（x2=0．049,P=0．825）、性别（x20．002,P=0．486）、肿瘤大小（x2=0．485,P=0．968）及TNM分期（x2=1．006,P=0．316）均无关;与包膜浸润（x2=4．299,p--0．038）和淋巴结转移（x2=5．889,P=0．015）密切相关。多因素Logistic回归分析显示,包膜浸润危险度（OR）最大。结论：HMGBl在甲状腺乳头状癌中高表达,预示着HMGBl可能参与肿瘤的发生、发展及转移。     

甲状腺癌中MCM7和p27的表达及临床意义

目的探讨MCM7和p27蛋白的表达与甲状腺癌发生、发展的关系。方法采用免疫组织化学S-P法检测50例甲状腺癌、30例甲状腺腺瘤、30例结节性甲状腺肿及20例正常甲状腺组织中MCM7和p27蛋白的表达。结果甲状腺癌组织中MCM7蛋白的阳性表达率为100.0%（50/50）,均显著高于甲状腺腺瘤20.0%（6/30）、结节性甲状腺肿23.3%（7/30）及正常甲状腺组织20.0%（4/20）（P〈0.01,P〈0.01,P〈0.01）。甲状腺癌组织中p27蛋白的阳性表达率为22.0%（11/50）,均显著低于甲状腺腺瘤100.0%（30/30）、结节性甲状腺肿100.0%（30/30）及正常甲状腺组织100.0%（20/20）（P〈0.01,P〈0.01,P〈0.01）。甲状腺癌中MCM7与p27蛋白的表达呈负相关关系（r=-0.326,P〈0.05）。结论 MCM7蛋白的高表达和p27蛋白的低表达可能涉及了甲状腺癌的发生过程。二者联合检测,可能可作为临床早期诊断和判断甲状腺肿瘤细胞增殖活性的生物学指标。     

p27,PCNA,TTF-1在甲状腺良恶性肿瘤中的表达及意义

目的：探讨p27、PCNA、TTF-1在甲状腺癌发生发展中的作用及其临床意义。方法：应用免疫组织化学S-P法检测15例结节性甲状腺肿组织、15例腺瘤、43例甲状腺癌组织中p27、PCNA及TTF-1的表达。结果：癌组织中p27与PCNA表达的阳性率分别为34．9％、72．1％，与结节性甲状腺肿组织中80％、26．7％比较，差异有显著性(P＜0．01)。TTF-1在良恶性病变中表达无差异。p27的表达与甲状腺肿瘤组织学分型密切相关。PCNA的表达与淋巴结转移相关(P＜0．05)。p27与PCNA在癌组织中的表达呈负相关(P＜0．01)。结论：p27表达降低与甲状腺肿瘤的组织学分型及浸润程度密切相关，联合检测p27、PCNA有助于甲状腺肿瘤的诊断及预后评估。TTF-1在甲状腺常见良恶性病变中阳性率均高，特异地表达在细胞核，是一种特异的甲状腺滤泡细胞标志物。     

趋化因子受体CXGR4在甲状腺乳头状癌的表达及临床意义

目的：探讨趋化因子CXCR4在甲状腺乳头状癌中的表达及其与临床病理学参数的相关性。方法：利用半定量RT—PCR和免疫组织化学法分别检测72例新鲜甲状腺乳头状癌组织及52例甲状腺乳头状癌石蜡标本中CXCR4 mRNA及蛋白的表达情况。结果：甲状腺乳头状癌组织中CXCR4 mRNA及蛋白的阳性表达率分别为77．8％（56／72）、76．6％（95／124）,而甲状腺良性病变组织及正常甲状腺组织均无表达,差异具有统计学意义（P〈0．01）;在甲状腺乳头状癌组织中,CXCR4 mRNA表达与蛋白表达成正相关关系（r=0．714,P〈0．01）。单因素分析显示CXCR4的蛋白表达与年龄、性别、肿瘤大小无关（P〉0．05）,但与肿瘤侵犯程度、淋巴结转移、远处转移、临床分期密切相关（P〈0．05）,且CXCR4蛋白阳性表达纽的预后显著差于CXCR4蛋白阳性表达组（P〈0．05）。结论：CXCR4阳性表达的甲状腺乳头状癌具有较高侵袭转移潜能,是预后不良的指标之一,CXCR4可作为抑制甲状腺乳头状癌侵袭转移的有效靶点。     

Susceptibility of Ureaplasma urealyticum to Tetracycline,Doxycycline, Erythromycin,Roxithromycin, Clarithromycin,Azithromycin, Levofloxacin and Moxifloxacin

Abstract

The in vitro activity of tetracycline, doxycycline, erythromycin, roxithromycin, clarithromycin, azithromycin, levofloxacin and moxifloxacin was tested against 63 clinical isolates of Ureaplasma urealyticum. The minimal inhibitory concentrations (MICs) and the minimal bactericidal concentrations (MBCs) were determined by the broth microdilution method in A7 medium. The miC50 and miC90 of the tested agents after 24 h of incubation were as follows: Tetracycline, 0.5 and 2.0 μg/ml; doxycycline, 0.125 and 0.25 μg/ml; erythromycin, 2.0 and 8.0 μg/ml; roxithromycin, 2.0 and 4.0 μg/ml; clarithromycin, 0.25 and 1.0 μg/ml; azithromycin, 2.0 and 4.0 μg/ml; levofloxacin, 1.0 and 2.0 μg/ml; and moxifloxacin, 0.5 and 0.5 μg/ml, respectively. The MIC values after 24 h and 48 h incubation differed by no more than one dilution for all the agents with the exception of doxycycline (two dilution difference for MIC₉₀). Overall, moxifloxacin was the most active agent in vitro against U. Urealyticum, with the narrowest difference between MIC and MBC values, followed closely by levofloxacin. Clarithromycin was the most active macrolide.     

Fat, fiber, fruits, vegetables, and risk of colorectal adenomas

A case-control study was conducted at the National Naval Medical Center (Maryland, USA) from 1994 to 1996 to investigate the possible association between dietary factors and colorectal adenomas. Cases (n = 239) were subjects diagnosed with adenomas (146 new and 93 recurrent) by sigmoidoscopy or colonoscopy. Those with no evidence of adenomas found by sigmoidoscopy were recruited as controls (n = 228). Dietary variables, assessed by a 100-item food frequency questionnaire, were analyzed by the logistic regression model, which was adjusted for age, gender and total energy intake. Variables of fat intake were further adjusted for red meat intake. An increased risk of 7% [odds ratio (OR): 1.07; 95% confidence interval (95% CI): 0.94-1.22] per 5% energy/day from total fat was observed. Every additional 5% unit of oleic acid intake/day significantly increased the adenoma risk by 115% (OR: 2.15; 95% CI: 1.05-4.39). Red meat fat increased the risk by 20% (OR: 1.20; 95% CI: 0.71-2.04), and white meat fat decreased the risk by 67% (OR: 0.33; 95% CI: 0.19-0.95) for every additional 5% unit of respective intake/day. Risk decreased by 41% (OR: 0.59; 95% CI: 0.41-0.86) for every additional 5% unit of fiber intake/day. Vegetable [OR per 100 g of vegetable intake/day: 0.83, 95% CI: 0.67-1.04] and fruit (OR per 100 g of fruit intake/day: 0.92, 95% CI: 0.82-1.03) intake showed an inverse association, and the results are suggestive of an association with the risk for adenomas. In conclusion, a strong positive association between oleic acid intake and colorectal adenoma risk was observed. This is likely to be an indicator of "unhealthy" food (meat, dairy, margarine, mayonnaise, sweet baked food) consumption in this population. Increased intake of dietary fiber was associated with a moderately decreased risk of adenomas.     

Occurrence,Efficacy, Metabolism,and Toxicity of Triclosan

Triclosan has broad-spectrum anti-microbial activity against most gram-negative and gram-positive bacteria. It is widely used in personal care products, household items, medical devices, and clinical settings. Due to its extensive use, there is potential for humans in all age groups to receive life-time exposures to triclosan, and, indeed, triclosan has been detected in human tissues and the environment. Data gaps exist regarding the chronic dermal toxicity and carcinogenicity of triclosan, which is needed for the risk assessment of triclosan. The US Food and Drug Administration (FDA) nominated triclosan to the National Toxicology Program (NTP) for toxicological evaluations. Currently, the NTP is conducting several dermal toxicological studies to determine the carcinogenic potential of triclosan, evaluate its endocrine and developmental-reproductive effects, and investigate the potential UV-induced dermal formation of chlorinated phenols and dioxins of triclosan. This paper reviews data on the human exposure, environmental fate, efficacy of anti-microbial activity, absorption, distribution, metabolism and elimination, endocrine disrupting effects, and toxicity of triclosan.     

Tobacco, alcohol, diet, occupation, and carcinoma of the esophagus

Information on occupation, smoking, food and beverage consumption, and medical history were compared between 275 incident cases of carcinoma of the esophagus and 275 neighborhood controls who were matched to the cases on age (within 5 years), race, and sex. Tobacco use, mainly cigarette smoking, was a significant risk factor for carcinoma of the esophagus. Ex-smokers of cigarettes showed a reduced risk relative to those who continued to smoke, and current smokers of two or more packs per day displayed a higher risk than those who smoked less. Alcohol consumption was another significant risk factor for carcinoma of the esophagus; there was a highly significant trend with average daily dose of ethanol. Relative to controls, cases also consumed significantly more fried bacon or ham, less fresh fruits and raw vegetables, and were more likely to prefer white than whole grain bread. Finally, there was a significant association between carcinoma of the esophagus and long-term occupational exposure to metal dust; this association was largely confined to the lower one-third section of the esophagus.     

Age,Race, Sex,Stage, and Incidence of Cutaneous Lymphoma

BackgroundThe incidence of the T- and B-cell CLs has been well documented, but information pertaining to racial incidence by age, and by burden of disease (stage) have not been extensively documented.Materials and MethodsThe SEER 2004-2008 public use database was investigated. The relative incidence of CL in different races and age groups was examined. Univariate and multivariate stepwise logistic regression was performed for the likelihood of presenting at a higher stage.ResultsOf 4496 patients diagnosed with CL between 2004 and 2008; 1713 patients were diagnosed with MF, 1518 with non-MF cutaneous T-cell lymphoma, and 1265 patients with cutaneous B-cell lymphoma. For MF, there was a trend for females to be less likely to present with a higher T-stage (T3-T4) than males (odds ratio [OR], 0.73) on multivariate analysis (P = .06). For race, AA had a significantly increased risk of presenting with higher T-stage (T3-T4) MF (OR, 1.72) on multivariate analysis (P = .02), compared with white patients. For white, AA, Asian/Pacific Islander, and Native American/other/unknown, the mean age at diagnosis was 59.2, 51.5, 51.3, and 53.8. These groups presented at a significantly different age than white (P = .0001, 0.0001, and 0.0006).ConclusionNonwhite racial groups present with MF at an earlier age compared with white, and AA have increased risk of presenting with higher T-stage compared with white. These findings have significant implications regarding need for earlier diagnosis and understanding the reasons for racial disparity in age and stage of presentation.     

Susceptibility of Ureaplasma urealyticum to tetracycline, doxycycline, erythromycin, roxithromycin, clarithromycin, azithromycin, levofloxacin and moxifloxacin

The in vitro activity of tetracycline, doxycycline, erythromycin, roxithromycin, clarithromycin, azithromycin, levofloxacin and moxifloxacin was tested against 63 clinical isolates of Ureaplasma urealyticum. The minimal inhibitory concentrations (MICs) and the minimal bactericidal concentrations (MBCs) were determined by the broth microdilution method in A7 medium. The MIC(50) and MIC(90) of the tested agents after 24 h of incubation were as follows: tetracycline, 0.5 and 2.0 μg/ml; doxycycline, 0.125 and 0.25 μg/ml; erythromycin, 2.0 and 8.0 μg/ml; roxithromycin, 2.0 and 4.0 μg/ml; clarithromycin, 0.25 and 1.0 μg/ml; azithromycin, 2.0 and 4.0 μg/ml; levofloxacin, 1.0 and 2.0 μg/ml; and moxifloxacin, 0.5 and 0.5 μg/ml, respectively. The MIC values after 24 h and 48 h incubation differed by no more than one dilution for all the agents with the exception of doxycycline (two dilution difference for MIC(90)). Overall, moxifloxacin was the most active agent in vitro against U. urealyticum, with the narrowest difference between MIC and MBC values, followed closely by levofloxacin. Clarithromycin was the most active macrolide.     

Cutaneous,gastrointestinal, hepatic,endocrine, and renal side-effects of anti-PD-1 therapy

BackgroundAnti-programmed cell death receptor-1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma as well as for other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects affect skin, gastrointestinal tract, liver, endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential.Methods and findingsIn total, 496 patients with metastatic melanoma from 15 skin cancer centers were treated with pembrolizumab or nivolumab; 242 side-effects were described in 138 patients. In 116 of the 138 patients, side-effects affected the skin, gastrointestinal tract, liver, endocrine, and renal system. Rare side-effects included diabetes mellitus, lichen planus, and pancreas insufficiency due to pancreatitis.ConclusionAnti-PD1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.     

Antitumor activity of halogen analogs of phosphoramide,isophosphoramide, and triphosphoramide mustards,the cytotoxic metabolites of cyclophosphamide,ifosfamide, and trofosfamide

A series of halogen analogs of phosphoramide mustard, isophosphoramide mustard, and triphosphoramide mustard, the cytotoxic metabolites of the antitumor drugs cyclophosphamide, ifosfamide, and trofosfamide, respectively, was evaluated in vitro against human tumor cell lines and in vivo against experimental tumors to investigate the effect of replacement of chlorine with bromine or fluorine on the antitumor activity of the parent phosphoramide mustards. In the experimental tumors L1210 leukemia, B16 melanoma, mammary adenocarcinoma 16/C, and ovarian sarcoma M5076, the antitumor activity of the analogs was observed to be generally comparable with that of the parent mustards when chlorine was replaced by bromine but uniformly lower when chlorine was replaced by fluorine. Furthermore, the monobromo analog of isophosphoramide mustard displayed equal or somewhat greater activity in comparison with cyclophosphamide when evaluated against subcutaneously implanted L1210 leukemia with intraperitoneal drug treatment and against mammary adenocarcinoma 16/C.This work was financially supported by NIH, NCI grant PO1 CA34200