BACKGROUND & AIMS: :The differential relative contribution of males and females from Africa and Europe to individual African American genomes is relevant to mapping genes utilizing admixture analysis. The assessment of ancestral population contributions to the four types of genomic DNA (autosomes, X and Y chromosomes, and mitochondrial) with their differing modes of inheritance is most easily addressed in males. A thorough evaluation of 93 African American males for 2,018 autosomal single nucleotide polymorphic (SNP) markers, 121 X chromosome SNPs, 10 Y chromosome haplogroups specified by SNPs, and six haplogroup defining mtDNA SNPs is presented. A distinct lack of correlation observed between the X chromosome and the autosomal admixture fractions supports separate treatment of these chromosomes in admixture-based gene mapping applications. The European genetic contributions were highest (and African lowest) for the Y chromosome (28.46%), followed by the autosomes (19.99%), then the X chromosome (12.11%), and the mtDNA (8.51%). The relative order of admixture fractions in the genomic compartments validates previous studies that suggested sex-biased gene flow with elevated European male and African female contributions. There is a threefold higher European male contribution compared with European females (Y chromosome vs. mtDNA) to the genomes of African American individuals meaning that admixture-based gene discovery will have the most power for the autosomes and will be more limited for X chromosome analysis.

背景与目标： ：非洲和欧洲的雄性和雌性对单个非裔美国人基因组的不同相对贡献与利用混合分析对基因进行定位有关。在男性中，最容易解决对祖先种群对四种基因组DNA（常染色体，X和Y染色体以及线粒体）及其不同遗传方式的贡献的评估。彻底评估了93名非洲裔美国男性的2018个常染色体单核苷酸多态性（SNP）标记，121个X染色体SNP，由SNP指定的10个Y染色体单倍群和六个定义mtDNA SNP的单倍群。在X染色体和常染色体混合物级分之间观察到的明显缺乏相关性支持了在基于混合物的基因作图应用中对这些染色体的单独处理。欧洲的遗传贡献在Y染色体上最高（非洲最低）（28.46％），其次是常染色体（19.99％），然后是X染色体（12.11％）和mtDNA（8.51％）。基因组区室中混合组分的相对顺序验证了以前的研究，该研究表明性别偏向的基因流与欧洲男性和非洲女性的贡献增加有关。在非裔美国人的基因组中，欧洲男性的贡献比欧洲女性高出三倍（Y染色体与mtDNA），这意味着基于混合物的基因发现将对常染色体具有最大的作用，并且在X染色体分析中将受到更大的限制。 。

BACKGROUND & AIMS: :Upregulation of lipogenesis is a hallmark of cancer and blocking the lipogenic pathway is known to cause tumor cell death by apoptosis. However, the exact role of lipogenesis in tumor initiation is as yet poorly understood. We examined the expression profile of key lipogenic genes in clinical samples of ductal carcinoma in situ (DCIS) of breast cancer and found that these genes were significantly upregulated in DCIS. We also isolated cancer stem-like cells (CSCs) from DCIS.com cell line using cell surface markers (CS24(-)CD44(+)ESA(+)) and found that this cell population has significantly higher tumor-initiating ability to generate DCIS compared with the non-stem-like population. Furthermore, the CSCs showed significantly higher level of expression of all lipogenic genes than the counterpart population from non-tumorigenic breast cancer cell line, MCF10A. Importantly, ectopic expression of SREBP1, the master regulator of lipogenic genes, in MCF10A significantly enhanced lipogenesis in stem-like cells and promoted cell growth as well as mammosphere formation. Moreover, SREBP1 expression significantly increased the ability of cell survival of CSCs from MCF10AT, another cell line that is capable of generating DCIS, in mouse and in cell culture. These results indicate that upregulation of lipogenesis is a pre-requisite for DCIS formation by endowing the ability of cell survival. We have also shown that resveratrol was capable of blocking the lipogenic gene expression in CSCs and significantly suppressed their ability to generate DCIS in animals, which provides us with a strong rationale to use this agent for chemoprevention against DCIS.

背景与目标： ：脂肪生成的上调是癌症的标志，已知阻断脂肪生成途径会通过凋亡导致肿瘤细胞死亡。然而，尚不清楚脂肪生成在肿瘤起始中的确切作用。我们检查了乳腺导管原位癌（DCIS）临床样品中关键脂肪形成基因的表达谱，发现这些基因在DCIS中显着上调。我们还使用细胞表面标记（CS24（-）CD44（）ESA（））从DCIS.com细胞系中分离了癌干样细胞（CSC），发现与该细胞群相比，该细胞群具有更高的产生DCIS的肿瘤启动能力与非茎状种群。此外，CSCs显示所有脂肪形成基因的表达水平均高于非致瘤性乳腺癌细胞系MCF10A的对应群体。重要的是，MCF10A中异源表达的主调节因子SREBP1在MCF10A中的异位表达显着增强了干样细胞的脂肪生成，并促进了细胞生长以及乳球形成。此外，SREBP1表达显着提高了来自MCF10AT的CSC在小鼠和细胞培养物中的细胞存活能力，MCF10AT是另一种能够产生DCIS的细胞系。这些结果表明，通过赋予细胞存活能力，脂肪生成的上调是DCIS形成的先决条件。我们还显示白藜芦醇能够阻断CSC中脂肪基因的表达，并显着抑制其在动物体内生成DCIS的能力，这为我们提供了使用这种药物化学预防DCIS的强大理由。

BACKGROUND & AIMS: :This paper reevaluates the recently reported excess mortality following transurethral resection of the prostate (TURP) for benign hypertrophy as compared with traditional open resection (OPEN). We studied survival through linkage of hospital discharge data with mortality data for the entire male population of Denmark (1977-85). For a maximum of 10.5 years 38,067 prostatectomy patients were followed. Adjusting for age and health status before surgery, TURP patients were subject to significantly higher levels of mortality than OPEN patients (RR = 1.19, 95% confidence interval (1.15-1.24). The extent to which this difference is attributable to the surgical intervention itself remains an open question. The two groups of patients are quite different with regard to age and preoperative health status, and available data may not be sufficient to control such differences through statistical analysis. On the other hand, the difference in mortality persisted over calendar time, even during periods when the pattern of utilization for the two procedures changed significantly (constant RR = 1.19, adjusting for age and comorbidity). The most important causes of death among Danish TURP patients differ from the causes suggested on the basis of previously reported Canadian data. The current evidence is thus ambiguous with regard to hypothetical biologic mechanisms behind the excess mortality over TURP patients. Further investigations are needed to evaluate the safety and effectiveness of prostate surgery.

背景与目标： ：本文重新评估了最近报道的与传统的开放性切除术（OPEN）相比，经尿道前列腺良性肥大手术（TURP）后的额外死亡率。我们通过将出院数据与丹麦整个男性人口（1977-85年）的死亡率数据相联系来研究生存率。在长达10.5年的时间里，对38,067例前列腺切除术患者进行了随访。调整手术前的年龄和健康状况后，TURP患者的死亡率要比OPEN患者高得多（RR = 1.19，95％置信区间（1.15-1.24）。两组患者在年龄和术前健康状况方面都存在很大差异，可用的数据可能不足以通过统计分析来控制这种差异；另一方面，死亡率的差异在整个日历时间内仍然存在，即使在这两种方法的使用方式发生显着变化的时期（恒定RR = 1.19，已根据年龄和合并症进行了调整），丹麦TURP患者中最重要的死亡原因也不同于先前报道的加拿大所建议的原因。因此，目前的证据对于超过T的超额死亡率背后的假设生物学机制尚不明确。 URP患者。需要进一步的研究以评估前列腺手术的安全性和有效性。

BACKGROUND & AIMS: The peroxisome proliferator activated receptor PPAR-gamma has been identified as a nuclear receptor for thiazolidenediones, which are compounds with insulin-sensitizing properties in several tissues, including skeletal muscle. To determine whether this receptor is expressed and possibly involved in insulin action/resistance in skeletal muscle, PPAR-gamma mRNA abundance and its regulation by insulin were quantified in muscle tissue and cultures from lean and obese nondiabetic and type II diabetic subjects using competitive reverse transcription-polymerase chain reaction (RT-PCR). In muscle biopsy specimens, PPAR-gamma mRNA was elevated in obese nondiabetic and type II diabetic subjects (23.4 +/- 4.2 and 28.0 +/- 5.69 x 10(3) copies/microg total RNA, respectively; both P < 0.05) compared with lean nondiabetic control subjects (9.4 +/- 2.3 x 10(3) copies/microg total RNA). Significant positive correlations were present among skeletal muscle PPAR-gamma mRNA levels, BMI (r = 0.67, P < 0.01), and fasting insulin concentration (r = 0.76, P < 0.001). PPAR-gamma mRNA levels were also elevated in muscle cultures from type II diabetic subjects compared with lean nondiabetic control subjects (330.1 +/- 52.9 vs. 192.1 +/- 27.0 x 10(3) copies/microg total RNA, P < 0.05). Insulin stimulation of muscle tissue (by hyperinsulinemic-euglycemic clamp for 3-4 h) or muscle cultures (30 nmol/l for 120 min) stimulated PPAR-gamma mRNA expression up to fourfold (10.0 +/- 2.7 to 41.3 +/- 7.4 x 10(3) copies/microg total RNA, P < 0.05, and 174.9 +/- 56.9 to 268.2 +/- 78.6 x 10(3) copies/microg total RNA, P < 0.05, respectively). In summary, PPAR-gamma mRNA expression in human skeletal muscle is acutely regulated by insulin and is increased in both obese nondiabetic and type II diabetic subjects in direct relation to BMI and fasting insulinemia. We conclude that abnormalities of PPAR-gamma may be involved in skeletal muscle insulin resistance of obesity and type II diabetes.

背景与目标： 过氧化物酶体增殖物激活受体PPAR-γ已被确定为噻唑烷二酮的核受体，噻唑烷二酮是在包括骨骼肌在内的多个组织中具有胰岛素敏感特性的化合物。为了确定该受体是否在骨骼肌中表达并且可能参与了胰岛素的作用/抗性，使用竞争性逆转录技术从瘦和肥胖的非糖尿病和II型糖尿病患者的肌肉组织和培养物中定量了PPAR-γmRNA的丰度及其受胰岛素的调节。 -聚合酶链反应（RT-PCR）。在肌肉活检标本中，肥胖的非糖尿病和II型糖尿病受试者的PPAR-γmRNA升高（分别为23.4 /-4.2和28.0 /-5.69 x 10（3）拷贝/微克总RNA；两者均P <0.05），与瘦肉相比非糖尿病对照受试者（9.4 /-2.3 x 10（3）拷贝/微克总RNA）。骨骼肌PPAR-γmRNA水平，BMI（r = 0.67，P <0.01）和空腹胰岛素浓度（r = 0.76，P <0.001）之间存在显着正相关。与瘦型非糖尿病对照受试者相比，II型糖尿病受试者的肌肉培养物中的PPAR-γmRNA水平也有所升高（330.1 /-52.9与192.1 /-27.0 x 10（3）拷贝/微克总RNA，P <0.05）。胰岛素刺激肌肉组织（通过高胰岛素-正常血糖钳夹3-4小时）或肌肉培养物（30 nmol / l持续120分钟）刺激的PPAR-γmRNA表达增加至四倍（10.0 /-2.7至41.3 /-7.4 x 10 （3）拷贝/微克总RNA，P <0.05和174.9 /-56.9至268.2 /-78.6 x 10（3）拷贝/微克总RNA，P <0.05）。总而言之，人骨骼肌中的PPAR-γmRNA表达受到胰岛素的急性调节，在肥胖的非糖尿病和II型糖尿病患者中，PPAR-γmRNA的表达均与BMI和空腹胰岛素血症直接相关。我们得出结论，肥胖和II型糖尿病的骨骼肌胰岛素抵抗可能与PPAR-γ异常有关。

BACKGROUND & AIMS: BACKGROUND:Hypertriglyceridemia is one of the three most common causes of AP, which is associated with the AP prognosis that has not been clearly defined. METHODS:In this retrospective study, 1539 AP patients, who had serum triglyceride (TG) levels measured within the first 72 h, were assessed. The study groups consisted of patients with normal, mild, moderate, and severe/very severe HTG levels based on the Endocrine Society Clinical Practice Guidelines. We collected baseline demographic information, laboratory values, complications, and clinical outcome data in different HTG severity groups to analyze the clinical significance of elevated TG levels in AP. RESULTS:Our study included 1539 AP patients; of these, 1078 (70%) had a normal TG levels, and 461 (30%) had elevated TG levels. The rates of severe AP increased in HTG groups of increasing severity (4% vs. 8% vs. 12%; P trend < 0.001). acute necrotic collection (ANC) and pancreatic necrosis developed in 32 and 39 of 112 patients (29% and 35%) (P trend = 0.001; P trend = 0.001) in the severe/very severe HTG group, respectively. The proportion of persistent organ failure (POF), multiple organ failure (MOF), and persistent Systemic Inflammatory Response Syndrome (SIRS) increased with higher grades of HTG (P trend < 0.001; P trend < 0.001; P trend < 0.001). The ICU admission rate was higher in the severe/very severe HTG group (57/112 patients; 51%; P trend < 0.001). A logistic multivariate regression analysis showed a positive correlation between HTG and certain AP complications. CONCLUSION:In addition to other factors, an elevated TG level could be associated with the severity and prognosis of AP, including pancreatic necrosis, POF, MOF, persistent SIRS, ICU admission, and mortality.

背景与目标： 背景：高甘油三酯血症是AP的三种最常见原因之一，与AP的预后相关，目前尚不清楚。
方法：在这项回顾性研究中，评估了1539名在前72小时内测得的血清甘油三酸酯（TG）水平的AP患者。根据内分泌学会临床实践指南，研究组包括正常，轻度，中度和重度/非常重度HTG水平的患者。我们收集了不同HTG严重程度组的基线人口统计学信息，实验室值，并发症和临床结果数据，以分析AP中TG水平升高的临床意义。
结果：我们的研究包括1539例AP患者。其中，1078（70％）的TG水平正常，461（30％）的TG水平升高。在严重程度更高的HTG组中，严重AP的发生率增加（4％vs. 8％vs. 12％； P趋势<0.001）。在重度/非常重度HTG组中，分别有112例患者中的32例和39例发生了急性坏死集合（ANC）和胰腺坏死（29％和35％）（P趋势= 0.001； P趋势= 0.001）。 HTG等级越高，持续性器官衰竭（POF），多器官衰竭（MOF）和持续性系统性炎症反应综合征（SIRS）的比例越高（P趋势<0.001； P趋势<0.001； P趋势<0.001）。重度/非常重度HTG组的ICU入院率更高（57/112例患者； 51％； P趋势<0.001）。 Logistic多元回归分析显示，HTG与某些AP并发症之间呈正相关。
结论：除其他因素外，TG水平升高可能与AP的严重程度和预后相关，包括胰腺坏死，POF，MOF，持续SIRS，ICU入院和死亡率。

BACKGROUND & AIMS: AIM:Biomarkers predicting sustained virological response (SVR) to pegylated interferon-α plus ribavirin (PEG IFN-α/RBV) were investigated. METHODS:Peptides in pretreatment sera from 107 patients with hepatitis C virus (HCV) genotype 1 were comprehensively analyzed by mass spectrometry. Ion intensity of the peptides was used to generate discriminant models between the responders who achieved SVR (R) and the non-responders (NR) to PEG IFN-α/RBV. RESULTS:In total, 107 peptides were detected in a training set (n = 23). A discriminant model using a peptide, complement 3f des-arginine (C3f-dR), showed sensitivity of 35% and specificity of 94% for SVR prediction in a testing set (n = 68). In all the R and NR (n = 96), an area under the receiver-operator curve (AUROC) of 0.64 in the C3f-dR model was increased to 0.78 by addition of platelet (PLT) counts (C3f-dR/PLT model). Another model using the 107 peptides (AUROC, 0.77) also showed higher AUROC (0.79) by addition of hemoglobin (Hb), body mass index (BMI) and age (107P/Hb/BMI/Age model). The sensitivity and specificity of the C3f-dR/PLT model were 59% and 88%, and those of the 107P/Hb/BMI/Age model were 70% and 92%, respectively. The C3f-dR/PLT model showed high AUROC (0.82), similar to that of interleukin-28B rs8099917 genotype analysis (0.86) in the 45 tested patients. Prediction by the combination of the C3f-dR/PLT model, the 107P/Hb/BMI/Age model and the rs8099917 genotype analysis was accurate in 44 out of the 45 patients (AUROC, 0.95). CONCLUSION:Serum peptides, especially C3f-dR, would be useful predictors for SVR to PEG IFN-α/RBV. The complements may be involved in the HCV elimination.

背景与目标： 目的：研究了预测对聚乙二醇化干扰素-α和利巴韦林（PEGIFN-α/ RBV）持续病毒学应答（SVR）的生物标志物。
方法：采用质谱法对107例丙型肝炎病毒（HCV）基因1型患者血清中的多肽进行了综合分析。肽的离子强度用于在获得SVR（R）的应答者和对PEGIFN-α/ RBV的非应答者（NR）之间生成判别模型。
结果：在一个训练集中总共检测到107个肽（n = 23）。使用肽补体3f des-精氨酸（C3f-dR）的判别模型在测试集中对SVR的预测显示35％的敏感性和94％的特异性（n = 68）。在所有R和NR（n = 96）中，通过添加血小板（PLT）计数（C3f-dR / PLT模型），C3f-dR模型中的接收者-操作者曲线（AUROC）下的面积为0.64 ）。另一种使用107种肽的模型（AUROC，0.77）通过添加血红蛋白（Hb），体重指数（BMI）和年龄（107P / Hb / BMI / Age模型）也显示出较高的AUROC（0.79）。 C3f-dR / PLT模型的敏感性和特异性分别为59％和88％，而107P / Hb / BMI / Age模型的敏感性和特异性分别为70％和92％。 C3f-dR / PLT模型在45位接受测试的患者中显示出较高的AUROC（0.82），与白细胞介素28B rs8099917基因型分析（0.86）相似。通过对C3f-dR / PLT模型，107P / Hb / BMI / Age模型和rs8099917基因型分析的组合进行的预测在45例患者中有44例是准确的（AUROC，0.95）。
结论：血清肽，特别是C3f-dR，将成为SVR转化为PEGIFN-α/ RBV的有用预测因子。补体可能参与HCV的消除。

BACKGROUND & AIMS: :Previous studies conducted in Western cultures have shown that negative emotions predict higher levels of pro-inflammatory biomarkers, specifically interleukin-6 (IL-6). This link between negative emotions and IL-6 may be specific to Western cultures where negative emotions are perceived to be problematic and thus may not extend to Eastern cultures where negative emotions are seen as acceptable and normal. Using samples of 1044 American and 382 Japanese middle-aged and older adults, we investigated whether the relationship between negative emotions and IL-6 varies by cultural context. Negative emotions predicted higher IL-6 among American adults, whereas no association was evident among Japanese adults. Furthermore, the interaction between culture and negative emotions remained even after controlling for demographic variables, psychological factors (positive emotions, neuroticism, extraversion), health behaviors (smoking status, alcohol consumption), and health status (chronic conditions, BMI). These findings highlight the role of cultural context in shaping how negative emotions affect inflammatory physiology and underscore the importance of cultural ideas and practices relevant to negative emotions for understanding of the interplay between psychology, physiology, and health.

背景与目标： ：以前在西方文化中进行的研究表明，负面情绪预示着较高的促炎性生物标志物，特别是白介素6（IL-6）。消极情绪与IL-6之间的这种联系可能特定于西方文化，在该文化中，消极情绪被认为是有问题的，因此可能不会扩展到东方文化，在东方文化中，消极情绪被视为可以接受并且是正常的。我们使用1044名美国人和382名日本中年和老年人的样本，调查了负面情绪与IL-6之间的关系是否因文化背景而异。负面情绪预示着美国成年人IL-6升高，而日本成年人却没有明显的关联。此外，即使在控制了人口统计学变量，心理因素（正性情绪，神经质，外向性），健康行为（吸烟状况，饮酒）和健康状况（慢性状况，BMI）之后，文化与负面情绪之间的相互作用仍然存在。这些发现凸显了文化背景在塑造负面情绪如何影响炎症生理方面的作用，并强调了与负面情绪相关的文化观念和实践对于理解心理学，生理学和健康之间相互作用的重要性。

BACKGROUND & AIMS: AIM:The aim of this study was to seek an association between the control of type 2 diabetes mellitus (T2DM), as determined by hemoglobin A1c (HbA1c) levels, and the outcome of colorectal cancer (CRC). METHODS:We performed a retrospective review of patients with T2DM who had CRC diagnosed between 1997 and 2001. We defined well-controlled T2DM as HbA1c < 7.5% and poorly controlled T2DM as HbA1c > or = 7.5%. A group of age- and gender-matched patients who had CRC without T2DM were used as controls. Forty clinical factors were reviewed, and those associated with poor clinical outcome in each group were examined by univariate analysis (UA) and by the maximum likelihood analysis of logistic regression to determine the independent predictors of cancer outcome. RESULTS:We identified 155 patients with T2DM and CRC, and 114 control patients who had CRC without T2DM. We found no significant differences in any clinical factor by UA between the patients with well-controlled T2DM and the patients who had CRC without T2DM. Compared to both of those patients groups, in contrast, the patients with poorly controlled T2DM had more right-sided CRCs (P = 0.04, OR = 2, 95% CI = 1-4.1), more advanced CRCs (P = 0.02, OR = 2.1, 95% CI = 1-4.4), a younger age of presentation (P = 0.05), greater use of exogenous insulin (P = 0.002), and a poorer 5-year survival (P = 0.001) by UA. Logistic regression showed that poorly controlled T2DM independently predicted the early onset of CRC, a more advanced stage at the time of presentation, poorer 5-year survival, and an increased incidence of right-sided CRCs. CONCLUSIONS:In patients with T2DM who have CRC, poor glycemic control is associated with a clinically aggressive course for the cancer.

背景与目标： 目的：本研究的目的是寻找通过血红蛋白A1c（HbA1c）水平确定的2型糖尿病（T2DM）控制与结直肠癌（CRC）的结局之间的关联。
方法：我们对1997年至2001年间被确诊为CRC的T2DM患者进行了回顾性研究。我们将控制良好的T2DM定义为HbA1c <7.5％，将控制不良的T2DM定义为HbA1c>或= 7.5％。一组年龄和性别匹配的无T2DM的CRC患者被用作对照。回顾了40种临床因素，并通过单因素分析（UA）和逻辑回归的最大似然分析检查了每组与临床结果差相关的因素，以确定癌症结果的独立预测因子。
结果：我们确定了155例T2DM和CRC的患者，以及114例没有T2DM的CRC的对照患者。我们发现，在控制良好的T2DM患者和患有CRC而无T2DM的患者之间，UA的任何临床因素均无显着差异。相比之下，与这两个患者组相比，控制不佳的T2DM患者的右侧CRC较多（P = 0.04，OR = 2，95％CI = 1-4.1），晚期CRC（P = 0.02，OR = 2.1，95％CI = 1-4.4），较年轻的患者（P = 0.05），更多使用外源性胰岛素（P = 0.002），UA的5年生存率较差（P = 0.001）。 Logistic回归显示，控制不佳的T2DM独立预测CRC的早期发作，出现时更晚期，5年生存期较差以及右侧CRC的发生率增加。
结论：在患有CRC的T2DM患者中，血糖控制不良与该癌症的临床侵袭性病程有关。

BACKGROUND & AIMS: BACKGROUND:Chemotherapy and intensity-modulated radiotherapy (IMRT) have decreased treatment-related complications in adult patients with nasopharyngeal carcinoma (NPC). Our aim was to evaluate the toxicity profile of IMRT plus chemotherapy in pediatric NPC patients. OBSERVATIONS:Five patients were treated with chemotherapy and IMRT. All patients experienced grade 3-4 acute toxicities. With a median follow-up of 6.3 years, all patients experienced >or=3 long-term toxicities. The most common toxicities were hypothyroidism, xerostomia, hearing loss, and dental disease. CONCLUSIONS:We did not observe a significant decrease in long-term toxicities with IMRT plus chemotherapy in our small cohort of pediatric NPC patients.

背景与目标： 背景：化学疗法和调强放射疗法（IMRT）减少了成人鼻咽癌（NPC）患者的治疗相关并发症。我们的目的是评估IMRT联合化疗对小儿NPC患者的毒性。
观察：5例患者接受了化疗和IMRT治疗。所有患者均经历3-4级急性毒性。中位随访时间为6.3年，所有患者均经历了≥3的长期毒性。最常见的毒性是甲状腺功能减退，口干，听力下降和牙齿疾病。
结论：在我们的小儿NPC患者队列中，我们未观察到IMRT加化疗的长期毒性显着降低。

BACKGROUND & AIMS: OBJECTIVES:To assess the extent to which prior hormone therapy modifies the breast cancer risk found with estrogen plus progestin (E+P) in the Women's Health Initiative (WHI) randomized trial. METHODS:Subgroup analyses of prior hormone use on invasive breast cancer incidence in 16,608 postmenopausal women in the WHI randomized trial of E+P over an average 5.6 years of follow-up. RESULTS:Small but statistically significant differences were found between prior HT users and non-users for most breast cancer risk factors but Gail risk scores were similar. Duration of E+P use within the trial (mean 4.4 years, S.D. 2.0) did not vary by prior use. Among 4311 prior users, the adjusted hazard ratio (HR) for E+P versus placebo was 1.96 (95% confidence interval [CI]: 1.17-3.27), significantly different (p=0.03) from that among 12,297 never users (HR 1.02; 95% CI: 0.77-1.36). The interaction between study arm and follow-up time was significant overall (p=0.01) and among never users (p=0.02) but not among prior users (p=0.10). The cumulative incidence over time for the E+P and placebo groups appeared to cross after about 3 years in prior users, and after about 5 years in women with no prior use. No interaction was found with duration (p=0.08) or recency of prior use (p=0.17). Prior hormone use significantly increased the E+P hazard ratio for larger, more advanced tumors. CONCLUSION:A safe interval for combined hormone use could not be reliably defined with these data. However, the significant increase in breast cancer risk in the trial overall after only 5.6 years of follow-up, initially concentrated in women with prior hormone exposure, but with increasing risk over time in women without prior exposure, suggests that durations only slightly longer than those in the WHI trial are associated with increased risk of breast cancer. Longer-term exposure and follow-up data are needed.

背景与目标： 目的：在妇女健康倡议（WHI）随机试验中，评估先前的激素治疗在多大程度上改变了雌激素加孕激素（EP）的乳腺癌风险。
方法：在平均5​​.6年的WHI随机对照试验中，对16608名绝经后女性进行既往激素使用对浸润性乳腺癌发病率的亚组分析。
结果：在大多数乳腺癌风险因素中，既往HT使用者与非HT使用者之间存在很小但统计学上的显着差异，但Gail风险评分相似。在试验中使用E P的持续时间（平均4.4年，S.D。2.0）没有因以前的使用而异。在4311位既往使用者中，EP与安慰剂的调整后危险比（HR）为1.96（95％置信区间[CI]：1.17-3.27），与12,297个从未使用过的使用者（HR 1.02; 95）相比有显着差异（p = 0.03）。 ％CI：0.77-1.36）。研究组与随访时间之间的相互作用总体上是显着的（p = 0.01），从未使用者中的相互作用（p = 0.02），以前使用者中的相互作用则不显着（p = 0.10）。 E P组和安慰剂组随时间的累积发生率在之前的使用者中大约3年后出现交叉，而在没有事先使用的妇女中大约5年后出现交叉。持续时间（p = 0.08）或先前使用的新近度（p = 0.17）未发现相互作用。先前使用激素会显着增加较大，更晚期肿瘤的E P风险比。
结论：这些数据不能可靠地确定激素联合使用的安全间隔。然而，在仅5.6年的随访中，该试验总体上使乳腺癌风险显着增加，最初集中于曾接受过激素的女性，但随着时间的推移，未曾接受过激素的女性的风险随着时间的推移而增加，这表明持续时间仅略长于WHI试验中的那些与乳腺癌风险增加相关。需要长期暴露和随访数据。

BACKGROUND & AIMS: :Allele frequencies for the nine STRs included in the AmpFlSTR Profiler Plus kit (D3S1358, VWA, FGA, D8S1179, D21S11, D18S51, D5S818, D13S317 and D7S820) were estimated from a sample of 365-427 unrelated individuals born in north Portugal.

背景与目标： ：AmpFlSTR Profiler Plus试剂盒（D3S1358，VWA，FGA，D8S1179，D21S11，D18S51，D5S818，D13S317和D7S820）中包含的9个STR的等位基因频率是根据葡萄牙北部出生的365-427个无关个体的样本估算的。

BACKGROUND & AIMS: :Silencing mediator of retinoic acid and thyroid hormone receptor (SMRT), also known as nuclear corepressor 2 (NCOR2) is a transcriptional corepressor for multiple members of the nuclear receptor superfamily of transcription factors, including estrogen receptor-α (ERα). In the classical model of corepressor action, SMRT binds to antiestrogen-bound ERα at target promoters and represses ERα transcriptional activity and gene expression. Herein SMRT mRNA and protein expression was examined in a panel of 30 breast cancer cell lines. Expression of both parameters was found to vary considerably amongst lines and the correlation between protein and mRNA expression was very poor (R (2) = 0.0775). Therefore, SMRT protein levels were examined by immunohistochemical staining of a tissue microarray of 866 patients with stage I-II breast cancer. Nuclear and cytoplasmic SMRT were scored separately according to the Allred score. The majority of tumors (67 %) were negative for cytoplasmic SMRT, which when detected was found at very low levels. In contrast, nuclear SMRT was broadly detected. There was no significant difference in time to recurrence (TTR) according to SMRT expression levels in the ERα-positive tamoxifen-treated patients (P = 0.297) but the difference was significant in the untreated patients (P = 0.01). In multivariate analysis, ERα-positive tamoxifen-untreated patients with high nuclear SMRT expression (SMRT 5-8, i.e., 2nd to 4th quartile) had a shorter TTR (HR = 1.94, 95 % CI, 1.24-3.04; P = 0.004) while there was no association with SMRT expression for ERα-positive tamoxifen-treated patients. There was no association between SMRT expression and overall survival for patients, regardless of whether they received tamoxifen. Thus while SMRT protein expression was not predictive of outcome after antiestrogen therapy, it may have value in predicting tumor recurrence in patients not receiving adjuvant tamoxifen therapy.

背景与目标： ：视黄酸和甲状腺激素受体（SMRT）的沉默介体，也称为核共抑制子2（NCOR2），是转录因子（包括雌激素受体-α（ERα））的核受体超家族的多个成员的转录共抑制子。在经典的核心升压作用模型中，SMRT在目标启动子处与抗雌激素结合的ERα结合，并抑制ERα的转录活性和基因表达。在此，在一组30种乳腺癌细胞系中检查了SMRT mRNA和蛋白质表达。发现这两个参数的表达在品系之间差异很大，蛋白质和mRNA表达之间的相关性非常差（R（2）= 0.0775）。因此，通过对866例I-II期乳腺癌患者的组织芯片进行免疫组织化学染色检查了SMRT蛋白水平。根据Allred评分分别对核和细胞质SMRT评分。大多数肿瘤（67％）呈胞质SMRT阴性，当被发现时水平很低。相反，核SMRT被广泛发现。在ERα阳性他莫昔芬治疗的患者中，根据SMRT表达水平的复发时间（TTR）没有显着差异（P = 0.297），但在未治疗的患者中差异显着（P = 0.01）。在多变量分析中，未接受ERα阳性他莫昔芬治疗且具有高核SMRT表达（SMRT 5-8，即第2至第4四分位数）的患者的TTR较短（HR = 1.94,95％CI，1.24-3.04; P = 0.004） ERα阳性他莫昔芬治疗的患者与SMRT表达无关。无论患者是否接受他莫昔芬治疗，SMRT表达与患者总生存率之间均无关联。因此，尽管SMRT蛋白表达不能预测抗雌激素治疗后的结局，但它可能在预测未接受他莫昔芬辅助治疗的患者的肿瘤复发中具有价值。

BACKGROUND & AIMS: :The influence of an immunosuppressive cytokine, interleukin-10 (IL-10), on the outcome of hepatitis C virus (HCV) infection has been increasingly reported recently. A number of polymorphisms appear to control the level of IL-10 production. Among them, -592C/A, -819C/T and -1082G/A in the IL-10 gene are three most studied single nucleotide polymorphisms. To provide a more definitive conclusion about their association with the risk of HCV infection, a meta-analysis was performed by combining and summarizing a total of 17 studies. A biological justification for the choice of genetic model was provided. The results indicated no significant association between these IL-10 polymorphisms and the susceptibility to HCV infection [-592C/A: odds ratio (OR) 0.99, 95% confidence interval (CI) 0.78-1.25; -819C/T: OR 0.90, 95% CI 0.69-1.18; -1082G/A: OR 1.34, 95% CI 0.90-2.00]. However, this analysis did not account for the possible risk modifications by other factors, such as ethnicity and virus persistence. Therefore, the effects of ethnicity and virus persistence were investigated using Bayesian meta-regression and subgroup analysis. Finally, an extended case-control association study was conducted in a Chinese population involving 1140 subjects. Both serum level and genotype data of IL-10 -1082G/A were determined. As a result, a low prevalence of G allele was observed. Significantly higher IL-10 production was observed in HCV patients, especially patients with the GG genotype.

背景与目标： 免疫抑制细胞因子白介素10（IL-10）对丙型肝炎病毒（HCV）感染结局的影响最近已有报道。许多多态性似乎可以控制IL-10的产生水平。其中，IL-10基因中的-592C / A，-819C / T和-1082G / A是三个研究最多的单核苷酸多态性。为了提供关于它们与HCV感染风险之间关系的更明确的结论，通过合并和总结总共17项研究进行了荟萃分析。提供了选择遗传模型的生物学依据。结果表明，这些IL-10多态性与HCV感染的易感性之间没有显着相关性[-592C / A：优势比（OR）0.99，95％置信区间（CI）0.78-1.25； -819C / T：OR 0.90，95％CI 0.69-1.18； -1082G / A：OR 1.34，95％CI 0.90-2.00]。但是，此分析未考虑其他因素（例如种族和病毒持久性）可能造成的风险调整。因此，使用贝叶斯元回归和亚组分析研究了种族和病毒持久性的影响。最后，在一个涉及1140名受试者的中国人群中进行了扩展的病例对照研究。测定IL-10 -1082G / A的血清水平和基因型数据。结果，观察到G等位基因的低流行。在HCV患者中，尤其是具有GG基因型的患者中，IL-10的产生明显增加。

BACKGROUND & AIMS: :The effect of leptin on ulcerative colitis (UC) has been controversial. The present study aimed to investigate the role of leptin and its receptor ob‑R in UC and the underlying mechanism of this role. The level of serum leptin and the protein expression of the leptin receptor ob‑R in the colonic mucosa were determined in patients with UC. Experimental colitis was induced through intrarectal administration of 2,4,6‑trinitrobenzene sulfonic acid (TNBS) in leptin receptor‑deficient Zucker rats (LR‑D). The body weight, disease activity index, colon length, and macroscopic and histopathological appearance were evaluated. Furthermore, the myeloperoxidase (MPO) enzyme activity and cytokine levels in colon tissues were also determined. The expression of the signal transducer and activator of transcription 3 (STAT3), phosphorylated STAT3 (p‑STAT3), nuclear factor (NF)‑κB‑p65, and Ras homolog gene family member A (RhoA) proteins in colon tissues was assessed. The results revealed that the expression of the leptin receptor ob‑R was increased in the colonic mucosa but the serum leptin level was not altered in patients with UC compared with healthy volunteers. The severity of experimental colitis, represented by body weight loss, disease activity index, colon length, and macroscopic and histological changes, was ameliorated in LR‑D rats compared with the wild‑type (WT) rats. Moreover, the MPO activity; levels of cytokines including interleukin (IL)‑1β, IL‑6, and tumor necrosis factor‑α; and expression of p‑STAT3, NF‑κB, and RhoA proteins were reduced in colon tissues of LR‑D rats compared with WT rats. In conclusion, activation of the leptin receptor ob‑R is an important pathogenic mechanism of UC, and leptin receptor deficiency may provide resistance against TNBS‑induced colitis by inhibiting the NF‑κB and RhoA signaling pathways.

背景与目标： 瘦素对溃疡性结肠炎（UC）的作用一直存在争议。本研究旨在研究瘦素及其受体ob-R在UC中的作用以及这种作用的潜在机制。测定UC患者结肠黏膜的血清瘦素水平和瘦素受体ob‑R的蛋白表达。实验性结肠炎是通过在瘦素受体缺陷型祖克大鼠（LR-D）中直肠内施用2,4,6-三硝基苯磺酸（TNBS）引起的。评估体重，疾病活动指数，结肠长度以及肉眼和组织病理学外观。此外，还确定了结肠组织中的髓过氧化物酶（MPO）酶活性和细胞因子水平。评估了信号转导和转录激活因子3（STAT3），磷酸化的STAT3（p-STAT3），核因子（NF）-κB-p65和Ras同源基因家族成员A（RhoA）蛋白在结肠组织中的表达。结果表明，与健康志愿者相比，UC患者的瘦素受体ob-R的表达在结肠粘膜中增加，但血清瘦素水平没有改变。与野生型（WT）大鼠相比，LR‑D大鼠的实验性结肠炎的严重程度得到了改善，其严重程度由体重减轻，疾病活动指数，结肠长度以及宏观和组织学变化表示。此外，MPO活性；细胞因子水平，包括白介素（IL）-1β，IL-6和肿瘤坏死因子-α；与野生型大鼠相比，LR-D大鼠结肠组织中p-STAT3，NF-κB和RhoA蛋白的表达降低。总之，瘦素受体ob-R的激活是UC的重要致病机制，瘦素受体的缺乏可能通过抑制NF-κB和RhoA信号通路来提供对TNBS诱导的结肠炎的抵抗力。

BACKGROUND & AIMS: BACKGROUND:The mammalian target of rapamycin (mTOR) pathway is dysregulated in small-cell lung cancer (SCLC) and everolimus is an oral mTOR inhibitor. METHODS:This phase-1b study assessed everolimus safety at the levels of 2.5, 5, or 10 mg once daily in combination with paclitaxel (175 mg m(-2)) once every 3 weeks in previously treated SCLC patients. The primary end point was to determine the maximum tolerated dose of everolimus. RESULTS:Among 21 enrolled patients, common drug-related adverse events were anaemia, neutropenia, thrombocytopenia, pain, hyperglycemia, and stomatitis. Out of 11 evaluable patients treated with everolimus at the level of 5 mg, 1 patient experienced dose-limiting toxicity (DLT) of grade 4 febrile neutropenia and grade 3 thrombocytopenia. The other two DLTs (grade 4 thrombocytopenia and grade 3 hyperglycemia) occurred in two out of three patients receiving everolimus 10 mg. The overall objective response rate was 28%. CONCLUSION:Everolimus showed an acceptable safety profile and preliminary antitumour activity at the dose of 5 mg once daily when combined with 3-weekly paclitaxel 175 mg m(-2) in patients with SCLC.

背景与目标： 背景：雷帕霉素（mTOR）途径的哺乳动物靶标在小细胞肺癌（SCLC）中失调，依维莫司是口服mTOR抑制剂。
方法：这项1b期研究评估了先前治疗的SCLC患者中每3周一次与紫杉醇（175 mg m（-2））联合使用的依维莫司安全性水平，每日一次为2.5、5或10 mg。主要终点是确定依维莫司的最大耐受剂量。
结果：21例患者中，常见的药物相关不良事件为贫血，中性粒细胞减少，血小板减少，疼痛，高血糖和口腔炎。在11名5 mg依维莫司治疗的可评估患者中，有1名患者出现了4级发热性中性粒细胞减少症和3级血小板减少症的剂量限制性毒性（DLT）。在接受依维莫司10 mg的三分之二的患者中，另外两个发生了DLT（4级血小板减少和3级高血糖）。总体客观回应率为28％。
结论：在SCLC患者中，当与3周一次的紫杉醇175 mg m（-2）联合使用时，依维莫司在每天一次5 mg的剂量下显示出可接受的安全性和初步的抗肿瘤活性。