Brachytherapy: An emblematic example of extreme hypofractionated regimen

In order to provide more convenient irradiation regimens for patient comfort, radiation facility organization and health expenses, new hypofractionated protocols have been evaluated. Moderately (dose/fraction: 2.3 to 3 Gy), then ultra (dose/fraction: 5.2 to 6.1 Gy) hypofractionated irradiations were first validated. The current question is: is it possible to go forward using extreme hypofractionated regimens (EHR) based on 1 to 3 fractions. Different irradiation techniques are under investigation. However, brachytherapy remains the smartest way to deliver a high dose in a small volume. We report prospective and retrospective study results which evaluated EHR for breast and prostate brachytherapy. While oncological outcome and toxicity profile appear extremely encouraging for low-risk breast cancer after a 1 to 4 fractions (6.25 to 20 Gy/fraction), the use of a single fraction of 19 to 23 Gy appears debatable for prostate cancer. Brachytherapy represents an emblematic example of EHR but longer follow-up and more mature results are awaited in order to specify the right indications and refine the EQD2 calculation method including new biological and technical factors.     

The association between the decreased expression levels of FOXJ1 and the activation of NF-κB pathway in interstitial lung disease of MRL/Lpr mice

Background: Pulmonary manifestations of systemic lupus erythematosus (SLE) are appearing in 4-5% of patients involving lung in almost half of the cases during the disease course. Objective: We compared the autoimmune pulmonary inflammation in the lung tissue of mice to determine the association between decreased expression levels of Forkhead Box J1 (FOXJ1) and the activation of the NF-κB pathway in autoimmune pulmonary inflammation of MRL/Lpr mice. Methods: The female BALB/c mice (n=6) and MRL/Lpr mice (n=30) were divided into 5 groups including a control group (BALB/c), and five MRL/Lpr mice groups (8W, 12W, 16W, 24W, and 32W). The infiltration of the inflammatory cells was determined in lung tissue by performing the histological analysis. The western blotting was used to examine the expression levels of the age-related FOXJ1, and p50 and p65 proteins in the lungs of MRL/Lpr mice. The expression levels of MMP2 and MMP9 were determined via immunohistochemistry and immunofluorescence. Results: There were severe infiltrates of lung cells with high levels of tracheal damage, perivascular injury and interstitial inflammatory cell infiltration when the MRL/Lpr mice from 16w to 32w comparing to the 8w old healthy MRL/Lpr mice in the control group (p <0.05). Moreover, the reduced expression levels of FOXJ1 were associated with the activation of the NF-κB pathway in interstitial lung disease of MRL/Lpr mice via the modulation of p50 and p65. In addition, the expression levels of MMP2 and MMP9 pro-inflammation factors increased in the lungs of the MRL/Lpr mice from 16w to 32w. Conclusions: The expression level of FOXJ1 might be an indicator of the degree of lung disease in lupus-prone mice.     

Understanding the Influence of Nanocarrier-Mediated Brain Delivery on Therapeutic Performance Through Pharmacokinetic-Pharmacodynamic Modeling

This study aimed at evaluating how encapsulation in a regular nanocarrier (NC) (providing extended circulation time) or in a brain-targeting NC (providing prolonged circulation time and increased brain uptake) may influence the therapeutic index compared with the unformulated drug and to explore the key parameters affecting therapeutic performance using a model-based approach. Pharmacokinetic (PK) models were built with chosen PK parameters. For a scenario where central effect depends on area under the unbound brain concentration curve and peripheral toxicity relates to peak unbound plasma concentration, dose-effect and drug-side effect curves were constructed, and the therapeutic index was evaluated. Regular NC improved the therapeutic index compared with the unformulated drug due to reduced peripheral toxicity, while brain-targeting NC enhanced the therapeutic index by lowering peripheral toxicity and increasing central effect. Decreasing drug release rate or systemic clearance of NC with drug still encapsulated could increase the therapeutic index. Also, a drug with shorter half-life would therapeutically benefit more from a NC encapsulation. This work provides insights into how a NC for brain delivery should be optimized to maximize the therapeutic performance and is helpful to predict if and to what extent a drug with certain PK properties would obtain therapeutic benefit from nanoencapsulation.     

枳术丸水煎液及其拆方含药血清对大鼠结肠Cajal间质细胞增殖和凋亡的影响

目的:探讨枳术丸水煎液及其拆方对大鼠结肠Cajal间质细胞(ICC)增殖和凋亡的影响及其分子机制,并从细胞分子层面分析中医攻补兼施法治疗慢传输型便秘可能的机制。方法:将40只大鼠随机分成白术组、枳实组、枳术丸组、空白血清组,每组10只。白术组灌以17.7 g·kg-1·d-1白术水煎液,枳实组灌以8.9 g·kg-1·d-1枳实水煎液,枳术丸组灌以26.4 g·kg-1·d-1枳术丸水煎液,空白血清组灌以无菌蒸馏水3 mL,每日1次,连续7 d,取血制备含药血清和空白血清。将4组含药血清分别配成5%,10%,15%,20%4个体积分数,干预24 h,观察ICC的数量、形态,用细胞增殖毒性检测试剂盒(CCK-8)检测各组细胞增殖情况,测定各组最佳干预体积分数。将大鼠结肠ICC细胞分为正常组、空白血清组、白术组、枳实组、枳术丸组,5-乙炔基-2'脱氧尿嘧啶核苷(EdU)检测各组ICC的增殖情况,流式细胞仪检测各组ICC的凋亡情况;蛋白免疫印迹法(Western blot)检测各组ICC中X连锁凋亡抑制蛋白(XIAP),增殖细胞核抗原(PCNA)蛋白表达情况。结果:与正常组比较,空白血清组、白术组、枳实组最佳干预体积分数均为10%,枳术丸组最佳干预体积分数为5%。与正常组比较,所有实验中空白血清组对ICC增殖和凋亡的影响没有明显差异;与正常组及空白血清组比较,白术组、枳实组、枳术丸组ICC增殖率有显著差异(P0.05,P0.01),与白术组和枳实组比较,枳术丸组对ICC增殖率明显增加(P0.05,P0.01);与枳实组比较,白术组对ICC增殖率变化不明显。与正常组及空白血清组比较,白术组、枳实组、枳术丸组ICC的凋亡率无明显差异;与正常组及空白血清组比较,白术组、枳实组、枳术丸组内的XIAP,PCNA蛋白水平均明显上调(P0.05,P0.01),三组间比较差异不明显。结论:枳术丸、枳实、白术在一定浓度下均能通过增加XIAP,PCNA蛋白表达促进ICC的增殖,且对ICC的凋亡无明显影响;以攻补兼施法立法的方剂枳术丸能促进ICC的增殖,并且其增殖效果优于攻伐单药枳实和补益单药白术。     

肾小管上皮细胞表型转化与糖尿病肾病

肾小管病变及肾间质纤维化在糖尿病肾病中的重要作用逐渐被认识,其中肾小管上皮细胞向间充质细胞转化(EMT)可能是其发挥作用的关键环节,与肾间质纤维化的程度相平行。在糖尿病肾病中引发EMT的因素主要有高血糖、晚期糖基化终末产物、蛋白尿、血管紧张素Ⅱ、结缔组织生长因子等。     

Ets-1、MMP-1及TIMP-1在膀胱移行细胞癌中的表达

目的研究Ets-1、基质金属蛋白酶1(MMP-1)及基质金属蛋白酶1抑制物(TIMP-1)在膀胱移行细胞癌(BTCC)中的表达及意义。方法用免疫组化方法检测40例BTCC组织和12例正常膀胱黏膜组织中Ets-1、MMP-1及TIMP-1的表达;分析Ets-1与BTCC临床病理特征间的关系;研究BTCC中MMP-1、TIMP-1表达与Ets-1表达的相关性。结果①Ets-1在BTCC中高度表达,阳性率为82.5%(P<0.01),且随BTCC临床分期和病理分级的升高而增加,肿瘤复发组高于无复发组,肿瘤转移组高于无转移组(P<0.05)。②MMP-1阳性表达率膀胱癌组(85.0%)明显高于对照组(58.3%)(p<0.05);TIMP-1阳性表达率对照组(83.3%)明显高于膀胱癌组(47.5%)(P<0.05)。③MMP-1与Ets-1表达呈正相关(Rs为0.824,P<0.01),而TIMP-1与Ets-1表达呈负相关(Rs为-0.821,P<0.01)。结论①Ets-1在BTCC中高度表达,并随BTCC分期分级升高而增加;Ets-1与BTCC转移及复发密切相关。②BTCC中Ets-1上调MMP-1表达,而下调TIMP-1表达,从而参与BTCC侵袭与转移。     

Racial and Ethnic Disparities in Idiopathic Pulmonary Fibrosis: A UNOS/OPTN Database Analysis

We previously reported poorer survival among non-Hispanic blacks and Hispanics with idiopathic pulmonary fibrosis (IPF) compared to non-Hispanic whites at our center. In the current study, we hypothesized that these disparities would exist in a nationwide cohort of wait-listed patients with IPF. We performed a retrospective cohort study of 2635 patients with IPF listed for lung transplantation between 1995 and 2003 at 94 transplant centers in the United States. The age-adjusted mortality rate was higher among non-Hispanic blacks [hazard ratio (HR) = 1.24, 95% confidence interval (CI) 1.06-1.45, p = 0.009] and Hispanics (HR = 1.29, 95% CI 1.06-1.56, p = 0.01) compared to non-Hispanic whites. These findings persisted after adjustment for transplantation, medical comorbidities and socioeconomic status. Worse lung function at the time of listing appeared to explain some of these differences (HR for non-Hispanic blacks after adjustment for forced vital capacity percent predicted = 1.16, 95% CI 0.98-1.36, p = 0.09; HR for Hispanics = 1.21, 95% CI 0.99-1.48, p = 0.056). In summary, black and Hispanic patients with IPF have worse survival than whites after listing for lung transplant.