Proliferation signal inhibitors in the treatment of lupus nephritis: Preliminary experience

Aim: Proliferation signal inhibitors (PSI) have demonstrated efficacy in prevention and treatment in an animal model of lupus nephritis (LN) but there are no data regarding the use of PSI in human LN. We report here our experience of using PSI treatment in seven patients with severe proliferative lupus nephritis. Methods: This is a retrospective study on patients with proliferative lupus nephritis who had received PSI treatment. Results: Seven patients were included. Two patients had concomitant membranous lupus nephropathy. The indications for PSI included mycophenolate mofetil intolerance (n = 4), history of malignancy (n = 2) and leucopoenia (n = 1). Five patients were given PSI when disease was active. Two had treatment discontinued because of acute cholecystitis and leucopoenia, respectively. In the other three patients combined steroid and PSI treatment as induction therapy led to improvements in serology, renal function and proteinuria. In two patients treated with PSI and low‐dose steroid as maintenance immunosuppression, both maintained stable lupus serology, renal function and proteinuria over 18 months. Side‐effects included dyslipidemia and oral ulcers. Conclusion: Proliferation signal inhibitors warrants further investigation as an alternative immunosuppressive treatment in lupus nephritis.     

Significant relationship of time-dependent uroflowmetric parameters to lower urinary tract symptoms as measured by the International Prostate Symptom Score

AIMS: The aim of the present paper is to elucidate the possible involvement of time-dependent parameters as obtained by uroflowmetry in the manifestation of lower urinary tract symptoms (LUTS) in elderly patients. METHODS: Using simple and multiple regression analyses, the correlation of the International Prostate Symptom Score (IPSS) with objective parameters including age, postvoid residual, uroflowmetry and transrectal ultrasonic measurements of the prostate was analyzed in 206 male patients (average age of 68.0 +/- 7.4 years) who visited our outpatient clinic complaining of LUTS. RESULTS: In the 206 patients, the mean maximum flow rate was 12.2 mL/s (13.7 mL/s in mild, 11.9 mL/s in moderate, and 11.2 mL/s in severe IPSS total score) and average flow rate was 4.4 mL/s (5.4 mL/s in mild, 4.3 mL/s in moderate, and 3.5 mL/s in severe IPSS total score). Simple regression analyses demonstrated that age, voiding time, and average and maximum flow rates correlate significantly with symptom scores. In particular, relatively strong relationships were found between average flow rate and scores of intermittency, weak stream and total and voiding symptoms scores. Serum prostate specific antigen level, postvoid residual and prostatic ultrasonic measurements did not show a significant correlation with symptom scores. Multiple regression analyses revealed age and average flow rate to be independent determinants for symptom scores. These results suggest that the time-dependent function in micturition interferes in the manifestation of LUTS in elderly men who have borderline or pathologic maximum flow rate. When evaluating uro flowmetry in elderly male patients with LUTS, attention should be paid to time-dependent parameters such as voiding time and average flow rate.     

米非司酮对子宫肌瘤培养细胞雌、孕激素受体和表皮生长因子受体表达的影响

目的 :探讨米非司酮对子宫肌瘤培养细胞的雌、孕激素受体 (ER、PR)和表皮生长因子受体 (EGFR)水平的影响。方法 :测定并比较不同浓度米非司酮干预的子宫肌瘤细胞上的ER、PR、EGFR水平。结果 :(1)米非司酮干预后ER表达量无明显改变。 (2 )PR和EGFR在分泌期高于增生期 ,PR和EGFR在 1.0 μmol·L- 1 和 10 μmol·L- 1 组表达量明显下降 ,与 0 μmol·L- 1 和 0 .1μmol·L- 1 组之间差异有显著性 (P <0 .0 5 )。而 1.0 μmol·L- 1 和 10 μmol·L- 1 组之间无显著性差异 (P >0 .0 5 )。结论 :(1)米非司酮通过下调PR、EGFR而不是ER来抑制肌瘤的生长。 (2 )米非司酮下调子宫肌瘤PR、EGFR的作用存在剂量阈值。 1.0 μmol·L- 1 的米非司酮是抑制子宫肌瘤细胞PR和EGFR表达的阈值剂量。     

Monoclonal antibodies against human T cell adhesion molecules--modulation of immune function in nonhuman primates.

The cytotoxic T cell is thought to be a primary effector of allograft rejection. In vitro studies have demonstrated that the interaction between cytotoxic T cells and target cells involves cell surface adhesion molecules that result in conjugate formation, with subsequent antigen recognition, T cell activation, and target cell lysis. Experiments have also demonstrated the ability of monoclonal antibodies with specificity for two human T cell adhesion molecules, lymphocyte function associated (LFA) antigen-1 (LFA-1, CD11a, alpha-chain/CD18, beta-chain) and LFA-2 (CD2), to inhibit conjugate formation in vitro. Studies in a nonhuman primate model were undertaken to determine whether the in vivo administration of monoclonal antibodies with specificity for the alpha chain of LFA-1 (CD11a) or with specificity for CD2 could modulate in vivo T cell function. Cynomolgus monkeys (Macaca fascicularis) received 10 daily intravenous infusions of either anti-CD11a, anti-CD2 or both anti-CD11a and anti-CD2 monoclonal antibodies. Antibody administration was well tolerated and resulted in high levels of circulating murine monoclonal antibody in the peripheral circulation. Nearly all the animals generated antimurine antibodies that were specific for both idiotypic and nonidiotypic determinants of the infused mouse protein. Circulating lymphocytes and T cells were not depleted by treatment with anti-CD11a or anti-CD2 mAbs; in fact, treatment with the combination of anti-CD11a plus anti-CD2 or anti-CD11a alone led to increased numbers of circulating lymphocytes and T cells. Modulation of the LFA-1 molecule on circulating T cells occurred as a result of treatment with anti-CD11a (or the combination of anti-CD11a plus anti-CD2), whereas treatment with anti-CD2 (or anti-CD11a plus anti-CD2) did not result in modulation of the CD2 antigen despite detectable levels of circulating anti-CD2 mAb. In vivo T cell function was assessed by placement of skin allografts. As compared with treatment with saline or a control mAb, allograft survival was significantly prolonged in animals treated with anti-CD11a or combination treatment but not in animals receiving anti-CD2 alone. We conclude that the in vivo administration of anti-LFA-1 mAb may be useful for the blockade of effector T cell activity during allograft rejection, that saturation of antigen and antigen modulation may be important for efficacy of such antibody effects in vivo, and that monoclonal antibodies with specificity for functionally important T cell surface molecules may alter T cell function in vivo without lymphocyte depletion.     

二烯丙基二硫化物诱导胃癌BGC823 细胞周期G2/M期阻滞的机制*

目的:以细胞周期作为抗癌药物新靶点的研究,可能是很有前途的。笔者的前期工作发现,二烯丙基二硫化物（diallyl disulfide,DADS）可抑制人胃癌BGC 823 细胞增殖,其增殖抑制与细胞周期G2/M期阻滞有关;DADS可能是通过抑制细胞分裂周期蛋白25C（Cell division cycle protein 25C,Cdc25C）、cyclinB 1 表达使部分BGC 823 细胞停滞在G2/M期,但G2/M期阻滞的机制还未完全阐明。本研究进一步探讨DADS诱导人胃癌BGC 823 细胞周期G2/M期阻滞的可能机制。方法:RT-PCR 检测Chk1 和Chk2 在mRNA 水平的改变;Western blot检测DADS处理BGC 823 细胞前后细胞周期相关蛋白ATM-RAD3 相关基因（ATM-RAD3-related gene,ATR ）、细胞周期检查点蛋白激酶1（checkpoint kinase1,Chk1）、细胞周期检查点蛋白激酶2（checkpoint kinase2,Chk2）表达和ATR 、Chk1、Chk2 的磷酸化程度;免疫共沉淀检测Chk1、Chk2 与Cdc25C 结合情况。结果:RT-PCR 检测显示,Chk1 和Chk2 的mRNA 水平在处理组与未处理组之间无显著性差异（P>0.05）。 Western blot检测显示,总Chk1 和Chk2 蛋白表达在细胞处理前后均无明显改变,但15mg/LDADS刺激BGC 823 细胞2h 后,处理组细胞Chk1 磷酸化程度明显增加,并呈时间依赖性（P<0.05）,而Chk2 磷酸化程度在处理组与未处理组之间无显著性差异（P>0.05）。 15mg/L DADS 作用15～120min,ATR 磷酸化程度明显增加,呈时间依赖性（P<0.05）,而ATR 表达无改变。免疫共沉淀分析表明,DADS 能促进BGC 823 细胞Chk1 与Cdc25C 结合,而对Chk2 与Cdc25C 结合无影响。结论:DAD诱导人胃癌BGC 823 细胞G2/M期阻滞与Chk1 的活化有关,DADS可能是通过激活ATR 、Chk1,调节Cdc25C 的表达引起人胃癌BGC 823 细胞G2/M期阻滞。