Targeting telomerase activity by BIBR1532 as a therapeutic approach in germ cell tumors

Summary Germ cell tumors (GCT) possess a high activity of telomerase, a ribonucleoprotein complex compensating the erosion of telomeres during cell division by adding TTAGGG-repeats to the telomeric ends of chromosomes. Cisplatin, the most important drug in the treatment of GCT, preferentially acts on G-rich regions like telomeres. Inhibiting telomerase in tumors can result in telomere shortening and senescence and could increase the efficacy of chemotherapy in refractory patients. The study evaluated the promise of the small molecule telomerase inhibitor BIBR1532 as single agent and assessed a possible synergism with cisplatin in a preclinical model of GCT. GCT-derived cell line 2102EP was cultured with or without 10 μM of BIBR1532. Cell expansion was quantified in population doublings (PD). Telomere length was analyzed by fluorescence in situ hybridization and flow cytometry (flow-FISH). The sensitivity of the cells towards cisplatin was determined by MTT-assay. Telomerase activity was assessed by TRAP assay. After 300 PD, telomere length diminished from 18.5 kb ± 0.59 kb to 8.9 ± 0.1 kb in BIBR1532 treated 2102 EP cells as compared to 14.5 ± 0.0 kb in untreated control cells. Treated cells did not show altered growth kinetics compared to untreated counterparts. Despite effective shortening of telomeres, the sensitivity of the treated cells towards cisplatin did not increase. Concomitant treatment with BIBR1532 and cisplatin did not result in accelerated telomere shortening. Telomere length can be shortened significantly by telomerase inhibition in GCT cell line models. However, possibly in view of their extensive telomere “reserve,” telomerase inhibition did neither result in increased sensitivity of 2102 EP cells to cisplatin nor did co-treated cells show accelerated telomere shortening. Sandra Mueller, Ulrike Hartmann and Frank Mayer contributed equally to the work. Tim H. Brummendorf and Carsten Bokemeyer contributed equally to the work.     

完全性左束支传导阻滞患者左心室心肌收缩功能的研究

目的 应用超声二维斑点追踪显像技术探讨完全性左束支传导阻滞患者左室心内膜下心肌收缩功能.方法 完全性左束支传导阻滞患者(CLBBB)20例,正常对照者20例,采用心尖长轴四腔心和二腔观的二维灰阶动态图像,应用二维应变软件测量左室壁各节段的心内膜下心肌收缩应变、应变率及整体长轴应变(GLS),心尖双平面Simpson法测量左室射血分数(LVEF﹑FS%).结果 与正常组比较,LBBB组,的左房内径、E/A、左室长轴心内膜下心肌的纵向收缩期峰值应变、应变率减低(P<0.05).结论 超声二维斑点追踪显像技术能准确地评价左束支患者的左室心内膜下心肌收缩功能.     

肝硬化伴脾亢患者肝移植术后脾功能变化的研究

目的观察肝硬化伴脾亢患者肝移植术后外周血细胞及脾脏大小的变化,探讨肝移植对脾功能亢进的影响。方法30例行肝移植保留脾脏手术的乙肝肝硬化伴脾亢患者,测定术前及术毕,术后1、2、3、5、7、14、21、28d红细胞、白细胞、血小板计数（PLT）、凝血酶原时间（PT）、活化部分凝血酶原时间（APTT）。术前,术后1、2、3、4周B超测定脾脏上下径、肋间厚度、脾门处脾静脉直径。结果术毕时PLT较切皮前明显增加（P〈0.05）,术后2d又显著降低。术后3dPLT和RBC均明显增加,一直持续至术后28d（P〈0.05或P〈0.01）;与切皮前相比,WBC从术毕开始增加,持续至术后2d（P〈0.05或P〈0.01）,术后3d开始下降到术前水平,并持续至术后28d（P〉0.05）;与术前相比,术后3周脾脏上下径及厚度开始明显减小（P〈0.05）,脾静脉直径术后4周明显减小（P〈0.05）;与切皮前相比,PT从术后2d开始降低并持续至术后28d（P〈0.05或P〈0.01）;术毕及术后1d APTT均较切皮前明显增加（P〉0.05）,术后2d又明显降低,并持续至术后28d（P〈0.01）。结论肝移植能有效的治疗肝硬化伴脾功能亢进症,肝移植可保留功能亢进的脾脏。     

二尖瓣环位移自动追踪技术评价蒽环类药物对乳腺癌病人左室收缩功能的影响

目的 应用二尖瓣环位移自动追踪技术评价蒽环类药物对乳腺癌病人左室收缩功能的影响,探讨反映左室功能受损较为准确和敏感的参数.方法 收集2018年10月至2019年12月于山西医科大学第二医院乳腺外科诊断为乳腺癌的女性病人50例,均行以表柔比星为主的化疗方案,分别于化疗前、化疗2及4周期后,行常规超声心动图、二维斑点追踪技...     

丹参多酚酸盐治疗糖尿病周围神经病变的临床疗效及对血清炎性细胞因子、血管内皮功能的影响

目的 探讨丹参多酚酸盐治疗糖尿病周围神经病变(DPN)的临床效果及对血清炎性细胞因子、血管内皮功能的影响.方法 按照随机数字表法将116例DPN病人分为观察组和对照组,对照组给予甲钴胺治疗,观察组在此基础上给予丹参多酚酸盐治疗,观察两组治疗效果.结果 两组病人治疗后空腹血糖、糖化血红蛋白水平对比,差异无统计学意义(P>0.05);观察组病人疗程结束后总有效率明显高于对照组,差异有统计学意义(P<0.05);观察组病人治疗后白细胞介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)下降幅度均显著高于对照组,差异有统计学意义(P<0.05);观察组病人治疗后一氧化氮(NO)升高幅度,可溶性细胞间黏附分子-1(sICAM-1)、内皮素-1(ET-1)下降幅度均显著高于对照组,差异有统计学意义(P<0.05);观察组病人治疗后超氧化物歧化酶(SOD)升高幅度、同型半胱氨酸(HCY)下降幅度均显著高于对照组,差异有统计学意义(P<0.05).结论 在甲钴胺基础上加用丹参多酚酸盐能够有效提高DPN治疗效果,改善病人血清炎性细胞因子水平和血管内皮功能,应用价值较高.     

临床药师对1例颅脑外伤并发癫痫患者的用药分析

目的:探讨颅脑外伤并发癫痫的药物治疗,提供临床合理用药依据。方法:对1例颅脑外伤并发癫痫的病例进行抗癫痫、抗感染、脑细胞保护的用药分析。结果:通过用药分析,临床药师提供了符合此类患者特点的药物治疗建议。结论:临床药师参与制订临床用药方案,可以解决用药过程中的实际问题,提高用药安全性。     

Rats fed soy protein isolate (SPI) have impaired hepatic CYP1A1 induction by polycyclic aromatic hydrocarbons as a result of interference with aryl hydrocarbon receptor signaling

Consumption of soy diets has been found to reduce cancer incidence in animals and is associated with reduced cancer risk in humans. Previously, we have demonstrated that female Sprague-Dawley rats fed purified AIN-93G diets with soy protein isolate (SPI) as the sole protein source had reduced CYP1A1 induction and basal aryl hydrocarbon receptor (AhR) levels relative to those fed the same diet containing casein (CAS). In the present study, the molecular mechanisms underlying reduced AhR expression have been studied. The SPI-effect on AhR was not observed after feeding diets containing the purified soy isoflavones genistein or daidzein. Rat hepatoma FGC-4 cells were treated with the serum obtained from rats fed CAS- or SPI-containing diets. Reduced AhR levels (P<0.05) were observed after 24 h exposure to SPI-serum without any changes in the overall expression of chaperone proteins--HSP90 and XAP2. SPI-serum-stimulated AhR degradation was inhibited by treating the cells with the proteasome inhibitor, MG132, and was observed to be preceded by ubiquitination of the receptor. A reduced association of XAP2 with the immunoprecipitated AhR complex was observed. SPI-serum-mediated AhR degradation was preceded by nuclear translocation of the receptor. However, the translocated receptor was found to be unable to heterodimerize with ARNT or to bind to XRE elements on the CYP1A1 enhancer. These data suggest that feeding SPI-containing diets antagonizes AhR signaling by a novel mechanism which differs from those established for known AhR antagonists.     

Preventing complications by persistence with iron replacement therapy: a comprehensive literature review

Objective: Iron deficiency and particularly iron deficiency anemia (IDA) can lead to negative health consequences. This review describes the importance of adherence and persistence (adhering to treatment for the recommended duration) with iron replacement therapy in the prevention of complications, particularly regarding its recommended dosing schedule.

Methods: Comprehensive literature searches were performed of Medline and the Cochrane library from 2000 to 2018. Keywords included iron deficiency or IDA, compliance or adherence, persistence, health beliefs, risk factor, complications, dosing cycles, oral iron replacement therapy and recommendations for duration, ferrous compounds, iron supplementation, dietary iron, and delayed-action/slow-release preparations.

Results: Identified articles focused on IDA as a risk factor (particularly for worsened comorbidities or surgical outcomes), guidelines, adherence and persistence, and differences between iron formulations. Current guidelines and expert opinion continue to support oral iron supplementation as first-line therapy. While it is recommended to take iron therapy for 2 months to normalize hemoglobin, then 2–3 months to build up iron stores, many patients face difficulties in adhering to and persisting with the full iron treatment regimen. Patient education and understanding, social support, simple dosing, perceived efficacy including reduced symptoms and tolerability were factors noted to promote medication adherence and persistence. Adherence to iron therapies appears to be facilitated by using ferrous sulfate due to its optimal absorption, and particularly extended-release forms due to their improved tolerability for iron deficiency.

Conclusions: Proper adherence and persistence with iron supplementation may prevent or reduce the risk of complications of iron deficiency and IDA.     

Effect of ustekinumab on physical function and health-related quality of life in patients with psoriatic arthritis: a randomized,placebo-controlled,phase II trial

Abstract

Objective:

To use data from a phase II clinical trial to evaluate the effect of ustekinumab, a human immunoglobulin monoclonal antibody that binds with high affinity to the shared p40 subunit of human interleukins-12 and -23, on physical disability and health-related quality of life (HRQoL) in patients with psoriatic arthritis (PsA).     

临床药师对1例乙肝后肝硬化腹水合并食管胃静脉曲张破裂出血患者的药学监护

目的:了解肝硬化失代偿期的药物治疗经过,探讨对该类患者的药学监护要点。方法:对1例乙肝后肝硬化腹水合并食管胃静脉曲张破裂出血患者治疗过程所用药物进行分析,发现存在多种治疗矛盾。药师以此为切入点,协助医师共同制订个体化用药方案:调整螺内酯、呋塞米剂量,应用特利加压素减少腹水;选用普萘洛尔降低门脉压;使用恩替卡韦保肝及抗乙肝病毒;合理使用凝血酶、抑酸剂、生长抑素等处理急性上消化道出血,监护患者用药全过程,并对患者开展用药教育。结果:在临床药师和临床医师共同参与下,患者肝硬化腹水明显减少,上消化道出血完全控制后出院。结论:当临床合并多种疾病或出现治疗矛盾时是临床药师工作的切入点。药师可协同临床医师优化治疗方案,实施药学监护,以促进临床合理用药。     

临床药师参与1例胰头占位致胆道梗阻患者的药学监护

目的通过临床药师对胆道梗阻患者的药学服务,为临床合理用药提供参考。方法临床药师在1例83岁男性因胰头占位致胆道梗阻患者的治疗过程中,与临床医师共同制订有效的治疗方案,为患者提供合理的用药监护。结果在临床药师积极配合下,临床医师逐步完善了治疗,最终患者治疗取得了明显的效果。结论临床药师通过药学监护,优化了胆道梗阻临床治疗方案,取得了良好的效果。     

DNA interactions of new antitumor platinum complexes with trans geometry activated by a 2-metylbutylamine or sec-butylamine ligand

The global modification of mammalian and plasmid DNAs by novel platinum compounds, trans-[PtCl(2)(NH(3))(Am)], where Am=2 -methylbutylamine or sec-butylamine was investigated in cell-free media using various biochemical and biophysical methods. These modifications were analyzed in the context of the activity of these new compounds in several tumor cell lines including those resistant to antitumor cis-diamminedichloroplatinum(II) (cisplatin). The results showed that the replacement of one amine group by 2-methylbutylamine or sec-butylamine ligand in clinically ineffective trans-diamminedichloroplatinum(II) (transplatin) resulted in a radical enhancement of its activity in tumor cell lines so that they are more cytotoxic than cisplatin and exhibited significant antitumor activity including activity in cisplatin-resistant tumor cells. Importantly, this replacement also markedly altered DNA binding mode of transplatin and reduced the efficiency of repair systems to remove the adducts of the new analogues from DNA. The results support the view that one strategy to activate trans geometry in bifunctional platinum(II) compounds including circumvention of resistance to cisplatin may consist in a chemical modification of the ineffective transplatin which results in an increased efficiency to form DNA interstrand cross-links.     

Classification and labeling of industrial products with extreme pH by making use of in vitro methods for the assessment of skin and eye irritation and corrosion in a weight of evidence approach

Classification and labeling of products with extreme pH values (?2 or ?11.5) is addressed in chemicals legislation. Following determination of pH and alkaline/acid reserve, additional in vitro tests are needed, especially to substantiate results less than corrosive. However, only limited experience with the practical application of in vitro methods to determine appropriate classifications for pH extreme products is available so far. Expert judgment and weight of evidence are given major roles under the globally harmonized system of classification and labeling of chemicals (GHS) and should be performed on a sound data basis. We have used a tiered testing strategy to assess 20 industrial products (cleaning and metal pretreatment) regarding their corrosive and irritating properties towards human skin models in vitro in the EpiDerm™ skin corrosion and/or skin irritation test. Nine dilutions of individual compounds were additionally tested. Non-corrosive samples were tested in the Hen’s egg test chorioallantoic membrane (HET-CAM). We demonstrate how data is combined in a weight of evidence expert judgment, and give examples of classification decisions. To our knowledge this is the first comprehensive analysis of industrial products with extreme pH values to determine irritating and corrosive properties by making use of in vitro methods in a weight of evidence approach.