Mechanism of enhancement of radiation-induced cytotoxicity by sorafenib in colorectal cancer

Sorafenib, an orally available multikinase inhibitor, combined with radiation has shown potential as an anticancer treatment in an in vitro and in vivo colon cancer model. In this study, we investigated the mechanism of enhancement of radiation-induced cytotoxicity by sorafenib in colorectal cancer. The effects of sorafenib on radiation-induced cytotoxicity of DLD-1 and HT-29 were evaluated via clonogenic assay. The impact of sorafenib on radiation-induced cell cycle kinetics and on apoptosis was analyzed using flow cytometry. Cyclin B1 was examined by western blot. As a measure of DNA damage after treatment, γ-H2AX foci and nuclear fragmentation were determined as a function of time after irradiation plus sorafenib combination. Tumor growth delay was used to evaluate the effects of sorafenib on in vivo radiation-induced cytotoxicity. Exposure of each cell line to sorafenib combined with irradiation resulted in an increased radiation-induced cytotoxicity with dose enhancement factors at a surviving fraction of 0.37 ranging from 1.13 to 1.76. Sorafenib strengthened radiation-induced accumulation of tumor cells in the G2-M phase with attenuated expression of cyclin B1, but had no effect on radiation-induced apoptosis. Exposure to sorafenib and radiation resulted in a greater number of remaining γ-H2AX foci and fragmented nuclei than radiation alone. In vivo tumor xenograft study confirmed that administration of sorafenib results in significant tumor growth inhibition when combined with radiation. These results indicate that sorafenib enhances radiation-induced cytotoxicity in colorectal cancer and suggest that the mechanism is associated with delaying repair of radiation-induced DNA damage and down-regulation of cyclin B1.     

Atrial Arrhythmia Management with Sensor Controlled Atrial Refractory Period and Automatic Mode Switching in Patients with Minute Ventilation Sensing Dual Chamber Rate Adaptive Pacemakers

Although a long postventricular atrial refractory period fPVARP) may prevent the occurrence of pacemaker mediated tachycardias and inadvertent tracking of atrial arrhythmias in dual chamber (DDD) pacing, the maximum upper rate will necessarily be compromised. We tested the feasibility of using minute ventilation sensing in a dual chamber rate adaptive pacemaker (DDDR) to shorten the PVARP during exercise in 13 patients with bradycardias (resting PVARP = 463 ± 29 msec) to avoid premature upper rate behavior. Graded treadmill exercise tests in the DDD and DDDR modes at this PVARP resulted in maximum ventricular rates of 98 ± 8 and 142 ± 3 beats/min, respectively (P < 0.0001), due to chronotropic incompetence and upper rate limitation in the DDD mode, both circumvened with the use of sensor. In order to simulate atrial arrhythmias, chest wall stimulation was applied for 30 seconds at a rate of 250 beats/min at a mean unipolar atrial sensitivity of 0.82 mV. Irregular ventricular responses occurred in the DDD mode fthe rates at a PVARP of 280 and 463 ± 29 msec were, respectively 92 ± 5 and 66 ± 3 msec; P < 0.0001). In the DDDR mode at a PVARP of 463 ± 29 msec, regular ventricular pacing at 53 ± 2 beats/min occurred due to mode switching to VVIR mode in the presence of repetitive sensed atrial events within the PVARP. One patient developed spontaneous atrial fibrillation on follow-up, which was correctly identified by the pacemaker algorithm, resulting in mode switch from DDDR to regular VVIR pacing and preservation of rate response. In conclusion, sensor controlled PVARP allows a long PVARP to be used at rest without limiting the maximum rate during exercise. In addition, to offer protection against retrograde conduction, a long PVARP and mode switching also limit the rate during atrial arrhythmias and allow regular ventricular rate responses according to the physiological demands.     

晚期慢性阻塞性肺疾病患者及晚期癌症患者的生存质量比较研究

目的比较晚期慢性阻塞性肺疾病(COPD)患者及晚期癌症患者的生存质量(Quality of life,QOL),探讨COPD患者对临终关怀的需求。方法访问COPD患者108例及癌症患者50例。采用晚期病患者生存质量量表(Quality-of-Lif Concerns in the End-of-Life Questionnaire,QOLC-E)作评估。通过统计分析,比较两组的QOL分数。结果COPD患者的基本活动程度及操作活动程度均明显低于癌症患者(t=-6.2,-4.7,P均<0.01)。而在QOLC-E的8个分类中,COPD患者在“身体不适”、“负面情绪”及“存在困扰”得分均比癌症患者低,但是“生活价值”一类却较高,差异均有显著性(P<0.05)结论研究结果显示晚期COPD患者及晚期癌症患者有相近的生存质量关注,但关注面各有不同。一方面意味临终关怀应扩展至晚期COPD患者,另一方面也显示COPD患者的诉求与晚期癌症患者不尽相同,故在发展有关服务的同时,要考虑COPD患者的独特性。     

Cryoablation versus Radiofrequency Ablation for Atrioventricular Nodal Reentrant Tachycardia: Patient Pain Perception and Operator Stress

Background: Cryoablation (CRYO) is an alternative to radiofrequency (RF) ablation in the treatment of atrioventricular nodal reentrant tachycardia (AVNRT). This study aims to evaluate the differences in patient pain perception and operator stress between CRYO and RF ablation in the treatment of AVNRT. Methods: Patients with supraventricular tachycardia underwent electrophysiology study. Twenty patients (eight males, age 46.5 ± 12.5 years) diagnosed with AVNRT were randomized to receive CRYO (11) with a 6‐mm‐tip catheter or RF (nine) with a 4‐mm‐tip catheter. Patients’ pain perception and operator stress were assessed with a visual analogue scale (VAS) from 0 to 10 at the end of procedure. Results: There was no significant difference in acute procedural success (CRYO 100% vs RF 89%, P = 0.257). There was no complication of permanent atrioventricular block in either group. The number of energy applications was significantly higher in the CRYO group (2.8 ± 1.2 vs 1.6 ± 0.9, P = 0.02). The fluoroscopic time was significantly reduced in the CRYO group (6.0 ± 4.9 vs 10.9 ± 5.4 minutes, P = 0.049) with no difference in procedure time (CRYO 49.3 ± 12.5 vs RF 54.5 ± 17.0 minutes, P = 0.462). Patients in the CRYO group experienced significantly less pain than patients in the RF group (VAS 2.3 ± 2.8 vs 5.4 ± 3.4, P = 0.024). The operator also experienced significantly less stress during CRYO than RF (VAS 1.9 ± 0.8 vs 6.2 ± 1.6, P < 0.001). There was no recurrence in both groups at 6‐month follow‐up. Conclusions: CRYO, as compared with RF, produces less pain in patients and less stress in operator in the treatment of AVNRT. (PACE 2011; 2–7)     

保护性免疫大鼠感染华支睾吸虫后吡喹酮化疗效果

[目的 ]研究吡喹酮与宿主保护性免疫对华支睾吸虫感染的协同作用。 [方法 ]用粗成虫抗原 (AWAg)和排泄分泌抗原 (ESAg)免疫大鼠或感染 2 0条华支睾吸虫囊蚴获得保护性免疫 ,用 5 0个华支睾吸虫囊蚴感染大鼠 ,用亚致死量吡喹酮(5 0 mg/ kg)治疗 ,以回收虫体数观察疗效。统计学上显著性差异用 PC- SAS系统的 ANOVA和 Nparlway Kruskal- Wallis检验法。 [结果 ]1在对照组 ,ESAg免疫接种组和 AWAg免疫接种组吡喹酮杀幼虫效果明显高于成虫 ,3组均为 P<0 .0 1。2感染后的减虫率 ,与对照组比较 ,ESAg免疫接种组 (35 .6 % ,P<0 .0 1)和华支睾吸虫囊蚴感染组 (97.5 % ,P<0 .0 1)较高 ,而在 AWAg免疫接种组 (2 3.4% )较低。吡喹酮的疗效在 ESAg免疫接种组显著增高。 [结论 ]吡喹酮对华支睾吸虫的疗效在大鼠具有获得性免疫的情况下相协性的提高。