Cyclin-dependent kinase inhibitor Dinaciclib (SCH727965) inhibits pancreatic cancer growth and progression in murine xenograft models

Pancreatic cancer is one of the most lethal of human malignancies, and potent therapeutic options are lacking. Inhibition of cell cycle progression through pharmacological blockade of cyclin-dependent kinases (CDK) has been suggested as a potential treatment option for human cancers with deregulated cell cycle control. Dinaciclib (SCH727965) is a novel small molecule multi-CDK inhibitor with low nanomolar potency against CDK1, CDK2, CDK5 and CDK9 that has shown favorable toxicity and efficacy in preliminary mouse experiments, and has been well tolerated in Phase I clinical trials. In the current study, the therapeutic efficacy of SCH727965 on human pancreatic cancer cells was tested using in vitro and in vivo model systems. Treatment with SCH727965 significantly reduced in vitro cell growth, motility and colony formation in soft agar of MIAPaCa-2 and Pa20C cells. These phenotypic changes were accompanied by marked reduction of phosphorylation of Retinoblastoma (Rb) and reduced activation of RalA. Single agent therapy with SCH727965 (40 mg/kg i.p. twice weekly) for 4 weeks significantly reduced subcutaneous tumor growth in 10/10 (100%) of tested low-passage human pancreatic cancer xenografts. Treatment of low passage pancreatic cancer xenografts with a combination of SCH727965 and gemcitabine was significantly more effective than either agent alone. Gene Set Enrichment Analysis identified overrepresentation of the Notch and Transforming Growth Factor-β (TGFβ) signaling pathways in the xenografts least responsive to SCH727965 treatment. Treatment with the cyclin-dependent kinase inhibitor SCH727965 alone or in combination is a highly promising novel experimental therapeutic strategy against pancreatic cancer.Key words: pancreatic cancer, xenograft mouse models, cyclin-dependent kinases, SCH727965, dinaciclib, cell cycle, translational research     

高位胸段硬膜外麻醉下清醒病人的冠状动脉搭桥手术

目的　了解在高位胸段硬膜外麻醉下避免全麻行非体外循环心脏跳动下冠状动脉搭桥手术的可行性。方法　硬膜外麻醉下对 2 5例清醒病人行非体外循环心脏跳动下冠状动脉搭桥手术 ,没有气管插管全麻 ,所有病人在手术前晚行硬膜外置管。结果　总共搭桥 71支 (1支 11例 ,2支 5例 ,3支 6例 ,4支 3例 )。除 1例因为术中出现室颤转为全麻和体外循环外 ,2 4例在硬外麻作为唯一麻醉下完成非体外循环心脏跳动下冠状动脉搭桥手术。除 2例行左胸小切口外其余行正中切口 ;其中 6例为再次手术 ;平均每例搭桥2 8支 ,没有手术死亡。术后在复苏室和病房住院时间分别为 (16 2± 4 2 )h和 (3 2 4± 1 2 )d。结论　本组的早期经验提示在没有气管插管全麻、病人清醒下可以行多支冠状动脉搭桥术     

Effects on growth of single short courses of fluoroquinolones

The aim of the study was to document the effects of short courses of fluoroquinolones given during an outbreak of multidrug resistant typhoid fever in southern Viet Nam on the growth of children over a period of two years. In a prospective cohort study, 326 Vietnamese children aged between 1 and 14 years were followed up for two years after receiving either ciprofloxacin (70 mg/kg given over 7 d) (n = 173) or ofloxacin (45-50 mg/kg given over 3-5 d) (n = 153) for suspected typhoid fever. Growth velocity and weight for height were compared with an age matched control group of children from the same locality (n = 223) who had not contracted typhoid or received any fluoroquinolones. In the ofloxacin and ciprofloxacin treated patients there was no evidence of acute joint toxicity, nor of any joint symptoms attributable to either of the fluoroquinolones. There was no difference in expected weight for height measurements between the three groups of children over the two year period. During the first year, height velocity in ciprofloxacin treated children was greater than in either ofloxacin treated children or untreated controls. Height velocity in the latter two groups was not significantly different. After two years height velocity was similar in the three groups. The results support the use of short course fluoroquinolone treatment in childhood typhoid, especially when caused by strains resistant to other antibiotics.     

Measurement of cardiac output: Comparison of four different methods

Background In off pump Coronary Artery Bypass Grafting (OPCAB), dislocation of the heart influences cardiac output (CO) rapidly. In this study, we compared bolus thermodilution technique (TDCO) with thermal based Continuous cardiac output (CCO), Pulse contour Cardiac Output (Pulse CO) technique and Non Invasive Cardiac Output (NICO) techniques of continuous cardiac output measurement. Methods 75 patients undergoing OPCAB were studied. In Group A (n=25), CO was measured by arterial waveform analysis. In Group B (n=25), NICO was measured by Carbon dioxide (CO₂) partial rebreathing and in Group C (n=25), it was measured continuously using CCO catheter. CO was also measured by TDCO in all patients. Data were analysed using Bland Altman and regression plot analysis. ANOVA test was applied to compare the groups. Results CO measurements were comparable in the three groups. However CCO showed closest agreement with TDCO. During distal coronary artery anastomosis and at low CO, all three techniques showed poor agreement with TDCO and showed a higher CO than TDCO. Conclusion All the methods were statistically comparable and hence interchangeable for CO measurement in OPCAB. However NICO is least expensive and easy to use.     

A prospective microbiologic surveillance program to detect and prevent the transfusion of bacterially contaminated platelets

After two patients received bacterially contaminated platelet transfusions, a prospective surveillance program was instituted to perform Gram staining and microbiologic culturing of platelets at the time of transfusion. In 12 months, 3141 random-donor platelet pools (prepared from 14,481 units) and 2476 single-donor apheresis units were cultured. All single-donor apheresis units were sterile, but 6 (0.19%) of the random-donor pools were found to be bacterially contaminated, with 1 unit of 5 in the pool being the source in each case. Contaminants were Staphylococcus epidermidis (4 cases), Bacillus cereus (1), and Staphylococcus aureus (1) at counts of 0.5 × 10(2) to 10(11) colony-forming units per mL in platelet pools and 10(3) to 10(13) colony-forming units per mL in source units. The contamination rate for units transfused at < or = 4 days (1.8/10,000) was significantly lower than that at 5 days (11.9/10,000; p < 0.05), as was the magnitude of contamination (p < 0.05). Use of the pretransfusion Gram stain on 4- and 5-day-old platelet pools was 100 percent sensitive (4/4 true positives) and 99.93 percent specific (1 false positive) in detecting contaminated pools. These data define the extent and magnitude of platelet bacterial contamination and demonstrate the efficacy of the pretransfusion Gram stain on platelet units stored for 4 and 5 days in preventing the transfusion of heavily contaminated units. It is concluded that the risk of platelet contamination is related to the duration of component storage.(ABSTRACT TRUNCATED AT 250 WORDS)     

单剂半量赛尼哌预防移植肾急性排斥的临床观察

目的观察单剂半量赛尼哌对肾移植急性排斥(AR)的预防作用及安全性评估。方法选择同期肾移植病人187例,根据术后肾功能恢复情况及术前是否使用赛尼哌分为A/90例、B/73例、C/11例、D/13例4组,其中A、B组移植后肾功能恢复良好,即术后1周血肌酐<176.6μmol/L,C、D组术后出现移植肾功能延迟恢复,术后1周血血肌酐>353μmol/L。A、C两组术前2h静滴赛尼哌25mg(0.5mg/kg)和口服霉酚酸酯0.75g,B、D组仅口服霉酚酸酯0.75g;术后四组病人均予甲基强的松龙500mg×3d冲击,常规强的松、环孢霉素A和霉酚酸酯三联抗排斥治疗。观察术后6个月内AR发生率、发生时间、强度及排斥逆转率,同时观察胃肠道反应、感染及血液系统损害等副作用。结果A组13例(14.4%)发生AR,B组18例(24.6%),C组6例(54.5%),D组7例(53.8%),A组AR发生率明显低于B、C、D三组(P均<0.01);B组AR发生率显著低于C、D组(P<0.01),C、D组差异不显著(P>0.05),A组排斥开始时间3-9d(6.2±3.2d)较B组2-8d(4.5±3.1d)、C组2-7d(4.3±4.2d)、D组2-9d(3.9±3.5d)明显延迟(P均<0.05)。但B、C、D三组排斥开始时间无明显差异(P>0.05)。A组AR经强化治疗均逆转,B组16例逆转,另2例失败,C组5例逆转,1例因移植肾排斥破裂出血切除,D组5例逆转,2例失败;C、D组各2例于术后13-32d再次排斥,经甲基强的松龙强化治疗逆转。感染、胃肠道反应及血液系统损害四组差异不显著(P均>0.05)。结论移植后肾功能恢复良好病人,术前25mg赛尼哌可显著降低AR发生率,且安全性好。但对于移植肾功能延迟恢复病人,术前25mg赛尼哌并不能有效预防排斥发生。     

Changes in rous virus and polyoma virus during their synthesis in cells of unnatural hosts

A line of human embryonic fibroblasts, transformed by Rous sarcoma virus (Schmidt-Ruppin strain) contained and produced Rous virus, as was shown by the complement fixation and immunofluorescent tests, by electron-microscopic investigation, and by the presence of an isotope peak in a sucrose gradient. By its biological properties the synthesized virus differed from the original Schmidt-Ruppin strain for, in particular, the range of cells sensitive to the virus and its protein membrane were changed. Similar data indicating a change in the biological properties of a virus produced in the tissue of an unnatural host also were obtained for polyoma virus, synthesized in human embryonic fibroblasts transformed by it.Laboratory of Virus Etiology of Tumors, N. F. Gamaleya Institute of Epidemiology and Microbiology, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR P. A. Vershilova.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 86, No. 12, pp. 710–713, December, 1978.     

Multivessel sequential bypass grafting without cardiopulmonary bypass

Background Multivessel sequential coronary artery bypass grafting without cardiopulmonary bypass has become a reality. Initially the revascularization of posterior coronary arteries (obtuse marginal branches of the circumflex artery) was difficult due to access and difficulty in stabilization of the heart as well as compromising the haemodynamic status of the heart. With stabilization of the heart with Octopus II (Medtronic, Inc. Minnesota, USA) we have demonstrated that sequential grafts as well as composite arterial grafts can easily and safely be used in complete arterial revascularization of the myocardium. Methods From January 1, 1996 till December 31, 1999, 832 consecutive patients underwent coronary artery bypass surgery without cardiopulmonary bypass. From July 1998, seventy-nine patients operated had atleast 1 conduit used as a sequential graft and 12 patients had composite ‘Y’ grafts. Before July 1999, 67 patients (61 sequential and 6 ‘Y’ conduits) underwent surgery without mechanical stabilization (Group A) and after July 1999 in 24 patients (18 sequential and 6 ‘Y’ conduits) mechanical stabilization (Octopus II) was used. Results Total number of sequential anastomosis including composite grafts was not significantly different in both groups. But due to Octopus II stabilization, number of anastomosis in composite ‘Y’ graft group significantly increased from 2.96 ±0.2 to 4.02 ±0.3. Also intramyocardial coronary artery revascularization which was only 10.4% in Group A increased to 20.8% in Group B. In Group A only 8.9% composite grafts were performed while in Group B it was 25% which was statistically significant. Conclusions Cardiac stabilization with Octopus II has improved ability for revascularization of remote coronary arteries arising from circumflex. Although overall anastomoses have not increased, the number of patients receiving composite grafts using all arterial conduits have increased significantly. Patency rates of all sequential conduits as well as composite grafts have remained equally good in both groups.