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     

Potential contributors to variation in weight-loss response to liraglutide

Obesity treatment requires a chronic state of negative energy balance. Obesity medications can help with this, increasing long-term dietary compliance by promoting satiety or reducing hunger. However, efficacy and safety of obesity medications vary for individuals. Early identification of non-responders to obesity medications may limit drug exposure while optimizing benefits for responders. This review summarizes factors that impact weight-loss response to liraglutide. Factors linked to greater weight loss on liraglutide include being female, not having diabetes, having relatively high baseline weight, and losing at least 4% of initial weight after 16 weeks of treatment. Other covariates that may predict treatment response but require further confirmation include central effects, nausea, gastric emptying of solids, and genotype. Baseline body mass index, race, and age seem less relevant for predicting weight-loss response to liraglutide. Lesser known and harder-to-measure factors such as cerebral blood flow, food cue reactivity, gut hormone levels, and dietary adherence possibly impact variability of response to liraglutide. This information should assist healthcare providers with establishing realistic weight-loss probability for individual patients. Future research should improve the ability to identify responders to liraglutide. Importantly, this review may provide a framework to identify responders to other obesity medications.     

Increased adiposity in animals due to a human virus

BACKGROUND: Four animal models of virus-induced obesity including adiposity induced by an avian adenovirus have been described previously. This is the first report of adiposity induced in animals by a human virus. OBJECTIVE: We investigated the adiposity promoting effect of a human adenovirus (Ad-36) in two different animal models. DESIGN: Due to the novel nature of the findings we replicated the experiments using a chicken model three times and a mammal model once. In four separate experiments, chickens and mice were inoculated with human adenovirus Ad-36. Weight matched groups inoculated with tissue culture media were used as non-infected controls in each experiment. Ad-36 inoculated and uninfected control groups were housed in separate rooms under biosafety level 2 or better containment. The first experiment included an additional weight matched group of chickens that was inoculated with CELO (chick embryo lethal orphan virus), an avian adenovirus. Food intakes and body weights were measured weekly. At the time of sacrifice blood was drawn and visceral fat was carefully separated and weighed. Total body fat was determined by chemical extraction of carcass fat. RESULTS: Animals inoculated with Ad-36 developed a syndrome of increased adipose tissue and paradoxically low levels of serum cholesterol and triglycerides. This syndrome was not seen in chickens inoculated with CELO virus. Sections of the brain and hypothalamus of Ad-36 inoculated animals did not show any overt histopathological changes. Ad-36 DNA could be detected in adipose tissue, but not skeletal muscles of randomly selected animals for as long as 16 weeks after Ad-36 inoculation. CONCLUSIONS: Data from these animal models suggest that the role of viral disease in the etiology of human obesity must be considered.     

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     

Human adenovirus Ad-36 promotes weight gain in male rhesus and marmoset monkeys

Although obesity has multiple etiologies, an overlooked possibility is an infectious origin. We previously identified two viruses, SMAM-1, an avian adenovirus (Ad), and Ad-36, a human adenovirus, that produce a syndrome of visceral obesity, with paradoxically decreased serum cholesterol and triglycerides in chickens and mice. In the two studies presented in this paper, we used nonhuman primates to investigate the adiposity-promoting potential of Ad-36. In study 1, we observed spontaneously occurring Ad-36 antibodies in 15 male rhesus monkeys, and a significant longitudinal association of positive antibody status with weight gain and plasma cholesterol lowering during the 18 mo after viral antibody appearance. In study 2, which was a randomized controlled experiment, three male marmosets inoculated with Ad-36 had a threefold body weight gain, a greater fat gain and lower serum cholesterol relative to baseline (P <0.05) than three uninfected controls at 28 wk postinoculation. These studies illustrate that the adiposity-promoting effect of Ad-36 occurs in two nonhuman primate species and demonstrates the usefulness of nonhuman primates for further evaluation of Ad-36-induced adiposity.     

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.     

Granular cell tumor of the clitoris in pregnancy

Granular cell tumors of the female genital organs represent 7-15% of all granular cell tumors reported in the literature. The majority of these genital lesions are located on the vulva. Granular cell tumor involving the clitoris is extremely rare and should be considered in the differential diagnosis of clitoral masses.     

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.