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     

Targeting the voltage sensor of Kv7.2 voltage-gated K+ channels with a new gating-modifier

The pore and gate regions of voltage-gated cation channels have been often targeted with drugs acting as channel modulators. In contrast, the voltage-sensing domain (VSD) was practically not exploited for therapeutic purposes, although it is the target of various toxins. We recently designed unique diphenylamine carboxylates that are powerful Kv7.2 voltage-gated K⁺ channel openers or blockers. Here we show that a unique Kv7.2 channel opener, NH29, acts as a nontoxin gating modifier. NH29 increases Kv7.2 currents, thereby producing a hyperpolarizing shift of the activation curve and slowing both activation and deactivation kinetics. In neurons, the opener depresses evoked spike discharges. NH29 dampens hippocampal glutamate and GABA release, thereby inhibiting excitatory and inhibitory postsynaptic currents. Mutagenesis and modeling data suggest that in Kv7.2, NH29 docks to the external groove formed by the interface of helices S1, S2, and S4 in a way that stabilizes the interaction between two conserved charged residues in S2 and S4, known to interact electrostatically, in the open state of Kv channels. Results indicate that NH29 may operate via a voltage-sensor trapping mechanism similar to that suggested for scorpion and sea-anemone toxins. Reflecting the promiscuous nature of the VSD, NH29 is also a potent blocker of TRPV1 channels, a feature similar to that of tarantula toxins. Our data provide a structural framework for designing unique gating-modifiers targeted to the VSD of voltage-gated cation channels and used for the treatment of hyperexcitability disorders.     

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     

Emergency endoprosthesis of the hip joint. Risk of hospital mortality

An analysis of case histories of 854 patients operated upon for fractures of the proximal part of the femoral bone at the R.R. Vreden Research Institute of Traumatology and Orthopedics for the period from September 1997 to December 2000 was made in order to assess the intrahospital lethality. The maximum season fluctuations were found to take place in October and March, minimum in September, December and April. The trend was characterized by a gradual rise from September to June. The authors associate these fluctuations with the action of external rhythmically changing factors, the growing trend--with the role of the factor of tiredness of the medical personnel. It was also shown that duration of the time interval from operation to the moment of death as well as the diversity of the value of this index was maximum in December-January and December correspondingly.