Background DNA aptamers represent a novel strategy in anti-cancer medicine. These compounds are short sequences of DNA that have protein binding effects via shape specific recognition of a target protein in an interaction which is analogous to antibody-antigen binding. AS1411, a DNA aptamer that targets nucleolin (a protein which is overexpressed in many tumor types), was evaluated in patients with metastatic, predominantly clear-cell, renal cell carcinoma (RCC) who had failed treatment with ≥1 previous tyrosine kinase inhibitor. We present the first manuscript reporting the use of this novel anti-cancer agent in humans. Methods In this phase II, single-arm study, AS1411 was administered at 40 mg/kg/day by continuous intravenous infusion on days 1–4 of a 28-day cycle, for two cycles. Primary endpoint was overall response rate; progression-free survival (PFS) and safety were secondary endpoints. Results 35 patients were enrolled and treated; 33 completed two treatment cycles. Median number of prior therapies was 2 (range 1–7). One patient (2.9%) had a response to treatment. The response was dramatic (84% reduction in the sum of longest diameters of selected target tumor lesions) and durable (the patient remains free of progression 2 years after completing therapy). No responses were seen in the other patients. Median PFS was 4 months. Only 34% of patients had an AS1411-related adverse event, all of which were mild or moderate. Conclusions AS1411 appears to have limited activity in unselected patients with metastatic RCC. However, rare, dramatic and durable responses can be observed and toxicity is low. Further studies with nucleolin targeted compounds may benefit from efforts to discover predictive biomarkers of response. Currently, promising pre-clinical studies are ongoing using AS1411 conjugated to traditional cytotoxic agents to selectively deliver these treatments to tumor cells. DNA aptamers represent a novel way to target cancer cells at a molecular level and continue to be developed with a view to improving treatment and imaging in cancer medicine.

Plane-wave density functional theory calculations have been carried out to explore possible pathways in methanol steam reforming (MSR) on Cu(111). We focus on reactions involving the adsorbed formaldehyde intermediate (CH(2)O) produced by methanol decomposition and the surface hydroxyl (OH) species generated by dissociative adsorption of H(2)O. Several possible pathways leading to the H(2) + CO(2) products have been identified. The two most likely pathways involve the formate (CHOO), rather than the carboxyl (COOH), intermediate, and they possess barriers lower than that of the rate-limiting step of MSR, namely the dehydrogenation of adsorbed methoxyl (CH(3)O) species.

Phosphorylation reactions catalyzed by kinases and phosphatases play an indispensible role in cellular signaling, and their malfunctioning is implicated in many diseases. A better understanding of the catalytic mechanism will help design novel and effective mechanism-based inhibitors of these enzymes. In this work, ab initio quantum mechanical/molecular mechanical studies are reported for the phosphoryl transfer reaction catalyzed by a cyclin-dependent kinase, CDK2. Our results suggest that an active-site Asp residue, rather than ATP as previously proposed, serves as the general base to activate the Ser nucleophile. The corresponding transition state features a dissociative, metaphosphate-like structure, stabilized by the Mg2+ ion and several hydrogen bonds. The calculated free-energy barrier is consistent with experimental values. Implications of our results in this and other protein kinases are discussed.

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The effect of Zn on the CO adsorption and oxidation reaction is examined experimentally and theoretically on two PdZn catalysts with different compositions, namely the intermetallic 1:1 β-PdZn and α-PdZn as a solid solution of 9 at% Zn in Pd. These bimetallic catalysts, made using an aerosol derived method, are homogeneous in phase and composition so that the measured reactivity excludes support effects. Both specific reactivities for CO oxidation on these two PdZn catalysts were measured. It was found that the initial rates are high and different between these catalysts, presumably due to the weakening of the CO adsorption and easier binding of oxygen to Pd sites modified by Zn. However, the rates decrease with time and become comparable to that on Pd at the steady state. With the help of density functional theory, it was suggested that the transient kinetics are due to the oxidation of Zn during the catalysis, which yields pure Pd where the reaction takes place.

The newly discovered bacterial phosphothreonine lyases perform a post-translational modification of host cell signaling proteins employing a novel catalytic mechanism that irreversibly removes the phosphate group from a phosphorylated threonine via β-elimination. This “eliminylation” reaction is shown by ab initio QM/MM studies to proceed via the E1cB-like pathway, in which the carbanion intermediate is stabilized by an enzyme oxyanion hole provided by Lys104 and Tyr158 of SpvC.

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Objective. To describe the implementation and effect of an emergency preparedness laboratory activity on student knowledge, willingness to participate in emergency preparedness training, current level of preparedness, and the importance of a pharmacist's role in disaster response. Design. Second-year pharmacy students in the infectious disease module participated in a laboratory activity based on a basic disaster response tabletop exercise format. Three case-based scenarios involving infectious diseases were created by participating faculty members. Assessment. Surveys before and after the laboratory were used to assess the activity's effect on student knowledge, willingness to participate in emergency preparedness training, current level of preparedness, and the importance of a pharmacist's role in disaster response. In addition, the postsurvey assessed student perceptions of the activity's success at accomplishing faculty-specified outcomes from Appendix B of the Accreditation Council for Pharmacy Education's (ACPE) Standards. Conclusion. Implementation of an emergency response laboratory activity may improve overall students' knowledge of, confidence in, and understanding of their role as pharmacists in an emergency response, while incorporating a variety of skills and knowledge outcomes.Keywords: emergency preparedness, disaster response, education, tabletop exercise, lab INTRODUCTIONThere are numerous types of disasters, natural and human. Natural disasters are physical events that occur spontaneously in nature, and can be geophysical (earthquakes), hydrological (floods), meteorological (hurricanes), climatological (temperature extremes), or biological (viral epidemics).1,2 Human disasters are man-made events that include chemical, biological, radiological, nuclear, and explosive terrorism, arson, riots, armed conflicts, and infrastructure failures.1,2 Any of these disasters most likely will involve provision of health care as part of the greater disaster response effort. Health care professionals may have to address treating injuries directly related to the disaster, providing mental health counseling for survivors, maintaining or re-establishing control of chronic diseases, or preventing infectious diseases outbreaks. Considering the unpredictable nature of disasters, community health professionals should be prepared to respond to disaster events when they occur.Public health emergency preparedness is defined as "the capability of the public health and health care systems, communities, and individuals, to prevent, protect against, quickly respond to, and recover from health emergencies, particularly those whose scale, timing, or unpredictability threatens to overwhelm routine capabilities."3 Acquiring this level of preparedness requires continuous preparation and execution of emergency response activities that examine performance and improve identified deficiencies. 3The 2014 Ebola outbreak demonstrated weaknesses in and the need for better public health emergency preparedness among health care workers. 4...